Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNß), would stimulate antitumor immunity and delay CRPC. METHODS: We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2'3'-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT. RESULTS: TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-ß), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-ß selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNß. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs. CONCLUSION: Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.

A Phase I Study to Determine the Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Capivasertib in Healthy Male Participants.

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 µg). After a 14­day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period (mean recovery: 95.1% [feces, 50.4%; urine, 44.7%]). Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. Significance Statement This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.

CO2 Laser Crystallization in Ambient for Highly Efficient FAPbI3 Perovskite Solar Cells.

Metal halide perovskite solar cells have achieved tremendous progress and have attracted enormous research and development efforts since the first report of demonstration in 2009. Due to fabrication versatility, many heat treatment methods can be utilized to achieve perovskite film crystallization. Herein, 10.6 µm carbon dioxide laser process is successfully developed for the first time for perovskite film crystallization. In addition, this is the first time formamidinium lead triiodide solar cells by laser annealing under ambient are demonstrated. The champion cell produces a power conversion efficiency of 21.8%, the highest for laser-annealed perovskite cells. And this is achieved without any additive, passivation, or post-treatment.

Influence of social determinants of health and adversity on computerized neurocognitive assessment.

Introduction: Social determinants of health and adversity, including poverty, maltreatment, and neighborhood deprivation, are individual-level factors that may significantly affect baseline neurocognitive testing and management that have yet to be thoroughly explored within the computerized neurocognitive assessment.Objectives: Examine individual-level experiences of poverty, abuse, neighborhood deprivation, and social mobility on computerized cognitive testing.Methods: The sample included 3,845 student-athletes who completed a baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and were enrolled in the Child-Household Integrated Longitudinal Data database. Multivariable linear regressions were used to assess independent variables of Supplemental Nutrition Assistance Program enrollment, abuse or neglect cases, Area Deprivation Index scores, and other demographic factors on four baseline ImPACT composite scores: verbal and visual memory, visuomotor, and reaction time.Results: Individual-level factors of persistent poverty and neighborhood deprivation were associated with lower composite scores; however, upward social mobility was not significantly associated with cognitive performance. The effects of mother's race on computerized cognitive testing performance were attenuated when accounting for measures of adversity.Conclusion: Findings highlight the importance of social determinants of health in computerized neurocognitive testing to ensure more culturally sensitive and precise understanding of athletic baselines.

Elevated Autoantibodies to the GluA1 Subunit of the AMPA Receptor in Blood Indicate Risk of Cognitive Impairment in Contact Sports Athletes, Irrespective of Concussion.

To address the need for objective tests of concussion in athletes, we conducted a prospective clinical study in National Collegiate Athletic Association athletes of the relationship between neurocognitive performance and blood levels of the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor peptides and autoantibodies to GluA1. Specifically, we compared 44 contact sport athletes to 16 noncontact sport athletes, with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), as well as blood sample collection, before the start of the season and at the end of the season. Contact sport athletes exhibited significantly elevated serum GluA1 autoantibodies at the end of season, compared with preseason levels, irrespective of whether they sustained a concussion. Noncontact sport athletes showed no change in serum GluA1 autoantibodies, and neither group showed differences in GluA1 peptides. Amongst contact-sport athletes, the 'high GluA1 autoantibody group' (≥4 ng/mL) displayed impaired reaction time, a measure of cognitive impairment, while the 'low GluA1 autoantibody group' (<4 ng/mL) displayed normal reaction time. Our results reveal that contact sport athletes are at risk for developing cognitive impairment even without sustaining a diagnosed concussion and that serum GluA1 autoantibodies provide a blood-based biomarker of this risk. This could guide future studies on the differing susceptibility to cognitive impairment in contact sport athletes and facilitate efficient allocation of resources to contact sport athletes identified as having increased risk of developing cognitive impairment.

Topping-Off a Long Thoracic Stabilization With Semi-Rigid Constructs May Have Favorable Biomechanical Effects to Prevent Proximal Junctional Kyphosis: A Biomechanical Comparison.

STUDY DESIGN: In-vitro cadaveric biomechanical study. OBJECTIVES: Long posterior spinal fusion is a standard treatment for adult spinal deformity. However, these rigid constructs are known to alter motion and stress to the adjacent non-instrumented vertebrae, increasing the risk of proximal junctional kyphosis (PJK). This study aimed to biomechanically compare a standard rigid construct vs constructs "topped off" with a semi-rigid construct. By understanding semi-rigid constructs' effect on motion and overall construct stiffness, surgeons and researchers could better optimize fusion constructs to potentially decrease the risk of PJK and the need for revision surgery. METHODS: Nine human cadaveric spines (T1-T12) underwent non-destructive biomechanical range of motion tests in pure bending or torsion and were instrumented with an all-pedicle-screw (APS) construct from T6-T9. The specimens were sequentially instrumented with semi-rigid constructs at T5: (i) APS plus sublaminar bands; (ii) APS plus supralaminar hooks; (iii) APS plus transverse process hooks; and (iv) APS plus short pedicle screws. RESULTS: APS plus transverse process hooks had a range of motion (ie, relative angle) for T4-T5 and T5-T6, as well as an overall mechanical stiffness for T1-T12, that was more favourable, as it reduced motion at adjacent levels without a stark increase in stiffness. Moreover, APS plus transverse process hooks had the most linear change for range of motion across the entire T3-T7 range. CONCLUSIONS: Present findings suggest that APS plus transverse process hooks has a favourable biomechanical effect that may reduce PJK for long spinal fusions compared to the other constructs examined.

Piperidine and Pyridine Series Lead-Free Dion-Jacobson Phase Tin Perovskite Single Crystals and Their Applications for Field-Effect Transistors.

Two-dimensional (2D) organic-inorganic metal halide perovskites have gained immense attention as alternatives to three-dimensional (3D) perovskites in recent years. The hydrophobic spacers in the layered structure of 2D perovskites make them more moisture-resistant than 3D perovskites. Moreover, they exhibit unique anisotropic electrical transport properties due to a structural confinement effect. In this study, four lead-free Dion-Jacobson (DJ) Sn-based phase perovskite single crystals, 3AMPSnI4, 4AMPSnI4, 3AMPYSnI4, and 4AMPYSnI4 [AMP = (aminomethyl)-piperidinium, AMPY = (aminomethyl)pyridinium] are reported. Results reveal structural differences between them impacting the resulting optical properties. Namely, higher octahedron distortion results in a higher absorption edge. Density functional theory (DFT) is also performed to determine the trends in energy band diagrams, exciton binding energies, and formation energies due to structural differences among the four single crystals. Finally, a field-effect transistor (FET) based on 4AMPSnI4 is demonstrated with a respectable hole mobility of 0.57 cm2 V-1 s-1 requiring a low threshold voltage of only -2.5 V at a drain voltage of -40 V. To the best of our knowledge, this is the third DJ-phase perovskite FET reported to date.

Factors associated with increased length of stay in degenerative cervical spine surgery: a cohort analysis from the Canadian Spine Outcomes and Research Network.

OBJECTIVE: Postoperative length of stay (LOS) significantly contributes to healthcare costs and resource utilization. The primary goal of this study was to identify patient, clinical, surgical, and institutional variables that influence LOS after elective surgery for degenerative conditions of the cervical spine. The secondary objectives were to examine the variability in LOS and institutional practices used to decrease LOS. METHODS: This was a multicenter observational retrospective cohort study of patients enrolled in the Canadian Spine Outcomes and Research Network (CSORN) between January 2015 and October 2020 who underwent elective anterior cervical discectomy and fusion (ACDF) (1-3 levels) or posterior cervical fusion (PCF) (between C2 and T2) with/without decompression for degenerative conditions of the cervical spine. Prolonged LOS was defined as LOS greater than the median for the ACDF and PCF populations. The principal investigators at each participating CSORN healthcare institution completed a survey to capture institutional practices implemented to reduce postoperative LOS. RESULTS: In total, 1228 patients were included (729 ACDF and 499 PCF patients). The median (IQR) LOS for ACDF and PCF were 1.0 (1.0) day and 5.0 (4.0) days, respectively. Predictors of prolonged LOS after ACDF were female sex, myelopathy diagnosis, lower baseline SF-12 mental component summary score, multilevel ACDF, and perioperative adverse events (AEs) (p < 0.05). Predictors of prolonged LOS after PCF were nonsmoking status, education less than high school, lower baseline numeric rating scale score for neck pain and EQ5D score, higher baseline Neck Disability Index score, and perioperative AEs (p < 0.05). Myelopathy did not significantly predict prolonged LOS within the PCF cohort after multivariate analysis. Of the 8 institutions (57.1%) with an enhanced recovery after surgery (ERAS) protocol or standardized protocol, only 3 reported using an ERAS protocol specific to patients undergoing ACDF or PCF. CONCLUSIONS: Patient and clinical factors predictive of prolonged LOS after ACDF and PCF are highly variable, warranting individual consideration for possible mitigation. Perioperative AEs remained a consistent independent predictor of prolonged LOS in both cohorts, highlighting the importance of preventing intra- and postoperative complications.

Pre-operative expectations of patients with degenerative cervical myelopathy: an observational study from the Canadian Spine Outcomes and Research Network.

BACKGROUND: Despite an abundance of literature on degenerative cervical myelopathy (DCM), little is known about pre-operative expectations of these patients. PURPOSE: The primary objective was to describe patient pre-operative expectations. Secondary objectives included identifying patient characteristics associated with high pre-operative expectations and to determine if expectations varied depending on myelopathy severity. STUDY DESIGN: This was a retrospective study of a prospective multicenter, observational cohort of patients with DCM. PATIENT SAMPLE: Patients who consented to undergo surgical treatment between January 2019 and September 2022 were included. OUTCOMES MEASURES: An 11-domain expectation questionnaire was completed pre-operatively whereby patients quantified the expected change in each domain. METHODS: The most important expected change was captured. A standardized expectation score was calculated as the sum of each expectation divided by the maximal possible score. The high expectation group was defined by patients who had an expectation score above the 75th percentile. Predictors of patients with high expectations were determined using multivariable logistic regression models. RESULTS: There were 262 patients included. The most important patient expectation was preventing neurological worsening (40.8%) followed by improving balance when standing or walking (14.5%), improving independence in everyday activities (10.3%), and relieving arm tingling, burning and numbness (10%). Patients with mild myelopathy were more likely to select no worsening as the most important expected change compared to patients with severe myelopathy (p<.01). Predictors of high patient expectations were: having fewer comorbidities (OR -0.30 for every added comorbidity, 95% CI -0.59 to -0.10, p=.01), a shorter duration of symptoms (OR 0.92, 95% CI 0.35-1.19, p=.02), no contribution from "failure of other treatments" on the decision to undergo surgery (OR 1.49, 95% CI 0.56-2.71, p=.02) and more severe neck pain (OR 0.19 for 1 point increase, 95% CI 0.05-0.37, p=.01). CONCLUSIONS: Most patients undergoing surgery for DCM expect prevention of neurological decline, better functional status, and improvement in their myelopathic symptoms. Stopping neurological deterioration is the most important expected outcomes by patients.

Effects of sex and hydration status on kappa opioid receptor-mediated diuresis in rats.

Understanding the function of the kappa opioid receptor (KOP) is crucial for the development of novel therapeutic interventions that target KOP for the treatment of pain, stress-related disorders and other indications. Activation of KOP produces diuretic effects in rodents and man. Sex is a vital factor to consider when assessing drug response in pre-clinical and clinical studies. In this study, the diuretic effect of the KOP agonist, U50488 (1-10 mg/kg), was investigated in both adult female and male Wistar rats that were either normally hydrated or water-loaded. The KOP antagonist norbinaltorphimine (norBNI, 10 mg/kg) was administered 24 h prior to U50488 to confirm the involvement of KOP. U50488 elicited a significant diuretic response at doses ≥ 3 mg/kg in both female and male rats independent of hydration status. U50488 diuretic effects were inhibited by norBNI pre-administration. Water-loading reduced data variability for urine volume in males, but not in females, compared with normally hydrated rats. Sex differences were also evident in U50488 eliciting a significant increase in sodium and potassium ion excretion only in males. This may suggest different mechanisms of U50488 diuretic action in males where renal excretion mechanisms are directly affected more than in females.

The Effects of Peri-Operative Adverse Events on Clinical and Patient-Reported Outcomes After Surgery for Degenerative Cervical Myelopathy: An Observational Cohort Study from the Canadian Spine Outcomes and Research Network.

BACKGROUND AND OBJECTIVES: There is a lack of data examining the effects of perioperative adverse events (AEs) on long-term outcomes for patients undergoing surgery for degenerative cervical myelopathy. We aimed to investigate associations between the occurrence of perioperative AEs and coprimary outcomes: (1) modified Japanese Orthopaedic Association (mJOA) score and (2) Neck Disability Index (NDI) score. METHODS: We analyzed data from 800 patients prospectively enrolled in the Canadian Spine Outcomes and Research Network multicenter observational study. The Spine AEs Severity system was used to collect intraoperative and postoperative AEs. Patients were assessed at up to 2 years after surgery using the NDI and the mJOA scale. We used a linear mixed-effect regression to assess the influence of AEs on longitudinal outcome measures as well as multivariable logistic regression to assess factors associated with meeting minimal clinically important difference (MCID) thresholds at 1 year. RESULTS: There were 167 (20.9%) patients with minor AEs and 36 (4.5%) patients with major AEs. The occurrence of major AEs was associated with an average increase in NDI of 6.8 points (95% CI: 1.1-12.4, P = .019) and reduction of 1.5 points for mJOA scores (95% CI: -2.3 to -0.8, P < .001) up to 2 years after surgery. Occurrence of major AEs reduced the odds of patients achieving MCID targets at 1 year after surgery for mJOA (odds ratio 0.23, 95% CI: 0.086-0.53, P = .001) and for NDI (odds ratio 0.34, 95% CI: 0.11-0.84, P = .032). CONCLUSION: Major AEs were associated with reduced functional gains and worse recovery trajectories for patients undergoing surgery for degenerative cervical myelopathy. Occurrence of major AEs reduced the probability of achieving mJOA and NDI MCID thresholds at 1 year. Both minor and major AEs significantly increased health resource utilization by reducing the proportion of discharges home and increasing length of stay.

FABRICATION OF MULTILUMEN MICROFLUIDIC TUBING FOR EX SITU DIRECT LASER WRITING.

Among the numerous additive manufacturing or "three-dimensional (3D) printing" techniques, two-photon Direct Laser Writing (DLW) is distinctively suited for applications that demand high geometric versatility with micron-to-submicron-scale feature resolutions. Recently, "ex situ DLW (esDLW)" has emerged as a powerful approach for printing 3D microfluidic structures directly atop meso/macroscale fluidic tubing that can be manipulated by hand; however, difficulties in creating custom esDLW-compatible multilumen tubing at such scales has hindered progress. To address this impediment, here we introduce a novel methodology for fabricating submillimeter multilumen tubing for esDLW 3D printing. Preliminary fabrication results demonstrate the utility of the presented strategy for resolving 743 µm-in-diameter tubing with three lumens-each with an inner diameter (ID) of 80 µm. Experimental results not only revealed independent flow of discrete fluorescently labelled fluids through each of the three lumens, but also effective esDLW-printing of a demonstrative 3D "MEMS" microstructure atop the tubing. These results suggest that the presented approach could offer a promising pathway to enable geometrically sophisticated microfluidic systems to be 3D printed with input and/or output ports fully sealed to multiple, distinct lumens of fluidic tubing for emerging applications in fields ranging from drug delivery and medical diagnostics to soft surgical robotics.

Synthesis of Stable Isotope, Tritiated, and Carbon-14 Labeled Balcinrenone.

As part of a medicinal chemistry program aimed at discovering a mineralocorticoid receptor modulator for treatment of kidney and cardiovascular indications, multiple labeled versions of the lead compound, balcinrenone (AZD9977), were prepared. Four stable isotope labeled versions of the compound were prepared for clinical bioanalysis and biological investigations. Three of these stable isotope labeled compounds were tritiated as well as the parent for biology applications and DMPK investigations. They were prepared using a standard iodination-tritiodehalogentation approach. Finally, AZD9977 was prepared in carbon-14 labeled form for preclinical and clinical applications.

Differences in the surgical management of degenerative lumbar spondylolisthesis based on self-reported sex: analysis of the CSORN prospective DLS study.

OBJECTIVE: Surgical treatment of degenerative lumbar spondylolisthesis (DLS) reliably improves patient-reported quality of life; however, patient population heterogeneity, in addition to other factors, ensures ongoing equipoise in choosing the ideal surgical treatment. Surgeon preference for fusion or decompression alone influences surgical treatment decision-making. Meanwhile, at presentation, patient-reported outcome measures (PROMs) differ considerably between females and males. The aims of this study were to determine whether there exists a difference in the rates of decompression and fusion versus decompression alone based on patient-reported sex, and to determine if widely accepted indications for fusion justify any observed differences or if surgeon preference plays a role. METHODS: This study is a retrospective cohort analysis of patients enrolled in the Canadian Spine Outcomes Research Network (CSORN) DLS study, a multicentered Canadian prospective study, investigating the surgical management and outcome of DLS. Decompression and fusion rates, patient characteristics, preoperative PROMs, and radiographic measures were compared between males and females before and after propensity score matching. RESULTS: In the unmatched cohort, female patients were more likely to undergo decompression and fusion than male patients. Females were more likely to have the recognized indications for fusion, including kyphotic disc angle, higher spondylolisthesis grade and slip percentage, and patient-reported back pain. Other radiographic findings associated with the decision to fuse, including facet effusion, facet distraction, or facet angle, were not more prevalent in females. After propensity score matching for demographic and radiographic characteristics, similar proportions of male and female patients underwent decompression and fusion and decompression alone. CONCLUSIONS: Although it remains unclear who should or should not undergo fusion, in addition to surgical decompression of DLS, female patients undergo fusion at a higher rate than their male counterparts. After matching baseline radiographic factors indicating fusion, this analysis showed that the decision to fuse was not biased by sex differences. Rather, the higher proportion of females undergoing fusion is largely explained by the radiographic and clinical indications for fusion, suggesting that specific clinical and anatomical features of this condition are indeed different between sexes.

Magnetic resonance - guided treatment of low-flow vascular malformations and the technologies to potentiate adoption.

Vascular malformations are congenital, non-neoplastic lesions that arise secondary to defects in angiogenesis. Vascular malformations are divided into high-flow (arteriovenous malformation) and low-flow (venous malformations and lymphatic malformations). Magnetic resonance imaging (MRI) is the standard for pre-and post-intervention assessments, while ultrasound (US), X-ray fluoroscopy and computed tomography (CT) are used for intra-procedural guidance. Sclerotherapy, an image-guided therapy that involves the injection of a sclerosant directly into the malformation, is typically the first-line therapy for treating low-flow vascular malformations. Sclerotherapy induces endothelial damage and necrosis/fibrosis with eventual involution of the malformation. Image-guided thermal therapies involve freezing or heating target tissue to induce cell death and necrosis. MRI is an alternative for intra-procedural guidance and monitoring during the treatment of vascular malformations. MR can provide dynamic, multiplanar imaging that delineates surrounding critical structures such as nerves and vasculature. Multiple studies have demonstrated that MR-guided treatment of vascular malformations is safe and effective. This review will detail (1) the use of MR for the classification and diagnosis of vascular malformations, (2) the current literature surrounding MR-guided treatment of vascular malformations, (3) a series of cases of MR-guided sclerotherapy and thermal ablation for the treatment of vascular malformations, and (4) a discussion of technologies that may potentiate interventional MRI adoption including high intensity focused ultrasound and guided laser ablation.

Parrot Dietary Habits and Consumption of Alternate Foodstuffs.

Inappropriate diets cause many of the health problems commonly reported in parrots by psittaculturists and veterinarians. The dietary management of captive parrots would benefit from information derived from studies of dietary habits of wild parrots; however, it is unclear how complete this body of knowledge is at this time. Documentation of parrots' dietary habits appears to have grown dramatically over the past century. Reports of parrots consuming a number of foodstuffs beyond the reproductive parts of plants (alternate foodstuffs) have increased. The extent of alternate foodstuffs in parrot diets is currently unknown. We used Google search engines (ie, Scholar, Videos, Images) to determine how well psittaciform dietary habits have been studied to date and to quantify reports of alternate foodstuffs consumption among genera of Psittaciformes. We found that the dietary habits of over 43% of parrot species are poorly resolved. The dietary habits of 71.5% of parrot species classified by the International Union for Conservation of Nature as at risk of extinction are not well resolved. Parrots' consumption of alternate foodstuffs occurred at the following rates at the genus level: 91.2% foliage, 76.9% terrestrial invertebrates and fine earthen materials, 74.7% wood, 44% pure minerals, 34.1% vertebrates (9.9% dung), 29.7% sap, 19.8% roots, 17.6% charcoal, 18.7% epiphytes, 16.5% coarse earthen materials, 8.8% algae, and 6.6% aquatic invertebrates. Of these reports, 79.1% involved observations of wild parrots. Many parrot species may be more omnivorous than previously realized. Alternate foodstuffs are generally absent from current veterinary-based dietary recommendations for captive parrots. Future studies are needed to determine whether providing alternate foodstuffs to captive parrots can be used as a means to improve their diets and thus their health, welfare, and reproductive success.

Anterior vs Posterior Surgery for Patients With Degenerative Cervical Myelopathy: An Observational Study From the Canadian Spine Outcomes and Research Network.

BACKGROUND AND OBJECTIVES: The advantages and disadvantages of anterior vs posterior surgical approaches for patients with progressive degenerative cervical myelopathy (DCM) remain uncertain. Our primary objective was to evaluate patient-reported disability at 1 year after surgery. Our secondary objectives were to evaluate differences in patient profiles selected for each approach in routine clinical practice and to compare neurological function, neck and arm pain, health-related quality of life, adverse events, and rates of reoperations. METHODS: We analyzed data from patients with DCM who were enrolled in an ongoing multicenter prospective observational cohort study. We controlled for differences in baseline characteristics and numbers of spinal levels treated using multivariable logistic regression. Adverse events were collected according to the Spinal Adverse Events Severity protocol. RESULTS: Among 559 patients, 261 (47%) underwent anterior surgery while 298 (53%) underwent posterior surgery. Patients treated posteriorly had significantly worse DCM severity and a greater number of vertebral levels involved. After adjusting for confounders, there was no significant difference between approaches for odds of achieving the minimum clinically important difference for the Neck Disability Index (odds ratio 1.23, 95% CI 0.82 to 1.86, P = .31). There was also no significant difference for change in modified Japanese Orthopedic Association scores, and differences in neck and arm pain and health-related quality of life did not exceed minimum clinically important differences. Patients treated anteriorly experienced greater rates of dysphagia, whereas patients treated posteriorly experienced greater rates of wound complications, neurological complications, and reoperations. CONCLUSION: Patients selected for posterior surgery had worse DCM and a greater number of vertebral levels involved. Despite this, anterior and posterior surgeries were associated with similar improvements in disability, neurological function, pain, and quality of life. Anterior surgery had a more favorable profile of adverse events, which suggests it might be a preferred option when feasible.

Pim Kinase Inhibitors Increase Gilteritinib Cytotoxicity in FLT3-ITD Acute Myeloid Leukemia Through GSK-3ß Activation and c-Myc and Mcl-1 Proteasomal Degradation.

Acute myeloid leukemia (AML) with fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) has poor outcomes. FLT3-ITD drives constitutive and aberrant FLT3 signaling, activating STAT5 and upregulating the downstream oncogenic serine/threonine kinase Pim-1. FLT3 inhibitors are in clinical use, but with limited and transient efficacy. We previously showed that concurrent treatment with Pim and FLT3 inhibitors increases apoptosis induction in FLT3-ITD-expressing cells through posttranslational downregulation of Mcl-1. Here we further elucidate the mechanism of action of this dual targeting strategy. Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. Pim inhibitor and gilteritinib cotreatment increased apoptosis induction, produced synergistic cytotoxicity, downregulated c-Myc protein expression, earlier than Mcl-1, increased turnover of both proteins, which was rescued by proteasome inhibition, and increased efficacy and prolonged survival in an in vivo model. Gilteritinib and Pim inhibitor cotreatment of Ba/F3-ITD cells infected with T58A c-Myc or S159A Mcl-1 plasmids, preventing phosphorylation at these sites, did not downregulate these proteins, increase their turnover or increase apoptosis induction. Moreover, concurrent treatment with gilteritinib and Pim inhibitors dephosphorylated (activated) the serine/threonine kinase glycogen synthase kinase-3ß (GSK-3ß), and GSK-3ß inhibition prevented c-Myc and Mcl-1 downregulation and decreased apoptosis induction. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3ß as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3ß activation as a therapeutic strategy in FLT3-ITD AML. SIGNIFICANCE: FLT3-ITD is present in 25% of in AML, with continued poor outcomes. Combining Pim kinase inhibitors with the FDA-approved FLT3 inhibitor gilteritinib increases cytotoxicity in vitro and in vivo through activation of GSK-3ß, which phosphorylates and posttranslationally downregulates c-Myc and Mcl-1. The data support efficacy of GSK-3ß activation in FLT3-ITD AML, and also support development of a clinical trial combining the Pim inhibitor TP-3654 with gilteritinib.

Development of the cervical myelopathy severity index: a new patient reported outcome measure to quantify impairments and functional limitations.

BACKGROUND CONTEXT: Existing degenerative cervical myelopathy (DCM) severity scales have significant shortcomings, creating a strong impetus for the development of a practical measurement tool with sound psychometric properties. PURPOSE: This work reports the item generation and reduction of the Cervical Myelopathy Severity Index (CMSI), a new DCM patient-reported outcome measure of symptoms and functional limitations. DESIGN: Prospective observational study. PATIENT SAMPLE: Adult DCM patients belonging to one of three distinct treatment groups: (1) observation cohort, (2) preoperative surgical cohort, (3) 6 to 12 months postoperative cohort. OUTCOME MEASURES: Patient-reported outcome measure of symptoms and functional limitations. METHODS: Item generation was performed using semi-structured patient focus groups emphasizing symptoms experienced and functional limitations. Readability was assessed through think-aloud patient interviews. Item reduction involved surveys of DCM patients with a spectrum of disease severity and board-certified spine surgeons experienced in the treatment of DCM. A priori criteria for item removal included: patient median importance/severity <2 (of 4), 30% or more no severity (response of zero), item severity correlations ≤ 0.80 (Spearman), item severity reliability (weighted kappa <0.60) based on a 2-week interval and clinician median importance <2 with retention of items with very high clinical importance. RESULTS: There were 42 items generated from a combination of specialist input and patient focus groups. Items captured sensorimotor symptoms and limitations related to upper and lower extremities as well as sphincter dysfunction. Ninety-eight patients (43, 30, 25 observation, pre- and postsurgery respectively) and 51 surgeons completed the assessment. Twenty-three items remained after application of median importance and severity thresholds and weighted kappa cutoffs. After elimination of highly correlated (>0.80) items and combining two similar items, the final CMSI questionnaire list included 14 items. CONCLUSIONS: The CMSI is a new DCM patient-reported clinical measurement tool developed using patient and clinician input to inform item generation and reduction. Future work will evaluate the reliability, validity, and responsiveness of the CMSI in relation to existing myelopathy measurement indices.