Modulation of vaccine response by concomitant probiotic administration

Evidence suggests that probiotic bacteria modulate both innate and adaptive immunity in the host, and in some situations can result in reduced severity of common illnesses, such as acute rotavirus infection and respiratory infections. Responses to vaccination are increasingly being used to provide high quality information on the immunomodulatory effects of dietary components in humans. The present review focuses on the effect of probiotic administration upon vaccination response. The majority of studies investigating the impact of probiotics on responses to vaccination have been conducted in healthy adults, and at best they show modest effects of probiotics on serum or salivary IgA titres. Studies in infants and in elderly subjects are very limited, and it is too early to draw any firm conclusions regarding the potential for probiotics to act as adjuvants in vaccination. Although some studies are comparable in terms of duration of the intervention and age and characteristics of the subjects, most differ in terms of the probiotic selected. Further well designed, randomized, placebo-controlled studies are needed to fully understand the immunomodulatory properties of probiotics, whether the effects exerted are strain-dependent and age-dependent, and their clinical relevance in enhancing immune protection following vaccination.

Layer-by-layer coating of alginate matrices with chitosan–alginate for the improved survival and targeted delivery of probiotic bacteria after oral administration

The oral administration of probiotic bacteria has shown potential in clinical trials for the alleviation of specific disorders of the gastrointestinal tract. However, cells must be alive in order to exert these benefits. The low pH of the stomach can greatly reduce the number of viable microorganisms that reach the intestine, thereby reducing the efficacy of the administration. Herein, a model probiotic, Bifidobacterium breve, has been encapsulated into an alginate matrix before coating in multilayers of alternating alginate and chitosan. The intention of this formulation was to improve the survival of B. breve during exposure to low pH and to target the delivery of the cells to the intestine. The material properties were first characterized before in vitro testing. Biacore™ experiments allowed for the polymer interactions to be confirmed; additionally, the stability of these multilayers to buffers simulating the pH of the gastrointestinal tract was demonstrated. Texture analysis was used to monitor changes in the gel strength during preparation, showing a weakening of the matrices during coating as a result of calcium ion sequestration. The build-up of multilayers was confirmed by confocal laser-scanning microscopy, which also showed the increase in the thickness of coat over time. During exposure to in vitro gastric conditions, an increase in viability from <3 log(CFU) per mL, seen in free cells, up to a maximum of 8.84 ± 0.17 log(CFU) per mL was noted in a 3-layer coated matrix. Multilayer-coated alginate matrices also showed a targeting of delivery to the intestine, with a gradual release of their loads over 240 min.

Description and process evaluation of pharmacists’ interventions in a pharmacist-led information technology-enabled multicentre cluster randomised controlled trial for reducing medication errors in general practice (PINCER trial)

Objective To undertake a process evaluation of pharmacists' recommendations arising in the context of a complex IT-enabled pharmacist-delivered randomised controlled trial (PINCER trial) to reduce the risk of hazardous medicines management in general practices. Methods PINCER pharmacists manually recorded patients’ demographics, details of interventions recommended, actions undertaken by practice staff and time taken to manage individual cases of hazardous medicines management. Data were coded and double entered into SPSS v15, and then summarised using percentages for categorical data (with 95% CI) and, as appropriate, means (SD) or medians (IQR) for continuous data. Key findings Pharmacists spent a median of 20 minutes (IQR 10, 30) reviewing medical records, recommending interventions and completing actions in each case of hazardous medicines management. Pharmacists judged 72% (95%CI 70, 74) (1463/2026) of cases of hazardous medicines management to be clinically relevant. Pharmacists recommended 2105 interventions in 74% (95%CI 73, 76) (1516/2038) of cases and 1685 actions were taken in 61% (95%CI 59, 63) (1246/2038) of cases; 66% (95%CI 64, 68) (1383/2105) of interventions recommended by pharmacists were completed and 5% (95%CI 4, 6) (104/2105) of recommendations were accepted by general practitioners (GPs), but not completed at the end of the pharmacists’ placement; the remaining recommendations were rejected or considered not relevant by GPs. Conclusions The outcome measures were used to target pharmacist activity in general practice towards patients at risk from hazardous medicines management. Recommendations from trained PINCER pharmacists were found to be broadly acceptable to GPs and led to ameliorative action in the majority of cases. It seems likely that the approach used by the PINCER pharmacists could be employed by other practice pharmacists following appropriate training.

Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: abnormal salience circuitry and relations to positive emotionality

Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n=25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject’s connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic-cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.

Anti-platelet effect of aspirin is substantially reduced after administration of heparin during carotid endarterectomy

OBJECTIVES: Aspirin therapy is usually continued throughout the perioperative period to reduce the risk for thromboembolic stroke and myocardial infarction after carotid endarterectomy (CEA). Aspirin irreversibly binds cyclooxygenase-1, thereby reducing platelet aggregation for the lifetime of each platelet. However, recent research from this unit has shown that aggregation in response to arachidonic acid increases significantly, but transiently, during CEA, which suggests that the anti-platelet effect of aspirin is temporarily reversed. The purpose of the current study was to determine when this phenomenon occurs and to identify the possible mechanisms involved. METHODS: Platelet aggregation was measured in platelet-rich plasma from 41 patients undergoing CEA who were stabilized with 150 mg of aspirin daily. Blood was taken at 8 time points: before anesthesia, after anesthesia, before heparinization, 3 minutes after heparinization, 3 minutes after shunt insertion, 10 minutes after flow restoration, 4 hours postoperatively, and 24 hours postoperatively. Platelet aggregation was also measured at similar times in a group of 18 patients undergoing peripheral angioplasty without general anesthesia. RESULTS: All patient platelets were effectively inhibited by aspirin at the start of the operation. There was a significant intraoperative increase in platelet response to arachidonic acid in both groups of patients, which occurred within 3 minutes of administration of unfractionated heparin. In the CEA group this resulted in a greater than 10-fold increase in mean aggregation, to 5 mmol/L of arachidonic acid (5 mmol/L), rising from 3.9% +/- 2.2% preoperatively to 45.1% +/- 29.3% after administration of heparin ( P <.0001). This increased aggregation persisted into the early postoperative period, but by 24 hours post operation aggregation had returned to near preoperative values. Aggregation in response to other platelet agonists (adenosine diphosphate, thrombin receptor agonist peptide) showed only a small increase at the same time, which could be accounted for by a parallel increase in the level of spontaneous aggregation. CONCLUSION: Administration of heparin significantly increases platelet aggregation in response to arachidonic acid, despite adequate inhibition by aspirin administered preoperatively. This apparent reversal in anti-platelet activity persisted into the immediate early postoperative period, and could explain why a small proportion of patients are at increased risk for acute cardiovascular events after major vascular surgery, despite aspirin therapy.

SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex

Recent evidence suggests that an area in the dorsal medial prefrontal cortex (dorsal nexus) shows dramatic increases in connectivity across a network of brain regions in depressed patients during the resting state;1 this increase in connectivity is suggested to represent hotwiring of areas involved in disparate cognitive and emotional functions.1, 2, 3 Sheline et al.1 concluded that antidepressant action may involve normalisation of the elevated resting state functional connectivity seen in depressed patients. However, the effects of conventional pharmacotherapy for depression on this resting state functional connectivity is not known and the effects of antidepressant treatment in depressed patients may be confounded by change in symptoms following treatment.

Probiotic administration attenuates myocardial hypertrophy and heart failure following myocardial infarction in the rat

Background—Probiotics are extensively used to promote gastrointestinal health and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of post-infarction heart failure. Methods and Results—Rats were subjected to six weeks of sustained coronary artery occlusion and administered the probiotic Lactobacillus rhamnosus GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment as well as gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the six week follow-up period including a marked preservation of left ventricular ejection fraction as well as fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at four weeks suggesting persistence of the GR-1 effects following cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin to adiponectin plasma concentration ratio in rats subjected to coronary ligation which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels. Conclusions—The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.

Drug holidays from ADHD medication: international experience over the past four decades

Objective: ADHD is managed by stimulants that are effective but can cause growth retardation. Prescribers should ideally monitor children and trial a “drug holiday” to enable catch-up growth. Our aim was to map the experience of drug holidays from ADHD medication in children and adolescents. Method: A comprehensive search of the literature identified 22 studies published during the period 1972 to 2013. Results: Drug holidays are prevalent in 25% to 70% of families and are more likely to be exercised during school holidays. They test whether medication is still needed and are also considered for managing medication side effects and drug tolerance. The impact of drug holidays was reported in terms of side effects and ADHD symptoms. There was evidence of a positive impact on child growth with longer breaks from medication, and shorter breaks could reduce insomnia and improve appetite. Conclusion: Drug holidays from ADHD medication could be a useful tool with multiple purposes: assessment, management, prevention, and negotiation.

Memory for medication side effects in younger and older adults: the role of subjective and objective importance

Older adults often experience memory impairments, but can sometimes use selective processing and schematic support to remember important information. The current experiments investigate to what degree younger and healthy older adults remember medication side effects that were subjectively or objectively important to remember. Participants studied a list of common side effects, and rated how negative these effects were if they were to experience them, and were then given a free recall test. In Experiment 1, the severity of the side effects ranged from mild (e.g., itching) to severe (e.g., stroke), and in Experiment 2, certain side effects were indicated as critical to remember (i.e., “contact your doctor if you experience this”). There were no age differences in terms of free recall of the side effects, and older adults remembered more severe side effects relative to mild effects. However, older adults were less likely to recognize critical side effects on a later recognition test, relative to younger adults. The findings suggest that older adults can selectively remember medication side effects, but have difficulty identifying familiar but potentially critical side effects, and this has implications for monitoring medication use in older age.

Work Domain Analysis for understanding medication safety in care homes in England: an exploratory study

Medication safety and errors are a major concern in care homes. In addition to the identification of incidents, there is a need for a comprehensive system description to avoid the danger of introducing interventions that have unintended consequences and are therefore unsustainable. The aim of the study was to explore the impact and uniqueness of Work Domain Analysis (WDA) to facilitate an in-depth understanding of medication safety problems within the care home system and identify the potential benefits of WDA to design safety interventions to improve medication safety. A comprehensive, systematic and contextual overview of the care home medication system was developed for the first time. The novel use of the Abstraction Hierarchy (AH) to analyse medication errors revealed the value of the AH to guide a comprehensive analysis of errors and generate system improvement recommendations that took into account the contextual information of the wider system.

Proposed feasibility oversight for pre-pack administration in England and Wales: window dressing or effective reform?

The 2014 Graham proposals aimed at reducing recidivism are unlikely to achieve the desired goals. It is argued that due consideration must be had for the future of the rescued entity. Further, both the viability review and the proposed capital structure of the rescued entity must be carefully assessed.

Targeting medication non-adherence behavior in selected autoimmune diseases: a systematic approach to digital health program development

Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns.

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD

Background Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. Method Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. Results Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. Conclusions The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.