Lidocaine-Associated CNS Toxicity at Therapeutic Dosage: A Case Report and Literature Review.

Lidocaine is a commonly used anesthetic. High doses or intravenous administration of lidocaine, as well as other local anesthetics, may result in systemic effects involving the cardiovascular and neurologic systems. Typically, effects are dependent on the serum concentrations of the offending agent. This is a case where a patient presented with symptoms of systemic lidocaine toxicity despite therapeutic dosage and an undetectable serum lidocaine concentration. A 47-year-old Caucasian male received a lumbar medial branch injection of lidocaine and presented with symptoms of perioral numbness, seizure-like activity, and confusion. The patient had a workup, including a CT head without acute findings and an undetectable serum lidocaine level. Due to symptoms consistent with systemic local anesthetic toxicity, intravenous lipid emulsion (ILE) was administered with resolution and without recurrence of symptoms. There should be a low threshold of suspicion for local anesthetic systemic toxicity when patients have neurologic or cardiovascular symptoms following exposure. Toxicity may be present despite therapeutic dosages and low serum concentrations. ILE may be beneficial and should be considered.

Comparative Analysis of Thermal Adaptations of Extremophilic Prolyl Oligopeptidases.

Prolyl oligopeptidases (POPs) from psychrophilic, mesophilic, and thermophilic organisms found in a range of natural environments are studied using a combination of protein structure prediction, atomistic molecular dynamics, and trajectory analysis to determine how the S9 protease family adapts to extreme thermal conditions. We compare our results with hypotheses from the literature regarding structural adaptations that allow proteins to maintain structure and function at extreme temperatures, and find that in the case of POPs, only a subset of proposed adaptations are employed for maintaining stability. The catalytic and propeller domains are highly structured, limiting the range of mutations that can be made to enhance hydrophobicity or form disulfide bonds without disrupting the formation of necessary secondary structure. Rather, we observe a pattern in which overall prevalence of bound interactions (salt bridges and hydrogen bonds) is conserved by using increasing numbers of increasingly short-lived interactions as temperature increases. This suggests a role for an entropic rather than energetic strategy for thermal adaptation in this protein family.

The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins.

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for lifelong lens transparency, so one might expect the ubiquitous lens crystallin superfamilies (α and ßγ) to contain little cysteine. Yet, the Cys content of γ-crystallins is well above the average for human proteins. We review literature relevant to this longstanding puzzle and take advantage of expanding genomic databases and improved machine learning tools for protein structure prediction to investigate it further. We observe remarkably low Cys conservation in the ßγ-crystallin superfamily; however, in γ-crystallin, the spatial positioning of Cys residues is clearly fine-tuned by evolution. We propose that the requirements of long-term lens transparency and high lens optical power impose competing evolutionary pressures on lens ßγ-crystallins, leading to distinct adaptations: high Cys content in γ-crystallins but low in ßB-crystallins. Aquatic species need more powerful lenses than terrestrial ones, which explains the high methionine content of many fish γ- (and even ß-) crystallins. Finally, we discuss synergies between sulfur-containing and aromatic residues in crystallins and suggest future experimental directions.

Automated test apparatus for bench-testing the magnetic field homogeneity of NMR transceiver coils.

We describe an automated hands-off bench testing method for measuring the magnetic field profile of transceiver coils for nuclear magnetic resonance (NMR). The scattering parameter (S-parameter) data is measured using a portable network analyzer, and the results are automatically exported to a computer for plotting and viewing. This assay dramatically reduces the time needed to measure the magnetic field (B1) homogeneity profile of a transceiver coil while also improving accuracy relative to manual operation. Here, we demonstrate the method on a saddle coil of a solution-state NMR probe in comparison to profiles obtained using NMR spectroscopy measurements. We also measure the axial and radial homogeneity of a variable-pitch solenoid.

Use of removable support boot versus cast for early mobilisation after ankle fracture surgery: cost-effectiveness analysis and qualitative findings of the Ankle Recovery Trial (ART).

OBJECTIVES: To estimate the cost-effectiveness of using a removable boot versus a cast following ankle fracture from the National Health Service and Personal Social Services (NHS+PSS) payer and societal perspectives and explore the impact of both treatments on participants' activities of daily living. DESIGN: Cost-effectiveness analyses and qualitative interviews performed alongside a pragmatic multicentre randomised controlled trial. SETTING: Eight UK NHS secondary care trusts. PARTICIPANTS: 243 participants (60.5% female, on average 48.2 years of age (SD 16.4)) with ankle fracture. Qualitative interviews with 16 participants. Interventions removable air boot versus plaster cast 2 weeks after surgery weight bearing as able with group-specific exercises. PRIMARY AND SECONDARY OUTCOME MEASURES: Quality-adjusted life years (QALYs) estimated from the EQ-5D-5L questionnaire, costs and incremental net monetary benefit statistics measured 12 weeks after surgery, for a society willing-to-pay £20 000 per QALY. RESULTS: Care in the boot group cost, on average, £88 (95% CI £22 to £155) per patient more than in the plaster group from the NHS+PSS perspective. When including all societal costs, the boot saved, on average, £676 per patient (95% CI -£337 to £1689). Although there was no evidence of a QALY difference between the groups (-0.0020 (95% CI -0.0067 to 0.0026)), the qualitative findings suggest participants felt the boot enhanced their quality of life. Patients in the boot felt more independent and empowered to take on family responsibilities and social activities. CONCLUSIONS: While the removable boot is slightly more expensive than plaster cast for the NHS+PSS payer at 12 weeks after surgery, it reduces productivity losses and the need for informal care while empowering patients. Given that differences in QALYs and costs to the NHS are small, the decision to use a boot or plaster following ankle surgery could be left to patients' and clinicians' preferences. TRIAL REGISTRATION NUMBER: ISRCTN15497399, South Central-Hampshire A Research Ethics Committee (reference 14/SC/1409).

Spatially resolved detection of small molecules from press-dried plant tissue using MALDI imaging.

Premise: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a chemical imaging method that can visualize spatial distributions of particular molecules. Plant tissue imaging has so far mostly used cryosectioning, which can be impractical for the preparation of large-area imaging samples, such as full flower petals. Imaging unsectioned plant tissue presents its own difficulties in extracting metabolites to the surface due to the waxy cuticle. Methods: We address this by using established delipidation techniques combined with a solvent vapor extraction prior to applying the matrix with many low-concentration sprays. Results: Using this procedure, we imaged tissue from three different plant species (two flowers and one carnivorous plant leaf). Material factorization analysis of the resulting data reveals a wide range of plant-specific small molecules with varying degrees of localization to specific portions of the tissue samples, while facilitating detection and removal of signal from background sources. Conclusions: This work demonstrates applicability of MALDI-MSI to press-dried plant samples without freezing or cryosectioning, setting the stage for spatially resolved molecule identification. Increased mass resolution and inclusion of tandem mass spectrometry are necessary next steps to allow more specific and reliable compound identification.

Premisa: Matrix­assisted laser desorption/ionization mass spectrometry imaging (MALDI­MSI) es un método de imagen química que puede visualizar distribuciones espaciales de moléculas particulares. Hasta ahora, las imágenes de tejido vegetal han utilizado principalmente la criosección, lo cual puede ser poco práctico para la preparación de muestras de imágenes con áreas grandes, tales como los pétalos completos de una flor. La obtención de imágenes de tejido vegetal no seccionado presenta sus propias dificultades durante la extracción de metabolitos a la superficie, debido a la cutícula cerosa de la planta. Métodos: Abordamos esto usando técnicas establecidas de deslipidación combinados con una extracción de vapor por solvente antes de aplicar por aspersión la matriz en bajas concentraciones. Resultados: Usando este procedimiento, obtuvimos imágenes de tejido de tres especies de plantas diferentes (dos flores y una hoja de planta carnívora). Análisis de factorización material de los datos obtenidos revelaron una amplia gama de pequeñas moléculas específicas en plantas con diversos grados de localización en porciones específicas de las muestras de tejido, al igual que facilitó la detección y remoción de las señales de fondo. Conclusión: Nuestro trabajo demuestra la aplicabilidad de MALDI­MSI hacía muestras de plantas secadas a presión sin congelación o criosección, creando el marco para la identificación de moléculas resueltas espacialmente. Aumento de la resolución de masas e inclusión de la espectrometría de masas en tándem son pasos necesarios para obtener identificación de compuestos más específica y confiable.

Understanding patient preferences for student clinician attire: a cross-sectional study of a student chiropractic clinic in Australia.

Objectives: Previous studies have investigated the role of clinical attire in establishing patient-held perceptions of professionalism and knowledgeability across various healthcare settings. This study aimed to understand patients' preferences for chiropractic student attire. Methods: Three hundred and twenty patients were recruited from a university chiropractic clinic and asked to complete an online questionnaire. The patients' preferences for five different attires were rated and calculated as the composite score of five domains (knowledgeable, trustworthy, caring, professional, and comfortable). Results: While 71.9% of participants indicated that how students dress was important to them, most (63.4%) disagreed that wearing a white coat was essential for chiropractic student clinicians. The most preferred form of attire was the current clinic shirt. Conclusion: The attire worn by chiropractic student clinicians at a single institution was found to be an influential attribute. Student chiropractic clinicians should dress professionally to make a good first impression. This study provided some guidance with the ongoing debate around students' dress code.

Objectif: Des études antérieures ont examiné le rôle de la tenue vestimentaire en clinique dans l'établissement des perceptions des patients quant au professionnalisme et à la compétence dans divers environnements de soins de santé. Cette étude visait à comprendre les préférences des patients en matière de tenue vestimentaire des étudiants en chiropratique. Méthodologie: Trois cent vingt patients ont été recrutés dans une clinique chiropratique universitaire et invités à remplir un questionnaire en ligne. Les préférences des patients pour cinq tenues différentes ont été évaluées et calculées en tant que score composite de cinq domaines (bien informé, digne de confiance, attentionné, professionnel et confortable). Résultats: Si 71,9 % des participants ont indiqué que la tenue vestimentaire des étudiants était importante pour eux, la plupart (63,4 %) n'étaient pas d'accord avec le fait que le port d'une blouse blanche était essentiel pour les étudiants cliniciens en chiropratique. La tenue vestimentaire la plus appréciée était la chemise de clinique actuelle. Conclusion: La tenue vestimentaire des étudiants cliniciens en chiropratique d'un même établissement s'est révélée être un attribut influent. Les étudiants en chiropratique doivent s'habiller de manière professionnelle pour faire une bonne première impression. Cette étude a permis d'éclairer le débat en cours sur le code vestimentaire des étudiants.

Strategies to integrate oral health into primary care: a systematic review.

OBJECTIVES: Integration of oral health into primary care has been proposed as a primary healthcare approach for efficient and sustainable delivery of oral health services, and the effective management of oral diseases. This paper aimed to synthesise evidence on the effectiveness of strategies to integrate oral health into primary care. DESIGN: Systematic review. DATA SOURCES: MEDLINE, CINAHL, Embase, Scopus, ProQuest, Cochrane and Google Scholar were searched without date limits until the third week of June 2022. Reference lists of eligible studies were also searched. Experts in the field and existing professional networks were consulted. ELIGIBILITY CRITERIA: Only studies that evaluated integration strategies were included in the review. Eligibility was restricted to English language studies published in academic peer-reviewed journals. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and performed the risk of bias assessments. A narrative synthesis approach was used to report review findings. Heterogeneity among included studies precluded a meta-analysis. RESULTS: The search identified 8731 unique articles, of which 49 were included in the review. Majority of the studies explored provision of oral healthcare by primary care professionals in primary care settings, where integration was primarily via training/education and/or policy changes. Most studies reported results favouring the integration strategy, such as improvements in referral pathways, documentation processes, operating efficiencies, number of available health staff, number of visits to non-dental primary care professionals for oral health issues, proportion of children receiving fluoride varnish applications/other preventive treatment, proportion of visits to an oral health professional and dental caries estimates. CONCLUSION: The findings from this review demonstrate that the majority of identified strategies were associated with improved outcomes and can be used to inform decision-making on strategy selection. However, more research and evaluation are required to identify best practice models of service integration. PROSPERO REGISTRATION NUMBER: CRD42020203111.

Analyzing Child Firearm Assault Injuries by Race and Ethnicity During the COVID-19 Pandemic in 4 Major US Cities.

This cross-sectional study examines changes in rates and disparities of fatal and nonfatal firearm assaults among children in New York, Los Angeles, Chicago, and Philadelphia before and during the COVID-19 pandemic.

Comparative Modeling and Analysis of Extremophilic D-Ala-D-Ala Carboxypeptidases.

Understanding the molecular adaptations of organisms to extreme environments requires a comparative analysis of protein structure, function, and dynamics across species found in different environmental conditions. Computational studies can be particularly useful in this pursuit, allowing exploratory studies of large numbers of proteins under different thermal and chemical conditions that would be infeasible to carry out experimentally. Here, we perform such a study of the MEROPS family S11, S12, and S13 proteases from psychophilic, mesophilic, and thermophilic bacteria. Using a combination of protein structure prediction, atomistic molecular dynamics, and trajectory analysis, we examine both conserved features and trends across thermal groups. Our findings suggest a number of hypotheses for experimental investigation.

The importance of high-quality partner support for reducing stress during pregnancy and postpartum bonding impairments.

The current study investigated the extent to which interparental support reduced pregnancy stress and subsequent postpartum bonding impairments with infant. We hypothesized that receiving higher quality partner support would be associated with decreased maternal pregnancy-related concerns, and less maternal and paternal pregnancy stress which, in turn, would predict fewer parent-infant bonding impairments. One hundred fifty-seven cohabiting couples completed semi-structured interviews and questionnaires once during pregnancy and twice postpartum. Path analyses with tests of mediation were employed to test our hypotheses. Higher quality support received by mothers was associated with lower maternal pregnancy stress which, in turn, predicted fewer mother-infant bonding impairments. An indirect pathway of equal magnitude was observed for fathers. Dyadic pathways also emerged such that higher quality support received by fathers was associated with lower maternal pregnancy stress which reduced mother-infant bonding impairments. Similarly, higher quality support received by mothers reduced paternal pregnancy stress and subsequent father-infant bonding impairments. Hypothesized effects reaching statistical significance (p < .05) were small to moderate in magnitude. These findings have important theoretical and clinical implications in demonstrating the critical role of both receiving and providing high-quality interparental support to reduce pregnancy stress and subsequent postpartum bonding impairments for mothers and fathers. Results also highlight the utility of investigating maternal mental health in the couple context.

Mutation Effects on Structure and Dynamics: Adaptive Evolution of the SARS-CoV-2 Main Protease.

The main protease of SARS-CoV-2 (Mpro) plays a critical role in viral replication; although it is relatively conserved, Mpro has nevertheless evolved over the course of the COVID-19 pandemic. Here, we examine phenotypic changes in clinically observed variants of Mpro, relative to the originally reported wild-type enzyme. Using atomistic molecular dynamics simulations, we examine effects of mutation on protein structure and dynamics. In addition to basic structural properties such as variation in surface area and torsion angles, we use protein structure networks and active site networks to evaluate functionally relevant characters related to global cohesion and active site constraint. Substitution analysis shows a continuing trend toward more hydrophobic residues that are dependent on the location of the residue in primary, secondary, tertiary, and quaternary structures. Phylogenetic analysis provides additional evidence for the impact of selective pressure on mutation of Mpro. Overall, these analyses suggest evolutionary adaptation of Mpro toward more hydrophobicity and a less-constrained active site in response to the selective pressures of a novel host environment.

MDA5 signaling induces type 1 IFN- and IL-1-dependent lung vascular permeability which protects mice from opportunistic fungal infection.

Lungs balance threat from primary viral infection, secondary infection, and inflammatory damage. Severe pulmonary inflammation induces vascular permeability, edema, and organ dysfunction. We previously demonstrated that poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice from Cryptococcus gattii (Cg) via local iron restriction. Here we show pICLC increased serum protein and intravenously injected FITC-dextran in the lung airspace suggesting pICLC induces vascular permeability. Interestingly, pICLC induced a pro-inflammatory signature with significant expression of IL-1 and IL-6 which depended on MDA5 and t1IFN. Vascular permeability depended on MDA5, t1IFN, IL-1, and IL-6. T1IFN also induced MDA5 and other MDA5 signaling components suggesting that positive feedback contributes to t1IFN dependent expression of the pro-inflammatory signature. Vascular permeability, induced by pICLC or another compound, inhibited Cg by limiting iron. These data suggest that pICLC induces t1IFN which potentiates pICLC-MDA5 signaling increasing IL-1 and IL-6 resulting in leakage of antimicrobial serum factors into lung airspace. Thus, induced vascular permeability may act as an innate defense mechanism against opportunistic fungal infection, such as cryptococcosis, and may be exploited as a host-directed therapeutic target.

Developing and pilot testing an oral health screening tool for diabetes care providers.

BACKGROUND: People with poorly managed diabetes are at greater risk of periodontal disease. Periodontal disease that is not effectively managed can affect glycaemic levels. Diabetes care providers, including general practitioners and diabetes educators, are encouraged to promote oral health of their clients. However, valid and reliable oral health screening tools that assess the risk of poor oral health, that are easy to administer among non-dental professionals, currently do not exist. Existing screening tools are difficult to incorporate into routine diabetes consultations due to their length. Thus, this study aimed to develop and pilot a short oral health screening tool that would identify risk of existing oral diseases and encourage appropriate referrals to the dental service. METHODS: A three-item screening tool was developed after a comprehensive review of the literature and consensus from an expert panel. The tool was then piloted as part of a larger cross-sectional survey of 260 adults with diabetes who were accessing public diabetes clinics at two locations in Sydney, Australia. As part of the survey, participants completed the three-item screening tool and a 14-item validated tool, the Oral Health Impact Profile (OHIP-14), which has been used previously in the preliminary validation of screening tools. Sensitivity and specificity analyses were then undertaken comparing the results of the two tools. RESULTS: A statistically significant correlation was found between the shorter screening tool and the OHIP-14 (rho = 0.453, p < 0.001), indicating adequate validity. The three-item tool had high sensitivity (90.5%, 95% CI 84.9%, 94.7%), with a specificity of 46.3% (95% CI 37.7%, 55.2%). The negative predictive value was 81.4% (95% CI 71.3, 89.3). No single item performed as well regarding sensitivity and negative predictive value when compared to the three items collectively. CONCLUSIONS: The three-item screening tool developed was found to be valid and sensitive in identifying risk of poor oral health, requiring oral health referrals, among people with diabetes in this pilot. This is a simple, accessible tool that diabetes care providers could incorporate into their routine consultations. Further validation against comprehensive dental assessments is needed to reassess the tool's specificity and sensitivity in diverse settings.

New-Onset Psychotic Symptoms Following Abrupt Buprenorphine/Naloxone Discontinuation in a Female Patient with Bipolar Disorder: A Case Report.

Buprenorphine and naloxone (Suboxone) is a combination medication-assisted treatment (MAT) for opioid use disorder. MAT withdrawal-induced psychosis is a rare clinical presentation. To our best knowledge, only three reports have summarized the characteristic manifestations of buprenorphine withdrawal psychosis, yet all of them were male. In this case report, we present a 41-year-old female patient with bipolar disorder and comorbid substance use disorder who developed new-onset psychosis and relapse of manic symptoms following abrupt discontinuation of Suboxone. Manic and psychotic symptoms remitted after a short-term hospitalization with the treatment of an antipsychotic and a mood stabilizer. In addition to discussing this case presentation and treatment approach, we review existing literature and discuss possible underlying mechanisms to enhance understanding of this clinical phenomenon.

Long-Term Effects of Developmental Exposure to Oxycodone on Gut Microbiota and Relationship to Adult Behaviors and Metabolism.

Opioid drugs are commonly prescribed analgesic to pregnant women. Direct exposure to such drugs may slow gut motility, alter gut permeability, and affect the gut microbiome. While such drugs affect gut microbiome in infants, no study to date has determined whether developmental exposure to such drugs results in longstanding effects on gut microbiota and correspondingly on host responses. We hypothesized developmental exposure to oxycodone (OXY) leads to enduring effects on gut microbiota and such changes are associated with adult neurobehavioral and metabolic changes. Female mice were treated daily with 5 mg OXY/kg or saline solution (control [CTL]) for 2 weeks prior to breeding and then throughout gestation. Male and female offspring pups were weaned, tested with a battery of behavioral and metabolic tests, and fecal boli were collected adulthood (120 days of age). In females, relative abundance of Butyricimonas spp., Bacteroidetes, Anaeroplasma spp., TM7, Enterococcus spp., and Clostridia were greater in OXY versus CTL individuals. In males, relative abundance of Coriobacteriaceae, Roseburia spp., Sutterella spp., and Clostridia were elevated in OXY exposed individuals. Bacterial changes were also associated with predictive metabolite pathway alterations that also varied according to sex. In males and females, affected gut microbiota correlated with metabolic but not behavioral alterations. The findings suggest that developmental exposure to OXY leads to lasting effects on adult gut microbiota that might affect host metabolism, possibly through specific bacterial metabolites or other bacterial-derived products. Further work is needed to characterize how developmental exposure to OXY affects host responses through the gut microbiome. IMPORTANCE This is the first work to show in a rodent model that in utero exposure to an opioid drug can lead to longstanding effects on the gut microbiota when examined at adulthood. Further, such bacterial changes are associated with metabolic host responses. Given the similarities between rodent and human microbiomes, it raises cause for concern that similar effects may become evident in children born to mothers taking oxycodone and other opioid drugs.

Racial Disparities in Child Exposure to Firearm Violence Before and During COVID-19.

INTRODUCTION: Childhood exposure to neighborhood firearm violence adversely affects mental and physical health across the life course. Study objectives were to (1) quantify racial disparities in these exposures across the U.S. and (2) assess changes during the COVID-19 pandemic, when firearm violence increased. METHODS: The study used counts of children aged 5-17 years, disaggregated by U.S. Census racial category, for every census tract (N=73,056). Neighborhood firearm violence was the number of fatal shootings per census tract, based on 2015-2021 Gun Violence Archive data. Quasi-Poisson regressions were used to estimate baseline disparities and COVID-19‒related changes and examined differences across geographic regions. RESULTS: Prepandemic exposure was lowest among White children and highest among Black children, who experienced 4.44 times more neighborhood firearm violence exposure (95% CI=4.33, 4.56, p<0.001) than White children. The pandemic increased exposure by 27% in the lowest risk group (i.e., White children; 95% CI=20%, 34%, p<0.001), but pandemic effects were even greater for children in nearly all non-White categories. Baseline violence levels and racial disparities varied considerably by region, with the highest levels in the South and the largest magnitude disparities observed in the Northeast and Midwest. CONCLUSIONS: Large-scale racial disparities exist in child exposure to neighborhood firearm violence, and these disparities grew during the pandemic. Equitable access to trauma-informed programs, community-based prevention, and structural reforms are urgently needed.

Deamidation of the human eye lens protein γS-crystallin accelerates oxidative aging.

Cataract, a clouding of the eye lens from protein precipitation, affects millions of people every year. The lens proteins, the crystallins, show extensive post-translational modifications (PTMs) in cataractous lenses. The most common PTMs, deamidation and oxidation, promote crystallin aggregation; however, it is not clear precisely how these PTMs contribute to crystallin insolubilization. Here, we report six crystal structures of the lens protein γS-crystallin (γS): one of the wild-type and five of deamidated γS variants, from three to nine deamidation sites, after sample aging. The deamidation mutations do not change the overall fold of γS; however, increasing deamidation leads to accelerated disulfide-bond formation. Addition of deamidated sites progressively destabilized protein structure, and the deamidated variants display an increased propensity for aggregation. These results suggest that the deamidated variants are useful as models for accelerated aging; the structural changes observed provide support for redox activity of γS-crystallin in the lens.