PI3Kγδ inhibition suppresses key disease features in a rat model of asthma.

BACKGROUND: Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma. METHODS: Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays. Subsequently, a time-course study was conducted in a rat model of asthma to assess PI3K activity in the lung and how it is temporally associated with other key transcription pathways and asthma like features of the model. Finally, the impact on lung dosed AZD8154 on target engagement, pathway specificity, airway inflammation and lung function changes was assessed. RESULTS: Data showed that AZD8154 could inhibit rat PI3K γ & δ isoforms and, in a rat model of allergic asthma the PI3K pathway was activated in the lung. Intratracheal administration of AZD8154 caused a dose related suppression PI3K pathway activation (reduction in pAkt) and unlike after budesonide treatment, STAT and NF-κB pathways were not affected by AZD8154. The suppression of the PI3K pathway led to a marked inhibition of airway inflammation and reduction in changes in lung function. CONCLUSION: These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma.

Medication Adherence Support Applications for Chronic Arthritis Patients: Healthcare Providers' Perspective in Saudi Arabia.

Mobile health applications provide chronic disease patients with different capabilities and resources to support medication adherence. The study aims to understand the health care providers' (HCP) perceptions and recommendations about the design features and content of medication adherence support apps for individuals with chronic arthritis conditions in Saudi Arabia. Individual interviews were conducted with ten participants, such as rheumatologists, health educators, pharmacists, informaticians, and representatives from the Saudi Arthritis Association. The thematic analysis is utilised to code data and develop themes that help researchers in the design process. Four themes are identified: informational content, utilitarian, motivational, and socialisation features. The app content should improve arthritis patient awareness about medication management and adherence. Provide features that enable patients to set medication management and self-monitoring goals. The application design should be trustworthy, usable, enjoyable, and accessible for a diverse group of patients and respect patient privacy.

First molecular identification of the trematode Pulmonicola cochleotrema (Platyhelminthes: Opisthotrematidae) in West Indian manatees (Trichechus manatus, Sirenia: Trichechidae) from Puerto Rico and Florida.

West Indian manatees (Trichechus manatus) harbor a variety of endoparasites, including the nasal trematode Pulmonicola cochleotrema, which infects the respiratory tract, especially the nasal passages. Previous studies have described and identified this digenean using morphological data only. This study presents the first molecular identification of P. cochleotrema in West Indian manatees from Puerto Rico and Florida. Samples of the trematode were collected from seven manatees found stranded dead at both locations. The small subunit ribosomal DNA (18S rDNA) was amplified from each sample using universal primers for different regions of the gene, resulting in a consensus sequence of 1871 base pairs. The phylogenetic reconstruction was carried out using DNA sequences of other species of digenean parasites from other hosts, including a trematode of the same taxonomic family from another sirenian species. Specimens collected from both locations show the same molecular identity using SSU rDNA sequence data. The identity of P. cochleotrema was confirmed using the Basic Local Alignment Search Tool from the National Center for Biotechnology Information database, yielding a high similarity of 98.8 % with Opisthotrema dujonis and 98.2 % with Lankatrema mannarense located in the same clade in our analysis. The latter two digeneans belong to the Opisthotrematidae as does P. cochleotrema and previous studies reported them infecting the Eustachian tubes, esophagus, and digestive tract in dugongs (Dugong dugon). These findings evidence that the nasal trematode of manatees in Florida and Puerto Rico and the dugong, all inhabiting and feeding in marine environments, will have a marine mollusk as an intermediate host, probably a gastropod. The question remains, which species of nasal trematode are harbored by lotic-dwelling manatees in other parts of their distribution like South America.

A combined diagnostic approach for the investigation of lesions resembling aspergillosis in Caribbean sea fans (Gorgonia spp.).

Aspergillosis of gorgonian sea fans is a Caribbean-wide disease characterized by focal, annular purple pigmentation with central tissue loss. We applied a holistic diagnostic approach including histopathology and a combination of culture and direct molecular identification of fungi to evaluate these lesions with the goal of determining the diversity of associated micro-organisms and pathology. Biopsies were collected from 14 sea fans without gross lesions and 44 sea fans with lesions grossly consistent with aspergillosis in shallow fringing reefs of St. Kitts. Histologically, the tissue loss margin had exposure of the axis and amoebocyte encapsulation with abundant mixed micro-organisms. Polyp loss, gastrodermal necrosis, and coenenchymal amoebocytosis were at the lesion interface (purpled area transitioning to grossly normal tissue) with algae (n = 21), fungus-like hyphae (n = 20), ciliate protists (n = 16), cyanobacteria (n = 15), labyrinthulomycetes (n = 5), or no micro-organisms (n = 8). Slender, septate hyaline hyphae predominated over other morphological categories, but were confined to the axis with little host response other than periaxial melanization. Hyphae were absent in 6 lesioned sea fans and present in 5 control biopsies, questioning their pathogenicity and necessary role in lesion causation. From cultivation, different fungi were isolated and identified by sequencing of the nuclear ribosomal internal transcribed spacer region. In addition, 2 primer pairs were used in a nested format to increase the sensitivity for direct amplification and identification of fungi from lesions, thereby circumventing cultivation. Results suggest mixed and opportunistic infections in sea fans with these lesions, requiring longitudinal or experimental studies to better determine the pathogenesis.

A Forage Allowance by Forage Type Interaction Impacts the Daily Milk Yield of Early Lactation Dairy Cows.

We tested for a forage allowance effect on the milk yield of early lactation dairy cow herds grazing swards sown with perennial ryegrass (Lolium perenne L.), white clover (Trifolium repens L.) and plantain (Plantago lanceolata L.) relative to perennial ryegrass alone. The examined allowances consisted of offering 12, 14, 16, 18, 20 or 25 kg of dry matter (DM)/cow per day of grazeable herbage, with diverse swards sown as mixtures and spatially adjacent monocultures. After adapting cows to their assigned forage type for 8 days, treatment effects on milk yield and composition, blood metabolites (beta-hydroxybutyrate, non-esterified fatty acids and urea concentrations), body weight change, forage intake and selection differentials for forage species and certain nutrients were monitored over 7 days. We confirmed a forage allowance effect on milk yield improvements in dairy cows grazing diverse swards relative to perennial ryegrass monocultures. Improvements in milk yield were evident at forage allowances of 14 to 20 kg of DM/cow per day, diminishing at the highest allowance of 25 kg of DM/cow per day. Improvements in milk yield for the mixture and spatially adjacent monocultures peaked at forage allowances of 18 and 16 kg of DM/cow per day, equalling increases of 1.3 and 1.2 kg of milk/cow per day, respectively.

Tetracapsuloides bryosalmonae and proliferative kidney disease in Icelandic salmonids - Comparative data from two different time periods.

Tetracapsuloides bryosalmonae is a myxozoan parasite and the causative agent of proliferative kidney disease (PKD), a serious, temperature-dependent and emerging disease affecting salmonid fish. It was first identified in Iceland in 2008, from Arctic charr inhabiting a shallow lowland lake. The aim of this study was to investigate the distribution and prevalence of macroscopic and subclinical T. bryosalmonae infections in Icelandic salmonids and compare different time periods, in context with depths, volumes, altitudes and areas of the lakes and fish age. Arctic charr (Salvelinus alpinus) and brown trout (Salmo trutta) from 34 lakes, sampled between 1994-1998 and 2009-2017, were examined for macroscopic signs of PKD (n = 2,151) and the presence of T. bryosalmonae infections (n = 1,424). In the earlier period, 43% of lakes (10/23) harboured T. bryosalmonae -infected fish. The mean prevalence in those lakes was 62.1%, being most common in shallow lowland lakes whilst deeper lakes at high altitudes were all free from infection. Only a single fish from one lake showed macroscopic signs of PKD, a shallow lowland lake in southwestern Iceland. In the latter period, T. bryosalmonae was found in 16/18 lakes studied (89%), with a mean prevalence of 78-79% (excluding T.b. free lakes), being most common in the smaller, shallower lakes at lower alttudes. Macroscopic signs of PKD were observed in 11 of 18 of the lakes studied (61%) with prevalences up to 67%, most common in younger fish inhabiting small shallow lowland lakes. The results indicate that the distribution of T. bryosalmonae and the presence of PKD in Iceland have increased over the last few decades. The disease was almost non-existent in the 1990s but has become very common during the last decade or two. With further water temperature increases, as predicted by climate models, PKD is likely to increasingly affect wild salmonid populations in Iceland.

Non-coagulopathic hemothorax in a dog: A case report.

An 8-year-old, female-spayed, Blue Heeler presented with suspected non-coagulopathic spontaneous, hemothorax with neoplasia as the most likely differential as coagulation parameters were normal and no obvious history of trauma was reported. Computed tomography scan was crucial for diagnosis of a traumatic partial vascular avulsion injury that was successfully managed supportively.

Karnofsky Performance Status (KPS) ≤60 Is Strongly Associated With Shorter Brain-Specific Progression-Free Survival Among Patients With Metastatic Breast Cancer With Brain Metastases.

Objective: To examine the association between Karnofsky Performance Status ("KPS") and brain-specific progression-free survival ("bsPFS") among patients with breast cancer brain metastases ("BCBrM"). Methods: Using a previously compiled retrospective cohort of 683 patients who were treated for BCBrM with surgery and/or radiotherapy at the Sunnybrook Odette Cancer Centre from 2008-2018, electronic records were reviewed to impute KPS scores at the time of BCBrM diagnosis. Patients were then grouped into KPS ≤60 and KPS >60 cohorts. The dataset was analyzed to identify variables that were prognostic for bsPFS and/or overall survival ("OS") using univariable and multivariable Cox proportional hazards models. Results: The mean age of patients was 57 (range 24-93). Most patients (n=622, 91%) had extracranial metastatic disease and 174 (25%) had leptomeningeal disease. 247 patients (36%) had hormone receptor ("HR")-positive/human endothelial growth factor receptor 2 ("HER2")-negative tumours, 189 (28%) had HER2-positive disease, and 153 (22%) had triple-negative breast cancer. Of the 331 patients (48%) who could be assigned a KPS cohort, 102 (31%) had KPS ≤60. Most patients were treated with whole brain radiotherapy (n=498, 73%) and/or stereotactic radiosurgery ("SRS") (n=128, 19%). Median bsPFS was 9 months (95% CI 8-10 months) and median OS was not reached. In univariable analyses, KPS ≤60, presence of leptomeningeal disease, neurological symptoms, ≥2 brain metastases, and not undergoing SRS were factors associated with shorter bsPFS. In a multivariable analysis, KPS ≤60 was the only statistically significant determinant of bsPFS (HR 1.86, 95% CI 1.20-2.88). Although survival data was limited, KPS ≤60 was associated with shorter OS in both univariable (HR 3.12, 95% CI 1.85-5.26) and multivariable (HR 2.95, 95% CI 1.55-5.58) analyses. Conclusion: Patients with BCBrM who have a KPS ≤60 have significantly shorter bsPFS and OS than those with KPS >60. KPS should be documented routinely at the time of diagnosis of brain metastases to improve prognostication.

A phylogenetically unresolved apicomplexan (APXSc) causing swirl lesions in the Tehuelche scallop, Aequipecten tehuelchus, from the Southwest Atlantic coast.

The study reports a previously unknown apicomplexan (APXSc) parasite infecting wild scallops Aequipecten tehuelchus (d'Orbigny, 1842) from two separate areas (La Tapera and Punta Conos) of the San José gulf, in Patagonia Argentina. Histology, transmission electron microscope, molecular analyses and in situ hybridization were performed to describe the morphology of APXSc, and confirm its phylogenetic status. The prevalence of APXSc infection was 24% and 72% in scallops from La Tapera and Punta Conos, respectively. Seasonal variation was observed for scallops from La Tapera, recording highest prevalence in summer. A positive relationship between the presence of the APXSc and the size of the scallops was observed. A SSU rDNA consensus sequence of 1758 base pairs was generated which has a 94.8% identity to sequences obtained from a pathogenic apicomplexan parasite infecting Ostrea chilensis in New Zealand, but not closely related to other apicomplexans. The asexual reproduction, i.e. merogony, occurs in the Tehuelche scallop whilst the gamogonic and sporogonic stages were absent, suggesting a yet unknown definitive host. Severe host inflammation response involving fibroblast-like hemocytes surrounding the APXSc in the form of granuloma-like "swirls" is characteristic for this apicomplexan infection. Further studies are needed to reveal the life cycle, and presumable pathogenicity of APXSc.

A case report and statewide surveillance of "weak meat" condition of Alaska weathervane scallops, Patinopecten caurinus, linked to a recently identified pathogenic parasite, Merocystis kathae (Apicomplexa: Aggregatidae).

Weathervane scallop, Patinopecten caurinus, the largest scallop species in the world, is distributed from northern California, U.S.A., to the Bering Sea, and is only commercially harvested in Alaska. The fishery is considered well managed by the State of Alaska (U.S.A) Department of Fish and Game (ADF&G) and federal government, with many precautionary measures in place to avoid overharvest. There have been episodic declines in some management areas due to unknown causes. Fishermen also encounter scallops with abnormal adductor muscles, a condition colloquially termed "weak meat", characterized by the retention of muscle when shucked, an obvious darkened discoloration, and/or an abnormal texture making the product unacceptable for marketing. A similar syndrome in Atlantic sea scallops, Placopecten magellanicus, described as "gray meat", occurs in the eastern U.S. and Canada, and proposed causes include senescence, loss of bioenergetics due to chronic infestations, or a synergism of these factors. Recently a severe apicomplexan infection was found to cause a gray meat condition in Iceland scallops, Chlamys islandica, and the collapse of that stock. This parasite was subsequently detected in Atlantic sea scallops with the gray meat condition off the U.S. East Coast. Studies that followed identified the parasite as Merocystis kathae, previously described from the common whelk, Buccinum undatum, more than 100 years ago. In 2015 Bering Sea fishermen reported weak meat in their catch, so samples were submitted to ADF&G for diagnosis. Adductor muscles from all affected scallops had many large foci of an apicomplexan associated with necrosis, fibrosis, and muscular atrophy. Given the reduced quality, marketability, and possibly fitness of affected scallops, we performed a survey to estimate prevalence, intensity, and geographic distribution of this apicomplexan in Alaskan weathervane scallops. We sampled 180 scallops, from individual beds within each of the three major geographically broad scallop areas in Alaska. Overall prevalence was about 82%, ranging from 69 to 100% by district. Overall mean infection intensity, based on the number of parasite foci/section, was about 9 (range of 5-29, by location), with scallops from the Bering Sea and Southwest Kodiak being most severely infected. Molecular analyses confirmed that the Alaskan parasite is M. kathae, i.e., the same apicomplexan that caused the collapse of Icelandic scallops and a suspected cause for gray meat and mass mortality of Atlantic sea scallops in northeast North America.

The presence of sporogonic stages of Tetracapsuloides bryosalmonae in Icelandic salmonids detected using in situ hybridisation.

Proliferative kidney disease (PKD) is a widespread temperature-dependent disease in salmonids caused by the myxozoan parasite, Tetracapsuloides bryosalmonae (Canning, Curry, Feist, Longshaw et Okamura, 1999) (Tb). Tb has a two-host life cycle, involving fish as an intermediate host and freshwater bryozoans as the definitive host. Although salmonids are acknowledged as hosts for the parasite, it is less clear which fish species are active hosts in the life cycle of Tb. Differences in infection dynamics have been observed between some fish species, which are thought to be related to the existence of two main Tb-strains, the American and European. Iceland, having three species of indigenous salmonids and positioned geographically between Europe and North America, is an ideal location to study the natural development of Tb in wild fish. The main aim of this study was to determine the genetic origin of Tb in Iceland and confirm whether mature spores are produced in Icelandic salmonids. In this study, Icelandic salmonids were infected with the European Tb-strain. In situ hybridisation revealed that intraluminal sporogonic stages, including mature spores, were commonly observed in all three salmonid species. The presence of intraluminal stages has previously been confirmed in brown trout Salmo trutta Linnaeus and Atlantic salmon S. salar Linnaeus in Europe, but they have only been observed in Arctic charr Salvelinus alpinus (Linnaeus) in North America, infected by the local strain. This is, therefore, the first time that sporogonic stages have been observed in Arctic charr in Europe, where fish are infected with the European Tb-strain. Our data strongly suggest that all the three salmonid species inhabiting Icelandic waters serve as active hosts in the life cycle of Tb. However, for full confirmation, transmission trials are needed.

An in-depth comparison of well-being among Latinx and non-Latinx White adults: A cautionary tale.

Understanding how to optimize the health and well-being of Latinxs is crucial and will aid in informing actions to address inequities. Latinxs' unique cultural backgrounds and lived experiences could have implications for their well-being, which may differ from other racial/ethnic groups. We compared overall and domain-specific well-being and their socio-demographic correlates among two samples of Latinxs and a sample of non-Latinx Whites. Cross-sectional samples were independently drawn from the Stanford WELL Initiative (n = 217 Latinxs, n = 943 non-Latinx Whites) and the On the Move Trial (n = 238 Latinxs), both recruiting in Northern California. Well-being was assessed using the Stanford WELL scale, a novel multifaceted measure. Propensity score matching and mixed effect regressions were employed to compare well-being between samples. Overall well-being levels did not differ between groups. However, when examining constituent domains of well-being, several differences were found. Both Latinx samples reported experiencing more stress, having worse physical health, and being more religious than did the matched non-Latinx White sample. However, on four other well-being domains, only one of the Latinx samples differed from the non-Latinx White sample. Moreover, the two Latinx samples differed from each other in four out of nine domains examined. When evaluating well-being across racial/ethnic groups, we recommend employing multidimensional measures and multiple samples to promote greater confidence in the conclusions. This approach can better inform future research and the tailoring of public health efforts by furthering our understanding of the nature of group well-being differences. Our methods offer a blueprint for similar studies examining well-being in multi-ethnic groups.

Virtual fencing technology to intensively graze lactating dairy cattle. I: Technology efficacy and pasture utilization.

Virtual fencing is promoted as the next advancement for rotational grazing systems. This experiment compared the capacity of conventional temporary electric versus virtual fencing to contain a herd of 30 lactating dairy cows within the boundaries of their daily pasture allocation (inclusion zone). Cows were moved each day to a new rectangular paddock that was divided crosswise into an inclusion and exclusion zone by a single linear electric (first 10 d) or virtual (second 10 d) front-fence. A 3-d virtual fence training period separated the 2 treatments. Virtual fences were imposed using a pre-commercial prototype of the eShepherd virtual fencing system (Agersens Pty Ltd.). Neckband-mounted devices replaced the visual cue of an electric fence with benign audio cues, which if ignored were accompanied by an aversive electrical stimulus. Cows learned to respond to the audio cues to avoid receiving electrical stimuli, with the daily ratio of electrical to audio signals for individual cows averaging (± standard deviation) 0.18 ± 0.27 over the 10 d of virtual fence deployment. Unlike the electric fence, the virtual fence did not fully eliminate cow entry into the exclusion zone, but individual cows were generally contained within the inclusion zone ≥99% of the time. Pasture depletion within the inclusion zone reduced the efficacy of the virtual fence in preventing cows from entering the exclusion zone, but the magnitude of this effect was insignificant in practical terms (i.e., increased time spent in the exclusion zone by ≤28 s/h per cow). This highlights the potential for virtual fences to control grazing dairy cow movement even when pasture availability is limited (i.e., 1 kg of dry matter/cow above a target residual of 1,500 kg of dry matter/ha), but requires confirmation under longer and more complex virtual fencing applications. Within each treatment period, uniform daily pasture utilization (% of pasture consumed above a target residual of 1,500 kg of dry matter/ha) within inclusion zones indicates that cows did not avoid grazing near electric or virtual front-fences. Overall, this study demonstrated a successful simple application of this virtual fencing system to contain a herd of grazing lactating dairy cows within the boundaries of their daily pasture allocation.

Phylogenomics Identifies a New Major Subgroup of Apicomplexans, Marosporida class nov., with Extreme Apicoplast Genome Reduction.

The phylum Apicomplexa consists largely of obligate animal parasites that include the causative agents of human diseases such as malaria. Apicomplexans have also emerged as models to study the evolution of nonphotosynthetic plastids, as they contain a relict chloroplast known as the apicoplast. The apicoplast offers important clues into how apicomplexan parasites evolved from free-living ancestors and can provide insights into reductive organelle evolution. Here, we sequenced the transcriptomes and apicoplast genomes of three deep-branching apicomplexans, Margolisiella islandica, Aggregata octopiana, and Merocystis kathae. Phylogenomic analyses show that these taxa, together with Rhytidocystis, form a new lineage of apicomplexans that is sister to the Coccidia and Hematozoa (the lineages including most medically significant taxa). Members of this clade retain plastid genomes and the canonical apicomplexan plastid metabolism. However, the apicoplast genomes of Margolisiella and Rhytidocystis are the most reduced of any apicoplast, are extremely GC-poor, and have even lost genes for the canonical plastidial RNA polymerase. This new lineage of apicomplexans, for which we propose the class Marosporida class nov., occupies a key intermediate position in the apicomplexan phylogeny, and adds a new complexity to the models of stepwise reductive evolution of genome structure and organelle function in these parasites.

Gross and microscopic pathology of West Indian sea eggs (Tripneustes ventricosus).

In this study, we performed comprehensive pathology examinations on 83 Tripneustes ventricosus from 11 locations on St. Kitts to build baseline data necessary for disease diagnosis in this species. Gross abnormalities were observed in 23/83 (28%) urchins and included spine loss, visceral hyperpigmentation, test discoloration, and test ulceration. Ciliates were the only protists identified in this study via examination of tissue wet mounts and histology, documented in 50/83 (60%) urchins. Microscopic observations associated with visibly abnormal status included muscle necrosis, test and appendage inflammation, appendage (tube feet, spines, and pedicellariae) degeneration, severe coelomocytosis, and generalized hypermelanosis. Enterocyte intranuclear inclusion bodies, microbial aggregates, nerve pigmentation, enteric pigmentation, integument-associated crustaceans, and encysted metazoan parasites were of uncertain pathological significance. The etiology for any lesion was not microscopically apparent, contrasting literature implicating common marine bacteria in urchin diseases. This study highlights the importance of histopathology in urchin disease investigations and facilitates the recognition of disease in T. ventricosus.

In Vivo Knee Kinematics: How Important Are the Roles of Femoral Geometry and the Cruciate Ligaments?

BACKGROUND: While posterior cruciate-retaining (PCR) implants are a more common total knee arthroplasty (TKA) design, newer bicruciate-retaining (BCR) TKAs are now being considered as an option for many patients, especially those that are younger. While PCR TKAs remove the ACL, the BCR TKA designs keep both cruciate ligaments intact, as it is believed that the resection of the ACL greatly affects the overall kinematic patterns of TKA designs. The objectives of this study are to assess the in vivo kinematics for subjects implanted with either a PCR or BCR TKA and to compare the in vivo kinematic patterns to the normal knee during flexion. These objectives were achieved with an emphasis on understanding the roles of the cruciate ligaments, as well as the role of changes in femoral geometry of nonimplanted anatomical femurs vs implanted subjects having a metal femoral component. METHODS: Tibiofemoral kinematics of 50 subjects having a PCR (40 subjects) or BCR (10 subjects) TKA were analyzed using fluoroscopy while performing a deep knee bend activity. The kinematics were compared to previously published normal knee data (10 subjects). Kinematics were determined during specific intervals of flexion where the ACL or PCL was most dominant. RESULTS: In early flexion, subjects having a BCR TKA experienced more normal-like kinematic patterns, possibly attributed to the ACL. In mid-flexion, both TKA groups exhibited variable kinematic patterns, which could be due to the transitional cruciate ligament function period. In deeper flexion, both TKA functioned more similar to the normal knee, leading to the assumption that the PCL was properly balanced and functioning in the TKA groups. Interestingly, during late flexion (after 90°), the kinematic patterns for all three groups appeared to be statistically similar. CONCLUSION: Subjects having a PCR TKA experienced greater weight-bearing flexion than the BCR TKA group. Subjects having a BCR TKA exhibited a more normal-like kinematic pattern in early and late flexion. The normal knee subjects achieved greater lateral condyle rollback and axial rotation compared to the TKA groups.

Development of autotaxin inhibitors: A series of tetrazole cinnamides.

A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments.

Well-Being without a Roof: Examining Well-Being among Unhoused Individuals Using Mixed Methods and Propensity Score Matching.

The morbidity and mortality experiences of people who are unhoused have been well-described, but much less is known about the overall well-being of these individuals. In this mixed methods study, housed and unhoused participants completed a multi-faceted 10 domain measure of well-being (the Stanford WELL Survey), and a subset of unhoused participants shared their experiences during qualitative interviews. Using propensity score matching, unhoused participants (n = 51) were matched at a ratio of 1:5 with housed participants (n = 255). The mean overall well-being score of the unhoused participants was significantly lower than that of the matched housed participants (B = -5.022, p = 0.013). Additionally, the two groups differed on some of the constituent domains of well-being, with unhoused participants reporting statistically significantly lower mean scores on social connectedness (B = -1.086, p = 0.000), lifestyle and daily practices (B = -1.219, p = 0.000), stress and resilience (B = -0.493, p = 0.023), experience of emotions (B = -0.632, p = 0.009), physical health (B = -0.944, p = 0.0001), and finances (B = -3.099, p = 0.000). The unhoused participants had a statistically significantly higher mean score for spirituality and religiosity (B = 2.401, p = 0.000) than their matched housed counterparts. The qualitative interviews further highlighted spirituality and religion as a coping mechanism for the unhoused. The results of this study highlight both unexpected strengths exhibited by the unhoused individuals and areas of challenge.