MRI-derived Articular Cartilage Strains Predict Patient-Reported Outcomes Six Months Post Anterior Cruciate Ligament Reconstruction.

Key terms: Multicontrast and Multiparametric, Magnetic Resonance Imaging, Osteoarthritis, Functional Biomechanical Imaging, Knee Joint Degeneration What is known about the subject: dualMRI has been used to quantify strains in a healthy human population in vivo and in cartilage explant models. Previously, OA severity, as determined by histology, has been positively correlated to increased shear and transverse strains in cartilage explants. What this study adds to existing knowledge: This is the first in vivo use of dualMRI in a participant demographic post-ACL reconstruction and at risk for developing osteoarthritis. This study shows that dualMRI-derived strains are more significantly correlated with patient-reported outcomes than any MRI relaxometry metric. Background: Anterior cruciate ligament (ACL) injuries lead to an increased risk of osteoarthritis, characterized by altered cartilage tissue structure and function. Displacements under applied loading by magnetic resonance imaging (dualMRI) is a novel MRI technique that can be used to quantify mechanical strain in cartilage while undergoing a physiological load. Purpose: To determine if strains derived by dualMRI and relaxometry measures correlate with patient-reported outcomes at six months post unilateral ACL reconstruction. Study Design: Cohort study. Methods: Quantitative MRI (T2, T2*, T1ρ) measurements and transverse, axial, and shear strains were quantified in the medial articular tibiofemoral cartilage of 35 participants at six-months post unilateral ACL reconstruction. The relationships between patient-reported outcomes (WOMAC, KOOS, MARS) and all qMRI relaxation times were quantified using general linear mixed-effects models. A combined best-fit multicontrast MRI model was then developed using backwards regression to determine the patient features and MRI metrics that are most predictive of patient-reported outcome scores. Results: Higher femoral strains were significantly correlated with worse patient-reported functional outcomes. Femoral shear and transverse strains were positively correlated with six-month KOOS and WOMAC scores, after controlling for covariates. No relaxometry measures were correlated with patient-reported outcome scores. We identified the best-fit model for predicting WOMAC score using multiple MRI measures and patient-specific information, including sex, age, graft type, femoral transverse strain, femoral axial strain, and femoral shear strain. The best-fit model significantly predicted WOMAC score (p<0.001) better than any one individual MRI metric alone. When we regressed the model-predicted WOMAC scores against the patient-reported WOMAC scores, we found that our model achieved a goodness of fit exceeding 0.52. Conclusions: This work presents the first use of dualMRI in vivo in a cohort of participants at risk for developing osteoarthritis. Our results indicate that both shear and transverse strains are highly correlated with patient-reported outcome severity could serve as novel imaging biomarkers to predict the development of osteoarthritis.

Evaluating the comparability of osteoporosis treatments using propensity score and negative control outcome methods in UK and Denmark electronic health record databases.

Evidence on the comparative effectiveness of osteoporosis treatments is heterogeneous. This may be attributed to different populations and clinical practice, but also to differing methodologies ensuring comparability of treatment groups before treatment effect estimation and the amount of residual confounding by indication. This study assessed the comparability of denosumab vs oral bisphosphonate (OBP) groups using propensity score (PS) methods and negative control outcome (NCO) analysis. A total of 280 288 women aged ≥50 years initiating denosumab or OBP in 2011-2018 were included from the UK Clinical Practice Research Datalink (CPRD) and the Danish National Registries (DNR). Balance of observed covariates was assessed using absolute standardised mean difference (ASMD) before and after PS weighting, matching, and stratification, with ASMD >0.1 indicating imbalance. Residual confounding was assessed using NCOs with ≥100 events. Hazard ratio (HR) and 95% confidence interval (CI) between treatment and NCO was estimated using Cox models. Presence of residual confounding was evaluated with two approaches1: >5% of NCOs with 95% CI excluding 1,2 >5% of NCOs with an upper CI <0.75 or lower CI >1.3. The number of imbalanced covariates before adjustment (CPRD 22/87; DNR 18/83) decreased, with 2-11% imbalance remaining after weighting, matching or stratification. Using approach 1, residual confounding was present for all PS methods in both databases (≥8% of NCOs), except for stratification in DNR (3.8%). Using approach 2, residual confounding was present in CPRD with PS matching (5.3%) and stratification (6.4%), but not with weighting (4.3%). Within DNR, no NCOs had HR estimates with upper or lower CI limits beyond the specified bounds indicating residual confounding for any PS method. Achievement of covariate balance and determination of residual bias were dependent upon several factors including the population under study, PS method, prevalence of NCO, and the threshold indicating residual confounding.

Treatment groups in clinical practice may not be comparable as patient characteristics differ according to the need for the prescribed medication, known as confounding. We assessed comparability of two common osteoporosis treatments, denosumab and oral bisphosphonate, in 280 288 postmenopausal women using electronic health records from UK Clinical Practice Research Datalink (CPRD) and Danish National Registries (DNR). We evaluated comparability of recorded patient characteristics with three propensity score (PS) methods, matching, stratification, and weighting. We assessed residual confounding from unrecorded patient characteristics via negative control outcomes (NCO), events known not to be associated with treatment such as delirium. We found that achieving comparability of osteoporosis treatment groups depended on the study population, PS method, and definition of residual confounding. Weighting and stratification performed the best in DNR and CPRD, respectively. Using a stricter threshold based on statistical significance for the NCO suggested the treatment groups were not comparable, except for PS stratification in DNR. Applying clinically significant thresholds of treatment effect size showed comparability using weighting in CPRD and all PS methods in DNR. Studies should consider more than one PS method to test robustness and identify the largest number of NCO to give the greatest flexibility in detecting residual confounding.

[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Viral PIC-pocketing: RSV sequestration of translational preinitiation complexes into bi-phasic biomolecular condensates.

Orthopneumoviruses characteristically form membrane-less cytoplasmic inclusion bodies (IBs) wherein RNA replication and transcription occur. Here, we report a strategy whereby the orthopneumoviruses sequester various components of the translational preinitiation complex machinery into viral inclusion bodies to facilitate translation of their own mRNAs-PIC-pocketing. Electron microscopy of respiratory syncytial virus (RSV)-infected cells revealed bi-phasic organization of IBs, specifically, spherical "droplets" nested within the larger inclusion. Using correlative light and electron microscopy, combined with fluorescence in situ hybridization, we showed that the observed bi-phasic morphology represents functional compartmentalization of the inclusion body and that these domains are synonymous with the previously reported inclusion body-associated granules (IBAGs). Detailed analysis demonstrated that IBAGs concentrate nascent viral mRNA, the viral M2-1 protein as well as components of eukaryotic translation initiation factors (eIF), eIF4F and eIF3, and 40S complexes involved in translation initiation. Interestingly, although ribopuromycylation-based imaging indicates that the majority of viral mRNA translation occurs in the cytoplasm, there was some evidence for intra-IBAG translation, consistent with the likely presence of ribosomes in a subset of IBAGs imaged by electron microscopy. Mass spectrometry analysis of sub-cellular fractions from RSV-infected cells identified significant modification of the cellular translation machinery; however, interestingly, ribopuromycylation assays showed no changes to global levels of translation. The mechanistic basis for this pathway was subsequently determined to involve the viral M2-1 protein interacting with eIF4G, likely to facilitate its transport between the cytoplasm and the separate phases of the viral inclusion body. In summary, our data show that these viral organelles function to spatially regulate early steps in viral translation within a highly selective bi-phasic biomolecular condensate. IMPORTANCE: Respiratory syncytial viruses (RSVs) of cows and humans are a significant cause of morbidity and mortality in their respective populations. These RNA viruses replicate in the infected cells by compartmentalizing the cell's cytoplasm into distinct viral microdomains called inclusion bodies (IBs). In this paper, we show that these IBs are further compartmentalized into smaller structures that have significantly different density, as observed by electron microscopy. Within smaller intra-IB structures, we observed ribosomal components and evidence for active translation. These findings highlight that RSV may additionally compartmentalize translation to favor its own replication in the cell. These data contribute to our understanding of how RNA viruses hijack the cell to favor replication of their own genomes and may provide new targets for antiviral therapeutics in vivo.

Transitioning insomnia patients from zolpidem to lemborexant: A multicenter, open-label study evaluating a next-dose transition approach to insomnia pharmacotherapy.

Objective: Few clinical studies have assessed real-world abrupt transitioning between insomnia medications. This study assessed strategies for directly transitioning patients from zolpidem tartrate (ZOL) immediate/extended release to the dual orexin receptor antagonist, lemborexant (LEM). Methods: This randomized, open-label, multicenter study (Study 312; E2006-A001-312) enrolled 53 adults age ≥18 years with insomnia disorder and ≥1-month history of intermittent (3-4 nights/week) or frequent (≥5 nights/week) ZOL use. Subjects recorded their ZOL use in a 3-week Pretreatment Phase, followed by a 2-week Treatment Phase (TRT; Titration) during which ZOL was discontinued. Intermittent ZOL users transitioned to LEM 5 mg (LEM5), Cohort 1, and frequent ZOL users were randomized 1:1 to LEM5, Cohort 2A, or LEM 10 mg (LEM10), Cohort 2B. One dose adjustment was permitted during the TRT. Subjects completing the TRT could continue LEM in the 12-week Extension Phase (EXT). The primary outcome was proportion of subjects who successfully transitioned and remained on LEM at the end of the TRT. Results: Most subjects (43 [81.1 %]) successfully transitioned to LEM (9 [90 %], 17 [81.0 %], and 17 [77.3 %] in Cohorts 1, 2A, and 2B, respectively). By the end of the EXT, 66.7 % in Cohort 1 and 60.0 % in Cohort 2A up-titrated to LEM10, whereas 41.2 % in Cohort 2B down-titrated to LEM5; 61.0 % were receiving LEM10 at study end. At the end of the TRT, more subjects taking LEM reported that it helped them return to sleep after waking, compared with those taking ZOL (71.7 % vs. 49.1 %). There were no important differences between treatments regarding how subjects reported feeling as they fell asleep. Most of the treatment-emergent adverse events with LEM were mild in severity. Conclusions: Most subjects transitioned successfully to LEM from ZOL (intermittent or frequent use). LEM was well tolerated.

Painting the Way Forward: An Ecological Cultural Visual Analysis of Anti-VAW Public Art in Rural Ecuador.

Despite efforts within Ecuador to combat violence against women (VAW), the country still claims some of the highest rates of violence in the Americas. In this study, we complete a cultural visual analysis of anti-VAW public art in a small Ecuadorian city. Visual data is examined and interpreted by way of the social-ecological model (SEM). Specifically, our analysis considers how murals engage with the depiction of (a) VAW, (b) agentic responses to VAW, and (c) the different layers of the SEM. Our analysis identifies four specific strategies for constructing public art messaging to help achieve freedom from VAW.

Treatment persistence and switching patterns of ABP 501 in European patients with inflammatory bowel disease.

Background: Approval of the adalimumab (ADA) biosimilar ABP 501 for inflammatory bowel disease (IBD) indications was based on the principle of extrapolation, without indication-specific clinical trial data. Objectives: To evaluate the real-world treatment patterns of ABP 501 in patients with IBD. Design: Retrospective analysis of pharmacy claims data from Germany and France. Methods: Continuously insured adult IBD patients who initiated ABP 501 between October 2018 and March 2020 were included. Treatment persistence, adherence, and post-ABP 501 switching patterns were evaluated for two mutually exclusive groups: ADA-naïve patients (i.e. no baseline use of ADA products) and ADA-experienced patients (i.e. previously treated with ADA products). Results: A total of 3362 German patients and 733 French patients were included, with 54.4% and 65.3% being ADA-naïve patients, respectively. Median persistence (95% CI) on ABP 501 was 10.9 months (9.8-11.6) in ADA-naïve patients and 14.2 months (12.7-15.2) in ADA-experienced patients in Germany; for the French cohort, ADA-naïve and -experienced patients had median persistence of 12.8 months (10.2-14.7) and 11.5 months (8.8-14.4), respectively. During the first 12 months of ABP 501 initiation, 53.7% of German patients and 51.0% of French patients were adherent to the therapy. About 20% of patients in both countries switched from ABP 501 to another targeted therapy. In the German cohort, ADA-naïve patients most frequently switched to non-tumor necrosis factor inhibitor biologics, but ADA-experienced patients most commonly switched to reference product (RP); in the French cohort, patients most often switched to RP regardless of prior exposure to ADA products. Conclusion: About 50% of patients persisted on and were adherent to ABP 501 therapy during the first 12 months after treatment initiation in two large European countries. Post-ABP 501, switching patterns varied between countries, indicating diversified treatment practices warranting further research on reason(s) for switching and potential overall treatment outcomes.

Expanding the Health Narrative Frame.

How might we expand the frame of health narratives so as to avoid genre calcification and more effectively harness these stories' transformative potential? This essay builds on the continued success of the "Defining Moments" forum while responding to Harter et al.'s 2020 call for "new stories shaped and shared in novel ways." Drawing on interdisciplinary research and theorizing, I suggest three narrative strategies for storytelling based on, respectively, the extended duration of a health context, the agentic power of nonhuman kinds, and the implicit collectivity of polyphonic narratives. Brief examples precede my discussion of each strategy. I invite others to join me in shaping innovative narratives that further challenge tacit assumptions of embodied health.

Reliability assessment of new radiographic scales to evaluate radiolucency and bony in-between fin growth of partially cemented all-polyethylene glenoid components.

BACKGROUND: Current methods available for assessment of radiolucency and in-between fin (IBF) growth of a glenoid component have not undergone interobserver reliability testing for an all-polyethylene fluted central peg (FCP) glenoid. The purpose of this study was to evaluate anteroposterior radiographs of an FCP glenoid component at ≥48 months comparing commonly used scales to a new method adapted to the FCP. Our hypothesis was that the new method would result in acceptable intra- and interobserver agreement and a more accurate description of radiographic findings. METHODS: We reviewed ≥48-month follow-up radiographs of patients treated with a primary aTSA using an FCP glenoid. Eighty-three patients were included in the review. Radiographs were evaluated by 5 reviewers using novel IBF radiodensity and radiolucency assessments and the Wirth and Lazarus methods. To assess intraobserver reliability, a subset of 40 images was reviewed. Kappa statistics were calculated to determine intra- and interobserver reliability; correlations were assessed using Pearson correlation. RESULTS: Interobserver agreement (κ score) was as follows: IBF 0.71, radiolucency 0.68, Wirth 0.48, and Lazarus 0.22. Intraobserver agreement ranges were as follows: IBF radiodensity 0.36-0.67, radiolucency 0.55-0.62, Wirth 0.11-0.73, and Lazarus 0.04-0.46. Correlation analysis revealed the following: IBF to Wirth r = 0.93, radiolucency to Lazarus r = 0.92 (P value <.001 for all). CONCLUSION: This study introduces a radiographic assessment method developed specifically for an FCP glenoid component. Results show high interobserver and acceptable intraobserver reliability for the method presented in this study. The new scales provide a more accurate description of radiographic findings, helping to identify glenoid components that may be at risk for loosening.

Real-World Effectiveness of Osteoporosis Medications in France: A Nationwide Cohort Study.

Although drugs for osteoporosis have been demonstrated to be effective in reducing fracture risk in placebo-controlled clinical trials, data on effectiveness in real-world practice is limited. Data from the French national health insurance claims database (SNDS) were used to follow five cohorts of women aged ≥55 years after initiating treatment for ≥6 months with either denosumab, zoledronic acid, oral bisphosphonates, raloxifene, or teriparatide in 2014-2016. Fracture incidence was compared within each cohort between the 3 months following initiation (baseline fracture risk) and the 12month, 18month, and 24 month postinitiation periods. Data are presented as incidence rate ratios (IRRs) with their 95% confidence intervals (CIs)s. Overall, 67,046 women were included in the denosumab cohort, 52,914 in the oral bisphosphonate cohort, 41,700 in the zoledronic acid cohort, 11,600 in the raloxifene cohort, and 7510 in the teriparatide cohort. The baseline vertebral fracture rate ranged from 1.74 per 1000 person years (‰PY) in the raloxifene cohort to 34.75‰PY in the teriparatide cohort, and the baseline hip fracture rate from 0.70‰PY in the raloxifene cohort to 10.52‰PY in the zoledronic acid cohort. Compared with the baseline fracture rate, vertebral fractures involving hospitalization were significantly reduced in the 3-24-month postinitiation period with denosumab (IRR 0.6; 95% CI, 0.5-0.7), zoledronic acid (IRR 0.4; 95% CI, 0.3-0.4), teriparatide (IRR 0.3; 95% CI, 0.2-0.5), and oral bisphosphonates (IRR 0.6; 95% CI, 0.4-0.8). Hip fracture incidence was reduced with denosumab (IRR 0.8; 95% CI, 0.6-0.9), but higher for oral bisphosphonates (IRR 1.7; 95% CI, 1.2-2.3); no significant change in hip fracture rate was observed for zoledronic acid, teriparatide, or raloxifene. A reduction in nonvertebral, non-hip fracture incidence was observed only in the denosumab cohort (IRR 0.8; 95% CI, 0.7-0.9). These findings indicate that treatment with osteoporosis drugs is effective in the real-world setting. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid.

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

Radiation therapy promotes unsaturated fatty acids to maintain survival of glioblastoma.

Radiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT might stimulate mechanisms of resistance that limits its efficacy. GBM is recognized for its metabolic plasticity, but whether RT-induced resistance relies on metabolic adaptation remains unclear. Here, we show in vitro and in vivo that irradiated GBM tumors switch their metabolic program to accumulate lipids, especially unsaturated fatty acids. This resulted in an increased formation of lipid droplets to prevent endoplasmic reticulum (ER) stress. The reduction of lipid accumulation with genetic suppression and pharmacological inhibition of the fatty acid synthase (FASN), one of the main lipogenic enzymes, leads to mitochondrial dysfunction and increased apoptosis of irradiated GBM cells. Combination of FASN inhibition with focal RT improved the median survival of GBM-bearing mice. Supporting the translational value of these findings, retrospective analysis of the GLASS consortium dataset of matched GBM patients revealed an enrichment in lipid metabolism signature in recurrent GBM compared to primary. Overall, these results demonstrate that RT drives GBM resistance by generating a lipogenic environment permissive to GBM survival. Targeting lipid metabolism might be required to develop more effective anti-GBM strategies.

Accelerating the development of a psychological intervention to restore treatment decision-making capacity in patients with schizophrenia-spectrum disorder: a study protocol for a multi-site, assessor-blinded, pilot Umbrella trial (the DEC:IDES trial).

BACKGROUND: A high proportion of patients diagnosed with schizophrenia-spectrum disorders will at some point in their lives be assessed as not having the capacity to make their own decisions about pharmacological treatment or inpatient care ('capacity'). Few will be helped to regain it before these interventions proceed. This is partly because effective and safe methods to do so are lacking. Our aim is to accelerate their development by testing, for the first time in mental healthcare, the feasibility, acceptability and safety of running an 'Umbrella' trial. This involves running, concurrently and under one multi-site infrastructure, multiple assessor-blind randomised controlled trials, each of which is designed to examine the effect on capacity of improving a single psychological mechanism ('mechanism'). Our primary objectives are to demonstrate feasibility of (i) recruitment and (ii) data retention on the MacArthur Competence Assessment Tool-Treatment (MacCAT-T; planned primary outcome for a future trial) at end-of-treatment. We selected three mechanisms to test: 'self-stigma', low self-esteem and the 'jumping to conclusions' bias. Each is highly prevalent in psychosis, responsive to psychological intervention, and hypothesised to contribute to impaired capacity. METHODS: Sixty participants with schizophrenia-spectrum diagnoses, impaired capacity and one or more mechanism(s) will be recruited from outpatient and inpatient mental health services in three UK sites (Lothian, Scotland; Lancashire and Pennine; North West England). Those lacking capacity to consent to research could take part if the key criteria were met, including either proxy consent (Scotland) or favourable Consultee advice (England). They will be allocated to one of three randomised controlled trials, depending on which mechanism(s) they have. They will then be randomised to receive, over an 8-week period and in addition to treatment as usual (TAU), 6 sessions of either a psychological intervention which targets the mechanism, or 6 sessions of assessment of the causes of their incapacity (control condition). Participants are assessed at 0 (baseline), 8 (end-of-treatment) and 24 (follow-up) weeks post-randomisation using measures of capacity (MacCAT-T), mechanism, adverse events, psychotic symptoms, subjective recovery, quality of life, service use, anxiety, core schemata and depression. Two nested qualitative studies will be conducted; one to understand participant and clinician experiences and one to investigate the validity of MacCAT-T appreciation ratings. DISCUSSION: This will be the first Umbrella trial in mental healthcare. It will produce the first 3 single-blind randomised controlled trials of psychological interventions to support treatment decision-making in schizophrenia-spectrum disorder. Demonstrating feasibility will have significant implications not only for those seeking to support capacity in psychosis, but also for those who wish to accelerate the development of psychological interventions for other conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04309435 . Pre-registered on 16 March 2020.

Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1ß to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.

Phenotype based clustering, and diversity of common bean genotypes in seed iron concentration and cooking time.

Common bean is the world's most important directly consumed legume food crop that is popular for calories, protein and micronutrients. It is a staple food in sub-Saharan Africa, and a significant source of iron for anemic people. However, several pests, soil and weather challenges still impede its production. Long cooking time, and high phytic acid and polyphenols that influence bioavailable iron also limit the health benefits. To inform population improvement strategies and selection decisions for resilient fast cooking and iron biofortified beans, the study determined diversity and population structure within 427 breeding lines, varieties, or landraces mostly from Alliance Uganda and Columbia. The genotypes were evaluated for days to flowering and physiological maturity, yield, seed iron (FESEED) and zinc (ZNSEED) and cooking time (COOKT). Data for all traits showed significant (P≤0.001) differences among the genotypes. Repeatability was moderate to high for most traits. Performance ranged from 52 to 87 ppm (FESEED), 23-38 ppm (ZNSEED), 36-361 minutes (COOKT), and 397-1299 kg/ha (yield). Minimal differences existed between the gene pools in the mean performance except in yield, where Mesoamerican beans were better by 117 kg/ha. The genotypes exhibited high genetic diversity and thus have a high potential for use in plant breeding. Improvement of FESEED and ZNSEED, COOKT and yield performance within some markets such as red and small white beans is possible. Hybridization across market classes especially for yellow beans is essential but this could be avoided by adding other elite lines to the population. Superior yielding and fast cooking, yellow and large white beans were specifically lacking. Adding Fe dense elite lines to the population is also recommended. The population was clustered into three groups that could be considered for specific breeding targets based on trait correlations.

Cystine rather than cysteine is the preferred substrate for ß-elimination by cystathionine γ-lyase: implications for dietary methionine restriction.

Dietary methionine restriction (MR) increases longevity by improving health. In experimental models, MR is accompanied by decreased cystathionine ß-synthase activity and increased cystathionine γ-lyase activity. These enzymes are parts of the transsulfuration pathway which produces cysteine and 2-oxobutanoate. Thus, the decrease in cystathionine ß-synthase activity is likely to account for the loss of tissue cysteine observed in MR animals. Despite this decrease in cysteine levels, these tissues exhibit increased H2S production which is thought to be generated by ß-elimination of the thiol moiety of cysteine, as catalyzed by cystathionine ß-synthase or cystathionine γ-lyase. Another possibility for this H2S production is the cystathionine γ-lyase-catalyzed ß-elimination of cysteine persulfide from cystine, which upon reduction yields H2S and cysteine. Here, we demonstrate that MR increases cystathionine γ-lyase production and activities in the liver and kidneys, and that cystine is a superior substrate for cystathionine γ-lyase catalyzed ß-elimination as compared to cysteine. Moreover, cystine and cystathionine exhibit comparable Kcat/Km values (6000 M-1 s-1) as substrates for cystathionine γ-lyase-catalyzed ß-elimination. By contrast, cysteine inhibits cystathionine γ-lyase in a non-competitive manner (Ki ~ 0.5 mM), which limits its ability to function as a substrate for ß-elimination by this enzyme. Cysteine inhibits the enzyme by reacting with its pyridoxal 5'-phosphate cofactor to form a thiazolidine and in so doing prevents further catalysis. These enzymological observations are consistent with the notion that during MR cystathionine γ-lyase is repurposed to catabolize cystine and thereby form cysteine persulfide, which upon reduction produces cysteine.

Comparability of Osteoporosis Treatment Groups Among Female Medicare Beneficiaries in the United States.

It is often difficult to obtain valid estimates of comparative treatment effectiveness and safety owing to differences across patient populations taking different medications in the real world. One approach for assessing comparability between treatment groups in effectiveness studies is to use negative control outcomes (NCOs). NCOs share similar sources of bias with the primary outcomes but have no plausible causal relationship to the treatment of interest. Observing differences in the risk of NCOs thus provides evidence for residual confounding between groups. This retrospective study assessed the comparability of postmenopausal women, treated with osteoporosis medications with various mechanisms of action such as denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor), zoledronic acid (bisphosphonate derivative), or oral bisphosphonates including alendronate. Administrative claims data were extracted from the US Centers for Medicare and Medicaid Services' Chronic Condition Warehouse database (May 2010-December 2016). Propensity scores were used to match denosumab patients 1:1 to comparators. Four nonfracture NCOs and three early fracture NCOs (before substantial biologic effects of treatment would be expected) were assessed over 1-year and 3-month follow-up periods, respectively. According to comparability decision rules established a priori, patients initiating denosumab were comparable to those initiating zoledronic acid or alendronate, irrespective of prior osteoporosis treatment experience. Among new users, new switchers, and in the historical fracture subgroup, no meaningful differences were observed in the cumulative incidence of the seven NCOs comparing denosumab to zoledronic acid. This empirical examination can assist in the selection of appropriate comparator groups for future comparability research using real-world data. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Combination of meta-analysis of QTL and GWAS to uncover the genetic architecture of seed yield and seed yield components in common bean.

Increasing seed yield in common bean could help to improve food security and reduce malnutrition globally due to the high nutritional quality of this crop. However, the complex genetic architecture and prevalent genotype by environment interactions for seed yield makes increasing genetic gains challenging. The aim of this study was to identify the most consistent genomic regions related with seed yield components and phenology reported in the last 20 years in common bean. A meta-analysis of quantitative trait locus (QTL) for seed yield components and phenology (MQTL-YC) was performed for 394 QTL reported in 21 independent studies under sufficient water and drought conditions. In total, 58 MQTL-YC over different genetic backgrounds and environments were identified, reducing threefold on average the confidence interval (CI) compared with the CI for the initial QTL. Furthermore, 40 MQTL-YC identified were co-located with 210 SNP peak positions reported via genome-wide association (GWAS), guiding the identification of candidate genes. Comparative genomics among these MQTL-YC with MQTL-YC reported in soybean and pea allowed the identification of 14 orthologous MQTL-YC shared across species. The integration of MQTL-YC, GWAS, and comparative genomics used in this study is useful to uncover and refine the most consistent genomic regions related with seed yield components for their use in plant breeding.