Immune biomarker evaluation of sequential tyrosine kinase inhibitor and nivolumab monotherapies in renal cell carcinoma: the phase I TRIBE trial.

Background: Predictive biomarkers for immune checkpoint blockade in the second-line treatment of metastatic renal cell carcinoma (mRCC) are lacking. Materials and methods: Patients with histologically confirmed RCC who started nivolumab after at least 4 months of tyrosine kinase inhibitors (TKIs) were recruited for this study. Serial tissue and blood samples were collected for immune biomarker evaluation. The primary endpoint was to determine the association of specific T-cell subsets with clinical outcomes tested using Wilcoxon rank sum for clinical benefit rate (CBR) and log-rank test for progression-free survival (PFS). Results: Twenty patients were included in this trial with a median age of 64 years and followed-up for a median of 12 months. The median PFS for patients who received TKI was 13.8 months, while for those subsequently treated with nivolumab following TKI therapy, the median PFS was 2.6 months. CBR of nivolumab was 20% with two partial responses. Functionally active programmed cell death protein 1+ CD4+ T cells were enriched in non-responders (q = 0.003) and associated with worse PFS on nivolumab (P = 0.04). Responders showed a significant reduction in the effector CD4+T-cell (TEF) fraction compared to non-responders at 3 months on nivolumab (0.40 versus 0.80, P = 0.0005). CD127+CD4+ T cells were enriched in patients who developed immune-related adverse effects (q = 0.003). Using in-house validated multiplex immunohistochemistry for six markers, we measured tumour-associated immune cell densities in tissue samples. Responders to nivolumab showed a significantly higher mean of immune cell densities in tissue samples compared to non-responders (346 versus 87 cells/mm2, P = 0.04). Conclusions: In this small study, analysis of tissue-based and peripheral blood immune cell subsets predicted clinical outcomes of nivolumab. Further studies are warranted with larger populations to validate these observations.

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial.

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2 -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 µg.kg-1 .h-1 ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.

Stratified medicine using invasive coronary function testing in angina: A cost-effectiveness analysis of the British Heart Foundation CorMicA trial.

AIM: Coronary angiography is indicated in many patients with known or suspected angina for the investigation of coronary artery disease (CAD). However, up to half of patients with symptoms of ischaemia have no obstructive coronary arteries (INOCA). This large subgroup includes patients with suspected microvascular angina (MVA) and/or vasospastic angina (VSA). Clinical guidelines relating to the management of patients with INOCA are limited. Uncertainty regarding the diagnosis of patients with INOCA presents a health economic challenge, both in terms of healthcare resource utilisation and of quality-of-life impact on patients. METHODS: A cost-effectiveness analysis of the introduction of stratified medicine into the invasive management of INOCA, based on clinical and resource-use data obtained in the CorMicA trial, from a UK NHS perspective. The intervention included an invasive diagnostic procedure (IDP) of coronary vascular function during coronary angiography to define clinical endotypes to target with linked medical therapy. Outcomes of interest were mean total cost and QALY gain between treatment groups, and the incremental cost-effectiveness ratio. We undertook probabilistic sensitivity and scenario analyses. RESULTS: The incremental cost per QALY gained at 12 months was £4500 (£2937, £33264). Compared with a willingness-to-pay (WTP) threshold of £20,000 per QALY, the use of the IDP test is cost-effective. At this WTP threshold there is a 96% probability of the IDP being cost-effective, based on the uncertainty described by bootstrap analysis. CONCLUSIONS: The burden of INOCA, particularly in women, is known to be significant. These findings provided new evidence to inform this unmet clinical need.

"I Like and Prefer to Work Alone": Social Anxiety, Academic Self-Efficacy, and Students' Perceptions of Active Learning.

Although active learning improves student outcomes in science, technology, engineering, and mathematics (STEM) programs, it may provoke anxiety in some students. We examined whether two psychological variables, social anxiety (psychological distress relating to the fear of negative evaluation by others) and academic self-efficacy (confidence in one's ability to overcome academic challenges), interact with student perceptions of evidence-based instructional practices (EBIPs) and associate with their final grades in a STEM-related course. Human anatomy and physiology students in community college courses rated various EBIPs for their perceived educational value and their capacity to elicit anxiety (N = 227). In general, practices causing students the most anxiety (e.g., cold calling) were reported by students as having the least educational value. When controlling for students' self-reported grade point averages, socially anxious students rated several EBIPs as more anxiety inducing, whereas high-efficacy students reported less anxiety surrounding other EBIPs. Furthermore, mediation analysis revealed that individual differences in academic self-efficacy at the beginning of the term explained some of the negative association between students' social anxiety levels and final grades in the course. Our results, obtained in a community college context, support a growing body of evidence that social anxiety and academic self-efficacy are linked with how students perceive and perform in an active-learning environment.

Effects of SSRI medication on heart rate and blood pressure in individuals with hypertension and depression.

OBJECTIVE: To test the role of escitalopram on blood pressure and heart rate of individuals with hypertension and depression. METHODS: A total of 30 individuals participated in this study who were being treated for hypertension and were diagnosed with major depression. Escitalopram (10-20 mg) was administered to 15 individuals, while the other 15 received placebo. These individuals were followed for 8 weeks with regular monitoring of blood pressure and heart rate. Scores on the Hamilton Depression Rating Scale were evaluated within the first, second, fourth, and eighth weeks of the study onset. RESULTS: Comparing with placebo, heart rate was lower in the escitalopram group (66.79 ± 9.85 vs. 74.10 ± 9.52 bpm, p = 0.044). There was not a significant decrease of systolic blood pressure (140.80 ± 16.48 vs 139.61 ± 18.92 mmHg, p = 0.85) and diastolic blood pressure (80.55 ± 12.64 vs 80.18 ± 16.36 mmHg, p = 0.94). CONCLUSION: Escitalopram decreases HR, but not BP, in individuals with hypertension and depression. Abbreviation: SH: systemic hypertension; BP: blood pressure; DSM: Diagnostic and Statistical Manual of Mental Disorders; SRQ 20: Self-Report Questionnaire; SCID: Structured Clinical Interview for DSM-IV; HR: heart rate; SNS: Sympathetic nervous system; HPA: hypothalamus-pituitary-adrenal axis; RAA: renin, angiotensin, aldosterone system; NE: norepinephrine; CSF: cerebrospinal fluid; HAM-D: Hamilton Depression Rating Scale; CRF: corticotropin releasing factor; ACTH: adrenocorticotropic hormone; BMI: Body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; t: time.

Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass.

Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts.

Don't panic. A guide to tryptophan depletion with disorder-specific anxiety provocation.

The 2002 paper "Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine" by Bell and colleagues - reprinted in this issue of the Journal - reports on a study undertaken in the halcyon days of David Nutt's Psychopharmacology Unit at the University of Bristol, England. In this invited commentary authors of the original work discuss the impact of this paper on the field of acute tryptophan depletion research (especially in the field of clinical anxiety disorders) and the development of disorder-specific anxiogenic provocations over the past decade.

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications.

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.

Mental health and welfare in Australian anaesthetists.

This survey was designed to evaluate the factors affecting mental health and welfare in Australian anaesthetists and to investigate current sources of support. An electronic survey was sent to 500 randomly selected Fellows and trainees of the Australian and New Zealand College of Anaesthetists. Questions were related to: anxiety, stress, depression, substance misuse, self-medication, suicide, reporting illness, and help-seeking. Current psychological wellbeing was assessed using the Kessler Psychological Distress Scale (K10). A total of 191 completed surveys were received (a response rate of 38%): 26% had attended their general practitioner for mental health issues, of whom half had been diagnosed with a mental illness; 7% of all respondents were currently prescribed medication for this; 25% had previously self-prescribed psychoactive medication; 17% admitted to using alcohol to deal with stress, anxiety or depression; and 8% responded that mental illness had at some point impaired clinical care. Sixteen percent of all respondents reported previous suicidal ideation. Despite a low response rate, and the possibility of responder bias, the mental health of Australian anaesthetists would appear to be subject to common and persistent risk factors, many of which are well described in previous studies. We identify general practitioners as particularly valuable in targeting initiatives for improvements in mental health and welfare. The significant prevalence of suicidal ideation and reluctance to approach senior colleagues with concerns about mental health or welfare issues are specific causes for concern and suggest that further investigation, education and a potential review of support networks is required.

Central noradrenergic responsiveness to a clonidine challenge in Generalized Anxiety Disorder: a Single Photon Emission Computed Tomography study.

Generalized Anxiety Disorder (GAD) may involve hypo-responsiveness of noradrenaline a2 receptors. To test this hypothesis, we used (99m)Tc-hexa-methyl-propylene-amine-oxime (HMPAO) Single Photon Emission Computed Tomography to measure regional cerebral perfusion in patients with untreated GAD, venlafaxine-treated patients and healthy controls during word generation before and after clonidine. Concurrent psychological and physiological measures supported noradrenergic hypofunction in GAD in some cases. A single-day split-dose technique was used. Images were processed using SPM5 (Institute of Neurology). Factorial analysis revealed no significant results. Exploratory analyses were done. Regional perfusion during verbal fluency differed by group pre-clonidine. Compared with healthy controls, patients with untreated GAD displayed increased perfusion in the left Broca's area and left occipitotemporal region. Treated GAD patients displayed increased cerebellar perfusion bilaterally. Clonidine was associated with different changes in cerebral perfusion in each group. Increases were seen in the right supra-marginal gyrus in healthy subjects, in the left pre-central gyrus in treated GAD patients and in the right cerebellum and middle frontal gyrus in untreated GAD patients. Despite these differences, the findings were not consistent with a noradrenergic hypo-responsiveness hypothesis, as the treated group showed a different pattern of response rather than a normalization of response.

Daily morphine injection and withdrawal disrupt 24-h wheel running and PERIOD2 expression patterns in the rat limbic forebrain.

Symptoms of opiate withdrawal include disturbances in circadian rhythms. We examined in male Wistar rats (n=48) the effects of a daily, mid-morning morphine injection (5-40 mg/kg, i.p.) and its withdrawal on 24-h wheel-running activity and on the expression of the clock protein, PERIOD2 (PER2), in the suprachiasmatic nucleus (SCN), oval nucleus of the bed nucleus of the stria terminalis (BNSTov), central amygdala (CEA), and dorsal striatum. Rats were killed over 2 days at 10, 22, 46, and 58 h after the last daily morphine injection at zeitgeber times (ZT) 1 or ZT13. Daily morphine injections and their withdrawal suppressed nighttime wheel running, but did not entrain any increase in activity in advance of the injection. Neither morphine injection nor its withdrawal affected PER2 expression in the SCN, whereas the normal daily peaks of PER2 in the BNSTov, CEA, and dorsal striatum were blunted both during morphine administration and its withdrawal. Treatment with a dopaminergic agonist (the D2/3 agonist, quinpirole, 1.0 mg/kg) or a noradrenergic agonist (alpha2 agonist, clonidine, 0.1 mg/kg) in morphine withdrawal did not restore normal PER2 patterns in each affected region; however, both quinpirole and clonidine themselves altered normal daily PER2 expression patterns in morphine-naive rats. These findings confirm and extend previous observations that opiates disrupt daily patterns of clock gene expression in the limbic forebrain. Furthermore, catecholaminergic drugs, which have been previously found to alleviate symptoms of opiate withdrawal, do not alleviate the effects of morphine withdrawal on PER2, but do modulate daily patterns of PER2 expression in saline controls.

Phylogenetic relationships of the Orang Asli and Iban of Malaysia based on maternal markers.

Malaysia remains as a crossroad of different cultures and peoples, and it has long been recognized that studying its population history can provide crucial insight into the prehistory of Southeast Asia as a whole. The earliest inhabitants were the Orang Asli in Peninsular Malaysia and the indigenous groups in Sabah and Sarawak. Although they were the earliest migrants in this region, these tribes are divided geographically by the South China Sea. We analyzed DNA sequences of 18 Orang Asli using mitochondrial DNA extracted from blood samples, each representing one sub-tribe, and from five Sarawakian Iban. Mitochondrial DNA was extracted from hair samples in order to examine relationships with the main ethnic groups in Malaysia. The D-loop region and cytochrome b genes were used as the candidate loci. Phylogenetic relationships were investigated using maximum parsimony and neighbor joining algorithms, and each tree was subjected to bootstrap analysis with 1000 replicates. Analyses of the HVS I region showed that the Iban are not a distinct group from the Orang Asli; they form a sub-clade within the Orang Asli. Based on the cytochrome b gene, the Iban clustered with the Orang Asli in the same clade. We found evidence for considerable gene flow between Orang Asli and Iban. We concluded that the Orang Asli, Iban and the main ethnic groups of Malaysia are probably derived from a common ancestor. This is in agreement with a single-route migration theory, but it does not dismiss a two-route migration theory.

Noradrenergic function in generalized anxiety disorder: impact of treatment with venlafaxine on the physiological and psychological responses to clonidine challenge.

Serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants have evidence of efficacy in the treatment of generalized anxiety disorder (GAD); however, it is not clear whether there is an advantage over selective serotonin reuptake inhibitor (SSRI) medicines and there is limited evidence for noradrenergic dysfunction in GAD. We tested whether a dysfunctional alpha-2 adrenoceptor system is present in patients with GAD and the effects of SNRI treatment on this system. The method used was an infusion of clonidine (a selective alpha-2 adrenergic receptor agonist) on psychological and physiological outcomes in three subject groups: 10 untreated GAD patients, five SNRI-treated GAD patients and seven normal controls. The clonidine challenge elicited sedation, a rise in growth hormone, decrease in blood pressure, decline in saccadic eye movement (SEM) variables, and improvement in verbal fluency as anticipated in the 22 subjects examined. Lower cortisol levels were found in controls and higher blood pressure readings in GAD-treated subjects, as well as evidence that GAD-treated subjects had SEMs that were intermediate between control and GAD subjects' scores and have less clonidine-induced sedation. The implications of these findings with reference to the study hypothesis in this small study are discussed.

Network models of psychopathology and comorbidity: philosophical and pragmatic considerations.

Cramer et al.'s account of comorbidity comes with a substantive philosophical view concerning the nature of psychological disorders. Although the network account is responsive to problems with extant approaches, it faces several practical and conceptual challenges of its own, especially in cases where the individual differences in network structures require the analysis of intra-individual time-series data.

Specific control of sympathetic nerve activity to the mammalian heart and kidney.

There is a large body of evidence indicating that sympathetic nerves to individual organs are specifically controlled, but only few studies have compared the control of cardiac sympathetic nerve activity (CSNA) with activity in other sympathetic nerves. In this review, changes in sympathetic activity to the heart and kidneys are described during increases in brain [Na+] and in heart failure (HF). In conscious sheep, increases in brain [Na+] increased CSNA and arterial pressure and, conversely, decreased renal sympathetic nerve activity (RSNA), promoting urinary sodium loss. These organ-specific effects are mediated via a neural pathway that includes an angiotensinergic synapse, the lamina terminalis and the paraventricular nucleus of the hypothalamus. There is also evidence of differential control of SNA in HF. In normal sheep, the resting burst incidence of CSNA was much lower than that of RSNA, whereas in HF they increased to similar, almost maximal levels in both nerves. Arterial baroreflex control of both these nerves was unchanged in HF, but the response of CSNA to changes in blood volume was almost absent. These data indicate that in HF the lower arterial pressure leads to reduced baroreflex inhibition of SNA, which, together with the lack of an inhibitory response to the increased volume and cardiac pressures, would contribute to the sympathoexcitation observed. These studies demonstrate differences in the control of CSNA and RSNA, enabling selective actions on the heart and kidney to restore fluid and electrolyte homeostasis in the case of elevated brain [Na+] and to increase cardiac output in HF.