SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling.

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since its emergence in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation of double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections including murine coronavirus and Middle East respiratory syndrome (MERS)-CoV. To determine how nsp15 functions during SARS-CoV-2 infection, we constructed a recombinant SARS-CoV-2 (nsp15mut) expressing catalytically inactivated nsp15, which we show promoted increased dsRNA accumulation. Infection with SARS-CoV-2 nsp15mut led to increased activation of the IFN signaling and PKR pathways in lung-derived epithelial cell lines and primary nasal epithelial air-liquid interface (ALI) cultures as well as significant attenuation of replication in ALI cultures compared to wild-type virus. This replication defect was rescued when IFN signaling was inhibited with the Janus activated kinase (JAK) inhibitor ruxolitinib. Finally, to assess nsp15 function in the context of minimal (MERS-CoV) or moderate (SARS-CoV-2) innate immune induction, we compared infections with SARS-CoV-2 nsp15mut and previously described MERS-CoV nsp15 mutants. Inactivation of nsp15 had a more dramatic impact on MERS-CoV replication than SARS-CoV-2 in both Calu3 cells and nasal ALI cultures suggesting that SARS-CoV-2 can better tolerate innate immune responses. Taken together, SARS-CoV-2 nsp15 is a potent inhibitor of dsRNA-induced innate immune response and its antagonism of IFN signaling is necessary for optimal viral replication in primary nasal ALI cultures.

Colloidal Stability of PFSA-Ionomer Dispersions. Part I. Single-Ion Electrostatic Interaction Potential Energies.

Charged colloidal particles neutralized by a single counterion are increasingly important for many emerging technologies. Attention here is paid specifically to hydrogen fuel cells and water electrolyzers whose catalyst layers are manufactured from a perfluorinated sulfonic acid polymer (PFSA) suspended in aqueous/alcohol solutions. Partially dissolved PFSA aggregates, known collectively as ionomers, are stabilized by the electrostatic repulsion of overlapping diffuse double layers consisting of only protons dissociated from the suspended polymer. We denote such double layers containing no added electrolyte as "single ion". Size-distribution predictions build upon interparticle interaction potential energies from the Derjaguin-Landau-Verwey-Overbeek (DLVO) formalism. However, when only a single counterion is present in solution, classical DLVO electrostatic potential energies no longer apply. Accordingly, here a new formulation is proposed to describe how single-counterion diffuse double layers interact in colloidal suspensions. Part II (Srivastav, H.; Weber, A. Z.; Radke, C. J. Langmuir 2024 DOI: 10.1021/acs.langmuir.3c03904) of this contribution uses the new single-ion interaction energies to predict aggregated size distributions and the resulting solution pH of PFSA in mixtures of n-propanol and water. A single-counterion diffuse layer cannot reach an electrically neutral concentration far from a charged particle. Consequently, nowhere in the dispersion is the solvent neutral, and the diffuse layer emanating from one particle always experiences the presence of other particles (or walls). Thus, in addition to an intervening interparticle repulsive force, a backside osmotic force is always present. With this new construction, we establish that single-ion repulsive pair interaction energies are much larger than those of classical DLVO electrostatic potentials. The proposed single-ion electrostatic pair potential governs dramatic new dispersion behavior, including dispersions that are stable at a low volume fraction but unstable at a high volume fraction and finite volume-fraction dispersions that are unstable with fine particles but stable with coarse particles. The proposed single-counterion electrostatic pair potential provides a general expression for predicting colloidal behavior for any charged particle dispersion in ionizing solvents with no added electrolyte.

Colloidal Stability of PFSA-Ionomer Dispersions Part II: Determination of Suspension pH Using Single-Ion Potential Energies.

Perfluorosulfonic acid (PFSA) ionomers serve a vital role in the performance and stability of fuel-cell catalyst layers. These properties, in turn, depend on the colloidal processing of precursor inks. To understand the colloidal structure of fuel-cell catalyst layers, we explore the aggregation of PFSA ionomers dissolved in water/alcohol solutions and relate the predicted aggregation to experimental measurements of solution pH. Not all side chains contribute to measured pH because of burying inside particle aggregates. To account for the measured degree of dissociation, a new description is developed for how PFSA aggregates interact with each other. The developed single-counterion electrostatic repulsive pair potential from Part I is incorporated into the Smoluchowski collision-based kinetics of interacting aggregates with buried side chains. We demonstrate that the surrounding solvent mixture affects the degree of aggregation as well as the pH of the system primarily through the solution dielectric permittivity, which drives the strength of the interparticle repulsive energies. Successful pH prediction of Nafion ionomer dispersions in water/n-propanol solutions validates the numerical calculations. Nafion-dispersion pH measurements serve as a surrogate for Nafion particle-size distributions. The model and framework can be leveraged to explore different ink formulations.

Defining Populations and Predicting Future Suitable Niche Space in the Geographically Disjunct, Narrowly Endemic Leafy Prairie-Clover (Dalea foliosa; Fabaceae).

Conservation actions for rare species are often based on estimates of population size and number, which are challenging to capture in natural systems. Instead, many definitions of populations rely on arbitrarily defined distances between occurrences, which is not necessarily biologically meaningful despite having utility from a conservation management perspective. Here, we introduce a case study using the narrowly endemic and highly geographically disjunct leafy prairie-clover (Dalea foliosa), for which we use nuclear microsatellite loci to assess the current delimitations of populations and management units across its entire known range. We model future potential suitable niche space for the species to assess how currently defined populations could fare under predicted changes in climate over the next 50 years. Our results indicate that genetic variation within the species is extremely limited, particularly so in the distal portions of its range (Illinois and Alabama). Within the core of its range (Tennessee), genetic structure is not consistent with populations as currently defined. Our models indicate that predicted suitable niche space may only marginally overlap with the geology associated with this species (limestone glades and dolomite prairies) by 2070. Additional studies are needed to evaluate the extent to which populations are ecologically adapted to local environments and what role this could play in future translocation efforts.

Pediatric Multidrug-Resistant Disseminated Tuberculosis Presenting as Small Finger Tuberculous Osteomyelitis: A Case Report.

CASE: We report a case in the United States of a 12-year-old girl with multidrug-resistant tuberculous (MDR-TB) osteomyelitis of the hand managed with surgical debridement and second-line anti-TB therapy. The disease course was complicated by dissemination and multifocal progression. CONCLUSION: Despite early intervention, multidrug resistance makes TB treatment challenging and facilitated progression to disseminated disease in this case. We review the difficulties in diagnosis and treatment of pediatric MDR-TB.

Maternal blood pressure and birth weight associations in U.S.-born and foreign-born Latinas.

OBJECTIVES: Research suggests that acculturating to the United States is detrimental for immigrants' health. Consistent with this pattern, higher levels of U.S. acculturation among Latina-American women have been associated with giving birth to lower birth weight babies. The mechanisms that shape this shift in pregnancy health are not clear, but researchers have begun to consider the role of physiological systems that are sensitive to social experience. The present study examined the association of cultural orientation with blood pressure (BP) trajectories over the course of pregnancy. METHOD: In a study of 1,011 U.S.- and foreign-born Latina-American women, cultural orientation was assessed and multiple BP measures were collected throughout pregnancy. Postpregnancy data, including gestational age-adjusted birth weight, were extracted from medical records. Bayesian structural equation models examined average BP and slopes of BP change during pregnancy while accounting for psychosocial stress, support, and pregnancy health-related factors (e.g., maternal age, smoking). RESULTS: We found evidence that greater U.S. orientation was associated with higher diastolic blood pressure (DBP) and steeper increases in DBP, which was associated with less fetal growth. CONCLUSIONS: This is the first evidence that BP may mediate the association between cultural orientation and pregnancy outcomes in Latina-American women. These findings advance our understanding of the biopsychosocial pathways through which acculturation to the U.S. links with health. As scholars seek to better understand the influence of U.S. acculturation on health, focusing on the cardiovascular system and other physiological systems that are sensitive to social experience is warranted and likely to prove valuable. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Symptomatic carotid webs require aggressive intervention.

OBJECTIVE: Carotid web (CaWeb) is a rare form of fibromuscular dysplasia that can produce embolic stroke. Misdiagnosis of symptomatic CaWeb as "cryptogenic stroke" or "embolic stroke of unknown source" is common and can lead to recurrent, catastrophic neurologic events. Reports of CaWeb in the literature are scarce, and their natural history is poorly understood. Appropriate management remains controversial. METHODS: CaWeb was defined as a single, shelf-like, linear projection in the posterolateral carotid bulb causing a filling defect on computed tomography angiography (CTA) or cerebral angiography. Cases of symptomatic CaWeb at a single institution with a high-volume stroke center were identified through collaborative evaluation by vascular neurologists and vascular surgeons. RESULTS: Fifty-two patients with symptomatic CaWeb were identified during a 6-year period (2016-2022). Average age was 49 years (range, 29-73 years), 35 of 52 (67%) were African American, and 18 of 52 (35%) were African American women under age 50. Patients initially presented with stroke (47/52; 90%) or transient ischemic attack (5/52; 10%). Stenosis was <50% in 49 of 52 patients (94%) based on NASCET criteria, and 0 of 52 (0%) CaWebs were identified with carotid duplex. Definitive diagnosis was made by CTA examined in multiple planes or cerebral angiography examined in a lateral projection to adequately assess the posterolateral carotid bulb, where 52 of 52 (100%) of CaWebs were seen. Early in our institutional experience, 10 of 52 patients (19%) with symptomatic CaWeb were managed initially with dual antiplatelet and statin therapy or systemic anticoagulation; all suffered ipsilateral recurrent stroke at an average interval of 43 months (range, 1-89 months), and five were left with permanent deficits. Definitive treatment included carotid endarterectomy in 27 of 50 (56%) or carotid stenting in 23 of 50 (46%). Two strokes were irrecoverable, and intervention was deferred. Web-associated thrombus was observed in 20 of 50 (40%) on angiography or grossly upon carotid exploration. Average interval from initial stroke to intervention was 39 days. After an average follow-up of 38 months, there was no reported postintervention stroke or mortality. CONCLUSIONS: To our knowledge, this is the largest single-institution analysis of symptomatic CaWeb yet reported. Our series demonstrates that carotid duplex is inadequate for diagnosis, and that medical management is unacceptable for symptomatic CaWeb. Recurrent stroke occurred in all patients managed early in our experience with medical therapy alone. We have since adopted an aggressive interventional approach in cases of symptomatic CaWeb, with no postoperative stroke reported over an average follow-up of 38 months. In younger patients presenting with cryptogenic stroke, especially African American women, detailed review of lateral cerebral angiography or multi-planar, fine-cut CTA images is required to accurately rule out or diagnose CaWeb and avoid recurrent neurologic events.

Current Medicare reimbursement for complex endovascular aortic repair is inadequate based on results from a multi-institutional cost analysis.

OBJECTIVE: Complex endovascular juxta-, para- and suprarenal abdominal aortic aneurysm repair (comEVAR) is frequently accomplished with commercially available fenestrated (FEVAR) devices or off-label use of aortoiliac devices with parallel branch stents (chEVAR). We sought to evaluate the implantable vascular device costs incurred with these procedures as compared with standard Medicare reimbursement to determine the financial viability of comEVAR in the modern era. METHODS: Five geographically distinct institutions with high-volume, complex aortic centers were included. Implantable aortoiliac and branch stent device cost data from 25 consecutive, recent, comEVAR in the treatment of juxta-, para-, and suprarenal aortic aneurysms at each center were analyzed. Cases of rupture, thoracic aneurysms, reinterventions, and physician-modified EVAR were excluded, as were ancillary costs from nonimplantable equipment. Data from all institutions were combined and stratified into an overall cost group and two, individual cost groups: FEVAR or chEVAR. These groups were compared, and each respective group was then compared with weighted Medicare reimbursement for Diagnosis-Related Group codes 268/269. Median device costs were obtained from an independent purchasing consortium of >3000 medical centers, yielding true median cost-to-institution data rather than speculative, administrative projections or estimates. RESULTS: A total of 125 cases were analyzed: 70 FEVAR and 53 chEVAR. Two cases of combined FEVAR/chEVAR were included in total cost analysis, but excluded from direct FEVAR vs chEVAR comparison. Median Medicare reimbursement was calculated as $35,755 per case. Combined average implantable device cost for all analyzed cases was $28,470 per case, or 80% of the median reimbursement ($28,470/$35,755). Average FEVAR device cost per case ($26,499) was significantly lower than average chEVAR cost per case ($32,122; P < .002). Device cost was 74% ($26,499/$35,755) of total reimbursement for FEVAR and 90% ($32,122/$35,755) for chEVAR. CONCLUSIONS: Results from this multi-institutional analysis show that implantable device cost alone represents the vast majority of weighted total Medicare reimbursement per case with comEVAR, and that chEVAR is significantly more costly than FEVAR. Inadequate Medicare reimbursement for these cases puts high-volume, high-complexity aortic centers at a distinct financial disadvantage. In the interest of optimizing patient care, these data suggest a reconsideration of previously established, outdated, Diagnosis-Related Group coding and Medicare reimbursement for comEVAR.

A network approach to the investigation of childhood irritability: probing frustration using social stimuli.

BACKGROUND: Self-regulation in early childhood develops within a social context. Variations in such development can be attributed to inter-individual behavioral differences, which can be captured both as facets of temperament and across a normal:abnormal dimensional spectrum. With increasing emphasis on irritability as a robust early-life transdiagnostic indicator of broad psychopathological risk, linkage to neural mechanisms is imperative. Currently, there is inconsistency in the identification of neural circuits that underlie irritability in children, especially in social contexts. This study aimed to address this gap by utilizing a functional magnetic resonance imaging (fMRI) paradigm to investigate pediatric anger/frustration using social stimuli. METHODS: Seventy-three children (M = 6 years, SD = 0.565) were recruited from a larger longitudinal study on irritability development. Caregivers completed questionnaires assessing irritable temperament and clinical symptoms of irritability. Children participated in a frustration task during fMRI scanning that was designed to induce frustration through loss of a desired prize to an animated character. Data were analyzed using both general linear modeling (GLM) and independent components analysis (ICA) and examined from the temperament and clinical perspectives. RESULTS: ICA results uncovered an overarching network structure above and beyond what was revealed by traditional GLM analyses. Results showed that greater temperamental irritability was associated with significantly diminished spatial extent of activation and low-frequency power in a network comprised of the posterior superior temporal sulcus (pSTS) and the precuneus (p < .05, FDR-corrected). However, greater severity along the spectrum of clinical expression of irritability was associated with significantly increased extent and intensity of spatial activation as well as low- and high-frequency neural signal power in the right caudate (p < .05, FDR-corrected). CONCLUSIONS: Our findings point to specific neural circuitry underlying pediatric irritability in the context of frustration using social stimuli. Results suggest that a deliberate focus on the construction of network-based neurodevelopmental profiles and social interaction along the normal:abnormal irritability spectrum is warranted to further identify comprehensive transdiagnostic substrates of the irritability.

In toto imaging of glial JNK signaling during larval zebrafish spinal cord regeneration.

Identification of signaling events that contribute to innate spinal cord regeneration in zebrafish can uncover new targets for modulating injury responses of the mammalian central nervous system. Using a chemical screen, we identify JNK signaling as a necessary regulator of glial cell cycling and tissue bridging during spinal cord regeneration in larval zebrafish. With a kinase translocation reporter, we visualize and quantify JNK signaling dynamics at single-cell resolution in glial cell populations in developing larvae and during injury-induced regeneration. Glial JNK signaling is patterned in time and space during development and regeneration, decreasing globally as the tissue matures and increasing in the rostral cord stump upon transection injury. Thus, dynamic and regional regulation of JNK signaling help to direct glial cell behaviors during innate spinal cord regeneration.

Effectiveness of take ACTION online naloxone training for law enforcement officers.

BACKGROUND: Training law enforcement officers (LEOs) to administer naloxone is a recommended strategy to reduce overdose deaths in the United States. To achieve this, an evidence-based and scalable naloxone training curriculum that is easy to use and readily scalable is needed. Convenient web-based training is a flexible method for delivering educational interventions particularly for LEOs who have irregular or shifting schedules. This study examined the effectiveness of a comprehensive web-based naloxone training that was created in partnership with LEOs on their knowledge, confidence, and attitudes regarding naloxone. METHODS: From May 2019 to September 2020, five law enforcement departments from Michigan participated in web-based naloxone training. A total of 182 LEOs (77% male) were in the final sample based on matching pre-and post-test surveys. LEOs were assessed on knowledge, confidence, and attitudes towards naloxone. Negative binomial and Poisson regression was conducted to assess associations between knowledge, confidence, and attitudes towards naloxone before and after training. RESULTS: Significant improvements in overdose knowledge and confidence were revealed across all departments with median (IQR) total composite scores for knowledge increasing from 35 (32, 37) to 40 (39, 42) (p < 0.01) and confidence increasing from 18.5 (15, 20) to 20 (20, 25) (p < 0.01). Median (IQR) attitude scores did not change. CONCLUSION: Our web-based naloxone training was effective in improving knowledge and confidence for LEOs but did not significantly improve LEOs attitudes towards naloxone across most departments. The web-based format is readily scalable and quickly disseminated and meets the immediate need for LEO overdose training. Additional intervention is needed to address the negative attitudes of LEOs regarding naloxone.

SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling.

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since emerging in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation of double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections including murine coronavirus and Middle East respiratory syndrome (MERS)-CoV. To determine how nsp15 functions during SARS-CoV-2 infection, we constructed a mutant recombinant SARS-CoV-2 (nsp15mut) expressing a catalytically inactive nsp15. Infection with SARS-CoV-2 nsp15 mut led to increased activation of the IFN signaling and PKR pathways in lung-derived epithelial cell lines and primary nasal epithelial air-liquid interface (ALI) cultures as well as significant attenuation of replication in ALI cultures compared to wild-type (WT) virus. This replication defect was rescued when IFN signaling was inhibited with the Janus activated kinase (JAK) inhibitor ruxolitinib. Finally, to assess nsp15 function in the context of minimal (MERS-CoV) or moderate (SARS-CoV-2) innate immune induction, we compared infections with SARS-CoV-2 nsp15mut and previously described MERS-CoV nsp15 mutants. Inactivation of nsp15 had a more dramatic impact on MERS-CoV replication than SARS-CoV-2 in both Calu3 cells and nasal ALI cultures suggesting that SARS-CoV-2 can better tolerate innate immune responses. Taken together, SARS-CoV-2 nsp15 is a potent inhibitor of dsRNA-induced innate immune response and its antagonism of IFN signaling is necessary for optimal viral replication in primary nasal ALI culture.

Improved Culture Methods for Human Coronaviruses HCoV-OC43, HCoV-229E, and HCoV-NL63.

HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1 are four of the seven known human coronaviruses (HCoVs) and, unlike the highly pathogenic SARS-CoV, MERS-CoV, and SARS-CoV-2, these four so-called seasonal HCoVs generally cause mild upper-respiratory-tract illness. As Biosafety Level 2 (BSL-2) pathogens, the seasonal HCoVs are more accessible and can be used as surrogates for studying the highly pathogenic HCoVs. However, scientists have for many years found these difficult to study because of the lack of a universal culture system and the inability of typical culture methods to yield high-titer infectious stocks. We have developed assays to grow and quantify infectious virus and viral RNA for HCoV-OC43, -229E, and -NL63. We identified which immortalized cell lines should be used to optimize the replication of HCoV-OC43, -229E, and -NL63 in order to generate high titers (Vero E6, Huh-7, and LLC-MK2 cells, respectively). Here we present protocols for improved propagation and quantification of each seasonal HCoV. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Growth of HCoVs Basic Protocol 2: Quantification of HCoV by plaque assay Basic Protocol 3: Quantification of HCoV RNA products of replication Basic Protocol 4: Concentrating HCoVs via ultracentrifugation.

Infection of Primary Nasal Epithelial Cells Grown at an Air-Liquid Interface to Characterize Human Coronavirus-Host Interactions.

Three highly pathogenic human coronaviruses (HCoVs) - SARS-CoV (2002), MERS-CoV (2012), and SARS-CoV-2 (2019) - have emerged and caused significant public health crises in the past 20 years. Four additional HCoVs cause a significant portion of common cold cases each year (HCoV-NL63, -229E, -OC43, and -HKU1), highlighting the importance of studying these viruses in physiologically relevant systems. HCoVs enter the respiratory tract and establish infection in the nasal epithelium, the primary site encountered by all respiratory pathogens. We use a primary nasal epithelial culture system in which patient-derived nasal samples are grown at an air-liquid interface (ALI) to study host-pathogen interactions at this important sentinel site. These cultures recapitulate many features of the in vivo airway, including the cell types present, ciliary function, and mucus production. We describe methods to characterize viral replication, host cell tropism, virus-induced cytotoxicity, and innate immune induction in nasal ALI cultures following HCoV infection, using recent work comparing lethal and seasonal HCoVs as an example1. An increased understanding of host-pathogen interactions in the nose has the potential to provide novel targets for antiviral therapeutics against HCoVs and other respiratory viruses that will likely emerge in the future.

Integrating Neonatal Intensive Care Into a Family Birth Center: Describing the Integrated NICU (I-NIC).

BACKGROUND: Parent-infant separation resulting from admission to a neonatal intensive care unit (NICU) is often reported as the most challenging and distressing experience for parents. Aiming to mitigate the stress of parent-infant separation, a new neonatal care model was designed to integrate NIC with delivery and postpartum care. Yet, little is known about the model and its implementation. METHODS: Using a qualitative descriptive design with field observations, we describe the characteristics of an integrated-neonatal intensive care (I-NIC) model and examined perceptions of clinical staff (n = 8) and parents (n = 3). RESULTS: The physical layout of the I-NIC rooms required additional oxygen and suction columns and new signage to specify them as NICU-equipped. Other NICU-related equipment was mobile, thus moved into rooms when necessary. Nurses were cross-trained in labor/delivery, postpartum, neonatal care; however, nurses primarily worked within their specific area of expertise. Clinician and parent perceptions of the model were notably positive, reporting decreased anxiety related to separation, increased ability for chest feeding and skin-to-skin care, and improved interdisciplinary care. CONCLUSION: Future work is needed to understand implementation of the model in other settings, with specific attention to unit architecture, level of NICU care services, patient census, and staff and patient outcomes.

Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer.

Unlike adult mammals, zebrafish regenerate spinal cord tissue and recover locomotor ability after a paralyzing injury. Here, we find that ependymal cells in zebrafish spinal cords produce the neurogenic factor Hb-egfa upon transection injury. Animals with hb-egfa mutations display defective swim capacity, axon crossing, and tissue bridging after spinal cord transection, associated with disrupted indicators of neuron production. Local recombinant human HB-EGF delivery alters ependymal cell cycling and tissue bridging, enhancing functional regeneration. Epigenetic profiling reveals a tissue regeneration enhancer element (TREE) linked to hb-egfa that directs gene expression in spinal cord injuries. Systemically delivered recombinant AAVs containing this zebrafish TREE target gene expression to crush injuries of neonatal, but not adult, murine spinal cords. Moreover, enhancer-based HB-EGF delivery by AAV administration improves axon densities after crush injury in neonatal cords. Our results identify Hb-egf as a neurogenic factor necessary for innate spinal cord regeneration and suggest strategies to improve spinal cord repair in mammals.

Use of Opioid-Sparing Protocols and Perceived Postpartum Pain in Patients with Opioid Use Disorder and Chronic Prenatal Opioid Exposure.

INTRODUCTION: Opioid-sparing protocols reduce postpartum opioid prescribing in opioid-naïve patients; however, patients with opioid use disorder (OUD) and complex pain needs who may benefit from these protocols are typically excluded from them. We assessed postpartum pain experiences of patients with OUD and chronic prenatal opioid exposure after implementation of an opioid-sparing protocol. METHODS: A phone survey assessed postpartum pain experiences for people with chronic prenatal opioid exposure who delivered between January 2020 and August 2021 at an academic hospital. Analyses included descriptive statistics, qualitative content analysis, and a joint display comparing themes. RESULTS: Of 25 patients, 18 (72%) participated; most were non-Hispanic White (100%, 18/18), publicly insured (78%, 14/18), multiparous (78%, 14/18), with OUD (100%, 18/18). No patients with a vaginal birth received an opioid prescription; half (4/8) with a cesarean birth received one at discharge. Over one-third (7/18, 39%) reported poor pain control (≥ 5/10) in the hospital and one week post-discharge; scores were higher for cesarean versus vaginal birth. Qualitative sub-analyses of open-ended responses revealed patient perceptions of postpartum pain and treatment. The most effective strategies, stratified by birth type and pain level, ranged from non-opioid medications for vaginal births and minor pain to prescription opioids for cesarean births and moderate-to-intense pain. DISCUSSION: Postpartum opioid prescribing for patients with chronic prenatal opioid use was low for vaginal and cesarean birth following implementation of an opioid-sparing protocol. Patients with OUD reported good pain management with opioid-sparing pain regimens; however, many reported poorly controlled pain immediately postpartum. Future work should assess approaches to postpartum pain management that minimize the risks of opioid medication-particularly in at-risk groups.

What is already known on this subject? Opioid-sparing protocols can reduce postpartum opioid prescribing in opioid-naïve patients; however, there are currently no clear guidelines for opioid prescribing for people with opioid use disorder (OUD) in the postpartum period.What this study adds?Postpartum opioid prescribing for patients with chronic prenatal opioid use was less than the national average and one-third of patients reported poor pain control. Opioid-sparing protocols postpartum should be expanded to patients with OUD to improve pain control and minimize risks associated with opioid medication.

Tear-film evaporation flux and its relationship to tear properties in symptomatic and asymptomatic soft-contact-lens wearers.

PURPOSE: With soft-contact-lens wear, evaporation of the pre-lens tear film affects the osmolarity of the post-lens tear film and this can introduce a hyperosmotic environment at the corneal epithelium, leading to discomfort. The purposes of the study are to ascertain whether there are differences in evaporation flux (i.e., the evaporation rate per unit area) between symptomatic and asymptomatic soft-contact-lens wearers, to assess the repeatability of a flow evaporimeter, and to assess the relationship between evaporation fluxes, tear properties, and environmental conditions. METHODS: Closed-chamber evaporimeters commonly used in ocular-surface research do not control relative humidity and airflow, and, therefore, misestimate the actual tear-evaporation flux. A recently developed flow evaporimeter overcomes these limitations and was used to measure accurate in-vivo tear-evaporation fluxes with and without soft-contact-lens wear for symptomatic and asymptomatic habitual contact-lens wearers. Concomitantly, lipid-layer thickness, ocular-surface-temperature decline rate (i.e., °C/s), non-invasive tear break-up time, tear-meniscus height, Schirmer tear test, and environmental conditions were measured in a 5 visit study. RESULTS: Twenty-one symptomatic and 21 asymptomatic soft-contact-lens wearers completed the study. A thicker lipid layer was associated with slower evaporation flux (p < 0.001); higher evaporation flux was associated with faster tear breakup irrespective of lens wear (p = 0.006). Higher evaporation flux was also associated with faster ocular-surface-temperature decline rate (p < 0.001). Symptomatic lens wearers exhibited higher evaporation flux than did asymptomatic lens wearers, however, the results did not reach statistical significance (p = 0.053). Evaporation flux with lens wear was higher than without lens wear but was also not statistically significant (p = 0.110). CONCLUSIONS: The repeatability of the Berkeley flow evaporimeter, associations between tear characteristics and evaporation flux, sample-size estimates, and near statistical significance in tear-evaporation flux between symptomatic and asymptomatic lens wearers all suggest that with sufficient sample sizes, the flow evaporimeter is a viable research tool to understand soft-contact-lens wear comfort.

Multicenter interactions and ligand field effects in platinum(II) tripyrrindione radicals.

The tripyrrin-1,14-dione biopyrrin, which shares the scaffold of several naturally occurring heme metabolites, is a redox-active platform for metal coordination. We report the synthesis of square planar platinum(II) tripyrrindiones, in which the biopyrrin binds as a tridentate radical and the fourth coordination position is occupied by either aqua or tert-butyl isocyanide ligands. These complexes are stable through chromatographic purification and exposure to air. Electron paramagnetic resonance (EPR) data and density functional theory (DFT) analysis confirm that the spin density is located predominantly on the tripyrrindione ligand. Pancake bonding in solution between the Pt(II) tripyrrindione radicals leads to the formation of diamagnetic π dimers at low temperatures. The identity of the monodentate ligand (i.e., aqua vs. isocyanide) affects both the thermodynamic parameters of dimerization and the tripyrrindione-based redox processes in these complexes. Isolation and structural characterization of the oxidized complexes revealed stacking of the diamagnetic tripyrrindiones in the solid state as well as a metallophilic Pt(II)-Pt(II) contact in the case of the aqua complex. Overall, the properties of Pt(II) tripyrrindiones, including redox potentials and intermolecular interactions in solution and in the solid state, are modulated through easily accessible changes in the redox state of the biopyrrin ligand or the nature of the monodentate ligand.