Development of a sensitive LC-MS/MS assay to support human microdose study for an oral agonist of the GLP-1 receptor.

Aim: The purpose of this work was to determine the feasibility of supporting a clinical microdose study for PF-06882961 (danuglipron), an oral small molecule agonist of the GLP-1 receptor, by LC-MS/MS. Methodology: Statistical instrument parameter optimization using response surface methodology was employed to develop a LC-MS/MS method for the analyte, PF-06882961. Results: An LC-MS/MS method was developed and validated to support a proof of concept microdose pharmacokinetics preclinical study in monkeys, administered PF-06882961 (0.005 mg total, average dose = 0.0007 mg/kg) via intravenous bolus injection. Conclusion: The present study demonstrated the feasibility of analyzing human microdose plasma samples for PF-06882961 by LC-MS/MS, instead of accelerator mass spectrometry, thereby reducing cost and eliminating synthesis and exposure to 14C labeled material.

[Box: see text].

Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer's disease dementia with high accuracy in an African American cohort.

Introduction: African Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer's disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD. Methods: Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy. Results: A plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94). Discussion: This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.

Does format matter? A naturalistic study of digital and provider-led cognitive behavioral therapy for insomnia implemented in a healthcare system.

OBJECTIVES: Cognitive Behavioral Therapy for Insomnia (CBTi) is a first-line treatment for a prevalent and impairing disorder. Digital CBTi programs increase access to internet-based self-directed care. However, the clinical effect of offering different forms of CBTi in a healthcare setting is not clearly understood. This study examines treatment engagement and clinical outcomes for individuals referred to either digital or provider-led CBTi. METHODS: Over two years, providers at a Veterans Health Administration (VHA) facility referred patients to digital CBTi with telephone coaching support or traditional provider-led CBTi. Characteristics of those referred, proportions engaging in and completing treatment, as well as insomnia severity were compared among those referred to each format. RESULTS: Providers referred 139 individuals to digital CBTi, 340 to provider-led CBTi, and 14 to both formats. Individuals referred to digital CBTi were older with less severe insomnia. Despite lower levels of program engagement and completion in the digital CBTi cohort, measures of insomnia symptom change were similar between the groups. CONCLUSIONS: This is the first study to evaluate both digital and provider-led evidence-based treatments for insomnia disorder simultaneously deployed in a healthcare setting. While engagement in digital CBTi lagged that for provider-led CBTi, offering both formats may expand access to different groups, while fostering similar outcomes.

Evaluating Geospatial Sampling Frames with a Novel Field Census for a Malaria Household Survey in Artibonite, Haiti.

The Ministry of Public Health and Population in Haiti is committed to malaria elimination. In 2017, we used novel methods to conduct a census, monitor progress, and return to sampled households (HH) before a cross-sectional survey in La Chapelle and Verrettes communes in Artibonite department ("the 2017 Artibonite HH census"). Geospatial PDFs with digitized structures and basemaps were loaded onto tablets. Enumerators captured GPS coordinates and details of each HH and points of interest. The census used 1 km2 enumeration areas (EAs) to draw a representative sample. Three remote sampling frames were compared with the 2017 Artibonite HH census. First, 2003 census EAs with 2012 population estimates from the Haitian Institute of Statistics and Informatics were standardized to the study EAs. The second sampling frame used the 2016 LandScanTM population estimates and study EAs. The third sampling frame used structures ≥3 m2 manually digitized using Maxar satellite images. In each study EA, 70% of structures were estimated to be inhabited with 4.5 persons/HH. The census identified 33,060 inhabited HHs with an estimated population of 121,593 and 6,126 points of interest. Using daily coverage maps and including digitized structures were novel methods that improved the census quality. Manual digitization was closest to the census sampling frame results with 30,514 digitized structures in the study area. The LandScanTM method performed better in urban areas; however, it produced the highest number of HHs to sample. If a census is not possible, when feasible, remotely digitizing structures and estimating occupancy may provide a close estimate.

Electrochemical Quantification of Enkephalin Peptides Using Fast-Scan Cyclic Voltammetry.

Endogenous opioid neuropeptides serve as important chemical signaling molecules in both the central and peripheral nervous systems, but there are few analytical tools for directly monitoring these molecules in situ. The opioid peptides share the amino acid motif, Tyr-Gly-Gly-Phe-, at the N-terminus. Met-enkephalin is a small opioid peptide comprised of only five amino acids with methionine (Met) incorporated at the C-terminus. Tyrosine (Tyr) and Met are electroactive, and their distinct electrochemical signatures can be utilized for quantitative molecular monitoring. This work encompasses a thorough voltammetric characterization of Tyr and Met redox chemistry as individual amino acids and when incorporated into small peptide fragments containing the shared Tyr-Gly-Gly-Phe- motif. NMR spectroscopy was used to determine the structure and conformation at near-physiological conditions. Voltammetric data demonstrate how the peak oxidation potential and the rate of electron transfer are dependent on the local chemical environment. Both the proximity of the electroactive residue to the C- or N-terminus and the hydrophobicity of the additional nonelectroactive amino acids profoundly affect sensitivity. Finally, the work uses the electrochemical signal for individual amino acids in a "training set", with a combination of principal component analysis and least-squares regression to accurately predict the voltammetric signal for short peptides comprising different combinations of those amino acids. Overall, this study demonstrates how fast-scan cyclic voltammetry can be utilized to discriminate between peptides with small differences in the chemical structure, thus establishing a framework for reliable quantification of small peptides in a complex signal, broadly speaking.

Measuring the Magnetic Anisotropy of Metal-Metal Multiple Bonds: The Importance of Correcting for Ligand Effects.

We describe the synthesis and characterization of the quadruply-bonded dimer Mo2(CH2NMe2BH3)4 in which each molybdenum(II) center is bound to two chelating boranatodimethylaminomethyl (BDAM) ligands. The BDAM anions bind to the metal at one end by a metal-carbon σ bond and at the other by a three-center M-H-B interaction. Each BDAM ligand chelates to a single Mo atom so that the metal-metal bond is unbridged; the Mo-Mo distance is 2.114(2) Å. Structural and solution NMR data, analyzed via McConnell's equation and supported by DFT calculations, show that the magnetic anisotropies associated with highly polarizable and π-bonding ligands (such as chloride groups and aryl rings) can greatly affect the NMR chemical shifts of reporter groups, so that ignoring their contributions leads to significant overestimates of the anisotropy due just to the metal-metal bond. We propose a method to quantify and correct for the magnetic anisotropy effects arising from the ligands. Application of this method to Mo2(BDAM)4 indicates that the magnetic anisotropy of the Mo-Mo quadruple bond in this molecule is about -800 × 10-36 m3 molecule-1. Anisotropies significantly higher than this value (as sometimes reported in the prior literature) are most likely incorrect.

The Determining Influence of the Phase Composition on the Mechanical Properties of Titanium-Iron Alloys after High-Pressure Torsion.

Three titanium alloys with 0.5, 6, and 9 wt.% iron were investigated, and the samples were pre-annealed in three different regions of the Ti-Fe phase diagram, namely ß, α+ß, and α+FeTi. After annealing, five samples of different phases and structural compositions were studied. They were then subjected to the high-pressure torsion (HPT). The microstructure of the samples before and after HPT treatment was studied using transmission and scanning electron microscopy. The microstructure of the samples obtained during heat treatment before HPT treatment had a fundamental effect on the microstructure after HPT. Grain boundary layers and chains of particles formed during the annealing process made it difficult to mix the material during HPT, which led to the formation of areas with non-uniform mixing of components. Thus, the grain boundary layers of the α-phase formed in the Ti-6wt % Fe alloy after annealing at 670 °C significantly decreased the mixing of the components during HPT. Despite the fact that the microstructure and phase composition of Ti-6wt % Fe alloys pre-annealed in three different regions of the Ti-Fe phase diagram had significant differences, after HPT treatment, the phase compositions of the studied samples were quite similar. Moreover, the measured micro- and nanohardness as well as the Young's modulus of Ti-6wt % Fe alloy had similar values. It was shown that the microhardness of the studied samples increased with the iron content. The values of nanohardness and Young's modulus correlated well with the fractions of ß- and ω-phases in the studied alloys.

Early Adversity and Socioeconomic Factors in Pediatric Multiple Sclerosis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS: This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS: MS cases (64% female, mean age 15.4 years, SD 2.8) were demographically similar to controls (60% female, mean age 14.9 years, SD 3.9). Cases were less likely to have a mother with a bachelor's degree or higher (OR 0.42, 95% CI 0.22-0.80, p = 0.009) and were more likely to experience childhood neighborhood disadvantage (OR 1.04 for each additional point on the neighborhood socioeconomic disadvantage score, 95% CI 1.00-1.07; p = 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION: Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN.

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.

The effect of occlusal loading on secondary tooth eruption: An experimental study using a rat model.

This study aimed to assess the impact of occlusal loading on secondary tooth eruption and to determine the extent to which altering the occlusal loading influences the magnitude of secondary eruption through an experimental rat model. The present sample consisted of 48 male Wistar rats. At the onset of the experiment, 24 rats were 4 weeks old (young rats) and 24 rats were 26 weeks old (adult). Within each age group, the rats were further divided into two equal subgroups (12 rats each), receiving either a soft- or hard-food diet for the 3-month duration of the experiment. The primary outcome was the tooth position changes relative to stable references in the coronal plane by evaluating the distance between the mandibular first molars and the inferior alveolar canal. Microcomputed tomography scans were taken from all rats at three standardized intervals over the 3-month study period. Descriptive statistics were calculated by age and diet over time, and the evolution of the outcomes were plotted by age and diet over time. Longitudinal data analysis via generalized estimating equations was performed to examine the effect of age, diet and time on the primary outcomes. Secondary tooth eruption was observed in all age groups (young and adult) regardless of diet consistency (soft or hard food). In young rats, the secondary eruption was greater in the animals fed a soft diet than those fed a hard diet. In adult rats, minimal difference in secondary tooth eruption were found between different diet consistencies. Occlusal loading influences secondary tooth eruption in teeth with an established occlusal contact. The quantity of eruption in growing rats is higher when occlusal loading is less, providing a certain amount of secondary tooth eruption occurs. This difference, however, is not evident in adult rats, at least during the given 3-month time frame.

The Impact of Endplate Coverage on Heterotopic Ossification Following Cervical Disc Replacement: A Systematic Review and Meta Analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Describe the impact of endplate coverage on HO in Cervical disc replacement (CDR). SUMMARY OF BACKGROUND DATA: CDR is a motion-sparing alternative to anterior cervical discectomy and fusion. However, the high prevalence of heterotopic ossification threatens to diminish range of motion and limit this benefit associated with CDR. METHODS: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. EMBASE and PubMed databases were queried. Results were deduplicated and screened. Relevant studies were included. All metrics that were reported in ≥3 studies were aggregated for analysis. SPSS was used to perform the meta-analysis. RESULTS: A total of 10 studies were included in the systematic review. Endplate coverage was assessed using a wide variety of measurements, including anteroposterior implant depth (ID), endplate depth (ED), exposed endplate depth (EED), implant depth to endplate depth ratio (ID:ED), EED to ED ratio (EED:ED), implant width (IW) to endplate width (EW) ratio (IW:EW), and the implant area (IA) to endplate area (EA) ratio (IA:EA). No evidence has linked ID (3 studies) to HO. Mixed evidence has linked ID:ED (3/5) and IW:ED (1/2) to HO. All available evidence has linked ED (2), EED (4), EED:ED (2), and IA:EA (1) to HO. In our meta-analysis, ID was not found to be a significant risk factor for HO. However, EED and ID:ED were found to be significant risk factors for HO formation. CONCLUSIONS: Exposed endplate, especially as assessed by EED and ID:ED, is a significant risk factor for HO. Surgeons should focus on preoperative planning and intraoperative implant selection to maximize endplate coverage. While optimizing technique and implant selection is crucial, improved implant design may also be necessary to ensure that appropriate implant-endplate footprint matching is possible across the anatomic spectrum.

Tibial Spine Avulsion Fracture Fixation Using a Re-tensionable All-Suture Construct.

Tibial spine avulsion injuries, including fractures, are a variant of anterior cruciate ligament injuries. Treatment historically consisted of open reduction and internal fixation of the avulsion fracture, with anterior cruciate ligament reconstruction considered in cases of failed open reduction and internal fixation or residual laxity. However, improved instrumentation has led to the advancement of various arthroscopic techniques for addressing these injuries. The emergence of newer implants designed for all-suture fixation has also overcome the limitations associated with screw fixation, such as hardware-related complications, challenges in treating comminuted fractures, and potential physeal injury. The purpose of this article is to describe a technique consisting of arthroscopic-assisted reduction and internal fixation of a tibial spine avulsion fracture with a re-tensionable all-suture-based construct using multiple looped cinch stitches and a cortical suspensory suture button device.

Early-life risperidone alters locomotor responses to apomorphine and quinpirole in adulthood.

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.

SOX2 represses c-MYC transcription by altering the co-activator landscape of the c-MYC super-enhancer and promoter regions.

Our previous studies determined that elevating SOX2 in a wide range of tumor cells leads to a reversible state of tumor growth arrest. Efforts to understand how tumor cell growth is inhibited led to the discovery of a SOX2:MYC axis that is responsible for downregulating c-MYC (MYC) when SOX2 is elevated. Although we had determined that elevating SOX2 downregulates MYC transcription, the mechanism responsible was not determined. Given the challenges of targeting MYC clinically, we set out to identify how elevating SOX2 downregulates MYC transcription. In this study, we focused on the MYC promoter region and an upstream region of the MYC locus that contains a MYC super-enhancer encompassing five MYC enhancers and which is associated with several cancers. Here we report that BRD4 and p300 associate with each of the MYC enhancers in the upstream MYC super-enhancer as well as the MYC promoter region and that elevating SOX2 decreases the recruitment of BRD4 and p300 to these sites. Additionally, we determined that elevating SOX2 leads to increases in the association of SOX2 and H3K27me3 within the MYC super-enhancer and the promoter region of MYC. Importantly, we conclude that the increases in SOX2 within the MYC super-enhancer precipitate a cascade of events that culminates in the repression of MYC transcription. Together, our studies identify a novel molecular mechanism able to regulate MYC transcription in two distinctly different tumor types and provide new mechanistic insights into the molecular interrelationships between two master regulators, SOX2 and MYC, widely involved in multiple cancers.

Extended shortwave infrared absorbing antiaromatic fluorenium-indolizine chromophores.

Shortwave infrared (SWIR, 1000-1700 nm) and extended SWIR (ESWIR, 1700-2700 nm) absorbing materials are valuable for applications including fluorescence based biological imaging, photodetectors, and light emitting diodes. Currently, ESWIR absorbing materials are largely dominated by inorganic semiconductors which are often costly both in raw materials and manufacturing processes used to produce them. The development of ESWIR absorbing organic molecules is thus of interest due to the tunability, solution processability, and low cost of organic materials compared to their inorganic counterparts. Herein, through the combination of heterocyclic indolizine donors and an antiaromatic fluorene core, a series of organic chromophores with absorption maxima ranging from 1470-2088 nm (0.84-0.59 eV) and absorption onsets ranging from 1693-2596 nm (0.73-0.48 eV) are designed and synthesized. The photophysical and electrochemical properties of these chromophores, referred to as FluIndz herein, are described via absorption spectroscopy in 17 solvents, cyclic voltammetry, solution photostability, and transient absorption spectroscopy. Molecular orbital energies, predicted electronic transitions, and antiaromaticity are compared to higher energy absorbing chromophores using density functional theory. The presence of thermally accessible diradical states is demonstrated using density functional theory and EPR spectroscopy, while XRD crystallography confirms structural connectivity and existence as a single molecule. Overall, the FluIndz chromophore scaffold exhibits a rational means to access organic chromophores with extremely narrow optical gaps.

Mapping coexisting hotspots of multidimensional food market (in)accessibility and climate vulnerability.

With the increasing likelihood of agricultural production failures under a warmer global climate, the importance of markets in providing access to nutrient-dense foods (NDFs) through trade is predicted to grow. However, regions with relatively poor access to markets and supporting infrastructures (e.g. roads and storage facilities) are potentially ill-equipped to deal with both short-term hydrometeorological hazards such as droughts and floods, and longer-term shifts in agricultural productivity. Despite the increasing focus upon markets within academic and policymaking circles, a regional-scale assessment of these potentially coexisting hotspots of vulnerability has not been conducted. We conduct a two-stage geospatial analysis integrating three publicly available datasets across the Indian states of Bihar, Chhattisgarh, Jharkhand, and Odisha. Combining the 2011 national census with the new PMGSY-GeoSadak database, we conduct nearest neighbour analysis to measure multidimensional market inaccessibility by: (i) distance from a settlement to its nearest village, town or city with a market, (ii) distance from a settlement to its nearest major road, and (iii) distance from a settlement to its subdistrict headquarters. We then correlate these measures with India's only district-wise assessment of climate vulnerability to identify hotspots of market inaccessibility and climate hazards. We find that the three market access measures are spatially autocorrelated and positively interrelated at the settlement (n = 129 555) and district (n = 107) levels, meaning that settlements located further from their nearest market tend to experience poorer road connectivity and access to the subdistrict economic hub. Approximately 18.5-million people live in districts with relatively high climate vulnerability and relatively high and multidimensional market inaccessibility. Hotspots of coexisting vulnerabilities are also disproportionately populated by 'Schedule Castes and Schedule Tribes' (SC/ST) communities. The identification of coexisting hotspots has important implications for the development of equitable and resilient markets that bolster NDF access for climate vulnerable and nutritionally insecure populations.

Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa After Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis.

Rationale Evaluating approaches to reduce treatment burden is a research priority among people with CF (pwCF) on highly effective modulators including elexacaftor/tezacaftor/ivacaftor (ETI). Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods SIMPLIFY participants ≥12 years old on ETI and comprising a subgroup using both HS and DA at study entry were randomized to the HS or DA trial, and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY versus a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth and percent predicted forced expiratory volume in one second (ppFEV1) at study entry. Results There were 43 participants who discontinued both therapies by the end of SIMPLIFY and 63 who remained on both, with overall average ppFEV1 at study entry 96.7% and average duration of follow up from beginning of the first trial to completion of the second trial 3.9 months, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued versus remained on both therapies (difference: 0.22% Off-On, 95% CI: -1.60,2.03). Changes in LCI2.5, patient reported, and safety outcomes were also comparable. Patient reported treatment burden, as measured by a CFQ-R subscale, significantly decreased in those discontinuing both therapies. Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

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.

Alliance for Scientific Autism Intervention: System Components and Outcome Data from High-Quality Service Delivery Organizations.

Promoting excellence in autism intervention is arguably more urgent than ever for the field of applied behavior analysis. To fulfill this objective, autism agencies must operate from validated program systems and do so with fidelity. Program components include, but are not limited to, staff training and evaluation of clinical skills, functional personnel roles designed to promote positive outcomes for those served, and professional staff-communication-skill repertoires. Data on client outcomes must be tied to implementation of core program variables; and, contingencies between the data on client outcomes and staff performance must exist. Furthermore, these contingencies must be yoked across members of the organization to ensure a sustainable and effective program model. Finally, data on consumer satisfaction must be collected and used to evaluate program components and agency practices. Members of the Alliance for Scientific Autism Intervention have implemented key program-wide systems based upon the work of McClannahan and Krantz Journal of Applied Behavior Analysis, 26, 589-596 (1993) for decades and across various agency cultures. Data collected by six independent educational agencies on client outcomes, program implementation, and consumer feedback for a 10-year time span demonstrate the sustainability of the model and support the importance of key organizational systems and the relationship between implementation of the model and high-quality outcomes for individuals with autism.