Cognitive performance and mortality among patients receiving autologous hematopoietic stem cell transplant.

OBJECTIVES: Patients undergoing autologous hematopoietic stem cell transplant (HCT) are at risk for death and remain understudied relative to those undergoing allogeneic HCT. Cognitive functioning may be a useful indicator of mortality risk. We examined cognition among patients who underwent autologous HCT and its relationship to mortality. METHODS: Participants (N = 51; 11 patients deceased) completed tasks of processing speed, working memory, executive-mediated learning, and visual recall using the computerized CogState battery prior to HCT, 30 days post-autologous HCT, and 100 days post-autologous HCT. RESULTS: Slower processing speed (HR = 3.00) and more errors on an executive-mediated visual learning task (HR = 2.78) prior to HCT were associated with an increased risk of death following HCT. Our sample size limited longitudinal analyses of whether cognitive change predicted survival, however descriptive cognitive data of the deceased versus living patient's performances over time suggested different patterns of performance across groups. CONCLUSIONS: Pre-HCT cognition may have utility as an indicator of mortality risk following autologous HCT. More research is needed to examine whether cognitive changes after HCT could also predict mortality.

Neurocognitive change over the course of a multiday external lumbar drain trial in patients with suspected normal pressure hydrocephalus.

Objective: To characterize neurocognitive response to cerebrospinal fluid (CSF) diversion during a multiday external lumbar drainage (ELD) trial in patients with suspected normal pressure hydrocephalus (NPH). Methods: Inpatients (N = 70) undergoing an ELD trial as part of NPH evaluation participated. Cognition and balance were assessed using standardized measures before and after a three-day ELD trial. Cognitive change pre- to post-ELD trial was assessed in relation to change in balance, baseline neuroimaging findings, NPH symptoms, demographics, and other disease-relevant clinical parameters. Results: Multiday ELD resulted in significant cognitive improvement (particularly on measures of memory and language). This improvement was independent of demographics, test-retest interval, number of medical and psychiatric comorbidities, NPH symptom duration, estimated premorbid intelligence, baseline level of cognitive impairment, cerebrovascular disease burden, degree of ventriculomegaly, or other NPH-related morphological brain alterations. Balance scores evidenced a greater magnitude of improvement than cognitive scores and were weakly, but positively correlated with cognitive change scores. Conclusions: Findings suggest that cognitive improvement associated with a multiday ELD trial can be sufficiently captured with bedside neurocognitive testing. These findings support the utility of neuropsychological consultation, along with balance assessment, in informing clinical decision-making regarding responsiveness to temporary CSF diversion for patients undergoing elective NPH evaluation. Implications for the understanding of neuroanatomical and cognitive underpinnings of NPH are discussed.

Is age a risk factor for cognitive changes following hematopoietic cell transplantation?

Cognitive deficits following hematopoietic cell transplantation (HCT) are common and affect post-HCT treatment regimen adherence and quality-of-life. Little is known about effects of age on cognition following HCT. The current study aimed to identify the effects of age on cognition one-year post-HCT, compared to pre-HCT baseline functioning. Participants were 78 autologous and allogeneic transplant recipients who underwent neuropsychological assessments at baseline and one-year post-HCT. Mixed model analyses indicated that no statistically significant main effect of age was observed for any cognitive variable. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Index Score and Trail Making Test (parts A and B) showed significant interaction effects between age and transplant type. These findings indicate that older autologous and allogeneic transplant recipients were predicted to perform similarly; however, young allogeneic HCT recipients were predicted to perform substantially below young autologous transplant recipients. Hierarchical regressions indicated that age failed to predict changes in neuropsychological test performance between baseline and one-year post-HCT. These findings indicate that advanced age may not be a risk factor for worse cognitive outcome post-HCT, though younger allogeneic transplant recipients may be at risk for worse cognitive outcomes, relative to younger autologous recipient counterparts. Clinical implications are discussed.

The utility of cognitive changes in identifying those with acute graft vs. host disease following allogeneic hematopoietic cell transplant.

Objectives: Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and mortality. Identifying those at risk for developing aGVHD is crucial for early intervention. The current study assessed whether scores on a brief cognitive screening measure could identify those that develop aGVHD by 100 days post-HCT.Methods: Participants were 37 patients undergoing allogeneic HCT, assessed prior to transplant, and at 30- and 100-days post-HCT. Of those completing all evaluations, patients were divided into those who did (n = 14) and did not (n = 16) develop aGVHD by day 100 post-HCT. At 100 days post-transplant, groups did not differ on relevant demographic factors, disease, conditioning regimen, relatedness of donor, stem cell source, steroid use, total body irradiation use, human leukocyte antigens (HLA) match, or frequency of infection.Results: At 100 days post-HCT, those with aGVHD performed significantly worse on a working memory measure than those without aGvHD. The presence of aGVHD at day 100 increased significantly with every one standard deviation decrease in working memory from baseline to 30 days post-HCT (odds ratio = 3.08; 95% CI: 1.00-9.36). These findings were observed despite a small sample size and statistically controlling for multiple analyses.Conclusions: While this study is exploratory in nature, and has a small sample size, findings suggest that early detection of working memory declines could coincide with, or signal the development of, aGVHD. Potential etiologies are discussed. Implementing early cognitive screening within the first 30 days post-HCT may be useful in identifying patients at risk for aGVHD.

Institutionalizing One Health: From Assessment to Action.

A One Health approach is critical to strengthening health security at country, regional, and global levels. However, operationally its uptake remains limited. Recent momentum in assessing capacity to effectively prevent, detect, and respond to disease threats has resulted in identification of gaps that require dedicated action. This article highlights relevant tools, standards, and guidance to assist countries and institutions in meeting the collective vision articulated at the 2018 Prince Mahidol Award Conference on "Making the World Safe from the Threats of Emerging Infectious Diseases." Taking stock of assessment findings, resources, priorities, and implementation initiatives across human and animal health, environment and disaster risk reduction sectors can help expand participation in global health security, target risk drivers, and form synergies for collective action and shared gains for both emerging and endemic disease challenges. In addition to health security gains, a multisectoral, One Health approach can drive benefits for wider health sector and global development goals.

Differences in Neuropsychological Functioning Between Homicidal and Nonviolent Schizophrenia Samples.

Few studies have compared performance on neurocognitive measures between violent and nonviolent schizophrenia samples. A better understanding of neurocognitive dysfunction in violent individuals with schizophrenia could increase the efficacy of violence reduction strategies and aid in risk assessment and adjudication processes. This study aimed to compare neuropsychological performance between 25 homicide offenders with schizophrenia and 25 nonviolent schizophrenia controls. The groups were matched for age, race, sex, and handedness. Independent t-tests and Mann-Whitney U-tests were used to compare the schizophrenia groups' performance on measures of cognition, including composite scores assessing domain level functioning and individual neuropsychological tests. Results indicated the violent schizophrenia group performed worse on measures of memory and executive functioning, and the Intellectual Functioning composite score, when compared to the nonviolent schizophrenia sample. These findings replicate previous research documenting neuropsychological deficits specific to violent individuals with schizophrenia and support research implicating fronto-limbic dysfunction among violent offenders with schizophrenia.

Murder and psychosis: Neuropsychological profiles of homicide offenders with schizophrenia.

BACKGROUND: Neurocognitive dysfunction, a core feature of schizophrenia, is thought to contribute to the impulsive violent aggression manifested by some individuals with schizophrenia, but not enough is known about how homicidal individuals with schizophrenia perform on neuropsychological measures. AIMS: The primary aim of our study was to describe the neuropsychological profiles of homicide offenders with schizophrenia. Supplementary analyses compared the criminal, psychiatric and neuropsychological features of schizophrenic homicide offenders with and without God/Satan/demon-themed psychotic symptoms. METHODS: Twenty-five men and women diagnosed with schizophrenia who had killed another person - 21 convicted of first-degree murder and 4 found not guilty by reason of insanity - completed neuropsychological testing during forensic evaluations. RESULTS: The sample was characterised by extensive neurocognitive impairments, involving executive dysfunction (60%), memory dysfunction (68%) and attentional dysfunction (50%), although those with God/Satan/demon-themed psychotic symptoms performed better than those with nonreligious psychotic content. CONCLUSIONS: Our findings indicate that impaired cognition may play an important role in the commission of homicide by individuals with schizophrenia. A subgroup with God/Satan/demon delusions seem sufficiently less impaired that they might be able to engage in metacognitive treatment approaches, aimed at changing their relationship to their psychotic symptoms, thus reducing the perception of power and omnipotence of hallucinated voices and increasing their safety. Copyright © 2016 John Wiley & Sons, Ltd.

Exercise training bradycardia is largely explained by reduced intrinsic heart rate.

INTRODUCTION: Resting heart rate (RHR) declines with exercise training. Possible mechanisms include: 1) increased parasympathetic tone, 2) decreased responsiveness to beta-adrenergic stimulation, 3) decreased intrinsic heart rate or 4) combination of these factors. OBJECTIVE: To determine whether an increase in resting parasympathetic tone or decrease in response to beta-adrenergic stimulation contributes to the decrease in RHR with training. METHODS: 51 screened healthy subjects aged 18-32 (n=20, mean age 26, 11 female) or 65-80 (n=31, mean age 69, 16 female) were tested before and after 6months of supervised exercise training. Heart rate response to parasympathetic withdrawal was assessed using atropine and beta-adrenergic responsiveness during parasympathetic withdrawal using isoproterenol. RESULTS: Training increased VO2 max by 17% (28.7±7.7 to 33.6±9.20ml/kg/min, P<0.001). RHR decreased from 62.8±6.6 to 57.6±7.2 beats per minute (P<0.0001). The increase in heart rate in response to parasympathetic withdrawal was unchanged after training (+37.3±12.8 pre vs. +36.4±12.2 beats per min post, P=0.41). There was no change in the heart rate response to isoproterenol after parasympathetic blockade with training (+31.9±10.9 pre vs. +31.0±12.0 post beats per min, P=0.56). The findings were similar in all four subgroups. CONCLUSIONS: We did not find evidence that an increase in parasympathetic tone or a decrease in responsiveness to beta-adrenergic activity accounts for the reduction in resting heart rate with exercise training. We suggest that a decline in heart rate with training is most likely due to decrease in the intrinsic heart rate.

Assessment of the Effects of Age, Gender, and Exercise Training on the Cardiac Sympathetic Nervous System Using Positron Emission Tomography Imaging.

BACKGROUND: Using positron emission tomography (PET) imaging, we sought to determine whether normal age or exercise training cause changes in the cardiac sympathetic nervous system function in male or female healthy volunteers. METHODS: Healthy sedentary participants underwent PET studies before and after 6 months of supervised exercise training. Presynaptic uptake by the norepinephrine transporter-1 function was measured using PET imaging of [(11)C]-meta-hydroxyephedrine, a norepinephrine analog, and expressed as a permeability-surface area product (PSnt in mL/min/mL). Postsynaptic function was measured as ß-adrenergic receptor density (ß'max in pmol/mL tissue) by imaging the ß-receptor antagonist [(11)C]-CGP12177. Myocardial blood flow (MBF in mL/min/mL tissue) was measured by imaging [(15)O]-water. RESULTS: At baseline, there was no age difference in ß'max or MBF but PSnt declined with age (1.12±0.11 young vs 0.87±0.06 old, p = .036). Before training, women had significantly greater MBF (0.87±0.03 vs 0.69±0.03, p < .0001) and PSnt (1.14±0.08 vs 0.75±0.07, p < .001) than men. Training increased VO2 max by 13% (p < .0001), but there were no training effects on ß'max, PSnt, or MBF. Greater MBF in females and a trend to increased PSnt post-training persisted. CONCLUSION: With age, presynaptic uptake as measured by PSnt declines, but there were no differences in ß'max. Endurance training significantly increased VO2 max but did not cause any changes in the measures of cardiac sympathetic nervous system function. These findings suggest that significant changes do not occur or that current PET imaging methods may be inadequate to measure small serial differences in a highly reproducible manner.

Insight, neurocognition, and schizophrenia: predictive value of the wisconsin card sorting test.

Lack of insight in schizophrenia is a key feature of the illness and is associated with both positive and negative clinical outcomes. Previous research supports that neurocognitive dysfunction is related to lack of insight, but studies have not examined how neurocognition relates to change in insight over time. Therefore, the current study sought to understand how performance on the Wisconsin Card Sorting Test (WCST) differed between participants with varying degrees of change in insight over a 6-month period. Fifty-two patients with schizophrenia or schizoaffective disorder were administered the WCST and Positive and Negative Syndrome Scale (PANSS) at baseline, and the PANSS was again administered at a 6-month follow-up assessment. Results indicated that while neurocognition was related to insight at baseline, it was not related to subsequent change in insight. The implications of findings for conceptualization and assessment of insight are discussed.

Further case of Rubinstein-Taybi syndrome due to a deletion in EP300.

Rubinstein-Taybi syndrome (RSTS) is a heterogeneous disorder with approximately 45-55% of patients showing mutations in the CREB binding protein and a further 3% of patients having mutations in EP300. We report a male child with a deletion of exons 3-8 of the EP300 gene who has RSTS. He has a milder skeletal phenotype, a finding that has been described in other cases with EP300 mutations. The mother suffered from pre-eclampsia and HELLP syndrome in the pregnancy. She subsequently developed a mullerian tumor of her cervix 6 years after the birth of her son.

Evidence for pre- to postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure.

UNLABELLED: Pre- and postsynaptic cardiac sympathetic function is altered in ischemic congestive heart failure (CHF). Whether there is a presynaptic-to-postsynaptic mismatch or whether mismatch is related to adverse cardiac events is unknown. METHODS: In 13 patients with ischemic CHF and 25 aged-matched healthy volunteers, presynaptic function was measured by PET of (11)C-meta-hydroxyephedrine ((11)C-mHED), a norepinephrine (NE) analog. Postsynaptic function, beta-adrenergic receptor (BAR) density (B'(max)), was measured by imaging (11)C-CGP12177. Myocardial blood flow (MBF) was measured by imaging (15)O-water. Each heart was analyzed both globally and regionally, excluding infarcted regions, and a mismatch score, defined as the ratio of B'(max) to NE uptake (PS(nt))(,) was used to indicate mismatch of post- and presynaptic function. RESULTS: Global and regional MBF was not different between CHF and healthy subjects. The global measure of PS(nt) was lower in CHF (0.32 +/- 0.34) than that in healthy subjects (0.81 +/- 0.33, P < 0.0001) and in all 12 regions. Global B'(max) tended to be lower in CHF than that in healthy subjects (10.0 +/- 6.4 pmol/mL vs. 13.4 +/- 4.2, P = 0.056) and in all 12 regions. The global mismatch score (B'(max):PS(nt)) in CHF patients was significantly greater than that in healthy subjects (50.3 +/- 50.7 vs. 19.3 +/- 9.7, P = 0.005) and also greater in 11 of 12 regions. After 1.5 y of follow-up, 4 individuals had an adverse outcome (CHF death, new or recurrent sudden death, or progressive CHF leading to transplantation). Three of the 4 had mismatch scores > 3 times that of the healthy subjects or the CHF patients without an adverse outcome. CONCLUSION: Mismatch between pre- and postsynaptic left ventricular sympathetic function is present in patients with severe CHF and may be more marked in those with adverse outcomes.

Normal aging impairs upregulation of the beta-adrenergic but not the alpha-adrenergic response: aging and adrenergic upregulation.

OBJECTIVES: To determine if centrally reducing sympathetic tone with clonidine will reverse the downregulation in the alpha-adrenergic (alphaAR) and beta-adrenergic (betaAR) responses seen with normal aging. METHODS: Twelve rigorously screened young adult (mean age, 26 years) and 15 older adult (mean age, 69 years) subjects were studied before and after using the clonidine patch (TTS-2) for 2 weeks. betaAR (isoproterenol at 35 ng/kg/min) and alphaAR (phenylephrine at 1.0 microg/kg/min) were assessed using radionuclide measures of end diastolic, end systolic, and stroke volume indices, cardiac index, and ejection fraction. RESULTS: Clonidine reduced resting plasma norepinephrine and this reduction was greater in older subjects (-47 +/- 3 versus -26 +/- 6%, P = 0.001). After 2 weeks of clonidine patch, upregulation of the betaAR was significantly higher in young subjects for heart rate (+10.7 +/- 1.5 versus +4.6 +/- 1.5 bpm; P = 0.01). There was no significant age-associated difference in the upregulation of the alphaAR with clonidine for systolic, diastolic, and mean blood pressure or systemic vascular resistance. CONCLUSIONS: With aging, there is an impaired resensitization of the chronotropic betaAR response with central sympathetic downregulation that is not seen with the alphaAR.

The influence of age, gender, and training on exercise efficiency.

OBJECTIVES: The aim of this study was to determine whether changes in oxygen efficiency occur with aging or exercise training in healthy young and older subjects. BACKGROUND: Exercise capacity declines with age and improves with exercise training. Whether changes in oxygen efficiency, defined as the oxygen cost per unit work, contributes to the effects of aging or training has not yet been defined. METHODS: Sixty-one healthy subjects were recruited into four groups of younger women (ages 20 to 33 years, n = 15), younger men (ages 20 to 30 years, n = 12), older women (ages 65 to 79 years, n = 16), and older men (ages 65 to 77 years, n = 18). All subjects underwent cardiopulmonary exercise testing to analyze aerobic parameters before and after three to six months of supervised aerobic exercise training. RESULTS: Before training, younger subjects had a much higher exercise capacity, as shown by a 42% higher peak oxygen consumption (VO2) (ml/kg/min, p < 0.0001). This was associated with an 11% lower work VO2/W (p = 0.02) and an 8% higher efficiency than older subjects (p = 0.03). With training, older subjects displayed a larger increase in peak W/kg (+29% vs. +12%, p = 0.001), a larger decrease in work VO2/W (-24% vs. -2%, p < 0.0001), and a greater improvement in exercise efficiency (+30% vs. 2%, p < 0.0001) compared to the young. CONCLUSIONS: Older age is associated with a decreased exercise efficiency and an increase in the oxygen cost of exercise, which contribute to a decreased exercise capacity. These age-related changes are reversed with exercise training, which improves efficiency to a greater degree in the elderly than in the young.

Exercise training and heart rate variability in older adult female subjects.

INTRODUCTION: Prior investigations in post-myocardial infarction and healthy elderly subjects have established that heart rate variability (HRV) predicts mortality. Predominantly cross-sectional studies have shown an association between endurance training and measures of HRV. In a randomized trial, this study sought to prospectively compare the effects of endurance and strength training on HRV in 45 healthy elderly females (average age 69.9 +/- 0.9 years). METHODS: All subjects were rigorously screened to be normal by history, physical, blood tests, ECG, ETT and echocardiogram. All subjects were monitored for 24 hours by a 2-channel Holter before and after training. Artifacts and arrhythmias were manually removed. Tapes were examined for standard measures of HRV. INTERVENTION: 15 subjects were randomized to endurance trained (ET), 15 subjects to strength training (ST), and 15 subjects to no training (NT) for six months. RESULTS: Training resulted in a significant increase in VO2max in the ET (+7.4%, p = 0.005) group only. There was a small but not significant decrease in HR with both the ET and ST groups. ET resulted in a significant increase in most time domain and all frequency domain measures of HRV. ST resulted in no significant change in HRV measures. CONCLUSION: Strength training, as opposed to endurance training has no significant impact on HRV. This suggests that exercise interventions designed to improve strength (such as weight-lifting) will have little to no impact on HRV, suggesting that aerobic and strength training operate through different mechanisms to reduce cardiac risk.

Polymorphisms in DNA repair genes and epithelial ovarian cancer risk.

DNA repair gene polymorphisms and mutations are known to influence cancer risk. We studied whether polymorphisms in DNA double strand break (DSB) repair genes are associated with epithelial ovarian cancer (EOC) risk. Up to 1,600 cases and 4,241 controls from 4 separate genetic association studies from 3 countries were genotyped for 13 single nucleotide polymorphisms (SNP) in 6 genes (BRCA1, NBS1, RAD51, RAD52, XRCC2 and XRCC3) involved in homologous recombination of DNA double strand breaks. Genotype specific risks were estimated as odds ratios (OR) by unconditional logistic regression. No association was detected between EOC risk and BRCA1 Q356R, BRCA1 P871L, RAD51 g135c, RAD51 g172t, RAD52 c2259t, NBS1 L34L, NBS1 E185Q, NBS1 A399A, NBS1 P672P, XRCC2 g4324c, XRCC2 c41657t and XRCC3 T241M. The XRCC2 R188H polymorphism was associated with a modest reduction in EOC risk: OR for heterozygotes was 0.8 (95% confidence interval [CI] = 0.7-1.0) and for rare homozygotes 0.3 (0.1-0.9). The XRCC3 a4541g polymorphism, situated in the 5'UTR, and the intronic XRCC3 a17893g polymorphism were not associated with EOC risk in general, but when the serous EOC subset only was analysed, the OR for heterozygotes for a4541g was 1.0 (0.9-1.2) and for the rare homozygotes 0.5 (0.3-0.9). For the XRCC3 a17893g polymorphism, the OR for the heterozygotes and the rare homozygotes were 0.8 (0.7-0.9) and 0.9 (0.7-1.2), respectively. In our study, some polymorphisms in XRCC2 and XRCC3 genes were associated with EOC risk. Further research on the role of these genes on epithelial ovarian cancer is warranted.

Comparison of tissue Doppler and propagation velocity to invasive measures for measuring left ventricular filling pressures.

The utility of tissue Doppler and propagation velocity in identifying patients with abnormal left ventricular filling pressures was assessed in 50 patients who underwent catheterization and echocardiography on the same day. The ratios of the peak velocity of early mitral inflow to early mitral annular velocity (E/Ea) and the velocity of propagation (E/Vp) were compared with invasive measurements of pre-A-wave left ventricular pressures. Echocardiography measures were 77% to 92% accurate in identifying patients with a pre-A-wave pressure >15 mm Hg. Tissue Doppler imaging is more accurate than propagation velocity.