Safety of primary nasotracheal intubation in the pediatric intensive care unit (PICU).

Background: Nasal tracheal intubation (TI) represents a minority of all TI in the pediatric intensive care unit (PICU). The risks and benefits of nasal TI are not well quantified. As such, safety and descriptive data regarding this practice are warranted. Methods: We evaluated the association between TI route and safety outcomes in a prospectively collected quality improvement database (National Emergency Airway Registry for Children: NEAR4KIDS) from 2013 to 2020. The primary outcome was severe desaturation (SpO2 > 20% from baseline) and/or severe adverse TI-associated events (TIAEs), using NEAR4KIDS definitions. To balance patient, provider, and practice covariates, we utilized propensity score (PS) matching to compare the outcomes of nasal vs. oral TI. Results: A total of 22,741 TIs [nasal 870 (3.8%), oral 21,871 (96.2%)] were reported from 60 PICUs. Infants were represented in higher proportion in the nasal TI than the oral TI (75.9%, vs 46.2%), as well as children with cardiac conditions (46.9% vs. 14.4%), both p < 0.001. Severe desaturation or severe TIAE occurred in 23.7% of nasal and 22.5% of oral TI (non-adjusted p = 0.408). With PS matching, the prevalence of severe desaturation and or severe adverse TIAEs was 23.6% of nasal vs. 19.8% of oral TI (absolute difference 3.8%, 95% confidence interval (CI): - 0.07, 7.7%), p = 0.055. First attempt success rate was 72.1% of nasal TI versus 69.2% of oral TI, p = 0.072. With PS matching, the success rate was not different between two groups (nasal 72.2% vs. oral 71.5%, p = 0.759). Conclusion: In this large international prospective cohort study, the risk of severe peri-intubation complications was not significantly higher. Nasal TI is used in a minority of TI in PICUs, with substantial differences in patient, provider, and practice compared to oral TI.A prospective multicenter trial may be warranted to address the potential selection bias and to confirm the safety of nasal TI.

Reference genome for the Mojave poppy bee (Perdita meconis), a specialist pollinator of conservation concern.

The Mojave poppy bee, Perdita meconis Griswold (Hymenoptera: Anthophila: Andrenidae), is a species of conservation concern that is restricted to the eastern Mojave Desert of North America. It is a specialist pollinator of two poppy genera, Arctomecon and Argemone (Papaveraceae), and is being considered for listing under the US Endangered Species Act along with one of its pollinator hosts, the Las Vegas bearpoppy (Arctomecon californica). Here, we present a near chromosome-level genome of the Mojave poppy bee to provide a genomic resource that will aid conservation efforts and future research. We isolated DNA from a single, small (<7 mm), male specimen collected using non-ideal preservation methods then performed whole-genome sequencing using PacBio HiFi technology. After quality and contaminant filtering, the final draft genome assembly is 327 Mb, with an N50 length of 17.5 Mb. Annotated repetitive elements compose 37.3% of the genome, although a large proportion (24.87%) of those are unclassified repeats. Additionally, we annotated 18,245 protein-coding genes and 19,433 transcripts. This genome represents one of only a few genomes from the large bee family Andrenidae and one of only a few genomes for pollinator specialists. We highlight both the potential of this genome as a resource for future research, and how high-quality genomes generated from small, non-ideal (in terms of preservation) specimens could facilitate biodiversity genomics.

Impact of the COVID-19 Pandemic on Childhood Lead Testing and Blood Lead Levels.

OBJECTIVE: To evaluate the effect of the COVID-19 pandemic on childhood lead testing and blood lead levels. METHODS: A retrospective analysis of lead tests and results was performed across 3 urban medical centers during the pre-COVID-19 (March 10, 2019-March 9, 2020) and COVID-19 (March 10, 2020-March 10, 2022) periods. Interrupted time series analysis with quasi-Poisson regression was used to evaluate changes in lead testing between study periods. The relationship between sociodemographic features with detectable (≧2 µg/dL) and elevated (≧3.5 µg/dL) blood lead levels (BLLs) was assessed with multivariable logistic regression. RESULTS: Among a total of 16,364 lead tests across 10,362 patients, weekly testing rates significantly decreased during COVID-19 (relative risk (RR) 0.64, 95% (confidence interval) CI 0.53-0.78). Census tracts with the greatest proportion of pre-1950s housing had a stronger association with detectable BLLs during the COVID-19 period (pre-COVID-19 adjusted odds ratio (aOR) 1.73, 95% CI 1.35-2.20; aOR 2.58, 95% CI 2.13-3.12; interaction P value .014). When limited to 1 year following COVID-19 (March 10, 2020-March 10, 2021), the association between both elevated BLLs (pre-COVID-19: aOR 1.49, 95% CI 0.87-2.53; COVID-19: aOR 3.51, 95% CI 1.98-6.25; interaction P value .032) and detectable BLLs with pre-1950s housing were greater during the COVID-19 period (pre-COVID-19: aOR 1.73, 95% CI 1.35-2.20; COVID-19: aOR 2.56, 95% CI 1.95-3.34; interaction P value .034). CONCLUSIONS: The COVID-19 pandemic led to a significant reduction in lead surveillance and magnified the effect of known risk factors for lead exposure. Concerted clinical, public health, and community advocacy are needed to address care gaps and excess cases of lead poisoning.

Did COVID-19 Change the Availability and Use of Clean Energy for Cooking? Evidence From Ghana.

A major part of Ghana's current household energy policy is focused on using a branded cylinder recirculation model (BCRM) to promote the safe use of Liquefied Petroleum Gas (LPG) for primary cooking. The implementation of the BCRM is expected to increase LPG adoption by households to the announced policy goal of 50% of the population by 2030. We investigated the impact of the COVID-19 pandemic on the implementation of the BCRM, availability, and household use of cleaner fuels. This was assessed using existing data on clean fuel use prior to the COVID-19 pandemic. Additional data was collected using questionnaire-based household surveys and qualitative interviews. It was found that the expansion of BCRM was significantly impacted by the COVID-19 pandemic. Planning activities such as baseline data collection and stakeholder engagement were delayed due to the COVID-19 restrictions. Changes in household incomes during the pandemic had the biggest percentage effect on household choice of cooking fuel, causing a regression in some cases, to polluting fuel use. This study provides insights that could be valuable in future understanding of the interactions between pandemic control measures and economic disruptions that may affect household energy choices for cooking.

The development of diphenyleneiodonium analogs as GPR3 agonists.

G protein-coupled receptor 3 (GPR3) is an orphan receptor potentially involved in many important physiological processes such as drug abuse, neuropathic pain, and anxiety and depression related disorders. Pharmacological studies of GPR3 have been limited due to the restricted number of known agonists and inverse agonists for this constitutively active receptor. In this medicinal chemistry study, we report the discovery of GPR3 agonists based off the diphenyleneiodonium (DPI) scaffold. The most potent full agonist was the 3-trifluoromethoxy analog (32) with an EC50 of 260 nM and 90% efficacy compared to DPI. Investigation of a homology model of GPR3 from multiple sequence alignment resulted in the finding of a binding site rich in potential π-π and π-cation interactions stabilizing DPI-scaffold agonists. MMGBSA free energy analysis showed a good correlation with trends in observed EC50s. DPI analogs retained the same high receptor selectivity for GPR3 over GPR6 and GPR12 as observed with DPI. Collectively, the DPI analog series shows that order of magnitude improvements in potency with the scaffold were attainable; however, attempts to replace the iodonium ion to make the scaffold more druggable failed.

The Creation of a Multidomain Neighborhood Environmental Vulnerability Index Across New York City.

Compared to previous studies commonly using a single summary score, we aimed to construct a multidomain neighborhood environmental vulnerability index (NEVI) to characterize the magnitude and variability of area-level factors with the potential to modify the association between environmental pollutants and health effects. Using the Toxicological Prioritization Index framework and data from the 2015-2019 U.S. Census American Community Survey and the 2020 CDC PLACES Project, we quantified census tract-level vulnerability overall and in 4 primary domains (demographic, economic, residential, and health status), 24 subdomains, and 54 distinct area-level features for New York City (NYC). Overall and domain-specific indices were calculated by summing standardized feature values within the subdomains and then aggregating and weighting based on the number of features within each subdomain within equally-weighted primary domains. In citywide comparisons, NEVI was correlated with multiple existing indices, including the Neighborhood Deprivation Index (r = 0.91) and Social Vulnerability Index (r = 0.87) but provided additional information on features contributing to vulnerability. Vulnerability varied spatially across NYC, and hierarchical cluster analysis using subdomain scores revealed six patterns of vulnerability across domains: 1) low in all, 2) primarily low except residential, 3) medium in all, 4) high demographic, economic, and residential 5) high economic, residential, and health status, and 6) high demographic, economic and health status. Created using methods that offer flexibility for theory-based construction, NEVI provided detailed vulnerability metrics across domains that can inform targeted research and public health interventions aimed at reducing the health impacts from environmental exposures across urban centers.

Resilience in development: Neighborhood context, experiences of discrimination, and children's mental health.

An understanding of child psychopathology and resilience requires attention to the nested and interconnected systems and contexts that shape children's experiences and health outcomes. In this study, we draw on data from the National Survey of Children's Health, 2016 to 2021 (n = 182,375 children, ages 3- to 17 years) to examine associations between community social capital and neighborhood resources and children's internalizing and externalizing problems, and whether these associations were moderated by experiences of racial discrimination. Study outcomes were caregiver-report of current internalizing and externalizing problems. Using logistic regression models adjusted for sociodemographic characteristics of the child and household, higher levels of community social capital were associated with a lower risk of children's depression, anxiety, and behaviors. Notably, we observed similar associations between neighborhood resources and child mental health for depression only. In models stratified by the child's experience of racial/ethnic discrimination, the protective benefits of community social capital were specific to those children who did not experience racial discrimination. Our results illustrate heterogeneous associations between community social capital and children's mental health that differ based on interpersonal experiences of racial/ethnic discrimination, illustrating the importance of a multilevel framework to promote child wellbeing.

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. FUNDING: Department for Health and Social Care, Medical Research Council.

Recognizing invasive breast carcinoma of no special type with medullary pattern.

Invasive breast carcinoma of no special type (IBC-NST) with medullary pattern is an uncommon histologic type of invasive breast carcinoma. It is associated with high-grade, poorly differentiated tumor cells that form large sheets of irregular confluent tumor cells associated with a prominent lymphocytic infiltrate. Patients with IBC-NST with medullary pattern are often postmenopausal women with a high body mass index and multiparity. We report the case of a 71-year-old woman who presented for routine screening mammography and breast mass suspicious for malignancy, initially thought to be invasive ductal carcinoma with an associated prominent lymphoid infiltrate. However, it was ultimately diagnosed as IBC-NST with medullary pattern, and radiologic imaging (particularly ultrasound and mammography) along with pathology review were critical in making the diagnosis. We make the case of the importance of radiographic imaging in diagnosing this condition, as the prognosis of IBC-NST with medullary pattern is typically more favorable compared to IBC-NST.

Evaluation of QuantiFERON SARS-CoV-2 interferon-γ release assay following SARS-CoV-2 infection and vaccination.

T cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T-cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T-cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines. Forty-eight participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established 'Protective Immunity from T Cells in Healthcare workers' (PITCH) ELISpot, which can evaluate spike-specific T-cell responses. The primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared with the PITCH ELISpot. The QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12-21 days post positive PCR) from naïve individuals (P < 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172-444 days post positive test) and was inferior to the PITCH ELISpot (75%). Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55-166 days since second vaccination), the latter also had reduced sensitivity (44.4%) compared to the PITCH ELISpot (66.6%). The QuantiFERON SARS-CoV-2 assay showed potential as a T- cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.

Assessing Müllerian mimicry in North American bumble bees using human perception.

Despite the broad recognition of mimicry among bumble bees, distinct North American mimicry rings have yet to be defined, due in part to the prevalence of intermediate and imperfect mimics in this region. Here we employ a generalization approach using human perception to categorize mimicry rings among North American bumble bees. We then map species distributions on North American ecoregions to visually test for geographic concordance among similarly-colored species. Our analyses suggest that there are five mimicry rings in the North American bumble bee mimicry complex, and one broadly distributed group of mixed and intermediate color forms. We describe the Black Mimicry Ring, Black-cloaked Mimicry Ring, Eastern Yellow Mimicry Ring, Red Mimicry Ring, and Western Yellow Mimicry Ring as well as the mixed group. We then test these hypothesized mimicry rings by examining other insects that participate in these mimicry rings. Describing these mimicry rings is a vital step that will enable future analyses of imperfect mimicry, intermediate mimicry, and additional analyses of other insects that mimic bumble bees.

Cluster Analysis of Clozapine Consumer Perspectives and Comparison to Consumers on Other Antipsychotics.

Despite its unique efficacy, clozapine remains underutilized in the United States. Perceptions about clozapine and barriers to its use have been examined among prescribers, but insufficiently studied among consumers. We surveyed 211 antipsychotic consumers (86 on clozapine and 125 on other antipsychotics) on their medication-related perspectives in a public hospital system in Atlanta, Georgia, USA. In contrast to their previous regimen, 72% of clozapine consumers reported they were more satisfied with clozapine. When compared with consumers taking other antipsychotics, clozapine consumers reported more side effects but did not differ on other measures of satisfaction or efficacy. We found Caucasians to be overrepresented among clozapine, as compared to other antipsychotic consumers. Side effects most strongly associated with poor safety ratings were sedation, limb jerking, and dizziness when standing. However, clozapine was only rated less safe by consumers who experienced more than one of these side effects. We used an unsupervised clustering approach to identify three major groups of clozapine consumers. Cluster A (19%) had the lowest safety ratings, aversion to blood work, and a high rate of side effects that associate with lower safety ratings. Cluster B (25%) experienced more hospitalizations and reported satisfaction with clozapine that correlated with efficacy ratings, irrespective of safety ratings. Cluster C (56%) experienced fewer hospitalizations, fewer previous drug trials, greater educational attainment, lower rates of smoking, and rated clozapine more highly. This work identifies common side effects that influence the subjective safety of clozapine and suggests that attitudes toward clozapine depend on context-specific factors.

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and high and low affinity monoamine transporters.

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC50 values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC50 values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.

T cell phenotypes in COVID-19 - a living review.

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.

Framing the past (and future): Effects of generic photos on autobiographical judgments.

Do the images we see every day influence how we remember our lives? Research on this matter often concerns how entire memories of events can be created or shaped through the use of doctored photographs of personal (Wade et al., Psychonomic bulletin & review, 9 (3), 597-603, 2002) and public events (Sacchi et al., Applied Cognitive Psychology, 21 (8), 1005-1022, 2007). Although this paradigm has yielded insights into false memory production, it may underestimate the extent to which photographs can bias or distort memory in a subtler manner (i.e., without the use of doctored photographs or suggestion). In Experiments 1 (N = 95) and 2 (N = 186) of the present study, we examined whether the mere presence of generic images, typical of stock photography, could influence aspects of our memories. Given the parallel between autobiographical remembering and forecasting (Berntsen & Bohn, Memory & Cognition, 38(3), 265-278, 2010), we also examined (Experiment 3: N=204) how such images would influence future autobiographical judgments. Specifically, three experiments investigated whether photographs would bias autobiographical judgments for either quantitative (e.g., How many movies have you seen in the past year?) or affective (e.g., How enjoyable do you think your next date will be?) aspects of events in everyday life. We found that photographs reliably influenced judgments related to quantitative aspects of autobiographical events. Moreover, though less robustly, there was an indication that these photos could bias our affective construal of such events as well. Overall, we conclude that the mere presence of generic photographs may exert an influence on the way we think about our lives to an extent previously under-recognized.

Carcinoma of unknown primary with hepatic metastases: a need of judicious and contemplative diagnostic algorithm.

Carcinoma of Unknown Primary presenting primarily as hepatic metastases encompasses a dismal subgroup of tumors with a median survival of 5.9 months. Adenocarcinoma is the most common histological subtype identified upon biopsy and the primary tumor remains undetectable in the majority of cases despite extensive workup. It is important to have a validated and standardized algorithm to follow these tumors to avoid unnecessary tests, as the wishes and health status of the patient represent the principal concerns. The purpose of this paper is to briefly review the current literature on carcinoma of unknown primary with hepatic metastases and propose a standardized diagnostic approach.

Implementing a negative pressure isolation space within a skilled nursing facility to control SARS-CoV-2 transmission.

BACKGROUND: Isolation space must be expanded during pandemics involving airborne transmission. Little to no work has been done to establish optimal design strategies and implementation plans to ease surge capacity and expand isolation capacity over long periods in congregate living facilities. The COVID-19 pandemic has an airborne transmission component and requires isolation, which is difficult to accomplish in skilled nursing facilities. METHODS: In this study we designed, implemented, and validated an isolation space at a skilled nursing facility in Lancaster, PA. The overall goal was to minimize disease transmission between residents and staff within the facility. We created an isolation space by modifying an existing HVAC system of the SNF. We measured pressure on-site and performed computational fluid dynamics and Lagrangian particle-based modeling to test containment and possible transmission extent given the isolation space is considered negative rather than individual rooms. RESULTS: Pressure data shows the isolation space maintained an average (standard deviation) hourly value of -2.3 Pa (0.12 Pa) pressure differential between it and the external hallway connected to the rest of the facility. No transmission of SARS-CoV-2 between residents isolated to the space occurred, nor did any transmission to the staff or other residents occur. The isolation space was successfully implemented and, as of writing, continues to be operational through the pandemic. CONCLUSION: Skilled nursing facilities can be retrofitted to provide negative pressure isolation space in a reasonable time frame and a cost effective manner to minimize airborne disease transmission within that space.

Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.

Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.

The exploration of aza-quinolines as hematopoietic prostaglandin D synthase (H-PGDS) inhibitors with low brain exposure.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.