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By M. Myxir. West Virginia University. 2018.

More patients have been reported to be able to put the babies to the breast at 8 hours (Kuppuvelumani 1993) generic eriacta 100 mg otc. Neuraxial opioid is currently the “gold standard” treatment for pain after cesarean delivery eriacta 100mg overnight delivery. Bilateral ultrasound-guided TAPB in patients undergoing cesarean delivery under subarachnoid anesthesia with fentanyl resulted in significantly reduced total morphine use for 24 h (Belavy 2009, Baaj 2010). TAPB and subarachnoid anesthesia with fentanyl compared to intravenous morphine and regular non-steroidal analgesics reduced total morphine requirements by 60%-70% and postoperative pain in the first 48 hours (McDonnell 2008, Baaj 2010). Opioid-related, dose-dependent, side-effects including nausea, vomiting, pruritus and sedation, may occur. Delayed maternal respiratory depression due to cephalic spread of hydrophilic 9. Obstetric and Gynecologic Surgery | 77 opioids is another risk. Side effects reduce overall patient satisfaction, and techniques that reduce opioid requirements may be of benefit. Some authors state that IIB or TAPB may offer no benefit on pain control compared to neuraxial morphine (Costello 2009, Kanazi 2010, McMorrow 2011). The addition of morphine to the local anesthetic is easier to perform, is less time-consuming and does not require extra equipment or skills to be performed (Kanazi 2010). In a study, patients receiving both subarachnoid anesthesia with 0,1 mg morphine and a TAPB had a higher incidence of pruritus and anti-emetic use. Less pain on movement and later postoperative morphine request were shown by patients receiving subarachnoid morphine compared to saline (McMorrow 2011). Gynecologic Surgery Few trials have evaluated abdominal blocks for gynecologic surgery. Bilateral IIB for total abdominal hysterectomy or prolapse repair through a Pfannenstiel incision under general anesthesia has shown to reduce prevalently dynamic pain and morphine need. In a study the reduction of morphine was 51% (21 +/- 9 mg vs. Bilateral TAPB in total abdominal hysterectomy significantly reduced morphine requirements at all time points for 48 hours. A longer time to first morphine request and reduced postoperative pain scores at rest and on movement were shown compared to the placebo (Carney 2008 (2)). The reduction in pain scores is often not significant, suggesting the existence of additional pain from deep pelvic dissection and suturing of the vaginal vault during hysterectomy 78 | Ultrasound Blocks for the Anterior Abdominal Wall (Kelly 1996). Recently, a trial on women undergoing pubic to umbilical midline incision for heterogeneous gynecologic malignancy, showed no benefit of ultrasound-guided TAPB on analgesic requirement, pain scores, adverse effects and satisfaction over multimodal analgesia (Griffiths 2010). Other Abdominal Surgery Procedures Andrea Pradella, Tommaso Mauri Lower Abdominal Surgery Lower abdominal surgery includes varicocelectomy, appen- dicectomy, open prostatectomy, lumbectomy and intra-aortic procedures with femoral artery cannulation. Surgical reports on awake varicocelectomy show the efficacy of local anesthetic infiltration beneath the aponeurosis of the EOM into the inguinal canal to block the ilioinguinal and genitofemoral nerves (Hsu 2005). Recently, an effective ultrasound-guided spermatic cord block was reported (Wipfli 2011). In the only randomized study in adults undergoing varicocelectomy under general anesthesia and an IIB before surgery, patients experienced significantly reduced postoperative pain scores at rest and during mobilization, less analgesic consumption, less nausea and vomiting and were all discharged at 6 hours (Yazigi 2002). The IIB and the TAPB have also been evaluated in the performance of appendicectomy. The IIB performed before surgery in children undergoing appendicectomy showed better 80 | Ultrasound Blocks for the Anterior Abdominal Wall pain scores and less analgesic consumption for 6 hours (Courrèges 1996). The reduced pain and postoperative morphine consumption effects of ultrasound-guided TAPB in appendicectomy may last for 24 hours (Niraj 2009 (2)). TAPB for laparoscopic appendicectomy in children has been shown to offer no important clinical benefit over local anesthetic port-site infiltration (Sandeman 2011). Ultrasound-guided TAPB has also been evaluated in patients scheduled for major orthopedic surgery and anterior iliac crest harvest for autologous bone graft, with pain abolished for the first 48 hours (Chiono 2010). Upper Abdominal Surgery TAPB is an effective method of blocking the sensory afferents supplying the anterior abdominal wall. However, the classical TAPB may not reliably produce analgesia above the umbilicus (Shibata 2007). The subcostal TAPB involves injection immediately inferior to the costal margin. It has been reported to provide analgesia for incisions extending above the umbilicus (Hebbard 2008). A further development of the subcostal TAPB is the possibility to place a catheter along the oblique subcostal line in the TAM plane for continuous infusion of local anesthetic (Niraj 2011, Hebbard 2010). An ultrasound-guided technique with a Tuohy epidural needle and catheter may be used in this case. Bowel surgery TAPB in adults undergoing large bowel resection via a midline abdominal incision resulted in a significant reduction of pain scores and morphine requirements for the first 24 postoperative hours (21. Other Abdominal Surgery Procedures | 81 TAPB employed for laparoscopic colonic-rectal resections reduces overall postoperative morphine (31. In a retrospective analysis of patients undergoing laparoscopic colonic-rectal resection, an ultrasound-guided TAPB significantly reduced time to the resumption of diet and postoperative hospital stay (Zafar 2010).

Genetic variation of the corticotropin-releasing hormone receptor 1 (CRHR1) gene appears to increase the risk of anxiety disorders (Rogers order eriacta 100 mg without a prescription, 2013) discount 100mg eriacta with visa. Epigenetics Epigenetics is of great interest throughout psychiatry – a process by which gene expression can be altered without alteration of the DNA sequence. All anxiety disorders may be influenced by experience, and evidence suggest that some anxiety disorders may be underpinned by epigenetic marks/mechanisms (McGhee and Bell, 2014; Hommers et al, 2015). Amygdala structures: 1) BLA (Basolateral Amygdala complex), and CeA (Central Amygdala). The neurobiology of anxiety and anxiety disorders is yet to be fully explained. The amygdala, in the median temporal lobe, is activated by threatening stimuli. Patients with anxiety disorders activate the amygdala in response to given stimuli more than non-anxious controls. It is composed of a number of nuclei, including the basolateral amygdala complex (BAL) and the central nucleus of the amygdala (CeA). The BAL receives negative emotional signals from the thalamus, and the sensory association cortex. It (BAL) activates the CeA, which in turn activates the bed nucleus of the stria terminalis (BNST). Neurons from both the CeA and the BNST project to the brainstem, hypothalamus and basal forebrain. Activation of the brainstem and hypothalamus structures produces the somatic manifestations of anxiety (tachycardia etc). Activation of basal forebrain nuclei (ventral tegmental area and locus ceruleus) may produce the dysphoria of anxiety. Further, the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) both send input to and receive input from the BAL. The mPFC can modulate the activity of the BLA (and the anxious experience). The mPFC may enable conscious and unconscious control of anxiety. Pregnenolone, which is secreted by the adrenals is an example; others are believed to be produced by nervous system cells. The above illustration is provided for any trainee psychiatrist who may be slumming. The subgenual cortex refers to the cortex inferior to the anterior bend (L. Palomero- Gallagher et al (2015), using cytoarchitectural methods have identified region s32 as being associated with fear processing (and s24 as being associated with sadness). Neuroimaging In GAD, amygdala connection variations have been observed, including increased connectivity to the parietal lobe, and decreased connection with the insula and cingulate. Further, the CeA may have increased volume (Etkin et al, 2009). A recent DTI study (Trop do, et al, 2012) found bilateral decreased functional connectivity between the anterior cingulate cortex and the amygdala – specifically, in GAD; the integrity of the uncinate fasciculus was reduced. Alemany et al (2013) report volume reductions observed in the bilateral fusiform gyrus and the amygdala in mz twins concordant for anxiety. Psychosocial mechanisms Stressful life events may trigger GAD. The greater the number of negative life events experienced, the greater the likelihood of GAD (Blazer et al, 1987). A healthy parent-child relationship leads to the child developing a sense of control over the environment and a repertoire of adaptive responses. In the absence of such a relationship and development, the child may be vulnerable to anxiety (Chorpita & Barlow, 1998). In a large study (Yonkers et al, 1996), the mean age of onset was 21 years and the average duration was 20 years. Although 80% received treatment, only 15% remitted after one year, and 27% had remitted after 3 years. Remission rates are even lower in the presence of comorbid psychiatric disorders. Treatment Self-help books and activities may have a place (Hirai & Clum, 2006). Psychological treatments take many forms, from a behavioural approach at one end of the spectrum, to psychodynamic psychotherapy at the other. Most therapists would claim to use some form of cognitive behaviour therapy (CBT).

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If the ischemic insult is sufficiently severe buy eriacta 100mg fast delivery, cell death and/or Thus cheap 100 mg eriacta overnight delivery, important insights into the basic and applied biology of detachment leads to loss of cells from the epithelium lining the tight junctions are likely to be forthcoming from further analy- kidney tubules. To recover from such a severe insult, cell regen- sis of the ATP depletion-repletion model. Nevertheless, it is like- eration, differentiation, and possibly morphogenesis, are neces- ly that, as in the calcium switch model, tight junction reassem- sary. To a limited extent, the recovery of kidney tubule function bly is regulated by classical signaling pathways that might after such a severe ischemic insult can be viewed as a recapitu- potentially be pharmacologically modulated to enhance recov- lation of various steps in renal development. M any of these involved in kidney development) appears necessary to amelio- (eg, the tight junction protein, occludin, and the adherens junction rate renal recovery after acute ischemic injury [21–30]. The Ischemic Epithelial Cell FIGURE 16-1 Functional renal tubules Ischem ic acute renal failure (ARF). Flow chart illustrates the cellu- lar basis of ischem ic ARF. As described above, renal tubule epithe- Uninjured cells lial cells undergo a variety of biochem ical and structural changes in Ischemic insult response to ischem ic insult. If the duration of the insult is suffi- ciently short, these alterations are readily reversible, but if the Injured cells insult continues it ultim ately leads to cell detachm ent and/or cell death. Interestingly, unlike other organs in which ischem ic injury ↓ATP; ↑[CA2+]; ↑Free radicals; Other changes? Tight junction Apical-basolateral M icrofilament disruption polarity disruption disruption Dysfunctional renal tubular epithelial cells Remove insult Continued insult Cell loss Cellular (detachment repair or death) Cell regenertation, differentiation, and morphogenesis Remove insult Acute Renal Failure: Cellular Features of Injury and Repair 16. Sublethal injury to polarized epithelial cells leads to m ultiple Brush lesions, including loss of the perm eability barrier and apical-basolat- border eral polarity [7–12]. To recover, cells m ust reestablish intercellular junctions and repolarize to form distinct apical and basolateral dom ains characteristic of functional renal epithelial cells. These Tight junction junctions include those necessary for m aintaining the perm eability barrier (ie, tight junctions), m aintaining cell-cell contact (ie, Adherens Terminal web adherens junctions and desm osom es), and those involved in cell-cell junction Actin cortical ring com m unication (ie, gap junctions). In addition, the cell m ust estab- lish and m aintain contact with the basem ent m em brane through its integrin receptors. Thus, to understand how kidney cells recover from sublethal ischem ic injury it is necessary to understand how renal epithelial cells form these junctions. Furtherm ore, after lethal Desmosome Intermediate injury to tubule cells new cells m ay have to replace those lost during filaments the ischem ic insult, and these new cells m ust differentiate into epithelial cells to restore proper function to the tubules. Gap junction Na+, K+, ATPase Integrins Extracellular matrix FIGURE 16-3 Symplekin Occludin The tight junction. The tight junction, the m ost apical com ponent of the junctional com plex of epithelial cells, serves two m ain functions in epithelial cells: 1) It separates the apical and 7H6 p130 basolateral plasm a m em brane dom ains of the cells, allowing for vectorial transport of ions Cingulin ZO–1 and m olecules; 2) it provides the m ajor fram ework for the paracellular perm eability barrier, allowing for generation of chem ical and electrical gradients. These functions are criti- cally im portant to the proper functioning of renal tubules. The tight junction is com prised ZO–2 of a num ber of proteins (cytoplasm ic and transm em brane) that interact with a sim ilar group of proteins between adjacent cells to form the perm eability barrier [16, 32–37]. Actin These proteins include the transm em brane protein occludin [35, 38] and the cytosolic pro- filaments teins zonula occludens 1 (ZO -1), ZO -2, p130,, cingulin [33, 40], 7H 6 antigen and sym plekin, although other as yet unidentified com ponents likely exist. The Fodrin Paracellular tight junction also appears to interact with the actin-based cytoskeleton, probably in part space through ZO -1–fodrin interactions. This model of short-term ATP Intact intercellular Compromised Damaged disassembled junctions intercellular junctions intercellular junctions depletion-repletion is probably most relevant to transient sublethal ischemic injury of renal tubule cells. However, in a model of Short-term Long-term Severe longterm ATP depletion (2. The disruption of the perme- (message and protein) and bioassembly of ability barrier, mediated by the tight junction, is a key lesion in the pathogenesis of tubular new tight junction components. M any of dysfunction after ischemia and reperfusion. Cell culture models employing ATP depletion these components (membrane proteins) are and repletion protocols are a commonly used approach for understanding the molecular assembled in the endoplasmic reticulum. This is dem onstrated control here by indirect im m unofluorescent localization of these two pro- teins in norm al kidney epithelial cells. After 1 hour of ATP deple- tion this association appears to change, occludin can be found in the cell interior, whereas ZO -1 rem ains at the apical border of the ATP depletion (1 hr) plasm a m em brane. Interestingly, the intracellular distribution of the actin-cytoskeletal–associated protein fodrin also changes after ATP depletion. Fodrin m oves from a random , intracellular distrib- ution and appears to becom e co-localized with ZO -1 at the apical ATP repletion (3hrs) border of the plasm a m em brane. These changes are com pletely reversible after ATP repletion. These findings suggest that disrup- tion of the perm eability barrier could be due, at least in part, to altered association of ZO -1 with occludin.

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Crain There have been only limited studies of the time course and Shen hypothesized that proven eriacta 100mg, although most -opioid recep- of all these dopaminergic responses during investigator-ad- tors are coupled with inhibitory Gi/oprotein purchase 100 mg eriacta with amex, a small propor- ministered morphine or heroin on an intermittent basis, tion may be coupled at the stimulatory Gs protein, which mimicking the human pattern of heroin abuse, or during can be suppressed with small amounts of opioid antagonists. It would be assumed These findings of enhanced morphine analgesia are, in part, that possibly, as with cocaine, one sees a progressive diminu- very similar to the findings of Bohn, Caron, Lefkowitz, and tion of the responsivity, with a resultant lowering of basal colleagues, in mice with deletion of -arrestin (60). These level and stimulant-induced rise of absolute levels of dopa- researchers also showed that -arrestin is important in sev- mine (78). Numerous human studies suggest this may in- eral distinct functions, including events leading to the inter- deed happen. It has been repeatedly shown in heroin addicts nalization of an agonist bound -opioid receptor, which, that the short acting -opioid agonist heroin will cause a after the phosphorylation of the bound form, binds to - prompt increase in serum prolactin levels, resulting directly arrestin, along with binding by G-protein–receptor kinases from an abrupt lowering of dopamine levels in the tuberoin- (60). This event of -arrestin binding has been described fundibular dopaminergic systems (85). In humans, and to a as potentially part of the process that desensitizes, that is, greater extent than in rodents, prolactin release is essentially leads to G-protein uncoupling of the -opioid receptors, solely under tonic inhibition by dopaminergic tone in the as well as being actually involved in the internalization of tuberoinfundibular dopaminergic system. However, it was endogenous and some exogenous agonist-bound -opioid found that during chronic methadone treatment, there is receptors (44–52,60). The role of internalization in the de- adaptation or tolerance to this phenomenon, an attenua- velopment of tolerance and the independent process of de- tion, but not a complete removal or ablation of this response pendence remain unclear because there are many conflicting caused by dopamine lowering and resulting in elevation of results, including the finding that most exogenous opioid serum prolactin levels (85). Even during long-term metha- ligands, including morphine, that do not induce prompt done maintenance treatment, as reported in 1978, it was internalization of -opioid receptors once bound, clearly found that peak plasma levels of the -opiate agonist metha- lead to the development of both tolerance and physical de- done are related temporally to the peak plasma levels of pendence (44–52). In sharp contrast, methadone and etor- prolactin (85). These findings suggest that the long-acting phine do lead to prompt internalization of -opioid recep- opioid methadone administered orally continues to have tors, just as do all the natural endogenous opioid peptides an impact at least on the tuberoinfundibular dopaminergic such as Met-enkephalin and -endorphin (44–52). Intrigu- system, with a lowering of dopaminergic tone, resulting in ingly, in the mice with deletion at the -arrestin-2 gene, a modest increase of prolactin levels, although not exceeding enhanced morphine analgesia was seen, and further studies upper levels of normal. However, that attenuation occurs revealed that tolerance does not develop to morphine effects, suggests that there may be either a lowering of dopaminergic and yet objective signs reflecting the development of physi- levels and tone in the turberoinfundibular dopaminergic cal dependence are present after chronic morphine adminis- system of that region or, alternatively, an attenuation of tration (60). These studies again dissociated the develop- responsivity of the -opiate-receptor system. It has been ment of tolerance from the development of physical shown that the -opiate-receptor system similarly plays a dependence. The studies of the group of Crain, as well as role in modulating prolactin levels in humans (86). In nor- the studies of the group of Caron and Lefkowitz, suggested mal healthy volunteers, dynorphin A causes a prompt rise that either deletion of -arrestin or suppression, by opioid in serum prolactin levels, resulting again presumably from antagonists in very small doses, of opioid receptor coupled a lowering of dopaminergic tone in the tuberoinfundibular to G , the stimulatory G-protein pathway, will enhance opi-s system (86). This is a , but also a -opioid-receptor effect, oid analgesia and also may attenuate or prevent develop- as documented by use of two different opioid antagonists ment of tolerance. It is not known whether blocking of the with different receptor selectivity (86). In preliminary stud- G coupling alters the development of physical dependence,s ies, the Kreek laboratory showed that there is altered respon- however. In possibly related studies, Jeziorski and White sivity both in former heroin addicts and in former cocaine showed that the NMDA antagonist, MK-801, prevents de- addicts, as well as those with combined heroin opioid and velopment of behavioral sensitization during chronic mor- cocaine dependency (87). Sensitization has been suggested to be ters; this group comprises fast-acting neurotransmitters in- related to drug reward or craving. Possibly in contrast, cluding excitatory amino acids such as glutamate and Churchill, Roques, and Kalivas found that dopamine deple- slower-acting neurotransmitters such as norepinephrine, tion, such as may happen during chronic opiate, as well as epinephrine, and serotonin, as well as dopamine, and a vari- 1498 Neuropsychopharmacology: The Fifth Generation of Progress ety of neuropeptides. Very few studies have been conducted to novelty or to risk and used different strains of rats, as well in models using chronic heroin or morphine administration, as mice. Similarly, more recent studies looked not simply at or self-administration, using long-term, high-dose, regularly the acute effects of drugs of abuse, but also at the subacute spaced intermittent administration or by long-access, high- and chronic effects of drugs of abuse and the impact of dose, self-administration, mimicking the human pattern of withdrawal from such drugs on components of the stress- heroin abuse. Further work will be central to detail the long- responsive axis. Even more recent studies went on to study term effects and, also of special interest, the effects of the levels of gene expression and the impact of exposure to drugs withdrawal and reexposure to mimic relapse. However, of abuse over a defined time course of exposure on gene qualitatively and quantitatively different changes have been expression, first on 'early gene response' and then, more found during chronic morphine or heroin administration recently, on changes of expression of many other specific by different patterns, dose, and routes of administration. The interactions of the dopaminergic system on the HPA Physiologic Systems and Behaviors axis as well as the effects of catecholamines on this axis have Primarily Altered been studied in both animal models and in humans. It is clear that opiates, like cocaine but to a much lesser extent, Stress Responsivity: Possible Implications for cause an elevation in dopaminergic tone, especially in the Opiate Addiction mesolimbic-mesocortical dopaminergic system. However, An atypical responsivity to stress and stressors existing on as discussed earlier, several groups have shown that although a drug-induced basis or possibly a priori, on a genetic or this is a reproducible phenomenon, the mesolimbic-meso- environmental basis, as one component of the 'metabolic cortical dopaminergic system is not essential for heroin or basis' of heroin addiction was a concept that was hypothe- morphine self-administration, and animals that have re- sized by the Kreek group in 1964, and it was therefore ceived lesions abolishing this mesolimbic-mesocortical do- addressed directly in our prospective studies started at that paminergic system readily self-administer opiates such as time and completed in 1972, as well as in other early basic morphine. This finding is in sharp contrast to that which clinical research studies (6,85,88–92). Several laboratories pertains for cocaine self-administration in which lesions of went on to study, in humans, the impact of drugs of abuse the mesolimbic-mesocortical dopaminergic system abolish and specifically heroin, but also morphine, (as used in a cocaine self-administration. Thus, the role of dopamine in single dose or on a chronic basis in the pharmacotherapy the well-established acute morphine activation of the HPA of pain), on one component of stress response, the hypotha- axis in rodents is of interest, but it may be a related, but lamic-pituitary-adrenal (HPA) axis (6,93–108). Long-term not central, component of the mechanism underlying self- studies in animal models came later, however, and were administration.

Research has shown that trials with higher levels of PPI are four times more likely to recruit to target buy eriacta 100 mg lowest price. These can help to identify necessary adjustments to improve recruitment and retention 100 mg eriacta sale. The PPI partners in this study did indeed help to shape the recruitment strategy for patients, which was to opt in to either a focus group study or involved opting in to completing questionnaires and a possible interview. The outcomes needed to include measures of physical health, mental health and social needs. We also required information on actions undertaken by nurses (advice, referrals, signposting) and on whether or not patients had taken up this advice, referral or signposting to services. The complexity of the study design, and its attempt to gather multiple outcomes at both the nurse level and the patient level, was not lost on our PPI members, as we worked together to gather the required knowledge in the most efficient manner. This was probably helped by the degree of knowledge of research that our PPI members had and their enthusiasm for the study. They contributed to the many discussions throughout the study on how to address this and were reassured that the team had tried all possible avenues within the time scale available to achieve practice recruitment and retention. In reflecting on our PPI as a team, we thought it best to allow our PPI members to write their own contributions to this. We asked them to reflect on their experience of working with us and whether or not we could have done anything differently to enable their participation in the study. Their responses are included in the following two subsections. My experience and comments on the Patient Centred Assessment Method process; by patient representative 1 As a patient representative I appreciate the requirement and desirability for academia to be sometimes balanced by a lay point of view and if not present the journey from concept to publication may not be as comprehensive as it could be. I sit as a patient representative (I prefer the term representative patient) on several committees and research groups so feel qualified to state that my experience with this feasibility study was one of the best in terms of support, inclusiveness, consideration and birthday cakes. The panel made an effort to explain any terms or acronyms I or my fellow PR [patient representative] were unfamiliar with and always listened to our viewpoints and took the time to solicit our thoughts. As to the actual content of the study I share the disappointment on the paucity of the total numbers of patients and practices involved but strongly believe that this holistic approach will show many benefits. My particular thanks must go to Professor Maxwell, Dr Carina Hibberd and Ms Nadine Dougall. My experience and comments on the Patient Centred Assessment Method process; by patient representative 2 As a sufferer from a sluggish (not to say absent) NHS protocol in dealing with anxiety issues caused by the diagnosis of a cardiac problem, I joined the Living Better Project Steering Committee which was an RCGP-led study aiming to improve the care of people with LTCs in primary care, hoping for procedural improvement. Unfortunately the results of the research resulting from the Living Better project did not translate into the hoped for improved protocol to establish a route to identify co-lateral problems which frequently resulted alongside a chronic disease diagnosis. But, in PCAM, I saw an opportunity to introduce a method to improve this situation within the existing structure. Encouraged to be involved from the start in discussing the initial documentation and to join the Steering Committee by the key researchers it has been a pleasure to be involved with and to follow the development of this ambitious project. Always encouraged to participate fully in committee discussions and to contribute ideas throughout, and to feel free to criticise, my lay colleague and I were kept involved in all of the developing problems by the project leaders as well as in the successes. Our involvement in the discussion of the final report has also been thorough. The infectious enthusiasm of the researchers and their stoicism when things were difficult have been singular. There is no doubt in my mind that, in PCAM, there is the germ of an idea which will become part of NHS protocol in the years to come. 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 75 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. DISCUSSION Strengths and limitations The strength of this study is that it was designed as a feasibility study that has fully tested practice, nurse and patient recruitment and retention. The combination of the five studies, which all contribute to the overall aims of the study, means that, often, multiple sources of information could be used to contribute to overall study findings. For example, studies A, C and D contributed to the acceptability and feasibility of using the PCAM in primary care nurse-led annual reviews, as well as the overall process evaluation (study E). Practices were recruited from very different areas of Scotland, for example from NHS GGC, which has the highest proportion of deprived practices in Scotland, and from NHS Grampian, which has small urban towns and rural areas. There is no doubt that the recruitment and retention figures are a big limitation for this study; however, this was what the study was designed to test, so it is a finding rather than a limitation in this case. The lack of nurse participation in study C is probably one of the most disappointing aspects, because it resulted in very few consultation recordings, and yet, these showed great promise in demonstrating that the PCAM may actually achieve its goals of changing nurse behaviour in consultations. The fact that researchers delivered training as well as being involved in study data collection may have introduced some bias into practices allocated to the PCAM arm; nurses may have felt that they had to be positive about the PCAM with the researcher with whom they had developed a relationship over time.

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