Assessing frailty in elderly patients with hip fractures: A retrospective review comparing geriatrician and orthopedic trainee assessments.

To assess the correlation of orthopedic surgery residents compared with expert geriatricians in the assessment of frailty stage using the Clinical Frailty Scale (CFS) in patients with hip fractures. A retrospective chart review was performed from January 1, 2015 to December 31, 2019. Patients admitted with a diagnosis of hip fracture were identified. Those patients with a CFS score completed by orthopedic residents with subsequent CFS score completed by a geriatrician during their admission were extracted. Six hundred and forty-eight patients over age 60 (mean 80.5 years, 73.5% female) were admitted during the study period. Orthopaedic residents completed 286 assessments in 44% of admissions. Geriatric medicine consultation was available for 215 patients such that 93 patients were assessed by both teams. Paired CFS data were extracted from the charts and tested for agreement between the 2 groups of raters. CFS assessments by orthopedic residents and geriatrician experts were significantly different at P < .05; orthopedic residents typically assessed patients to be one CFS grade less frail than geriatricians. Despite this, the CFS assessments showed good agreement between residents and geriatricians. Orthopaedic surgery residents are reliable assessors of frailty but tend to underestimate frailty level compared with specialist geriatricians. Given the evidence to support models such as orthogeriatrics to improve outcomes for frail patients, our findings suggest that orthopedic residents may be well positioned to identify patients who could benefit from such early interventions. Our findings also support recent evidence that frailty assessments by orthopedic surgeons may have predictive validity. Low rates of initial frailty assessment by orthopedic residents suggests that further work is required to integrate more global comprehensive care.

Dietary Therapy to Improve Nutrition and Gut Health in Paediatric Crohn's Disease; A Feasibility Study.

Bovine colostrum (BC) has anti-inflammatory, anti-infective, growth and intestinal repair factors that may be beneficial in Crohn's disease (CD). We assessed whether daily BC for up to 3 months was acceptable to children and young people (CYP) with CD in remission or of mild/moderate severity. CYP were randomised to receive either BC or matching placebo milk daily for 6 weeks (blinded phase); all received BC for the following 6 weeks (open phase). In 23 CYP, median (inter-quartile range) age was 15.2 (13.9-16.1) years and 9 (39.1%) were girls. A similar proportion of CYP in the BC and placebo arms completed the blinded phase (8/12, 75.0% and 9/11, 81.8% respectively). Twelve (70.6%) CYP completed the open phase with 7 (58.3%) tolerating BC for 3 months. Diaries in weeks 2, 6 and 12 revealed that most CYP took BC every day (5/7, 71.4%; 5/8, 62.5% and 6/11, 54.5% respectively). In interviews, opinions were divided as to preference of BC over the placebo milk and some preferred BC over other nutritional supplements. Symptoms, clinical and laboratory variables and quality of life were similar in the two arms. BC may be an acceptable nutritional supplement for daily, longer-term use in CYP with CD.

Perineural local anaesthetic catheter after major lower limb amputation trial (PLACEMENT): results from a randomised controlled feasibility trial.

OBJECTIVES: To determine the feasibility of undertaking a randomised controlled effectiveness trial evaluating the use of a perineural catheter (PNC) after major lower limb amputation with postoperative pain as the primary outcome. DESIGN: Randomised controlled feasibility trial. SETTING: Two vascular Centres in South Wales, UK. PARTICIPANTS: 50 patients scheduled for major lower limb amputation (below or above knee) for complications of peripheral vascular disease. INTERVENTIONS: The treatment arm received a PNC placed adjacent to the sciatic or tibial nerve at the time of surgery, with continuous infusion of levobupivacaine hydrochloride 0.125% for up to 5 days. The control arm received neither local anaesthetic nor PNC. Both arms received usual perioperative anaesthesia and postoperative analgesia. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of eligible patients who were randomised and the proportion of recruited patients who provided primary effectiveness outcome data. Secondary outcomes were: the proportion of recruited patients reaching 2 and 6 month follow-up and supplying pain data; identification of key cost drivers; development of an economic analysis framework for a future effectiveness trial; identification of barriers to recruitment and site set-up; and identification of the best way to measure postoperative pain. RESULTS: Seventy-six of 103 screened patients were deemed eligible over a 10 month period. Fifty (64.5%) of these patients were randomised, with one excluded in the perioperative period. Forty-five (91.3%) of 49 recruited patients provided enough pain scores on a 4-point verbal rating scale to allow primary effectiveness outcome evaluation. Attrition rates were high; 18 patients supplied data at 6 month follow-up. Costs were dominated by length of hospital stay. Patients and healthcare professionals reported that trial processes were acceptable. CONCLUSIONS: Recruitment of patients into a trial comparing PNC use to usual care after major lower limb amputation with postoperative pain measured on a 4-point verbal rating scale is feasible. Evaluation of longer-term symptoms is difficult. TRIAL REGISTRATION NUMBER: ISRCTN: 85 710 690. EudraCT: 2016-003544-37.

Supporting parents through stillbirth: A qualitative study exploring the views of health professionals and health care staff in three hospitals in England.

OBJECTIVE: To investigate the views of a range of hospital based health professionals and health care staff involved in the management of stillbirth. STUDY DESIGN: A qualitative pilot study informed by grounded theory conducted in three hospital trusts in the North East of England. In total, 21 consultant obstetricians, 3 trainees (including 1 senior trainee), 29 midwives, 3 midwife sonographers and 4 chaplains took part in six focus groups and two semi-structured interviews. RESULTS: Two different approaches in stillbirth management could be detected in our study. One approach emphasised the existing evidence-base and patient directed choice whilst the other emphasised tradition and profession-directed care. These differences were particularly apparent in choices over mode of delivery, and the location of women as well as the time interval between diagnosis of an IUD and delivery. The existence of these two approaches was underscored by a lack of high quality evidence. CONCLUSION: Robust, high quality evidence is needed regarding the longer term psychological and emotional sequelae of different modes of delivery and varying time intervals and locations of women between diagnosis and delivery in stillbirth. If the competing discourses demonstrated here are found elsewhere then such need to be considered in any future policy development, evidence implementation and training programmes.

The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison.

BACKGROUND: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. METHODS: In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. RESULTS: There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). CONCLUSIONS: These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS.

Adequate Iodine Status in New Zealand School Children Post-Fortification of Bread with Iodised Salt.

Iodine deficiency re-emerged in New Zealand in the 1990s, prompting the mandatory fortification of bread with iodised salt from 2009. This study aimed to determine the iodine status of New Zealand children when the fortification of bread was well established. A cross-sectional survey of children aged 8-10 years was conducted in the cities of Auckland and Christchurch, New Zealand, from March to May 2015. Children provided a spot urine sample for the determination of urinary iodine concentration (UIC), a fingerpick blood sample for Thyroglobulin (Tg) concentration, and completed a questionnaire ascertaining socio-demographic information that also included an iodine-specific food frequency questionnaire (FFQ). The FFQ was used to estimate iodine intake from all main food sources including bread and iodised salt. The median UIC for all children (n = 415) was 116 µg/L (females 106 µg/L, males 131 µg/L) indicative of adequate iodine status according to the World Health Organisation (WHO, i.e., median UIC of 100-199 µg/L). The median Tg concentration was 8.7 µg/L, which was <10 µg/L confirming adequate iodine status. There was a significant difference in UIC by sex (p = 0.001) and ethnicity (p = 0.006). The mean iodine intake from the food-only model was 65 µg/day. Bread contributed 51% of total iodine intake in the food-only model, providing a mean iodine intake of 35 µg/day. The mean iodine intake from the food-plus-iodised salt model was 101 µg/day. In conclusion, the results of this study confirm that the iodine status in New Zealand school children is now adequate.

Empiric antibiotic treatment for urinary tract infection in preschool children: susceptibilities of urine sample isolates.

BACKGROUND: Antibiotic treatment recommendations based on susceptibility data from routinely submitted urine samples may be biased because of variation in sampling, laboratory procedures and inclusion of repeat samples, leading to uncertainty about empirical treatment. OBJECTIVE: To describe and compare susceptibilities of Escherichia coli cultured from routinely submitted samples, with E. coli causing urinary tract infection (UTI) from a cohort of systematically sampled, acutely unwell children. METHODS: Susceptibilities of 1458 E. coli isolates submitted during the course of routine primary care for children <5 years (routine care samples), compared to susceptibilities of 79 E. coli isolates causing UTI from 5107 children <5 years presenting to primary care with an acute illness [systematic sampling: the Diagnosis of Urinary Tract infection in Young children (DUTY) cohort]. RESULTS: The percentage of E. coli sensitive to antibiotics cultured from routinely submitted samples were as follows: amoxicillin 45.1% (95% confidence interval: 42.5-47.7%); co-amoxiclav using the lower systemic break point (BP) 86.6% (84.7-88.3%); cephalexin 95.1% (93.9-96.1%); trimethoprim 74.0% (71.7-76.2%) and nitrofurantoin 98.2% (97.4-98.8%). The percentage of E. coli sensitive to antibiotics cultured from systematically sampled DUTY urines considered to be positive for UTI were as follows: amoxicillin 50.6% (39.8-61.4%); co-amoxiclav using the systemic BP 83.5% (73.9-90.1%); co-amoxiclav using the urinary BP 94.9% (87.7-98.4%); cephalexin 98.7% (93.2-99.8%); trimethoprim 70.9% (60.1-80.0%); nitrofurantoin 100% (95.3-100.0%) and ciprofloxacin 96.2% (89.4-98.7%). CONCLUSION: Escherichia coli susceptibilities from routine and systematically obtained samples were similar. Most UTIs in preschool children remain susceptible to nitrofurantoin, co-amoxiclav and cephalexin.

Childhood urinary tract infection in primary care: a prospective observational study of prevalence, diagnosis, treatment, and recovery.

BACKGROUND: The prevalence of targeted and serendipitous treatment for, and associated recovery from, urinary tract infection (UTI) in pre-school children is unknown. AIM: To determine the frequency and suspicion of UTI in children who are acutely ill, along with details of antibiotic prescribing, its appropriateness, and whether that appropriateness impacted on symptom improvement and recovery. DESIGN AND SETTING: Prospective observational cohort study in primary care sites in urban and rural areas in England and Wales. METHOD: Systematic urine sampling from children aged <5 years presenting in primary care with acute illness with culture in NHS laboratories. RESULTS: Of 6079 children's urine samples, 339 (5.6%) met laboratory criteria for UTI and 162 (47.9%) were prescribed antibiotics at the initial consultation. In total, 576/7101 (8.1%) children were suspected of having a UTI prior to urine sampling, including 107 of the 338 with a UTI (clinician sensitivity 31.7%). Children with a laboratory-diagnosed UTI were more likely to be prescribed antibiotics when UTI was clinically suspected than when it was not (86.0% versus 30.3%, P<0.001). Of 231 children with unsuspected UTI, 70 (30.3%) received serendipitous antibiotics (that is, antibiotics prescribed for a different reason). Overall, 176 (52.1%) children with confirmed UTI did not receive any initial antibiotic. Organism sensitivity to the prescribed antibiotic was higher when UTI was suspected than when treated serendipitously (77.1% versus 26.0%; P<0.001). Children with UTI prescribed appropriate antibiotics at the initial consultation improved a little sooner than those with a UTI who were not prescribed appropriate antibiotics initially (3.5 days versus 4.0 days; P = 0.005). CONCLUSION: Over half of children with UTI on culture were not prescribed antibiotics at first presentation. Serendipitous UTI treatment was relatively common, but often inappropriate to the organism's sensitivity. Methods for improved targeting of antibiotic treatment in children who are acutely unwell are urgently needed.

Hepcidin is suppressed by erythropoiesis in hemoglobin E ß-thalassemia and ß-thalassemia trait.

Hemoglobin E (HbE) ß-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE ß-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE ß-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, ß-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE ß-thalassemia and indicates that the epidemiology of ß-thalassemia trait requires consideration when planning public health iron interventions.

Point of care testing for urinary tract infection in primary care (POETIC): protocol for a randomised controlled trial of the clinical and cost effectiveness of FLEXICULT™ informed management of uncomplicated UTI in primary care.

BACKGROUND: Urinary tract infections (UTI) are the most frequent bacterial infection affecting women and account for about 15% of antibiotics prescribed in primary care. However, some women with a UTI are not prescribed antibiotics or are prescribed the wrong antibiotics, while many women who do not have a microbiologically confirmed UTI are prescribed antibiotics. Inappropriate antibiotic prescribing unnecessarily increases the risk of side effects and the development of antibiotic resistance, and wastes resources. METHODS/DESIGN: 614 adult female patients will be recruited from four primary care research networks (Wales, England, Spain, the Netherlands) and individually randomised to either POCT guided care or the guideline-informed 'standard care' arm. Urine and stool samples (where possible) will be obtained at presentation (day 1) and two weeks later for microbiological analysis. All participants will be followed up on the course of their illness and their quality of life, using a 2 week self-completed symptom diary. At 3 months, a primary care notes review will be conducted for evidence of further evidence of treatment failures, recurrence, complications, hospitalisations and health service costs. DISCUSSION: Although the Flexicult™ POCT is used in some countries in routine primary care, it's clinical and cost effectiveness has never been evaluated in a randomised clinical trial. If shown to be effective, the use of this POCT could benefit individual sufferers and provide evidence for health care authorities to develop evidence based policies to combat the spread and impact of the unprecedented rise of infections caused by antibiotic resistant bacteria in Europe. TRIAL REGISTRATION NUMBER: ISRCTN65200697 (Registered 10 September 2013).

Targeting chronic recurrent low back pain from the top-down and the bottom-up: a combined transcranial direct current stimulation and peripheral electrical stimulation intervention.

BACKGROUND: Mechanisms such as neural sensitization and maladaptive cortical organization provide novel targets for therapy in chronic recurrent low back pain (CLBP). OBJECTIVE: We investigated the effect of a transcranial direct current stimulation (tDCS) and peripheral electrical stimulation (PES) treatment on pain, cortical organization, sensitization and sensory function in CLBP. METHODS: Using a placebo-controlled crossover design, 16 individuals received four treatments in separate sessions: (i) anodal tDCS/PES; (ii) anodal tDCS/sham PES; (iii) sham tDCS/PES; or (iv) sham tDCS/sham PES. Pain was assessed at baseline, immediately following, and at 1 and 3 days after treatment. Motor cortical organization, sensitization and sensory function were measured before and immediately after treatment. RESULTS: Combined tDCS/PES reduced pain and sensitization, normalized motor cortical organization and improved sensory function. The reduction in pain was greater in individuals with more pronounced sensitization. Applied alone, tDCS or PES also reduced pain. However, with the exception of improved sensory function and reduced map volume following PES, clinical and neurophysiological outcomes were unaltered by tDCS or PES applied separately. No changes were observed following sham treatment. CONCLUSION: Our data suggest a combined tDCS/PES intervention more effectively improves CLBP symptoms and mechanisms of cortical organization and sensitization, than either intervention applied alone or a sham control.

Drug repositioning for Alzheimer's disease.

Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.

Synaptic protein expression is regulated by a pro-oxidant diet in APPxPS1 mice.

Dietary factors may play a role in Alzheimer's disease (AD) pathogenesis. In an effort to recapitulate some of the synaptic protein changes observed in the disease, AD transgenic and wild-type mice were fed either a normal or pro-oxidant diet for 3 months from three months of age. Pro-oxidant diet treatment resulted in altered expression of vesicular glutamate transporter-1 and glutamine synthetase, suggesting changes in glutamatergic synaptic function, and increased expression of urokinase plasminogen activator receptor, possibly reflecting oxidative stress.

Enabling lead discovery for histone lysine demethylases by high-throughput RapidFire mass spectrometry.

A high-throughput RapidFire mass spectrometry assay is described for the JMJD2 family of Fe(2+), O(2), and α-ketoglutarate-dependent histone lysine demethylases. The assay employs a short amino acid peptide substrate, corresponding to the first 15 amino acid residues of histone H3, but mutated at two positions to increase assay sensitivity. The assay monitors the direct formation of the dimethylated-Lys9 product from the trimethylated-Lys9 peptide substrate. Monitoring the formation of the monomethylated and des-methylated peptide products is also possible. The assay was validated using known inhibitors of the histone lysine demethylases, including 2,4-pyridinedicarboxylic acid and an α-ketoglutarate analogue. With a sampling rate of 7 s per well, the RapidFire technology permitted the single-concentration screening of 101 226 compounds against JMJD2C in 10 days using two instruments, typically giving Z' values of 0.75 to 0.85. Several compounds were identified of the 8-hydroxyquinoline chemotype, a known series of inhibitors of the Lys9-specific histone demethylases. The peptide also functions as a substrate for JMJD2A, JMJD2D, and JMJD2E, thus enabling the development of assays for all 3 enzymes to monitor progress in compound selectivity. The assay represents the first report of a RapidFire mass spectrometry assay for an epigenetics target.

Vitamins and psychological functioning: a mobile phone assessment of the effects of a B vitamin complex, vitamin C and minerals on cognitive performance and subjective mood and energy.

OBJECTIVES: Despite being widely consumed, the effects of multi-vitamin supplements on psychological functioning have received little research attention. METHODS: Using a mobile phone testing paradigm, 198 males (30-55 years) in full-time employment took part in this randomised, placebo-controlled, double-blind, parallel-groups trial assessing the effects of a multi-vitamin/mineral on cognitive performance and psychological state/mood. Participants completed two cognitive tasks and a number of visual analogue scales (VAS) before and after a full day's work, on the day before, and 7, 14, 21 and 28 days after, commencing their treatment. RESULTS: Participants in the vitamin/mineral group rated themselves as having greater 'physical stamina' across assessments and weeks. They also rated themselves as having had greater 'concentration' and 'mental stamina' during the working day at the assessment carried out after a day's work, but not at the time of the assessment completed prior to work. Participants in this group also reported greater subjective 'alertness' on Bond-Lader mood scales during the post-work assessment on day 14 and both the pre and post-work assessments on day 28. CONCLUSIONS: These findings complement the results from the laboratory-based, randomised-controlled trial in the same cohort and suggest that healthy members of the general population may benefit from augmented levels of vitamins/minerals via direct dietary supplementation.

Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors.

AT1R (angiotensin type 1 receptor) and AT2R (angiotensin type 2 receptor) are well known to be involved in the complex cardiovascular actions of AngII (angiotensin II). However, shorter peptide fragments of AngII are thought to have biological activity in their own right and elicit effects that oppose those mediated by AngII. In the present study, we have used HEK (human embryonic kidney)-293 cells stably transfected with either AT1R or AT2R to perform a systematic analysis of binding affinities of all the major angiotensin peptides. Additionally, we tested the novel AT2R agonist Compound 21, as well as the MasR (Mas receptor) agonist and antagonist AVE0991 and A-779 respectively, for their ability to bind to AT1R or AT2R. Candesartan, CGP42214 and PD123319 were used as reference compounds. Binding studies using 125I-[Sar1Ile8]AngII on the AT1R-transfected HEK-293 cells revealed only AngII, AngIII [angiotensin III; angiotensin-(2-8)] and candesartan to have high affinity for AT1R. In the AT2R-transfected HEK-293 cells, competition for 125I-[Sar1Ile8]AngII binding was observed for all ligands except candesartan, AVE0991 and A-779, the latter two compounds having negligible affinity at either AT1R or AT2R. The rank order of affinity of ligands at AT2R was CGP42112>AngII≥AngIII>Compound 21≥PD123319≫AngIV [angiotensin IV; angiotensin-(3-8)]>Ang-(1-7) [angiotensin-(1-7)]. Of note, although AngIV and Ang-(1-7) exhibited only modest affinity at AT2R compared with AngII, these two angiotensin peptides, together with AngIII, had substantial AT2R selectivity over AT1R. Collectively, our results suggest that shorter angiotensin peptides can act as endogenous ligands at AT2R.

Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking.

Orexinergic signalling is critical to drug relapse-like behaviour; however, the CNS sites(s) of action remain unknown. Two candidate brain regions are the paraventricular thalamus (PVT) and ventral tegmental area (VTA). We assessed the effect of intra-PVT or -VTA administration of the orexin-1 receptor (OrxR1) antagonist SB-334867 on discriminative cue-induced cocaine-seeking. Animals received either PVT- or VTA-directed SB-334867 (0, 3 or 6 µg; 0, 1 or 3 µg, respectively) prior to reinstatement testing elicited by presenting cocaine-paired stimuli (S+). The effect of VTA-directed injections of SB-334867 (0 or 3 µg) on locomotor activity was also assessed. Intra-VTA, but not -PVT, SB-334867 dose-dependently attenuated S+-induced reinstatement (3 µg dose, p<0.01). Intra-VTA SB-334867 had no effect on locomotor activity. We conclude that OrxR1 signalling within the VTA, but not the PVT, mediates cue-induced cocaine-seeking behaviour. We hypothesize that blockade of VTA OrxR1 signalling may reduce nucleus accumbens dopamine in response to drug cue presentation.

Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour.

BACKGROUND: Cocaine- and amphetamine-regulated transcript (CART) has been demonstrated to play a role in regulating the rewarding and reinforcing effects of various drugs of abuse. A recent study demonstrated that i.c.v. administration of CART negatively modulates reinstatement of alcohol seeking, however, the site(s) of action remains unclear. We investigated the paraventricular thalamus (PVT) as a potential site of relapse-relevant CART signaling, as this region is known to receive dense innervation from CART-containing hypothalamic cells and to project to a number of regions known to be involved in mediating reinstatement, including the nucleus accumbens (NAC), medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). METHODOLOGY/PRINCIPAL FINDINGS: Male rats were trained to self-administer cocaine before being extinguished to a set criterion. One day following extinction, animals received intra-PVT infusions of saline, tetrodotoxin (TTX; 2.5 ng), CART (0.625 µg or 2.5 µg) or no injection, followed by a cocaine prime (10 mg/kg, i.p.). Animals were then tested under extinction conditions for one hour. Treatment with either TTX or CART resulted in a significant attenuation of drug-seeking behaviour following cocaine-prime, with the 2.5 µg dose of CART having the greatest effect. This effect was specific to the PVT region, as misplaced injections of both TTX and CART resulted in responding that was identical to controls. CONCLUSIONS/SIGNIFICANCE: We show for the first time that CART signaling within the PVT acts to inhibit drug-primed reinstatement of cocaine seeking behaviour, presumably by negatively modulating PVT efferents that are important for drug seeking, including the NAC, mPFC and BLA. In this way, we identify a possible target for future pharmacological interventions designed to suppress drug seeking.

Effects of a multi-vitamin/mineral supplement on cognitive function and fatigue during extended multi-tasking.

OBJECTIVES: A significant minority of the population consume multi-vitamins/minerals for their putative health benefits, including potentially beneficial effects on cognitive performance, fatigue and mood. The current study investigated the effect of supplementation with a multi-vitamin/mineral on fatigue and cognitive function in healthy females. METHODS: In this placebo-controlled, double blind, randomized, parallel groups trial the effect of a multi-vitamin/mineral (Supradyn) was assessed in 216 females aged 25-50 years. Participants attended the laboratory before and 9 weeks after commencing treatment. During both visits cognitive function and the modulation of task related mood/fatigue were assessed in two discrete 20-min assessment periods during which participants completed a four-module version of the Multi-Tasking Framework. RESULTS: Those in the vitamin/mineral group exhibited an attenuation of the negative effects of extended task completion on mood/fatigue. Multi-tasking performance for this group was also improved in terms of accuracy across all tasks, and on two of the individual tasks (Mathematical Processing and Stroop) in terms of both faster and more accurate responses. Analysis of a subsection (N = 102) demonstrated significant reductions in homocysteine levels following the vitamins/mineral supplement. CONCLUSIONS: These findings suggest that healthy members of the general population may benefit from augmented levels of vitamins/minerals via direct dietary supplementation.

Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males.

RATIONALE: A significant proportion of the general population report supplementing their diet with one or more vitamins or minerals, with common reasons for doing so being to combat stress and fatigue and to improve mental functioning. Few studies have assessed the relationship between supplementation with vitamins/minerals and psychological functioning in healthy cohorts of non-elderly adults. OBJECTIVES: The present randomised, placebo-controlled, double-blind, parallel groups trial assessed the cognitive and mood effects of a high-dose B-complex vitamin and mineral supplement (Berocca(R)) in 215 males aged 30 to 55 years, who were in full-time employment. METHODS: Participants attended the laboratory prior to and on the last day of a 33-day treatment period where they completed the Profile of Mood States (POMS), Perceived Stress Scale (PSS) and General Health Questionnaire (GHQ-12). Cognitive performance and task-related modulation of mood/fatigue were assessed with the 60 min cognitive demand battery. On the final day, participants also completed the Stroop task for 40 min whilst engaged in inclined treadmill walking and subsequent executive function was assessed. RESULTS: Vitamin/mineral supplementation led to significant improvements in ratings on the PSS, GHQ-12 and the 'vigour' subscale of the POMS. The vitamin/mineral group also performed better on the Serial 3s subtractions task and rated themselves as less 'mentally tired' both pre- and post-completion of the cognitive demand battery. CONCLUSIONS: Healthy members of the general population may benefit from augmented levels of vitamins/minerals via direct dietary supplementation. Specifically, supplementation led to improved ratings of stress, mental health and vigour and improved cognitive performance during intense mental processing.