A comparative cohort study of surgical approaches for adult spinal deformity at a minimum 2-year follow-up.

STUDY DESIGN: This study was a retrospective multi-center comparative cohort study. MATERIALS AND METHODS: A retrospective institutional database of operative adult spinal deformity patients was utilized. All fusions > 5 vertebral levels and including the sacrum/pelvis were eligible for inclusion. Revisions, 3 column osteotomies, and patients with < 2-year clinical follow-up were excluded. Patients were separated into 3 groups based on surgical approach: 1) posterior spinal fusion without interbody (PSF), 2) PSF with interbody (PSF-IB), and 3) anteroposterior (AP) fusion (anterior lumbar interbody fusion or lateral lumbar interbody fusion with posterior screw fixation). Intraoperative, radiographic, and clinical outcomes, as well as complications, were compared between groups with ANOVA and χ2 tests. RESULTS: One-hundred and thirty-eight patients were included for study (PSF, n = 37; PSF-IB, n = 44; AP, n = 57). Intraoperatively, estimated blood loss was similar between groups (p = 0.171). However, the AP group had longer operative times (547.5 min) compared to PSF (385.1) and PSF-IB (370.7) (p < 0.001). Additionally, fusion length was shorter in PSF-IB (11.4) compared to AP (13.6) and PSF (12.9) (p = 0.004). There were no differences between the groups in terms of change in alignment from preoperative to 2 years postoperative. There were no differences in clinical outcomes. While postoperative complications were largely similar between groups, operative complications were higher in the AP group (31.6%) compared to the PSF (5.4%) and PSF-IB (9.1) groups (p < 0.001). CONCLUSION: While there were differences in intraoperative outcomes (operative time and fusion length), there were no differences in postoperative clinical or radiographic outcomes. AP fusion was associated with a higher rate of operative complications.

Hip Osteoarthritis in Patients Undergoing Surgery for Severe Adult Spinal Deformity: Prevalence and Impact on Spine Surgery Outcomes.

BACKGROUND: Hip osteoarthritis (OA) is common in patients with adult spinal deformity (ASD). Limited data exist on the prevalence of hip OA in patients with ASD, or on its impact on baseline and postoperative alignment and patient-reported outcome measures (PROMs). Therefore, this paper will assess the prevalence and impact of hip OA on alignment and PROMs. METHODS: Patients with ASD who underwent L1-pelvis or longer fusions were included. Two independent reviewers graded hip OA with the Kellgren-Lawrence (KL) classification and stratified it by severity into non-severe (KL grade 1 or 2) and severe (KL grade 3 or 4). Radiographic parameters and PROMs were compared among 3 patient groups: Hip-Spine (hip KL grade 3 or 4 bilaterally), Unilateral (UL)-Hip (hip KL grade 3 or 4 unilaterally), or Spine (hip KL grade 1 or 2 bilaterally). RESULTS: Of 520 patients with ASD who met inclusion criteria for an OA prevalence analysis, 34% (177 of 520) had severe bilateral hip OA and unilateral or bilateral hip arthroplasty had been performed in 8.7% (45 of 520). A subset of 165 patients had all data components and were examined: 68 Hip-Spine, 32 UL-Hip, and 65 Spine. Hip-Spine patients were older (67.9 ± 9.5 years, versus 59.6 ± 10.1 years for Spine and 65.8 ± 7.5 years for UL-Hip; p < 0.001) and had a higher frailty index (4.3 ± 2.6, versus 2.7 ± 2.0 for UL-Hip and 2.9 ± 2.0 for Spine; p < 0.001). At 1 year, the groups had similar lumbar lordosis, yet the Hip-Spine patients had a worse sagittal vertebral axis (SVA) measurement (45.9 ± 45.5 mm, versus 25.1 ± 37.1 mm for UL-Hip and 19.0 ± 39.3 mm for Spine; p = 0.001). Hip-Spine patients also had worse Veterans RAND-12 Physical Component Summary scores at baseline (25.7 ± 9.3, versus 28.7 ± 9.8 for UL-Hip and 31.3 ± 10.5 for Spine; p = 0.005) and 1 year postoperatively (34.5 ± 11.4, versus 40.3 ± 10.4 for UL-Hip and 40.1 ± 10.9 for Spine; p = 0.006). CONCLUSIONS: This study of operatively treated ASD revealed that 1 in 3 patients had severe hip OA bilaterally. Such patients with severe bilateral hip OA had worse baseline SVA and PROMs that persisted 1 year following ASD surgery, despite correction of lordosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Expanding chemistry through in vitro and in vivo biocatalysis.

Living systems contain a vast network of metabolic reactions, providing a wealth of enzymes and cells as potential biocatalysts for chemical processes. The properties of protein and cell biocatalysts-high selectivity, the ability to control reaction sequence and operation in environmentally benign conditions-offer approaches to produce molecules at high efficiency while lowering the cost and environmental impact of industrial chemistry. Furthermore, biocatalysis offers the opportunity to generate chemical structures and functions that may be inaccessible to chemical synthesis. Here we consider developments in enzymes, biosynthetic pathways and cellular engineering that enable their use in catalysis for new chemistry and beyond.

Surface Mapping of Gastric Motor Functions Using MRI: A Comparative Study between Humans and Rats.

BACKGROUND: The stomach's ability to store, mix, propel, and empty its content requires highly coordinated motor functions. However, current diagnostic tools cannot simultaneously assess these motor processes. This study aimed to use magnetic resonance imaging (MRI) to map multifaceted gastric motor functions, including accommodation, tonic and peristaltic contractions, and emptying, through a single non-invasive experiment for both humans and rats. METHODS: Ten humans and ten Sprague-Dawley rats consumed MRI-visible semi-solid meals and underwent MRI scans. We used a surface model to analyze MRI data, capturing the deformation of the stomach wall upon ingestion or during digestion. We inferred muscle activity, mapped motor processes, parcellated the stomach into functional regions, and revealed cross-species distinctions. RESULTS: In humans, both the fundus and antrum distended post-meal, followed by sustained tonic contractions to regulate intragastric pressure. Peristaltic contractions initiate from the distal fundus, including three concurrent wavefronts oscillating at 3.3 cycles per minute (cpm) and traveling at 1.7 to 2.9 mm/s. These motor functions facilitate linear gastric emptying with a 61-min half-time. In contrast, rats exhibited peristalsis from the mid-corpus, showing two wavefronts oscillating at 5 cpm and traveling at 0.3 to 0.9 mm/s. For both species, motility features allowed functional parcellation of the stomach along a mid-corpus division. CONCLUSIONS: This study maps region- and species-specific gastric motor functions. We demonstrate the value of MRI with surface modeling in understanding gastric physiology and its potential to become a new standard for clinical and preclinical investigations of gastric disorders at both individual and group levels.

Restoring L4-S1 Lordosis Shape in Severe Sagittal Deformity: Impact of Correction Techniques on Alignment and Complication Profile.

BACKGROUND: Severe sagittal plane deformity with loss of L4-S1 lordosis is disabling and can be improved through various surgical techniques. However, data are limited on the differing ability of anterior lumbar interbody fusion (ALIF), pedicle subtraction osteotomy (PSO), and transforaminal lumbar interbody fusion (TLIF) to achieve alignment goals in severely malaligned patients. METHODS: Severe adult spinal deformity patients with preoperative PI-LL >20°, L4-S1 lordosis <30°, and full body radiographs and PROMs at baseline and 6-week postoperative visit were included. Patients were grouped into ALIF (1-2 level ALIF at L4-S1), PSO (L4/L5 PSO), and TLIF (1-2 level TLIF at L4-S1). Comparative analyses were performed on demographics, radiographic spinopelvic parameters, complications, and PROMs. RESULTS: Among the 96 included patients, 40 underwent ALIF, 27 underwent PSO, and 29 underwent TLIF. At baseline, cohorts had comparable age, sex, race, Edmonton frailty scores, and radiographic spinopelvic parameters (P > 0.05). However, PSO was performed more often in revision cases (P < 0.001). Following surgery, L4-S1 lordosis correction (P = 0.001) was comparable among ALIF and PSO patients and caudal lordotic apex migration (P = 0.044) was highest among ALIF patients. PSO patients had higher intraoperative estimated blood loss (P < 0.001) and motor deficits (P = 0.049), and in-hospital ICU admission (P = 0.022) and blood products given (P = 0.004), but were otherwise comparable in terms of length of stay, blood transfusion given, and postoperative admission to rehab. Likewise, 90-day postoperative complication profiles and 6-week PROMs were comparable as well. CONCLUSIONS: ALIF can restore L4-S1 sagittal alignment as powerfully as PSO, with fewer intraoperative and in-hospital complications. When feasible, ALIF is a suitable alternative to PSO and likely superior to TLIF for correcting L4-S1 lordosis among patients with severe sagittal malalignment.

Differences in intratumor innate lymphoid cell composition between orthotopic and spontaneous pancreatic mouse models.

Pancreatic cancer remains an unmet medical need. Late diagnosis and the lack of efficient treatment significantly impact the prognosis of patients suffering from pancreatic cancer. Improving patient outcomes requires a deeper comprehension of the tumor ecosystem. To achieve this, a thorough exploration of the tumor microenvironment using pre-clinical models that accurately replicate human disease is imperative, particularly in understanding the dynamics of immune cell subsets. Surprisingly, the impact of model variations on the composition of the tumor microenvironment has been largely neglected. In this study, we introduce an orthotopic model of pancreatic ductal adenocarcinoma and a spontaneous model of insulinoma. Our findings reveal striking differences in the innate lymphoid cell infiltrate, highlighting the importance of considering model-specific influences when investigating the tumor microenvironment.

RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED FOR LUNG CANCER GROWTH AND SURVIVAL.

Mitochondrial function is important for both energetic and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations directly impact these functions, resulting in the detrimental consequences seen in human mitochondrial diseases. The role of pathogenic mtDNA mutations in human cancers is less clear; while pathogenic mtDNA mutations are observed in some cancer types, they are almost absent in others. We report here that the proofreading mutant DNA polymerase gamma ( PolG D256A ) induced a high mtDNA mutation burden in non-small-cell lung cancer (NSCLC), and promoted the accumulation of defective mitochondria, which is responsible for decreased tumor cell proliferation and viability and increased cancer survival. In NSCLC cells, pathogenic mtDNA mutations increased glycolysis and caused dependence on glucose. The glucose dependency sustained mitochondrial energetics but at the cost of a decreased NAD+/NADH ratio that inhibited de novo serine synthesis. Insufficient serine synthesis, in turn, impaired the downstream synthesis of GSH and nucleotides, leading to impaired tumor growth that increased cancer survival. Unlike tumors with intact mitochondrial function, NSCLC with pathogenic mtDNA mutations were sensitive to dietary serine and glycine deprivation. Thus, mitochondrial function in NSCLC is required specifically to sustain sufficient serine synthesis for nucleotide production and redox homeostasis to support tumor growth, explaining why these cancers preserve functional mtDNA. In brief: High mtDNA mutation burden in non-small-cell lung cancer (NSCLC) leads to the accumulation of respiration-defective mitochondria and dependency on glucose and glycolytic metabolism. Defective respiratory metabolism causes a massive accumulation of cytosolic nicotinamide adenine dinucleotide + hydrogen (NADH), which impedes serine synthesis and, thereby, glutathione (GSH) and nucleotide synthesis, leading to impaired tumor growth and increased survival. Highlights: Proofreading mutations in Polymerase gamma led to a high burden of mitochondrial DNA mutations, promoting the accumulation of mitochondria with respiratory defects in NSCLC.Defective respiration led to reduced proliferation and viability of NSCLC cells increasing survival to cancer.Defective respiration caused glucose dependency to fuel elevated glycolysis.Altered glucose metabolism is associated with high NADH that limits serine synthesis, leading to impaired GSH and nucleotide production.Mitochondrial respiration defects sensitize NSCLC to dietary serine/glycine starvation, further increasing survival.

A multi-institutional machine learning algorithm for prognosticating facial nerve injury following microsurgical resection of vestibular schwannoma.

Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients' quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II-VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures.

Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice.

Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).

Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials.

BACKGROUND AND AIMS: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12. METHODS: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism. RESULTS: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo. CONCLUSIONS: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.

Contemporary utilization of three-column osteotomy techniques in a prospective complex spinal deformity multicenter database: implications on full-body alignment and perioperative course.

BACKGROUND: Research has focused on the increased correction from a three-column osteotomy (3CO) during adult spinal deformity (ASD) surgery. However, an in-depth analysis on the performance of a 3CO in a cohort of complex spinal deformity cases has not been described. STUDY DESIGN/SETTING: This is a retrospective study on a prospectively enrolled, complex ASD database. PURPOSE: This study aimed to determine if three-column osteotomies demonstrate superior benefit in correction of complex sagittal deformity at the cost of increased perioperative complications. METHODS: Surgical complex adult spinal deformity patients were included and grouped into thoracolumbar 3COs compared to those who did not have a 3CO (No 3CO) (remaining cohort). Rigid deformity was defined as ΔLL less than 33% from standing to supine. Severe deformity was defined as global (SVA > 70 mm) or C7-PL > 70 mm, or lumbopelvic (PI-LL > 30°). Means comparison tests assessed correction by 3CO grade/location. Multivariate analysis controlling for baseline deformity evaluated outcomes up to six weeks compared to No 3CO. RESULTS: 648 patients were included (Mean age 61 ± 14.6 years, BMI 27.55 ± 5.8 kg/m2, levels fused: 12.6 ± 3.8). 126 underwent 3CO, a 20% higher usage than historical cohorts. 3COs were older, frail, and more likely to undergo revision (OR 5.2, 95% CI [2.6-10.6]; p < .001). 3COs were more likely to present with both severe global/lumbopelvic deformity (OR 4), 62.4% being rigid. 3COs had greater use of secondary rods (OR 4st) and incurred 4 times greater risk for: massive blood loss (> 3500 mL), longer LOS, SICU admission, perioperative wound and spine-related complications, and neurologic complications when performed below L3. 3COs had similar HRQL benefit, but higher perioperative opioid use. Mean segmental correction increased by grade (G3-21; G4-24; G5-27) and was 4 × greater than low-grade osteotomies, especially below L3 (OR 12). 3COs achieved 2 × greater spinopelvic correction. Higher grades properly distributed lordosis 50% of the time except L5. Pelvic compensation and non-response were relieved more often with increasing grade, with greater correction in all lower extremity parameters (p < .01). Due to the increased rate of complications, 3COs trended toward higher perioperative cost ($42,806 vs. $40,046, p = .086). CONCLUSION: Three-column osteotomy usage in contemporary complex spinal deformities is generally limited to more disabled individuals undergoing the most severe sagittal and coronal realignment procedures. While there is an increased perioperative cost and prolongation of length of stay with usage, these techniques represent the most powerful realignment techniques available with a dramatic impact on normalization at operative levels and reciprocal changes.

Space radiation damage rescued by inhibition of key spaceflight associated miRNAs.

Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage.

Non-resonant Bragg scattering four-wave mixing at near-visible wavelengths in low-confinement silicon nitride waveguides.

Quantum state coherent frequency conversion processes-such as Bragg-scattering four-wave mixing (BSFWM)-hold promise as a flexible technique for networking heterogeneous and distant quantum systems. In this Letter, we demonstrate BSFWM within an extended (1.2-m) low-confinement silicon nitride waveguide and show that this system has the potential for near-unity frequency conversion in visible and near-visible wavelength ranges. Using sensitive classical heterodyne laser spectroscopy at low optical powers, we characterize the Kerr coefficient (∼1.55 W-1m-1) and linear propagation loss (∼0.0175 dB/cm) of this non-resonant waveguide system, revealing a record-high nonlinear figure of merit (NFM = γ/α ≈ 3.85 W-1) for BSFWM of near-visible light in non-resonant silicon nitride waveguides. We predict how, at high yet achievable on-chip optical powers, this NFM would yield a comparatively large frequency conversion efficiency, opening the door to near-unity flexible frequency conversion without cavity enhancement and resulting bandwidth constraints.

Corneal injury repair and the potential involvement of ZEB1.

The cornea, consisting of three cellular and two non-cellular layers, is the outermost part of the eyeball and frequently injured by external physical, chemical, and microbial insults. The epithelial-to-mesenchymal transition (EMT) plays a crucial role in the repair of corneal injuries. Zinc finger E-box binding homeobox 1 (ZEB1), an important transcription factor involved in EMT, is expressed in the corneal tissues. It regulates cell activities like migration, transformation, and proliferation, and thereby affects tissue inflammation, fibrosis, tumor metastasis, and necrosis by mediating various major signaling pathways, including transforming growth factor (TGF)-ß. Dysfunction of ZEB1 would impair corneal tissue repair leading to epithelial healing delay, interstitial fibrosis, neovascularization, and squamous cell metaplasia. Understanding the mechanism underlying ZEB1 regulation of corneal injury repair will help us to formulate a therapeutic approach to enhance corneal injury repair.

Critical Dialogue and Capacity-Building Projects Reduced Alcohol and Substance Use in a Randomized Clinical Trial Among Formerly Incarcerated Men.

Background: Rates of alcohol and/or substance use (ASU) among residents of predominantly Black and marginalized communities are similar to ASU rates in White communities. Yet ASU has worse consequences in predominantly Black and marginalized communities (e.g., higher incarceration). Objective: We randomized participants to one of 16 intervention conditions using a 24 full factorial design to optimize a multilevel intervention reducing ASU among 602 formerly incarcerated men with substance-use-disorders (SUD). Candidate intervention components included (1) critical dialogue (CD; six weekly 2-hour-long group sessions vs. no CD sessions), (2) Quality of Life Wheel (QLW; six weekly 1-hour-long group sessions vs. no QLW sessions), (3) capacity building projects (CBP; six weekly 1-hour-long group sessions vs. no CBP sessions), and (4) delivery by a trained peer versus licensed facilitators. Outcome was percentage of days in which participants used alcohol, cocaine, opioid, and/or cannabis in previous 30 days. Results: Intent-to-treat analysis did not meet a priori component selection criteria due to low intervention attendance. After controlling for intervention group attendance (percentage of sessions attended), peer-delivered CD and CBP produced statistically and clinically significant main and interaction effects in ASU over 5 months. Per the multiphase optimization strategy framework, we selected peer-delivered CD and CBP for inclusion as the optimized version of the intervention with a cost of US$1,380 per 10 individuals. No adverse intervention effects occurred. Conclusion: CD and CBP were identified as the only potentially effective intervention components. Future research will examine strategies to improve attendance and test the optimized intervention against standard of care in a randomized-controlled-trial.

Acid accumulation is associated with metabolic alterations; higher energy, fat, and protein intake; and energy expenditure.

OBJECTIVE: The objective of this study was to study how acid accumulation (lower plasma bicarbonate and higher anion gap [AG] and corrected anion gap [CAG]) correlates with metabolic parameters, food intake, and 24-h energy expenditure (EE). METHODS: Acid accumulation was measured in 286 healthy adults with estimated glomerular filtration rate > 60 mL/min/1.73 m2. Measurements included body composition by dual-energy x-ray absorptiometry scan, ad libitum energy intake by a vending machine paradigm over 3 days, and 24-h EE in a whole-room indirect calorimeter. RESULTS: Lower bicarbonate, higher AG, and higher CAG were correlated with higher waist and thigh circumferences, body fat (percentage), fat mass, triglycerides, and lower high-density lipoprotein cholesterol. Acid accumulation markers were correlated with higher total energy (CAG partial r = 0.17; p = 0.02), fat (CAG partial r = 0.17; p = 0.02), protein intake (CAG partial r = 0.20; p = 0.006), and 24-h EE (CAG partial r = 0.24; p = 0.0007). A mediation analysis of CAG and total energy intake found that 24-h EE was a partial mediator (40%), but the association remained significant (ß = 0.15; p < 0.0001). CONCLUSIONS: In healthy individuals, acid accumulation was associated with an unfavorable metabolic phenotype; higher 24-h EE; and increased total energy, fat, and protein intake. Acid accumulation markers, as putative markers of higher dietary acid load (e.g., from protein), may affect energy balance physiology promoting weight gain.

Assessing human carcinogenicity risk of agrochemicals without the rodent cancer bioassay.

The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment.

Canadian Cost-Effectiveness of Coronary Artery Calcium Screening Based on the Multi-Ethnic Study of Atherosclerosis.

Background: Cost-effectiveness of testing for coronary artery calcium (CAC) relative to other treatment strategies is not established in Canada. Objectives: The purpose of this study was to evaluate the cost-effectiveness of using CAC score-guided statin treatment compared with universal statin therapy among intermediate-risk, primary prevention patients eligible for statins. Methods: A state transition, microsimulation model used data from Canadian sources and the Multi-Ethnic Study of Atherosclerosis to simulate clinical and economic consequences of cardiovascular disease from a Canadian publicly funded health care system perspective. In the CAC score-guided treatment arm, statins were started when CAC ≥1. Outcome of interest was the incremental cost-effectiveness ratio at 5 and 10 years; an incremental cost-effectiveness ratio <$50,000 per quality-adjusted life year (QALY) gained was considered cost-effective. Sensitivity analyses examined uncertainty in model parameters. Results: Compared with universal statin treatment at 5 and 10 years, CAC score-guided statin treatment was projected to increase mean costs by $326 (95% CI: $325-$326) and $172 (95% CI: $169-$175), increase mean QALYs by 0.01 (95% CI: 0.01-0.01) and 0.02 (95% CI: 0.02-0.02), and cost $54,492 (95% CI: $52,342-$56,816) and $8,118 (95% CI: $7,968-$8,279) per QALY gained, respectively. The model was most sensitive to statin cost, CAC testing cost, adherence to statin monitoring, and disutility associated with daily statin use. At 5 years, CAC score-guided statin treatment was cost-effective when CAC test costs ranged from $80 to $160 in different scenarios. Conclusions: CAC score-guided statin initiation in comparison to universal statin treatment was borderline cost-neutral at 5 years and cost-effective at 10 years in statin-eligible Canadian patients at intermediate cardiovascular disease risk.

Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights.

This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136° and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less-electron rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and DFT studies suggest that all these data can be explained based on the reactivity of a key intermediate: a Ni0-π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve the Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.