Cross-sectional evaluation of health resource use in patients with functional neurological disorders referred to a tertiary neuroscience centre.

Introduction: Functional neurological disorder (FND) is a common cause of referral to neurology services. FND has been shown to lead to significant healthcare resource use and is associated with significant disability, comorbidity and distress. This leads to substantial direct, indirect and intangible costs to the patient and society. Methods: We recruited consecutive patients with FND referred to a tertiary FND specialist clinic. We assessed health and social care resource use in the 6 months preceding their consultation through a modified version of the Client Service Receipt Inventory in the form of a postal questionnaire. The total cost was estimated by combining the number and frequency of health resource use with standard national unit costs. We also assessed indirect costs such as informal care and loss of income. Results: We collected data on 118 subjects. Patients with comorbid anxiety or depression had higher costs in the preceding 6 months, as did patients who had a longer duration of FND symptoms. Indirect costs were higher than the already substantial direct costs and a large proportion of patients with FND were receiving government support. Conclusion: This study highlights the high cost of FND to both patients and health systems. Adequate reform of the patient pathway and reorganisation of services to make diagnoses and initiate treatment more quickly would likely reduce these costs.

Availability, cost and affordability of essential medicines for chronic respiratory diseases in low-income and middle-income countries: a cross-sectional study.

Contemporary data on the availability, cost and affordability of essential medicines for chronic respiratory diseases (CRDs) across low-income and middle-income countries (LMICs) are missing, despite most people with CRDs living in LMICs. Cross-sectional data for seven CRD medicines in pharmacies, healthcare facilities and central medicine stores were collected from 60 LMICs in 2022-2023. Medicines for symptomatic relief were widely available and affordable, while preventative treatments varied widely in cost, were less available and largely unaffordable. There is an urgent need to address these issues if the Sustainable Development Goal 3 is to be achieved for people with asthma by 2030.

Geochemistry and the optics of geospatial analysis as a preposition of water quality on a macroscale.

The water treatment depends exclusively on the identification of residues containing toxic chemical elements accumulated in NPs (nanoparticles), and ultrafine particles sourced from waste piles located at old, abandoned sulfuric acid factories containing phosphogypsum requires global attention. The general objective of this study is to quantify and analyze the hazardous chemical elements present in the leachate of waste from deactivated sulfuric acid factories, coupled in NPs and ultrafine particles, in the port region of the city of Imbituba, Santa Catarina, Brazil. Samples were collected in 2020, 2021, and 2022. Corresponding images from the Sentinel-3B OLCI satellite, taken in the same general vicinity, detected the levels of absorption coefficient of Detritus and Gelbstoff (ADG443_NN) in 443 m-1, chlorophyll-a (CHL_NN (m-3)), and total suspended matter (TSM_NN (g m-3) at 72 points on the marine coast of the port region. The results of inductively coupled plasma atomic-emission spectrometry (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS) demonstrate that the leaching occurring in waste piles at the port area of Imbituba was the likely source of hazardous chemical elements (e.g., Mg, Sr, Nd, and Pr) in the environment. These leachates were formed due to the presence of coal pyrite and Fe-acid sulfates in said waste piles. The mobility of hazardous chemical elements potentiates changes in the marine ecosystem, in relation to ADG443_NN (m-1), CHL_NN (m-3), and TSM NN (g m-3), with values greater than 20 g m-3 found in 2021 and 2022. This indicated changes in the natural conditions of the marine ecosystem up to 30 km from the coast in the Atlantic Ocean, justifying public initiatives for water treatment on a global scale.

Nanoparticles in terrestrial sediments and the behavior of the spectral optics of Sentinel-3B OLCI Satellite images in a river basin of UNESCO World Cultural and Natural Heritage.

The dangerous chemical elements associated with nanoparticles (NPs) and ultra-fine sediment particles in hydrological bays have the capacity to move contaminants to large oceanic regions. The general objective of this study is to quantify the major chemical elements present in NPs and ultra-fine particles in aquatic sediments sampled from Guanabara Bay and compare these data to values determined through spectral optics using the Sentinel-3B Satellite OLCI (Ocean Land Color Instrument) during the winter and summer seasons of 2018, 2019, 2020, 2021, and 2022. This is done to highlight the impacts anthropogenic environmental hazards have on the marine ecosystem and human beings. Ten aquatic sediment field collection points were selected by triangulated irregular network (TIN). Samples were subjected to analysis by X-ray diffraction (XRD), scanning electron microscopy (SEM), electron dispersion spectroscopy (EDS), and transmission electron microscopy (TEM), which enabled a detailed analysis using scanning transmission electron microscopy (STEM). Geospatial analyses using Sentinel-3B OLCI Satellite images considered Water Full Resolution (WFR) at 300 m resolution, in neural network (NN), normalized at 0.83 µg/mg. A maximum average spectral error of 6.62% was utilized for the identification of the levels of Absorption Coefficient of Detritus and Gelbstoff (ADG443_NN) at 443 m-1, Chlorophyll-a (CHL_NN) (m-3), and Total Suspended Matter (TSM_NN) (g m-3) at 581 sample points. The results showed high levels of ADG443_NN, with average values as high as of 4444 m-1 (summer 2021). When related to the analyses of nanoparticulate sediments and ultrafine particles collected in the field, they showed the presence of major chemical elements such as Ge, As, Cr, and others, highly toxic to human health and the aquatic environment. The application of satellite and terrestrial surveys proved to be efficient, in addition to the possibility of this study being applied to other hydrological systems on a global scale.

Decrease in Rates of Hearing Loss From Pediatric Bacterial Meningitis Over Time: A Database Review.

OBJECTIVES: Bacterial meningitis is a leading cause of acquired sensorineural hearing loss (SNHL). Treatment and prevention of bacterial meningitis have improved over time, but rates of neurologic complications have not been recently studied. The objective here is to present an updated population-based review of hearing loss as a sequela of bacterial meningitis. METHODS: A retrospective cohort study was conducted between 2010 and 2022 of children discharged with bacterial meningitis, using the Pediatric Health Information System's (PHIS) database. Rates of hearing loss and mortality were evaluated over time. RESULTS: A total of 6138 children with a primary diagnosis of bacterial meningitis were identified (3520 male [57.3%], mean age 5.8 months [2.0, 61.2]). Of these, 277 (4.51%) were diagnosed with hearing loss. Children with hearing loss were significantly older (23.6 vs. 5.3 months, p < 0.01), but differences in gender, race, or ethnicity had no association with hearing loss. Streptococcus pneumoniae, Hemophilus influenzae, and Neisseria meningiditis were associated with significantly higher rates of hearing loss than other etiologies (p < 0.01). Children with hearing loss had a higher rate of receiving dexamethasone than children without hearing loss. Overall mortality rate was 2.1%. Hearing loss and mortality demonstrated significant decreases over the study period. CONCLUSION: Hearing loss remains a common sequela of bacterial meningitis despite widespread uptake of vaccines for preventing S. pneumoniae, H. influenzae, and N. meningitidis. Dexamethasone was not associated with decreased rates of hearing loss in this cohort. From 2010 to 2022, there was a significant decrease in overall rates of mortality and hearing loss for children with bacterial meningitis. LEVEL OF EVIDENCE: Level 3: retrospective case-control series Laryngoscope, 2024.

Detection of atmospheric aerosols and terrestrial nanoparticles collected in a populous city in southern Brazil.

The main objective of this study is to analyze hazardous elements in nanoparticles (NPs) (smaller than 100 nm) and ultrafine particles (smaller than 1 µm) in Porto Alegre City, southern Brazil using a self-made passive sampler and Sentinel-3B SYN satellite images in 32 collection points. The Aerosol Optical Thickness proportion (T550) identification was conducted using images of the Sentinel-3B SYN satellite at 634 points sampled in 2019, 2020, 2021, and 2022. Focused ion beam scanning electron microscopy analyses were performed to identify chemical elements present in NPs and ultrafine particles, followed by single-stage cascade impactor to be processed by high-resolution transmission electron microscopy. This process was coupled with energy-dispersive X-ray spectroscopy and later analysis via secondary ion mass spectrometry. Data was acquired from Sentinel-3B SYN images, normalized to a standard mean of 0.83 µg/mg, at moderate spatial resolution (260 m), and modeled in the Sentinel Application Platform (SNAP) software v.8.0. Statistical matrix data was generated in the JASP software (Jeffreys's Amazing Statistics Program) v.0.14.1.0 followed by a K-means cluster analysis. The results demonstrate the presence of between 1 and 100 nm particles of the following chemical elements: Si, Al, K, Mg, P, and Ti. Many people go through these areas daily and may inhale or absorb these elements that can harm human health. In the Sentinel-3B SYN satellite images, the sum of squares in cluster 6 is 168,265 and in cluster 7 a total of 21,583. The use of images from the Sentinel-3B SYN satellite to obtain T550 levels is of great importance as it reveals that atmospheric pollution can move through air currents contaminating large areas on a global scale.

Nanoparticles containing hazardous elements and the spatial optics of the Sentinel-3B OLCI satellite in Amazonian rivers: a potential tool to understand environmental impacts.

The Amazon River is the longest river in the world. The Tapajós River is a tributary to the Amazon. At their junction, a marked decrease in water quality is evident from negative impacts from the constant activity of clandestine gold mining in the Tapajós River watershed. The accumulation of hazardous elements (HEs), capable of compromising environmental quality across large regions is evident in the waters of the Tapajós. Sentinel-3B OLCI (Ocean Land Color Instrument) Level-2 satellite imagery with Water Full Resolution (WFR) of 300 m was utilized to detect the highest potential for the absorption coefficient of detritus and gelbstoff in 443 m-1 (ADG443_NN), chlorophyll-a (CHL_NN) and total suspended matter concentration (TSM_NN), at 25 points in the Amazon and Tapajós rivers (in 2019 and 2021). Physical samples of riverbed sediment collected in the field at the same locations were analyzed for NPs and ultra-fine particles to verify the geospatial findings. The riverbed sediment samples collected in the field were studied by Transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM), with selected area electron diffraction (SAED), following laboratory analytical procedures. The Sentinel-3B OLCI images, based on the Neural Network (NN) were calibrated by the European Space Agency (ESA), with a standard average normalization of 0.83 µg/mg, containing a maximum error of 6.62% applied to the sampled points. The analysis of the riverbed sediment samples revealed the presence of the following hazardous elements: As, Hg, La, Ce, Th, Pb, Pd, among several others. The Amazon River has significant potential to transport ADG443_NN (55.475 m-1) and TSM_NN (70.787 gm-3) in sediments, with the possibility of negatively impacting marine biodiversity, in addition to being harmful to human health over very large regions.

Hazardous elements in urban cemeteries and possible architectural design solutions for a more sustainable environment.

The general objective of this study is to identify the presence of hazardous elements in the soils of five urban cemeteries in the city of Passo Fundo, in southern Brazil, and to design solutions (architecturally) for future cemeteries to be more sustainable by mitigating toxicological risks to the population residing in the area. A total of 250 soil samples were obtained from points within the cemeteries and in areas surrounding the two oldest cemeteries at a distance of up to 400 m. Twelve architects who design cemeteries primarily focused on sustainability were interviewed, and presented their suggestions for sustainable urban cemetery design. The Building Information Modeling (BIM) computer modeling system was utilized to present a visual representation of suggested architectural features by these architects. The concentration of Pb in the vicinity of cemeteries deserves special attention, as concentrations of this neurotoxin exceed the federal limits set by Brazil. Soil Pb values were found to exceed the limit of 72 mg kg-1 up to a distance of 400 m from the walls of cemeteries A and B, indicating the presence of a danger to human health even at greater distances. This manuscript highlights construction features that enable future burial structures to adequately mitigate the very real problem of contaminants entering the environment from current cemetery design. Two-thirds of the technicians interviewed for this manuscript, each of whom specialize in Brazilian cemetery design, highlighted the importance of revitalizing urban vegetation both when constructing and revitalizing urban vertical cemeteries.

Terrestrial nanoparticle contaminants and geospatial optics using the Sentinel-3B OLCI satellite in the Tinto River estuary region of the Iberian Peninsula.

The Tinto River is known globally for having a reddish color due to the high concentration of dissolved metals in its waters. The general objective of this study is to analyze the dispersion of nanoparticles (NPs) and ultra-fine particles in terrestrial and geospatial suspended sediments (SSs) using Sentinel-3B OLCI (Ocean Land Color Instrument) satellite images; by examining water turbidity levels (TSM_NN), suspended pollution potential (ADG_443_NN) and presence of chlorophyll-a (CHL_NN). The images were collected in the estuary of the Tinto River, in the city of Nerva, Spanish province of Huelva, between 2019 and 2021. The following hazardous elements were identified in nanoparticles and ultra-fine particles by FE-SEM/EDS: As, Cd, Ni, V, Se, Mo, Pb, Sb and Sn. Sentinel-3B OLCI satellite images detected a 2019 TSM_NN of 23.47 g-3, and a 2021 reading of 16.38 g-3.

Metals in the soil of urban cemeteries in Carazinho (South Brazil) in view of the increase in deaths from COVID-19: projects for cemeteries to mitigate environmental impacts.

The increasing mortality of COVID-19 can aggravate soil contamination by metals, harmful to the health of the population, requiring new projects for future cemeteries capable of mitigating these impacts to the environment, justifying the importance of studying the concentrations of metals in the soil of urban cemeteries. The paper analyzed the levels of metals in the soil of urban cemeteries in the City of Carazinho, in the state of Rio Grande do Sul, located in southern Brazil, considering the increase in deaths by COVID-19, for the purpose of future projects for cemeteries aimed at mitigating the impacts generated on the environment. The soils of the three urban cemeteries in Carazinho were sampled, with 5 internal and external points, with 3 repetitions at depths of 0-20 and 20-40 cm, adding 180 samples to measure the concentrations of Fe, Mn, Cu, Zn, Cr and Pb (g kg-1), considering the analytical sequence: (1) analysis in triplicate with mean deviation (RDS); (2) R2 of the analytical curve; (3) traceability of the pattern of each metal; (4) quantification limit of each metal (QL), with the performance of nitroperchloric digestion of the samples and the determinations of metals by flame modality atomic absorption spectrometry. Quantitative data on deaths by COVID-19 were analyzed by univariate modeling of time series, in the integrated autoregressive moving averages model. The results of this study were made available to fifteen architects, who attributed future solutions for environmentally sustainable cemeteries. The results showed high levels of copper (Cu) and iron (Fe) in the soil of the cemeteries studied. Considering the increase in deaths and subsequent burials per COVID-19 revealed a prediction for the death toll of 6,082,306 for June 9, 2022, it is assumed that metal contamination can reach even higher levels. To mitigate these levels of contamination by metals, 80% of the architect respondents expressed their preference for a vertical cemetery, with treatment of gases and effluents to mitigate environmental impacts.

Patient Outcomes After Unsuccessful Endoscopic Sialolith Extraction.

OBJECTIVE/HYPOTHESIS: To evaluate clinical outcomes following failed endoscopic extraction of salivary calculi and to assess any relation between clinical outcome and calculi location, number, size, and mobility. If sialendoscopy fails to extract the calculus, subsequent spontaneous passage of the calculus out of the ductoglandular system or secondary effects of sialendoscopy could mitigate the clinical impact of a residual sialolithiasis. STUDY DESIGN: Prospective observational study. METHODS: Prospective comparative study of endoscopic procedures for sialolithiasis performed in the Manukau Surgery Center, in Auckland, New Zealand, from 2010 to 2020. The recurrent symptoms and the variables related to the need for additional surgical intervention for salivary calculi were analyzed. RESULTS: Among the 465 sialendoscopy procedures, 154 (33.1%) were for obstructive sialolithiasis. Among these, there were 30 (19.4%) with unsuccessful stone extraction with re-operation for these failures performed in 14 of the 27 failed submandibular cases (52%) and 2 of the 3 parotids (66.7%). Location of calculi was a significant factor in predicting the need of further surgery. Patients with perihilar stones were 5 times more likely to have a failed procedure (P = .001). If the stone was intraglandular, the likelihood increased to 8.5 times (P = .005). The likelihood for a revision procedure increased almost 11 times if the stone was intraglandular (P = .004). Calculi size, mobility, multiple calculi, and presence of concurrent stenosis did not correlate with need for further surgery. CONCLUSIONS: A significant proportion of "failed" sialendoscopy did not require further intervention. Stone location was a significant factor in predicting a failed procedure and the need for re-intervention. Laryngoscope, 132:1029-1033, 2022.

Use of geospatial tools to predict the risk of contamination by SARS-CoV-2 in urban cemeteries.

Urban cemeteries are increasingly surrounded by areas of high residential density as urbanization continues world-wide. With increasing rates of mortality caused by the novel coronavirus, SARS-CoV-2, urban vertical cemeteries are experiencing interments at an unprecedented rate. Corpses interred in the 3rd to 5th layer of vertical urban cemeteries have the potential to contaminate large adjacent regions. The general objective of this manuscript is to analyze the reflectance of altimetry, normalized difference vegetation index (NDVI) and land surface temperature (LST) in the urban cemeteries and neighbouring areas of the City of Passo Fundo, Rio Grande do Sul, Brazil. It is assumed that the population residing in the vicinity of these cemeteries may be exposed to SARS-CoV-2 contamination through the displacement of microparticles carried by the wind as a corpse is placed in the burial niche or during the first several days of subsequent fluid and gas release through the process of decomposition. The reflectance analyses were performed utilizing Landsat 8 satellite images applied to altimetry, NDVI and LST, for hypothetical examination of possible displacement, transport and subsequent deposition of the SARS-CoV-2 virus. The results showed that two cemeteries within the city, cemeteries A and B could potentially transport SARS-CoV-2 of nanometric structure to neighboring residential areas through wind action. These two cemeteries are located at high relative altitudes in more densely populated regions of the city. The NDVI, which has been shown to control the proliferation of contaminants, proved to be insufficient in these areas, contributing to high LST values. Based on the results of this study, the formation and implementation of public policies that monitor urban cemeteries is suggested in areas that utilize vertical urban cemeteries in order to reduce the further spread of the SARS-CoV-2 virus.

Geo-environmental parametric 3D models of SARS-CoV-2 virus circulation in hospital ventilation systems.

The novel coronavirus, SARS-CoV-2, has the potential to cause natural ventilation systems in hospital environments to be rendered inadequate, not only for workers but also for people who transit through these environments even for a limited duration. Studies in of the fields of geosciences and engineering, when combined with appropriate technologies, allow for the possibility of reducing the impacts of the SARS-CoV-2 virus in the environment, including those of hospitals which are critical centers for healthcare. In this work, we build parametric 3D models to assess the possible circulation of the SARS-CoV-2 virus in the natural ventilation system of a hospital built to care infected patients during the COVID-19 pandemic. Building Information Modeling (BIM) was performed, generating 3D models of hospital environments utilizing Revit software for Autodesk CFD 2021. The evaluation considered dimensional analyses of 0°, 45°, 90° and 180°. The analysis of natural ventilation patterns on both internal and external surfaces and the distribution of windows in relation to the displacement dynamics of the SARS-CoV-2 virus through the air were considered. The results showed that in the external area of the hospital, the wind speed reached velocities up to 2.1 m/s when entering the building through open windows. In contact with the furniture, this value decreased to 0.78 m/s. In some internal isolation wards that house patients with COVID-19, areas that should be equipped with negative room pressure, air velocity was null. Our study provides insights into the possibility of SARS-CoV-2 contamination in internal hospital environments as well as external areas surrounding hospitals, both of which encounter high pedestrian traffic in cities worldwide.

Biophysical matter in a marine estuary identified by the Sentinel-3B OLCI satellite and the presence of terrestrial iron (Fe) nanoparticles.

The analysis of marine matter using the Sentinel-3B OLCI (Ocean Land Color Instrument) satellite is the most advanced technique for evaluating: the absorption of colored detrital and dissolved material (ADG_443_NN), total suspended matter concentration (TSM_NN) and of chlorophyll-a (CHL_NN) on a global scale. The objective is to analyze ADG_443_NN, TSM_NN and CHL_NN using the Sentinel-3B OLCI satellite and the presence of Fe-nanoparticles (NPs) + hazardous elements (HEs) in suspended sediments (SSs) in the maritime estuary of the Colombian city of Barranquilla. The study used the unpublished image of the Sentinel-3B OLCI satellite in the evaluation of ADG_443_NN, TSM_NN and CHL_NN in 72 sampled points. Subsequently, 36 samples of SSs were carried out in the Magdalena River, in the identification of Fe-NPs by advanced electron microscopies. The Sentinel-3B satellite revealed particulate accumulations in OCE1 through the intensity of OLCI in ocean. There was also a high Fe-NPs intensity of SSs in the Magdalena channel, spreading contamination to large regions.

Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.

BACKGROUND: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. OBJECTIVE: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE). METHODS: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count. RESULTS: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]). CONCLUSION AND CLINICAL RELEVANCE: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

Hazardous elements in the soil of urban cemeteries; constructive solutions aimed at sustainability.

Urban cemeteries on a global scale raise concerns due to their potential to concentrate differing levels of hazardous pollutants in their native soils due to the unnatural concentration of burials in a limited space. It is paramount for sustainability that designers of future cemeteries take this into account in order to minimize the deposition and movement of these contaminants within the soil profile. The objective of this manuscript is to identify the levels of certain hazardous element contamination, specifically heavy metals, in the soil of horizontal urban cemeteries that do not utilize herbicides for weed control. In this, solutions were sought for the construction of future urban cemeteries capable of mitigating further contamination of the environment by the increase in interments. The soils of three urban cemeteries (A, B and C) in the Brazilian city of Carazinho, in Rio Grande do Sul State, were sampled with 5 monitoring points in the internal area and 5 points in the external area of the cemeteries. At each point, 3 replications were performed at two depths (0-20 and 20-40 cm), totaling 180 samples in all, to determine the concentration of the following metals: copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), lead (Pb), and chromium (Cr) (g kg-1). In addition, online interviews with 15 architects who design cemeteries were conducted. Architectural design solutions to mitigate environmental contamination were modeled utilizing the Building Information Modeling system (BIM). The results showed an excess of Cu in the soil of cemeteries A, B and C, surpassing the standards allowed by Brazilian federal regulations. A total of 80% of the interviewed architects expressed their preference for the vertical cemetery, with gas and effluent treatment systems to mitigate environmental impacts.

Intranasal administration of a stapled relaxin-3 mimetic has anxiolytic- and antidepressant-like activity in rats.

BACKGROUND AND PURPOSE: Depression and anxiety are common causes of disability, and innovative tools and potential pharmacological targets are actively sought for prevention and treatment. Therapeutic strategies targeting the relaxin-3 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug-like properties. We proposed that a hydrocarbon-stapled mimetic of relaxin-3, when administered intranasally, might be uniquely applicable to the treatment of these disorders. EXPERIMENTAL APPROACH: We designed a series of hydrocarbon-stapled relaxin-3 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin-3 and the lead stapled mimetic in rat models of anxiety and depression. KEY RESULTS: We developed an i,i+7 stapled relaxin-3 mimetic that manifested a stabilized α-helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead i,i+7 stapled peptide or relaxin-3 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead i,i+7 stapled peptide exerted anxiolytic and antidepressant-like activity in anxiety- and depression-related behaviour paradigms. CONCLUSIONS AND IMPLICATIONS: Our preclinical findings demonstrate that targeting the relaxin-3/RXFP3 receptor system via intranasal delivery of an i,i+7 stapled relaxin-3 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug-Drug Interaction and Associated Biomarker Levels in Healthy Volunteers.

Understanding transporter-mediated drug-drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)-I, and CP-III as clinical biomarkers for evaluating organic anion-transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1-Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP-I, and CP-III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) was similar among the four biomarkers (1.8-2.5-fold, paired t-test P value < 0.05) in individuals who were homozygotes or heterozygotes of the major allele, c.521T. However, the fold change in AUC and Cmax for HDA and TDA was significantly abolished in the subjects who were c.521-CC, whereas the respective fold change in AUC and Cmax for pravastatin and CP-I and CP-III were slightly weaker in individuals who were c.521-CC compared with c.521-TT/TC genotypes. In addition, this study provides the first evidence that SLCO1B1 c.521T>C genotype is significantly associated with CP-I but not CP-III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.