The impact of a computerised decision support system on antibiotic usage in an English hospital.

Background Antimicrobial resistance is correlated with the inappropriate use of antibiotics. Computerised decision support systems may help practitioners to make evidence-based decisions when prescribing antibiotics. Objective This study aimed to evaluate the impact of computerized decision support systems on the volume of antibiotics used. Setting A very large 1200-bed teaching hospital in Birmingham, England. Main outcome measure The primary outcome measure was the defined daily doses/1000 occupied bed-days. Method A retrospective longitudinal study was conducted to examine the impact of computerised decision support systems on the volume of antibiotic use. The study compared two periods: one with computerised decision support systems, which lasted for 2 years versus one without which lasted for 2 years after the withdrawal of computerised decision support systems. Antibiotic use data from June 2012 to June 2016 were analysed (comprising 2 years with computerised decision support systems immediately followed by 2 years where computerised decision support systems had been withdrawn). Regression analysis was applied to assess the change in antibiotic consumption through the period of the study. Result From June 2012 to June 2016, total antibiotic usage increased by 13.1% from 1436 to 1625 defined daily doses/1000 bed-days: this trend of increased antibiotic prescribing was more pronounced following the withdrawal of structured prescribing (computerised decision support systems). There was a difference of means of - 110.14 defined daily doses/1000 bed days of the total usage of antibiotics in the period with and without structured prescribing, and this was statistically significant (p = 0.026). From June 2012 to June 2016, the dominant antibiotic class used was penicillins. The trends for the total consumption of all antibiotics demonstrated an increase of use for all antibiotic classes except for tetracyclines, quinolones, and anti-mycobacterial drugs, whereas aminoglycoside usage remained stable. Conclusion The implementation of computerised decision support systems appears to influence the use of antibiotics by reducing their consumption. Further research is required to determine the specific features of computerised decision support systems, which influence increased higher adoption and uptake of this technology.

Prefrontal and parietal contributions to spatial working memory.

Functional neuroimaging studies consistently implicate a widespread network of human cortical brain areas that together support spatial working memory. This review summarizes our recent functional magnetic resonance imaging studies of humans performing delayed-saccades. These studies have isolated persistent activity in dorsal prefrontal regions, like the frontal eye fields, and the posterior parietal cortex during the maintenance of positional information. We aim to gain insight into the type of information coded by this activity. By manipulating the sensory and motor demands of the working memory task, we have been able to modulate the frontal eye fields and posterior parietal cortex delay-period activity. These findings are discussed in the context of other neurophysiological and lesion-based data and some hypotheses regarding the differential contributions of frontal and parietal areas to spatial working memory are offered. Namely, retrospective sensory coding of space may be more prominent in the posterior parietal cortex, while prospective motor coding of space may be more prominent in the frontal eye fields.

Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification.

Multiplex ligation-dependent probe amplification (MLPA) is a recently described method for detecting gross deletions or duplications of DNA sequences, aberrations which are commonly overlooked by standard diagnostic analysis. To determine the incidence of copy number variants in cancer predisposition genes from families in the Wessex region, we have analysed the hMLH1 and hMSH2 genes in patients with hereditary nonpolyposis colorectal cancer (HNPCC), BRCA1 and BRCA2 in families with hereditary breast/ovarian cancer (BRCA) and APC in patients with familial adenomatous polyposis coli (FAP). Hereditary nonpolyposis colorectal cancer (n=162) and FAP (n=74) probands were fully screened for small mutations, and cases for which no causative abnormality were found (HNPCC, n=122; FAP, n=24) were screened by MLPA. Complete or partial gene deletions were identified in seven cases for hMSH2 (5.7% of mutation-negative HNPCC; 4.3% of all HNPCC), no cases for hMLH1 and six cases for APC (25% of mutation negative FAP; 8% of all FAP). For BRCA1 and BRCA2, a partial mutation screen was performed and 136 mutation-negative cases were selected for MLPA. Five deletions and one duplication were found for BRCA1 (4.4% of mutation-negative BRCA cases) and one deletion for BRCA2 (0.7% of mutation-negative BRCA cases). Cost analysis indicates it is marginally more cost effective to perform MLPA prior to point mutation screening, but the main advantage gained by prescreening is a greatly reduced reporting time for the patients who are positive. These data demonstrate that dosage analysis is an essential component of genetic screening for cancer predisposition genes.

Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives. A parametric study of the effects of increasing inhibitory load.

Several studies have reported that patients with schizophrenia and their relatives perform poorly on antisaccade tasks and have suggested that this deficit represents saccadic disinhibition. If this proposition is correct, then varying task parameters that specifically increase the difficulty with which unwanted saccades can be inhibited should exacerbate deficits. Forty-two schizophrenia patients, 42 of their first-degree biological relatives, 21 psychotic affective disorder patients, and 38 nonpsychiatric comparison subjects were given fixation and antisaccade tasks. The introduction of distracters and the presence of visible fixation stimuli were parameters used to vary the difficulty in suppressing unwanted saccades (inhibitory load). It is known that the presence of a fixation stimulus at the time when a saccade must be inhibited results in fewer reflexive errors on antisaccade tasks. Performance on fixation tasks without (low load) vs with distracters (high load) and antisaccade tasks that had fixation stimuli still visible (low load) vs already extinguished (high load) at the time when the reflexive saccade must be inhibited was compared. The schizophrenia patients and their first-degree biological relatives showed evidence of increased saccadic disinhibition that was most pronounced during high inhibitory load conditions. These data indicate that dysfunctional inhibitory processes, at least in the oculomotor domain, are associated with the liability to schizophrenia. Results also suggest that this genetic liability may be related to dysfunctional prefrontal cortical areas that provide top-down inhibitory control over reflexive saccade generation.

Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives.

OBJECTIVE: Performance on measures of saccadic inhibition and control was investigated in a large family study of schizophrenia to evaluate the utility of using antisaccade task performance as an endophenotypic marker of genetic liability for schizophrenia. METHOD: Ninety-five patients with acute schizophrenia and 116 of their first-degree biological relatives, 13 schizophrenia patients whose illness was in full remission, 35 patients with acute psychotic affective disorder, and 109 nonpsychiatric comparison subjects were administered antisaccade and prosaccade tasks. RESULTS: Both schizophrenia patient groups had a greater number of errors on the antisaccade task than did the first-degree relatives and the affective disorder group, which both had more errors than the comparison subjects. Among the first-degree relatives of the probands with acute schizophrenia, relatives of poor-performing patients performed worse on the antisaccade task than relatives of patients with good performance. Reflexive errors were not likely the result of interfering psychotic symptoms, medication, or medication side effects. Although the schizophrenia patients demonstrated other signs of saccadic abnormalities, these problems, which were not observed in their relatives even though they had high antisaccade error rates, seem unlikely to account for the higher antisaccade error rate of the schizophrenia patients. CONCLUSIONS: These findings suggest that saccadic disinhibition is strongly associated with the genetic liability for schizophrenia.

Behavioral and neurophysiological correlates of episodic coding, proactive interference, and list length effects in a running span verbal working memory task.

Updating refers to (1) discarding items from, (2) repositioning items in, and (3) adding items to a running working memory span. Our behavioral and fMRI experiments varied three factors: trial length, proactive interference (PI), and group integrity. Group integrity reflected whether the grouping of items at the encoding stage was violated at discarding. Behavioral results were consistent with the idea that updating processes have a relatively short refractory period and may not fatigue, and they revealed that episodic information about group context is encoded automatically in working memory stimulus representations. The fMRI results did not show evidence that updating requirements in a task recruit executive control processes other than those supporting performance on nonupdating trials. They did reveal an item-accumulation effect, in which signal increased monotonically with the number of items presented during the trial, despite the insensitivity of behavioral measures to this factor. Behavioral and fMRI correlates of PI extended previous results and rejected an alternative explanation of PI effects in working memory.

Object and spatial alternation tasks with minimal delays activate the right anterior hippocampus proper in humans.

Substantial evidence indicates that the hippocampus plays a critical role in long-term declarative memory. In contrast, the role of the human hippocampus in working memory, particularly when information needs to be maintained only for a few seconds, remains controversial. Using PET, we show robust activation of the right anterior hippocampus proper during the performance of both object and spatial alternation tasks. Hippocampal activation emerged even though subjects only had to remember a single, simple stimulus over a minimum delay of 1 s. No hippocampal activation occurred when the delay was increased to 5 s. This suggests that the role of the hippocampus in working memory is not to maintain information across a delay interval. Instead, its activity reflects a more transient function during encoding and/or retrieval. These data are among the first observations to demonstrate human hippocampal involvement in working memory.

Organization of working memory within the human prefrontal cortex: a PET study of self-ordered object working memory.

The prefrontal cortex plays a critical role in working memory, the active maintenance of information for brief periods of time for guiding future motor and cognitive processes. Two competing models have emerged to account for the growing human and non-human primate literature examining the functional neuroanatomy of working memory. One theory holds that the lateral frontal cortex plays a domain-specific role in working memory with the dorsolateral and ventrolateral cortical regions supporting working memory for spatial and non-spatial material, respectively. Alternatively, the lateral frontal cortex may play a process-specific role with the more dorsal regions becoming recruited whenever active manipulation or monitoring of information in working memory becomes necessary. Many working memory tasks do not allow for direct tests of these competing models. The present study used a novel self-ordered working memory task and positron emission tomography to identify whether dorsal or ventral lateral cortical areas are recruited during a working memory task that required extensive monitoring of non-spatial information held within working memory. We observed increased blood flow in the right dorsolateral, but not ventrolateral, prefrontal cortex. Increases in blood flow in the dorsolateral region correlated strongly with task performance. Thus, the results support the process-specific hypothesis.

Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task.

OBJECTIVE: The evidence for verbal working memory deficits in schizophrenia has been inconsistent. Few studies have evaluated verbal working memory in the first-degree relatives of schizophrenia patients, who likely share the genetic diathesis for schizophrenia but not the potential confounds associated with chronic mental illness. METHOD: The Wechsler Digit Span Task was used to investigate verbal working memory in 52 schizophrenia patients, 56 of their first-degree relatives, and 73 nonpsychiatric comparison subjects. RESULTS: The nonpsychotic relatives showed no impairment on the forward digit span task, a measure of general attention, but did show impairment on the backward digit span task, a measure of verbal working memory. Schizophrenia patients showed impairment on both the forward and backward digit span tasks. CONCLUSIONS: These results indicate that the forward and backward digit span tasks tap different cognitive abilities that are differentially associated with the diathesis for schizophrenia. Working memory deficits associated with schizophrenia appear to be generalized and not limited to the spatial modality.

Acoustic startle reflex in schizophrenia patients and their first-degree relatives: evidence of normal emotional modulation.

We investigated emotional disturbances in 36 schizophrenia patients, 48 of their first-degree relatives, and 56 controls to determine if abnormal affective startle modulation could be associated with genetic risk for schizophrenia. Both patients and relatives had a pattern of startle modulation indistinguishable from controls, with potentiated startle amplitude while viewing negative valence slides and attenuation while viewing positive slides. Patients with flat affect did not differ from those without in startle modulation or slide ratings. The patients and their relatives had lower pleasantness ratings of positive slides and the patients had higher pleasantness ratings of the negative slides than controls. The startle paradigm may not be useful for identifying individuals with a genetic liability for schizophrenia. The results suggest that low-level defensive and appetitive behaviors are unaffected in schizophrenia.

Neuropsychological and oculomotor correlates of spatial working memory performance in schizophrenia patients and controls.

Recent reports of spatial working memory deficits in schizophrenia provide evidence for dorsolateral prefrontal cortical (DLPFC) dysfunction. However, the question of how spatial working memory performance relates to other task impairments in schizophrenia considered reflective of frontal dysfunction, such as the Wisconsin Card Sorting Test (WCST) and smooth pursuit eye tracking, has been largely unexplored. Spatial working memory, as measured by a computerized visual-manual delayed response task (DRT), was evaluated in 42 schizophrenia patients and 54 normal controls. Subjects also completed a battery of neuropsychological and oculomotor tasks. Schizophrenia patients performed as accurately as controls on a no-delay, sensory-motor control condition, but showed a significant impairment in spatial accuracy with the addition of an 8-s delay and verbal distraction task. For the patients, working memory impairment was associated with fewer categories on the WCST, impaired eye tracking, fewer words learned on the Rey Auditory Verbal Learning Test, but not with measures of general cognitive and clinical functioning. Results suggest the presence of a sub-group of schizophrenia patients with common pathophysiology that accounts for the co-variance of several tasks implicating prefrontal dysfunction.

Relationship between nailfold plexus visibility and clinical, neuropsychological, and brain structural measures in schizophrenia.

BACKGROUND: Although all published studies investigating the association between nailfold plexus visibility and schizophrenia have found the subpapillary plexus (the vascular network into which capillaries drain) to be unusually visible in many schizophrenia patients, little else is known about this putative marker for schizophrenia liability. METHODS: Plexus visibility was rated in 63 chronic schizophrenia, 67 first-episode schizophrenia, 9 schizophreniform, and 66 unipolar and bipolar depressed patients, all with psychosis, and 119 nonpsychiatric controls. Smooth-pursuit eye tracking, clinical features, neuropsychological performance, and lateral ventricle size were assessed. RESULTS: Approximately 21% of chronic schizophrenia, 22% of first-episode schizophrenia, and 22% of schizophreniform patients had highly visible plexus compared to only 8% of unipolar, bipolar, and nonpsychiatric controls. Schizophrenia patients with visible plexus had worse oculomotor performance. Additionally, chronic schizophrenia patients with visible plexus had more negative symptoms, worse course, more severe illness, worse occupational functioning, and worse neuropsychological performance on tasks thought to be sensitive to frontal dysfunction. An inverse relationship between plexus visibility and lateral ventricle size was found. CONCLUSIONS: This study provides evidence that schizophrenia patients with plexus visibility are characterized by oculomotor dysfunction, negative symptoms, severe symptomatology, chronic course, neuropsychological dysfunction, and an absence of enlarged ventricles.

Mutagenesis of the a subunit of the F1F0-ATP synthase from Escherichia coli in the region of Asn-192.

Site-directed cassette mutagenesis was used to generate a series of amino acid substitutions in the a subunit of the Escherichia coli F1F0-ATP synthase. The following substitutions for Asn-192 were analyzed and shown to inhibit partially the ATP-dependent proton translocation without disrupting F1-F0 interactions: Leu, Val, Pro, Ser, Thr, and Arg. A group of multiple substitutions at residues Gln-181, Asn-184, and His-185 had no significant effect on ATP synthase function, as judged by growth yields, or by assays of ATP-dependent proton translocation, indicating that this region of the a subunit is not involved in function. Three double mutants were constructed in order to assess the independence of residues Asn-192, Glu-196, and Asn-214. Results of proton translocation assays of membranes from cells containing these double mutations are consistent with the interpretation that each of these residues is involved with proton movement, and that residues Asn-192 and Glu-196 may be coupled. Finally, the relationship between the mechanism of proton translocation by the E. coli ATP synthase and the chloroplast enzyme was probed by constructing variants of the E. coli a subunit containing several features of homologous chloroplast proteins. It was determined that these chloroplast features, in the region of Glu-196 of the E. coli a subunit,, were detrimental to ATP synthase function.