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BackgroundThe successful recruitment and retention of health professionals to rural and remote areas of Australia is a health policy priority. Nursing or allied health professional students’ learning placements in the Northern Territory (NT) of Australia, most of which is considered remote, may influence rural or remote work location decisions. ObjectiveThe aim of this study is to determine where allied health professionals and nurses who have had a student placement in the NT of Australia end up practicing. MethodsThis research is an observational cohort study, with data collection occurring at baseline and then repeated annually over 10 years (ie, 2017-2018 to 2029). The baseline data collection includes a demographic profile of allied health and nursing students and their evaluations of their NT placements using a nationally consistent questionnaire (ie, the Student Satisfaction Survey). The Work Location Survey, which will be administered annually, will track work location and the influences on work location decisions. ResultsThis study will generate unique data on the remote and rural work locations of nursing and allied health professional students who had a placement in the NT of Australia. It will be able to determine what are the most important characteristics of those who take up remote and rural employment, even if outside of the NT, and to identify barriers to remote employment. ConclusionsThis study will add knowledge to the literature regarding rates of allied health and nursing professionals working in remote or rural settings following remote or rural learning placements. The results will be of interest to government and remote health workforce planners. Trial RegistrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000797976; https://www.anzctr.org.au/ACTRN12620000797976.aspx International Registered Report Identifier (IRRID)PRR1-10.2196/21832

This study aimed to investigate integration of alternating speech, a stimulus which classically produces a V-shaped speech intelligibility function with minimum at 2-6 Hz in typical-hearing (TH) listeners. We further studied how degraded speech impacts intelligibility across alternating rates (2, 4, 8, and 32 Hz) using vocoded speech, either in the right ear or bilaterally, to simulate single-sided deafness with a cochlear implant (SSD-CI) and bilateral CIs (BiCI), respectively. To assess potential cortical signatures of across-ear integration, we recorded activity in the bilateral auditory cortices (AC) and dorsolateral prefrontal cortices (DLPFC) during the task using functional near-infrared spectroscopy (fNIRS). For speech intelligibility, the V-shaped function was reproduced only in the BiCI condition; TH (with ceiling scores) and SSD-CI conditions had significantly higher scores across all alternating rates compared to the BiCI condition. For fNIRS, the AC and DLPFC exhibited significantly different activity across alternating rates in the TH condition, with altered activity patterns in both regions in the SSD-CI and BiCI conditions. Our results suggest that degraded speech inputs in one or both ears impact across-ear integration and that different listening strategies were employed for speech integration manifested as differences in cortical activity across conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sobczak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Individuals with asthma breathe at higher operating lung volumes during exercise compared with healthy individuals, which contributes to increased exertional dyspnoea. In health, females are more likely to develop exertional dyspnoea than males at a given workload or ventilation, and therefore, it is possible that females with asthma may develop disproportional dyspnoea on exertion. The purpose of this study was to compare operating lung volume and dyspnoea responses during exercise in females with and without asthma., Methods: Sixteen female controls and 16 females with asthma were recruited for the study along with 16 male controls and 16 males with asthma as a comparison group. Asthma was confirmed using American Thoracic Society criteria. Participants completed a cycle ergometry cardiopulmonary exercise test to volitional exhaustion. Inspiratory capacity manoeuvres were performed to estimate inspiratory reserve volume (IRV) and dyspnoea was evaluated using the Modified Borg Scale., Results: Females with asthma exhibited elevated dyspnoea during submaximal exercise compared with female controls (p<0.05). Females with asthma obtained a similar IRV and dyspnoea at peak exercise compared with healthy females despite lower ventilatory demand, suggesting mechanical constraint to tidal volume (V T ) expansion. V T -inflection point was observed at significantly lower ventilation and V̇ O 2 in females with asthma compared with female controls. Forced expired volume in 1 s was significantly associated with V T -inflection point in females with asthma (R 2 =0.401; p<0.01) but not female controls (R 2 =0.002; p=0.88)., Conclusion: These results suggest that females with asthma are more prone to experience exertional dyspnoea, secondary to dynamic mechanical constraints during submaximal exercise when compared with females without asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Vaccine hesitancy is a complex, context-specific issue that negatively impacts vaccine uptake. During the COVID-19 pandemic, vaccine mis- and dis-information on social media negatively impacted on COVID-19 vaccine acceptance. University students' beliefs and behaviors surrounding vaccine decision-making is less studied, but this population is important in disease transmission, vaccine uptake and effectiveness. Here, we surveyed students in a third-level Irish university, in September 2022, when pandemic restrictions had been removed, to primarily determine if their use of, and influence by, mainstream and social media correlated with their willingness to receive a COVID-19 vaccine or any vaccine. We analyzed 151 responses and found no significant correlation between students' willingness to receive either a COVID-19 vaccine or any vaccine and their use of social media. There were significant links between vaccine acceptance and a range of factors, namely accommodation type, social media behaviors, perceived exposure to vaccine mis- or dis-information and previous vaccine uptake. This study provides a preliminary insight into drivers of university student COVID-19 and general vaccine willingness. It provides initial data, in the context of post-pandemic restrictions, to support further development of interventions to enhance vaccine uptake in third-level students in Ireland.

Competing Interests: AH is a member of the editorial board. Another editor was assigned to handle the peer review of this manuscript. Outside the context of this manuscript, she also reports two CIHR Team Grants, a grant from the Lung Association of Alberta, one from the Alberta Medical Association and one from the Environmental Health Foundation of Canada as well as support from the American Thoracic Society and the Canadian Paediatric Society for travel costs. AH is also the past President of the Canadian Paediatric Society Section of Environmental Health (2021-2023) and a past Member of the American Thoracic Society Environmental Health Policy Committee (2019-2022). None of this support was used to generate this manuscript. There are no other disclosures. All three authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Background: Preventing poor childhood asthma control is crucial for short-term and long-term respiratory health. This study evaluated associations between perinatal and early-life factors and early childhood asthma control., Methods: This retrospective study used administrative health data from mothers and children born 2010-2012 with a diagnosis of asthma before age 5 years, in Alberta, Canada. The outcome was asthma control within 2 years after diagnosis. Associations between perinatal and early-life factors and risk of partly and uncontrolled asthma were evaluated by multinomial logistic regression., Results: Of 7206 preschoolers with asthma, 52% had controlled, 37% partly controlled and 12% uncontrolled asthma 2 years after diagnosis. Compared with controlled asthma, prenatal antibiotics (adjusted risk ratio (aRR): 1.19; 95% CI 1.06 to 1.33) and smoking (aRR: 1.18; 95% CI 1.02 to 1.37), C-section delivery (aRR: 1.11; 95% CI 1.00 to 1.25), summer birth (aRR: 1.16; 95% CI 1.00 to 1.34) and early-life hospitalisation for respiratory illness (aRR: 2.24; 95% CI 1.81 to 2.76) increased the risk of partly controlled asthma. Gestational diabetes (aRR: 1.41; 95% CI 1.06 to 1.87), C-section delivery (aRR: 1.18; 95% CI 1.00 to 1.39), antibiotics (aRR: 1.32; 95% CI 1.08 to 1.61) and hospitalisation for early-life respiratory illness (aRR: 1.65; 95% CI 1.19 to 2.27) were associated with uncontrolled asthma., Conclusion: Maternal perinatal and early-life factors including antibiotics in pregnancy and childhood, gestational diabetes, prenatal smoking, C-section and summertime birth, and hospitalisations for respiratory illness are associated with partly or uncontrolled childhood asthma. These results underline the significance of perinatal health and the lasting effects of early-life experiences on lung development and disease programming., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: People experiencing asthma exacerbations are at increased risk of cardiovascular events. To better understand the relationship between asthma exacerbations and cardiovascular risk, this randomized case-control, cross-over controlled trial assessed the immediate systemic inflammatory and vascular responses to acutely induced pulmonary inflammation and bronchoconstriction in people with asthma and controls., Methods: Twenty-six people with asthma and 25 controls underwent three airway challenges (placebo, mannitol, and methacholine) in random order. Markers of cardiovascular risk, including serum C-reactive protein, interleukin-6, and tumor necrosis factor, endothelial function (flow-mediated dilation), microvascular function (blood-flow following reactive hyperemia), and arterial stiffness (pulse wave velocity) were evaluated at baseline and within one hour following each challenge. The systemic responses in a) asthma/control and b) positive airway challenges were analyzed. (ClinicalTrials.gov reg# NCT02630511)., Results: Both the mannitol and methacholine challenges resulted in clinically significant reductions in forced expiratory volume in 1 second (FEV1) in asthma (-7.6% and -17.9%, respectively). Following positive challenges, reduction in FEV1 was -27.6% for methacholine and -14.2% for mannitol. No meaningful differences in predictors of cardiovascular risk were observed between airway challenges regardless of bronchoconstrictor response., Conclusion: Neither acutely induced bronchoconstriction nor pulmonary inflammation and bronchoconstriction resulted in meaningful changes in systemic inflammatory or vascular function. These findings question whether the increased cardiovascular risk associated with asthma exacerbations is secondary to acute bronchoconstriction or inflammation, and suggest that other factors need to be further evaluated such as the cardiovascular impacts of short-acting inhaled beta-agonists., Competing Interests: MB has received consulting fees from AstraZeneca, GSK, Sanofi, Covis, BI, and Valeo, payment or honoraria from AstraZeneca, GSK, Valeo, Covis, and has held leadership or fiduciary role for Alberta Health Services and the Canadian Thoracic Society. MSK holds grants from The Lung Association of Alberta and Northwest Territories, has received speaker honoraria from GSK and was a board member for the Lung Association of Alberta and Northwest Territories. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Moore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Long-term noninvasive positive airway pressure (PAP) treatment is effective treatment for sleep-related breathing disorders and chronic hypercarbic respiratory failure secondary to chronic obstructive pulmonary disease (COPD). PAP treatment may be delivered as continuous positive airway pressure or noninvasive ventilation. Success in initiating PAP treatment and barriers to its use in adult patients with COPD are largely unknown. This systematic review aims to identify the acceptance of and adherence to PAP treatment prescribed for long-term use in adult patients with COPD and to summarize variables associated with these measures., Methods: Seven online electronic databases will be searched by an experienced medical librarian to identify records containing the concepts "obstructive airways disease" and "noninvasive positive airway pressure" and "acceptance" or "adherence". Randomized and non-randomized studies of interventions will be included. Citation lists from relevant articles will be reviewed, and experts will be contacted regarding unpublished studies. Abstracts from key conferences between 2018-2023 and Google Scholar search results will be reviewed for inclusion. Titles, abstracts and full texts will be reviewed independently for inclusion by two reviewers. Data extraction will be completed by one author using a pre-established form and primary outcomes confirmed by a second author. Methodological quality will be evaluated. If sufficient data are available for meta-analysis, a pooled summary statistic for the primary outcome will be calculated using a random-effects generic inverse-variance meta-analysis, weighted proportion or weighted medians-based approach. Subgroup analysis will explore clinically meaningful sources of heterogeneity. Variables that are associated with acceptance and adherence will be described., Discussion: Long-term PAP treatment is a complex intervention prescribed to patients with COPD for several indications. Synthesis of the evidence on success with PAP treatment and variables associated with acceptance or adherence will inform program and policy development for supporting patients with COPD who are prescribed this therapy., Trial Registration: Systematic review registration: This protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on July 13, 2021 (registration number CRD42021259262), with revisions submitted on April 17, 2023., Competing Interests: CRL receives renumeration for the interpretation of home sleep apnea tests by Careica Health. SRP reports an unrestricted grant from Jazz Pharmaceuticals and consulting fees from Paladin Labs, Jazz Pharmaceuticals and the International Centre for Professional Development in Health and Medicine. The other authors have no relevant conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Laratta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The aim of this study was to investigate whether risk estimates for childhood acute lymphoblastic leukemia change when restricting model comparison groups to "nonpesticide exposure" (NPE10) households., Methods: Cases ( n = 1810) 15 years or younger were identified through Children's Cancer Group institutions between 1989 and 1993 and age-/sex-matched to controls ( n = 1951). Household pesticide use during pregnancy/month prior was collected via telephone. NPE10 comparison group reporting no parental exposure to 10 pesticide classes was identified., Results: Adjusted odds ratios increased from 15% to 49% when limiting the comparison to NPE10. Maternal termite insecticide exposure was associated with greatest risk (adjusted odds ratio, 4.21; 95% confidence interval, 2.00-8.88). There was minimal evidence of interaction by child sex or occupational pesticide exposure, and no monotonic dose-response pattern with frequency of use (times per year)., Conclusions: Elevated risks are consistent with published pooled-/meta-analyses and DNA damage. The consistency and magnitude of these associations warrant product labeling, exposure reduction interventions, or both., Competing Interests: Conflict of interest: None declared., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Introduction: Social determinants of health (SDH) may influence children's weight status. Our objective was to examine relationships between SDH and preschoolers' weight status., Methods: This retrospective cohort study included 169 465 children (aged 4-6 years) with anthropometric measurements taken at immunization visits from 2009 to 2017 in Edmonton and Calgary, Canada. Children were categorized by weight status based on WHO criteria. Maternal data were linked to child data. The Pampalon Material and Social Deprivation Indexes were used to assess deprivation. We used multinomial logistic regression to generate relative risk ratios (RRRs) to examine associations between ethnicity, maternal immigrant status, neighbourhood-level household income, urban/ rural residence and material and social deprivation with child weight status., Results: Children of Chinese ethnicity were less likely than those in the General Population to have overweight (RRR = 0.64, 95% CI: 0.61-0.69) and obesity (RRR = 0.51, 0.42-0.62). Children of South Asian ethnicity were more likely than those in the General Population to have underweight (RRR = 4.14, 3.54-4.84) and more likely to have obesity (RRR = 1.39, 1.22-1.60). Children with maternal immigrant status were less likely than those without maternal immigrant status to have underweight (RRR = 0.72, 0.63-0.82) and obesity (RRR = 0.71, 0.66-0.77). Children were less likely to have overweight (RRR = 0.95, 0.94-0.95) and obesity (RRR = 0.88, 0.86-0.90) for every CAD 10 000 increase in income. Relative to the least deprived quintile, children in the most materially deprived quintile were more likely to have underweight (RRR = 1.36, 1.13-1.62), overweight (RRR = 1.52, 1.46-1.58) and obesity (RRR = 2.83, 2.54-3.15). Relative to the least deprived quintile, children in the most socially deprived quintile were more likely to have overweight (RRR = 1.21, 1.17-1.26) and obesity (RRR = 1.40, 1.26-1.56). All results are significant to p < 0.001., Conclusion: Our findings suggest the need for interventions and policies to address SDH in preschoolers to optimize their weight and health., Competing Interests: GDCB served as a member of the Novo Nordisk Canada Pediatric Expert Obesity National Advisory Board. The other authors have no conflicts of interest to declare.

Background: Assisted human reproduction (AHR) can be used to help individuals and couples overcome infertility issues. We sought to describe trends in pregnancies using AHR and to evaluate the impact of AHR on perinatal outcomes in a large population-based cohort in Alberta, Canada., Methods: We linked maternal and child administrative data for all live births occurring July 1, 2009, to Dec. 31, 2018, in Alberta, Canada, for this retrospective study. We identified AHR pregnancies from pharmaceutical claims or codes from the International Classification of Diseases and Related Health Problems (9th or 10th revision). Our main outcome measures were the incidence and temporal trends of live births in AHR pregnancies. We also compared maternal characteristics and perinatal outcomes of AHR and non-AHR pregnancies, and by maternal age group., Results: Of 518 293 live births during the study period, 26 270 (5.1%) were conceived with AHR. The incidence of AHR pregnancies increased from 30.8 per 1000 pregnancies in 2009 to 54.7 per 1000 pregnancies in 2018. Females who used AHR were older (33.9 yr v. 30.1 yr, p < 0.001) and the number of females aged 30-35 years and older than 35 years who delivered following AHR increased over the study period (30-35 yr: 36.9 to 55.3 per 1000 pregnancies; > 35 yr: 79.1 to 95.2 per 1000 pregnancies). The proportion of live births with cesarean delivery (40.5% v. 23.3%, p < 0.001), low birth weight (26.9% v. 7.6%, p < 0.001), congenital malformation (0.5% v. 0.3%, p = 0.002) and admission to the neonatal intensive care unit (25.3% v. 9.7%, p < 0.001) was higher in the AHR group than the non-AHR group., Interpretation: The incidence of live births following AHR pregnancies in Alberta was 5.1% between 2009 and 2018, and increased by 0.26% per year; newborns in the AHR group appeared smaller and showed signs of poorer health. This study provides insights on potential perinatal complications following AHR that may be important when caring for the newborn child., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

We have developed a Triangular Spatial Relationship (TSR)-based computational method for protein structure comparison and motif discovery that is both sequence and structure alignment-free. A protein 3D structure is modeled by all possible triangles that are constructed with every three C α atoms of amino acids as vertices. Every triangle is represented using an integer (a key). The keys are calculated by a rule-based formula which is a function of a representative length, a representative angle, and the vertex labels associated with amino acids. A 3D structure is thereby represented by a vector of integers (TSR keys). Global or local structure comparisons are achieved by computing all keys or a set of keys, respectively. Many enzymatic reactions and notable marketed drugs are highly stereospecific. Thus, in this paper, we propose a modified key calculation formula by including a mechanism for discriminating mirror-image keys to capture stereo geometry. We assign a positive or a negative sign to the integers representing mirror-image keys. Applying the new key calculation function provides the ability to further discriminate mirror-image keys that were previously considered identical. As the result, applying the mirror-image discrimination capability (i) significantly increases the number of distinct keys; (ii) decreases the number of common keys; (iii) decreases structural similarity; (iv) increases the opportunity to identify specific keys for each type of the receptors. The specific keys identified in this study for the cases of without (not applying) and with (applying) mirror-image discrimination can be considered as the structure signatures that exclusively belong to a certain type of receptors. Applying mirror-image discrimination introduces stereospecificity to keys for allowing more precise modeling of ligand - target interactions. The development of mirror-image TSR keys of C α atom, in conjunction with the integration of C α TSR keys with all-atom TSR keys for amino acids and drugs, will lead to a new and promising computational method for aiding drug design and discovery., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Wildfires are increasing yearly in number and severity as a part of the evolving climate crisis. These fires are a significant source of air pollution, a common driver of flares in cardiorespiratory disease, including asthma, which is the most common chronic disease of childhood. Poorly controlled asthma leads to significant societal costs through morbidity, mortality, lost school and work time and healthcare utilization. This retrospective cohort study set in Calgary, Canada evaluates the relationship between asthma exacerbations during wildfire smoke events and equivalent low-pollution periods in a pediatric asthma population. Air pollution was based on daily average levels of PM 2.5 . Wildfire smoke events were determined by combining information from provincial databases and local monitors. Exposures were assumed using postal codes in the health record at the time of emergency department visits. Provincial claims data identified 27,501 asthma exacerbations in 57,375 children with asthma between 2010 to 2021. Wildfire smoke days demonstrated an increase in asthma exacerbations over the baseline (incidence rate ratio: 1.13; 95% CI: 1.02-1.24); this was not seen with air pollution in general. Increased rates of asthma exacerbations were also noted yearly in September. Asthma exacerbations were significantly decreased during periods of COVID-19 healthcare precautions.

Background: The relationship between intraoperative physiology and postoperative stroke is incompletely understood. Preliminary data suggest that either hypo- or hypercapnia coupled with reduced cerebrovascular inflow (e.g., due to hypotension) can lead to ischemia. This study tested the hypothesis that the combination of intraoperative hypotension and either hypo- or hypercarbia is associated with postoperative ischemic stroke., Methods: We conducted a retrospective, case-control study via the Multicenter Perioperative Outcomes Group. Noncardiac, nonintracranial, and nonmajor vascular surgical cases (18 yr or older) were extracted from five major academic centers between January 2004 and December 2015. Ischemic stroke cases were identified via manual chart review and matched to controls (1:4). Time and reduction below key mean arterial blood pressure thresholds (less than 55 mmHg, less than 60 mmHg, less than 65 mmHg) and outside of specific end-tidal carbon dioxide thresholds (30 mmHg or less, 35 mmHg or less, 45 mmHg or greater) were calculated based on total area under the curve. The association between stroke and total area under the curve values was then tested while adjusting for relevant confounders., Results: In total, 1,244,881 cases were analyzed. Among the cases that screened positive for stroke (n = 1,702), 126 were confirmed and successfully matched with 500 corresponding controls. Total area under the curve was significantly associated with stroke for all thresholds tested, with the strongest combination observed with mean arterial pressure less than 55 mmHg (adjusted odds ratio per 10 mmHg-min, 1.17 [95% CI, 1.10 to 1.23], P < 0.0001) and end-tidal carbon dioxide 45 mmHg or greater (adjusted odds ratio per 10 mmHg-min, 1.11 [95% CI, 1.10 to 1.11], P < 0.0001). There was no interaction effect observed between blood pressure and carbon dioxide., Conclusions: Intraoperative hypotension and carbon dioxide dysregulation may each independently increase postoperative stroke risk., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Introduction: Asthma is associated with increased risk of cardiovascular diseases. Despite many presenting with symptoms of asthma, asthma cannot always be confirmed by physiological assessment. It is thus far unknown if the heightened cardiovascular risk applies to this group. The purpose of this study was to examine markers of cardiovascular risk, including endothelial function, arterial stiffness, and systemic inflammation, in individuals with confirmed asthma, unconfirmed asthma, and healthy controls. As short-acting beta agonist (SABA) use is associated with increased cardiovascular risk, a secondary analysis was conducted to investigate the impact of regular SABA use on vascular outcomes., Methods: Individuals with confirmed asthma (n = 26), unconfirmed asthma (n = 15), and healthy controls (n = 26) were recruited for this cross-sectional study. Asthma was confirmed by FEV 1 reversibility, methacholine challenge, or exercise challenge. Endothelial function was assessed using flow-mediated dilation (FMD), arterial stiffness using pulse wave velocity (PWV), and systemic inflammation by C-reactive protein (CRP) levels., Results: FMD was significantly lower in both asthma groups compared to controls (confirmed: 7.7 ± 3.6%, unconfirmed: 7.3 ± 3.5%, controls: 10.4 ± 3.6%, p = 0.02). No difference was found in PWV nor CRP. Asthma participants who used SABA had increased arterial stiffness compared to those without SABA (9.2 ± 2.7 m/s, 7.7 ± 1.1 m/s respectively, p = 0.03). No difference was seen in FMD or CRP between SABA groups., Conclusion: Individuals with a clinical history of asthma symptoms demonstrate vascular impairments regardless of physiological confirmation of disease. Regular SABA use increases arterial stiffness. Avoiding potentially inappropriate SABA use among people without physiologically confirmed asthma may thus be beneficial in curbing cardiovascular risk., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In order to image live cells for prolonged periods of time, an Arduino-based, low-cost imaging incubator was constructed. The imaging incubator keeps cells viable by controlling for temperature and CO 2 in order to maintain physiological conditions for cells during imaging. All devices and parts employed in the build were typical maker-type components in order to minimize the cost of the imaging incubator. The imaging incubator allows for real-time imaging of live cells exposed to any desired perturbation or stimulus. As a proof of the system's functionality, cells are imaged over 24 hours while remaining viable in the imaging incubator., Competing Interests: Disclosures. The authors declare no conflicts of interest.

Microneedlepatches, also called microarray patches(MAP),are an emergingtechnology for deliveryand samplingof drugs, vaccines and other materials. This review focuses on the materials and methods used to fabricate dissolvable microneedles(DMN)for pharmaceutical use.We outlinethe relative use ofexcipients, active pharmaceutical ingredients (API) and methods usedfor DMN fabrication. An extensive search of primary literature, up to April 2021,identified 328 papers under the key terms "dissolvable microneedles" or "polymeric microneedles".We based the classification of materials on pharmacopoeia definitions.The majority (76%) ofthe identifiedpublications examined licensed or model therapeutic small molecule drugs. Mostreports (58%)focused ondrugs or vaccinesthat are licensed for clinical use. Therelativeuse of excipientswith drug-containing compared to vaccine-containing DMN is discussed.Tenpolymers and sugarswereused for both drug and vaccine DMN.Themost frequentmethods to produce DMNwerecasting into moulds using centrifugationorvacuum filling. Novel methods reported include centrifugal lithography and 3D printing. This review provides insight intomaterialselection,thefeasibilityofproductionmethodsat industrial scaleand outlines considerations for novel DMN patch fabrication., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To report a case of atypical infectious crystalline keratopathy-like stromal infection secondary to microsporidia wherein diagnosis of the causative organism was aided by use of the Center for Disease Control (CDC) DPDx program., Methods: We report the case of a 73-year-old woman who presented with atypical infectious crystalline keratopathy-like corneal infection without previous surgical history., Results: The patient had previously been treated for recalcitrant corneal infection with topical antibiotics and steroids at an outside provider before referral. Further treatment with topical fortified antibiotics failed to improve the infection. Corneal biopsy was performed and sent to the CDC DPDx for diagnostic confirmation for presumptive microsporidia. The patient underwent therapeutic penetrating keratoplasty without recurrence of ocular infection., Conclusions: Utilization of the DPDx resource may help guide appropriate and timely diagnosis and management strategies in atypical presentations of infectious keratitis., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To determine whether higher coffee intake may reduce the risk of renal cell cancer (RCC) associated with lead (Pb) and other heavy metals with known renal toxicity., Methods: We conducted a nested case-control study of male smokers (136 RCC cases and 304 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cases diagnosed with RCC at 5 or more years following cohort enrollment were matched to controls on age (± 7 years) and whole blood draw date (± 30 days). Conditional logistic regression (using two-sided tests) was used to test for main effects and additive models of effect modification., Results: After a mean follow-up of 16.3 years, coffee consumption was not significantly associated with renal cell cancer risk, when adjusting for blood concentrations of Cd, Hg, and Pb and RCC risk factors (age, smoking, BMI, and systolic blood pressure) (p-trend, 0.134). The association with above median blood Pb and RCC (HR = 1.69, 95% CI 1.06, 2.85) appeared to be modified by coffee consumption, such that RCC risk among individuals with both increased coffee intake and higher blood lead concentration were more than threefold higher RCC risk (HR = 3.40, 95% CI 1.62, 7.13; p-trend, 0.003)., Conclusion: Contrary to our initial hypothesis, this study suggests that heavy coffee consumption may increase the previously identified association between higher circulating lead (Pb) concentrations and increased RCC risk. Improved assessment of exposure, including potential trace element contaminants in coffee, is needed., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Polytomous regression models generalize logistic models for the case of a categorical outcome variable with more than two distinct categories. These models are currently used in clinical research, and it is essential to measure their abilities to distinguish between the categories of the outcome. In 2012, van Calster et al proposed the polytomous discrimination index (PDI) as an extension of the binary discrimination c-statistic to unordered polytomous regression. The PDI is a summary of the simultaneous discrimination between all outcome categories. Previous implementations of the PDI are not capable of running on "big data." This article shows that the PDI formula can be manipulated to depend only on the distributions of the predicted probabilities evaluated for each outcome category and within each observed level of the outcome, which substantially improves the computation time. We present a SAS macro and R function that can rapidly evaluate the PDI and its components. The routines are evaluated on several simulated datasets after varying the number of categories of the outcome and size of the data and two real-world large administrative health datasets. We compare PDI with two other discrimination indices: M-index and hypervolume under the manifold (HUM) on simulated examples. We describe situations where the PDI and HUM, indices based on multiple comparisons, are superior to the M-index, an index based on pairwise comparisons, to detect predictions that are no different than random selection or erroneous due to incorrect ranking., (© 2021 John Wiley & Sons Ltd.)

Purpose: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information., Experimental Design: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors., Results: Non-silent KDM6A mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2- Signature mutations compared with former ( P = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; P = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( P = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; P = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with ERCC2- Signature mutations and APOBEC-Signature13 mutations among current ( P trend = 0.005) and former smokers ( P = 0.0004), respectively., Conclusions: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers., (©2021 American Association for Cancer Research.)

Objectives: The antepartum oral glucose tolerance test (OGTT) has re-emerged as associated with risk of diabetes among women with gestational diabetes (GDM). This systematic review summarized evidence on associations between antepartum OGTT and risk of diabetes in GDM (PROSPERO CRD42018100316)., Methods: MEDLINE, EMBASE, Web of Science, and CENTRAL were searched from January 1, 1982 to February 2020. Studies assessing associations between antepartum OGTT and risk of diabetes among women with GDM were included. Data on study characteristics, participants, OGTT values, and diabetes outcomes were extracted. Estimates on the association between antepartum OGTT and diabetes at follow-up were recorded. Pooled odds ratios for developing diabetes were calculated by study design., Findings and Conclusions: Of 6423 citations, 17 studies were included. Both elevated fasting blood glucose (FBG; OR: 3.62 ([95% CI 1.30, 10.12], I 2  = 36%, p < 0.05)) and 2 h OGTT (OR: 3.96 [1.17, 13.40], I 2  = 87%, p < 0.05) were associated with diabetes. These associations were attenuated (FBG: OR: 1.91 ([95% CI 0.80, 24.54], I 2  = 83%, p = NS) and 1.58 ([95% CI 0.92, 2.74] I 2  = 83%, p = NS) for prospective and retrospective data, respectively; 2 h OGTT: ORa: 1.95 ([95% CI 0.43, 8.93], I 2  = 94%, p = NS)) after adjustments for common confounders. Further research is needed before clinical recommendations can be made., Competing Interests: Declaration of competing interest Roseanne O. Yeung has been an invited speaker for Merck and consulted for Novo Nordisk. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stroke is associated with substantial morbidity and mortality. The aim of this review is to provide an evidence-based synthesis of the literature related to perioperative stroke, including its etiology, common risk factors, and potential risk reduction strategies. In addition, the authors will discuss screening methods for the detection of postoperative cerebral ischemia and how multidisciplinary collaborations, including endovascular interventions, should be considered to improve patient outcomes. Lastly, the authors will discuss the clinical and scientific knowledge gaps that need to be addressed to reduce the incidence and improve outcomes after perioperative stroke., (Copyright © 2021, the American Society of Anesthesiologists, Inc. All Rights Reserved.)

Purpose: To develop a more efficient and less traumatic method of Descemet membrane removal in endothelial surgery., Methods: A novel, vertically oriented, reverse-grasping microforceps (named the Rabiyah Descemet Membrane Removal Microforceps) were created to facilitate grasping and extraction of a host Descemet membrane., Results: This new instrument has been used successfully and safely in more than 85 endothelial keratoplasty cases among 4 surgeons., Conclusions: The Rabiyah Descemet Membrane Removal Microforceps provides surgeons with a safe and an efficient option to remove Descemet membrane in endothelial surgical procedures.

Perioperative stroke is associated with considerable morbidity and mortality. Stroke recognition and diagnosis are challenging perioperatively, and surgical patients receive therapeutic interventions less frequently compared with stroke patients in the outpatient setting. These updated guidelines from the Society for Neuroscience in Anesthesiology and Critical Care provide evidence-based recommendations regarding perioperative care of patients at high risk for stroke. Recommended areas for future investigation are also proposed.