Behavioural evidence on COVID-19 vaccine uptake.

OBJECTIVES: The World Health Organization has declared that COVID-19 is no longer a public health emergency of international concern. Nevertheless, it remains a public health issue, and seasonal vaccinations, at the same time of year as influenza vaccinations, will be necessary. When the first vaccines were administered in 2020, decision-makers had to make assumptions about the best methods to communicate and administer vaccines to increase uptake. Now, a body of evidence can inform these decisions. STUDY DESIGN: A narrative review written by three behavioural scientists who design research for policy. METHODS: We searched the PubMed database for: (i) reviews of interventions to increase uptake of COVID-19 or influenza vaccines and (ii) empirical studies on uptake of COVID-19 and influenza vaccines. In addition, registered trials gathered by a Cochrane scoping review of interventions to increase uptake of COVID-19 vaccines were searched for updated results. RESULTS: Results centre around two aspects of a vaccination campaign of interest to policymakers: communication and administration. Results suggest that communications highlighting the personal benefits of vaccination are likely to be more effective than those highlighting collective benefits. The efficacy of vaccination may be underestimated and stressing efficacy as a strong personal benefit may increase uptake. Keeping vaccines free, sending personalised messages, reminders and prebooked appointment times may also increase uptake. CONCLUSIONS: There is now a body of evidence from behavioural science that suggests how vaccination campaigns for COVID-19 can be structured to increase uptake. These recommendations may be useful to policymakers considering seasonal vaccination campaigns and to researchers generating hypotheses for country-specific trials.

Tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral vessels.

Major aortopulmonary collateral arteries (MAPCAs) provide significant issues during cardiopulmonary bypass, including flooding of the surgical field which requires significant blood volumes to be returned to the extracorporeal circuit via handheld suckers. This has been shown to be the major source of gaseous microemboli and is associated with adverse neurological outcome. Use of pH-stat has been previously shown to decrease the shunt through MAPCAs via an unknown mechanism. Here, we report the associated benefits of pH-stat in decreasing sucker usage and gaseous microemboli in a patient with known MAPCAs presenting for repair of tetralogy of Fallot and pulmonary atresia.

Influence of 5,7-dihydroxytryptamine lesions of the rat fornix-fimbria and cingulum bundles on spontaneous activity in an aversive maze.

Exposure to aversive environmental stimuli stimulates the serotonergic neurones that project to the forebrain and inhibit spontaneous activity when studied in a simple maze. This study explored the putative role of the principal 5-hydroxytryptamine (5-HT) neurones that project to the hippocampus from the median raphe nucleus in this response to an aversive environment by lesioning the 5-HT fibres that project through the fornix/fimbria and cingulum bundles. The effects of the lesions were investigated in independent groups of animals tested in an enclosed four-arm maze and a more aversive elevated maze of the same dimensions composed entirely of four open arms. The rats were significantly less active in the open maze, the principal effect of maze design being observed during the first 5 min sub-trial of a 15 min trial. This response to the more aversive environment was totally abolished by the lesion. It is concluded that exposure to an explicitly aversive environment elicits a brief stimulation of the 5-HT neurones that project to the hippocampus from the median raphe nucleus and that this stimulation inhibits the initial burst of exploratory activity that is observed in animals placed in a less aversive novel environment.

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform.

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.

Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress.

It has been suggested that physiological resistance to repeated stress is associated with increased 5-hydroxytryptamine (5-HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7-dihydroxytryptamine lesions to investigate the role of 5-HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex. Glucocorticoid receptor immunoreactivity in the dorsal hippocampus was decreased after 5 days but increased after 20 days of stress. Mineralocorticoid receptor immunoreactivity was increased after 5 or 10 days of stress. The increases in glucocorticoid and mineralocorticoid receptor immunoreactivity, evoked by repeated stress, were abolished by lesions of the principal 5-HT projections to the hippocampus. The lesions abolished the increased defecation observed in stressed animals, but had no effects on the plasma corticosterone response to the stressor or the habituation of this response observed following repeated stress. The experiments have revealed a dissociation in the regulation of corticosteroid receptor expression in the dorsal and ventral hippocampus by repeated stress and 5-HT. The data suggest that adaptation to inescapable stress is associated with regionally selective changes in corticosteroid receptor expression in dorsal hippocampus that are largely 5-HT-dependent, although these changes do not mediate habituation of the pituitary adrenocortical response to the stressor.

Endoscopic palliation and survival in malignant biliary obstruction.

Malignant biliary obstruction is a common problem that is regarded as having a poor prognosis and is usually managed with palliation. Our aim was to investigate the survival of 182 consecutive subjects with malignant biliary obstruction where management was palliative with an [corrected] endoscopically placed biliary stent. We undertook a retrospective longitudinal study with date of death or confirmed survival of at least 23 months, as the primary end point. Diagnosis and blood indices from the 24 hr prior to first ERCP were obtained from hospital records. Of the 182 eligible subjects follow-up of date of death or confirmed survival of at least 23 months was obtained in 181 (99.5%). Of these 181 patients, 37 (20.4%) survived for more than one year. Histological confirmation was obtained in 47 of 182 subjects (25.8%). Increased age at first ERCP predicted increased survival (P < 0.05). In conclusion, in patients with malignant biliary obstruction, where management was endoscopic and palliative, 20.4% survived for more than one year with increased age at diagnosis being the only significant predictive marker.

Regulatory role of phosphatidylinositol 3-kinase on TNF-alpha-induced cyclooxygenase 2 expression in colonic epithelial cells.

BACKGROUND AND AIMS: Cyclooxygenase (COX)-2 is up-regulated in most colonic cancers and in inflammatory bowel disease in which tumor necrosis factor (TNF)-alpha is believed to play a central role. There has been recent speculation on the activation of phosphatidylinositol 3-kinase (PI 3-kinase) by TNF-alpha and its role in the regulation of genes controlled by NF-kappaB. We investigated the regulatory role of PI 3-kinase on COX-2 expression in colonic epithelial cells. METHODS: In HT-29 and Caco-2 colonic epithelial cells, COX-2 expression was induced by either TNF-alpha or interleukin (IL)-1alpha as observed by Northern and Western analyses. COX-2 activity was assessed by measuring prostaglandin E(2) (PGE2) production by enzyme-linked immunosorbent assay. NF-kappaB binding activity was assessed by electrophoretic mobility shift assay. PI 3-kinase activity was measured by quantifying the accumulation of PI 3-kinase-dependent D-3 lipid products by high-performance liquid chromatography. RESULTS: The PI 3-kinase inhibitor wortmannin up-regulated induced COX-2 expression in a concentration-dependent manner in both HT-29 and Caco-2 cells. An alternative PI 3-kinase inhibitor, LY294002, caused up-regulation of induced COX-2 messenger RNA (mRNA) in HT-29 cells at concentrations of < or =1 micromol/L. IL-4 and IL-13, which are known to activate PI 3-kinase, down-regulated HT-29 COX-2 mRNA, protein, and PGE2 production. NF-kappaB binding activity was unaltered by PI 3-kinase inhibition in HT-29 cells, in which TNF-alpha was shown to activate PI 3-kinase directly. CONCLUSIONS: COX-2 is negatively regulated by PI 3-kinase; we propose that the inhibitory effect of IL-4 and IL-13 is mediated via a PI 3-kinase-dependent pathway. This mechanism does not appear to involve NF-kappaB because PI 3-kinase inhibition did not alter NF-kappaB binding activity. TNF-alpha can activate PI 3-kinase directly in addition to inducing COX-2.

The clinical impact of metabolic bone disease in coeliac disease.

Bone mineral density was measured by dual energy x ray absorptiometry (DEXA) at the lumbar spine and femoral neck in 15 adults who had metabolic bone disease in association with coeliac disease (mean age at diagnosis 53.5 years, range 37 to 66). Results were expressed as a T score (the number of standard deviations by which patient's bone density differed from the sex matched young adult mean). Three patients had no skeletal symptoms and normal routine calcium biochemistry but severely reduced axial bone mineral density on DEXA. Eleven patients had symptomatic skeletal fractures, including fractures of proximal femur (3), vertebrae (4), and radius (6). Three patients had osteomalacia confirmed on bone biopsy, two of whom had characteristic biochemistry. Secondary and tertiary hyperparathyroidism were seen. Seventy five further patients (60 female) with coeliac disease (mean age 52.0 years, median duration of gluten-free diet 3.4 years) and 75 paired healthy age and sex matched controls were questioned on past fracture history. Patients with coeliac disease underwent detailed studies of calcium biochemistry, dietary intake, and bone mineral density. Sixteen had a past history of fractures (chi(2) = 10.7, p = 0.0004, v controls), which were of typical osteoporotic type. Ten patients had fracture before diagnosis of coeliac disease and six after diagnosis. Patients who had a fracture were older (56.3 v 50.3 years, p < 0.02, Wilcoxon rank sum test) than those with no fracture. There was no significant difference in bone mineral density (z score -0.31 v -0. 77), serum calcium (2.30 v 2.26 mmol/l), 25-hydroxyvitamin D (19.7 v 23.7 nmol/l), parathyroid hormone (2.6 v 3.1 pmol/l), or dietary calcium intake (1021.0 v 1033.0 mg/day) in patients with fracture compared with those without fracture. Metabolic bone disease is common in coeliac disease and is associated with premature osteoporotic fractures.

Role of CD5 in growth regulation of B-1 cells.

CD5 is a membrane glycoprotein that is expressed on a subset of B lymphocytes called B-1 cells, thymocytes and T cells. The CD5+ B-1 cells are normally unresponsive to surface Ig receptor induced growth signals unless the CD5 gene is deleted or sequestered away. Here we show that CD5 mediated negative regulation is unique to B cell receptor (BCR) signaling. The CD5 molecule in normal B-1 cells is constitutively tyrosine phosphorylated and associates specifically with SHP-1, an SH2 domain containing protein tyrosine phosphatase. CD5 promotes a prolonged interaction between BCR and SHP-1, which may be inhibitory to BCR signaling. CD5 was shown to modulate the function of autoantibody producing B cells in transgenic mice expressing anti-DNA antibodies.

Process versus content in eyewitness metamemory monitoring.

Three studies (Ns = 200, 135, and 187 college undergraduates) contrasted process versus content accounts of eyewitness metamemory monitoring. Subjective vividness, a cue related to memory content, was a better predictor of confidence and accuracy than were cues related to the retrieval process. Participants who were asked to recall, rather than recognize, event details displayed greater insight into accuracy, primarily because vividness was a more valid accuracy cue under recall conditions. Results reinforce the value of recall-based protocols for eliciting eyewitness testimony and suggest some specific conditions (e.g., yes-no recognition) under which investigators should be especially cautious in relying on confidence to infer accuracy. In addition, results point to a general framework for understanding moderating effects on eyewitness metamemory accuracy.

Accessory cell defect in unresponsiveness of neonates and aged to polysaccharide vaccines.

T independent antigens elicit antibody responses in the absence of carrier specific T helper cells but require signals from accessory cells (macrophages and dendritic cells) or specific cytokines. They are further subdivided into TI-1 and TI-2 categories based on the ability of TI-1 but not TI-2 antigens to elicit immune responses from neonates. Most bacterial polysaccharides including the pneumococcal polysaccharide vaccines belong to the TI-2 class. It is hypothesized that defects in accessory cell function play a critical role in the failure of neonates to respond to such TI-2 antigens. Immune responses to these TI-2 stimuli are also reduced in the aged, also due to a quantitative deficiency in accessory cells. Agents that can stimulate accessory cell function may provide an alternative strategy to improve the immunogenicity of the polysaccharide vaccines in the neonates and the aged.

Interleukin-13 inhibits nitric oxide production in human colonic mucosa.

BACKGROUND/AIMS: Nitric oxide synthesis is increased in rectal biopsies from patients with ulcerative colitis and colonic epithelial cells are considered to be a major source of nitric oxide in intestinal inflammation. METHODOLOGY: Human colonic biopsies from normal bowel mucosa and colonic epithelial cell line HT-29 were cultured in the presence of the inflammatory cytokines IL-1 alpha + TNF-alpha + IFN-alpha added after 1 hour pretreatment with vehicle or Interleukin-13. Nitrite levels were determined at 30 hours in culture supernatants by a fluorometric assay. RESULTS: Unstimulated human colonic biopsies and HT-29 cells produced a basal amount of nitrite. Stimulation with IL-1 alpha + TNF-alpha + IFN-alpha induced a significant (P < 0.001) increase of nitrite generation by both human colonic biopsies and HT-29 cells. The presence of Interleukin-13 produced a significant (P < 0.001) suppression of the cytokine-induced nitrite generation from both colonic biopsies and HT-29 cells. CONCLUSIONS: Nitric oxide generation in human colonic mucosa is susceptible to manipulation by proinflammatory cytokines. Interleukin-13 has an inhibitory effect on cytokine induced nitrite production in colonic mucosa and could play an anti-inflammatory role in intestinal inflammation.

Functional neuroanatomy of the cognitive process of mapping during discourse comprehension.

We used functional magnetic resonance imaging (fMRI) to identify brain regions involved in the process of mapping coherent discourse onto a developing mental representation. We manipulated discourse coherence by presenting sentences with definite articles (which lead to more coherent discourse) or indefinite articles (which lead to less coherent discourse). Comprehending connected discourse, compared with reading unrelated sentences, produced more neural activity in the right than left hemisphere of the frontal lobe. Thus, the right hemisphere of the frontal lobe is involved in some of the processes underlying mapping. In contrast, left-hemisphere structures were associated with lower-level processes in reading (such as word recognition and syntactic processing). Our results demonstrate the utility of using fMRI to investigate the neural substrates of higher-level cognitive processes such as discourse comprehension.

Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53.

It has been well known that curcumin is a powerful inhibitor of proliferation of several tumor cells. However, the molecular basis of the anti-proliferative effect of curcumin has not been investigated in detail. In this paper, we present evidence to show that curcumin inhibited proliferation of a variety of B lymphoma cells. At low concentrations curcumin inhibited the proliferation of BKS-2, an immature B cell lymphoma, more effectively than that of normal B lymphocytes and caused the apoptosis of BKS-2 cells in a dose- and time-dependent manner. Furthermore, curcumin downregulated the expression of survival genes egr-1, c-myc, and bcl-X(L) as well as the tumor suppressor gene p53 in B cells. In addition, NF-kappaB binding activity was also downregulated almost completely by curcumin. Stimulation with CpG oligonucleotides or anti-CD40 overcame growth inhibition induced by low concentrations of curcumin. Our results suggest that curcumin caused the growth arrest and apoptosis of BKS-2 immature B cell lymphoma by downregulation of growth and survival promoting genes.

CpG oligodeoxynucleotides overcome the unresponsiveness of neonatal B cells to stimulation with the thymus-independent stimuli anti-IgM and TNP-Ficoll.

Neonates are very vulnerable to pathogenic encapsulated bacteria due to their inability to mount an antibody response to capsular polysaccharides, which are thymus-independent type 2 (TI-2) antigens (Ag). Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides induced neonatal B cells to proliferate to anti-IgM, a TI-2 stimulus. CpG ODN inhibited the spontaneous and B cell receptor-mediated apoptosis of neonatal B cells and reduced the amount of the pro-apoptotic Bcl-xS, strongly correlated with anti-IgM-induced apoptosis of neonatal B cells. CpG ODN protected neonatal B cells from apoptosis by down-regulation of the Bcl-xS protein. Neonatal B cells underwent polyclonal differentiation upon stimulation with CpG ODN, but unlike in adult B cells, this was not preceded by IL-6 secretion. CpG ODN stimulated neonatal B cells to mount an Ag-specific antibody response to TNP-Ficoll, another TI-2 Ag. Thus CpG ODN could provide a novel approach to induce the immune system in neonates to respond to harmful encapsulated bacteria.

CpG oligodeoxynucleotides rescue BKS-2 immature B cell lymphoma from anti-IgM-mediated growth inhibition by up-regulation of egr-1.

Cross-linking of the IgM antigen receptor on an immature B cell lymphoma (BKS-2) induces growth arrest and apoptosis. This is accompanied by down-regulation of the immediate early genes, egr-1 and c-myc, and a reduction in NF-kappaB activity. Anti-IgM-induced growth arrest and apoptosis of this murine B cell lymphoma were prevented by oligodeoxynucleotides (ODN) containing the CpG motif, which are also known to be stimulatory for mature and immature B cells. The CpG but not non-CpG ODN rescued BKS-2 cells from anti-IgM-mediated growth inhibition by up-regulation of egr-1 and c-myc expression as well as by restoring NF-kappaB activity. Interestingly, changes in egr-1 expression occurred more rapidly than in c-myc expression. Also the c-myc levels remained high up to 6 h after addition of the anti-IgM, which was also the time until which the addition of CpG could be delayed without affecting its ability to provide complete protection. This CpG-induced rescue of B lymphoma cells was blocked by antisense egr-1 ODN, suggesting that the expression of egr-1 is important for the effects of CpG ODN on the growth and survival of BKS-2 cells.

C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocyte-derived cytokines.

Differential chemokine production by colonic epithelial cells is thought to contribute to the characteristic increased infiltration of selected population of leukocytes cells in inflammatory bowel disease. We have previously demonstrated that IL-13 enhances IL-1alpha-induced IL-8 secretion by the colonic epithelial cell line HT-29. We have now explored the C-C chemokine expression and modulation in this system. The combination of TNF-alpha and IFN-gamma was the minimal stimulation required for regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein (MCP-1) mRNA expression and secretion by HT-29 cells. The same stimulation induced a stronger IL-8 mRNA expression and secretion. Pretreatment with IL-13 or IL-4, reduced significantly the RANTES, and MCP-1, but not IL-8 mRNA expression and secretion. In contrast, IL-10 had no effect on either MCP-1, or RANTES, or IL-8 generation. Pretreatment of HT-29 cells with wortmannin suggested that the IL-13-induced inhibition of C-C chemokine expression is via activation of a wortmannin-sensitive phosphatidylinositol 3-kinase. These data demonstrate that colonic epithelial cell chemokine production can be differentially regulated by T cell-derived cytokines and suggest an interplay between epithelial cells and T lymphocytes potentially important in the intestinal inflammation.

Expression of inducible nitric oxide synthase activity in human colon epithelial cells: modulation by T lymphocyte derived cytokines.

BACKGROUND: Nitric oxide (NO) synthesis and inducible nitric oxide synthase (iNOS) expression are increased in colonic biopsy specimens from patients with ulcerative colitis, but the cellular source of NO production is not known. AIMS: To examine the distribution of iNOS in human colonic mucosa and to explore the ability of T lymphocyte derived cytokines to regulate iNOS expression and activity in human colonic epithelial cells. METHODS: iNOS expression was examined using immunohistochemistry in colonic biopsy samples from 12 patients with ulcerative colitis and three with infectious colitis and compared with 10 normal controls. In vitro iNOS expression and activity were determined in HT-29 cell cultures; nitrite levels were measured using a fluorescent substrate, iNOS mRNA expression by northern blot analysis, and iNOS protein expression by western blot analysis. RESULTS: No iNOS expression was detected (10 of 10) in non-inflamed mucosa derived from normal controls. In 11 of 12 cases of newly diagnosed ulcerative colitis, iNOS protein was expressed in the epithelial cells, while no other positive cells were found in the lamina propria. Similar iNOS labelling was found in colonic biopsy samples from patients with infectious colitis in the acute phase, but when re-examined in samples from patients in total remission, no iNOS staining was observed. Both interleukin (IL)-13 and IL-4, but not IL-10, are potent inhibitors of iNOS expression and activity induced by an optimal combination of cytokines, namely IL-1 alpha, tumour necrosis factor alpha and interferon gamma. CONCLUSIONS: The data suggest that the epithelium is the major source of iNOS activity in ulcerative colitis and that IL-13 and IL-4 may act as intrinsic regulators of NO generation in intestinal inflammation.

Averting the gaze disengages the environment and facilitates remembering.

When people are asked moderately difficult questions, they often avert their gazes. We report five experiments in which we documented this phenomenon. They demonstrate that (1) the frequency of gaze aversion is related to the difficulty of cognitive processing, (2) this behavior cannot be due solely to demand characteristics or embarrassment, and (3) the behavior is functional: Averting the gaze improves performance. We speculate that averting the gaze helps people to disengage from environmental stimulation and thereby enhances the efficiency of cognitive processing directed by nonenvironmental stimulation.

Antibiotic prophylaxis for ERCP: a comparison of oral ciprofloxacin with intravenous cephazolin in the prophylaxis of high-risk patients.

BACKGROUND: Cholangitis and septicaemia are serious complications of endoscopic retrograde cholangiopancreatography (ERCP). They occur mainly following therapeutic ERCP in the setting of an obstructed biliary system. The optimum prophylactic antibiotic regimen in such patients is not yet defined but usually depends on intravenous agents. AIM: To compare the efficacy of oral ciprofloxacin with intravenous cephazolin. METHODS: One hundred and fifty patients at high risk from septic complications were randomized prospectively to either oral ciprofloxacin (750 mg b.d.) or intravenous cephazolin (1 g b.d.), commenced at least 90 min prior to the ERCP and continued for 3 days. Bacteriological cultures were taken from bile during the procedure and from blood both immediately and at 24 h post-procedure. RESULTS: There were no significant differences between the two treatment groups in the pre-ERCP clinical or radiological findings or in the types of procedure performed. One patient did not undergo an ERCP and was excluded from the final analysis. Of the 77 patients in the ciprofloxacin group there were no positive blood cultures and one positive culture from a nasobiliary drain. Two out of the 72 cephazolin patients had positive blood cultures immediately post-ERCP; one of these two patients and one other cephazolin patient had positive bile cultures. There were no cases of cholangitis or septicaemia in the ciprofloxacin group and three cases in the cephazolin group. One patient from each treatment group died within the 7-day study. Adverse drug reactions were minimal and none of the different clinical outcomes in the two groups reached statistical significance. CONCLUSION: Oral ciprofloxacin is a cost-effective prophylactic agent for high-risk ERCP.