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Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naive mice, mice with pegloticase-induced APA rapidly cleared 89Zr-labeled pegloticase, with ~75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naive mice. In contrast, pre-infusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to ~80% of that seen in naive mice, resulting in a similar biodistribution to pegloticase in naive mice over time. These results suggest that pre-infusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.

This study measured therapist behaviors in relation to subsequent habituation within exposure tasks, and also tested their direct and indirect relationships (via habituation) with clinical outcomes of exposure therapy. We observed 459 videotaped exposure tasks with 111 participants in three clinical trials for pediatric obsessive-compulsive disorder (POTS trials). Within exposure tasks, therapist behaviors and patient fear were coded continuously. Outcomes were habituation and post-treatment change in symptom severity, global improvement, and treatment response. More therapist behaviors that encourage approach—and less use of accommodation, unrelated talk, and externalizing language—predicted greater subsequent habituation during individual exposure tasks (exposure-level), and also predicted improved patient clinical outcomes via higher ‘total dose’ of habituation across treatment (patient-level indirect effect). For six of seven therapist behaviors analyzed, the relationship with subsequent habituation within exposure differed by patient fear (low, moderate, or high) at the time the behavior was used. Two therapist behaviors had direct effects in the opposite direction expected; more unrelated talk and less intensifying were associated with greater patient symptom reduction. Results shed light on the “black box” of in-session exposure activities and point to specific therapist behaviors that may be important for clinical outcomes. These behaviors might be best understood in the context of changing patient fear during exposure tasks. Future studies should test whether therapist behaviors can be experimentally manipulated to produce improvement in clinical outcomes.

Objective This article examined associations between change in youth and family characteristics during youth anxiety treatment and long-term anxiety severity and overall functioning. Method Participants (N = 488; age 7-17 years; 45% male; 82% white) were randomized to 12 weeks of cognitive behavioral therapy (Coping Cat), medication (sertraline), their combination, or pill placebo in the Child/Adolescent Anxiety Multimodal Study (CAMS). A subset participated in the naturalistic follow-up Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS; n = 319; 3.70-11.83 years post-treatment). The current secondary analyses examined how change in anxiety severity (Child Global Impression-Severity), overall functioning (Children's Global Assessment Scale), caregiver psychopathology (Brief Symptom Inventory), caregiver strain (Family Burden Assessment Scale), and family dysfunction (Brief Family Assessment Measure) during CAMS was associated with anxiety severity and overall functioning years later (M = 7.72 years). CAMS procedures were registered on clinialtrials.gov. Results Improvements in factors related to functioning (i.e., overall functioning, family dysfunction, caregiver strain) were associated with improvements in anxiety severity in CAMELS (|βys| ≥ .04, ps ≤ .04). Improvements in factors related to psychopathology (i.e., anxiety severity, caregiver psychopathology) were associated with improvements in overall functioning in CAMELS (|βys| ≥ .23, ps ≤ .04). It was changes in each of the variables examined (rather than baseline values) that predicted anxiety severity and overall functioning. Conclusions Both youth and family factors play a significant role in long-term treatment outcomes. Therapists would be wise to monitor how these factors change throughout treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Advancing mechanism-focused research in implementation science is a priority given its potential to improve tailoring and efficiency of implementation strategies. Experimental therapeutics, or experimental medicine, offers an approach for mechanism testing that has been promoted by the NIH Science of Behavior Change and endorsed by the National Institute for Mental Health. This approach has been applied across the translational spectrum - with initial applications to biological research and more recent applications to psychosocial treatment development research. We describe further advancement of experimental therapeutics along the translational spectrum and describe how it is ideally suited to inform precision experimental tests of implementation strategy mechanisms, which we term precision implementation. Such an approach to mechanism testing will allow for identification of causal dose-response relationships between implementation strategies, presumed mechanisms, and implementation outcomes. We discuss the tension between the scientific rigor required to conduct mechanism-focused research using experimental therapeutics and the "real world" conditions in which implementation research takes place. We provide a series of example studies that show "beginning to end" application of this framework in research focused on provider implementation of an evidence-based intervention in routine clinical care settings.

Findings have been mixed regarding the relationship between comorbid depression and anxiety and treatment outcomes for anxious youth. The current study compared a sample of anxious youth with a comorbid depressive disorder (n = 20) and those without comorbid depression (n = 137). All participants received 16 weekly sessions of Coping Cat and completed measures assessing anxiety/depression severity, impairment, and functioning at pretreatment and posttreatment. Results indicated that anxiety-focused CBT is efficacious for anxious youth with and without comorbid depressive disorders, with a higher rate of symptom improvement for youth with comorbid depression during treatment. However, comorbid depression was associated with higher severity at baseline and after treatment. Thus, despite the higher rate of symptom improvement, anxious youth with comorbid depression may benefit from additional treatment to address remaining symptoms.

OBJECTIVE Ample evidence exists that one's internal state (e.g., mindset, emotion) impacts one's performance. Both the military and sports organizations have focused on optimizing internal states of their service members and athletes, respectively, to improve performance and wellbeing. The internal states of surgical residents and the factors that influence their internal states have not yet been examined. Our goal is to better understand whether certain internal states are beneficial for resident operative performance, and how to optimize these during surgical training. DESIGN A 17-question survey, containing both open-ended and multiple-choice questions, was distributed to all (n = 134) surgical residents at the University of Wisconsin. In open-ended questions, recurring themes were identified utilizing content analysis. Recurring themes stated by 25% or more of the respondents are reported. SETTING Department of Surgery at the University of Wisconsin—Madison. PARTICIPANTS Surgical residents at the University of Wisconsin. RESULTS The survey response rate varied between n = 47 (35%) and n = 32 (24%), as not all respondents answered all questions. (1) Effective surgical educators were identified to demonstrate humanism and focus on teaching. (2) Nearly all residents affirmed that certain mindsets help them excel in the OR, including positive and confident mindsets. (3) Nearly all residents affirmed that faculty and senior residents influence their mindsets. (4) Constructive resident mindsets were promoted by positive faculty behaviors and personal preparation, while negative faculty behaviors were identified to stifle constructive mindsets. (5) Factors contributing to favorable OR performance included personal preparation and positive OR environments. (6) Factors contributing to poor OR performance included inadequate preparation and negative interactions with faculty. CONCLUSIONS Residents near unanimously believe that certain mindsets help them excel, and that faculty impact their mindsets. As teachers, we must strive to better understand how to foster constructive mindsets in residents to optimize learning, performance, and wellbeing.

Working memory (WM) develops rapidly during early childhood. In the present study, visual WM (VSM) was measured using the well-established Spin the Pots task (Hughes & Ensor, 2005), a complex non-verbal eight-location object occlusion task. A self-ordered hiding procedure was adopted to allow for an examination of children's strategy use during a VWM task. Participants (N = 640) between the ages of 2 and 4 years were tested under semi-naturalistic conditions, in the home or in a museum. Computational modeling was used to estimate an expected value for the total trials to complete Spin the Pots via a random search and child performance was compared to expected values. Based on this approach, we determined that children who found six stickers retrieved them in significantly fewer trials than the expected value, excluding chance performance and implicating VWM. Results also showed age-related and sex-related changes in VWM. Between 2 and 4 years of age, 4-year-olds performed significantly better than younger children and girls out-performed the boys. Spontaneous use of a color matching hiding strategy was associated with a higher success rate on the task. Implications of these findings for early development of VWM are discussed.

OBJECTIVE: Accommodation, or the ways in which families modify their routines and expectations in response to a child’s anxiety, is common and interferes with anxiety treatment outcomes. However, little research has examined family accommodation among youth with autism spectrum disorder and anxiety. The current study aimed to (a) identify pre-treatment correlates of accommodation, (b) examine changes in accommodation after treatment, and (c) assess relationships between accommodation and post-treatment anxiety severity. METHOD: The sample consisted of 167 youth (mean age=9.90 years; 79.6% male; 18% Latinx) with clinically significant anxiety and a diagnosis of autism spectrum disorder who were enrolled in a randomized clinical trial comparing two cognitive behavioral therapy interventions for anxiety and treatment as usual. Participants were evaluated for symptom severity and family accommodation at pre- and post-treatment. RESULTS: Results indicated that clinician-rated anxiety severity and parent-rated externalizing behaviors and autism spectrum disorder severity significantly predicted pre-treatment accommodation. Accommodation significantly decreased from pre- to post-treatment and non-responders showed significantly higher accommodation at post-treatment compared to responders. Finally, youth with higher pre-treatment accommodation had higher post-treatment anxiety. CONCLUSIONS: Findings indicate that accommodation for anxiety is common among youth with autism spectrum disorder and anxiety. Furthermore, accommodation is implicated in treatment outcomes and should be targeted in treatment for youth with autism spectrum disorder and anxiety.

BACKGROUND: Current approaches to increasing the rates of clinician use of exposure therapy for anxiety disorders in community settings are limited. Research underscores the importance of addressing contextual variables to facilitate clinician use of evidence-based practices; however, no studies have identified the innovation-specific organizational capacity necessary to implement exposure therapy. Such work is critical to ensure that treatment-seeking individuals with anxiety receive effective care. METHODS: We used a two-step process to identify the innovation-specific organizational capacity necessary to deliver exposure. First, 24 leaders of specialty anxiety clinics in the United States (50% female, mean [M]age = 47.7 years) completed a survey about the organizational innovation-specific capacity (e.g., policies and procedures) they employ to support their providers in delivering exposure therapy. Second, 19 community clinicians (79% female, M age = 42.9 years) reported on the extent to which these characteristics were present in their settings. RESULTS: In Step 1, specialty clinic leaders unanimously endorsed six organizational characteristics as essential and five as important within the areas of organizational policies, supervisory support, and peer clinician support. These characteristics were present in more than 90% of specialty clinics. In Step 2, therapists in community clinics reported these characteristics were minimally present in their organizations. CONCLUSIONS: Specialty clinic leaders exhibited consensus on the innovation-specific organizational capacity necessary to implement exposure therapy. Identified characteristics were largely absent from community clinics. Developing fiscal, policy, or organizational strategies that enhance the organizational capacity within community settings may improve the patients’ access to effective treatment for anxiety disorders.

The current study explored whether patient characteristics predicted patterns of antidepressant use (i.e., never used, single episode of use, or two or more episodes) in a naturalistic follow-up. Participants in the child/adolescent multimodal (CAMS) extended long-term study. (n = 318) indicated medication use over the course of eight follow-up visits, 3-12 years after receiving treatment in CAMS. 40.6% of participants reported never using an antidepressant during follow-up, 41.4% reported a single episode of antidepressant use, and 18.0% reported multiple episodes of antidepressant use. Greater baseline anxiety severity marginally predicted a single episode of antidepressant use; baseline depression severity predicted multiple episodes of use. Reasons for discontinuing antidepressants included perceived ineffectiveness (31.8%), side effects (25.5%), and improvement in symptoms (18.5%). Exploratory analyses examined predictors of medication use. Findings suggest that antidepressant use is common among anxious youth, as is discontinuation of antidepressant use. Clinical implications and future directions are discussed.

Moral bioenhancement, nudge-designed environments, and ambient persuasive technologies may help people behave more consistently with their deeply held moral convictions. Alternatively, they may aid people in overcoming cognitive and affective limitations that prevent them from appreciating a situation’s moral dimensions. Or they may simply make it easier for them to make the morally right choice by helping them to overcome sources of weakness of will. This paper makes two assumptions. First, technologies to improve people’s moral capacities are realizable. Second, such technologies will actually help people get morality right and behave more consistently with whatever the ‘real’ right thing to do turns out to be. The paper then considers whether or not humanity loses anything valuable, particularly opportunities for moral progress, when being moral is made much easier by eliminating difficult moral deliberation and internal moral struggle. Ultimately, the worry that moral struggle has value as a catalyst for moral progress is rejected. Moral progress is understood here as the discovery and application of new values or sensitization to new sources of harm.

The hippocampus contributes to both remembering specific events and generalization across events. Recent work suggests that information may be represented along the longitudinal axis of the hippocampus at varied levels of specificity: detailed representations in the posterior hippocampus and generalized representations in the anterior hippocampus. Similar distinctions are thought to exist within neocortex, with lateral prefrontal and lateral parietal regions supporting memory specificity and ventromedial prefrontal and lateral temporal cortices supporting generalized memory. Here, we tested whether functional connectivity of anterior and posterior hippocampus with cortical memory regions is consistent with these proposed dissociations. We predicted greater connectivity of anterior hippocampus with putative generalization regions and posterior hippocampus with putative memory specificity regions. Furthermore, we tested whether differences in connectivity are stable under varying levels of task engagement. Participants learned to categorize a set of stimuli outside the scanner, followed by an fMRI session that included a rest scan, passive viewing runs, and category generalization task runs. Analyses revealed stronger connectivity of ventromedial pFC to anterior hippocampus and of angular gyrus and inferior frontal gyrus to posterior hippocampus. These differences remained relatively stable across the three phases (rest, passive viewing, category generalization). Whole-brain analyses further revealed widespread cortical connectivity with both anterior and posterior hippocampus, with relatively little overlap. These results contribute to our understanding of functional organization along the long axis of the hippocampus and suggest that distinct hippocampal–cortical connections are one mechanism by which the hippocampus represents both individual experiences and generalized knowledge.

Supplemental Digital Content is available in the text., OBJECTIVES: To provide updated information on the burdens of sepsis during acute inpatient admissions for Medicare beneficiaries. DESIGN: Analysis of paid Medicare claims via the Centers for Medicare and Medicaid Services DataLink Project. SETTING: All U.S. acute-care hospitals, excluding federally operated hospitals (Veterans Administration and Defense Health Agency). Patients: All Medicare beneficiaries, January 2012—February 2020, with an explicit sepsis diagnostic code assigned during an inpatient admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The count of Medicare Part A/B (fee-for-service) plus Medicare Advantage inpatient sepsis admissions rose from 981,027 (CY2012) to 1,700,433 (CY 2019). The proportion of total admissions with sepsis in the Medicare Advantage population rose from 21.43% to 35.39%, reflecting the increasing beneficiary proportion enrolled in Medicare Advantage. In CY2019, 6-month mortality rates in Medicare fee-for-service beneficiaries for sepsis continued to decline, but remained high: 59.9% for septic shock, 35.5% for severe sepsis, 30.8% for sepsis attributed to a specific organism, and 26.5% for unspecified sepsis. Total fee-for-service-only inpatient hospital costs rose from $17.79B (CY2012) to $22.98B (CY2019). We estimated that the aggregate cost of sepsis hospital care for the entire U.S. population was at least $57.47B in 2019. Inclusion of 14 months’ (January 2019—February 2020) newer data exposed new trends: the cost per patient, number of admissions, and fraction of patients with sepsis labeled as present on admission inflected around November 2015, coincident with the change to International Classification of Diseases, 10th Edition, and introduction of the Severe Sepsis and Septic Shock Management Bundle (SEP-1) metric. CONCLUSIONS: Sepsis among Medicare beneficiaries precoronavirus disease 2019 imposed immense burdens upon patients, their families, and the taxpayers.

In human cells homologous recombination (HR) is critical for repair of DNA double strand breaks (DSBs) and rescue of stalled or collapsed replication forks. HR is facilitated by RAD51 which is loaded onto DNA by either BRCA2-BRCA1-PALB2 or RAD52. In human culture cells, double-knockdowns of RAD52 and genes in the BRCA1-BRCA2-PALB2 axis are lethal. Mutations in BRCA2, BRCA1 or PALB2 significantly impairs error free HR as RAD51 loading relies on RAD52 which is not as proficient as BRCA2-BRCA1-PALB2. RAD52 also facilitates Single Strand Annealing (SSA) that produces intra-chromosomal deletions. Some RAD52 mutations that affect the SSA function or decrease RAD52 association with DNA can suppress certain BRCA2 associated phenotypes in breast cancers. In this report we did a pan-cancer analysis using data reported on the Catalogue of Somatic Mutations in Cancers (COSMIC) to identify double mutants between RAD52 and BRCA1, BRCA2 or PALB2 that occur in cancer cells. We find that co-occurring mutations are likely in certain cancer tissues but not others. However, all mutations occur in a heterozygous state. Further, using computational and machine learning tools we identified only a handful of pathogenic or driver mutations predicted to significantly affect the function of the proteins. This supports previous findings that co-inactivation of RAD52 with any members of the BRCA2-BRCA1-PALB2 axis is lethal. Molecular modeling also revealed that pathogenic RAD52 mutations co-occurring with mutations in BRCA2-BRCA1-PALB2 axis are either expected to attenuate its SSA function or its interaction with DNA. This study extends previous breast cancer findings to other cancer types and shows that co-occurring mutations likely destabilize HR by similar mechanisms as in breast cancers.

Objective To evaluate whether cognitive reserve (CR) moderates the relationship between neuropathology and cognitive outcomes after traumatic brain injury (TBI). Setting Outpatient research organization. Participants Patients with complicated mild (n = 8), moderate (n = 9), and severe (n = 44) TBI. Design Prospective, cross-sectional study. Main measures Cognitive reserve was estimated using a test of word reading (Wechsler Test of Adult Reading). Diffusion tensor imaging (functional anisotropy) was used to quantify neuropathology. Neuropsychological test scores were submitted to principal components analyses to create cognitive composites for memory, attention, executive function, and processing speed domains. Results At lower levels of neuropathology, people with higher CR exhibited better memory than those with lower CR. This benefit diminished as neuropathology increased and disappeared at the highest levels of neuropathology. Cognitive reserve ceased exerting a protective effect at premorbid intelligence levels below average. Conclusion Cognitive reserve may differentially protect some cognitive domains against neuropathology relative to others. A clinical cutoff below which CR is no longer protective, together with a possible neuropathology ceiling effect, may be instructive for prognostication and clinical decision-making in cognitive rehabilitation.

Background 13‐Deoxy, 5‐iminodoxorubicin (GPX‐150) is a doxorubicin (DOX) analog synthesized to reduce the formation of reactive oxygen species and the cardiotoxic metabolite, doxorubiciniol, the two pathways that are linked to the irreversible, cumulative dose‐dependent cardiotoxicity of DOX. In a preclinical chronic models and a phase I clinical study of GPX‐150, no irreversible, cumulative dose‐dependent cardiotoxicity was demonstrated. Recent studies suggest that DOX cardiotoxicity may be mediated, at least in part, by the poisoning of topoisomerase IIβ. Patients and Methods An open‐label, single‐arm phase II clinical study in metastatic and unresectable soft tissue sarcoma (STS) patients was initiated to further evaluate the efficacy and safety of GPX‐150, including cardiac function, specifically left ventricular ejection fraction (LVEF). Results GPX‐150 was administered at 265 mg/m2 every 3 weeks for up to 16 doses with prophylactic G‐CSF until progression, death, or patient withdrawal from the study. GPX‐150 exhibited efficacy assessed as progression‐free survival (PFS) rates of 38% and 12% at 6 and 12 months and an overall survival rate of 74% and 45% at 6 and 12 months. GPX‐150–treated patients did not develop any evidence of irreversible, cumulative dose‐dependent chronic cardiotoxicity. Toxicities included grade 3 anemia, neutropenia, and one grade 4 leukopenia. Correlative analysis demonstrated that GPX‐150 was more selective than DOX for the inhibition of topoisomerase IIα over IIβ in vitro. Conclusion These results suggest future studies are warranted to further evaluate the clinical efficacy of GPX‐150 in STS, perhaps at doses higher than 265 mg/m2.

External motivation, such as a promise of future monetary reward for remembering an event, can affect which events are remembered. Reward-based memory modulation is thought to result from encoding and post-encoding interactions between dopaminergic midbrain, signaling reward, and hippocampus and parahippocampal cortex, supporting episodic memory. We asked whether hippocampal and parahippocampal interactions with other reward-related regions are related to reward modulation of memory and whether such relationships are stable over time. Individuals' memory sensitivity to reward was measured using a monetary incentive encoding task in which a cue indicated potential monetary reward (penny, dime, or dollar) for remembering an upcoming object pair. Functional connectivity between memory and reward regions was measured before, during, and following the task. Reward-related regions of interest were generated using a meta-analysis of existing studies on reward and included ventral striatum, medial and orbital prefrontal cortices and anterior cingulate cortex, in addition to midbrain. The results showed that connectivity between memory and reward regions tracked individual differences in reward modulation of memory, irrespective of when connectivity was measured. Connectivity patterns of anterior cingulate, orbitofrontal cortex, and ventral striatum covaried together and tracked behavior most strongly. These findings implicate a broader set of reward regions in reward modulation of memory than considered previously and provide new evidence that stable connectivity patterns between memory and reward centers relate to individual differences in how reward impacts memory.

Item does not contain fulltext BACKGROUND: Sepsis is a leading cause of morbidity and mortality after surgery. Most studies regarding sepsis do not differentiate between patients who have had recent surgery and those without. Few data exist regarding the risk factors for poor outcomes in pediatric postsurgical sepsis. Our hypothesis is pediatric postsurgical, and medical patients with severe sepsis have unique risk factors for mortality. METHODS: Data were extracted from a secondary analysis of an international point prevalence study of pediatric severe sepsis. Sites included 128 pediatric intensive care units from 26 countries. Pediatric patients with severe sepsis were categorized into those who had recent surgery (postsurgical sepsis) versus those that did not (medical sepsis) before sepsis onset. Multivariable logistic regression models were used to determine risk factors for mortality. RESULTS: A total of 556 patients were included: 138 with postsurgical and 418 with medical sepsis. In postsurgical sepsis, older age, admission from the hospital ward, multiple organ dysfunction syndrome at sepsis recognition, and cardiovascular and respiratory comorbidities were independent risk factors for death. In medical sepsis, resource-limited region, hospital-acquired infection, multiple organ dysfunction syndrome at sepsis recognition, higher Pediatric Index of Mortality-3 score, and malignancy were independent risk factors for death. CONCLUSIONS: Pediatric patients with postsurgical sepsis had different risk factors for mortality compared with medical sepsis. This included a higher mortality risk in postsurgical patients presenting to the intensive care unit from the hospital ward. These data suggest an opportunity to develop and test early warning systems specific to pediatric sepsis in the postsurgical population.

This study tested whether a new training tool, the Exposure Guide (EG), improved in-session therapist behaviors (i.e., indicators of quality) that have been associated with youth outcomes in prior clinical trials of exposure therapy. Six therapists at a community mental health agency (CMHA) provided exposure therapy for 8 youth with obsessive–compulsive disorder (OCD). Using a nonconcurrent multiple baseline design with random assignment to baseline lengths of 6 to 16 weeks, therapists received gold-standard exposure therapy training with weekly consultation (baseline phase) followed by addition of EG training and feedback (intervention phase). The primary outcome was therapist behavior during in-session exposures, observed weekly using a validated coding system. Therapist behavior was evaluated in relation to a priori benchmarks derived from clinical trials. Additional outcomes included training feasibility/acceptability, therapist response to case vignettes and beliefs about exposure, and independent evaluator-rated clinical outcomes. Three therapists reached behavior benchmarks only during the EG (intervention) phase. Two therapists met benchmarks during the baseline phase; one of these subsequently moved away from benchmarks but met them again after starting the EG phase. Across all therapists, the percentage of weeks meeting benchmarks was significantly higher during the EG phase (86.4%) vs. the baseline phase (53.2%). Youth participants experienced significant improvement in OCD symptoms and global illness severity from pre- to posttreatment. Results provide initial evidence that adding the EG to gold-standard training can change in-session therapist behaviors in a CMHA setting.

ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 was an open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48,p< 0.001) and a positive correlation (Spearmanr= 0.663;p< 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrials.gov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

PURPOSE: To evaluate which parameters may affect endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK) by comparing eyes in the low vs high quartile of endothelial cell loss over a follow-up period of 4 years.DESIGN: Retrospective cohort study.METHODS: Donor endothelial cell density (ECD) decline was evaluated for 351 eyes of 275 patients up to 4 years after DMEK for Fuchs endothelial corneal dystrophy (FECD). Eyes with a postoperative endothelial cell loss in the lower quartile at all available follow-up moments were assigned to Group 1 (n = 51) and those in the upper quartile to Group 2 (n = 42). Multinomial regression was used to assess which covariates were related to greater ECD decline.RESULTS: Mean endothelial cell loss as compared to preoperative donor ECD for the entire study group was 33 (+/- 16)%, 36 (+/- 17)%, and 52 (+/- 18)% at 1, 6, and 48 months postoperatively. Endothelial cell loss of Group 1 was 12 (+/- 7)%, 13 (6)%, and 26 (+/- 8)% at, respectively, 1, 6, and 48 months postoperatively, and 59 (+/- 10)%, 64 (+/- 9)%, and 75 (+/- 5)% in Group 2. Partial graft detachment, donor death cause cardiovascular/stroke (vs cancer), postoperative complications other than graft detachment, and severity of preoperative FECD (all P

Motivation enhances memory by increasing hippocampal engagement during encoding. However, whether such increased hippocampal activation reflects encoding of the value of highly rewarding events per se is less understood. Here, using a monetary incentive encoding task with a novel manipulation, we tested in humans whether the hippocampus represents abstract reward value, independent of perceptual content. During functional MRI scanning, men and women studied object pairs, each preceded by a monetary reward cue indicating the amount of money they would receive if they successfully remembered the object pair at test. Reward cues varied on both the level of reward (penny, dime, and dollar) and visual form (picture or word) across trials to dissociate hippocampal responses to reward value from those reflecting the perceptual properties of the cues. Behaviorally, participants remembered pairs associated with the high reward (dollar) more often than pairs associated with lower rewards. Neural pattern-similarity analysis revealed that hippocampal and parahippocampal cortex activation patterns discriminated between cues of different value regardless of their visual form, and that hippocampal discrimination of value was most pronounced in participants who showed the greatest behavioral sensitivity to reward. Strikingly, hippocampal patterns were most distinct for reward cues that differed in value but had similar visual appearance, consistent with theoretical proposals of hippocampal-pattern differentiation of competing representations. Our data illustrate how contextual representations within the hippocampus go beyond space and time to include information about the motivational salience of events, with hippocampal reward coding tracking the motivational impact on later memory.SIGNIFICANCE STATEMENTMotivation, such as the promise of future rewards, enhances hippocampal engagement during encoding and promotes successful retention of events associated with valuable rewards. However, whether the hippocampus explicitly encodes reward value, dissociable from sensory information, is unclear. Here, we show that the hippocampus forms abstract representation of valuable rewards, encoding conceptual rather than perceptual information about the motivational context of individual events. Reward representation within the hippocampus is associated with preferential retention of high-value events in memory. Furthermore, we show that hippocampal-pattern differentiation serves to emphasize differences between visually similar events with distinct motivational salience. Collectively, these findings indicate that hippocampal contextual representations enable individuals to distinguish the motivational value of events, leading to prioritized encoding of significant memories.

The reading frame rule suggests that Duchenne muscular dystrophy (DMD) results from DMD mutations causing an out-of-frame transcript, whereas the milder Becker muscular dystrophy results from mutations causing an in-frame transcript. However, predicted nonsense mutations may instead result in altered splicing and an in-frame transcript. Here we report a 10-year-old boy with a predicted nonsense mutation in exon 42 who had a 6-minute walk time of 157% of that of age matched DMD controls, characterized as intermediate muscular dystrophy. RNA sequencing analysis from a muscle biopsy revealed only 6.0–9.8% of DMD transcripts were in-frame, excluding exon 42, and immunoblot demonstrated only 3.2% dystrophin protein expression. Another potential genetic modifier noted was homozygosity for the protective IAAM LTBP4 haplotype. This case suggests that very low levels of DMD exon skipping and dystrophin protein expression may result in amelioration of skeletal muscle weakness, a finding relevant to current dystrophin-restoring therapies.

Natural olfactory stimuli are volatile-chemical mixtures in which relative perceptual saliencies determine which odor-components are identified. Odor identification also depends on rapid selective adaptation, as shown for 4 odor stimuli in an earlier experimental simulation of natural conditions. Adapt-test pairs of mixtures of water-soluble, distinct odor stimuli with chemical features in common were studied. Identification decreased for adapted components but increased for unadapted mixture-suppressed components, showing compound identities were retained, not degraded to individual molecular features. Four additional odor stimuli, 1 with 2 perceptible odor notes, and an added “water-adapted” control tested whether this finding would generalize to other 4-compound sets. Selective adaptation of mixtures of the compounds (odors): 3 mM benzaldehyde (cherry), 5 mM maltol (caramel), 1 mM guaiacol (smoke), and 4 mM methyl anthranilate (grape-smoke) again reciprocally unmasked odors of mixture-suppressed components in 2-, 3-, and 4-component mixtures with 2 exceptions. The cherry note of “benzaldehyde” (itself) and the shared note of “methyl anthranilate and guaiacol” (together) were more readily identified. The pervasive mixture-component dominance and dynamic perceptual salience may be mediated through peripheral adaptation and central mutual inhibition of neural responses. Originating in individual olfactory receptor variants, it limits odor identification and provides analytic properties for momentary recognition of a few remaining mixture-components.

To evaluate the clinical outcome of 500 consecutive cases up to 2 years after Descemet membrane endothelial keratoplasty (DMEK) and to assess which parameters may have influenced the clinical outcome.From a group of 500 eyes (393 patients), which underwent DMEK for Fuchs endothelial corneal dystrophy (FECD), bullous keratopathy, failed corneal transplants and other indications, clinical outcomes [best-corrected visual acuity (BCVA), central endothelial cell density (ECD), and central corneal thickness] were evaluated before, and at 6, 12, and 24 months after DMEK and postoperative complications were documented.At 12 months postoperatively, 81% of eyes reached a BCVA of ≥20/25 (≥0.8), 49% ≥20/20 (≥1.0), and 15% ≥20/18 (≥1.2) (n = 396) and remained stable up to 24 months (P = 0.828). Compared with preoperative ECD, mean postoperative ECD decreased by 37 (±18)%, 40 (±18)%, and 45 (±18)% at 6, 12, and 24 months, respectively (P0.05 for all time points). Surgery indication and graft attachment status were related to postoperative BCVA and ECD results. Eyes with FECD and attached grafts showed better BCVA outcomes and higher ECD (P0.05). Central corneal thickness decreased by 20 (±11)% to 525 (±46) μm from preoperative to 6 months postoperatively and remained stable thereafter (P0.05). Within the study period, retransplantation was required in 32 eyes (6.4%). Principal longer-term complications were secondary graft failure (1.4%) and allograft rejection (1.4%).Clinical outcomes remain excellent up to 2 years after DMEK, in particular for eyes operated on for FECD and with completely attached grafts.

Background Implementation researchers have typically studied organizational culture and climate by testing whether individual dimensions are linked to the implementation of evidence-based practices (EBPs) rather than examining how the overarching social context influences implementation. This approach may limit implementation theory and strategy development to the extent that individual dimensions of culture and climate interact, mutually reinforce or counteract one another, or exhibit non-linear relationships. This study tests whether empirically identifiable culture and climate profiles emerge in a sample of organizations and examines how these profiles relate to EBP fidelity and work attitudes that support EBP sustainment, focusing on three EBPs for youth with autism delivered in schools as an example. Methods The study included 65 elementary schools in the U.S. that implemented three EBPs—discrete trial training, pivotal response training, and visual schedules—for youth with autism. Organizational culture and climate and work attitudes were assessed using the Organizational Social Context measure at the beginning of the school year. Observations of EBP fidelity occurred mid school-year. We used bias-adjusted stepwise latent profile modeling to (1) identify subpopulations of schools that share similar culture and climate profiles, and (2) test for mean differences across profiles in observed EBP fidelity and teacher and staff work attitudes. Results Controlling for region, four profiles best characterized the organizational cultures and climates of schools. Teachers and staff in schools with a comprehensive profile (high proficiency culture, positive climate) exhibited higher fidelity to two of three EBPs (d’s = .95 to 1.64) and reported superior work attitudes (d’s = .71 to 1.93) than teachers and staff in all other schools. Teachers and staff in supportive schools (low rigidity culture, positive climate) had better work attitudes, but not better fidelity, than those in schools with indifferent (low culture/climate, elevated stress) and constrained (high rigidity and resistance, high stress) profiles. Conclusions Organizational culture and climate profiles are a strong predictor of EBP fidelity and work attitudes that support EBP sustainment, highlighting the importance of an organization’s overarching social context when developing implementation theory and strategies. Strategies that foster a comprehensive profile may improve EBP implementation. Electronic supplementary material The online version of this article (10.1186/s13012-019-0863-9) contains supplementary material, which is available to authorized users.

Sparrow (2019) makes an argument concerning what he calls the “ontological” consequences of genomic obsolescence through human genomic enhancement. The key consequence is a substantial (and negativ...

BACKGROUND: Although exposure is a key evidence-based intervention for anxiety, it is infrequently used in clinical settings. This study employed a novel training strategy, experiential learning, to improve exposure implementation. This study aimed to assess the feasibility and acceptability of experiential training and preliminary training effectiveness. METHODS: Participants were 28 therapists who were randomized to (a) training-as-usual or (b) experiential training (training-as-usual plus a one-session treatment for fear of spiders). Workshops lasted one day and were followed by three months of weekly consultation. RESULTS: Experiential training was viewed as feasible and acceptable. Participants, including those who were fearful of spiders, had a positive response to the training and reported it to be useful. There was a significant increase in the number of exposures used by therapists receiving experiential training compared to training-as-usual at 1-month follow-up. CONCLUSIONS: A one-day training resulted in significant improvements in knowledge, attitudes toward exposure, and self-efficacy in using exposure. Preliminary findings suggest that experiential training resulted in greater use of exposure post-training compared to training-as-usual. Results provide evidence for the feasibility and acceptability of experiential training as a strategy to increase the use of evidence-based interventions. TRIAL REGISTRATION: Clinicaltrials.gov: NCT0335497

Objective The goal of this study was to explore the association of timing of and frequency of meals with markers of cardiometabolic risk in patients with bipolar disorder in out-patient maintenance treatment. Methods We used Pittsburgh Sleep Diary and actigraphy measures for individuals with bipolar I disorder. Linear and logistic regression analyses were used to determine whether dinnertime, instability of dinnertime, and/or interval between meals were associated with metabolic syndrome and its components. Results Later dinnertime was associated with greater waist circumference (β = 0.25, P = 0.02) after adjusting for age, sex, dinner-to-bed interval, and sleep duration. Longer breakfast-to-lunch intervals were also associated with greater waist circumferences (β =−.35, P = .002) after adjusting for age, sex, and sleep duration. Neither instability of dinnertime nor number of meals per day was associated with the metabolic syndrome or its components. Conclusion Weight gain is often perceived as inevitable side-effect of medications. While patients often need to be on medication to function, a more careful lifestyle assessment with attention to social rhythms and timing of activities may be critical not only for mood stability, but also to reduce cardiovascular risk.

Objective Pudendal neuralgia is a recognized cause of chronic pelvic pain. The diagnosis is complex, and there is no consensus on ideal management. Many current methods do not provide adequate relief. Pulsed radiofrequency is a minimally invasive option that has been reported for its use in other neuropathies. This study aimed to evaluate the feasibility and safety of using transvaginal pulsed radiofrequency for the treatment of pudendal neuralgia and to generate a hypothesis on its efficacy. Methods A retrospective review was conducted of women who were treated with pulsed radiofrequency for chronic pelvic pain owing to pudendal neuralgia between January 2012 and December 2017 at an academic tertiary care centre. (Canadian Task Force Classification II-3). Results A total of seven patients were included. The mean age was 43.7 (standard deviation 7.97). The average number of pulsed radiofrequency treatments was 4.43 (range 1–12), and the duration of effect averaged 11.4 weeks (standard deviation 3.09). There were no major or minor complications at the time of procedure or at follow-up visits. Conclusions Pulsed radiofrequency may be an effective and safe treatment option for the management of pudendal neuralgia for women in whom conservative management has not been effective. Future controlled studies are needed to confirm this hypothesis.

Objective This study measured a variety of within-exposure fear changes and tested the relationship of each with treatment outcomes in exposure therapy. Method We coded 459 videotaped exposure tasks from 111 participants in 3 clinical trials for pediatric obsessive-compulsive disorder (OCD; POTS trials). Within exposures, fear level was observed continuously and alongside exposure process. Fear change metrics of interest were selected for relevance to mechanistic theory. Fear decreases were classified by function; nonhabituation decreases were associated with observed nonlearning processes (e.g., avoidance), whereas habituation decreases appeared to result from an internal and indirect process. Outcomes were posttreatment change in symptom severity, global improvement, and treatment response. Results Greater cumulative habituation across treatment was associated with larger reductions in symptom severity, greater global improvement, and increased odds of treatment response. Fear activation, fear variability, and nonhabituation fear decreases did not predict any outcomes. Exploratory analyses examined fear changes during habituation and nonhabituation exposures; higher peak fear during nonhabituation exposures was associated with attenuated global improvement. Conclusions Habituation is conceptually consistent with multiple mechanistic theories and should continue to be investigated as a practical marker of initial extinction learning and possible moderator of the relationship between fear activation and outcome. Results support the importance of functional and frequent fear measurement during exposures, and discussion considers implications of these findings for future studies aiming to understand learning during exposure and improve exposure delivery. (PsycINFO Database Record

Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.

Accomplishments of this program have provided numerous dividends and might benefit areas outside infectious diseases.

This study replicates and extends prior research on the relationship of childhood complex trauma (CCT) and complex posttraumatic stress disorder (cPTSD) in adulthood, examining the role of psychoform and somatoform dissociation as a potential mediator. CCT, dissociation, and cPTSD were assessed in a large sample of adult psychiatric inpatients. Almost two thirds of participants reported having experienced CCT. Path analyses with bootstrap confidence intervals demonstrated a relationship between CCT, psychoform (but not somatoform) dissociation, and cPTSD. In addition, psychoform dissociation partially mediated the relationship between CCT and adult cPTSD symptoms. Dissociation (pathological or nonpathological psychoform and somatoform symptoms) warrants further clinical and scientific study as a potential link between CCT and the presence of adult cPTSD symptoms and/or the dissociative subtype of PTSD.

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.

The present study developed parallel clinician- and parent-rated measures of family accommodation (Pediatric Accommodation Scale, PAS; Pediatric Accommodation Scale-Parent Report; PAS-PR) for youth with a primary anxiety disorder. Both measures assess frequency and impact of family accommodation on youth and families. Studying youth ages 5-17 (N=105 caregiver-youth dyads), results provide evidence for the psychometric properties of the PAS, including internal consistency, inter-rater reliability, and convergent and discriminant validity. The PAS-PR exhibited good internal consistency and convergent validity with the PAS. Nearly all parents (>95%) endorsed some accommodation and accommodation frequency was associated with parent-rated impairment (home and school), and with youth-rated impairment (school only). Greater impact of accommodation on parents was associated with parent self-reported depressive symptoms. Findings support the common occurrence of family accommodation in youth with anxiety disorders, as well as for the use of the PAS and PAS-PR to measure family accommodation in this population.

Upon entering the examination room, Caitlyn encounters a woman sitting alone and in distress. Caitlyn introduces herself as the hospital ethicist and tells the woman, Mrs. Dennis, that her aim is to help her reach a decision about whether to perform an autopsy on her recently deceased husband. Mrs. Dennis begins the encounter by telling the ethicist that she has to decide quickly, but that she is very torn about what to do. Mrs. Dennis adds, “My sons disagree about the autopsy.” As a standardized patient (SP), a specialized actor, the woman playing Mrs. Dennis has already delivered the same opening lines several times to different learners practicing their clinical ethics consultation skills. An SP encounter is a simulated patient encounter used for educational purposes that requires the standardization of verbal and behavioral responses. In the encounter, the simulator, or “patient,” uses a scripted medical history to enable the learner to employ a certain skill, say, the ability to perform a neurological exam. The use of standardized patients in the evaluation of clinical skills has become a staple in medical education. To tackle the challenge of teaching clinical ethics consultation skills, we have incorporated SP encounters into the curriculum of the Bioethics Program of The Union Graduate College and the Icahn School of Medicine at Mount Sinai. SP encounters are incorporated into one of our onsite classes, the Onsite Clinical Ethics Practicum, and they are part of the capstone examination, which all of our graduates must complete successfully. The inclusion of simulated encounters into the curriculum is one way in which we equip our students with the core competencies specified by the American Society for Bioethics and Humanities Task Force for clinical ethicists.

To report the 6-month clinical outcomes of a large cohort of Descemet membrane endothelial keratoplasty (DMEK) eyes operated by 55 starting or experienced surgeons.This is a retrospective, multicenter, interventional, cohort study with a total of 2485 eyes. Best-corrected visual acuity (BCVA), endothelial cell density (ECD) decrease, and intra- and post-operative complications were evaluated. Three groups based on case order were compared: group I (cases 1-24), group II (cases 25-99), and group III (cases ≥100). Forty-nine percent of the surgeons were in their learning curve (25 cases), representing 10.4% of the surgeries.Six months after DMEK, BCVA improved in 90.5% of eyes, remained unchanged in 4.6%, and deteriorated in 4.9% (n = 1936); 75.4% of eyes reached a BCVA of ≥20/40 (≥0.5), 45.4% ≥20/25 (≥0.8), and 25.8% ≥20/20 (≥1.0) (n = 1959) and ECD decreased by 40% (±19) (n = 1272, P0.05). BCVA and ECD outcomes did not differ between groups I and III (P0.05). Intraoperative complications were reported for 9.4% of eyes, whereas graft detachment was the main postoperative complication (27.4%), with lower intra- and post-operative complication rates in group III than group I (P0.05). Rebubbling was performed in 20.1% of eyes; 13.8% required secondary keratoplasty within 6 months.DMEK is applicable for surgeons in various settings with good clinical outcomes. After an arbitrary learning curve (25 cases), virtually all transplant-related complications declined with experience. Notably, surgeons with a higher annual caseload may pass faster through their learning curve than surgeons performing their first surgeries over an extended period.

Purpose To assess the clinical outcome after successful rebubbling procedures for visually significant graft detachment after Descemet membrane endothelial keratoplasty (DMEK). Methods From a total of 760 consecutive DMEK surgeries, 41 eyes required rebubbling. Of those, 33 eyes of 31 patients were successful and were included in our retrospective outcome analysis study. Main outcome measures were compared with those of matched controls with uneventful primary DMEK (attached DMEK grafts without rebubbling). Rebubbling was performed on average 25 (±20) days (range 7-91 days) after DMEK. All eyes were evaluated for best-corrected visual acuity, endothelial cell density (ECD), pachymetry, and complications up to 6 months after rebubbling. Results At 6 months after DMEK, best-corrected visual acuity in rebubbled eyes did not differ from that in control eyes (P = 0.514). The mean ECD decrease was higher in rebubbled than in control eyes (54% vs. 35%, respectively, P = 0.001). Pachymetry did not differ between both groups (P = 0.153). After rebubbling, one buphthalmic eye showed temporary intraocular pressure elevation and 5 eyes had minor graft edge detachment that did not require further treatment. Conclusions Rebubbling for DMEK graft detachment may result in similar visual outcomes as in uncomplicated DMEK, when performed within the first 6 to 8 postoperative weeks. However, rebubbled eyes may have lower ECD, which may be attributed to additional air bubble trauma and/or selection bias through more extensive manipulation during initial DMEK or higher risk of graft detachment in more complicated eyes.

To monitor refractive changes after Descemet membrane endothelial keratoplasty (DMEK) and to determine what may influence these changes and the time point of stabilization.From 67 pseudophakic DMEK eyes operated on for Fuchs endothelial dystrophy at a tertiary referral center, biomicroscopy, visual acuity, subjective refraction, and Scheimpflug-based corneal tomography data were obtained before and up to 2 years postoperatively. Visual acuity and changes in spherical equivalent (SE), mean anterior and posterior simulated keratometry (Km), and central pachymetry were analyzed.At 3 months postoperatively, both hyperopic (28/67 eyes) and myopic (21/67 eyes) shifts were observed; 18/67 eyes showed no SE change. The mean change in SE at 3 months was +0.33 diopters (D) (95% confidence interval = [0.11, 0.54], P = 0.028), which stabilized thereafter (P0.466). Initial flattening of mean anterior Km by 0.66D (95% confidence interval = [-0.81, -0.51], P0.001) at 3 months was followed by a slow steepening, which became significant between 1 and 2 years postoperatively (P0.001). Posterior Km stabilized after 3 months (P0.252). Preoperative to 3 months postoperative absolute changes in anterior Km were positively related to preoperative backscattered light from the central anterior cornea (P = 0.035), and the presence of partial graft detachment postoperatively (P = 0.013).After DMEK, SE and posterior corneal curvature were on average stable at 3 months after surgery, whereas the mean anterior corneal curvature showed an ongoing gradual change. Changes in anterior corneal curvature may be related to preoperative anterior corneal densitometry or postoperative partial graft detachment.

Background Bipolar disorder II (BPII) and unipolar depression (UD) are both characterized by episodes of major depression (MDE), however DSM-IV criteria for MDE are identical, regardless of diagnosis. As a result, misdiagnosis of BP II and UD is common, leading to inappropriate treatment. Because women are twice as likely as men to experience MDE, differentiating UD from BP II in the context of depression is especially important for women. We examined symptoms and clinical features of MDE in women with UD and BPII to compare presentations of the two disorders in women. Methods We compared characteristics of depressed women meeting DSM-IV criteria for BPII (n=48) or UD (n=48), matched on age. Results Feelings of worthlessness occurred in 98% of participants with UD versus 85% with BPII (p=0.03). Participants with UD experienced either insomnia or hypersomnia, but participants with BPII were more likely to experience both simultaneously (p=0.04). Those with UD were significantly less likely to have >5 prior mood episodes compared to those with BP II (12% versus 61%; p Limitations Small sample size and exclusion criteria (i.e., comorbid substance abuse) may limit generalizability of findings. Conclusions Among a sample of women, number of prior episodes, feelings of worthlessness, age of onset, and sleep patterns distinguished between UD and BP II depressive episodes. A better understanding of differential presentation of BP II versus UD depression in women may help guide clinicians to more accurate diagnoses and, ultimately, better treatment.

To evaluate the incidence and causes of anterior corneal surface irregularities after successful Descemet membrane endothelial keratoplasty (DMEK) and the efficacy of contact lens fitting in these cases.Tertiary referral center.Retrospective study of prospectively collected data.Eyes with a subnormal visual outcome or monocular diplopia after successful DMEK were fitted with a contact lens. These cases were evaluated with Pentacam rotating Scheimpflug camera imaging preoperatively and 6 months postoperatively, and outcomes were compared with those in a randomly selected DMEK control group.In a series of 262 surgeries, 23 eyes (21 patients) were fitted with contact lenses; the control group comprised 23 eyes. Indications for contact lens fitting included (1) obvious corneal surface irregularities due to preexisting corneal scarring, (2) surface irregularities associated with longstanding preoperative stromal edema, and (3) undetectable optical imperfections. The postoperative corrected distance visual acuity (CDVA) with spectacles improved after contact lens correction (P.001). Preoperative and postoperative irregularity indices were significantly higher in the contact lens group than in the DMEK control group (P.05). Positive correlations were found between the duration of preoperative stromal edema and postoperative Scheimpflug camera indices (P.02).After successful DMEK, 23 of 262 eyes (9%) showed subnormal spectacle CDVA and/or monocular diplopia due to corneal scarring, surface irregularities, or undetectable optical imperfections that could be managed by contact lens fitting. Prolonged preoperative corneal edema for more than 12 months may be a risk factor for diffuse irregular astigmatism after DMEK.Dr. Melles is a consultant to DORC International BV/Dutch Ophthalmic USA. No author has a financial or proprietary interest in any material or method mentioned.

Purpose A novel doxorubicin (DOX) analog, 13-deoxy, 5-iminodoxorubicin (DIDOX), was synthesized to prevent quinone redox cycling and alcohol metabolite formation, two prevailing hypotheses of anthracycline cardiotoxicity. The chronic cardiotoxicity of DOX and DIDOX was compared. Since a recent hypothesis posits that DOX-induced chronic cardiotoxicity may be mediated by inhibition of the topoisomerase IIβ/DNA reaction, we also compared potency of DOX and DIDOX to inhibit topoisomerase IIβ decatenation of kinetoplast DNA (kDNA) (a series or interlocking small rings of DNA). Methods We compared DIDOX with DOX to alter cardiac function in a chronic rabbit model. We also compared potency to inhibit decatenation of kDNA by purified topoisomerase IIβ in vitro. Results DOX and DIDOX caused similar decreases in white and red blood cell counts indicating similar positions on the dose-response curve for cytotoxic efficacy. However, DOX but not DIDOX elicited a decrease in left ventricular fractional shortening and contractility of isolated left atrial preparations obtained at sacrifice. Histological scoring of apex and left ventricular free wall samples showed that DOX-treated rabbits had significantly more cardiac injury than samples from DIDOX or saline-treated rabbits. DOX inhibited decatenation of DNA by topoisomerase IIβ with an EC50 of 40.1 μM while DIDOX did not have any apparent effect on topoisomerase IIβ at the concentrations used in the study (0.1–100 μM). Conclusions Unlike DOX, DIDOX did not cause chronic cardiotoxicity and did not appear to interact with topoisomerase IIβ in decatenation assays consistent with the hypothesis that inhibition of the topoisomerase IIβ/DNA reaction may be a contributor of the mechanism of chronic DOX cardiotoxicity.

Background and Objective: The hypoxia PET tracer, 1-[ 18 F]fluoro-3-(2-nitro-1Himidazol- 1-yl)-propan-2-ol ([ 18 F]FMISO) is the first radiotracer developed for hypoxia PET imaging and has shown promising for cancer diagnosis and prognosis. However, access to [ 18 F]FMISO radiotracer is limited due to the needed cyclotron and radiochemistry expertise. The study aimed to develop the automated production method on the [ 18 F]FMISO radiotracer with the novel fully automated platform of the BG75 system and validate its usage on animal tumor models. Method: [ 18 F]FMISO was produced with the dose synthesis cartridge automatically on the BG75 system. Validation of [ 18 F]FMISO hypoxia imaging functionality was conducted on two tumor mouse models (FaDu/U87 tumor). The distribution of [ 18 F]FMISO within tumor was further validated by the standard hypoxia marker EF5. Results: The average radiochemical purity was (99±1) % and the average pH was 5.5±0.2 with other quality attributes passing standard criteria (n=12). Overall biodistribution for [ 18 F]FMISO in both tumor models was consistent with reported studies where bladder and large intestines presented highest activity at 90 min post injection. High spatial correlation was found between [ 18 F]FMISO autoradiography and EF5 hypoxia staining, indicating high hypoxia specificity of [ 18 MF]FMISO. Conclusion: This study shows that qualified [ 18 F]FMISO can be efficiently produced on the BG75 system in an automated “dose-on-demand” mode using single dose disposable cards. The possibilities of having a low-cost, automated system manufacturing ([ 18 F]Fluoride production + synthesis + QC) different radiotracers will greatly enhance the potential for PET technology to reach new geographical areas and underserved patient populations.

We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC50 values as low as 19 nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFα production in peripheral human monocytes.

Effects of cathodal current, which draws cations away from the tongue and drives anions toward the tongue, depend on the ionic content of electrolytes through which the current is passed. To address the role of cations and anions in human salt tastes, cathodal currents of -40 microA to -80 microA were applied to human subjects' tongues through supra-threshold salt solutions. The salts were sodium chloride, sodium bromide, potassium chloride, ammonium chloride, calcium chloride, sodium nitrate, sodium sulfate, sodium saccharin, sodium acetate and sodium benzoate, which taken together encompass salty, bitter, sour and sweet taste qualities. The taste of NaCl, the salty and bitter tastes of the other chloride salts and the taste of NaNO(3) was inhibited, suggesting the current displaced stimulatory cations from salty and bitter receptors. However, bitter tastes of non-halide sodium salts were not inhibited, likely because other bitter receptors respond to anions. A discharge current at cathode-off ubiquitously evoked a metallic taste reminiscent of anodal taste used in clinical electrogustometry. Analogous effects on ambient NaCl responses were recorded from the hamster chorda tympani nerve. Increases in tastes of the saccharin and benzoate anions were not evoked during current flow, suggesting that cathodal current does not carry stimulatory anions to sweet receptors. Cathodal current may selectively inhibit salty and bitter-salty tastes for which proximal stimuli are cations.