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Motivated by the interesting magnetic anisotropy found in the heavy fermion family CeTX2 (T = transition metal and X = pnictogen), here, we study the novel parent compound CeAu1-xBi2-y by combining magnetization, pressure dependent electrical resistivity, and heat-capacity measurements. The magnetic properties of our nearly stoichiometric single crystal sample of CeAu1-xBi2-y (x = 0.92 and y = 1.6) revealed an antiferromagnetic ordering at TN = 12 K with an easy axis along the c-direction. The field dependent magnetization data at low temperatures reveal the existence of a spin-flop transition when the field is applied along the c-axis (Hc ∼ 7.5 T and T = 5 K). The heat capacity and pressure dependent resistivity data suggest that CeAu0.92Bi1.6 exhibits a weak heavy fermion behavior with strongly localized Ce3+ 4f electrons. Furthermore, the systematic analysis using a mean field model including anisotropic nearest-neighbors interactions and the tetragonal crystalline electric field (CEF) Hamiltonian allows us to extract a CEF scheme and two different values for the anisotropic J RKKY exchange parameters between the Ce3+ ions in this compound. Thus, we discuss a scenario, considering both the anisotropic magnetic interactions and the tetragonal CEF effects, in the CeAu1-xBi2-y compounds, and we compare our results with the isostructural compound CeCuBi2.

In this work we combine magnetization, pressure dependent electrical resistivity, heat capacity, Cu63 nuclear magnetic resonance (NMR), and x-ray resonant magnetic scattering experiments to investigate the physical properties of the intermetallic CeCuBi2 compound. Our single crystals show an antiferromagnetic ordering at TN≃16 K and the magnetic properties indicate that this compound is an Ising antiferromagnet. In particular, the low temperature magnetization data revealed a spin-flop transition at T=5 K when magnetic fields of about 5.5 T are applied along the c axis. Moreover, the x-ray magnetic diffraction data below TN revealed a commensurate antiferromagnetic structure with propagation wave vector (0012) with the Ce3+ moments oriented along the c axis. Furthermore, our heat capacity, pressure dependent resistivity, and temperature dependent Cu63 NMR data suggest that CeCuBi2 exhibits a weak heavy fermion behavior with strongly localized Ce3+ 4f electrons. We thus discuss a scenario in which both the anisotropic magnetic interactions between the Ce3+ ions and the tetragonal crystalline electric field effects are taking into account in CeCuBi2.

Electron Spin Resonance (ESR) experiments in the filled Cei 1-xYbxFe4P12 (x ≲ 0.0023) skutterudite compounds of Th cubic symmetry (Im3) reveal the coexistence of two distinct Yb3+ sites with large difference in their site occupation, hyperfine interaction and temperature dependence of the ESR parameters. These results suggest a scenario where the oversized (Fe 2P3)4-cages of the Ce1-xYb xFe4P12 compounds are occupied with small number of on-center-Yb3+ ions and a distribution of highly occupied off-center-Yb3+ions, rattling at ∼1 GHz and above ∼20 GHz, respectively. © 2010 IOP Publishing Ltd.

Electron-spin-resonance (ESR) measurements performed on the filled skutterudite system Ce1-x Ybx Fe4 P12 (x≲0.003) unequivocally reveal the coexistence of two Yb3+ resonances associated with sites of considerably different occupations and temperature behaviors. Detailed analysis of the ESR data suggests a scenario where the fraction of oversized (Fe2 P3) 4 cages that host Yb ions are filled with a low occupation of on-center Yb3+ sites and a highly occupied T -dependent distribution of off-center Yb3+ sites. Analysis of the Y 171 b3+ (I=1/2) isotope hyperfine splittings reveal that these two sites are associated with a low (∼1 GHz) and a high (≲ 15 GHz) rattling frequency, respectively. Our findings introduce Yb3+ in Th symmetry systems and use the Yb3+ ESR as a sensitive microscopic probe to investigate the Yb3+ ions dynamics. © 2009 The American Physical Society.

Electron-spin-resonance (ESR) measurements performed on the filled skutterudite system Ce1-x Ybx Fe4 P12 (x≲0.003) unequivocally reveal the coexistence of two Yb3+ resonances associated with sites of considerably different occupations and temperature behaviors. Detailed analysis of the ESR data suggests a scenario where the fraction of oversized (Fe2 P3) 4 cages that host Yb ions are filled with a low occupation of on-center Yb3+ sites and a highly occupied T -dependent distribution of off-center Yb3+ sites. Analysis of the Y 171 b3+ (I=1/2) isotope hyperfine splittings reveal that these two sites are associated with a low (∼1 GHz) and a high (≲ 15 GHz) rattling frequency, respectively. Our findings introduce Yb3+ in Th symmetry systems and use the Yb3+ ESR as a sensitive microscopic probe to investigate the Yb3+ ions dynamics. © 2009 The American Physical Society.

Background and Objectives: A quarter of ischemic strokes are of lacunar clinical subtype and have an underlying recent small subcortical infarct (RSSI), but their long-term outcomes remain poorly characterized. Hemosiderin deposits (HDs) have been noted in RSSIs at chronic stages and might mimic primary hemorrhage. We characterized HDs' morphology, frequency, and clinical relevance., Methods: Participants with RSSIs were identified from a prospective longitudinal study and evaluated on 3T MRI including susceptibility-weighted imaging (SWI) from stroke diagnosis to 12 months. We categorized HDs in RSSIs on SWI at all available time points into 4 types (spots, smudge, rim, cluster) and assessed their associations with demographic factors, stroke-related factors, and image markers with adjusted logistic regression., Results: HDs were observed in 43 (55.0%) of 108 participants within 3 months and 83 (76.9%) of 108 within 12 months after stroke onset. The mean time to first detection of HDs was 87 (interquartile range 53-164) days. A "rim" pattern (similar to late appearance of primary hemorrhage) occurred in at least 26.5% of RSSIs at all follow-up time points, mainly those located in the lentiform/internal capsule (50.0%) or thalamus (36.4%). Infarct volume (odds ratio [OR] 1.003, 95% CI 1.001-1.006; p = 0.004) and the total small vessel disease (SVD) score at baseline (OR 2.50, 95% CI 1.28-4.86, p = 0.007) independently predicted HDs at 12 months. HDs were positively associated with more lacunes (OR 1.60, 95% CI 1.13-2.26, p < 0.01), but not the Fazekas score, number of microbleeds, basal ganglia mineral deposit score, or clinical outcomes., Discussion: HDs occur commonly in RSSIs and may be associated with infarct volume and SVD score. Hemosiderin "rim" is common in RSSIs, urging caution to avoid mistaking ischemic RSSI for primary hemorrhage in subacute and chronic stages.

Objective: Cerebral small vessel diseases (SVDs) are associated with cerebrovascular dysfunction, such as increased blood-brain barrier leakage (permeability surface area product), vascular pulsatility, and decreased cerebrovascular reactivity (CVR). No studies assessed all 3 functions concurrently. We assessed 3 key vascular functions in sporadic and genetic SVD to determine associations with SVD severity, subtype, and interrelations., Methods: In this prospective, cross-sectional, multicenter INVESTIGATE-SVDs study, we acquired brain magnetic resonance imaging in patients with sporadic SVD/cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), including structural, quantitative microstructural, permeability surface area product, blood plasma volume fraction, vascular pulsatility, and CVR (in response to CO 2 ) scans. We determined vascular function and white matter hyperintensity (WMH) associations, using covariate-adjusted linear regression; normal-appearing white matter and WMH differences, interrelationships between vascular functions, using linear mixed models; and major sources of variance using principal component analyses., Results: We recruited 77 patients (45 sporadic/32 CADASIL) at 3 sites. In adjusted analyses, patients with worse WMH had lower CVR (B = -1.78, 95% CI -3.30, -0.27) and blood plasma volume fraction (B = -0.594, 95% CI -0.987, -0.202). CVR was worse in WMH than normal-appearing white matter (eg, CVR: B = -0.048, 95% CI -0.079, -0.017). Adjusting for WMH severity, SVD subtype had minimal influence on vascular function (eg, CVR in CADASIL vs sporadic: B = 0.0169, 95% CI -0.0247, 0.0584). Different vascular function mechanisms were not generally interrelated (eg, permeability surface area product~CVR: B = -0.85, 95% CI -4.72, 3.02). Principal component analyses identified WMH volume/quantitative microstructural metrics explained most variance in CADASIL and arterial pulsatility in sporadic SVD, but similar main variance sources., Interpretation: Vascular function was worse with higher WMH, and in WMH than normal-appearing white matter. Sporadic SVD-CADASIL differences largely reflect disease severity. Limited vascular function interrelations may suggest disease stage-specific differences. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In pediatric patients, esophageal diverticulum (ED) is rare and can be severe, especially when involving the cervical esophagus. Diagnosis and treatment typically start after birth, with some cases managed conservatively. This series presents four ED cases from Jose Marti y Perez Pediatric Teaching Hospital in Cuba (2003-2020). Symptoms included difficulty swallowing, regurgitation, and breathing problems. Three cases required surgery: a five-month-old post-esophageal-coloplasty (managed conservatively), a four-year-old post-esophageal atresia repair (diverticulum partially used to fix a narrow spot), and a 16-year-old with Zenker's diverticulum (requiring surgical removal). A 35-day-old baby with ED post-type C esophageal atresia surgery died from a pre-existing condition. Surviving patients lived healthy lives. ED in pediatrics can be congenital or iatrogenic post-esophageal repair. Reflux symptoms, respiratory distress, or a cervical mass should prompt suspicion of ED., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Garcia et al.)

Purpose: Opioid prescribing trends in medical oncology are poorly defined past 2017, the year after the CDC updated opioid prescription guidelines in noncancer settings. We aim to characterize pain management by medical oncologists by analyzing opioid and gabapentin prescribing trends from 2013 to 2019, identify physician-related factors associated with prescribing patterns, and assess whether CDC guidelines for nononcologic settings changed prescribing patterns., Methods: The Centers for Medicare & Medicaid Services (CMS) Medicare Part D Prescribers-by Provider, CMS Medicare Part D Prescribers-by Provider and Drug, and CMS Medicare Physician National Downloadable files from 2013 to 2019 were merged by National Provider Identification. The database included physicians' sex, years of practice, regions, and practice settings. Multivariable binary logistic regression identified significant predictors of total opioid, long-acting opioid, and gabapentin prescriptions., Results: Binary logistic regression modeling revealed no significant difference in mean daily total opioid prescriptions from 2013 to 2017. Daily opioid prescriptions by medical oncologists decreased significantly after 2017 ( P < .001). Increased opioid prescribing was associated with physician male sex ( P < .001), practicing over 10 years ( P < .001), and practice in nonurban areas ( P < .001). Opioid prescribing was greatest in the South and Midwest United States ( P < .001). The same patterns were observed with total long-acting opioid prescriptions, whereas gabapentin prescribing increased from 2013 to 2019 ( P < .001)., Conclusion: Opioid prescriptions by medical oncologists decreased significantly from 2013 to 2019, but this decrease was most substantial from 2017 to 2019. These results may imply that the 2016 CDC guidelines influenced medical oncologists, particularly more junior physicians in urban settings, to manage chronic cancer pain with alternative therapies.

Background: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease., Methods: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated., Findings: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10 -4 %/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10 -4 %/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10 -4 %/mm Hg [19·6; -45·5 to 31·1] for atenolol; p overall =0·39) but did differ in patients with CADASIL (15·7 × 10 -4 %/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10 -4 %/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10 -4 %/mm Hg [27·5; -77·7 to 30·0] for atenolol; p overall =0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10 -4 %/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10 -4 %/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake., Interpretation: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research., Funding: EU Horizon 2020 programme., Competing Interests: Declaration of interests MD has received consultancy and advisory board fees from Bayer Vital, and speaker's fees from Bayer Vital. MDu reports no competing interests directly related to this work, but declares the following interests outside the submitted work: MIAC (employment), Roche (consultant), Biogen (scientific advisory board), Hovid Berhad (adjudication board), Bayer Vital, and Sanofi Genzyme (speaker honoraria). BN has received consultancy fees from Simbec-Orion for data monitoring committee work. KWM has received consultancy fees from Boehringer Ingelheim, Biogen, Abbvie, Lumosa, and Woolsey, advisory board fees from Boehringer Ingelheim, and speaker's fees from Boehringer Ingelheim. PMR has received consultancy and advisory board fees from Bayer, Bristol Myers Squibb, Sanofi, and Abbott, and speaker fees from Sanofi and Abbott. RvO reports financial support by the European Union's Horizon 2020 project ‘CRUCIAL’ (grant number 848109), and the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium (financed by the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation, the Netherlands Brain Foundation, Stryker, Medtronic, and Cerenovus). JMW is part funded by the UK Dementia Research Institute (funded by the Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK) but has no competing interests. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Brain fluid dynamics remains poorly understood with central issues unresolved. In this study, we first review the literature regarding points of controversy, then pilot study if conventional MRI techniques can assess brain fluid outflow pathways and explore potential associations with small vessel disease (SVD). We assessed 19 subjects participating in the Mild Stroke Study 3 who had FLAIR imaging before and 20-30 minutes after intravenous Gadolinium (Gd)-based contrast. Signal intensity (SI) change was assessed semi-quantitatively by placing regions of interest, and qualitatively by a visual scoring system, along dorsal and basal fluid outflow routes. Following i.v. Gd, SI increased substantially along the anterior, middle, and posterior superior sagittal sinus (SSS) (82%, 104%, and 119%, respectively), at basal areas (cribriform plate, 67%; jugular foramina, 72%), and in narrow channels surrounding superficial cortical veins separated from surrounding cerebrospinal fluid (CSF) (96%) (all p < 0.001). The SI increase was associated with higher intraparenchymal perivascular spaces (PVS) scores (Std. Beta 0.71, p = 0.01). Our findings suggests that interstitial fluid drainage is visible on conventional MRI and drains from brain parenchyma via cortical perivenous spaces to dural meningeal lymphatics along the SSS remaining separate from the CSF. An association with parenchymal PVS requires further research, now feasible in humans., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Interval training (IT) is influenced by several variables and its design. However, there is no consensus about the acute effects of this type of training on running kinematics and gait patterns due to the variety of session designs., Research Question: The aim of this systematic review was to determine the acute effects of IT on gait patterns and running kinematics in endurance runners depending on the characteristics of the training sessions., Methods: A systematic search on four databases (Pubmed, WOS, Medline, and Scopus) was conducted on February 22, 2022. After analyzing 655 articles, studies were included if they met the inclusion criteria developed according to the PICO model. Nine studies were finally included., Results: Only two of these studies measured kinematics changes during IT bouts while seven measured pre-post changes of these parameters. The quality scores of the included studies in the review averaged 5.44 (good quality) points using the modified PEDro scale. The observed changes in running kinematics during IT sessions were an increase in stride frequency, contact time and vertical displacement of center of mass., Significance: Regarding the type of IT, anaerobic and short aerobic interval sessions (200-1000 m) should include long recovery periods (2-3 min) to avoid the increase of stride frequency, contact time and vertical oscillation of the center of mass as a results of muscle fatigue. For long aerobic interval sessions (>1000 m), a short recovery (1-2 min) between bouts do not induce a high level of muscle fatigue nor modifications in gait patterns. Coaches and athletes must consider the relative intensity and recovery periods of IT, and the type of IT, to prevent excessive fatigue which can negatively affect running kinematics., Competing Interests: Conflict of Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate whether gender barriers persist specifically in the cataract and refractive surgery (CRS) literature. In addition, no literature exists investigating the long-term effect of COVID-19 on female authorship in ophthalmology past 2020., Setting: Scopus 2015 to 2022., Design: Retrospective data review., Methods: Articles published in the Journal of Refractive Surgery and the Journal of Cataract & Refractive Surgery were recorded from January 2015 to February 2022 from Scopus. Articles with only 1 author or where gender could not be identified were excluded. The first author (FA) gender, senior author (SA) gender, affiliated country, type of literature, and number of citations were collected. Pearson chi-squared tests with phi coefficients and multivariate logistic regression were performed., Results: 3153 articles were included in analysis. There were 910 works with female FAs and 648 with female SAs. Gender did not predict publishing in one journal over the other (P > .050). Women made up less than 30% of authorship of all types of literature, except for prospective/observational studies as FA (31.3%). Compared with before 2020, female FAs from 2020 onward were associated with increased retrospective analysis (phi = 0.072, P = .030) and letters/editorials (phi = 0.134, P < .001) but decreased case reports (phi = 0.087, P = .009) and "others" (phi = -0.164, P < .001). Similar associations were observed for female SAs. Females were more likely to publish in Asian countries. Female SAs predicted an increased likelihood of female FAs (odds ratio, 1.401, 95% CI, 1.165-1.684, P < .001)., Conclusions: Gender disparities exist in authorship of the CRS literature. COVID-19 has altered the types of literature published by women, but men still publish most of all types of CRS research., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Introduction: Social determinants of health are particularly important in lung cancer epidemiology. Previous studies have primarily associated social determinants with long-term outcomes, such as survival, but fail to include short-term outcomes after surgery. The National Cancer Database (NCDB) was used to draw associations between social factors of patients with lung cancer and short-term post-surgical outcomes, while comparing them to prognostic factors, including stage at diagnosis and survival., Methods: The 2004-17 NCDB was queried for patients with primary epithelial tumor, squamous cell carcinoma, or adenocarcinoma of the lung treated with curative intent. Linear, binary logistic, Kaplan-Meier, and Cox proportional hazards regression models were utilized., Results: On logistic regression modeling, male gender, low income, lacking insurance, and facility in the central United States were associated with poor short-term outcomes (<0.05). Increased age, White race, and Black race were associated with increased length of hospital stay and mortality, but negatively correlated with readmission rates (<0.05). Medicare and Medicaid were associated with increased length of stay and mortality, respectively (<0.05). Similar patterns were observed for higher stage at diagnosis (<0.05). Hazard ratios were elevated with increased age, male gender, White race, lacking insurance, Medicaid, and facility in the central United States (<0.05)., Conclusion: Many social factors previously associated with poor prognosis after lung cancer diagnosis are also associated with poor short-term outcomes after surgery. This study implies that healthcare providers treating lung cancer should proceed with care while aware that patients with the discussed social factors are predisposed to complicated recoveries., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background and Purpose: Although stress is pertinent to all people, individuals with low-income and economic marginalization (LIEM) tend to experience greater psychosocial stressors as well as different relationship stressors than individuals with higher income. While mindfulness may be a particularly useful tool for individuals with LIEM, it has yet to be adapted for this community. Using a community-based participatory research (CBPR) approach, the present study conducted focus groups with community members with LIEM to identify effective dissemination strategies., Materials and Methods: Thirteen individuals with LIEM were recruited to participate in one of two focus groups. The focus groups collected information on how individuals with LIEM cope with stress, how these individuals perceive mindfulness, and how to reduce barriers to participating in a brief mindfulness intervention for stress. Focus groups were transcribed and coded by four coders using thematic analysis within a grounded theory framework., Results: Twelve themes were identified: movement-based coping, behavioral/tactile coping, interest in mindfulness, familiarity with mindfulness, tangible mindfulness, narrow understanding of practicing mindfulness, relaxing, affiliation, alliance with healthcare facility, storytelling, breaking bread, and mental health treatment stigma., Conclusion: Themes derived from the focus groups were discussed with community stakeholders. Findings from this study informed clinical considerations for using mindfulness with individuals with LIEM., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Therapy is an effective form of treatment for couple distress; yet, research shows that 20%-60% of couples terminate treatment prematurely. Predictors of couple retention in therapy and research are unclear, particularly for couples from marginalized populations, which has important implications for the quality and generalizability of research results, and the benefits derived from therapy are limited when participants are not retained. The purpose of this study (N = 1310) was to identify couple-level variables that predict (1) retention in a brief, two-session couple intervention (The Relationship Checkup) delivered as a home visitation program and (2) retention in research participation at 1- and 6-month follow-up. Hypotheses were tested using a two-level multi-level model. Couples are significantly less likely to be retained in the brief intervention if (1) at least one partner identifies as Asian, Pacific Islander, or Native American, (2) at least one partner identifies as Hispanic/Latinx, or (3) both partners report mental or emotional health as a concern in their relationship. Couples are significantly less likely to be retained in research if (1) at least one partner identifies as Asian, Pacific Islander, or Native American (1 month only), (2) at least one partner identifies as Hispanic/Latinx (1 and 6 months), (3) if either partner reports clinically significant relationship distress at baseline (1 and 6 months), or (4) if either partner reports relationship aggression at baseline (6 months only). These findings are discussed with relevance to clinicians and researchers to recruit and retain more diverse and marginalized participants in couple interventions and follow-up research., (© 2022 Family Process Institute.)

Background and Objectives: Magnetic resonance susceptibility-weighted imaging (SWI) can identify small brain blood vessels that contain deoxygenated blood due to its induced magnetic field disturbance. We observed focal clusters of possible dilated small vessels on SWI in white matter in severe small vessel disease (SVD). We assessed their prevalence, associations with SVD lesions, and vascular reactivity in patients with sporadic SVD and in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)., Methods: Secondary cross-sectional analysis of a prospective multicenter observational study of patients with either sporadic SVD or CADASIL (INVESTIGATE-SVD) studied with 3 Tesla MRI including blood-oxygen-level-dependent MRI cerebrovascular reactivity (CVR). Two independent raters evaluated SWI sequences to identify "vessel-clusters" in white matter as focal low-signal dots/lines with small vessel appearance (interrater agreement, kappa statistic = 0.66). We assessed per-patient and per-cluster associations with SVD lesion type and severity on structural MRI sequences. We also assessed CVR within and at 2-voxel concentric intervals around the vessel-clusters using contralateral volumes as a reference., Results: Among the 77 patients enrolled, 76 had usable SWI sequences, 45 with sporadic SVD (mean age 64 years [SD 11], 26 men [58%]) and 31 with CADASIL (53 years [11], 15 men [48%]). We identified 94 vessel-clusters in 36 of the 76 patients (15/45 sporadic SVD, 21/31 CADASIL). In covariate-adjusted analysis, patients with vessel-clusters had more lacunes (OR, 95% CI) (1.30, 1.05-1.62), higher white matter hyperintensity (WMH) volume (per-log10 increase, 1.92, 1.04-3.56), and lower CVR in normal appearing white matter (per %/mm Hg, 0.77, 0.60-0.99), compared with patients without vessel-clusters. Fifty-seven of the 94 vessel-clusters (61%) corresponded to noncavitated or partially cavitated WMH on fluid-attenuated inversion recovery, and 37 of 94 (39%) to complete cavities. CVR magnitude was lower than in the corresponding contralateral volumes (mean difference [SD], t , p ) within vessel-cluster volumes (-0.00046 [0.00088], -3.021, 0.005) and in the surrounding volume expansion shells up to 4 voxels (-0.00011 [0.00031], -2.140, 0.039; -0.00010 [0.00027], -2.295, 0.028) in vessel-clusters with complete cavities, but not in vessel-clusters without complete cavitation., Discussion: Vessel-clusters might correspond to maximally dilated vessels in white matter that are approaching complete tissue injury and cavitation. The pathophysiologic significance of this new feature warrants further longitudinal investigation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Cerebral small vessel disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes. The disease is characterised by patchy cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. This microvascular and tissue damage has been classically considered secondary to extrinsic factors, such as hypertension, but this fails to explain the patchy nature of the disease, the link to endothelial cell (EC) dysfunction even when hypertension is absent, and the increasing evidence of high heritability to SVD-related brain damage. We have previously shown the link between deletion of the phospholipase flippase Atp11b and EC dysfunction in an inbred hypertensive rat model with SVD-like pathology and a single nucleotide polymorphism (SNP) in ATP11B associated with human sporadic SVD. Here, we generated a novel normotensive transgenic rat model, where Atp11b is deleted, and show pathological, imaging and behavioural changes typical of those in human SVD, but that occur without hypertension. Atp11bKO rat brain and retinal small vessels show ECs with molecular and morphological changes of dysfunction, with myelin disruption in a patchy pattern around some but not all brain small vessels, similar to the human brain. We show that ATP11B/ATP11B is heterogeneously expressed in ECs in normal rat and human brain even in the same transverse section of the same blood vessel, suggesting variable effects of the loss of ATP11B on each vessel and an explanation for the patchy nature of the disease. This work highlights a link between inherent EC dysfunction and vulnerability to SVD white matter damage with a marked heterogeneity of ECs in vivo which modulates this response, occurring even in the absence of hypertension. These findings refocus our strategies for therapeutics away from antihypertensive (and vascular risk factor) control alone and towards ECs in the effort to provide alternative targets to prevent a major cause of stroke and dementia., (© 2022. The Author(s).)

SWI/SNF complexes are major targets of mutations in cancer. Here, we combined multiple "-omics" methods to assess SWI/SNF composition and aberrations in LUAD. Mutations in lung SWI/SNF subunits were highly recurrent in our LUAD cohort (41.4%), and over 70% of the mutations were predicted to have functional impact. Furthermore, SWI/SNF expression in LUAD suffered an overall repression that could not be explained exclusively by genetic alterations. Finally, SWI/SNF mutations were associated with poorer overall survival in TCGA-LUAD. We propose SWI/SNF-mutant LUAD as a separate clinical subgroup with practical implications., (© 2022. The Author(s).)

Purpose: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume v p , and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured., Methods: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and v p quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and B 1 + error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and B 1 + correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients., Results: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10 -4 min -1 ). However, these were reduced (≤0.56 × 10 -4 min -1 ) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10 -4 min -1 )., Conclusion: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples., Competing Interests: Disclosure statement None., (Copyright © 2021. Published by Elsevier Inc.)

Technical challenges remain in the sequencing of RNA viruses due to their high intra-host diversity. This bottleneck is particularly pronounced when interrogating long-range co-evolved genetic interactions given the read-length limitations of next-generation sequencing platforms. This has hampered the direct observation of these genetic interactions that code for protein-protein interfaces with relevance in both drug and vaccine development. Here we overcome these technical limitations by developing a nanopore-based long-range viral sequencing pipeline that yields accurate single molecule sequences of circulating virions from clinical samples. We demonstrate its utility in observing the evolution of individual HIV Gag-Pol genomes in response to antiviral pressure. Our pipeline, called Multi-read Hairpin Mediated Error-correction Reaction (MrHAMER), yields >1000s of viral genomes per sample at 99.9% accuracy, maintains the original proportion of sequenced virions present in a complex mixture, and allows the detection of rare viral genomes with their associated mutations present at <1% frequency. This method facilitates scalable investigation of genetic correlates of resistance to both antiviral therapy and immune pressure and enables the identification of novel host-viral and viral-viral interfaces that can be modulated for therapeutic benefit., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The construct composition of the Level of Personality Functioning Scale (LPFS; Criterion A) of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition alternative model for personality disorders (American Psychiatric Association, 2013) was examined in a clinical vignette rating study. Multiple indices of level of personality functioning, psychiatric and psychosocial impairment, Criterion B maladaptive personality traits, and conceptually divergent variables (intellectual level, socioeconomic status, and likability) were used to deconstruct the LPFS. Most variables were highly intercorrelated, but partial correlational analyses showed the LPFS possesses meaningful personality construct variance not fully explained by severity of pathological traits, psychiatric and psychosocial impairment, or the conceptually divergent variables. This exploratory study offers initial evidence that the LPFS contains substantive LPF variance beyond PD severity. Results are framed and discussed in terms of the known conceptual and empirical overlap between Criterion A and Criterion B as well as the differing ways a dimension of personality disorder (PD) severity may be interpreted. We propose the LPFS is more than statistical artifact created by empirical covariation but less than a true latent dimension of PD severity. The LPFS may be understood as a methodologically pragmatic but theoretically substantive dimension of PD severity. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres., Methods: We will recruit participants with sporadic SVDs (ischaemic stroke or vascular cognitive impairment) and CADASIL in Edinburgh, Maastricht and Munich. We will perform detailed clinical and neuropsychological phenotyping of the participants, and neuroimaging including structural MRI, cerebrovascular reactivity MRI (CVR: using carbon dioxide challenge), phase contrast MRI (arterial, venous and CSF flow and pulsatility), dynamic contrast-enhanced MRI (blood brain barrier (BBB) leakage) and multishell diffusion imaging. Participants will measure their blood pressure (BP) and its variability over seven days using a telemetric device., Discussion: INVESTIGATE-SVDs will assess the relationships of BBB integrity, CVR, pulsatility and CSF flow in sporadic SVD and CADASIL using a multisite, multimodal MRI protocol. We aim to establish associations between these measures of vascular function, risk factors particularly BP and its variability, and brain parenchymal lesions in these two SVD phenotypes. Additionally we will test feasibility of complex multisite MRI, provide reliable intermediary outcome measures and sample size estimates for future trials., Competing Interests: None declared., (© 2021 The Authors.)

Background: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease. Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543., Summary: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: UC, MS, MJT, GB, AM, OH, CM, FND and JMW hold academic grants from government and charitable funding agencies, outlined below., (© European Stroke Organisation 2020.)

Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.

The Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2013 ) Section III Alternative Model for Personality Disorders (AMPD) represents a novel approach to the diagnosis of personality disorder (PD). In this model, PD diagnosis requires evaluation of level of impairment in personality functioning (Criterion A) and characterization by pathological traits (Criterion B). Questions about clinical utility, complexity, and difficulty in learning and using the AMPD have been expressed in recent scholarly literature. We examined the learnability, interrater reliability, and clinical utility of the AMPD using a vignette methodology and graduate student raters. Results showed that student clinicians can learn Criterion A of the AMPD to a high level of interrater reliability and agreement with expert ratings. Interrater reliability of the 25 trait facets of the AMPD varied but showed overall acceptable levels of agreement. Examination of severity indexes of PD impairment showed the level of personality functioning (LPF) added information beyond that of global assessment of functioning (GAF). Clinical utility ratings were generally strong. The satisfactory interrater reliability of components of the AMPD indicates the model, including the LPF, is very learnable.

The DSM-5 Section III alternative model for personality disorders (AMPD) is a personality disorder (PD) nosology based on severity of personality dysfunction and pathological traits. We examined the degree to which the personality constructs identified by McAdams and Pals (2006; dispositional traits, characteristic adaptations, narrative identity) and the paradigms of personality assessment described by Wiggins (2003; psychodynamic, interpersonal, personological, multivariate, empirical) are represented within the AMPD. Nine raters expert with the AMPD and personality evaluated elements of Criterion A and the 25 trait facets of Criterion B for presence of type and degree of personality constructs and paradigms, as well as level of inference. Criterion B showed higher rater agreement compared to Criterion A. Criteria A and B reflect different configurations of construct, paradigm, and level of inference. The characteristic adaptation construct and interpersonal paradigm were strongly reflected in both Criteria A and B. The psychodynamic and personological paradigms and the narrative identity construct were highly correlated, and the multivariate, empirical, and dispositional traits variables were highly correlated. Results illustrate differential conceptual emphases as well as areas of overlap with Criteria A and B. This characterization highlights that PD nosology rests on personality theory and suggests implications for integrative PD assessment.

The VIrus Particle ExploreR database (VIPERdb) ( http://viperdb.scripps.edu ) is a database and web portal for primarily icosahedral virus capsid structures that integrates structure-derived information with visualization and analysis tools accessed through a set of web interfaces. Our aim in developing VIPERdb is to provide comprehensive structure-derived information on viruses comprising simple to detailed attributes such as size (diameter), architecture ( T number), genome type, taxonomy, intersubunit association energies, and surface-accessible residues. In addition, a number of web-based tools are provided to enable users to interact with the structures and compare and contrast structure-derived properties between different viruses. Recently, we have constructed a series of data visualizations using modern JavaScript charting libraries such as Google Charts that allow users to explore trends and gain insights based on the various data available in the database. Furthermore, we now include helical viruses and nonicosahedral capsids by implementing modified procedures for data curation and analysis. This article provides an up-to-date overview of VIPERdb, describing various data and tools that are currently available and how to use them to facilitate structure-based bioinformatics analysis of virus capsids.

Objective: The purpose of this study was to examine the relationship between youth motivation and psychotherapy outcomes in routine community mental health settings., Method: One hundred fifty youth, ages 12-17, from three community mental health clinics completed the Youth Outcome Questionnaire and Treatment Support Measure at frequent intervals over the course of treatment., Results: Increases in motivation followed a curvilinear trajectory. On average, youth motivation significantly increased over the course of therapy according to both self- and parent reports (p < .001). The slope for youth motivation over the course of therapy was negatively associated with the slope for mental health symptoms (p < .001). Initial youth motivation did not predict overall change or the rate of change in symptoms. However, there was significant individual variability in patterns of youth motivation., Conclusions: Our findings demonstrate that youth show increases in motivation over the course of therapy with most gains occurring in the first few sessions. Because increases in motivation over the course of therapy were related to decreases in mental health symptoms, further research is needed to examine how treatment interventions or other factors such as parent motivation may moderate this relationship. Additional research examining the likely complex relationship between initial youth motivation and treatment outcomes in community mental health settings is needed.

The purpose of this experiment was to examine when children identify their own experience as one of pride after they complete a difficult and competitive task (i.e., race a confederate in building a tower of blocks). A sample of 144 children between 3 and 6 years of age participated in one of three conditions. Children were told to try to build a tower of blocks taller than a confederate's tower (exceed standard) or tried and failed to build a tower of blocks taller than the confederate's tower (fail standard), or children were asked to build a tower of blocks alongside a confederate (no standard). Results revealed a developmental progression of recognizing pride in which children first began showing nonverbal behaviors that were reliably coded as conveying pride at around 4 years of age. Children began to apply the label/term "pride" to a photograph conveying pride in another peer at around 4 years of age and recognized their own experience as one of pride following a competitive task at around 5 years of age., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The purpose of this study was to examine the behavioral effects of adults' communicated affect on 5-month-olds' visual recognition memory. Five-month-olds were exposed to a dynamic and bimodal happy, angry, or neutral affective (face-voice) expression while familiarized to a novel geometric image. After familiarization to the geometric image and exposure to the affective expression, 5-month-olds received either a 5-min or 1-day retention interval. Following the 5-min retention interval, infants exposed to the happy affective expressions showed a reliable preference for a novel geometric image compared to the recently familiarized image. Infants exposed to the neutral or angry affective expression failed to show a reliable preference following a 5-min delay. Following the 1-day retention interval, however, infants exposed to the neutral expression showed a reliable preference for the novel geometric image. These results are the first to demonstrate that 5-month-olds' visual recognition memory is affected by the presentation of affective information at the time of encoding., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: To quantify the effect of two single-file reciprocating root canal preparation systems on Substance P (SP) and Calcitonin gene-related peptide (CGRP) expression in healthy human periodontal ligament (PDL)., Methodology: Forty PDL samples were obtained from healthy premolars where extraction was indicated for orthodontic reasons. Prior to extraction, 20 of these premolars were divided equally in two groups, and then, root canals were prepared using one of two different single-file systems: WaveOne and Reciproc. Ten premolars were prepared with hand files and served as a positive control group. The remaining 10 premolars where extracted without treatment and served as a negative control group. All PDL samples were processed, and SP and CGRP were measured by radioimmunoassay., Results: Greater SP and CGRP expression were found in the hand instrumentation group (1.220 pmol SP and 0.084 pmol CGRP per mg of PDL), followed by the WaveOne group (0.908 pmol SP and 0.046 pmol CGRP per mg of PDL) and the Reciproc group (0.511 pmol SP and 0.022 pmol CGRP per mg of PDL). The lower SP and CGRP values were associated with the intact control group (0.453 pmol SP and 0.018 pmol CGRP per mg of PDL). The Kruskal-Wallis test revealed significant differences between groups (P < 0.001). Post hoc Tukey HSD tests revealed significant differences in SP and CGRP expression between intact teeth in the control group and all the other groups (P < 0.001) except with the Reciproc group (P = 0.165 and P = 0.42 for SP and CGRP, respectively). Hand instrumentation was associated with significant differences with all the other groups (P < 0.001). Differences between the WaveOne and Reciproc groups were also significant (P < 0.001)., Conclusion: Substance P and CGRP expression in PDL cells increased when teeth were prepared with WaveOne as well as with hand instrumentation. Reciproc maintained SP and CGRP levels in line with the negative control group., (© 2012 International Endodontic Journal.)

Background: We observed that centhaquin, a cardiovascular active agent, reduces blood lactate levels. Because blood lactate is an important indicator of end-organ perfusion, we determined the resuscitative effect of centhaquin in hemorrhaged rats., Materials and Methods: Male, adult Sprague-Dawley rats (Harlan, Indianapolis, IN) were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery, and a pressure-volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and mean arterial pressure was maintained between 35 and 40 mm Hg for 30 min after which resuscitation was performed using normal saline (control), 3% hypertonic saline, or centhaquin dissolved in 3% hypertonic saline. Arterial blood pH, pO(2), pCO(2), lactate, hematocrit, and cardiovascular parameters were measured before the induction of hemorrhage (baseline), 30 min after induction of hemorrhagic shock, and every 60 min thereafter until the animal expired., Results: Hypertonic saline was effective in reducing blood lactate levels and improving cardiac output (CO) of hemorrhaged rats. Centhaquin dissolved in hypertonic saline produced a significantly greater decrease in blood lactate and increase in mean arterial pressure and CO compared with hypertonic saline in hemorrhaged rats. Fraction survival at 250 min was 0 when resuscitated with hypertonic saline, whereas it was 0.8 with centhaquin., Conclusions: Centhaquin significantly improved the resuscitative effect of hypertonic saline by increasing CO, reducing blood lactate, and improving survival time of hemorrhaged rats., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Surfaces that resist protein adsorption are important for many bioanalytical applications. Bovine serum albumin (BSA) coatings and multi-arm poly(ethylene glycol) (PEG) coatings display low levels of non-specific protein adsorption and have enabled highly quantitative single-molecule (SM) protein studies. Recently, a method was developed for coating a glass with PEG-BSA nanogels, a promising hybrid of these two low-background coatings. We characterized the nanogel coating to determine its suitability for SM protein experiments. SM adsorption counting revealed that nanogel-coated surfaces exhibit lower protein adsorption than covalently coupled BSA surfaces and monolayers of multi-arm PEG, so this surface displays one of the lowest degrees of protein adsorption yet observed. Additionally, the nanogel coating was resistant to DNA adsorption, underscoring the utility of the coating across a variety of SM experiments. The nanogel coating was found to be compatible with surfactants, whereas the BSA coating was not. Finally, applying the coating to a real-world study, we found that single ligand molecules could be tethered to this surface and detected with high sensitivity and specificity by a digital immunoassay. These results suggest that PEG-BSA nanogel coatings will be highly useful for the SM analysis of proteins.

We study numerically the one-dimensional Kondo and Hund lattices consisting of localized spins interacting antiferromagnetically or ferromagnetically with the itinerant electrons, respectively. Using the density-matrix renormalization group we find, for both models and in the small coupling regime, the existence of new magnetic phases where the local spins order forming ferromagnetic islands coupled antiferromagnetically. Furthermore, by increasing the interaction parameter |J| we find that this order evolves toward the ferromagnetic regime through a spiral-like phase with longer characteristic wavelengths. These results shed new light on the zero temperature magnetic phase diagram for these models.

Objective: To determine if amifostine could reduce the hematologic toxicity associated with topotecan., Methods: Thirty patients with recurrent/refractory gynecologic malignancies were randomized to receive topotecan (TOPO) (1.5 mg/m(2)/day days 1-5) with or without amifostine (AMI/TOPO) (500 mg/m(2)/day days 1-5) every 3 weeks for six cycles. The primary study endpoints were the incidence of grade 3 and 4 neutropenia., Results: Fifteen patients were randomized to each arm for a total of 49 TOPO and 53 AMI/TOPO cycles. Patient characteristics and pretreatment ANC were similar between groups. Topotecan 1.5 mg/m(2)/day days 1-5 was initially administered to seven patients. Five developed neutropenic fevers, one an uncomplicated grade 4 neutropenia, and the other an uncomplicated grade 3 neutropenia. There were two treatment-related deaths due to sepsis (one in each treatment arm). The starting dose was thereafter reduced to 1.25 mg/m(2)/day days 1-5 every 21 days. No treatment related deaths occurred after this dose reduction. The incidence of combined grade 3/4 neutropenia was reduced from 67% (33/49 cycles) to 38% (20/53 cycles) with the addition of amifostine (P = 0.003; OR 0.29; 95% CI 0.12-0.71)., Conclusions: Topotecan at 1.5 mg/m(2)/day days 1-5 in heavily pretreated patients resulted in excessive toxicity not manageable with amifostine. At the reduced topotecan dose (1.25 mg/m(2) x 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.

Recent studies suggest that research participants show reduced distortion of their taboo attitudes and behaviors when they take part in Internet-based procedures from outside the laboratory. We explored whether such procedures would reduce distortion in the assessment of racial bias. In Study 1, White participants who completed the study in the laboratory evaluated Black targets more favorably than White targets. This unexpected "outgroup-favoring" pattern occurred in both pencil-and-paper and Internet versions of the study, showing that modality did not produce it; but when participants worked outside the laboratory via the Internet, this pattern disappeared. Study 2 replicated the above findings and further indicated that the reduced distortion in Internet-based studies was due to the removal of the experimenter rather than removing the participants from the laboratory environment. The implications of these findings for the study of controlled processes of prejudice and the nature of Internet-based social communication are discussed., (Copyright 2003 Society for Personality and Social Psychology, Inc.)

Purpose: To study the human pharmacokinetics and in vitro cytotoxicity of Apomine, an p.o. administered, nonmyelosuppressive agent that selectively inhibits cell proliferation and induces tumor cell apoptosis through the farnesoid X receptor., Experimental Design: Seven solid cancer patients who participated in an ongoing Phase I study of Apomine and received the starting dose level of 125 mg/m(2)/day x 14 days every 3 weeks underwent a pharmacokinetic study on day 14 of the first course. Plasma concentrations of Apomine were assayed with a Hewlett Packard gas chromatograph using a nitrogen phosphorus detector and HP-5 15m x 0.32-mm column. Fresh human ovarian cancer tumor samples were obtained during initial exploratory laparotomy from 35 chemotherapy-naive, advanced stage epithelial ovarian cancer patients. Tumor samples were tested for sensitivity to Apomine, carboplatin, cisplatin, paclitaxel, and topotecan using an in vitro clonogenic [(3)H]thymidine end point assay., Results: Pharmacokinetic analysis revealed a mean Apomine plasma C(max) of 16.4 +/- 9.1 microg/ml (29.1 microM), a mean plasma AUC(0--12 h) of 173.4 +/- 105 microg. h/ml (308 microM. h), and a mean t(1/2 (24--192 h)) of 156.2 +/- 42.9 h. In vitro assay results showed that 63 and 91% of the ovarian cancers were sensitive (i.e., >70% inhibition of tumor cell growth) to Apomine at concentrations of 10 and 20 microM. The sensitivity rates were 91% for carboplatin (270 microM), 88% for cisplatin (33 microM), 41% for paclitaxel (5.9 microM), and 85% for topotecan (2.2 microM)., Conclusions: These in vitro assay results, taken together with our preliminary plasma pharmacokinetic data, suggest that Apomine should be clinically active at the 125 mg/m(2) dose level.

We study numerically the one dimensional ferromagnetic Kondo lattice, a model widely used to describe nickel and manganese perovskites. By including a nearest-neighbor Coulomb interaction ( V) and a superexchange interaction between the localized moments ( K), we obtain the phase diagram in parameter space for several dopings at T = 0. Because of the competition between double and superexchange, we find a region where the formation of magnetic polarons induces a charge-ordered state which survives also for V = 0. This mechanism should be taken into account in theories of charge ordering involving spin degrees of freedom.

Purpose: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of the standard platinum agents, cisplatin and carboplatin, against fresh human, epithelial ovarian cancers., Methods: The Hamburger-Salmon human tumor colony-forming assay (HTCA) was used to measure the chemosensitivity of 36 fresh tumor samples obtained during initial exploratory laparotomy from patients with newly diagnosed stage III-IV epithelial ovarian cancer who had received no prior chemotherapy or radiation therapy. Tumor samples were exposed to the platinum analogs for 1 h at concentrations of 10 and 100 micrograms/ml of nedaplatin and cisplatin and 100 and 1000 micrograms/ml of carboplatin. The resulting survival data were used to estimate the IC50 (drug concentration associated with 50% inhibition of tumor colony forming units, TCFUs) of each of the platinum analogs for each of the tumor samples, as well as the estimated survival following exposure to clinically achievable drug levels (i.e. the ultrafiltrable platinum area under the plasma disappearance curve, AUC, achieved in cancer patients following administration of standard or phase II doses)., Results: At the lowest concentration tested (i.e. 10 micrograms/ml nedaplatin and cisplatin and 100 micrograms/ml carboplatin) the percentages of tumor samples which were sensitive (as defined by 50% or less survival of TCFUs as compared with controls) were 42, 50, and 40% for nedaplatin, cisplatin and carboplatin, respectively. The median IC50 values were 28.5, 12 and 121 micrograms/ml for nedaplatin, cisplatin and carboplatin, respectively. The estimated percentage of tumors sensitive to clinically achievable dose levels was 42% for nedaplatin and 36% for cisplatin and carboplatin. Nedaplatin and carboplatin proved relatively crossresistant with cisplatin in vitro; of the 18 tumor samples which were resistant to cisplatin, only 5 (28%) were sensitive to nedaplatin and 3 of 17 (18%) were sensitive to carboplatin., Conclusion: Nedaplatin was associated with cytotoxicity similar to cisplatin and carboplatin in this study. Although nedaplatin appears to be crossresistant with cisplatin, its high rate of in vitro cytotoxicity, relative lack of neurotoxicity and nephrotoxicity, and large in vivo biovailability establish nedaplatin as a promising platinum analog for further clinical development as a salvage and primary chemotherapeutic agent for patients with advanced ovarian cancer.

Encapsulation in polyethylene glycol-coated (pegylated; Stealth) liposomes alters the pharmacokinetic characteristics, and hence the safety and tolerability profile, of doxorubicin. Pegylated liposomal doxorubicin administered as a single agent is generally well tolerated. Grade III/IV leucopenia, stomatitis and palmar-plantar erythrodysaesthesia affected 16, 6 and 18% of solid tumour patients, respectively. Other adverse effects included nausea and vomiting and alopecia. Acute hypersensitivity infusion reactions have been reported in up to 9% of patients in some studies. Recently published data from a phase II trial in patients with refractory ovarian cancer showed no alopecia or cardiotoxicity and little nausea and vomiting after pegylated liposomal doxorubicin. Unlike free doxorubicin, pegylated liposomal doxorubicin is not a vesicant. Preliminary data, not yet confirmed in comparative studies, suggest that the pegylated liposomal formulation may be less cardiotoxic than free doxorubicin. Mucositis, however, appears to be increased. Studies to determine optimal dosing schedules and safety of pegylated liposomal doxorubicin in combination with other agents are ongoing.

Cancer prevention aims to halt or reverse the development and progression of precancerous cells through the use of noncytotoxic nutrients and/or pharmacologic agents during the lengthy time period between tumor initiation and frank malignancy. This paper reviews cancer chemoprevention studies and focuses on Phase III trials, which are large, randomized, placebo-controlled studies that usually last several years. Studies may include multiple agents and dose levels, long-term toxicity evaluations or the modulation of surrogate endpoint biomarkers. Sample sizes of individual studies vary depending on statistical concerns and the demographics of the subject population. Recent Phase III trials include several promising agents: retinol; the retinoids 13-cis retinoic acid, all-trans-retinoic acid and 4-hydroxyphenyl retinamide; beta-carotene; finasteride and tamoxifen. Because one of the many actions of retinoids is the induction of epidermal differentiation, clinical trials with this class of agents have largely been conducted in epithelial or squamous cell tumor types. Several Phase III studies that have targeted the reversal of premalignant lesions or the prevention of second primary tumors have shown promising positive results. In contrast, some studies have shown that chemopreventive agents may have limited activity against the recurrence or progression of cells that have already undergone malignant transformation. Thus, the role of chemoprevention appears to lie in reversal of the premalignant process rather than suppression of malignant growth.

The purpose of this study was to assess the prognostic value of in vitro drug chemosensitivity testing using the Hamburger-Salmon human tumor colony-forming assay (HTCA) in fresh tumor samples obtained from newly diagnosed patients with stage II-IV ovarian cancer undergoing maximum cytoreductive surgery and prior to platinum-based chemotherapy. The HTCA was performed on fresh ovarian cancers obtained from 93 patients at their initial exploratory laparotomy to evaluate in vitro sensitivity to cisplatin, carboplatin, and cyclophosphamide following a 1-hr drug exposure. Prospective clinical follow-up was performed on all patients with the primary study endpoints being pathologically proven complete response at second-look surgery and disease-free and overall survival durations. In vitro drug sensitivity was strongly dose-dependent. At a concentration of 5 micrograms/ml only 23% of tumor samples were sensitive (as defined by a > or = 50% decrease in tumor colony-forming units compared to controls) to cisplatin; 13% of tumors were sensitive to carboplatin at a concentration of 50 micrograms/ml and 11% to 4-OH-cyclophosphamide at a concentration of 1 microgram/ml. At doses which were 10 times the previously stated concentrations, the sensitivity rates to cisplatin, carboplatin, and 4-OH-cyclophosphamide increased to 72, 63, and 53%, respectively. Subjects were categorized as having drug-sensitive disease if HTCA results showed in vitro drug sensitivity to at least one of the agents used in their primary chemotherapy. Multivariate analysis failed to show any advantage in clinical response rate, progression-free interval, or survival duration for patients with drug-sensitive disease compared to drug-resistant disease; however, there was evidence of a trend toward an enhanced pathologically proven complete response rate in patients who had chemosensitive tumors in vitro. Second-look surgery was performed in 28 of 55 patients with optimal surgical resections and no clinical evidence of disease at the completion of their primary chemotherapy. Fifty percent (5/10) of patients with drug-sensitive disease achieved a pathologic complete response, while only 3/18 (17%) patients with drug-resistant tumors had a documented pathologic complete response (P = 0.13). As reported in other ovarian cancer studies, patient characteristics which were found to be significantly associated with survival were stage of disease (II-III vs IV), optimal primary surgical resection (i.e., < 1 cm2 residual tumor) vs suboptimal resection, clinical measurability of disease at initiation of chemotherapy, and response to primary chemotherapy. In conclusion, in vitro drug sensitivity, as measured by the HTCA, does not appear to be an independent prognostic factor for survival in patients with stage II-IV epithelial ovarian cancer who undergo standard treatment with tumor debulking surgery and primary platinum-based chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Squamous cell cancer of the cervix is a relatively drug-resistant tumor. Therefore, chemotherapy is predominantly reserved for cervical cancer patients with recurrent or refractory disease following surgery and/or radiation therapy or for patients who present with far advanced, incurable disease. Objective responses to salvage chemotherapy are generally short lived (4 to 6 months) with few patients surviving more than 1 year. Complete clinical remissions primarily occur at extrapelvic sites (eg, lung, lymph node, and soft tissue metastases). Bulky pelvic tumor in an area of prior irradiation remains largely refractory to further therapy. At present, no chemotherapy regimen has proven superior to single-agent cisplatin, which is associated with an approximately 30% objective response rate. The most effective nonplatinum agents appear to be doxorubicin, ifosfamide, mitolactol, and vincristine. Multiple studies have documented improved partial response rates with platinum-based multiagent chemotherapy, but no regimen has been associated with an improved survival duration. To improve the poor prognosis of this patient group, identification of new agents with at least equivalent activity to cisplatin is mandatory. The development of new platinum-based regimens using currently available agents is unlikely to substantially improve patient survival, although better palliative therapy may result from this approach.