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In 2018, pegvaliase was approved as the first enzyme substitution treatment for phenylketonuria (PKU) and is now the second medication available for PKU patients since the approval of sapropterin dihydrochloride in 2007. Historically, dietary management has been the mainstay of treatment for PKU. While sapropterin response rate is limited to approximately 50% of PKU patients, pegvaliase has the potential to reduce phenylalanine levels in all PKU patients (Vockley et al., 2014; Longo et al., 2019 [1,3]). Current FDA labeling for pegvaliase includes a dose maximum of 60 mg daily (Longo et al., 2019; BioMarin Pharmaceutical Inc., 2020 [3,4]). We report a case series of four phenylalanine hydroxylase (PAH) deficient patients, previously treated with dietary management only, who initiated treatment with pegvaliase and were titrated to 80 mg daily dosing. The safety profile in these four cases did not differ from lower maintenance dosing (Longo et al., 2019 [3]). Subsequent decreases in Phe levels were observed on 80 mg maintenance dosing, allowing for individualized dietary liberalization in three out of four patients. We conclude that pegvaliase dosing must be personalized to achieve therapeutic goals and that some patients may require higher doses than those included on the product label.

In this study, a widely used colloid of Creighton AgNPs (ORI, 1-100 nm, mostly ≤ 40 nm, ∼10 μg mL -1 ) was rapidly manipulated via tangential flow filtration (TFF) for highly reproducible surface-enhanced (resonance) Raman spectroscopy (SE(R)RS) experiments down to the single-molecule (SM) level. The quasi-spherical AgNPs were size-selected, purified, and concentrated in two TFF fractions of a cutoff diameter of ∼40 nm: AgNP ≤ 40 (∼900 μg mL -1 ) and AgNP ≥ 40 (∼100 μg mL -1 ). The SE(R)S-based sensing capabilities of the two TFF fractions were then tested under pre-resonance (632.8 nm) and resonance (532.1 nm) excitation conditions for rhodamine 6G (R6G, 10 -6 -10 -15 M). Both TFF isolates, AgNP ≤ 40 and AgNP ≥ 40, were more effective in adsorbing the R6G analyte (≥91%) than the original colloid (≥78%) at submonolayer coverages. Furthermore, the surface enhancement factors (SEF) of the two TFF fractions were markedly superior to those of ORI under all excitation conditions. SERS at 632.8 nm: only AgNP ≥ 40 enabled the detection of R6G at 10 -9 M and produced the largest SEF (2.1 × 10 6 ). SE(R)RS and SM-SERRS at 532.1 nm: AgNP ≥ 40 gave rise to the largest SEF values (2.5 × 10 10 ) corresponding to the SM regime down to 10 -15 M of R6G. Nevertheless, AgNP ≤ 40 compensated for the size-dependence of the electromagnetic enhancements by an increase in the silver concentration, which led to SEF values comparable to those of AgNP ≥ 40 through additional resonance enhancements. TFF resulted into a ∼100-fold increase (AgNP ≤ 40) in the number of negatively charged AgNPs that were available to electrostatically bridge R6G cations and form SERRS "hot-spots" (AgNP-R6G-AgNP) within the focal volume. Evidently, the interplay between AgNP size, AgNP concentration, and excitation wavelength governs the SE(R)RS enhancements. This study demonstrated that TFF can facilitate the ecofriendly isolation of spherical AgNPs of controlled morphological and plasmonic properties for further enhancing their sensing capabilities as SE(R)RS substrates., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Phenylketonuria (PKU) is a genetic metabolic disorder that causes the accumulation of phenylalanine (Phe) in tissues, leading to intellectual disability, seizures, and socioemotional challenges. The role of social determinants of health (SDOH) in PKU management has not been formally studied, and this investigation evaluates the association between in-home and in-office factors on blood Phe levels in PKU patients. We conducted a retrospective chart review on over 200 patients attending the well-resourced PKU Clinic at Lurie Children's Hospital of Chicago. Data included patients' average Phe level, various demographic information, and CDC/ATSDR social vulnerability index (SVI) score. The analysis revealed no significant association between social vulnerability status and average Phe level. However, a significant correlation was found between sapropterin dihydrochloride use and average Phe level. Age interacted separately with sex assigned at birth, pegvaliase use, total Phe samples submitted, and the presence of genetic testing to significantly influence the average Phe level. This study highlights the multifactorial influences on PKU management and underscores the importance of social resources, such as clinic social workers and state-provided formula, in modulating the effects of SDOH on PKU control. Further research in different healthcare settings is needed to understand the social determinants affecting PKU patients comprehensively, which will strengthen advocacy efforts for this population., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

According to the facial feedback hypothesis, feedback from facial muscles can initiate and modulate a person's emotional state. This assumption is debated, however, and existing research has arguably suffered from a lack of control over which facial muscles are activated, when, to what degree, and for how long. To overcome these limitations, we carried out a preregistered experiment including 58 participants. Facial neuromuscular electrical stimulation (fNMES) was applied to the bilateral zygomaticus major and depressor anguli oris muscles for 5 s at 100% and 50% of the participants' individual motor threshold. After each trial, participants reported their emotional valence and intensity and levels of experienced discomfort. Facial muscle activations were verified with automatic video coding; heart rate and electrodermal activity were recorded throughout. Results showed that muscle activation through fNMES, even when controlling for fNMES-induced discomfort, modulated participants' emotional state as expected, with more positive emotions reported after stronger stimulation of the zygomaticus major than the depressor anguli oris muscle. The addition of expression-congruent emotional images increased the effect. Moreover, fNMES intensity predicted intensity ratings, reduced HR, and skin conductance response. The finding that changes in felt emotion can be induced through brief and controlled activation of specific facial muscles is in line with the facial feedback hypothesis and offers exciting opportunities for translational intervention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder (LSD) caused by reduced activity of the acid sphingomyelinase (ASM) enzyme, which leads to progressive storage of sphingomyelin and related lipids in the body. ASMD is caused by biallelic variants in the SMPD1 gene, which encodes for the ASM enzyme. Current estimates of disease incidence range from 0.4 to 0.6 in 100 000 livebirths, although this is likely an underestimation of the true frequency of the disorder. While there is no cure for ASMD, comprehensive care guidelines and enzyme replacement therapy are available, making an early diagnosis crucial. Newborn screening (NBS) for ASMD is possible through measurement of ASM activity in dried blood spots and offers the opportunity for early diagnosis. In 2015, Illinois (IL) became the first to initiate statewide implementation of NBS for ASMD. This study describes the outcomes of screen-positive patients referred to Ann & Robert H. Lurie Children's Hospital (Lurie). Ten infants were referred for diagnostic evaluation at Lurie, and all 10 infants were classified as confirmed ASMD or at risk for ASMD through a combination of molecular and biochemical testing. Disease incidence was calculated using data from this statewide implementation program and was ~0.79 in 100 000 livebirths. This study demonstrates successful implementation of NBS for ASMD in IL, with high screen specificity and a notable absence of false positive screens., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Argininosuccinic aciduria (ASA) is a disorder that results from a deficiency in the urea cycle enzyme argininosuccinate lyase. Variable manifestations of this hereditary disorder are associated with hyperammonemia and can include lethargy, somnolence, and respiratory alkalosis in neonates, and vomiting, headaches, and neurocognitive deficiencies later in life. Management of ASA includes rapid measures to address hyperammonemia and long-term steps to maintain metabolic stability. Management paradigms should also consider social determinants of health, which are non-medical factors that influence health outcomes. Here, we describe the case of a male pediatric patient with ASA whose treatment has included considerations for his family's refugee status, language barriers, cultural adjustments, limited income, and transportation challenges., Competing Interests: EV, JB, KH, KA, and SS have participated in advisory boards and/or received honoraria from Amgen Inc. EV has received consulting fees/honoraria from Takeda, BioMarin, and 10.13039/100013995Sanofi Genzyme. JB is principal investigator for a clinical trial sponsored by 10.13039/100013220Ultragenyx. He has received consulting fees/honoraria from Biomarin, Takeda, and 10.13039/100013220Ultragenyx. KB has no conflicts to disclose. KH has participated in advisory boards and/or received honoraria from BioMarin. KA has been involved in clinical trials sponsored by 10.13039/100013220Ultragenyx and Aeglea Therapeutics and has received honoraria from Vitaflo and Acer Therapeutics. SS has received consulting fees/honoraria from BioMarin., (© 2024 The Authors.)

Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The role of facial feedback in facial emotion recognition remains controversial, partly due to limitations of the existing methods to manipulate the activation of facial muscles, such as voluntary posing of facial expressions or holding a pen in the mouth. These procedures are indeed limited in their control over which muscles are (de)activated when and to what degree. To overcome these limitations and investigate in a more controlled way if facial emotion recognition is modulated by one's facial muscle activity, we used computer-controlled facial neuromuscular electrical stimulation (fNMES). In a pre-registered EEG experiment, ambiguous facial expressions were categorised as happy or sad by 47 participants. In half of the trials, weak smiling was induced through fNMES delivered to the bilateral Zygomaticus Major muscle for 500 ms. The likelihood of categorising ambiguous facial expressions as happy was significantly increased with fNMES, as shown with frequentist and Bayesian linear mixed models. Further, fNMES resulted in a reduction of P1, N170 and LPP amplitudes. These findings suggest that fNMES-induced facial feedback can bias facial emotion recognition and modulate the neural correlates of face processing. We conclude that fNMES has potential as a tool for studying the effects of facial feedback., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Multiple object tracking (MOT) is often used as a lab-based paradigm for investigating goal-driven attention as an indicator for "real-world" attention in tasks such as sport. When exploring MOT performance in the context of sporting expertise, we typically observe that individuals with sporting expertise outperform non-sporting individuals. There are a number of general explanations for performance differences such as cognitive transfer effects; however, the potential neurophysiological mechanisms explaining the relationship between sporting expertise and performance differences in MOT are not clear. Based on the role occipital alpha (posterior oscillations usually around 8-12 Hz) has been shown to have in visuospatial attention, the aim of this study was to examine whether individual differences in occipital peak alpha frequency (PAF) mediate the relationship between sporting expertise and performance in two object tracking tasks: a standard MOT task and a visuomotor-controlled object tracking task (multiple object avoidance [MOA])., Method: Using electroencephalography (EEG), participants, who either played sport competitively or did not, had their posterior PAF measured at rest (eyes closed) across a 2-min window. They completed the two tasks separately from the resting EEG measures., Results: Those who engaged in sport performed better in the MOT and MOA tasks and had higher PAF. Higher PAF predicted superior MOT performance. The mediation analysis revealed that sporting individuals had significantly higher PAF, and this was in turn related to superior MOT performance., Conclusions: It is suggested that PAF is a possible neurophysiological mediating mechanism as to why sporting individuals have superior MOT performance. There was no evidence that PAF mediated the relationship between sporting expertise and visuomotor MOA performance. Explanations and implications are discussed, and unanswered questions are proposed., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Chronic low back pain often progresses to widespread pain. Although many factors are associated with progression, their roles in contributing to chronic widespread pain (CWP) are often unclear., Objective: To determine if pain catastrophizing is an independent risk factor for CWP., Design: Retrospective cohort study within a national pain research registry from April 2016 through August 2022., Methods: A total of 1111 participants with chronic low back pain, but without CWP, were included. Participants were followed at quarterly intervals for up to 48 months to measure CWP risk. Survival analyses involved Kaplan-Meier plots and the Cox proportional hazards model to measure CWP risk according to pain catastrophizing and subscale scores for rumination, magnification, and helplessness., Results: Crude CWP risks for moderate pain catastrophizing (HR, 2.13; 95% CI, 1.54-2.95; P < 0.001) and high pain catastrophizing (HR, 3.98; 95% CI, 2.95-5.35; P < 0.001) were each elevated in comparison with low pain catastrophizing. Adjusted CWP risks for moderate pain catastrophizing (HR, 1.80; 95% CI, 1.27-2.53; P < 0.001) and high pain catastrophizing (HR, 2.82; 95% CI, 1.98-4.02; P < 0.001) remained elevated in analyses that controlled for potential confounders. Corresponding results were observed in the survival analyses involving rumination, magnification, and helplessness., Conclusions: Pain catastrophizing appears to be an independent risk factor for progression to CWP among patients with chronic low back pain. These findings provide a rationale for interventions aimed at reducing pain catastrophizing, including rumination, magnification, and helplessness, among patients with chronic low back pain., Competing Interests: Declaration of competing interest No conflicts of interest were reported by the authors of this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cobalamin-G deficiency is an inborn error of metabolism which disrupts the biochemical utilization of vitamin B12 to covert homocysteine to methionine in the remethylation pathway. Typically, affected patients present within the first year of life with anemia, developmental delay, and metabolic crisis. Few case reports of cobalamin-G deficiency reference a later onset phenotype primarily defined by neuropsychiatric symptoms. We report an 18-year-old woman who presented with a 4-year history of progressively worsening dementia, encephalopathy, epilepsy, and regression of adaptive functioning, with an initially normal metabolic workup. Whole-exome sequencing identified variants in the MTR gene, suspicious for cobalamin-G deficiency. Additional biochemical testing after genetic testing supported this diagnosis. Since treatment with leucovorin, betaine, and B12 injections, we have seen a gradual return to normal cognitive function. This case report expands the phenotypic range of cobalamin-G deficiency and offers rationale for genetic and metabolic testing in cases of dementia in the second decade of life., (© 2023 American Academy of Neurology.)

Objective: To describe levels of physical activity (PA) in older adults with rheumatic and musculoskeletal diseases (RMDs) and study the association between PA level and patient-reported outcomes., Methods: Using data from FORWARD, a cross-sectional analysis was performed among adults aged 65 years and older with RMDs to assess the levels of PA. PA was categorized as high (vigorously active for at least 30 minutes, 3 times per week), moderate (moderately active for at least 3 times per week) or low (seldom active). We assessed the self-reported levels of PA among patients with different types of RMDs and assessed the association between levels of PA and PROs, including the 29-item Patient Reported Outcomes Measurement Information System (PROMIS-29) assessment., Results: Among the 3343 eligible participants, rheumatoid arthritis (68%) was the most common RMD. High PA was reported by 457 (13.6%) participants, and 1820 (54.4%) reported moderate activity. Overall, participants reported a median of 7 (IQR 0-15) days of moderate to vigorous level of PA for ≥ 30 min per month. Obese participants were significantly more likely to report low levels of activity (44% of obese compared to 25% of nonobese individuals). Participants with low PA levels had higher (worse) pain scores, higher (worse) Health Assessment Questionnaire-Disability Index scores, higher depression rates, and worse PROMIS-29 scores related to pain, sleep and fatigue., Conclusion: Among patients with RMDs, levels of high PA were relatively low among older patients. These observations, though descriptive, support a relationship between physical inactivity and obesity, depression, poor sleep, and fatigue in patients with RMDs., (Copyright © 2023 by the Journal of Rheumatology.)

Importance: Involvement of palliative care specialists in the care of medical oncology patients has been repeatedly observed to improve patient-reported outcomes, but there is no analogous research in surgical oncology populations., Objective: To determine whether surgeon-palliative care team comanagement, compared with surgeon team alone management, improves patient-reported perioperative outcomes among patients pursuing curative-intent surgery for high morbidity and mortality upper gastrointestinal (GI) cancers., Design, Setting, and Participants: From October 20, 2018, to March 31, 2022, a patient-randomized clinical trial was conducted with patients and clinicians nonblinded but the analysis team blinded to allocation. The trial was conducted in 5 geographically diverse academic medical centers in the US. Individuals pursuing curative-intent surgery for an upper GI cancer who had received no previous specialist palliative care were eligible. Surgeons were encouraged to offer participation to all eligible patients., Intervention: Surgeon-palliative care comanagement patients met with palliative care either in person or via telephone before surgery, 1 week after surgery, and 1, 2, and 3 months after surgery. For patients in the surgeon-alone group, surgeons were encouraged to follow National Comprehensive Cancer Network-recommended triggers for palliative care consultation., Main Outcomes and Measures: The primary outcome of the trial was patient-reported health-related quality of life at 3 months following the operation. Secondary outcomes were patient-reported mental and physical distress. Intention-to-treat analysis was performed., Results: In total, 359 patients (175 [48.7%] men; mean [SD] age, 64.6 [10.7] years) were randomized to surgeon-alone (n = 177) or surgeon-palliative care comanagement (n = 182), with most patients (206 [57.4%]) undergoing pancreatic cancer surgery. No adverse events were associated with the intervention, and 11% of patients in the surgeon-alone and 90% in the surgeon-palliative care comanagement groups received palliative care consultation. There was no significant difference between study arms in outcomes at 3 months following the operation in patient-reported health-related quality of life (mean [SD], 138.54 [28.28] vs 136.90 [28.96]; P = .62), mental health (mean [SD], -0.07 [0.87] vs -0.07 [0.84]; P = .98), or overall number of deaths (6 [3.7%] vs 7 [4.1%]; P > .99)., Conclusions and Relevance: To date, this is the first multisite randomized clinical trial to evaluate perioperative palliative care and the earliest integration of palliative care into cancer care. Unlike in medical oncology practice, the data from this trial do not suggest palliative care-associated improvements in patient-reported outcomes among patients pursuing curative-intent surgeries for upper GI cancers., Trial Registration: ClinicalTrials.gov Identifier: NCT03611309.

A 22-year-old right-handed man with recently diagnosed gout and renal insufficiency presented with 3 months of progressive gait instability and cognitive changes. He initially presented to an outside institution and underwent a broad workup, but an etiology for his symptoms was not found. On subsequent presentation to our institution, his examination revealed multidomain cognitive dysfunction, spasticity, hyperreflexia, and clonus. A broad workup was again pursued and was notable for an MRI of the brain, revealing cortical atrophy advanced for his age, bland CSF, and a weakly positive serum acetylcholine receptor ganglionic neuronal antibody of unclear significance. The history of gout and inadequately explained renal insufficiency led to a workup for inborn errors of metabolism, including urine amino acid analysis, which revealed a homocysteine peak. This finding prompted further evaluation, revealing markedly elevated serum homocysteine and methylmalonic acid and low methionine. He ultimately developed superficial venous thromboses, a segmental pulmonary embolism, and clinical and electrographic seizures. He was initiated on appropriate treatment, and his symptoms markedly improved. The case serves as a reminder to include late-onset inborn errors of metabolism in the differential for young adult patients with onset of neurologic, psychiatric, renal, and thromboembolic symptoms., (© 2022 American Academy of Neurology.)

Continuous sensorimotor coordinations (CSCs) such as driving, walking, using control interfaces or maintaining the body's balance are often performed alongside concurrent cognitive tasks involving attention and executive function. A range of these task combinations show interference, particularly in older adults, but the timing, direction and reciprocity of interference is not yet understood at the level of the tasks' information-processing operations. This paper compares the chronometry of dual task interference between a visual oddball task and a continuous visuomanual tracking task performed by young and older adults. The oddball task's constituent operations were identified using electrophysiological correlates, and deviations in the tracking task reflected perturbations to state monitoring and adjustment characteristics of CSC tasks. Despite instructions to give equal priority to both tasks, older participants maintained a high level of resourcing of the oddball task when dual tasking whereas young participants reduced resourcing to accommodate the demands of the tracking task. Older participants had a longer period of tracking inaccuracy during the executive function component of the oddball task, and unlike in young participants, this decrement was also observed when the stimulus was not a target and the executive function of updating the target tally was not required. These detailed chronometric results clarify that age-related amplification of CSC-cognitive interference are largely due to greater inflexibility in task prioritization. Prioritization of the cognitive task over the CSC in this type of dual tasking may have safety implications in everyday task settings., (Copyright © 2022 Nottingham Trent University. Published by Elsevier B.V. All rights reserved.)

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency., Competing Interests: Joshua Baker, Lauren Hitchins, Erika Vucko, and Katherine Arduini have participated in advisory boards and received honoraria from Horizon Therapeutics plc. Joshua Baker is PI for a clinical trial sponsored by Ultragenyx. He has received consulting fees/honoraria from Biomarin, Horizon, Takeda, and Ultragenyx. Lauren Hitchins has received consulting fees/honoraria from Amicus and Acer Therapeutics. Erika Vucko has received consulting fees/honoraria from Takeda, BioMarin, and Sanofi Genzyme. Katherine Arduini has been involved in clinical trials sponsored by Ultragenyx, and has received consulting fees/honoraria from Acer Therapeutics. Kirsten Havens and Karen Becker have no conflicts to disclose. No authors received compensation for involvement with this manuscript. The authors confirm independence from the sponsor; the content of the article has not been influenced by the sponsor., (© 2022 The Authors.)

For the last several decades, the standard of care for the initial management of rheumatoid arthritis (RA) has been methotrexate. Methotrexate is effective as monotherapy and in combination with conventional, biologic, and targeted-synthetic therapies. Methotrexate is generally well-tolerated, but has important, albeit uncommon, potential side-effects including a risk of liver toxicity and cytopenias. Some studies suggest that more active monitoring in patients with fatty liver disease may be appropriate. With reassuring safety data, more rapid dose escalation and use of subcutaneous therapy may provide even greater success. Some off-target benefits such as a reduction in cardiovascular disease risk have also been demonstrated, though these studies may suffer from confounding. Recent published guidelines continue to endorse methotrexate as first-line therapy. Methotrexate is a low-cost, safe, and effective therapy for RA that should not be overlooked nor too quickly abandoned., Competing Interests: Conflict of interest statement JFB has received consulting fees from Bristol Myers-Squibb, Pfizer, and CorEvitas., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Visual acuity is a critical component of visual function assessment for all ages. Standardized vision testing protocols may help prevent testing inconsistencies resulting from variations in test administration and interpretation of different examiners. However, most vision assessments outside of research settings, including in doctor's offices, rarely employ standardized protocols. Validated protocols such as the Early Treatment for Diabetic Retinopathy Study (ETDRS) are frequently employed by vision researchers to ensure accurate and repeatable visual acuity measurements., Methods: This study evaluates a desktop-based standardized vision testing algorithm (EyeSpy 20/20) specifically designed for use on mobile electronic platforms. Subjects were tested on a desktop version of the EyeSpy software for both the accuracy and duration of measurement of visual acuity and compared to a e-ETDRS chart in a randomized sequence. Children were recruited for this study and tested between two different visual acuity measurement systems. Bland-Altman analysis and correlation tests were done., Results: Hundred and ten children were recruited for the study. The EyeSpy 20/20 visual acuity testing algorithm as tested with the desktop version was non-inferior to the gold standard e-ETDRS testing algorithm on a desktop platform, but statistically faster to implement when administered on the same electronic testing platform., Conclusion: EyeSpy 20/20 is a promising tool for vision screening and visual acuity evaluation in children., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Vasudevan et al.)

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common therapy for pediatric hematologic malignancies. With improved supportive care, addressing treatment-related late effects is at the forefront of survivor long-term health and quality of life. We previously demonstrated that alloHSCT survivors had increased adiposity, decreased lean mass, and lower bone density and strength, 7 years (median) from alloHSCT compared to their healthy peers. Yet it is unknown whether these deficits persist. Our longitudinal study characterized changes in muscle and bone over a period of 3.4 (range, 2.0 to 4.9) years in 47 childhood alloHSCT survivors, age 5-26 years at baseline (34% female). Tibia cortical bone geometry and volumetric density and lower leg muscle cross-sectional area (MCSA) were assessed via peripheral quantitative computed tomography (pQCT). Anthropometric and pQCT measurements were converted to age, sex, and ancestry-specific standard deviation scores, adjusted for leg length. Muscle-specific force was assessed as strength relative to MCSA adjusted for leg length (strength Z-score). Measurements were compared to a healthy reference cohort (n = 921), age 5-30 years (52% female). At baseline and follow-up, alloHSCT survivors demonstrated lower height Z-scores, weight Z-scores, and leg length Z-scores compared to the healthy reference cohort. Deficits in MCSA, trabecular volumetric bone density, and cortical bone size and estimated strength (section modulus) were evident in survivors (all p < 0.05). Between the two study time points, anthropometric, muscle, and bone Z-scores did not change significantly in alloHSCT survivors. Approximately 15% and 17% of alloHSCT survivors had MCSA and section modulus Z-score < -2.0, at baseline and follow-up, respectively. Furthermore, those with a history of total body irradiation compared to those without demonstrated lower MCSA at follow-up. The persistent muscle and bone deficits in pediatric alloHSCT survivors support the need for strategies to improve bone and muscle health in this at-risk population. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

A perceptual bias towards negative emotions is a consistent finding in mood disorders and a major target of therapeutic interventions. Placebo responses in antidepressant treatment are substantial, but it is unclear whether and how underlying expectancy effects can modulate response biases to emotional inputs. In a first attempt to approach this question, we investigated how placebo induced expectation can shape the perception of specific emotional stimuli in healthy individuals. In a controlled cross-over design, positive treatment expectations were induced by verbal instructions and a hidden training manipulation combined with an alleged oxytocin nasal spray before participants performed an emotion classification task on happy and fearful facial expressions with varying intensity. Analyses of response criterion and discrimination ability as derived from emotion-specific psychometric functions demonstrate that expectation specifically lowered participants' threshold for identifying happy emotions in general, while they became less sensitive to subtle differences in emotional expressions. These indications of a positivity bias were directly correlated with participants' treatment expectations as well as subjective experiences of treatment effects and went along with a significant mood enhancement. Our findings show that expectations can induce a perceptual positivity effect in healthy individuals which is probably modulated by top-down emotion regulation and which may be able to improve mood state. Clinical implications of these promising results now need to be explored in studies of expectation manipulation in patients with mood disorders., (© 2022. The Author(s).)

Background: Urate-lowering therapy (ULT) adherence is low in gout, and few, if any, effective, low-cost, interventions are available. Our objective was to assess if a culturally appropriate gout-storytelling intervention is superior to an attention control for improving gout outcomes in African-Americans (AAs)., Methods: In a 1-year, multicenter, randomized controlled trial, AA veterans with gout were randomized to gout-storytelling intervention vs. a stress reduction video (attention control group; 1:1 ratio). The primary outcome was ULT adherence measured with MEMSCap™, an electronic monitoring system that objectively measured ULT medication adherence., Results: The 306 male AA veterans with gout who met the eligibility criteria were randomized to the gout-storytelling intervention (n = 152) or stress reduction video (n = 154); 261/306 (85%) completed the 1-year study. The mean age was 64 years, body mass index was 33 kg/m 2 , and gout disease duration was 3 years. ULT adherence was similar in the intervention vs. control groups: 3 months, 73% versus 70%; 6 months, 69% versus 69%; 9 months, 66% versus 67%; and 12 months, 61% versus 64% (p > 0.05 each). Secondary outcomes (gout flares, serum urate and gout-specific health-related quality of life [HRQOL]) in the intervention versus control groups were similar at all time points except intervention group outcomes were better for the following: (1) number of gout flares at 9 months were fewer, 0.7 versus 1.3 in the previous month (p = 0.03); (2) lower/better scores on two gout specific HRQOL subscales: gout medication side effects at 3 months, 32.8 vs. 39.6 (p = 0.02); and unmet gout treatment need at 3 months, 30.9 vs. 38.2 (p = 0.003), and 6 months, 29.5 vs. 34.5 (p = 0.03), respectively., Conclusions: A culturally appropriate gout-storytelling intervention was not superior to attention control for improving gout outcomes in AAs with gout., Trial Registration: Registered at ClinicalTrials.gov NCT02741700., (© 2021. The Author(s).)

Error monitoring allows for the efficient performance of goal-directed behaviors and successful learning. Furthermore, error monitoring as a metacognitive ability may play a crucial role for neuropsychological interventions, such as rehabilitation. In the past decades, research has suggested two electrophysiological markers for error monitoring: the error-related negativity (ERN) and the error positivity (Pe), thought to reflect, respectively, error detection and error awareness. Studies on several neurological diseases have investigated the alteration of the ERN and the Pe, but these findings have not been summarized. Accordingly, a systematic review was conducted to understand what neurological conditions present alterations of error monitoring event-related potentials and their relation with clinical measures. Overall, ERN tended to be reduced in most neurological conditions while results related to Pe integrity are less clear. ERN and Pe were found to be associated with several measures of clinical severity. Additionally, we explored the contribution of different brain structures to neural networks underlying error monitoring, further elaborating on the domain-specificity of error processing and clinical implications of findings. In conclusion, electrophysiological signatures of error monitoring could be reliable measures of neurological dysfunction and a robust tool in neuropsychological rehabilitation., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Schizotypy denotes psychosis-like experiences, such as perceptual aberration, magical ideation, and social anxiety. Altered physiological arousal from social stress is found in people with high schizotypal traits. Two experiments aimed to determine the relationship of schizotypy to physiological arousal from social stress. Experiment 1 tested the hypotheses that heart rate from social stress would be greater in high, than mild-to-moderate, schizotypal traits, and disorganized schizotypy would explain this effect because of distress from disorganisation. Experiment 1 tested social stress in 16 participants with high schizotypal traits and 10 participants with mild-to-moderate schizotypal traits. The social stress test consisted of a public speech and an informal discussion with strangers. The high schizotypal group had a higher heart rate than the mild-to-moderate schizotypal group during the informal discussion with strangers, but not during the public speech. Disorganized schizotypy accounted for this group difference. Experiment 2 tested the hypothesis that mild-to-moderate schizotypal traits would have a linear relationship with physiological arousal from social stress. Experiment 2 tested 24 participants with mild-to-moderate schizotypal traits performing the abovementioned social stress test while their heart rate and skin conductance responses were measured. Mild-to-moderate schizotypal traits had a linear relationship with physiological arousal during the discussion with strangers. Distress in disorganized schizotypy may explain the heightened arousal from close social interaction with strangers in high schizotypy than mild-to-moderate schizotypy. Mild-to-moderate schizotypal traits may have a linear relationship with HR during close social interaction because of difficulty with acclimatizing to the social interaction.

Introduction: Surveillance systems have become a valuable tool to capture epidemiological data at multi-sport events, with findings serving to predict and prevent injury, reduce illness, and guide efficient utilization of medical resources. In 2016, the first injury and illness surveillance tool for the Department of Defense (DoD) Warrior Games was established to inform the required medical footprint. The purpose of this paper is to describe the methods and findings from the 2016 DoD Warrior Games surveillance system, which included a database of injuries and illness., Materials and Methods: A total of 245 wounded warrior (WW) athletes were followed over 19 days, to include train-up and competition periods, as they competed for their respective teams of Army, Navy, Air Force, Marines, Special Operations, and United Kingdom. Medical personnel recorded injuries and illnesses treated utilizing a standardized surveillance form and data were entered into a daily tracker to examine patterns or areas for prevention. Reports included sex, age, event discipline, previous injury or illness, reason for presentation, and treatment provided., Results: From June 3 to June 21, 2016, 114 individual encounters were recorded on the standard form and entered into the surveillance database. Athletes accounted for 67% of all encounters. Illness accounted for 30.7% of all visits, while injuries accounted for 69.2%. The incident proportion of injuries in athletes was 23.3 injuries per 100 athletes (95% CI 17.6, 30.1) and incident rate of 12.2 injuries per 1000 athlete days. Integrative medicine treatments including acupuncture, osteopathic manipulative treatment (OMT), massage therapy, and gua sha accounted for the largest forms of treatment (31%)., Conclusions: From the surveillance data, staff levels and treatment supplies can be adjusted. In addition an improved surveillance tool can be created. Continuous surveillance is required to provide information on trends in injury and illness to support prevention strategies., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2019.)

Schizotypy is a latent organisation of a cluster of personality styles, such as magical thinking, disorganisation and anhedonia, which are in the normal range of the psychosis continuum. Schizotypy relates to an increased likelihood of perceiving expressed emotion (EE). EE is characterised by criticism, rejection, and emotional over-involvement and less warmth from a close relative. Neuroimaging studies have found normal frontal lobe activation to EE-criticism in people with high schizotypy. Alternatively, electroencephalography measures emotion processing, such as frontal theta power and occipital alpha power. Frontal theta power responds to cognitive and affective processes and occipital alpha power denotes less consciousness and emotional attention. This study aimed to determine the relation of these electroencephalography responses during criticism and praise to perceived emotional support. Participants (n = 32) representing the full (low-to-high) range of positive schizotypy listened to and rated the self-relevance of EE-like criticism and praise and affectively neutral comments while undergoing electroencephalography. Participants completed self-report measures of schizotypy, depression and anxiety. A subset of those with a high positive schizotypy score (n = 22) completed a measure of perceived EE - lack of emotional support. Higher perceived EE - lack of emotional support correlated with lower frontal theta power and lower occipital alpha power during criticism and praise in schizotypal participants. The findings suggest that these neural responses may relate to less perceived emotional support in people with high schizotypy, of which a reduction of frontal theta power denotes less emotional arousal and lower occipital alpha power denotes more alertness to emotional information may relate to less perceived emotional support in people with high schizotypy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to compare the risk factors for caries between patients with primary Sjogren syndrome (SS) and those with non-Sjogren syndrome (NSS) salivary hypofunction and to identify the prevalence of incisal or cervical/root caries in each group., Study Design: This was a retrospective, cross-sectional study conducted at a single center between 2012 and 2015 for assessment of patients with possible SS. Two-hundred and twenty-five (225) patients (99 SS and 126 NSS) participated in the study., Results: Student t test and Wilcoxon's rank sum test were used to evaluate group differences in continuous variables and the χ 2 test was used to determined differences in categorical variables. Significant univariate associations were further assessed by using multivariate ordinal regression models. Patients with SS were more likely to have a greater number of total caries (odds ratio [OR] 1.72 [1.03-2.88]; P = .04). And a focus score greater than 1/4 mm 2 was associated with greater number of total caries (OR 2.88 [1.05, 7.93]; P = .04]. Adjusted analysis for salivary flow did not show a significant association between stimulated or unstimulated salivary flow or glandular-specific salivary flow and the total number of carious lesions., Conclusions: Patients with salivary hypofunction secondary to SS do have a greater caries risk compared with patients with salivary hypofunction caused by other factors. In this study cohort, this finding was not associated with salivary flow rates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study evaluates the influence of comprehensive health care coordination for children with special health care needs (CSHCN) in a resident continuity clinic. CSHCN patients were identified from 2 resident continuity panels. Patients were eligible with a score of 2 or greater on the CSHCN screener. Interventions included extended appointment times, a binder, and direct phone access to the social worker who facilitated follow-up appointment scheduling. Data measured included completed and no-show visits for primary care and subspecialty appointments, hospitalization and emergency department visits, use of binders, and parent satisfaction surveys. Patients with a baseline CSHCN screener score ≥4 were 15.6 times more likely to keep their appointment after enrollment ( P = .0035). Mental health no-show visits decreased significantly ( P < .0001). The utilization of components of comprehensive team-based care coordination, even with limited resources, can improve the delivery of health care for children with complex medical needs and mental health disorders in a resident-based clinic., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Light-flicker Ganzfeld (LFG) induces a lower to upper-alpha frequency shift. However, it is unclear how this neurophysiological response might relate to LFG-induced pseudo-hallucinatory phenomena. It is also unknown whether emotional states (e.g., fear) or traits associated with risk for psychosis (e.g., proneness to perceptual anomalies, ability to produce vivid mental imagery) affect such neurophysiological and/or perceptual responses to LFG. The present study investigated alpha sub-bands during LFG across several flicker frequencies, in relation to individual differences in propensity for Ganzfeld-induced imagery (GI), positive schizotypy and trait mental imagery, and in relation to manipulations of affective state. Given previously reported sex differences in risk for psychosis and response to Ganzfeld, the effect of sex on GI was also studied. Forty-six healthy adults (16 men) completed psychometric measures of trait mental imagery and positive schizotypy before undergoing three LFG (20 min each) conditions. In each condition, participants wore white-out goggles and listened to either mood-inducing soundscapes (fear, serenity) or pink noise (control) through headphones. Greatest propensity for GI arose between 13.1 and 16.0 Hz flicker, with a peak at 16.0 Hz flicker. Occipital lower-alpha was reduced for lower flicker frequencies (13.1-16.0 Hz) and was inversely associated with GI. Upper-alpha power was not significantly related to GI or to other measures. Fear-induction was associated with reduction in alpha power, but did not significantly affect GI. Men reported more GI than women. Findings support a role for cortical destabilisation, as reflected in reduced lower-alpha, in perceptual anomalies; and, by extension, LFG as an experimental model of liability for psychosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α 1 -subunit of the voltage-gated Ca V 2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca V 2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We previously reported significant gains in pQCT measures of tibia trabecular bone mineral density (BMD) and cortical structure following completion of therapy in children and adolescents with acute lymphoblastic leukemia (ALL). The objective of this study was to examine changes in DXA measures used in clinical practice and expressed as Z-scores using robust national reference data. Children and adolescents, ages 5 to 18 years were enrolled within 2 (median 0.8) years of completing ALL therapy. DXA total-body less-head bone mineral content (TBLH-BMC), and spine, total hip, femoral neck, and 1/3rd radius areal BMD (aBMD) were assessed in 45 participants at enrollment and 12-months later. Linear regression models examined correlates of changes in DXA Z-scores. Changes in DXA outcomes were compared to changes in tibia pQCT trabecular and cortical volumetric BMD (vBMD) and cortical area. At enrollment, DXA TBLH-BMC, spine and radius aBMD Z-scores were not significantly reduced in ALL survivors; however, total hip [median -0.74 (IQ range -1.51 to -0.04)] and femoral neck [-0.51 (-1.24 to 0.14)] aBMD Z-scores were lower (both p < 0.01) compared to reference data. DXA Z-scores at all skeletal sites increased over 12 months. Despite improvement, total hip Z-score remained lower at -0.55 (-1.05 to 0.18). The increases in TBLH-BMC, total hip and femoral neck aBMD Z-scores were more pronounced in those enrolled within 6 months of completing ALL therapy, compared to those enrolled at >6 months. Gains in TBLH-BMC, total hip, femoral neck and radius aBMD Z-scores were significantly associated with gains in tibia cortical area Z-scores (R = 0.56 to 0.67, p ≤ 0.001). Changes in TBLH and proximal femur sites were associated with gains in trabecular vBMD Z-scores (R = 0.37 to 0.40; p ≤ 0.01); these associations were not significant when adjusted for gains in cortical area. In summary, gains in DXA measures were most pronounced in total hip and femoral neck following ALL therapy. The gains in all DXA measures, with the exception of lumbar spine, reflected gains in cortical area. Overall, ALL survivors demonstrate skeletal recovery following completion of therapy; a small sub-group continue to demonstrate deficits and benefit from continued observation to ensure improvement over time., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Everyday cognitive tasks are frequently performed under dual-task conditions alongside continuous sensorimotor coordinations (CSCs) such as driving, walking, or balancing. Observed interference in these dual-task settings is commonly attributed to demands on executive function or attentional resources, but the time course and reciprocity of interference are not well understood at the level of information-processing components. Here we used electrophysiology to study the detailed chronometry of dual-task interference between a visual oddball task and a continuous visuomanual tracking task. The oddball task's electrophysiological components were linked to underlying cognitive processes, and the tracking task served as a proxy for the continuous cycle of state monitoring and adjustment inherent to CSCs. Dual-tasking interfered with the oddball task's accuracy and attentional processes (attenuated P2 and P3b magnitude and parietal alpha-band event-related desynchronization), but errors in tracking due to dual-tasking accrued at a later timescale and only in trials in which the target stimulus appeared and its tally had to be incremented. Interference between cognitive tasks and CSCs can be asymmetric in terms of timing as well as affected information-processing components. NEW & NOTEWORTHY Interference between cognitive tasks and continuous sensorimotor coordination (CSC) has been widely reported, but this is the first demonstration that the cognitive operation that is impaired by concurrent CSC may not be the one that impairs the CSC. Also demonstrated is that interference between such tasks can be temporally asymmetric. The asynchronicity of this interference has significant implications for understanding and mitigating loss of mobility in old age, and for rehabilitation for neurological impairments.

Objective: The objective of this study was to examine cause-specific mortality in patients with PsA compared with the general population and compared with patients with RA., Methods: A cohort study was performed using The Health Improvement Network among patients aged 18-89 years with data from 1994 to 2010. PsA and RA were defined by medical codes, and up to 10 unexposed controls were matched on practice and start date within the practice. Cause of death was classified using categories from UK death statistics. Each death was manually reviewed to ensure appropriate classification. Age- and sex-adjusted hazard ratios (HRs) and multivariable adjusted HRs were calculated using competing risks survival regression., Results: Among patients with PsA (8706), RA (41 752) and unexposed controls (81 573), 470, 7004 and 5269 deaths were observed, respectively. The most common causes of death among all patients were cardiovascular disease, followed by malignancy, respiratory deaths and infection. Cause of death was unknown in ∼25%. Among PsA patients, cardiovascular (1.09, 0.91-1.32), respiratory (0.97, 0.79-1.20), malignancy (1.03, 0.86-1.25) and infection deaths (1.05, 0.79-1.39) were not elevated. Among patients with RA, cardiovascular (1.55, 1.44-1.66), respiratory (1.85, 1.72-2.01), malignancy (1.18, 1.08-1.28) and infection deaths (2.21, 2.00-2.44) were significantly elevated compared with population controls. Although less common, suicide deaths were elevated in PsA and RA (HR 3.03 and 2.47, respectively)., Conclusion: Overall mortality and cause-specific mortality risk were not elevated among patients with PsA except for suicide deaths. Patients with RA were at increased risk of deaths from cardiovascular, respiratory, cancer and infectious diseases., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: To determine the risk of fracture and osteoporosis among patients with psoriatic arthritis (PsA) and psoriasis, compared with the general population and patients with rheumatoid arthritis (RA)., Methods: A population-based cohort study was performed in The Health Improvement Network in the UK using data from 1994 to 2014. Patients aged 18-89 years with PsA or psoriasis and up to five unexposed controls matched by practice and start date within that practice were included. Patients with RA and matched controls were included for comparison. Severe psoriasis was defined by a code for psoriasis and either phototherapy or a systemic medication for psoriasis. Incidence and adjusted HRs (aHR) for fracture (all, hip, vertebral) were calculated., Results: Patients with PsA (n=9788), psoriasis (n=158 323) and controls (n=821 834) were identified. Patients with PsA had an elevated risk of all fracture aHR 1.26 (1.06 to 1.27). Patients with mild psoriasis had elevated risk of all fractures, vertebral and hip fracture: aHR 1.07 (1.05 to 1.10), 1.17 (1.03 to 1.33) and 1.13 (1.04 to 1.22). Patients with severe psoriasis had significantly elevated risk of all fracture and vertebral fracture: aHR 1.26 (1.15 to 1.39) and 2.23 (1.54 to 3.22)., Conclusions: PsA and psoriasis are associated with an elevated risk for fracture., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The objective of this study was to determine health-related quality of life (HRQoL) in patients with ANCA-associated vasculitis (AAV) as measured by the "routine assessment of patient index data 3" (RAPID3) and whether RAPID3 is correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). Data from patients at an academic institution vasculitis clinic seen between Jan 2010 and Jan 2012 were collected using chart review. BVAS and RAPID3 scores were calculated at each patient visit. RAPID3 was compared between patients in remission (BVAS = 0) and patients with active disease (BVAS > =1) at all visits for four consecutive visits, when data available, at least 3 months apart during the period mentioned. Robust generalized estimating equations (GEE) in linear regression models evaluated associations between the RAPID3 and BVAS over all available observations, adjusting for intra-subject correlations. Thirty-four patients were included in the study, 26 had granulomatosis with polyangiitis (GPA), five microscopic polyangiitis (MPA), and three eosinophilic granulomatosis with polyangiitis (EGPA). Patients at first visit had impaired HRQoL as measured by RAPID3 [6.8 (3.1-12.6)]. The median RAPID3 scores were higher in patients with active disease as compared to patients in remission (7.0 vs. 3.0, p = 0.115; 8.8 vs. 1.0, p = 0.011; 6.1 vs. 2.0, p = 0.032; and 11.7 vs. 2.0, p = 0.128 for visits 1, 2, 3, and 4, respectively). In longitudinal GEE models incorporating all observations there was a strong association between the RAPID3 (per 1 unit) and BVAS (per 1 unit) [β 0.21 (0.10, 0.32) p < 0.001]. RAPID3 can be used to measure HRQoL in patients with AAV. RAPID3 correlated significantly with BVAS. RAPID3 can discriminate between disease states in AAV. This instrument may help document patient experience and add to clinical decisions.

Objective: To examine whether vascular calcifications on hand films in RA might aid in determining mortality risk., Methods: Hand radiographs from 906 RA patients were scored as positive or negative for vascular calcifications. Patient characteristics associated with vascular calcifications were assessed using multivariable logistic regression, and associations with mortality were examined using Cox proportional hazards regression. Cytokines and multiplex ACPA were measured in both groups., Results: A total of 99 patients (11%) demonstrated radiographic vascular calcifications. Factors independently associated with vascular calcifications included diabetes [odds ratio (OR) 2.85; 95% CI 1.43, 5.66], cardiovascular disease at enrolment (OR 2.48; 95% CI 1.01, 6.09), prednisone use (OR 1.90; 95% CI 1.25, 2.91), current smoking (OR 0.06; 95% CI 0.01, 0.23) and former smoking (OR 0.36; 95% CI 0.27, 0.48) vs never smoking. In cytokine and ACPA subtype analysis, IL-4 and anti-citrullinated apolipoprotein E were significantly increased in patients with vascular calcifications in fully adjusted multivariable models. After multivariable adjustment, vascular calcifications were associated with an increase in all-cause mortality (hazard ratio 1.41; 95% CI 1.12, 1.78; P = 0.004)., Conclusion: Vascular calcifications on hand radiographs were independently associated with increased all-cause mortality in RA. Mechanisms underpinning the associations of IL-4 and select ACPA with vascular calcifications and their utility as biomarkers predictive of cardiovascular disease risk in RA merit further study., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2015. This work is written by US Government employees and is in the public domain in the US.)

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) survivors treated with total body irradiation (TBI) exhibit bone deficits and excess adiposity, potentially related to altered mesenchymal stem cell differentiation into osteoblasts or adipocytes. We examined associations among fat distribution, bone microarchitecture, and insulin resistance in alloHSCT survivors after TBI. This was a cross-sectional observational study of 25 alloHSCT survivors (aged 12 to 25 years) a median of 9.7 (4.3 to 19.3) years after alloHSCT compared to 25 age-, race-, and sex-matched healthy controls. Vertebral MR spectroscopic imaging and tibia micro-MRI were used to quantify marrow adipose tissue (MAT) and trabecular microarchitecture. Additional measures included DXA whole-body fat mass (WB-FM), leg lean mass (Leg-LM), trunk visceral adipose tissue (VAT), and CT calf muscle density. Insulin resistance in alloHSCT survivors was estimated by HOMA-IR. AlloHSCT survivors had lower Leg-LM (p < 0.001) and greater VAT (p < 0.01), MAT (p < 0.001), and fat infiltration of muscle (p = 0.04) independent of WB-FM, versus matched controls; BMI did not differ. Survivors had lower bone volume fraction and abnormal microarchitecture including greater erosion and more rod-like structure versus controls (all p = 0.04); 14 had vertebral deformities and two had compression fractures. Greater WB-FM, VAT, MAT, and muscle fat infiltration were associated with abnormal trabecular microarchitecture (p < 0.04 for all). AlloHSCT HOMA-IR was elevated, associated with younger age at transplantation (p < 0.01), and positively correlated with WB-FM and VAT (both p < 0.01). In conclusion, the markedly increased marrow adiposity, abnormal bone microarchitecture, and abnormal fat distribution highlight the risks of long-term treatment-related morbidity and mortality in alloHSCT recipients after TBI. Trabecular deterioration was associated with marrow and visceral adiposity. Furthermore, long-term survivors demonstrated sarcopenic obesity, insulin resistance, and vertebral deformities. Future studies are needed to identify strategies to prevent and treat metabolic and skeletal complications in this growing population of childhood alloHSCT survivors., (© 2015 American Society for Bone and Mineral Research.)

Across a wide range of tasks, research has shown that people make poor probabilistic predictions of future events. Recently, the U.S. Intelligence Community sponsored a series of forecasting tournaments designed to explore the best strategies for generating accurate subjective probability estimates of geopolitical events. In this article, we describe the winning strategy: culling off top performers each year and assigning them into elite teams of superforecasters. Defying expectations of regression toward the mean 2 years in a row, superforecasters maintained high accuracy across hundreds of questions and a wide array of topics. We find support for four mutually reinforcing explanations of superforecaster performance: (a) cognitive abilities and styles, (b) task-specific skills, (c) motivation and commitment, and (d) enriched environments. These findings suggest that superforecasters are partly discovered and partly created-and that the high-performance incentives of tournaments highlight aspects of human judgment that would not come to light in laboratory paradigms focused on typical performance., (© The Author(s) 2015.)

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for surgical high-risk patients with severe aortic stenosis. The aim of this study was to determine the impact of atrial fibrillation (AF) on procedural outcomes. Data from 137 patients who underwent TAVR using Edwards SAPIEN valve were reviewed. The predictors of new-onset atrial fibrillation (NOAF) after the procedure were analyzed. In addition, the post-TAVR clinical outcomes and adverse events were compared according to the presence and absence of preprocedural and postprocedural AF. Previous AF was present in 49% of the patients who underwent TAVR. After the procedure, NOAF was detected in 21% of patients, and the cumulative incidence of post-TAVR AF was 60%. After TAVR, 50% of all the episodes of NOAF occurred in the initial 24 hours after the procedure. Transapical approach was observed to an important predictor of NOAF (adjusted odds ratio [OR] 5.05, 95% confidence interval [CI] 1.40 to 18.20, p = 0.013). The composite outcome of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after TAVR was significantly higher in patients with previous AF (33 of 67 vs 19 of 70, adjusted OR 2.60, 95% CI 1.22 to 5.54, p = 0.013) compared with patients who did not have previous AF. The presence of post-TAVR AF led to a prolongation in the duration of intensive care unit stay by an average of 70 hours (95% CI 25 to 114.7 hours, p = 0.002). Similarly, post-TAVR AF also led to the prolongation in the hospital stay by an average of 6.7 days (95% CI 4.69 to 8.73 days, p <0.0005). In conclusion, our study demonstrates that the presence of AF before TAVR is an important predictor of the composite end point of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after the procedure. AF after TAVR is more likely to be encountered with the transapical approach and is associated with a prolongation of intensive care unit and hospital stay., (Copyright © 2015 Elsevier Inc. All rights reserved.)

New and innovative tools have emerged for the treatment of massive and submassive pulmonary embolism (PE). These novel treatments, when considered alongside existing therapy, such as anticoagulation, systemic intravenous thrombolysis, and open surgical pulmonary embolectomy, have the potential to improve patient outcomes. However, data comparing different treatment modalities are sparse, and guidelines provide only general advice for their use. Treatment decisions rest on clinician expertise and institutional resources. Because various medical and surgical specialties offer different perspectives and expertise, a multidisciplinary approach to patients with massive and submassive PE is required. To address this need, we created a novel multidisciplinary program - the Massachusetts General Hospital (MGH) Pulmonary Embolism Response Team (PERT) - which brings together multiple specialists to rapidly evaluate intermediate- and high-risk patients with PE, formulate a treatment plan, and mobilize the necessary resources to provide the highest level of care. Development of a clinical, educational, and research infrastructure, as well as the creation of a national PERT consortium, will make our experience available to other institutions and serve as a platform for future studies to improve the care of complex patients with massive and submassive PE.

Background: A combined open surgical and endovascular approach to managing aneurysms of the distal aortic arch (hybrid arch repair) is evolving as a viable treatment option. Our aim is to describe a treatment strategy in high-risk patients and report the technical and clinical success of the hybrid approach to aneurysms involving the distal aortic arch., Methods: From July 2005 until December 2009, 27 consecutive patients with aneurysms of the distal aortic arch were treated via a hybrid arch repair. Of this group, 23 patients underwent aortic arch debranching and revascularization before endovascular stent deployment in the ascending aorta (type I). Four patients required ascending aortic and transverse arch replacement before stent graft deployment (type II)., Results: A stent graft was successfully deployed in 100% of patients after aortic arch vessel debranching via median sternotomy. The mean age of the patients was 71 ± 7.5 years. The average cardiopulmonary bypass time was 199 ± 84 minutes with an average crossclamp time of 57 ± 53 minutes. Deep hypothermic circulatory arrest was required in 4 patients (all type II). The average length of stay was 17.2 ± 14 days. The complications included stroke in 3 (11%) patients, permanent paralysis in 2 (7%), and perioperative death in 3 (11%) patients., Conclusions: Early results of type I and II hybrid arch repair, in this cohort of patients with mutiple comorbid risk factors, are acceptable and even encouraging. This evolving approach to aneurysms involving the aortic arch may extend the indications for use of endovascular prostheses in the treatment of patients with complex aortic arch disease., (Copyright © 2010. Published by Mosby, Inc.)

We have investigated the mechanisms that control the guidance of corticofugal projections as they extend along different subdivisions of the forebrain. To this aim, we analyzed the development of cortical projections in mice that lack Nkx2-1, a homeobox gene whose expression is restricted to two domains within the forebrain: the basal telencephalon and the hypothalamus. Molecular respecification of the basal telencephalon and hypothalamus in Nkx2-1-deficient mice causes a severe defect in the guidance of layer 5 cortical projections and ascending fibers of the cerebral peduncle. These axon tracts take an abnormal path when coursing through both the basal telencephalon and hypothalamus. By contrast, loss of Nkx2-1 function does not impair guidance of corticothalamic or thalamocortical axons. In vitro experiments demonstrate that the basal telencephalon and the hypothalamus contain an activity that repels the growth of cortical axons, suggesting that loss of this activity is the cause of the defects observed in Nkx2-1 mutants. Furthermore, analysis of the expression of candidate molecules in the basal telencephalon and hypothalamus of Nkx2-1 mutants suggests that Slit2 contributes to this activity.