Convergent evolution of plant prickles by repeated gene co-option over deep time.

An enduring question in evolutionary biology concerns the degree to which episodes of convergent trait evolution depend on the same genetic programs, particularly over long timescales. In this work, we genetically dissected repeated origins and losses of prickles-sharp epidermal projections-that convergently evolved in numerous plant lineages. Mutations in a cytokinin hormone biosynthetic gene caused at least 16 independent losses of prickles in eggplants and wild relatives in the genus Solanum. Homologs underlie prickle formation across angiosperms that collectively diverged more than 150 million years ago, including rice and roses. By developing new Solanum genetic systems, we leveraged this discovery to eliminate prickles in a wild species and an indigenously foraged berry. Our findings implicate a shared hormone activation genetic program underlying evolutionarily widespread and recurrent instances of plant morphological innovation.

Quantum chemical package Jaguar: A survey of recent developments and unique features.

This paper is dedicated to the quantum chemical package Jaguar, which is commercial software developed and distributed by Schrödinger, Inc. We discuss Jaguar's scientific features that are relevant to chemical research as well as describe those aspects of the program that are pertinent to the user interface, the organization of the computer code, and its maintenance and testing. Among the scientific topics that feature prominently in this paper are the quantum chemical methods grounded in the pseudospectral approach. A number of multistep workflows dependent on Jaguar are covered: prediction of protonation equilibria in aqueous solutions (particularly calculations of tautomeric stability and pKa), reactivity predictions based on automated transition state search, assembly of Boltzmann-averaged spectra such as vibrational and electronic circular dichroism, as well as nuclear magnetic resonance. Discussed also are quantum chemical calculations that are oriented toward materials science applications, in particular, prediction of properties of optoelectronic materials and organic semiconductors, and molecular catalyst design. The topic of treatment of conformations inevitably comes up in real world research projects and is considered as part of all the workflows mentioned above. In addition, we examine the role of machine learning methods in quantum chemical calculations performed by Jaguar, from auxiliary functions that return the approximate calculation runtime in a user interface, to prediction of actual molecular properties. The current work is second in a series of reviews of Jaguar, the first having been published more than ten years ago. Thus, this paper serves as a rare milestone on the path that is being traversed by Jaguar's development in more than thirty years of its existence.

Evaluating acute nipple inversion, imaging findings and outcomes.

PURPOSE: Acute nipple inversion can be unsettling for patients and is sometimes associated with an underlying breast malignancy. It also poses a diagnostic challenge with lack of consensus management guidelines. This study reviewed institutional experience with new nipple inversion, including malignant association, imaging utilization, and outcomes, in an effort to improve management. METHODS: A multisite institutional retrospective review was conducted of all breast imaging reports from 1/2010 to 6/2022 mentioning nipple inversion as an indication or finding. Patients with new nipple inversion, defined as arising since the time of last breast imaging exam or if reported as new by the patient/provider, were included for analysis. Retroareolar imaging findings, BI-RADS assessments/recommendations, pathology obtained from percutaneous or excisional biopsies, and follow-up imaging and clinical exams were collated. Cases of chronic or stable nipple inversion were excluded. Descriptive statistics were performed. RESULTS: A total of 414 patients had new nipple inversion, 387/414 (93.5 %) with benign or negative results at initial imaging and 27/414 (6.5 %) with malignant lesions. Diagnostic mammography/ultrasound detected 25/27 (92.6 %) cancers (sensitivity 92.6 %, specificity 75.5 %, PPV 20.8 %, NPV 99.3 %). Of 62 breast MRI exams performed in patients with negative mammogram/ultrasound, no cancers were detected in the retroareolar space with 2 incidental malignant lesions discovered distant from the nipple. CONCLUSION: Diagnostic mammography/ultrasound is reliable in workups of acute nipple inversion, with a high sensitivity and NPV for excluding malignancy. Breast MRI and surgical referral should be reserved for patients with suspicious associated symptoms or clinical findings.

Identifying pathways of pharmaceutical exposure in a mesoconsumer marine fish.

Pharmaceutical uptake involves processes that vary across aquatic systems and biota. However, single studies examining multiple environmental compartments, microhabitats, biota, and exposure pathways in mesoconsumer fish are sparse. We investigated the pharmaceutical burden in bonefish (Albula vulpes), pathways of exposure, and estimated exposure to a human daily dose. To evaluate exposure pathways, the number and composition of pharmaceuticals across compartments and the bioconcentration in prey and bonefish were assessed. To evaluate bioaccumulation, we proposed the use of a field-derived bioaccumulation factor (fBAF), due to variability inherent to natural systems. Exposure to a human daily dose was based on bonefish daily energetic requirements and consumption rates using pharmaceutical concentrations in prey. Pharmaceutical number and concentration were highest in prey, followed by bonefish, water and sediment. Fifteen pharmaceuticals were detected in common among bonefish, prey, and water; all of which bioconcentrated in prey and bonefish, and four bioaccumulated in bonefish. The composition of detected pharmaceuticals was compartment specific, and prey were most similar to bonefish. Bonefish were exposed to a maximum of 1.2 % of a human daily dose via prey consumption. Results highlight the need for multicompartment assessments of exposure and consideration of prey along with water as a pathway of exposure.

Suicidal ideation among non-physician hospital system staff: Prevalence and workplace correlates.

BACKGROUND: Research suggests that healthcare workers are at greater risk for suicide than other occupations, but most published studies focus on physicians. This study examines the prevalence of suicidal ideation (SI) and associated occupational factors among a broad group of non-physician healthcare staff. METHODS: An anonymous online survey was sent to a random sample of 30 % of non-physician healthcare staff at a large urban healthcare system between September and November 2022. Weighted multivariable binary logistic regressions were conducted to determine the workplace and mental health factors associated with SI. RESULTS: The 1084 respondents included nurses, administrative staff, research staff, medical assistants, nurse practitioners, physician assistants, and other roles. Of the sample, 8.8 % endorsed having SI over the prior two weeks. Results of the regression indicated that, after adjusting for demographic factors, greater odds of SI were associated with physical violence experienced from a patient or visitor (odds ratio [OR] = 2.15, 95 % confidence interval [CI] = 1.06-4.37), lower perceived leadership support (OR = 0.95, 95 % CI = 0.92-0.98), and positive screening for depression (OR = 4.66, 95 % CI = 2.45-8.86). Exploratory analysis suggests that depression may be a mediating factor between workplace stressors and SI. LIMITATIONS: Limitations include the response rate, the use of a single item to assess SI, and the cross-sectional design. CONCLUSION: Findings suggest that workplace violence and leadership support are important occupational factors associated with SI among healthcare workers. Reducing and mitigating workplace violence, enhancing leadership support, and improving access to mental health care should be considered targets for interventions to decrease suicide risk in this population.

Are Middle- or Older-Aged Adults With a Spinal Cord Injury Engaging in Leisure-Time Physical Activity? A Systematic Review and Meta-Analysis.

Objectives: To investigate the amount of Leisure-Time Physical Activity (LTPA) that people over 45 years with a spinal cord injury (SCI) performed and to determine the frequency, duration, intensity, and modality of LTPA performed. Data Sources: We searched 5 major electronic databases (CINAHL, SCOPUS, EMBASE, MEDLINE, and PubMed) from inception to March 2023. Study Selection: Cross-sectional, longitudinal studies and control arm of controlled trials that assessed LTPA in participants over 45 years old, with a SCI. We included 19 studies in the review and 11 in the meta-analysis. Data Extraction: We followed the PRISMA checklist for Systematic Reviews. Two review authors independently assessed the risk of bias and extracted data on participants' demographics, injury characteristics, and LTPA participation of the included studies. Risk of bias was assessed using the Joanne Briggs Institute critical appraisal tool for cross-sectional studies. Any conflicts were resolved by a third author. Data Synthesis: We found considerable variability in LTPA participation in adults 45 years and older with SCI. An estimated 27%-64% of participants did not take part in any LTPA. A random effects meta-analysis model was completed for studies that reported total or moderate-to-heavy LTPA scores in minutes per week. Overall, participants (n=1675) engaged in 260 [205;329] (mean [95% CI]) mins/week of total LTPA. Those participating in moderate-heavy intensity LTPA (n=364) completed 173 [118; 255] (mean [95% CI]) mins/week. LTPA modalities included walking, wheeling, hand-cycling, basketball, and swimming, among others. Conclusions: While many older adults with SCI seem to be meeting the recommended weekly physical activity volume, many still remain sedentary. There was significant variation in reporting of frequency, intensity, and duration of LTPA and reporting on modality was limited. Because of differences in reporting, it was challenging to compare results across studies. Data constraints prevented subgroup analysis of LTPA disparities between paraplegia and tetraplegia.

Tuning the Size of TiO2-Supported Co Nanoparticle Fischer-Tropsch Catalysts Using Mn Additions.

Modifying traditional Co/TiO2-based Fischer-Tropsch (FT) catalysts with Mn promoters induces a selectivity shift from long-chain paraffins toward commercially desirable alcohols and olefins. In this work, we use in situ gas cell scanning transmission electron microscopy (STEM) with energy-dispersive X-ray spectroscopy (EDS) elemental mapping, and near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) to demonstrate how the elemental dispersion and chemical structure of the as-calcined materials evolve during the H2 activation heat treatment required for industrial CoMn/TiO2 FT catalysts. We find that Mn additions reduce both the mean Co particle diameter and the size distribution but that the Mn remains dispersed on the support after the activation step. Density functional theory calculations show that the slower surface diffusion of Mn is likely due to the lower number of energetically accessible sites for the Mn on the titania support and that favorable Co-Mn interactions likely cause greater dispersion and slower sintering of Co in the Mn-promoted catalyst. These mechanistic insights into how the introduction of Mn tunes the Co nanoparticle size can be applied to inform the design of future-supported nanoparticle catalysts for FT and other heterogeneous catalytic processes.

Elusive Protein-Glycosphingolipid Interactions Revealed by Membrane Anchor-Assisted Native Mass Spectrometry.

Interactions between glycan-binding proteins (GBPs) and glycosphingolipids (GSLs) present in cell membranes are implicated in a wide range of biological processes. However, studying GSL binding is hindered by the paucity of purified GSLs and the weak affinities typical of monovalent GBP-GSL interactions. Native mass spectrometry (nMS) performed using soluble model membranes is a promising approach for the discovery of GBP ligands, but the detection of weak interactions remains challenging. The present work introduces MEmbrane ANchor-assisted nMS (MEAN-nMS) for the detection of low-affinity GBP-GSL complexes. The assay utilizes a membrane anchor, produced by covalent cross-linking of the GBP and a lipid in the membrane, to localize the GBP on the surface and promote GSL binding. Ligands are identified by nMS detection of intact GBP-GSL complexes (MEAN-nMS) or using a catch-and-release (CaR) strategy, wherein GSLs are released from GBP-GSL complexes upon collisional activation and detected (MEAN-CaR-nMS). To establish reliability, a library of purified gangliosides incorporated into nanodiscs was screened against human immune lectins, and the results compared with affinities of the corresponding ganglioside oligosaccharides. Without a membrane anchor, nMS analysis yielded predominantly false negatives. In contrast, all ligands were identified by MEAN-(CaR)-nMS, with no false positives. To highlight the potential of MEAN-CaR-nMS for ligand discovery, a natural library of GSLs was incorporated into nanodiscs and screened against human and viral proteins to uncover elusive ligands. Finally, nMS-based detection of GSL ligands directly from cells is demonstrated. This breakthrough paves the way for shotgun glycomics screening using intact cells.

Aversive memories can be weakened during human sleep via the reactivation of positive interfering memories.

Recollecting painful or traumatic experiences can be deeply troubling. Sleep may offer an opportunity to reduce such suffering. We developed a procedure to weaken older aversive memories by reactivating newer positive memories during sleep. Participants viewed 48 nonsense words each paired with a unique aversive image, followed by an overnight sleep. In the next evening, participants learned associations between half of the words and additional positive images, creating interference. During the following non-rapid-eye-movement sleep, auditory memory cues were unobtrusively delivered. Upon waking, presenting cues associated with both aversive and positive images during sleep, as opposed to not presenting cues, weakened aversive memory recall while increasing positive memory intrusions. Substantiating these memory benefits, computational modeling revealed that cueing facilitated evidence accumulation toward positive affect judgments. Moreover, cue-elicited theta brain rhythms during sleep predominantly predicted the recall of positive memories. A noninvasive sleep intervention can thus modify aversive recollection and affective responses.

Modifiable and Non-Modifiable Risk Factors for Dementia Among Non-Hispanic White and Black Populations Aged 50-64 in the United States, 2006-2016.

BACKGROUND AND OBJECTIVES: Non-Hispanic Black populations (NHB) have a significantly higher prevalence of dementia than non-Hispanic Whites in the U.S., and the underlying risk factors may play a role in this racial disparity. We aimed to calculate risk scores for dementia among non-Hispanic White (NHW) and non-Hispanic Black populations aged 50-64 years over a period of 10 years, and to estimate potential differences of scores between NHW and NHB. RESEARCH DESIGN AND METHODS: The Health and Retirement Study from 2006 to 2016 was used to calculate the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score, a validated score for predicting dementia risk. Weighted average CAIDE score, as well as CAIDE score for modifiable factors hypertension, obese, hypercholesterolemia, physical inactivity), and non-modifiable factors (age, sex, education) were calculated for adults aged 50-64 years with normal cognition for 2006-2008, 2010-2012, 2014-2016. The associations of race with CAIDE score and elevated CAIDE score were examined. RESULTS: A total of 10,871 participants were included in the analysis. The CAIDE score showed declining trends for NHB from 2006 to 2016, while NHB consistently had a higher total CAIDE score and CAIDE score for modifiable factors from 2006 to 2016, but not for non-modifiable factors. DISCUSSION AND IMPLICATIONS: NHB had a higher level of dementia risk factors than NHW among adults aged 50-64 years in the U.S. from 2006 to 2016, and the difference is attributable to modifiable risk factors, which holds promise for risk reduction of dementia.

Corrigendum: Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

[This corrects the article DOI: 10.3389/pore.2024.1611735.].

Choline-deficient high-fat diet-induced MASH in Göttingen Minipigs: Characterisation and effects of a chow reversal period.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) is increasing, and translational animal models are needed to develop novel treatments for this disease. The physiology and metabolism of pigs have a relatively high resemblance to humans, and the present study aimed to characterise choline-deficient, and high-fat diet (CDAHFD) fed Göttingen Minipigs as a novel animal model of MASLD/MASH. Göttingen Minipigs were fed CDAHFD for up to 5 months, and the phenotype was investigated by analysis of plasma parameters and repeated collection of liver biopsies. Furthermore, changes in hepatic gene expression during the experiment were explored by RNA sequencing. For a subset of the minipigs, the diet was changed from CDAHFD back to chow to investigate if the liver pathology was reversible. Göttingen Minipigs on CDAHFD gained bodyweight, and plasma levels of cholesterol, AST, ALT, ALP and GGT were increased. CDAHFD-fed minipigs developed hepatic steatosis, inflammation, and fibrosis, which in 5 of 16 animals progressed to cirrhosis. During an 11-week chow reversal period, steatosis regressed while fibrosis persisted. Regarding inflammation, the findings were less clear, depending on the type of readout. MASH Human Proximity Scoring (combined evaluation of transcriptional, phenotypic and histopathological parameters) showed that CDAHFD-fed Göttingen Minipigs resemble human MASLD/MASH better than most rodent models. In conclusion, CDAHFD-fed minipigs develop a MASH-like phenotype which in several aspects resemble the changes observed in human patients with MASLD/MASH. Furthermore, repeated collection of liver biopsies allow detailed characterisation of histopathological changes over time in individual animals.

Clinical Characteristics, Outcomes, and Interobserver Agreement of Point-of-Care Ultrasound Detected Mesenteric Adenitis in Nonsurgical Pediatric Abdominal Pain: A Retrospective Cohort Study.

OBJECTIVES: Point-of-care ultrasound (PoCUS) in the emergency department (ED) may facilitate the diagnosis of nonsurgical sources of abdominal pain after surgical causes are excluded. Identifying mesenteric adenitis is a feasible PoCUS application due to its ease of use and speed. However, there are scant data regarding the diagnosis of mesenteric adenitis by PoCUS. The objective of this study was to describe the clinical characteristics, outcomes, and interobserver agreement of mesenteric adenitis identified on PoCUS in pediatric patients with nonsurgical abdominal pain. METHODS: This was a retrospective review at a tertiary-care, urban pediatric ED. All cases of mesenteric adenitis diagnosed on PoCUS from January 2018 to August 2022 were reviewed. Demographics and clinical data, including relevant outcomes, were recorded. All PoCUS videos were reviewed by a senior sonologist-physician for determination of mesenteric adenitis in children 21 years and younger with nonsurgical abdominal pain. Interobserver agreement by Cohen κ was calculated between experienced and novice physician sonologists blinded to diagnosis, who reviewed 77 six-second video clips for presence or absence of mesenteric adenitis. RESULTS: Thirty-three subjects were identified by PoCUS to have mesenteric adenitis in the setting of nonsurgical abdominal pain presenting to our ED. Most common indications for PoCUS were for suspected appendicitis, suspected intussusception, or undifferentiated abdominal pain. Forty-six percent of patients were male; median age was 9 years (interquartile range, 4-14 years). On 4-week clinical follow-up, 1 patient returned to our ED with a surgical abdomen. Cohen κ values were 0.83 (95% confidence interval, 0.70-0.97) between experienced sonologist-physicians and 0.76 (95% confidence interval, 0.61-.90) between novice and experienced sonologist-physicians. CONCLUSIONS: PoCUS can identify mesenteric adenitis, typically a diagnosis of exclusion, in pediatric patients with nonsurgical abdominal pain, both by novice and experienced physician-sonologists. Use of PoCUS may help ED clinicians identify a common cause of nonsurgical abdominal pain in children.

The crystal structure of Shethna protein II (FeSII) from Azotobacter vinelandii suggests a domain swap.

The Azotobacter vinelandii FeSII protein forms an oxygen-resistant complex with the nitrogenase MoFe and Fe proteins. FeSII is an adrenodoxin-type ferredoxin that forms a dimer in solution. Previously, the crystal structure was solved [Schlesier et al. (2016), J. Am. Chem. Soc. 138, 239-247] with five copies in the asymmetric unit. One copy is a normal adrenodoxin domain that forms a dimer with its crystallographic symmetry mate. The other four copies are in an `open' conformation with a loop flipped out exposing the 2Fe-2S cluster. The open and closed conformations were interpreted as oxidized and reduced, respectively, and the large conformational change in the open configuration allowed binding to nitrogenase. Here, the structure of FeSII was independently solved in the same crystal form. The positioning of the atoms in the unit cell is similar to the earlier report. However, the interpretation of the structure is different. The `open' conformation is interpreted as the product of a crystallization-induced domain swap. The 2Fe-2S cluster is not exposed to solvent, but in the crystal its interacting helix is replaced by the same helix residues from a crystal symmetry mate. The domain swap is complicated, as it is unusual in being in the middle of the protein rather than at a terminus, and it creates arrangements of molecules that can be interpreted in multiple ways. It is also cautioned that crystal structures should be interpreted in terms of the contents of the entire crystal rather than of one asymmetric unit.

Lipoprotein(a) and Calcific Aortic Valve Stenosis Progression: A Systematic Review and Meta-Analysis.

Importance: There are currently no pharmacological treatments available to slow hemodynamic progression of aortic stenosis. Plasma lipoprotein(a) concentrations predict incident aortic stenosis but its association with hemodynamic progression is controversial. Objective: To determine the association between plasma lipoprotein(a) concentrations and hemodynamic progression in patients with aortic stenosis. Design, Settings and Participants: The study included patients with aortic stenosis from 5 longitudinal clinical studies conducted from March 2001 to March 2023 in Canada and the UK. Of 757 total patients, data on plasma lipoprotein(a) concentrations and rates of hemodynamic progression assessed by echocardiography were available for 710, who were included in this analysis. Data were analyzed from March 2023 to April 2024. Exposure: Cohort-specific plasma lipoprotein(a) concentration tertiles. Main Outcomes and Measures: Hemodynamic aortic stenosis progression on echocardiography as assessed by annualized change in peak aortic jet velocity, mean transvalvular gradient, and aortic valve area. Results: Among the included patients, 497 (70%) were male and 213 (30%) were female. The mean (SD) age was 65.2 (13.1) years. Patients in the top lipoprotein(a) tertile demonstrated 41% (estimate, 1.41; 95% CI, 1.13-1.75) faster progression of peak aortic jet velocity and 57% (estimate, 1.57; 95% CI, 1.18-2.10) faster progression of mean transvalvular gradient than patients in the bottom tertile. There was no evidence of heterogeneity across the individual cohorts. Progression of aortic valve area was comparable between groups (estimate, 1.23; 95% CI, 0.71-2.12). Similar results were observed when plasma lipoprotein(a) concentrations were treated as a continuous variable. Conclusions and Relevance: In this study, higher plasma lipoprotein(a) concentrations were associated with faster rates of hemodynamic progression in patients with aortic stenosis. Lowering plasma lipoprotein(a) concentrations warrants further investigation in the prevention and treatment of aortic stenosis.

Leisure-Time Physical Activity Participation in Middle-Aged and Older Adults With a Spinal Cord Injury in Australia.

Objectives: Adults with spinal cord injury (SCI) are often sedentary, increasing their risk of cardiometabolic diseases. Leisure-time Physical Activity (LTPA) is physical activity completed during recreation time for enjoyment. We aimed to quantify LTPA in people ≥45 years with SCI and to explore its relationship with participants' characteristics. Methods: This is a secondary analysis on a subset of the Australian International SCI Survey in participants ≥45 years, at least 12 months post-injury. We described levels of LTPA and used multivariable regressions to estimate the associations between participant characteristics and LTPA. Results: Of 1,281 participants (mean age: 62.7 years, mean time since injury: 18.7 years; 74% males) 44% reported no participation in LTPA. The average LTPA participation was 197 (SD 352) minutes per week (median: 50). Females (ß = -62.3, 95% CI [-112.9, -11.7]), and participants with non-traumatic injuries (ß = -105.2, 95% CI [-165.9, -44.6]) performed less LTPA. Time since injury was not associated with moderate-to-heavy LTPA (LR: Probability > F = 0.785). Conclusion: LTPA promotion in the SCI population ≥45 years focusing on females and non-traumatic injuries is warranted.

Hypothesis: the generation of T cells directed against neoepitopes employing immune-mediating agents other than neoepitope vaccines.

The development of vaccines, especially RNA-based, directed against patient-specific tumor neoepitopes is an active and productive area of cancer immunotherapy. Promising clinical results in melanoma and other solid tumor types are emerging. As with all cancer therapy modalities, neoepitope vaccine development and delivery also has some drawbacks, including the level of effort to develop a patient-specific product, accuracy of algorithms to predict neoepitopes, and with the exception of melanoma and some other tumor types, biopsies of metastatic lesions of solid tumors are often not available. We hypothesize that in some circumstances the use of rationally designed combinations of "off-the-shelf" agents may prove an additional path to enable the patient to produce his/her own "neoepitope vaccine" in situ. These combination therapies may consist of agents to activate a tumor-associated T-cell response, potentiate that response, reduce or eliminate immunosuppressive entities in the tumor microenvironment, and/or alter the phenotype of tumor cells to render them more susceptible to immune-mediated lysis. Examples are provided in both preclinical and clinical studies in which combinations of "off-the-shelf" agents lead to the generation of T cells directed against tumor-derived neoepitopes with consequent antitumor activity.

External skeletal fixation for the treatment of pelvic fractures in cats.

OBJECTIVE: To report the technique and the outcome for the repair of pelvic fractures in cats using external skeletal fixation (ESF). STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned cats (n = 125). METHODS: Medical records of cats with pelvic fractures, treated with an ESF between June 2001 and June 2009, were reviewed. Preoperative, immediate postoperative, and more than 4 weeks' postoperative radiographs were compared. Clinical examination was performed 4 to 9 weeks following surgery. Longer term follow up (4 to 80 months) was conducted by client questionnaire. RESULTS: No intraoperative complications occurred. There was no change in the pelvic canal width observed on follow-up radiographs (p = .16). Implant loosening was noted on follow-up radiographs in 16/125 (13%) of cases, and 67/803 (8%) pins were palpably loose at the time of frame removal. The mean time to frame removal was 37 ± 9 days. No long-term complications were reported. Long-term mean mobility score was 95 ± 5 and median lameness was 0 (range: 0-2). CONCLUSION: An ESF may be successfully applied for the stabilization of various pelvic fractures in cats. CLINICAL SIGNIFICANCE: The application of an ESF for the management of pelvic fractures in cats provides good outcomes.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.