Magnetic Amplification at Yb3+ "Designer Defects" in the van der Waals Ferromagnet CrI3.

The two-dimensional (2D) van der Waals ferromagnet CrI3 has been doped with the magnetic optical impurity Yb3+ to yield materials that display sharp multiline Yb3+ photoluminescence (PL) controlled by the magnetism of CrI3. Magneto-PL shows that Yb3+ magnetization is pinned to the magnetization of CrI3. An effective internal field of ∼10 T at Yb3+ is estimated, attributed to strong in-plane Yb3+-Cr3+ superexchange coupling. The anomalously low energy of Yb3+ PL in CrI3 reflects relatively high Yb3+-I- covalency, contributing to Yb3+-Cr3+ superexchange coupling. The Yb3+ PL energy and line width both reveal the effects of spontaneous zero-field CrI3 magnetic ordering within 2D layers below TC, despite the absence of net magnetization in multilayer samples. These results illustrate the use of optical impurities as "designer defects" to introduce unique functionality to 2D magnets.

Luminescence and Covalency in Ytterbium-Doped CrX3 (X = Cl, Br, I) van der Waals Compounds.

The layered 2D van der Waals ferromagnets CrX3 (X = Cl, Br, I) show broad d-d photoluminescence (PL). Here we report preparation, structural characterization, and spectroscopic studies of all three CrX3 compounds doped with the optical impurity, Yb3+. EXAFS measurements show very similar Cr K-edge and Yb L-edge data for each doped compound, and good fits of the latter are obtained for structures having Yb3+ occupying substitutional octahedral sites. Yb-X bond lengths are systematically ∼0.25 Å larger than their Cr-X counterparts. 4 K PL measurements show efficient sensitization of Yb3+ luminescence upon photoexcitation into lattice absorption bands [Cr3+ d-d and ligand-to-metal charge-transfer (LMCT)] for all three compounds, converting their nondescript broadband d-d PL into sharp f-f emission. The PL of CrCl3:Yb3+ and CrBr3:Yb3+ occurs at energies typical for [YbX6]3- with these halides, with PL decay times of 0.5-1.0 ms at 4 K, but CrI3:Yb3+ displays anomalously low-energy Yb3+ emission and an unusually short PL decay time of only 8 µs at 4 K. Data analysis and angular overlap model (AOM) calculations show that Yb3+ in CrI3:Yb3+ has a lower spin-orbit splitting energy than reported for any other Yb3+ in any other compound. We attribute these observations to exceptionally high covalency of the Yb3+ f orbitals in CrI3:Yb3+ stemming primarily from the shallow valence-shell ionization potentials of the iodide anions.

Effectiveness of a group intervention to reduce sexual transmission risk behavior among MSM living with HIV: a non-randomized controlled pilot study.

ABSTRACTWith an annual incidence of about 1.5 million new infections, HIV is an ongoing public health concern. Sexual transmission risk behavior (STRB) is a main driver of the HIV epidemic in most Western countries, particularly among specific populations such as men who have sex with men (MSM). This quasi-experimental pilot study examined the effectiveness of a ten-session group intervention, aiming to reduce STRB among a high-risk subpopulation of MSM living with HIV. Self-reported STRB, impulsivity, mental health symptoms, and functional impairment were compared between the intervention group (n = 12) and a control group (n = 16). At baseline, participants in the intervention group had higher levels of STRB, impulsivity, mental health problems, and functional impairment, compared to the control group. A significant time-by-group interaction effect revealed that after the intervention, STRB, impulsivity, and functional impairment reduced in the intervention group to levels comparable to the control group. These findings suggest that a targeted behavioral intervention might be an effective strategy to reduce persistent STRB and related factors in MSM living with HIV. Future studies should confirm these findings in larger samples, using randomized designs.

Selective colloidal bonds via polymer-mediated interactions.

Regioselectivity in colloidal self-assembly typically requires specific chemical interactions to guide particle binding. In this paper, we describe a new method to form selective colloidal bonds that relies solely on polymer adsorption. Mixtures of polymer-coated and bare particles are initially stable due to long-ranged electrostatic repulsion. When their charge is screened, the two species can approach each other close enough for polymer bridges to form, binding the particles together. By utilizing colloidal dumbbells, where each lobe is coated with polymer brushes of differing lengths, we demonstrate that the Debye screening length serves as a selective switch for the assembly of bare tracer particles onto the two lobes. We model the interaction using numerical self-consistent field lattice computations and show how regioselectivity arises from just a few nanometers difference in polymer brush length.

The impact of cardiorespiratory fitness on classical cardiovascular disease risk factors in rheumatoid arthritis: a cross-sectional and longitudinal study.

Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). Advanced measures of cardiorespiratory fitness (CRF) are associated with CVD risk factors. The present study aimed to examine whether CVD risk factors can predict clinic-based measures of CRF, using the Siconolfi step test and to determine if exercise can improve RA patients' cardiovascular health. Sixty-five RA patients (46 females, age 58 ± 11 years) completed assessments of CRF, CVD risk factors, body composition and RA characteristics. Ten patients participated in a follow-up 8-week exercise intervention. CRF was low (22 ml kg-1 min-1) and associated with higher diastolic blood pressure (r = - 0.37, p = 0.002), higher global CVD risk (r = - 0.267, p = 0.031) and worse body composition profile (body fat, r = - 0.48, p < 0.001; waist, r = - 0.65, p < 0.001; hip, r = - 0.58, p < 0.001). Regular exercise significantly improved CRF (p = 0.021), lower body strength (p < 0.001), agility (p < 0.001), systolic blood pressure (p = 0.021), body fat (p = 0.018), waist circumference (p = 0.035), hip circumference (p = 0.016), disease activity (p = 0.002), disability (p = 0.007) and QoL (p = 0.004). Elevated diastolic blood pressure and worse body composition profile are strong predictors of clinic-based measures of CRF. CRF is an important determinant of CVD risk and warrants inclusion in the routine assessment of RA patients. Regular exercise can improve CRF and CVD risk factors without any exacerbation of disease activity and should be offered as part of routine care.

Care recipients' physical frailty is independently associated with subjective burden in informal caregivers in the community setting: a cross-sectional study.

BACKGROUND: Physical frailty is associated with significant morbidity and mortality in community-dwelling older adults. Burden in informal caregivers of older adults causes significant physical and psychological distress. However, the relationship between these two clinical phenomena has not been extensively studied. This cross-sectional study evaluated the relationship between physical frailty of community-dwelling older adults attending an outpatient geriatric clinic and the subjective burden reported by their informal caregivers. METHODS: We measured the following characteristics of 45 patient-caregiver dyads attending an outpatient geriatric assessment clinic: Physical frailty using the Fried Frail Scale (FFS); self-reported independence in activities of daily living (ADL) using the Katz Index; clinical diagnosis of dementia; and subjective caregiver burden using the short 12-item version of the Zarit Burden Interview (ZBI). Multivariable linear regression was performed with FFS, Katz Index score, gender, age, and diagnosis of dementia as independent variables, and ZBI score as the dependent variable. RESULTS: Only physical frailty significantly predicted caregiver burden (ß = 8.98 95% confidence interval [CI]: 2.15, 15.82). CONCLUSIONS: Physical frailty is independently associated with caregiver burden in a population of community-dwelling older adults. Despite limitations related to sample size and lack of data about caregiver characteristics, this study suggests that the relationship between physical frailty and caregiver burden merits further study.

[Provision of outpatient specialist care for mental disorders : Minor regional differences in treatment needs, major regional differences in availability]. / Ambulante fachärztliche Versorgung psychischer Störungen : Kleine regionale Unterschiede im Bedarf, große regionale Unterschiede in der Versorgungsdichte.

BACKGROUND: Due to the high burden attributed to mental disorders, an important purpose of a general healthcare system is to provide comprehensive medical specialist care that is both locally available and in line with demand; however, the density of outpatient physicians and psychotherapists significantly varies between regions in Germany. To verify if these variations reflect regional variations of morbidity rates, routine data of statutory health insurance companies are analyzed on a regular basis. But these administrative data directly depend on the actual regional health care supply. Hence, independent epidemiological data on prevalence rates of mental disorders could be a valuable supplement. METHODS: Analyses are based on prevalence rates of the representative epidemiological German health interview and examination survey and its mental health module (DEGS1-MH) as well as supplemental data from the German national and regional associations of statutory health insurance physicians. The associations between prevalence rates and density of outpatient physicians and psychotherapists were computed for the DEGS sample points, representing 139 different German districts. Transregional care provision for neighboring regions was taken into account. RESULTS: There were neither significant associations of regional density of outpatient physicians and psychotherapists with prevalence rates of mental disorders in general nor with prevalence rates of severe mental disorders; however, taking into account transregional care provision for neighboring regions the huge variability of provider density decreases. DISCUSSION: The regional inequality of physician and psychotherapist density cannot be explained by regional differences in treatment needs. The results indicate potential improvements in healthcare provision for mental disorders in Germany through the adaptation to actual morbidity rates; however, the definition of treatment needs in mental disorders requires further evaluation.

Effects of type 1 diabetes, sprint training and sex on skeletal muscle sarcoplasmic reticulum Ca2+ uptake and Ca2+-ATPase activity.

Calcium cycling is integral to muscle performance during the rapid muscle contraction and relaxation of high-intensity exercise. Ca(2+) handling is altered by diabetes mellitus, but has not previously been investigated in human skeletal muscle. We investigated effects of high-intensity exercise and sprint training on skeletal muscle Ca(2+) regulation among men and women with type 1 diabetes (T1D, n = 8, 3F, 5M) and matched non-diabetic controls (CON, n = 8, 3F, 5M). Secondarily, we examined sex differences in Ca(2+) regulation. Subjects undertook 7 weeks of three times-weekly cycle sprint training. Before and after training, performance was measured, and blood and muscle were sampled at rest and after high-intensity exercise. In T1D, higher Ca(2+)-ATPase activity (+28%) and Ca(2+) uptake (+21%) than in CON were evident across both times and days (P < 0.05), but performance was similar. In T1D, resting Ca(2+)-ATPase activity correlated with work performed until exhaustion (r = 0.7, P < 0.01). Ca(2+)-ATPase activity, but not Ca(2+) uptake, was lower (-24%, P < 0.05) among the women across both times and days. Intense exercise did not alter Ca(2+)-ATPase activity in T1D or CON. However, sex differences were evident: Ca(2+)-ATPase was reduced with exercise among men but increased among women across both days (time × sex interaction, P < 0.05). Sprint training reduced Ca(2+)-ATPase (-8%, P < 0.05), but not Ca(2+) uptake, in T1D and CON. In summary, skeletal muscle Ca(2+) resequestration capacity was increased in T1D, but performance was not greater than CON. Sprint training reduced Ca(2+)-ATPase in T1D and CON. Sex differences in Ca(2+)-ATPase activity were evident and may be linked with fibre type proportion differences.

Alopecia in three macaque species housed in a laboratory environment.

Alopecia is a persistent problem in captive macaque populations and despite recent interest, no factors have been identified that can unequivocally explain the presence of alopecia in a majority of cases. Seasonal, demographic, and environmental factors have been identified as affecting alopecia presentation in rhesus macaques, the most widely studied macaque species. However, few studies have investigated alopecia rates in other macaque species. We report alopecia scores over a period of 12 months for three macaque species (Macaca nemestrina, M. mulatta, and M. fascicularis) housed at three indoor facilities within the Washington National Primate Research Center (WaNPRC) in Seattle. Clear species differences emerged with cynomolgus (M. fascicularis) showing the lowest alopecia rates and pigtails (M. nemestrina) the highest rates. Further analysis of pigtail and rhesus (M. mulatta) macaques revealed that sex effects were apparent for rhesus but not pigtails. Age and seasonal effects were evident for both species. In contrast to previous reports, we found that older animals (over 10 years of age) had improved alopecia scores in comparison to younger adults. This is the first report on alopecia rates in pigtail macaques and the first comparison of alopecia scores in pigtail, cynomolgus, and rhesus macaques housed under similar conditions.

An investigation of different aspects of overgeneralization in patients with major depressive disorder and borderline personality disorder.

OBJECTIVE: The aim of this study was to investigate whether (a) overgeneralization is restricted to negative attributions directed at the self; or whether it also extends to positive self-attributions and to attributions of situations in the outside world, and (b) whether the valence and direction (positively or negatively, to the self- or across situations) of overgeneralization processes vary among different patient populations. METHODS: Patients with major depressive disorder (MDD, n = 34), borderline personality disorder (BPD, n = 18), or both (n = 35), and never-depressed non-patients (NPs; n = 50) completed various measures of overgeneralization. RESULTS: Patients with MDD show higher levels of negative overgeneralization but lower levels of positive overgeneralization to the self- and across situations than NPs. Patients with MDD show more negative than positive overgeneralization to the self: a negative bias. They, however, do show higher levels of positive than negative overgeneralization across situations. Patients with BPD show the same pattern for overgeneralization to the self, but their higher levels of negative overgeneralization across situations are not exceeded by their positive counterpart. CONCLUSIONS: Results indicate that patient groups differ from NPs not only with respect to negative, but also with respect to positive overgeneralization. Furthermore, the valence and direction of overgeneralization processes vary among MDD and BPD patient populations. More specifically, findings suggest that, as compared to never-depressed individuals, patients with BPD and patients with MDD alike, lack a buffer against negative overgeneralization directed at the self. In patients with BPD, not only the high level of overgeneralization to the self, but also the high level of overgeneralization across situations seems to be problematic, since both types of overgeneralization appear not to be buffered by their positive counterparts.

Amygdala response predicts clinical symptom reduction in patients with borderline personality disorder: A pilot fMRI study.

Borderline personality disorder (BPD) is a prevalent, devastating, and heterogeneous psychiatric disorder. Treatment success is highly variable within this patient group. A cognitive neuroscientific approach to BPD might contribute to precision psychiatry by identifying neurocognitive factors that predict who will benefit from a specific treatment. Here, we build on observations that BPD is accompanied by the enhanced impact of the aversive effect on behavior and abnormal neural signaling in the amygdala. We assessed whether BPD is accompanied by abnormal aversive regulation of instrumental behavior and associated neural signaling, in a manner that is predictive of symptom reduction after therapy. We tested a clinical sample of 15 female patients with BPD, awaiting dialectical behavior therapy (DBT), and 16 matched healthy controls using fMRI and an aversive Pavlovian-to-instrumental transfer (PIT) task that assesses how instrumental behaviors are influenced by aversive Pavlovian stimuli. Patients were assessed 1 year after the start of DBT to quantify changes in BPD symptom severity. At baseline, behavioral aversive PIT and associated neural signaling did not differ between groups. However, the BOLD signal in the amygdala measured during aversive PIT was associated with symptom reduction at 1-year follow-up: higher PIT-related aversive amygdala signaling before treatment was associated with reduced clinical improvement at follow-up. Thus, within the evaluated group of BPD patients, the BOLD signal in the amygdala before treatment was related to clinical symptom reduction 1 year after the start of treatment. The results suggest that less PIT-related responsiveness of the amygdala increases the chances of treatment success. We note that the relatively small sample size is a limitation of this study and that replication is warranted.

Improving chemotherapy infusion operations through the simulation of scheduling heuristics: a case study.

Over the last decade, chemotherapy treatments have dramatically shifted to outpatient services such that nearly 90% of all infusions are now administered outpatient. This shift has challenged oncology clinics to make chemotherapy treatment as widely available as possible while attempting to treat all patients within a fixed period of time. Historical data from a Veterans Affairs chemotherapy clinic in the United States and staff input informed a discrete event simulation model of the clinic. The case study examines the impact of altering the current schedule, where all patients arrive at 8:00 AM, to a schedule that assigns patients to two or three different appointment times based on the expected length of their chemotherapy infusion. The results identify multiple scheduling policies that could be easily implemented with the best solutions reducing both average patient waiting time and average nurse overtime requirements.

Renal replacement therapy in critically ill patients with COVID-19: A retrospective study investigating mortality, renal recovery and filter lifetime.

PURPOSE: This study aims to investigate mortality and renal recovery in patients with Acute Kidney Injury (AKI) and Renal Replacement Therapy (RRT) due to COVID-19. A secondary aim is to investigate the filter life time in Continuous VenoVenous Hemofiltration (CVVH) and the effect of different methods of anticoagulation. METHODS: All patients with COVID-19 infection admitted to the ICU between March 16th 2020 to May 10th 2020 were retrospectively studied. Patients were categorized in a AKI-group and a non-AKI-group. RESULTS: Thirty-seven patients were included. Twenty-two (60%) patients developed AKI. Mortality in the AKI-group was 41% compared to 20% in the non-AKI group, p = 0.275. Comparable mortality was seen in the RRT (39%) and the non-RRT group (44%), p = 1.000. Renal function recovered to a KDIGO-stage 1 in 64% of the patients with AKI when discharged from the ICU. Life time for the CVVH filters (n = 53) was 27 h (14-63)[2-78]. No difference was found with various methods of anticoagulation. CONCLUSION: The need for RRT in critically ill patients with COVID-19 was reversible in our cohort and RRT was not associated with an increased mortality compared to AKI without the need for RRT. Higher levels of anticoagulation were not associated with prolonged filter life.

Sex, Drugs, and Impulse Regulation: A Perspective on Reducing Transmission Risk Behavior and Improving Mental Health Among MSM Living With HIV.

Unprotected sexual contact continues to be a main cause of HIV transmission and poses certain key populations at increased risk for HIV infection. One of the populations at high risk are men who have sex with men. A subset of MSM engages in chemsex, whereby consumption of illicit drugs is used to facilitate or enhance sexual activity. This practice can have several negative consequences, such as sexually transmitted infections (including HIV) and mental health problems (including compulsive sexual behavior, addiction, and mood disorders). In this article, we provide our perspective on the current situation that medical professionals dealing with MSM living with HIV often feel empty-handed in how to deal with these behavioral and psychological issues. Close collaboration between somatic and mental health professionals is key to address treatment needs of people living with HIV, regarding the negative consequences of chemsex and their overall quality of life. In this article, we discuss possibilities for psychological treatment, including behavioral skills training to improve impulse control and reduce compulsive sexual behaviors among MSM living with HIV who persistently engage in sexual transmission risk behavior, based on our experience with implementing such an intervention. Important barriers and facilitators for further implementation of behavioral interventions will be discussed. Reduction of HIV transmission risk behavior is needed to achieve the WHO aim to end HIV as a public health threat by 2030. We propose that close collaboration between somatic and mental health professionals and implementation of behavioral interventions for risk populations are key to achieve this goal.

Doctor-patient communication, health-related beliefs, and adherence in glaucoma results from the Glaucoma Adherence and Persistency Study.

OBJECTIVE: To use multiple data sources to determine drivers of patient adherence to topical ocular hypotensive therapy. DESIGN: Retrospective database and chart reviews in combination with prospective patient surveys. Diverse medical environments where insured patients in the research database seek care. PARTICIPANTS: Three hundred patients with a new claim diagnosis for open-angle glaucoma who initially were prescribed one of three prostaglandins and 103 physicians participating in the same medical plans. METHODS: A structured interview addressing self-reported adherence, experiences with medication, communication with the physician, and health-related beliefs associated with adherence behavior was administered to surveyed patients. Phone interviews were conducted with participating ophthalmologists. MAIN OUTCOME MEASURE: Of adherence, medication possession ratio. RESULTS: Eight variables were associated independently with a lower medication possession ratio: (1) hearing all of what you know about glaucoma from your doctor (compared with some or nothing); (2) not believing that reduced vision is a risk of not taking medication as recommended; (3) having a problem paying for medications; (4) difficulty while traveling or away from home; (5) not acknowledging stinging and burning; (6) being nonwhite; (7) receiving samples; and (8) not receiving a phone call visit reminder. The multivariate model explained 21% of the variance. CONCLUSIONS: These findings indicate that doctor-patient communications and health-related beliefs of patients contribute to patient adherence. Patient learning styles that are associated with less concern about the future effects of glaucoma and the risks of not taking medications are associated with lower adherence. Specifically, knowledge about potential vision loss from glaucoma is a critical element that tends to be missed by more passive doctor-dependent patients who tend to be poorly adherent. These findings suggest that educational efforts in the office may improve patient adherence to medical therapies.

Canadian Study of Health and Aging Clinical Frailty Scale: Does It Predict Adverse Outcomes among Geriatric Trauma Patients?

BACKGROUND: The Canadian Study of Health and Aging Clinical Frailty Scale (CFS) and the laboratory Frailty Index (FI-lab) are validated tools based on clinical and laboratory data, respectively. Their utility as predictors of geriatric trauma outcomes is unknown. Our primary objective was to determine whether pre-admission CFS is associated with adverse discharge destination. Secondary objectives were to evaluate the relationships between CFS and in-hospital complications and between admission FI-lab and discharge destination. STUDY DESIGN: We performed a 4-year (2011 to 2014) retrospective cohort study with patients 65 years and older admitted to a level I trauma center. Admission FI-lab was calculated using 23 variables collected within 48 hours of presentation. The primary outcome was discharge destination, either adverse (death or discharge to a long-term, chronic, or acute care facility) or favorable (home or rehabilitation). The secondary outcome was in-hospital complications. Multivariable logistic regression was used to evaluate the relationship between CFS or FI-lab and outcomes. RESULTS: There were 266 patients included. Mean age was 76.5 ± 7.8 years and median Injury Severity Score was 17 (interquartile range 13 to 24). There were 260 patients and 221 patients who had sufficient data to determine CFS and FI-lab scores, respectively. Pre-admission frailty as per the CFS (CFS 6 or 7) was independently associated with adverse discharge destination (odds ratio 5.1; 95% CI 2.0 to 13.2; p < 0.001). Severe frailty on admission, as determined by the FI-lab (FI-lab > 0.4), was not associated with adverse outcomes. CONCLUSIONS: Pre-admission clinical frailty independently predicts adverse discharge destination in geriatric trauma patients. The CFS may be used to triage resources to mitigate adverse outcomes in this population. The FI-lab determined on admission for trauma may not be useful.

A Hybrid III stepped wedge cluster randomized trial testing an implementation strategy to facilitate the use of an evidence-based practice in VA Homeless Primary Care Treatment Programs.

BACKGROUND: Homeless veterans often have multiple health care and psychosocial needs, including assistance with access to housing and health care, as well as support for ongoing treatment engagement. The Department of Veterans Affairs (VA) developed specialized Homeless Patient Alignment Care Teams (HPACT) with the goal of offering an integrated, "one-stop program" to address housing and health care needs of homeless veterans. However, while 70% of HPACT's veteran enrollees have co-occurring mental health and substance use disorders, HPACT does not have a uniform, embedded treatment protocol for this subpopulation. One wraparound intervention designed to address the needs of homeless veterans with co-occurring mental health and substance use disorders which is suitable to be integrated into HPACT clinic sites is the evidence-based practice called Maintaining Independence and Sobriety through Systems Integration, Outreach, and Networking-Veterans Edition, or MISSION-Vet. Despite the promise of MISSION-Vet within HPACT clinics, implementation of an evidence-based intervention within a busy program like HPACT can be difficult. The current study is being undertaken to identify an appropriate implementation strategy for MISSION-Vet within HPACT. The study will test the implementation platform called Facilitation and compared to implementation as usual (IU). The aims of this study are as follows: (1) Compare the extent to which IU or Facilitation strategies achieve fidelity to the MISSION-Vet intervention as delivered by HPACT homeless provider staff. (2) Compare the effects of Facilitation and IU strategies on the National HPACT Performance Measures. (3) Compare the effects of IU and Facilitation on the permanent housing status. (4) Identify and describe key stakeholders' (patients, providers, staff) experiences with, and perspectives on, the barriers to, and facilitators of implementing MISSION. DESIGN: Type III Hybrid modified stepped wedge implementation comparing IU to Facilitation across seven HPACT teams in three sites in the greater Los Angeles VA system. This is a cluster randomized trial. DISCUSSION: Integrating MISSION-Vet within HPACT has the potential to improve the health of thousands of veterans, but it is crucial to implement the intervention appropriately in order for it to succeed. The lessons learned in this protocol could assist with a larger roll-out of MISSION within HPACT. This protocol is registered with clinicaltrials.gov and was assigned the number NCT 02942979.

Protein Z gene polymorphisms, protein Z concentrations, and ischemic stroke.

BACKGROUND AND PURPOSE: We aimed to determine whether A-13G or G79A polymorphisms of the protein Z gene that have been reported to be an important determinant of blood concentrations of protein Z are associated with risk of ischemic stroke in a broad range of stroke patients and controls. METHODS: We conducted a case control study of 151 hospital cases of first-ever ischemic stroke and 164 randomly selected community controls. Protein Z genotype was determined for the A-13G promoter polymorphism and the G79A intron F polymorphism, and plasma protein Z concentrations were measured during the first 7 days and at 3 to 6 months after the acute stroke event. RESULTS: Geometric mean concentrations of protein Z measured within 7 days of acute stroke were significantly higher in cases compared with controls (1.51 microg/mL versus 1.13 microg/mL; P<0.0001). Protein Z concentrations were highest among subjects with the A-13G AA genotype, intermediate among those with the AG genotype, and lowest among those with the GG genotype (1.39 microg/mL versus 1.05 microg/mL versus 0.76 microg/mL; P<0.0001); and highest among those with the G79A GG genotype, intermediate among those with the GA genotype, and lowest among those with the AA genotype (1.47 microg/mL versus 1.13 microg/mL versus 0.66 microg/mL; P<0.0001). The prevalence of A-13G and G79A genotypes was not significantly different between cases of ischemic stroke and controls. However, compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (odds ratio [OR], 0.83; 95% CI, 0.52 to 1.33) and the homozygote AA genotype (OR, 0.63; 95% CI, 0.20 to 1.98). A pooled analysis showed that compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (OR, 0.78; 95% CI, 0.57 to 1.07) and the homozygote AA genotype (OR, 0.31; 95% CI, 0.14 to 0.69). CONCLUSIONS: The consistency of the association between protein Z genotypes, blood concentrations of protein Z, and ischemic stroke, determined using 2 different methods that have different sources of bias strengthens the evidence that increased blood concentrations of protein Z concentrations are associated causally with an increased risk of ischemic stroke.

Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: a randomized substudy of the VITATOPS trial.

BACKGROUND AND PURPOSE: Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine (total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. METHODS: We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B12 0.5 mg, and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. RESULTS: At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P=0.32]; soluble CD40L [P=0.33]; IL-6 [P=0.77]), endothelial dysfunction (vascular cell adhesion molecule-1 [P=0.27]; intercellular adhesion molecule-1 [P=0.08]; von Willebrand factor [P=0.92]), and hypercoagulability (P-selectin [P=0.33]; prothrombin fragment 1 and 2 [P=0.81]; D-dimer [P=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-micromol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). CONCLUSIONS: Lowering tHcy by 3.7 micromol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: (1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); (2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or (3) elevated tHcy is a noncausal marker of increased vascular risk.

Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial.

OBJECTIVE: We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin. METHODS: We performed a randomized, double-blind, placebo-controlled, crossover trial, comparing clopidogrel 75 mg day(-1) versus placebo, in 36 aspirin-treated patients with symptomatic objectively confirmed peripheral arterial disease. RESULTS: The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B2 concentrations, or soluble markers of platelet activation markers (P-selectin, CD40-ligand) and inflammation (high sensitivity serum C-reactive protein, interleukin-6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3-31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2-9.3%, P = 0.0003). The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid-induced platelet aggregation: 2.8% (95% CI: -0.8 to 6.3%) reduction in mean collagen-induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4-7.6%); upper tertile 12.6% (95% CI: 4.5-20.8%); P-value for interaction 0.01]. CONCLUSIONS: The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.