Describing primary care patterns before and during the COVID-19 pandemic across Canada: a quasi-experimental pre-post design cohort study using national practice-based research network data.

OBJECTIVE: The objective was to analyse how the pandemic affected primary care access and comprehensiveness in chronic disease management by comparing primary care patterns before and during the early COVID-19 pandemic. DESIGN: We conducted a quasi-experimental pre-post design cohort study and reported indicators for the 21 months before and after the onset of the COVID-19 pandemic. SETTING: We used electronic medical record data from primary care clinics enrolled in the Canadian Primary Care Sentinel Surveillance Network from 1 January 2018 to 31 December 2021. POPULATION: The study population included patients (n=919 928) aged 18 years or older with at least one primary care contact from 12 March 2018 to 12 March 2020, in Canada. OUTCOME MEASURES: The study indicators included three indicators measuring access to primary care (encounters, blood pressure measurements and lab tests) and three for comprehensiveness (diagnoses, non-COVID-19 vaccines administered and referrals). RESULTS: 67.3% of the cohort was aged ≥40 years, 56.4% were female and 53.5% were from Ontario, Canada. Fewer patients received an encounter during the pandemic (91.5% to 81.5%), while the median (IQR) number of encounters remained the same (5 (2-1)) for those with access. Fewer patients received a blood pressure measurement (47.9% to 31.8%), and patients received fewer measurements during the pandemic (2 (1-4) to 1 (0-2)). CONCLUSIONS: Encounters with primary care remained consistent during the pandemic, but in-person care, such as lab tests and blood pressure measurements, decreased. In-person care indicators followed temporally to national COVID-19 case counts during the pandemic.

Development of a curricular thread to foster medical students' critical reflection and promote action on climate change, health, and equity.

INTRODUCTION: Due to the health consequences arising from climate change, medical students will inevitably interact with affected patients during their training and careers. Accordingly, medical schools must incorporate education on the impacts of climate change on health and equity into their curricula. We created a curricular thread called "Climate Change, Health, and Equity" in the first-year preclinical medical program to teach foundational concepts and foster self-reflection and critical consciousness. METHODS: The authors developed a continuum of practice including administrators, educators and faculty members, students, and community partners to plan and design curricular activities. First-year medical students at Duke University School of Medicine participated in seven mandatory foundational lectures and two experiential learning opportunities in the local community. Following completion of activities, students wrote a critical reflection essay and completed a self-directed learning exercise. Essays were evaluated using the REFLECT rubric to assess if students achieved critical reflection and for thematic analysis by Bloom's Taxonomy. RESULTS: All students (118) submitted essays. A random sample of 30 (25%) essays underwent analysis. Evaluation by the REFLECT rubric underscored that all students were reflecting or critically reflecting on thread content. Thematic analysis highlighted that all students (30/30, 100%) were adept at identifying new areas of medical knowledge and connecting concepts to individual experiences, institutional practices, and public health and policy. Most students (27/30; 90%) used emotionally laden words, expressing negative feelings like frustration and fear but also positive sentiments of solidarity and hope regarding climate change and effects on health. Many students (24/30; 80%) expressed actionable items at every level including continuing self-directed learning and conversing with patients, minimizing healthcare waste, and advocating for climate-friendly policies. CONCLUSION: After participating in the curricular thread, most medical students reflected on cognitive, affective, and actionable aspects relating to climate change, health, and equity.

Phenotypic Screening of Prospective Analgesics Among FDA-Approved Compounds using an iPSC-Based Model of Acute and Chronic Inflammatory Nociception.

Classical target-based drug screening is low-throughput, largely subjective, and costly. Phenotypic screening based on in vitro models is increasingly being used to identify candidate compounds that modulate complex cell/tissue functions. Chronic inflammatory nociception, and subsequent chronic pain conditions, affect peripheral sensory neuron activity (e.g., firing of action potentials) through myriad pathways, and remain unaddressed in regard to effective, non-addictive management/treatment options. Here, a chronic inflammatory nociception model is demonstrated based on induced pluripotent stem cell (iPSC) sensory neurons and glia, co-cultured on microelectrode arrays (MEAs). iPSC sensory co-cultures exhibit coordinated spontaneous extracellular action potential (EAP) firing, reaching a stable baseline after ≈27 days in vitro (DIV). Spontaneous and evoked EAP metrics are significantly modulated by 24-h incubation with tumor necrosis factor-alpha (TNF-α), representing an inflammatory phenotype. Compared with positive controls (lidocaine), this model is identified as an "excellent" stand-alone assay based on a modified Z' assay quality metric. This model is then used to screen 15 cherry-picked, off-label, Food and Drug Administration (FDA)-approved compounds; 10 of 15 are identified as "hits". Both hits and "misses" are discussed in turn. In total, this data suggests that iPSC sensory co-cultures on MEAs may represent a moderate-to-high-throughput assay for drug discovery targeting inflammatory nociception.

The association between patients' frailty status, multimorbidity, and demographic characteristics and changes in primary care for chronic conditions during the COVID-19 pandemic: a pre-post study.

BACKGROUND: The purpose of this study was to assess the impact of SARS-COV-2 (Severe acute respiratory syndrome coronavirus 2) pandemic on primary care management (frequency of monitoring activities, regular prescriptions, and test results) of older adults with common chronic conditions (diabetes, hypertension, and chronic kidney disease) and to examine whether any changes were associated with age, sex, neighbourhood income, multimorbidity, and frailty. METHODS: A research database from a sub-set of McMaster University Sentinel and Information Collaboration family practices was used to identify patients ≥65 years of age with a frailty assessment and 1 or more of the conditions. Patient demographics, chronic conditions, and chronic disease management information were retrieved. Changes from 14 months pre to 14 months since the pandemic were described and associations between patient characteristics and changes in monitoring, prescriptions, and test results were analysed using regression models. RESULTS: The mean age of the 658 patients was 75 years. While the frequency of monitoring activities and prescriptions related to chronic conditions decreased overall, there were no clear trends across sub-groups of age, sex, frailty level, neighbourhood income, or number of conditions. The mean values of disease monitoring parameters (e.g. blood pressure) did not considerably change. The only significant regression model demonstrated that when controlling for all other variables, patients with 2 chronic conditions and those with 4 or more conditions were twice as likely to have reduced numbers of eGFR (Estimated glomerular filtration rate) measures compared to those with only 1 condition ((OR (odds ratio) = 2.40, 95% CI [1.19, 4.87]); (OR = 2.19, 95% CI [1.12, 4.25]), respectively). CONCLUSION: In the first 14 months of the pandemic, the frequency of common elements of chronic condition care did not notably change overall or among higher-risk patients.

Effects of the COVID-19 Pandemic on Primary Health Care for Chronic Conditions in Canada: Protocol for a Retrospective Pre-Post Study Using National Practice-Based Research Network Data.

BACKGROUND: Since the COVID-19 pandemic began, there have been concerns that interruptions to the health care system may have led to changes in primary care, especially for care of chronic conditions such as diabetes and heart failure. Such changes may have longer term implications for population health. OBJECTIVE: This study aims to describe the impacts of the COVID-19 pandemic on indicators of primary care access, comprehensiveness, and appropriateness among adult patients, as well as on specific indictors of chronic conditions. Additionally, this study aims to determine whether any identified changes were associated with patient sociodemographic characteristics and multimorbidity. METHODS: This is a retrospective, single-arm, pre-post study using Canadian Primary Care Sentinel Surveillance Network (CPCSSN) data. CPCSSN is a research network supported by a primary care electronic medical record database, comprising over 1500 physicians and nearly 2 million patients. We are examining changes in care (eg, frequency of contacts, laboratory tests and investigations, referrals, medications prescribed, etc) among adults. We will also examine indicators specific to evidence-based recommendations for care in patients with diabetes and those with heart failure. We will compare rates of outcomes during key periods of the pandemic between March 13, 2020, and December 31, 2022, with equal time periods before the pandemic. Differences will be examined among specific subgroups of adults, including by decade of age, number of comorbidities, and socioeconomic status. Regression models appropriate to outcome distributions will be used to estimate changes, adjusting for potential confounders. This analysis is part of a mixed-methods study with a qualitative component investigating how patients with diabetes with or without concurrent heart failure perceived the impact of the pandemic on access to primary care and health care-related decisions. This study was approved by the Hamilton Integrated Research Ethics Board (14782-C). RESULTS: The start date of this study was October 5, 2022, and the prospective end date is January 31, 2024. As of May 2023, the study cohort (n=875,934) is defined, data cleaning is complete, and exploratory analyses have begun. Extended analyses using 2022 data are planned once the new data becomes available. We will disseminate results through peer-reviewed publications and academic conference, as well as creating evidence briefs, infographics, and a video for policy maker and patient audiences. CONCLUSIONS: This study will investigate whether the COVID-19 pandemic has resulted in changes in the provision of primary care in Canada and whether these potential changes have led to gaps in care. This study will also identify patient-level characteristics associated with changes in care patterns across the COVID-19 pandemic. Indicators specific to chronic conditions, namely diabetes and heart failure, will also be explored to determine whether there were changes in care of these conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05813652; https://clinicaltrials.gov/ct2/show/NCT05813652. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/49131.

Electrically-evoked oscillating calcium transients in mono- and co-cultures of iPSC glia and sensory neurons.

Activated glia are known to exhibit either neuroprotective or neurodegenerative effects, depending on their phenotype, while participating in chronic pain regulation. Until recently, it has been believed that satellite glial cells and astrocytes are electrically slight and process stimuli only through intracellular calcium flux that triggers downstream signaling mechanisms. Though glia do not exhibit action potentials, they do express both voltage- and ligand-gated ion channels that facilitate measurable calcium transients, a measure of their own phenotypic excitability, and support and modulate sensory neuron excitability through ion buffering and secretion of excitatory or inhibitory neuropeptides (i.e., paracrine signaling). We recently developed a model of acute and chronic nociception using co-cultures of iPSC sensory neurons (SN) and spinal astrocytes on microelectrode arrays (MEAs). Until recently, only neuronal extracellular activity has been recorded using MEAs with a high signal-to-noise ratio and in a non-invasive manner. Unfortunately, this method has limited compatibility with simultaneous calcium transient imaging techniques, which is the most common method for monitoring the phenotypic activity of astrocytes. Moreover, both dye-based and genetically encoded calcium indicator imaging rely on calcium chelation, affecting the culture's long-term physiology. Therefore, it would be ideal to allow continuous and simultaneous direct phenotypic monitoring of both SNs and astrocytes in a high-to-moderate throughput non-invasive manner and would significantly advance the field of electrophysiology. Here, we characterize astrocytic oscillating calcium transients (OCa2+Ts) in mono- and co-cultures of iPSC astrocytes as well as iPSC SN-astrocyte co-cultures on 48 well plate MEAs. We demonstrate that astrocytes exhibit OCa2+Ts in an electrical stimulus amplitude- and duration-dependent manner. We show that OCa2+Ts can be pharmacologically inhibited with the gap junction antagonist, carbenoxolone (100 µM). Most importantly, we demonstrate that both neurons and glia can be phenotypically characterized in real time, repeatedly, over the duration of the culture. In total, our findings suggest that calcium transients in glial populations may serve as a stand-alone or supplemental screening technique for identifying potential analgesics or compounds targeting other glia-mediated pathologies.

Association between frailty, chronic conditions and socioeconomic status in community-dwelling older adults attending primary care: a cross-sectional study using practice-based research network data.

OBJECTIVES: Frailty is a multidimensional syndrome of loss of reserves in energy, physical ability, cognition and general health. Primary care is key in preventing and managing frailty, mindful of the social dimensions that contribute to its risk, prognosis and appropriate patient support. We studied associations between frailty levels and both chronic conditions and socioeconomic status (SES). DESIGN: Cross-sectional cohort study SETTING: A practice-based research network (PBRN) in Ontario, Canada, providing primary care to 38 000 patients. The PBRN hosts a regularly updated database containing deidentified, longitudinal, primary care practice data. PARTICIPANTS: Patients aged 65 years or older, with a recent encounter, rostered to family physicians at the PBRN. INTERVENTION: Physicians assigned a frailty score to patients using the 9-point Clinical Frailty Scale. We linked frailty scores to chronic conditions and neighbourhood-level SES to examine associations between these three domains. RESULTS: Among 2043 patients assessed, the prevalence of low (scoring 1-3), medium (scoring 4-6) and high (scoring 7-9) frailty was 55.8%, 40.3%, and 3.8%, respectively. The prevalence of five or more chronic diseases was 11% among low-frailty, 26% among medium-frailty and 44% among high-frailty groups (χ2=137.92, df 2, p<0.001). More disabling conditions appeared in the top 50% of conditions in the highest-frailty group compared with the low and medium groups. Increasing frailty was significantly associated with lower neighbourhood income (χ2=61.42, df 8, p<0.001) and higher neighbourhood material deprivation (χ2=55.24, df 8, p<0.001). CONCLUSION: This study demonstrates the triple disadvantage of frailty, disease burden and socioeconomic disadvantage. Frailty care needs a health equity approach: we demonstrate the utility and feasibility of collecting patient-level data within primary care. Such data can relate social risk factors, frailty and chronic disease towards flagging patients with the greatest need and creating targeted interventions.

Structural maturation of SYCP1-mediated meiotic chromosome synapsis by SYCE3.

In meiosis, a supramolecular protein structure, the synaptonemal complex (SC), assembles between homologous chromosomes to facilitate their recombination. Mammalian SC formation is thought to involve hierarchical zipper-like assembly of an SYCP1 protein lattice that recruits stabilizing central element (CE) proteins as it extends. Here we combine biochemical approaches with separation-of-function mutagenesis in mice to show that, rather than stabilizing the SYCP1 lattice, the CE protein SYCE3 actively remodels this structure during synapsis. We find that SYCP1 tetramers undergo conformational change into 2:1 heterotrimers on SYCE3 binding, removing their assembly interfaces and disrupting the SYCP1 lattice. SYCE3 then establishes a new lattice by its self-assembly mimicking the role of the disrupted interface in tethering together SYCP1 dimers. SYCE3 also interacts with CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment. Thus, SYCE3 remodels the SYCP1 lattice into a CE-binding integrated SYCP1-SYCE3 lattice to achieve long-range synapsis by a mature SC.

OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis.

PURPOSE: Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC. METHODS: Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized. RESULTS: Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ2 = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca2+ uptake, demonstrating loss of function. CONCLUSION: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.

Clinical variants in Caenorhabditis elegans expressing human STXBP1 reveal a novel class of pathogenic variants and classify variants of uncertain significance.

Purpose: Modeling disease variants in animals is useful for drug discovery, understanding disease pathology, and classifying variants of uncertain significance (VUS) as pathogenic or benign. Methods: Using Clustered Regularly Interspaced Short Palindromic Repeats, we performed a Whole-gene Humanized Animal Model procedure to replace the coding sequence of the animal model's unc-18 ortholog with the coding sequence for the human STXBP1 gene. Next, we used Clustered Regularly Interspaced Short Palindromic Repeats to introduce precise point variants in the Whole-gene Humanized Animal Model-humanized STXBP1 locus from 3 clinical categories (benign, pathogenic, and VUS). Twenty-six phenotypic features extracted from video recordings were used to train machine learning classifiers on 25 pathogenic and 32 benign variants. Results: Using multiple models, we were able to obtain a diagnostic sensitivity near 0.9. Twenty-three VUS were also interrogated and 8 of 23 (34.8%) were observed to be functionally abnormal. Interestingly, unsupervised clustering identified 2 distinct subsets of known pathogenic variants with distinct phenotypic features; both p.Tyr75Cys and p.Arg406Cys cluster away from other variants and show an increase in swim speed compared with hSTXBP1 worms. This leads to the hypothesis that the mechanism of disease for these 2 variants may differ from most STXBP1-mutated patients and may account for some of the clinical heterogeneity observed in the patient population. Conclusion: We have demonstrated that automated analysis of a small animal system is an effective, scalable, and fast way to understand functional consequences of variants in STXBP1 and identify variant-specific intensities of aberrant activity suggesting a genotype-to-phenotype correlation is likely to occur in human clinical variations of STXBP1.

Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability.

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-ß burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-ß in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes.

The RNA-Binding Protein HuR Is Integral to the Function of Nociceptors in Mice and Humans.

HuR is an RNA-binding protein implicated in RNA processing, stability, and translation. Previously, we examined protein synthesis in dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We found that the HuR consensus binding element was enriched in transcripts with elevated translation. HuR is expressed in the soma of nociceptors and their axons. Pharmacologic inhibition of HuR with the small molecule CMLD-2 reduced the activity of mouse and human sensory neurons. Peripheral administration of CMLD-2 in the paw or genetic elimination of HuR from sensory neurons diminished behavioral responses associated with NGF- and IL-6-induced allodynia in male and female mice. Genetic disruption of HuR altered the proximity of mRNA decay factors near a key neurotrophic factor (TrkA). Collectively, the data suggest that HuR is required for local control of mRNA stability and reveals a new biological function for a broadly conserved post-transcriptional regulatory factor.SIGNIFICANCE STATEMENT Nociceptors undergo long-lived changes in excitability, which may contribute to chronic pain. Noxious cues that promote pain lead to rapid induction of protein synthesis. The underlying mechanisms that confer specificity to mRNA control in nociceptors are unclear. Here, we identify a conserved RNA-binding protein called HuR as a key regulatory factor in sensory neurons. Using a combination of genetics and pharmacology, we demonstrate that HuR is required for signaling in nociceptors. In doing so, we report an important mechanism of mRNA control in sensory neurons that ensures appropriate nociceptive responses to inflammatory mediators.

A Novel 3D Helical Microelectrode Array for In Vitro Extracellular Action Potential Recording.

Recent advances in cell and tissue engineering have enabled long-term three-dimensional (3D) in vitro cultures of human-derived neuronal tissues. Analogous two-dimensional (2D) tissue cultures have been used for decades in combination with substrate integrated microelectrode arrays (MEA) for pharmacological and toxicological assessments. While the phenotypic and cytoarchitectural arguments for 3D culture are clear, 3D MEA technologies are presently inadequate. This is mostly due to the technical challenge of creating vertical electrical conduction paths (or 'traces') using standardized biocompatible materials and fabrication techniques. Here, we have circumvented that challenge by designing and fabricating a novel helical 3D MEA comprised of polyimide, amorphous silicon carbide (a-SiC), gold/titanium, and sputtered iridium oxide films (SIROF). Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) testing confirmed fully-fabricated MEAs should be capable of recording extracellular action potentials (EAPs) with high signal-to-noise ratios (SNR). We then seeded induced pluripotent stems cell (iPSC) sensory neurons (SNs) in a 3D collagen-based hydrogel integrated with the helical MEAs and recorded EAPs for up to 28 days in vitro from across the MEA volume. Importantly, this highly adaptable design does not intrinsically limit cell/tissue type, channel count, height, or total volume.

Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain.

Nociceptors are a type of sensory neuron that are integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high-throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse dorsal root ganglion (DRG) tissues, and mouse DRG cultures. Co-culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveal that many key transcripts linked to pain are present. Markers indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique posttranslational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo and diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a demonstration for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.

Making white spots disappear! Do minimally invasive treatments improve incisor opacities in children with molar-incisor hypomineralisation?

BACKGROUND: Children with molar-incisor hypomineralisation (MIH) frequently seek aesthetic treatment for incisor opacities. Surprisingly, few studies have evaluated the clinical success of such interventions. AIM: To quantify the effectiveness of minimally invasive treatments in reducing enamel opacity visibility in children with MIH. DESIGN: This in vitro study used digital clinical images of 23 children aged 8-16 years with MIH who underwent microabrasion and/or resin infiltration for the management of incisor opacities. Standard images were taken pre-treatment and 6 months post-treatment. Image software (Image-Pro Plus® V7) was employed to convert 24-bit RGB images to 16-bit greyscale and 145× magnification. Measurement repeatability was assessed using intra-class correlation coefficients (ICCs). Post-treatment changes in visible opacity area (mm2 ) and brightness (greyscale value) were tested using the Wilcoxon signed-rank test for related samples. RESULTS: The mean total opacity surface area significantly reduced from 14.3 mm2 (SD = 7.5) to 9.4 mm2 (SD = 9.0) post-treatment. The proportion of tooth surface affected by the opacity also significantly reduced from 22.5% (SD = 10.5) to 14.7% (SD = 12.7). The mean maximum opacity brightness significantly reduced from 53 066 greyscale value (SD = 4740) to 49 040 (SD = 3796). ICC was good/excellent (0.75-1.0). CONCLUSION: Minimally invasive treatment is effective in reducing the size and brightness of discrete incisor opacities. Future research should compare objective findings with patient-reported outcomes.

Morally Injurious Experiences and Emotions of Health Care Professionals During the COVID-19 Pandemic Before Vaccine Availability.

Importance: Moral injury in health care professionals (HPs) has worsened over the course of the COVID-19 pandemic. The trauma and burnout associated with moral injury has profound implications for the mental health of HPs. Objective: To explore the potential factors associated with moral injury for HPs who were involved in patient care during the COVID-19 pandemic in 2020, prior to the availability of vaccines. Design, Setting, and Participants: In this qualitative study, HPs were actively recruited to participate in a survey via snowball sampling via email and social media in 2 phases of 5 weeks each: April 24 to May 30, 2020 (phase 1), and October 24 to November 30, 2020 (phase 2). Overall, 1831 respondents answered demographic questions and assessments for moral injury, intrinsic religiosity, and burnout. Of those, 1344 responded to the open-ended questions. Responses to open-ended questions were coded iteratively and thematically analyzed within the framework of moral injury. Exposures: Working in a patient care setting during the COVID-19 pandemic prior to the availability of vaccines. Main Outcomes and Measures: Inductive thematic analysis of open-response survey answers identified dominant emotions and common stressors associated with moral injury. Results: There were 335 individuals (109 [32.6%] aged 35-44 years; 288 [86.0%] women; 294 [87.8%] White) in phase 1 and 1009 individuals (384 [38.1%] aged 35-44 years; 913 [90.5%] women; 945 [93.7%] White) in phase 2. In phase 1, the respondents were predominantly nurses (100 [29.9%]), physicians (78 [23.3%]), advanced practice practitioners (APPs) (70 [20.9%]), and chaplains (55 [16.4%]). In phase 2, the respondents were predominantly nurses (589 [58.4%]), physicians (114 [11.3%]), and APPs (104 [10.3%]). HPs faced numerous stressors, such as fear of contagion, stigmatization, short-staffing, and inadequate personal protective equipment. The emotions experienced were (1) fear in phase 1, then fatigue in phase 2; (2) isolation and alienation; and (3) betrayal. Conclusions and Relevance: These findings suggest that HPs experienced moral injury during the COVID-19 pandemic. Moral injury was not only experienced after a single moral dilemma but also from working in morally injurious environments. These experiences can serve as potential starting points for organizations to engender and enhance organizational and individual recovery, team building, and trust. System-level solutions that address shortages in staffing and personal protective equipment are needed to promote HP well-being.

Moral Injury and Burnout in Health Care Professionals During the COVID-19 Pandemic.

ABSTRACT: The coronavirus pandemic (COVID-19) is predicted to increase burnout in health professionals (HPs), but little is known about moral injury (MI) in this context. We administered the Moral Injury Symptoms Scale for Health Professionals (MISS-HP) and the abbreviated Maslach Burnout Inventory via online survey to a global sample of 1831 HPs in April and October 2020. Mean MISS-HP increased from 27.4 (SD, 11.6) in April to 36.4 (SD, 13.8) in October (p < 0.001), with an accompanying increase in personal accomplishment (April: 4.7; SD, 3.1; October: 9.3; SD, 3.1; p < 0.001) and no change in other burnout subscales. In April, 26.7% of respondents reported at least moderate functional impairment from MI, increasing to 45.7% in October (p < 0.001). Predictors of MISS-HP included younger age and being a nurse. Odds of functional impairment were higher in respondents who were widowed, divorced, never married, or had direct experience caring for patients with COVID-19. COVID-19 has increased MI but not burnout in HPs; younger or unmarried individuals, nurses, and frontline workers may benefit from targeted outreach to reduce downstream effects of MI, depression, and/or posttraumatic stress disorder.

Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function.

Shuttling RNA-binding proteins coordinate nuclear and cytoplasmic steps of gene expression. The SR family proteins regulate RNA splicing in the nucleus and a subset of them, including SRSF1, shuttles between the nucleus and cytoplasm affecting post-splicing processes. However, the physiological significance of this remains unclear. Here, we used genome editing to knock-in a nuclear retention signal (NRS) in Srsf1 to create a mouse model harboring an SRSF1 protein that is retained exclusively in the nucleus. Srsf1NRS/NRS mutants displayed small body size, hydrocephalus, and immotile sperm, all traits associated with ciliary defects. We observed reduced translation of a subset of mRNAs and decreased abundance of proteins involved in multiciliogenesis, with disruption of ciliary ultrastructure and motility in cells and tissues derived from this mouse model. These results demonstrate that SRSF1 shuttling is used to reprogram gene expression networks in the context of high cellular demands, as observed here, during motile ciliogenesis.

Physician moral injury in the context of moral, ethical and legal codes.

After 40 years of attributing high rates of physician career dissatisfaction, attrition, alcoholism, divorce and suicide to 'burnout', there is growing recognition that these outcomes may instead be caused by moral injury. This has led to a debate about the relative diagnostic merits of these two terms, a recognition that interventions designed to treat burnout may be ineffective, and much perplexity about how-if at all-this changes anything.The current research seeks to develop the construct of moral injury outside military contexts, generate more robust validity tests and more fully describe and measure the experiences of persons exposed to moral harms. Absent from the literature is a mechanism through which to move from the collective moral injury experience of physicians to a systematic change in the structure of medical practice. To address this, after providing a brief history, definitions and contrasts between burnout, moral distress and moral injury, we review the interplay of moral and ethical codes in the context of moral injury. We conclude by suggesting that professional associations can potentially prevent moral injury by providing protections for physicians within their codes of ethics.