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By L. Lee. Rhode Island School of Design.

MRISIM has been used in validation stud- parameter linear [three rotation discount apcalis sx 20mg fast delivery erectile dysfunction overweight, three translation buy apcalis sx no prescription erectile dysfunction doctor kolkata, three ies for correction of MRI intensity nonuniformity (67) and scale discount 20mg apcalis sx free shipping erectile dysfunction treatment costs, (15)] transformation to match the image volume to tissue classification (84) purchase apcalis sx with american express erectile dysfunction ayurvedic drugs in india. It has been used to create a database a master data set already resident in stereotaxic space. The of 108 simulate MRI images [3 slice thicknesses 3 tissue master data set therefore defines the gross dimensions and contrasts (T1/T2/PD) 3 noise levels 4 levels of radio- orientation of stereotaxic space. MRI image before (left) and after (mid- dle) correction for nonuniformity field (right), estimated using N3. Note the increased uniformity of white matter regions. The algo- 305 normal subjects, sampled on a 1-mm voxel grid (24), rithm operates upon multispectral (typically T1-, T2-, PD- as that master data set. In a series of preprocessing steps, each ICBM305, has been circulated to over 100 international MRI data set is corrected for intensity nonuniformity (67), sites and defines the stereotaxic space for the SPM statistical interslice normalization, and intersubject intensity normal- package. That data set was derived from T1-weighted data ization (Fig. Stereotaxic transformation is then per- with 2-mm-thick slice data. An artificial neural network (ANN) classifier superseded by a composite data set derived from 1-mm- with one hidden layer is used to assign each voxel to a tissue thick data collected within the ICBM project (see below). The algorithm also employs tissue likelihood, based more anatomic detail than the original ICBM305, was on the spatial location of the voxel in stereotaxic space, as nevertheless mapped into the space of the ICBM305 using orthogonal prior information to constrain the feature-space the nine-parameter MRITOTAL and is therefore a deriva- assignment. For example, periorbital fat exhibits a similar tive of that first data set. Spatial masks expressing the normal distribution of tissue Tissue Classification—INSECT classes in the population (see Fig. Classification withand without correction for intensity nonuniformity: tissue classi- fication withINSECT withand without correction for nonuniformity using N3. An idealized 3D digital phantom was created from by segmentation of a high–signal-to-noise ratio (SNR) data set (17, 37). The initial phantom data (top left) contains three classes: cerebrospinal fluid (CSF) (black), gray matter (dark gray), and white matter (light gray). This phantom was used to generate a simulated MRI image with(top middle) and without (top right) a 20% inhomogeneity running fromtoplefttobottomrightofthe image. TheINSECT-classifiedimagewithoutpriorN3correction (bottom left) exhibits artifactually thicker cortex at bottom right and thinner cortex at top left of the image, respectively, a consequence of the field inhomogeneity gradient. This artifact is removed in the N3-corrected classification (bottom right). Anatomic labels are defined in the new volume by interpolation from the original labels, via the spatial mapping of the 3D deformation field. Originally, ANIMAL used 3D gradient magnitude as the image prop- erty to be matched. The ridge-tracking Lvv operator is now used to extract additional topologic information on brain shape in each image. Furthermore, the surface trace of major sulci, represented as 3D line segments, can be used as local constraints on image deformation (14,16). The left image was warped to matchthe right, with crease the correspondence of cortical anatomy across brains. Cortical Surface Segmentation and Unfolding—ASP We have previously developed a fully automated procedure ation. INSECT operates on an arbitrary number of input for unfolding the entire human cortex, using an algorithm images and generates a user-selected number of output tissue that automatically fits a 3D mesh model to the cortical maps. This algorithm, MSD, uses an iterative minimization of a cost function that bal- ances the distance of the deforming surface from (a) the Regional Parcellation—ANIMAL target surface, and (b) the previous iteration surface (Fig. Manual labeling of brain voxels is both time-consuming 24. Specification of the relative weight of these compet- and subjective. We have previously developed an automated ing forces allows MSD to range from unconstrained (data- algorithm to perform this labeling in 3D (13). The ANI- driven) deformation to tightly constrained (model-preserv- MAL algorithm (Automated Nonlinear Image Matching ing) deformation. Further shape-preserving constraints to and Anatomical Labeling), deforms one MRI volume to penalize excessive local stretching and bending of the model match another, previously labeled, MRI volume. The initial mesh surface can be up the 3D nonlinear deformation field in a piecewise linear chosen arbitrarily to be a simple geometric object, such as fashion, fitting cubical neighborhoods in sequence using a a sphere, an ellipsoid, or two independently fitted hemi- mutual information residual for parameter optimization spheres. The MSD algorithm has formed the basis of corti- (Fig. The algorithm is applied iteratively in a mul- cal analysis at both MNI and UCLA within the ICBM tiscale hierarchy. At each step, image volumes are convolved project (71–73). Recently, the algorithm has been extended with a 3D gaussian blurring kernel of successively smaller to allow multiple concentric surfaces to be mapped simul- width [32-, 16-, 8-, 4-, and 2-mm full-width at half-maxi- taneously. The new algorithm, Automatic Segmentation FIGURE 24. Note the promi- nence of the major gyral and sulcal features common to all brains. Since ASP iteratively de- A boundary search along the normal local surface is used forms a starting 3D polygonal mesh onto the 3D cortical to increase the range of attraction of edges. Individual anatomic features such as gyral secting surface configurations. Automatic identification of the total cerebral cortical sur- face from MR images is achieved in a robust way with Sulcal Extraction and Labeling—SEAL respect to partial volume effects. A preliminary map of cortical gray matter thickness has We have implemented an automated sulcal extraction and been produced and related to previous studies. At every voxel on the ASP- A higher resolution average brain surface has been created generated exterior cortical isosurface, SEAL calculates the using the deeper sulcal penetration of ASP compared to two principal curvatures: k1, the mean curvature, and k2, earlier versions of this algorithm (47). Mean cortical thickness in 150 normal adult brains, color-coded and texture-mapped onto the average cortical surface obtained from the same population. Use of spatial priors for automatic sulcus labeling within the sulcal extraction and labeling algorithm (SEAL). Differ- ent colors represent different sulcal labels, e. The automated and manual labeling of the sulci are in broad agreement, although some differences are apparent. We have de- at each voxel), termed a statistical probability anatomy map fined a relational graph structure that stores, for each sulcus, (SPAM), can be constructed and used to test for group its length, depth, and orientation, as well as attributes, e. Sulcal For visualization purposes, these statistical maps can the labeling is performed semiautomatically by tagging a sulcal thresholded at any level of structural probability to create trace in the 3D graph and selecting from a menu of candi- probability isosurfaces suitable for surface-rendering and 3D date labels. The menu is restricted to most likely candidates display. Example SPAMs are shown for (a) gray/white/CSF by the use of sulcal probabilistic maps. SAMPLE APPLICATIONS Multicenter Clinical Trial Image Analysis ICBM: Multicenter Consortium on The principles of pipeline analysis described above for large Statistical Neuroanatomy databases of normal brain MRI data are equally applicable The International Consortium for Brain Mapping (ICBM) for population analysis of neuropathology or for tracking multicenter initiative was launched in 1993 as part of the structural change over time, such as the progressive tissue Human Brain Project (52). Its overall goal is to create a 3D atrophy, which occurs in some degenerative diseases. In- probabilistic brain atlas, based on MRI volumes from 450 deed, the MRI analysis employed within the ICBM project normal adult brains. Within the ICBM project, all scans was originally developed for a multicenter phase III clinical at all sites were collected with a strictly defined protocol, trial of a new pharmaceutical for treatment of multiple scle- specifying three MRI volumes per subject (a 1-mm-thick, rosis. This database as been seg- collection was coordinated by the BIC clinical trials group, mented using the pipeline environment described above and which performed quality control before trial launch and for the variability captured in the form of probability maps all data shipped to the BIC for processing. Neuroanatomic variability can be conveniently of the database was used to generate 3D statistical maps of represented in the form of 3D stereotaxic maps where each normal tissues and of MS lesions. In validation studies, the 24: Automated 3D Analysis of Large Brain MRI Databases 309 FIGURE 24. Left: Cuts through INSECT-generated 3D tissue class maps for gray matter, white matter, and cerebrospinal fluid (CSF). Right: Serial sagittal sections through Talairachatlas withANIMAL-generated probabilistic frontal cortex SPAM (statistical probability anatomy map) overlaid. In bothcases 100 subjects were used to generate the SPAMs. Tests of drug effect manual methods at seven established MRI/MS sites in Eu- are reduced to testing for a significant group difference in rope and North America. The results of the comparison the overall volume of this distribution above a given thresh- indicated no significant differences between the BIC ap- old when partitioned into drug and placebo groups. They also indicate considerable variability among the sites themselves when analyzing the same data, which emphasizes NIMH Intramural Pediatric Database the importance of the reproducibility of results obtained with a fully automated approach. Jay Giedd and After correction for MRI intensity inhomogeneity, in- Judy Rapoport at the National Institute of Mental Health terslice and intervolume intensity normalization, and stereo- (NIMH) Child Psychiatry Branch, the BIC image analysis taxic transformation, the multispectral data were tissue clas- pipeline has been used to process a large pediatric MRI sified to identify MS lesion voxels for each patient time database collected at the NIMH. Approximately 1,800 T1-weighted images with shows the most likely locations for MS lesions within a slice thickness of 1. Volume rendering (top left) and surface ren- derings (all others) of the 3D probabilistic atlas (N 100). For the surface renderings, the SPAMs were thresholded at the 40% level to generate regional probability isosurfaces. Serial scanning in children aged 3 to 15 years across time spans of up to 4 years revealed a rostrocaudal wave of growth in the corpus callosum, a fiber system that relays information between brain hemi- spheres (Fig.

This compound is is absorbed quantitatively at a medium rate from the gastro- extremely useful in subjects with severe sleepiness who need intestinal tract order genuine apcalis sx on line erectile dysfunction bipolar medication, and the peak blood concentration is reached high doses order discount apcalis sx online erectile dysfunction treatment in india. The addition of a methyl group makes this deriv- after 2 to 4hours buy discount apcalis sx 20 mg on line erectile dysfunction relationship. The wide- spread misuse of methamphetamine has led to severe legal Modafinil and Other Wake-Promoting restriction on its manufacture buy apcalis sx 20mg lowest price erectile dysfunction medicines, sale, and prescription in Agents many countries (112), but it is available in the United States. It should also be noted that the molecular weight Modafinil, a compound structurally distinct from ampheta- of the most commonly used form of methamphetamine mines, has recently been approved in the United States for (hydrochloride) is about half that of d- and l-amphetamine the treatment of narcolepsy and essential hypersomnia. Methamphetamine preparations thus contain compound is also increasingly explored to treat other condi- twice as many active amphetamine molecules when com- tions, such as residual sleepiness in treated obstructive sleep 1912 Neuropsychopharmacology: The Fifth Generation of Progress apnea or fatigue in multiple sclerosis. Third, data obtained to date available in France since 1986, and long-term follow-up suggest that tolerance and dependence are limited with this suggests no remarkable side-effect profile and low abuse compound (15), although a recent animal study reports a potential. Clinical trials in France and Canada have shown cocaine-like discriminative stimulus and reinforcing effects that 100 to 300 mg of modafinil is effective for improving of modafinil in rats and monkeys, respectively (42). Finally, daytime sleepiness in narcoleptic and hypersomnolent sub- clinical studies suggest that the alerting effect of modafinil jects without interfering with nocturnal sleep. In general, patients feel less irritable sleep (15,19,21). Recent double-blind trials on 283 narco- and/or agitated with modafinil than the amphetamines (15). However, it is also reported that patients who have abuse potential, lower levels of tolerance, and less rebound been previously treated with methylphenidate may respond sleep), modafinil may replace amphetamine-like stimulants more poorly to modafinil (26). Modafinil is well tolerated as a first-line treatment for excessive daytime sleepiness. In humans, and widely consumed stimulant in the world. The average modafinil exhibits a linear pharmacokinetic profile for doses cup of coffee contains about 50 to 150 mg of caffeine. Tea ranging from 50 to 400 mg, with a terminal elimination (25 to 90 mg/5 oz), cola drinks (35 to 55 mg/12 oz), choco- half-life (t1/2) of 9 to 14hours (159). Modafinil is exten- late (15 to 30 mg/1 oz), and cocoa (2 to 20 mg/5 oz) also sively metabolized to two major pharmacologically inactive contain significant amounts of caffeine. Taken orally, caf- metabolites, modafinil acid and modafinil sulfone, which feine is rapidly absorbed, taking 47 minutes to reach maxi- are renally excreted. Less than 10% of the oral dose of mo- mum plasma concentration. The half-life of caffeine is about dafinil is excreted unchanged, and 40% to 60% is excreted 3. A slow-release soft gelatin caffeine as unconjugated acid in urine (159). Fatigue is reduced, and the need for sleep is delayed interacts with the dopaminergic system at high doses and (121). Recent pertension, and increased secretion of gastric acid and in- work by our group rather suggests that selective, but low- creased urine output (121). Heavy consumption (12 or potency, dopamine reuptake inhibition mediates the wake- more cups a day, or 1. In rats, modafinil anxiety, tremors, rapid breathing, and insomnia (121). This contrasts with the intense re- neuronal inhibition (121). Considering the fact that 100 covery sleep seen after amphetamine administration (34). Nevertheless, caf- netics profile of the compound (modafinil has a significantly feine in the form of tablets can be bought without a prescrip- longer half-life than amphetamine or methylphenidate) tion (NoDoz, 100 mg caffeine; Vivarin, 200 mg caffeine), (159). Alternatively, this important difference may be owing and is used by many patients with narcolepsy prior to diag- to its unique pharmacodynamic profile, for example, dopa- nosis. Antidepressants and the Pharmacologic Several factors make modafinil an attractive alternative Treatment of Cataplexy to amphetamine-like stimulants. First, animal studies sug- gest that the compound does not affect blood pressure as Amphetamine stimulants have little effect on cataplexy, and much as amphetamines do (50) (potentially the result of its additional compounds are most often needed to control lack of effects on adrenergic release or reuptake). This sug- cataplexy if the symptom is severe enough to warrant treat- gests that modafinil might be useful for patients with a ment. Since the 1960s, it has been known that imipramine heart condition or high blood pressure. Second, animal data is very effective in reducing cataplexy (2). Desipramine 25–200 mg Effects and side effects similar to those of imipramine demethylated metabolite of imipramine (51). Protryptiline 5–60 mg Some reports suggest improvement in vigilance measures (49), whereas other reports are negative (no improvement in performance or daytime sleepiness) (93). Clomipramine 10–150 mg Digestive problem, dry mouth, sweating, tiredness, impotence (45,140). Its active metabolite, desmethylclomipramine, is shown to be more potent in the canine model (97). Fluoxetinea 20–60 mg Nausea, dry mouth, fewer side effects, long half-life (60 hours); no anticholinergic or antihistaminergic effects; good anticataplectic effect but less potent than clomipramine (63). Some clinical trials, but less commonly used Zimelidinea 100 mg Less sedative effect; no anticholinergic or antihistaminergic effects; potent anticataplectic compound (94). Its active metabolite, norzimelidine, is shown to be more potent than zimelidine in the canine model (97). Femoxitinea 600 mg Fewer side effects than clomipramine but less potent (136) pharmacologic effects similar to fluoxetine. Fluvoxaminea 50–300 mg Gastrointestinal side effects (134). No active metabolities; pharmacologic profile similar to fluoxetine; less active than clomipramine. Paroxetinea 20–60 mg Less anticholinergic effects; cardiovascular side effects; effective on cataplexy (with yohimbine) (119). Viloxazine 100–300 mg Few side effects; selective but low potency adrenergic uptake inhibitor, active on human cataplexy and possibly sleepiness, but not available in most countries (40,43); effective anticataplectic agent in canines (85). Venlafaxine 150–375 mg New serotonergic and adrenergic uptake blocker; no anticholinergic effects, effective on cataplexy sleepiness in a small pilot study (146), low potency. Other antidepressant compounds sants is their ability to inhibit the reuptake of norepineph- of the tricyclic family have also been used with some success rine (and epinephrine) and serotonin (14). The use of tricyclic antidepressants in the uptake inhibition of norepinephrine and serotonin is quite treatment of cataplexy, however, is hampered by a number variable depending on the compound and the existence of of problems. The first is the relatively poor side-effect profile active metabolites (mostly active on adrenergic uptake) (14). These are mostly owing to Additionally, some tricyclic compounds, such as protripty- their anticholinergic properties, leading to dry mouth (and line, are also weak dopamine reuptake inhibitors (14). Additional serotonergic uptake inhibition properties (e. In this respect, protriptyline is often preferred be- clinicians have been less impressed with the potency of the cause of its previously reported mild stimulant effect (49). This ex- Nighttime sleep might also become more disturbed because perience parallels experiments in canine narcolepsy suggest- of increased muscle tone and leg movements (122,152). The compound is especially useful in patients ble alternative to tricyclic compounds (63). Fluoxetine has with severe insomnia and cataplexy who do not tolerate a good side-effect profile and may induce less weight gain, well the side effects of antidepressant medication on sexual a significant advantage for some patients. Mono- The elimination half-life is 20 minutes (111,157). However, because of the short half-life of the com- available (104). Overdoses (a single dose of 60 to 100 mg/ Hypnagogic Hallucinations kg) induce dizziness, nausea, vomiting, confusion, agitation, The treatment of these two symptoms is not well codified. Sleep paralysis only rarely requires treatment, but ceptors may interplay functionally (71). Sev- cologically dissect the mechanisms involved in the control eral studies reported that benzodiazepine hypnotics are of cataplexy and alertness. Activation of for consolidating nighttime sleep, an effect that leads to cholinergic systems using the acetylcholinesterase inhibitor decreased sleepiness and cataplexy the following day (24, physostigmine, for example, greatly exacerbates cataplexy 25,137,138). All therapeutic agents currently used to absolutely no effect on cataplexy (85). Using newer uptake inhibi- for the management of sleepiness in narcolepsy presynapti- tors and releasing agents with selective monoamine effects, cally enhance monoaminergic transmission; however, these we have demonstrated that the presynaptic activation of compounds also lack pharmacologic specificity. In order to adrenergic, but not dopaminergic or serotonergic, systems study the mode of action of these compounds on daytime mediates the anticataplectic effects of currently available an- sleepiness, the stimulant properties of several dopaminergic tidepressive treatments (85,97). Interestingly, presynaptic 6-hour daytime polygraphic recordings in the canine narco- activation of dopamine transmission with dopamine uptake lepsy model (103). In spite of their lack of effects on cata- inhibitors had potent alerting effects (103) but no effect on plexy, all dopaminergic uptake inhibitors induced signifi- cataplexy (85). These results are consistent with the gics, and adenosinergics) have been studied in the narcolep- hypothesis that presynaptic modulation of dopamine me- tic canine model. The stimulation of muscarinic M2 Midbrain Dopaminergic Systems Are (non-M1) receptors significantly aggravates cataplexy. Involved in the Regulation of Cataplexy Among monoaminergic receptors, the postsynaptic adrener- and Excessive Daytime Sleepiness in gic 1b receptors (79,99) and presynaptic 2 receptors Narcolepsy (100) were also found to aggravate cataplexy, a result consis- tent with a primary adrenergic control of cataplexy. It was The site of action for dopaminergic modulation of cataplexy also found that dopamine D2(3) agonists significantly ag- recently has been identified using microdialysis experi- gravated cataplexy and induced drowsiness in these animals. D2(3) agonist injections into the ventral tegmental To date, no other receptor ligands (e.

The researchers drew on a semistandard interview schedule comprising semistructured interview questions generic apcalis sx 20 mg with mastercard impotence drugs for men. These had to be adapted to the varying situations including purchase discount apcalis sx online erectile dysfunction treatment in lahore, for example purchase apcalis sx 20mg overnight delivery erectile dysfunction treatment in bangalore, the subject of the service redesign under scrutiny and the role and vantage point of the interviewee buy generic apcalis sx line impotence drug. The semistructured interview schedule was adapted accordingly. Appendix 4 shows a typical example of one such interview guideline. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 15 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. PROJECT DESIGN AND METHODOLOGY Case study data analysis As mentioned, members of the research team worked in pairs for each main case study. These subteams undertook the first stage of each data analysis process. In this way a coherent narrative of the flow of events within each case could be constructed. This was combined with a descriptive account of the issues and challenges encountered by the actors involved. These first-level reports used a common framework: (1) context, (2) focus and narrative of the case, (3) clinical leadership themes emerging and (4) emerging ideas for cross-case comparisons. The first three sections of these initial draft reports were fed back to informants in the case studies concerned, as a way of validating the accuracy of the data collected and the descriptive interpretations made. Next, the first-level case reports were discussed, in turn, at a monthly series of research team meetings. From these discussions emerged ideas for explanatory concepts that could be applied to understand differences and similarities in the nature of clinical leadership across the cases. This process of discussion, conceptualisation and comparison between the cases led to the development of the conceptual framework for analysing the cases set out at the beginning of Chapter 4. This second-level analysis was carried out by two members of the research team, who were also the main authors of this report. That analysis brings together the descriptive summary of events with an explanatory analysis of the forms of clinical leadership and their relationship to the achievements and difficulties encountered in bringing about service innovation. The analyses are compared and discussed further in Chapter 5. TABLE 2 Interviews for the case studies Interviewee role Number of interviews GP chairpersons, clinical leads, other GPs 65 CCG accountable officers and other managers 36 Nurses 8 Lay members 7 Acute sector doctors and managers, mental health 25 Community health managers and nurses 10 NHSE, CQC, NHS Improvement, CSU and other agencies 10 LA representatives, councillors, chief executives and directors, public health 9 Voluntary sector 9 GP practice managers 7 Patient representatives 8 Ambulance service, paramedics 8 Total 202 16 NIHR Journals Library www. First, the responses to each of the questions were gathered together and the results presented as tables and charts. Second, a number of cross-tabulations were made in order to investigate whether or not occupants of different roles answered questions in particular ways. Third, comparisons were made between our data and the ratings of CCGs made separately by NHSE. These correlations produced some very interesting findings. A notable feature of the completed questionnaires were the free-form questions. As a result of the careful preparation of the questionnaires in conjunction with a range of informants from the scoping phase, respondents readily recognised the relevance of the issues being raised and were very keen to share their thoughts. In the next chapter, the statistical results stemming from the structured questions are presented and analysed along with the free-text responses. Public and patient involvement We sought to involve the public and patients as far as was feasible, relevant and practicable at all stages. In the first instance, a nationally renowned patient and public involvement (PPI) representative with very extensive experience of PPI was appointed as co-chairperson of the Project Steering Committee. This representative was involved in all aspects of the research from the initial design, the oversight of research instrument construction and the review of findings at all stages, to the discussions about the dissemination of findings. During the course of the project, PPI was used mainly in relation to the specific service redesign initiatives that were the focal component of this study. These initiatives often had PPI arrangements in place and we tapped into these rather than seek to set-up new arrangements. One extension of this approach was that a member of the project team sought permission to become an active participant member of a PPI group that was associated with one of the service redesign initiatives in the core case studies. Full ethics approval from the Research Ethics Committee overseeing the project was sought and full disclosure was made to members of the PPI group. Another dimension was that in the surveys and the case studies we took steps to find out how patients and the public had been involved in the redesign of services. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 17 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. The populations targeted were the members of the governing boards of all CCGs. This included chairpersons, accountable officers, finance directors, GP members (often these were clinical leads of particular service areas), other clinicians such as nurses and the secondary care doctor representatives, directors of public health and lay members. The first survey gleaned 385 usable responses and these represented 12. For the second survey there were 380 responses, which represented 12. The 18- to 19-month interval between the two surveys was designed to allow tracking of unfolding events in a time series and the possible maturation (or decline) of the CCGs. The questionnaires in both phases contained many shared themes, but the 2016 questionnaire included additional questions which were derived from the case study work that had taken place during the intervening period. Patterns of responses were also correlated with a separate data set: the ratings allocated to CCGs by NHSE for 2015/16. In comparing our survey results with the NHSE data, we used the headline rating. We considered using the component ratings that were most relevant to our study (i. However, we found such high correlations between these components and the headline rating that, in practice, the headline rating proved to be sufficient. A number of core issues were investigated in both phases. This was assessed relative to other bodies such as NHSE, NHS Improvement and the CQC. In other words, the initial objective was to understand how important and influential the CCGs were in the wider scheme of the NHS. A second continuing theme was the relative influence of clinicians – most especially GPs – within the CCGs. This aspect was central to the project aim: do the CCGs in practice provide a platform for the meaningful exercise of clinical leadership? A third core question area was an examination of the nature of the contribution made by clinical leaders. Other more subsidiary questions covered in both surveys were: the degree of wider GP engagement; training and development offered to GP members of CCG boards; conflicts of interest; and assessments about the future role of CCGs. The questionnaire was a combination of structured questions and a set of more open-ended questions with space for free-form answers. There was a very high response to the free-form questions – with 96% of respondents taking time to write in these sections. This was a strong indication of the extent to which respondents were engaged with the questionnaire and found it relevant and interesting. The respondents were keen to express their views and many did so with passion. Copies of the questionnaire can be found in Appendix 3. The profile of respondents As can be seen from Figure 1, responses were received from all role categories with the numbers broadly reflecting the relative numbers sitting in these boards. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 19 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. FINDINGS FROM THE NATIONAL SURVEYS 30 25 20 Year 2014 15 2016 10 5 0 FIGURE 1 Roles of respondents. The first thematic question examined was the perceived influence of CCGs. We wanted to understand what respondents thought was the scope to make a difference through these institutions. Perceived influence of Clinical Commissioning Groups The first main substantive question asked about the perceived influence of CCGs relative to other NHS organisations. The reason for asking about this was that the overall research question was essentially about the scope for leadership influence using CCGs as an institutional platform. We asked board members to make a comparison of the perceived influence of their CCG relative to other bodies such as NHSE and NHS trusts. The form of the question asked for a rank ordering of the bodies most influential in shaping local health services. Half of the respondents judged that their CCG was the most influential in this regard, and NHSE was ranked second. However, nearly half of the respondents did not rate their own CCG as the most influential. NHSE was seen as the next most influential institution in shaping service redesign and the growing importance of collaboration between CCGs is also indicated.

Hippocampal formation: the newspaper and the advertising pamphlet cheap 20 mg apcalis sx visa erectile dysfunction operations. The name hippocampus comes from the similarity in cross section to a sea horse cheap 20 mg apcalis sx fast delivery erectile dysfunction pills cost. Greek: hippos = horse (the hippocampus is not to be confused with the hippopotamus 20 mg apcalis sx visa erectile dysfunction treatment bodybuilding, the “horse of the river”) buy generic apcalis sx 20 mg erectile dysfunction medications for sale. The hippocampal formation lies in the temporal lobe, immediately below (indenting the floor of) the inferior horn of the lateral ventricle. Therefore, looking at the medial aspect of the temporal lobe, not much of the hippocampal formation can be seen. On this aspect, the parahippocampal gyrus is the dominant feature (that is, the cortex overlying the hippocampus). The part of the parahippocampal gyrus closest to the hippocampal formation is called the entorhinal cortex. The hippocampal formation (composed of the dentate gyrus, hippocampus proper and subiculum) in cross-section (coronal) pushing up into the floor of the inferior horn of the lateral ventricle (in the temporal lobe). On an histological basis this structure has been divided into 4 regions: (cornus ammonis) CA1 to CA4 (see numbers 1 to 4 in the illustration). Then comes the subclinium, which is continuous with the entorhinal cortex. Both of these tracts have ingoing and outgoing pathways (afferent and efferent), but the perforant pathway is predominantly afferent, and the fornix is predominantly efferent. The perforant pathway is largely within the parahippocampal gyrus and cannot be seen from the outside. The fornix is a more prominent structure, which will be described in greater detail shortly. It is mentioned here because it can be seen on the medial surface of the temporal lobe, and appears in cross section illustrations. The major route of information flow through the hippocampal formation. Information passes in both directions, but the predominant direction is as shown, and can be considered as four steps: Step 1, fibres in the perforant pathway enter via the entorhinal cortex and end in the dentate gyrus; Step 2, fibres passing from the dentate gyrus to the hippocampus proper; Step 3, fibres passing from the hippocampus proper to the subiculum (the illustration is oversimplified at this point, as there is usually at least some connection between different parts of the hippocampus proper before fibres pass to the entorhinal cortex); Step 4, fibres passing from the subiculum through the hippocampal formation to reach the fornix. The circuitry of the hippocampal formation makes it well suited to memory function, but also makes it vulnerable to damage. One neuron from the dentate gyrus connects with about 12 neurons in the hippocampus proper, each of which then communicates (via axon collaterals) with about 50 excitatory and about 25 inhibitory hippocampus proper cells. Thus, there is potentially a 60 000 % amplification of excitation, and 30 000 % amplification of inhibition. This also makes it well suited to memory function, and may offer the potential for repair. Two main mechanisms are reported: dendritic remodelling and neurogenesis. Dendritic remodelling includes dendritic retraction and simplification during stressful experiences (Sousa et al, 2000). Interestingly, in hibernating animals, dendritic Pridmore S. Neurogenesis, until recently, has been thought to be limited to intrauterine life. However, evidence now indicates that new neurons are born in the dentate nucleus throughout life. In animal studies, stress has been shown to stimulate dendritic remodelling (Popov et al, 1992) and suppress neurogenesis (Gould et al, 1997). Three are of particular interest: the “strengthening” of synapses (Shashoua, 1985), synaptogenesis (the formation of new synapses), and dendritic pruning. In strengthening of synapses, the microscopic structures becomes darker and thicker, and function more efficiently (transmit signals more readily). Synaptogenesis is usually accompanied by some sprouting of dendrites. These changes are associated with learning, and presumably, psychotherapy. Dendritic pruning (which continues during early adulthood) is the removal of dendrites which are superfluous and may actually be making the organism less efficient. This form of pruning is a normal process, and is probably distinct from the dendritic remodelling arising from stress. One theory of the aetiology of schizophrenia proposes excessive pruning leading to that disorder. Damage to both hippocampi results in failure to lay down new memories (anterograde amnesia), but old memories are retained (presumably old memories are stored elsewhere, probably the cortical association areas). Difficulty with laying down new memories is observed with bilateral damage: chronic temporal lobe epilepsy, surgical resection and trauma. It is seen as a temporary phenomenon with bilateral electroconvulsive therapy (ECT; an electrical treatment of severe depression). While temporary, post-ECT amnesia can be distressing, unilateral ECT (applying energy to one side of the head only) is not associated with the same degree of memory disturbance, and is the preferred method (depending on various clinical factors). Studies have demonstrated reduced declarative memory in PTSD (Brewin, 2001); this is consistent with hippocampal damage. Recent work has found that major depressive disorder (but not bipolar depression) is associated with smaller hippocampi (Kempton, et al, 2011). Fornix The fornix is a white matter structure with carries information from and to (predominantly from) the hippocampal formation. A crus (leg) of fornix emerges from each hippocampal formation posteriorly and arches forward and toward the midline. These legs join to form a single midline structure (body of the fornix) which is attached to the septum pellucidum (a thin vertical membrane which separates the lateral ventricles) on the roof of the third ventricle. The body continues forward and divides into left and right columns, which pass through the hypothalamus to enter the mamillary bodies. The fornix sends fibres to the septal area, thalamus and hypothalamus. Psychiatric disorders do not appear to be associated with isolated fornix pathology, however, one diffusion tensor imaging (DTI) study suggests fornix pathology is associated with anorexia nervosa (Kazlouski et al, 2011), and increasingly, schizophrenia is being associated with widespread white matter abnormalities, including the fornix (Lee et al, 2013). A post-mortem study suggests the mammillary bodies are compromised in depression (Bernstein et al, 2012). The hippocampal formation is immediately beneath the floor of the inferior horn of the lateral ventricle, and the body of the fornix is shown at the bottom of the septum pellucidum, which separates the lateral ventricles. Papez Circuit In 1937, James Papez described a neural loop which could theoretically allow the coordination of the neocortex, limbic structures and the hypothalamus, and form the anatomical substrate of emotion. While an oversimplification (given current knowledge), Papez Circuit stimulated much research, and remains a fair summary of some aspects of this complicated topic. The first part of the loop has been described under the headings of Hippocampus and Fornix. Information passes 1) from the entorhinal cortex to the hippocampal formation, 2) forward in the fornix to the mamillary bodies. Papez described information passing, 3) from the mamillary bodies to the thalamus, and 4) from the thalamus via the cingulum (within the cingulate gyrus) back to the entorhinal cortex. It causes a bulge on the parahippocampal gyrus which is known as the uncus. It also abuts the putamen and the tail of the cordate within the temporal lobe (which led to it being considered part of the basal ganglia, rather than the limbic system, by early authors). The amygdala receives a vast amount of highly processed sensory information. Visceral inputs (particularly olfactory) are prominent. Fibers leave the amygdala through two main pathways: stria terminalis and the ventral amygdalofugal pathway. The stria terminalis passes forward in the lateral ventricle in the groove between the caudate nucleus and the thalamus, and distributes fibres to the caudate, putamen, septal nuclei, ventral striatum (nucleus accumbens) and hypothalamus. The letters “fug” in amygdalofugal have the same root as those letters in the word “fugitive”, where they indicate running away, usually in an indiscriminate manner. The ventral amygdalofugal pathway passes beneath the basal ganglia structures and relays information to a wide array of structures at the base of the brain and beyond: thalamus, hypothalamus, septal nuclei, ventral striatum and brainstem structures. In addition to the two large outflows, locally, fibres extend from the amygdala to the entorhinal cortex and other temporal lobe structures. Diagrammatic representation of the outputs of the amygdala. Two main pathways: stria terminalis and ventral amygdalofugal (arriving at some common destinations). Also, there are also outputs to local temporal lobe structures including the entorhinal cortex. The connections of the amygdala with the septal nuclei, hypothalamus and prefrontal cortex suggest it has a role in drive-related behaviours and the subjective feelings which accompany them. While the hippocampus is involved in learning that an event has happened (the fact), the amygdala is involved with learning whether to consider something is “good” or “bad”. Stimulation of the amygdala (man and other animals) causes fear, with the full autonomic accompaniments. Disorders and the amygdala Bilateral damage to the amygdalae produces the Kluver-Bucy (1939) syndrome: 1) placidity and failure to respond to threats (predators), 2) males become hypersexual and are indiscriminate regarding gender and species, 3) inordinate attention to all sensory stimuli, examining objects orally, and eating them (if at all possible) resulting in weight gain, and 4) incessantly examining the same objects. The animal has the behaviour patterns for satisfying the basic drives, but cannot determine the appropriate context in which to do so. Imaging studies demonstrate exaggerated amygdala activity when the PTSD patient is exposed to fear stimuli. This may be due to a primary increase in the activity in the amygdala, or secondary to a loss of inhibition of the amygdala by the medial prefrontal cortex (Brown et al, 2013).

Two studies were conducted in the UK order apcalis sx 20 mg with visa erectile dysfunction scrotum pump, two in Seoul discount apcalis sx generic impotence education, South 50 85 order 20 mg apcalis sx otc erectile dysfunction doctors in colorado springs, 86 87 88 30 30 85 86 buy 20 mg apcalis sx mastercard erectile dysfunction treatment mayo clinic, , Korea, and one each in Spain, Poland, Romania and Europe. Three studies were multicentred 50 82 83 87 88, , , , and the remaining five studies were conducted in single dialysis centres. Six studies involved 30 50 85, , –88 82 83, patients receiving HD and the remaining two studies involved solely patients treated with PD. The length of follow-up in the eight non-randomised studies ranged from 16 weeks85 to 3. Three studies had no 50 83 87, , apparent links with Fresenius Medical Care and the other five studies reported either funding from 85 30 82 86 88, , , Fresenius Medical Care or some form of connection with the company. The technique used to measure blood pressure in the remaining study is unclear. TABLE 1 Summary of baseline characteristics of included studies Included studies (N = 13) Characteristic RCTs (N = 5) NRS (N = 8) Enrolled 1032 (n = 5) 993 (n = 3) Randomised 939 (n = 5) N/A Analysed 904 (n = 5) 4915 (n = 8)a Age (years): median (range) of means 60 (51. Note Dialysis vintage refers to the length of time on dialysis. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 15 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ASSESSMENT OF CLINICAL EFFECTIVENESS Randomised controlled trials 60 61 63 76 77, , , , The five RCTs randomised a total of 939 participants: 469 to bioimpedance measurements and 470 to standard clinical assessment. Study populations tended to involve approximately equal proportions of men and women, with the exception of the studies by Hur et al. The prevalence of diabetes mellitus among participants varied 60 61 63 76 77, , , , across trials. The proportion of participants with diabetes mellitus was reported by all five trials and ranged from 10%60 to 39. The mean dialysis vintage was reported in three RCTs and ranged from 35. Non-randomised studies 3050828385 88, , , , – The eight included non-randomised cohort studies assessed a total of 4915 participants. The studies were of two main types: in some studies, the BCM was used to classify patients into groups 3088, (e. Six cohort studies reported the mean age of participants, which ranged from 53. The two remaining cohort studies reported the median ages of participants of 57. Three studies reported the mean age for normohydrated and overhydrated groups. The proportion of men in the seven studies reporting this 50 82 83 85 88, , , – 88 87 information ranged from 52. The proportion of participants with diabetes mellitus was reported by six of the observational 30828386 88, , , – 88 83 studies and ranged from 10. The mean dialysis vintage was reported by half of the studies and ranged from 10. Frequency of Body Composition Monitor measurements Randomised controlled trials The frequency of measurements using the BCM in the RCTs was at least every 3 months. The most frequent use of the device was twice monthly in the bioimpedance intervention group (and every 3 months in the control group). Only one trial provided details of its control intervention; Onofriescu et al. Bioimpedance analysis was carried out on both intervention and control groups of all studies at the frequencies reported in Frequency of Body Composition Monitor measurements (with the difference between the groups being that treated physicians in the control groups were blinded to the results). It was not explicitly stated by any of the studies whether or not standard clinical assessment was also carried out at these visits, and no further information on the frequency of standard clinical assessments was reported. Risk of bias Randomised controlled trials Figure 3 presents the summary of risk-of-bias assessments for all included trials. Risk-of-bias assessments of individual studies are presented in Figure 4. According to the prespecified criteria for the assessment of the overall risk of bias, one of the five RCTs was rated as being at a high risk of bias,63 and the remaining four trials did not provide sufficient 60 61 76 77, , , information on which to make a robust judgement. Selection bias Two trials reported sufficient information on which to make a full assessment of selection bias. Full details of allocation concealment were not reported, but the method of generation of sequence (i. No details of the randomisation process were reported. The remaining two trials merely stated that they were randomised trials, but provided no details of how 60 63 77, , randomisation was achieved. Performance and detection bias Only one trial reported that participants were blinded. Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Risk of bias Blinding of outcome assessment (detection bias) Low Unclear Incomplete outcome data (attrition bias) High Selective reporting (reporting bias) Other bias 0% 25% 50% 75% 100% FIGURE 3 Summary of risk-of-bias assessments for all included trials. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 17 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ASSESSMENT OF CLINICAL EFFECTIVENESS Huan-Sheng et al. Attrition bias One trial reported a low number of dropouts63 and was, therefore, rated as being at a low risk of attrition bias. The remaining four studies were rated as being at a high risk of bias because of the high number of 60 61 76 77, , , 61 participants who dropped out. The proportion of participants within each of these categories and distribution of dropouts across centres were, however, not given. Reporting bias In four of the five included trials, the outcomes reported were in accordance with those specified in the 60 61 63 76, , , 77 respective methods section. Two trials 63 76, were supported by grants from independent sources. No other sources of bias were apparent in the included trials. The results of individual study-level assessments are presented in Appendix 8. The majority of studies identified important prognostic factors, provided information on non-respondents/ dropouts, included a sufficient length of follow-up, used objective outcome measures, considered important outcomes, delivered the intervention in an appropriate setting and by an experienced person, clearly defined the intervention, collected data prospectively, clearly defined the inclusion/exclusion criteria and involved a representative sample. None of the studies involved blinding of participants or study personnel. Two studies enrolled participants who entered the study at varying points in their disease progression. The majority of studies failed to provide 30 50 82 83 85 88, , , , , information on the characteristics of participants who withdrew or did not complete follow-up. Clinical effectiveness results Data on the following relevant outcomes were not reported by any of the included studies: number and length of HD sessions, number of unplanned hospital visits/admissions as a result of fluid overload or dehydration, incidence of anaemia, incidence of overhydration or underhydration (although absolute overhydration and ROH were reported), changes of dialysis modality as a result of fluid overload, adherence with recommended fluid intake, incidence of oedema, incidence of peritonitis and health- related quality of life. Evidence from randomised controlled trials: meta-analyses results Meta-analyses of relevant clinical outcomes were performed, when appropriate, using random-effects models. Analysis adjusted for confounding factors Important prognostic factors identified Similar length of follow-up between groups Withdrawals likely to introduce bias Information on non-respondents, dropouts Follow-up long enough Blind assessment of main outcome Objective outcome measures used Yes Important outcomes considered No Intervention delivered in an appropriate setting Unclear Intervention delivered by an experienced person Intervention clearly defined Data collection undertaken prospectively Selection of patients consecutive Participants in similar point in disease progression Inclusion/exclusion criteria clearly defined Representative sample 0 FIGURE 5 Summary risk of bias for non-randomised cohort studies. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 19 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ASSESSMENT OF CLINICAL EFFECTIVENESS TABLE 2 Uninflated summary data for the Ponce et al. Full details of the relevant outcome measures extracted from the included RCTs are presented in Appendix 9. Blood pressure Five trials (one rated as being at a high risk of bias and four as being at an unclear risk of bias) reported SBP 60 61 63 7677, , , , measurements, which were included in a meta-analysis. Figure 6 shows that SBP was lower in participants who underwent bioimpedance measurements using the BCM device than in those assessed by standard clinical assessment, but the difference was not statistically significant (mean difference –2. Arterial stiffness Two trials (both rated as being at an unclear risk of bias) reported arterial stiffness results, which were 60 77, included in a meta-analysis. The measurement of pulse wave velocity (PWV) is generally accepted as the most simple, non-invasive, robust and reproducible method of determining arterial stiffness, with carotid–femoral PWV regarded as the gold standard. The PWV increases from 4–5 m/second in the ascending aorta to 5–6 m/s in the abdominal aorta and 8–9 m/s in the iliac and femoral arteries. Substantial statistical heterogeneity between trials was observed. Mortality 60 61 76, , Three of the included trials (all rated as being at an unclear risk of bias) reported mortality data. As mortality was reported with a HR, the log-HR and log-SE for the three trials were input manually (Table 3). Figure 8 shows that, compared with standard clinical assessment, the use of the BCM had no significant effects on mortality (HR 0. Moderate statistical heterogeneity was evident among trials. Absolute overhydration Four trials (one rated as being at a high risk of bias and three rated as being at an unclear risk of bias) 61 63 76 77, , , assessed absolute overhydration, which was defined as the difference between expected ECW and actual ECW.

Appropriate chlamydial test- from fetal monitoring through scalp electrodes purchase apcalis sx 20mg otc do herbal erectile dysfunction pills work. Presumptive treatment gonococcal infection in neonates who have sepsis cheap 20 mg apcalis sx with mastercard erectile dysfunction treatment by yoga, arthritis cheap apcalis sx 20 mg visa impotence lack of sleep, for N buy apcalis sx 20mg overnight delivery erectile dysfunction pills walmart. Specimens obtained from increased WBCs (but not gonococci) in a Gram-stained smear the conjunctiva, vagina, oropharynx, and rectum that are cul- of conjunctival exudate. Positive Gram-stained smears of exudate, CSF, or joint susceptibility before a defnitive diagnosis is made. A defni- aspirate provide a presumptive basis for initiating treatment tive diagnosis is vital because of the public health and social for N. Diagnoses based on Gram-stained smears consequences of a diagnosis of gonorrhea. Nongonococcal or presumptive identifcation of cultures should be confrmed causes of neonatal ophthalmia include Moraxella catarrhalis with defnitive tests on culture isolates. Ceftriaxone 25–50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10–14 days, if meningitis is documented Recommended Regimen OR Ceftriaxone 25–50 mg/kg IV or IM in a single dose, not to exceed Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration 125 mg of 10–14 days, if meningitis is documented Topical antibiotic therapy alone is inadequate and is unnec- essary if systemic treatment is administered. Prophylactic Treatment for Infants Whose Mothers Have Gonococcal Infection other Management Considerations Infants born to mothers who have untreated gonorrhea are Simultaneous infection with C. Both mother and infant should be tested for chlamydial infec- Recommended Regimen in the Absence of Signs of Gonococcal Infection tion at the same time that gonorrhea testing is conducted (see Ophthalmia Neonatorum Caused by C. Ceftriaxone 25–50 mg/kg IV or IM, not to exceed 125 mg, in a single dose Ceftriaxone should be administered cautiously to hyperbiliru- binemic infants, especially those born prematurely. Follow-Up other Management Considerations Infants who have gonococcal ophthalmia should be hospi- Both mother and infant should be tested for chlamydial talized and evaluated for signs of disseminated infection (e. One dose of ceftriaxone is Follow-Up adequate therapy for gonococcal conjunctivitis. No data are available regarding the use of oral cefxime to treat gonococcal infections in children. Gonococcal Infections Among All children found to have gonococcal infections should be Children evaluated for coinfection with syphilis and C. For preadolescent girls, vaginitis is the ophthalmia neonatorum Prophylaxis most common manifestation of this infection; gonococcal- associated PID after vaginal infection is likely less common in To prevent gonococcal ophthalmia neonatorum, a prophy- preadolescents than adults. Among sexually abused children, lactic agent should be instilled into the eyes of all newborn anorectal and pharyngeal infections with N. However, the efcacy of these Diagnostic Considerations preparations in preventing chlamydial ophthalmia is less clear, Because of the legal implications of a diagnosis of and they do not eliminate nasopharyngeal colonization by C. Te diagnosis and treatment of gonococcal and ferred method for diagnosis. Gram stains are inadequate for chlamydial infections in pregnant women is the best method evaluating prepubertal children for gonorrhea and should not for preventing neonatal gonococcal and chlamydial disease. NAATs for the detec- Not all women, however, receive prenatal care, and therefore tion of N. Ocular prophylaxis is warranted for neonates, (see Sexual Assault or Abuse of Children) because it can prevent sight-threatening gonococcal ophthalmia and because it is safe, easy to administer, and inexpensive. Recommended Regimen for Children Who Weigh >45 kg Treat with one of the regimens recommended for adults (see Recommended Regimen Gonococcal Infections) Erythromycin (0. Ideally, ointment Ceftriaxone 125 mg IM in a single dose should be applied using single-use tubes or ampules rather than multiple-use tubes. All Ceftriaxone 50 mg/kg (maximum dose: 1 g) IM or IV in a single dose infants should be administered ocular prophylaxis, regardless of daily for 7 days whether they are delivered vaginally or by cesarean section. Erythromycin is the only antibiotic ointment recommended Recommended Regimen for Children Who Weigh >45 kg and for use in neonates. Silver nitrate and tetracycline ophthalmic Who Have Bacteremia or Arthritis ointment are no longer manufactured in the United States, baci- Ceftriaxone 50 mg/kg IM or IV in a single dose daily for 7 days tracin is not efective, and povidone iodine has not been studied adequately. If erythromycin ointment is not available, infants at risk for exposure to N. Te KOH specimen typically is used to identify the yeast or pseudohyphae of Candida Discharge species. However, the absence of trichomonads or pseudohyphae Most women will have a vaginal infection, characterized in KOH samples does not rule out these infections, because the by discharge, itching, or odor, during their lifetime. With the sensitivity of microscropy is approximately 50% compared with availability of complementary and alternative therapies and NAAT (trichomoniasis) or culture (yeast). Obtaining a medical history alone has been shown to be Te presence of objective signs of vulvar infammation in the insufcient for accurate diagnosis of vaginitis and can lead to absence of vaginal pathogens after laboratory testing, along the inappropriate administration of medication. Terefore, with a minimal amount of discharge, suggests the possibil- a careful history, examination, and laboratory testing to ity of mechanical, chemical, allergic, or other noninfectious determine the etiology of vaginal complaints are warranted. Information on sexual behaviors and practices, gender of sex partners, menses, vaginal hygiene practices (such as douch- Bacterial Vaginosis ing), and other medications should be elicited. Te three diseases most frequently associated with vaginal discharge BV is a polymicrobial clinical syndrome resulting from are BV (caused by the replacement of the vaginal fora by replacement of the normal hydrogen peroxide producing an overgrowth of anaerobic bacteria including Prevotella sp. Some women experience transient by Candida albicans). Cervicitis also can sometimes cause a vaginal microbial changes, whereas others experience them vaginal discharge. Although vulvovaginal candidiasis (VVC) for a longer intervals of time. Among women presenting for usually is not transmitted sexually, it is included in this section care, BV is the most prevalent cause of vaginal discharge or because it is frequently diagnosed in women who have vaginal malodor; however, in a nationally representative survey, most complaints or who are being evaluated for STDs. Various diagnostic methods are available to identify the BV is associated with having multiple male or female etiology of an abnormal vaginal discharge. Clinical labora- partners, a new sex partner, douching, lack of condom use, tory testing can identify the cause of vaginitis in most women and lack of vaginal lactobacilli; women who have never been and is discussed in detail in the sections of this report dedi- sexually active can also be afected. Nonetheless, women with BV are at increased risk samples of the discharge. Te pH of the vaginal secretions can for the acquisition of some STDs (e. Because surgery, complications of pregnancy, and recurrence of BV. Cover slips are then placed stain (considered the gold standard laboratory method for on the slides, and they are examined under a microscope at diagnosing BV) is used to determine the relative concentration low and high power. If a Gram WBCs without evidence of trichomonads or yeast in this solution Vol. Douching might increase the risk for three of the following symptoms or signs: relapse, and no data support the use of douching for treatment • homogeneous, thin, white discharge that smoothly coats or relief of symptoms. Tinidazole 1 g orally once daily for 5 days Detection of three of these criteria has been correlated with OR results by Gram stain (320). Other tests, including a DNA probe- Clindamycin 300 mg orally twice daily for 7 days based test for high concentrations of G. Although a card test is available (323) or clindamycin (oral or intravaginal) (324). Additional for the detection of elevated pH and trimethylamine, it has low regimens include metronidazole (750-mg extended release sensitivity and specifcity and therefore is not recommended. PCR tablets once daily for 7 days), or a single dose of clindamycin also has been used in research settings for the detection of a variety intravaginal cream, although data on the performance of these of organisms associated with BV, but evaluation of its clinical alternative regimens are limited. Detection of one organism or group of organ- Several studies have evaluated the clinical and microbiologic isms might be predictive of BV by Gram stain (321). However, efcacy of using intravaginal lactobacillus formulations to treat additional evaluations are needed to confrm these associations. Cervical Pap tests have no clinical utility prevention are ongoing. Follow-Up Treatment Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is common, women should be Te established benefts of therapy in nonpregnant women advised to return for evaluation if symptoms recur. Detection are to relieve vaginal symptoms and signs of infection. Other of certain BV-associated organisms have been associated with potential benefts to treatment include reduction in the risk antimicrobial resistance and might determine risk for subse- for acquiring C. Using a diferent treatment regimen might be an option in patients who have a recurrence; however, re- Metronidazole 500 mg orally twice a day for 7 days* treatment with the same topical regimen is another acceptable OR approach for treating recurrent BV during the early stages of Metronidazole gel 0. For women with multiple recurrences after OR completion of a recommended regimen, metronidazole gel Clindamycin cream 2%, one full applicator (5 g) intravaginally at twice weekly for 4-6 months has been shown to reduce recur- bedtime for 7 days† rences, although this beneft might not persist when suppressive * Consuming alcohol should be avoided during treatment and for 24 hours therapy is discontinued (335). Monthly oral metronidazole administered with fuconazole has also been Providers should consider patient preference, possible evaluated as suppressive therapy (337). Women should be advised to refrain from intercourse or to use condoms consistently and correctly during 58 MMWR December 17, 2010 Management of Sex Partners Treatment of asymptomatic BV among pregnant women who are at high risk for preterm delivery (i. Seven trials have evaluated afected by treatment of her sex partner(s). Terefore, routine treatment of pregnant women with asymptomatic BV at treatment of sex partners is not recommended. Terefore, evidence is insufcient to assess Allergy or Intolerance to the Recommended the impact of screening for BV in pregnant women at high Therapy risk for preterm delivery (85). Intravaginal clindamycin cream is preferred in case of allergy Similarly, data are inconsistent regarding whether the or intolerance to metronidazole or tinidazole. Intravaginal met- treatment of asymptomatic pregnant women with BV who ronidazole gel can be considered for women who do not toler- are at low risk for preterm delivery reduces adverse outcomes ate systemic metronidazole. Although USPSTF recommends against screen- not be administered to women allergic to metronidazole. Several Treatment is recommended for all pregnant women with additional trials have shown that intravaginal clindamycin symptoms. Additional potential benefts include reducing the risk Providers should be aware that intravaginal clindamycin cream for infectious complications associated with BV during pregnancy might be associated with adverse outcomes if used in the latter and reducing the risk for other infections (other STDs or HIV).