Understanding and including 'pink-collar' workers in employment-based travel demand models.

The segmentation of commuters into either blue or white-collar workers remains is still common in urban transport models. Internationally, models have started to use more elaborate segmentations, more reflective of changes in labour markets, such as increased female participation. Finding appropriate labour market segmentations for commute trip modelling remains a challenge. This paper harnesses a data-driven approach using unsupervised clustering-applied to 2017-20 South East Queensland Travel Survey (SEQTS) data. Commuter types are grouped by occupational, industry, and socio-demographic variables (i.e., gender, age, household size, household vehicle ownership and worker skill score). The results show that at a large number of clusters (i.e., k = 8) a highly distinct set of commuter types can be observed. But model run times tend to require a much smaller number of market segments. When only three clusters are formed (k = 3) a market segmentation emerges with one female-dominated type ('pink collar'), one male-dominated type ('blue collar') and one with both genders almost equally involved ('white collar'). There are nuances as to which workers are included in each segment, and differences in travel behaviours across the three types. 'Pink collar' workers are mostly comprised of female clerical and administrative workers, community and personal service workers and sales workers. They have the shortest median commutes for both private motorised and active transport modes. The approach and methods should assist transport planners to derive more accurate and robust market segmentations for use in large urban transport models, and, better predict the value of alternative transport projects and policies for all types of commuters.

Harnessing Placebo Effects for the Treatment of Functional Cognitive Disorder: A Feasibility Pilot Study.

OBJECTIVE: Limited research has directly investigated whether and how placebo effects can be harnessed for the treatment of functional neurological disorder (FND), despite a long-standing and controversial history of interest in this area. METHODS: A small exploratory study was conducted with adults with a cognitive subtype of FND recruited from a single cognitive neurology center in the United States. Participants were given the expectation of receiving cranial stimulation that could benefit their memory symptoms; however, the intervention was sham transcranial magnetic stimulation (placebo). Outcomes included measures of short-term memory testing, subjective memory rating, and state anxiety before and after stimulation. After the study, the true objective and rationale for investigating placebo effects were explained in a scripted debriefing session. Acceptability of the study design and qualitative feedback were collected. Institutional ethics approval and signed consent were obtained. RESULTS: Three patients (female, N=2; male, N=1; average age=57 years) were recruited. Outcome data were analyzed descriptively at the patient level. Trends of improvement in subjective memory rating, but not objective cognitive test scores, and decreases in state anxiety were observed. After the debriefing session, all patients found the study design to be acceptable (ratings of 70%, 90%, and 100%), and two of the three patients believed that withholding mechanistic information about the intervention was needed to leverage placebo effects as treatment. CONCLUSIONS: In the first study to prospectively investigate the feasibility of harnessing placebo effects for the treatment of FND, promising preliminary findings were obtained, and methods and resources for use in larger future studies are offered.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

CONNECTing Concussion Care with Research Across Ontario.

Common data elements (CDEs) for concussion, as established by international bodies, are not being widely used in Ontario, resulting in significant variability in the data being assessed and collected across clinics. CDEs support standardization of care as well as large-scale data sharing for high impact research. A collaborative network - Concussion Ontario Network: Neuroinformatics to Enhance Clinical care and Translation (CONNECT) - comprised of health care professionals, researchers, members from advocacy groups, and patients was formed to establish and implement CDEs for concussion care and research. While the seeds have been planted and initial effectiveness demonstrated, future challenges exist.

Quantification and characterization of microplastics in coastal environments: Insights from laser direct infrared imaging.

The study identified and quantified nine plastic polymers frequently detected in the environment by collecting sediment and seawater samples from coastal areas in Auckland, New Zealand. Polymer types, size distributions, and number of microplastics (MPs) were analyzed using a laser direct infrared (LDIR) imaging technique. Compared to conventional spectroscopic or microscopic methods, LDIR enabled capturing and quantifying MPs in much lower size ranges (20-5000 µm). The results demonstrated the widespread occurrence of MPs in the Auckland coastal environment, with polyethylene terephthalate (PET) being the most frequently detected plastic polymer. MP contamination levels ranged from 13 to 83 particles per liter of coastal water and from 1200 to 3400 particles/kg of dry sand in beach sediments. Six additional locations were investigated to assess the contribution of MPs from stormwater drains to the coastal environment. The total count of identified MPs extracted from sediments near stormwater drains reached a maximum of 18,000 particles/kg of dry sand, representing an order of magnitude increase compared to MP levels found in beach sediments at the same location. In contrast to the prevalence of PET and polyamide observed in beach sediments and coastal waters, polyurethane and polyethylene emerged as the predominant plastic polymers in the vicinity of stormwater drain sediments, implying that the variation could potentially stem from distinct sources of plastics. This significant disparity in quality and quantity underscored the potential link between urban runoff and MP pollution in marine ecosystems. A sample preparation method using 100 g sediment samples was developed and used to assess and compare MPs detection in sediment samples. The commonly used 5 g sample method showed higher extraction efficiency and better detection of the most abundant MPs, but the new 100 g method enabled the detection of previously missed, less abundant plastics.

Dynamic regulation of airway surface liquid pH by TMEM16A and SLC26A4 in cystic fibrosis nasal epithelia with rare mutations.

In cystic fibrosis (CF), defects in the CF transmembrane conductance regulator (CFTR) channel lead to an acidic airway surface liquid (ASL), which compromises innate defence mechanisms, predisposing to pulmonary failure. Restoring ASL pH is a potential therapy for people with CF, particularly for those who cannot benefit from current highly effective modulator therapy. However, we lack a comprehensive understanding of the complex mechanisms underlying ASL pH regulation. The calcium-activated chloride channel, TMEM16A, and the anion exchanger, SLC26A4, have been proposed as targets for restoring ASL pH, but current results are contradictory and often utilise nonphysiological conditions. To provide better evidence for a role of these two proteins in ASL pH homeostasis, we developed an efficient CRISPR-Cas9-based approach to knock-out (KO) relevant transporters in primary airway basal cells lacking CFTR and then measured dynamic changes in ASL pH under thin-film conditions in fully differentiated airway cultures, which better simulate the in vivo situation. Unexpectantly, we found that both proteins regulated steady-state as well as agonist-stimulated ASL pH, but only under inflammatory conditions. Furthermore, we identified two Food and Drug Administration (FDA)-approved drugs which raised ASL pH by activating SLC26A4. While we identified a role for SLC26A4 in fluid absorption, KO had no effect on cyclic adenosine monophosphate (cAMP)-stimulated fluid secretion in airway organoids. Overall, we have identified a role of TMEM16A in ASL pH homeostasis and shown that both TMEM16A and SLC26A4 could be important alternative targets for ASL pH therapy in CF, particularly for those people who do not produce any functional CFTR.

Auditory brainstem response (ABR) waveform analysis program.

Auditory brainstem responses (ABR) are a high-throughput assessment of auditory function. Many studies determine changes to the threshold at frequencies that span the normal hearing range of their test subjects, but fewer studies evaluate changes in waveform morphology. The goal of developing this program was to make a user-friendly semiautomatic peak-detection algorithm to encourage widespread analysis of the amplitudes and latencies of the ABR, which may yield informative details about the integrity of the auditory system with development, aging, genetic manipulations, or damaging conditions. This method incorporates automated peak detection with manual override and inter-rater validation to calculate the amplitude and latency for waves 1-5, as well as interpeak latencies and amplitude ratios between waves. The output includes raw data and calculations in a format compatible with graphical and statistical software.•The method yields a high-throughput peak-detection algorithm with manual override and inter-rater capabilities to streamline ABR waveform analysis.•Data output includes amplitudes, latencies, amplitude ratios, and interpeak latencies for generation of input-output curves.•While complete automation of peak detection with this tool is dependent on good signal-to-noise ratios, relevant amplitude and latency calculations are fully automated, and manual spot-checking is simplified to significantly reduce the time to analyze waveforms.

Characterizing the profiles of patients with acute concussion versus prolonged post-concussion symptoms in Ontario.

Identifying vulnerability factors for developing persisting concussion symptoms is imperative for determining which patients may require specialized treatment. Using cross-sectional questionnaire data from an Ontario-wide observational concussion study, we compared patients with acute concussion (≤ 14 days) and prolonged post-concussion symptoms (PPCS) (≥ 90 days) on four factors of interest: sex, history of mental health disorders, history of headaches/migraines, and past concussions. Differences in profile between the two groups were also explored. 110 patients with acute concussion and 96 patients with PPCS were included in our study. The groups did not differ on the four factors of interest. Interestingly, both groups had greater proportions of females (acute concussion: 61.1% F; PPCS: 66.3% F). Patient profiles, however, differed wherein patients with PPCS were significantly older, more symptomatic, more likely to have been injured in a transportation-related incident, and more likely to live outside a Metropolitan city. These novel risk factors for persisting concussion symptoms require replication and highlight the need to re-evaluate previously identified risk factors as more and more concussions occur in non-athletes and different risk factors may be at play.

Litigation, Performance Validity Testing, and Treatment Outcomes in Adults With Mild Traumatic Brain Injury.

OBJECTIVE: To investigate whether involvement in litigation and performance validity test (PVT) failure predict adherence to treatment and treatment outcomes in adults with persistent symptoms after mild traumatic brain injury (mTBI). SETTING: Outpatient concussion clinics in British Columbia, Canada. Participants were assessed at intake (average 12.9 weeks postinjury) and again following 3 to 4 months of rehabilitation. PARTICIPANTS: Adults who met the World Health Organization Neurotrauma Task Force definition of mTBI. Litigation status was known for 69 participants (n = 21 reported litigation), and 62 participants completed a PVT (n = 13 failed the Test of Memory Malingering) at clinic intake. DESIGN: Secondary analysis of a clinical trial (ClinicalTrials.gov #NCT03972579). MAIN MEASURES: Outcomes included number of completed sessions, homework adherence, symptoms (Rivermead Post Concussion Symptoms Questionnaire), disability ratings (World Health Organization Disability Assessment Schedule 2.0), and patient-rated global impression of change. RESULTS: We did not observe substantial differences in session and homework adherence associated with litigation or PVT failure. Disability and postconcussion symptoms generally improved with treatment. Involvement in litigation was associated with a smaller improvement in outcomes, particularly disability (B = 2.57, 95% confidence interval [CI] [0.25-4.89], P = .03) and patient-reported global impression of change (odds ratio [OR] = 4.19, 95% CI [1.40-12.57], P = .01). PVT failure was not associated with considerable differences in treatment outcomes. However, participants who failed the PVT had a higher rate of missing outcomes (31% vs 8%) and perceived somewhat less global improvement (OR = 3.47, 95% CI [0.86-14.04]; P = .08). CONCLUSION: Adults with mTBI who are in litigation or who failed PVTs tend to adhere to and improve following treatment. However, involvement in litigation may be associated with attenuated improvements, and pretreatment PVT failure may predict lower engagement in the treatment process.

Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Placebo Effects and Neuromodulation: Ethical Considerations and Recommendations.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Molecular and Biochemical Assessment of Gene Therapy in the Canine Model of Duchenne Muscular Dystrophy.

Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disease. Adeno-associated virus (AAV) mediated gene replacement, and CRISPR/Cas9-mediated genome editing hold the potential to treat DMD. Molecular and biochemical analyses are essential to determine gene transfer efficiency and therapeutic efficacy. In this chapter, we present a series of methods routinely used in our laboratory to extract and quantify DNA, RNA, and protein in gene therapy studies performed in the canine DMD model.

The Implication of Hinge 1 and Hinge 4 in Micro-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by dystrophin deficiency. Dystrophin consists of the amino terminus, central rod domain with 24 spectrin-like repeats and four hinges (H), cysteine-rich domain, and carboxyl terminus. Several highly abbreviated micro-dystrophins (µDys) are currently in clinical trials. They all carry H1 and H4. In this study, we investigated whether these two hinges are essential for µDy function in murine DMD models. Three otherwise identical µDys were engineered to contain H1 and/or H4 and were named H1/H4 (with both H1 and H4), ΔH1 (without H1), and ΔH4 (without H4). These constructs were packaged in adeno-associated virus serotype-9 and delivered to the tibialis anterior muscle of 3-month-old male mdx4cv mice (1E12 vector genome particles/muscle). Three months later, we detected equivalent µDys expression in total muscle lysate. However, only H1/H4 and ΔH1 showed correct sarcolemmal localization. ΔH4 mainly existed as sarcoplasmic aggregates. H1/H4 and ΔH1, but not ΔH4, fully restored the dystrophin-associated protein complex and significantly improved the specific muscle force. Eccentric contraction-induced force decline was best protected by H1/H4, followed by ΔH1, but not by ΔH4. Next, we compared H1/H4 and ΔH1 in 6-week-old male mdx mice by intravenous injection (1E13 vector genome particles/mouse). Four months postinjection, H1/H4 significantly outperformed ΔH1 in extensor digitorum longus muscle force measurements but two constructs yielded comparable electrocardiography improvements. We conclude that H4 is essential for µDys function and H1 facilitates force production. Our findings will help develop next-generation µDys gene therapy.

Neuromodulation Therapies in Pre-Clinical Models of Traumatic Brain Injury: Systematic Review and Translational Applications.

Traumatic brain injury (TBI) has been associated with several lasting impairments that affect quality of life. Pre-clinical models of TBI have been studied to further our understanding of the underlying short-term and long-term symptomatology. Neuromodulation techniques have become of great interest in recent years as potential rehabilitative therapies after injury because of their capacity to alter neuronal activity and neural circuits in targeted brain regions. This systematic review aims to provide an overlook of the behavioral and neurochemical effects of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) in pre-clinical TBI models. After screening 629 abstracts, 30 articles were pooled for review. These studies showed that tDCS, TMS, DBS, or VNS delivered to rodents restored TBI-induced deficits in coordination, balance, locomotor activity and improved cognitive impairments in memory, learning, and impulsivity. Potential mechanisms for these effects included neuroprotection, a decrease in apoptosis, neuroplasticity, and the restoration of neural circuit abnormalities. The translational value, potential applicability, and the interpretation of these findings in light of outcome data from clinical trials in patients with TBI are discussed.

Depressive Symptoms in Individuals With Persistent Postconcussion Symptoms: A Systematic Review and Meta-Analysis.

Importance: Approximately 15% to 30% of individuals with a history of concussion present with persistent postconcussion symptoms (PPCS). Individuals with PPCS are at greater risk of experiencing depressive symptoms. Objective: To synthesize the association between depressive symptoms and PPCS in children, adolescents, and adults via meta-analysis and to investigate potential moderators of that association. Data Sources: Systematic search of Ovid Medline, CINAHL, PsycInfo, and Embase from 1995 to January 2022 was performed. Additionally, references from included studies were hand-searched to ensure relevant articles were captured in the search. Study Selection: Studies that involved participants who experienced PPCS and quantified depressive symptoms were included. The definition of PPCS was limited to physician-diagnosed or self-reported concussion, with symptoms lasting for a minimum of 4 weeks postinjury. Two authors independently screened all articles to determine study eligibility. Data Extraction and Synthesis: Study characteristics were extracted independently by 2 trained investigators. Study data were meta-analyzed using a random-effects meta-analysis. Exposure: PPCS. Main Outcomes and Measures: The the primary outcome was depressive symptoms. Results: Data were extracted from 18 studies with a total of 9101 participants. Of the 18 studies, all were cohort studies, and 13 (72%) comprised adult populations. The mean (SD) time since concussion was 21.3 (18.7) weeks. After accounting for potential publication bias, the random-effects meta-analysis found a significant positive association between PPCS and depressive symptoms, (odds ratio, 4.56; 95% CI, 2.82-7.37; P < .001). There were no significant moderators, likely due to the small number of studies included. Conclusions and Relevance: In this meta-analysis, experiencing PPCS was associated with a higher risk of experiencing depressive symptoms. There are several important clinical and health policy implications of the findings. Most notably, the development of strategies for effective prevention and earlier intervention to optimize mental health recovery following a concussion should be supported.

A bovine antibody possessing an ultralong complementarity-determining region CDRH3 targets a highly conserved epitope in sarbecovirus spike proteins.

Broadly neutralizing antibodies have huge potential as novel antiviral therapeutics due to their ability to recognize highly conserved epitopes that are seldom mutated in viral variants. A subset of bovine antibodies possess an ultralong complementarity-determining region (CDR)H3 that is highly adept at recognizing such conserved epitopes, but their reactivity against Sarbecovirus Spike proteins has not been explored previously. Here, we use a SARS-naïve library to isolate a broadly reactive bovine CDRH3 that binds the receptor-binding domain of SARS-CoV, SARS-CoV-2, and all SARS-CoV-2 variants. We show further that it neutralizes viruses pseudo-typed with SARS-CoV Spike, but this is not by competition with angiotensin-converting enzyme 2 (ACE2) binding. Instead, using differential hydrogen-deuterium exchange mass spectrometry, we demonstrate that it recognizes the major site of vulnerability of Sarbecoviruses. This glycan-shielded cryptic epitope becomes available only transiently via interdomain movements of the Spike protein such that antibody binding triggers destruction of the prefusion complex. This proof of principle study demonstrates the power of in vitro expressed bovine antibodies with ultralong CDRH3s for the isolation of novel, broadly reactive tools to combat emerging pathogens and to identify key epitopes for vaccine development.