Could paramedics use the HEART Pathway to identify patients at low-risk of myocardial infarction in the prehospital setting?

In the Emergency Department, patients with suspected myocardial infarction can be risk stratified using the HEART pathway, which has recently been amended for prehospital use and modified for the incorporation of a high-sensitivity cardiac troponin test. In a prospective analysis, the performance of both HEART pathways in the prehospital setting, with a high-sensitivity cardiac troponin test using 3 different thresholds, was evaluated for major adverse cardiac events at 30 days. We found that both low-risk HEART pathways, when using the most conservative cardiac troponin thresholds, approached but did not reach accepted rule-out performance in the Emergency Department.

The Effect of Macular Hole Duration on Surgical Outcomes: An Individual Participant Data Study of Randomized Controlled Trials.

TOPIC: To define the effect of symptom duration on outcomes in people undergoing surgery for idiopathic full-thickness macular holes (iFTMHs) by means of an individual participant data (IPD) study of randomized controlled trials (RCTs). The outcomes assessed were primary iFTMH closure and postoperative best-corrected visual acuity (BCVA). CLINICAL RELEVANCE: Idiopathic full-thickness macular holes are visually disabling with a prevalence of up to 0.5%. Untreated BCVA is typically reduced to 20/200. Surgery can close holes and improve vision. Symptom duration is thought to affect outcomes with surgery, but the effect is unclear. METHODS: A systematic review identified eligible RCTs that included adults with iFTMH undergoing vitrectomy with gas tamponade in which symptom duration, primary iFTMH closure, and postoperative BCVA were recorded. Bibliographic databases were searched for articles published between 2000 and 2020. Individual participant data were requested from eligible studies. RESULTS: Twenty eligible RCTs were identified. Data were requested from all studies and obtained from 12, representing 940 eyes in total. Median symptom duration was 6 months (interquartile range, 3-10). Primary closure was achieved in 81.5% of eyes. There was a linear relationship between predicted probability of closure and symptom duration. Multilevel logistic regression showed each additional month of duration was associated with 0.965 times lower odds of closure (95% confidence interval [CI], 0.935-0.996, P = 0.026). Internal limiting membrane (ILM) peeling, ILM flap use, better preoperative BCVA, face-down positioning, and smaller iFTMH size were associated with increased odds of primary closure. Median postoperative BCVA in eyes achieving primary closure was 0.48 logarithm of the minimum angle of resolution (logMAR) (20/60). Multilevel logistic regression showed for eyes achieving primary iFTMH closure, each additional month of symptom duration was associated with worsening BCVA by 0.008 logMAR units (95% CI, 0.005-0.011, P < 0.001) (i.e., ∼1 Early Treatment Diabetic Retinopathy Study letter loss per 2 months). ILM flaps, intraocular tamponade using long-acting gas, better preoperative BCVA, smaller iFTMH size, and phakic status were also associated with improved postoperative BCVA. CONCLUSIONS: Symptom duration was independently associated with both anatomic and visual outcomes in persons undergoing surgery for iFTMH. Time to surgery should be minimized and care pathways designed to enable this.

Performance of a prehospital HEART score in patients with possible myocardial infarction: a prospective evaluation.

INTRODUCTION: The History, Electrocardiogram (ECG), Age, Risk Factors and Troponin (HEART) score is commonly used to risk stratify patients with possible myocardial infarction as low risk or high risk in the Emergency Department (ED). Whether the HEART score can be used by paramedics to guide care were high-sensitivity cardiac troponin testing available in a prehospital setting is uncertain. METHODS: In a prespecified secondary analysis of a prospective cohort study where paramedics enrolled patients with suspected myocardial infarction, a paramedic Heart, ECG, Age, Risk Factors (HEAR) score was recorded contemporaneously, and a prehospital blood sample was obtained for subsequent cardiac troponin testing. HEART and modified HEART scores were derived using laboratory contemporary and high-sensitivity cardiac troponin I assays. HEART and modified HEART scores of ≤3 and ≥7 were applied to define low-risk and high-risk patients, and performance was evaluated for an outcome of major adverse cardiac events (MACEs) at 30 days. RESULTS: Between November 2014 and April 2018, 1054 patients were recruited, of whom 960 (mean 64 (SD 15) years, 42% women) were eligible for analysis and 255 (26%) experienced a MACE at 30 days. A HEART score of ≤3 identified 279 (29%) as low risk with a negative predictive value of 93.5% (95% CI 90.0% to 95.9%) for the contemporary assay and 91.4% (95% CI 87.5% to 94.2%) for the high-sensitivity assay. A modified HEART score of ≤3 using the limit of detection of the high-sensitivity assay identified 194 (20%) patients as low risk with a negative predictive value of 95.9% (95% CI 92.1% to 97.9%). A HEART score of ≥7 using either assay gave a lower positive predictive value than using the upper reference limit of either cardiac troponin assay alone. CONCLUSIONS: A HEART score derived by paramedics in the prehospital setting, even when modified to harness the precision of a high-sensitivity assay, does not allow safe rule-out of myocardial infarction or enhanced rule-in compared with cardiac troponin testing alone.

Open versus laparoscopic repair of inguinal hernia: an overview of systematic reviews of randomised controlled trials.

BACKGROUND: Inguinal hernia has a lifetime incidence of 27% in men and 3% in women. Surgery is the recommended treatment, but there is no consensus on the best method. Open repair is most popular, but there are concerns about the risk of chronic groin pain. Laparoscopic repair is increasingly accepted due to the lower risk of chronic pain, although its recurrence rate is still unclear. The aim of this overview is to compare the risk of recurrence and chronic groin pain in laparoscopic versus open repair for inguinal hernia. METHODS: We searched Ovid MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses. Only reviews of randomised controlled trials (RCTs) in adults published in English were included. Conference proceedings and editorials were excluded. The quality of the systematic reviews was assessed using the AMSTAR 2 checklist. Two outcomes were considered: hernia recurrence and chronic pain. RESULTS: Twenty-one systematic reviews and meta-analyses were included. Laparoscopic repair was associated with a lower risk of chronic groin pain compared with open repair. In the four systematic reviews assessing any laparoscopic versus any open repairs, laparoscopic repair was associated with a statistically significant (range: 26-46%) reduction in the odds or risk of chronic pain. Most reviews showed no difference in recurrence rates between laparoscopic and open repairs, regardless of the types of repair considered or the types of hernia that were studied, but most reviews had wide confidence intervals and we cannot rule out clinically important effects favouring either type of repair. CONCLUSION: Meta-analyses suggest that laparoscopic repairs have a lower incidence of chronic groin pain than open repair, but there is no evidence of differences in recurrence rates between laparoscopic and open repairs.

Customized Three-Dimensional Printed Splints for Neonates in the Neonatal Intensive Care Unit: Three Case Reports.

IMPORTANCE: Critically ill neonates can be vulnerable to positional deformities and joint contractures. Early splints, along with dynamic exercise, may lead to long-term functional improvement. Making splints to perfectly contour neonates' small joints and bodies is challenging. An ill-fitted splint can lead to skin ulcers, nerve damage, poor compliance, and discomfort. Three-dimensional (3D) printing has been applied to create customized, cost-effective, and lightweight orthoses that may be promising for neonates. OBJECTIVE: To explore the feasibility of scanning, designing, and printing 3D splints for neonates. SETTING: A large neonatal intensive care unit (NICU) in a university teaching hospital. METHOD: Case series of three neonates in a NICU who had deformities or joint contractures that would benefit from early static splints. We created customized splints for neonates using 3D scanning, digital design software, and 3D printing technology. We monitored the neonates' comfort and clinical improvement. RESULTS: One neonate with a congenital neck deformity had a neck splint created from 3D body-scanned images. Another neonate with a hand deformity was measured and had 3D digitally designed hand splints made. The same hand splint design was modified to fit a third neonate's hand with new measurements. All splints were 3D printed using specialized lightweight materials. The neonates tolerated the splints well. CONCLUSIONS AND RELEVANCE: 3D printing technology is feasible for and applicable to NICU neonates. Advancing 3D technology should focus on upgrading scanning quality, improving splint design, and speeding up printing. Further research to evaluate the long-term benefits of early splinting is needed. What This Article Adds: This is the first published article to discuss the feasibility of using 3D printing technology to create customized splints for fragile neonates. Neonates, especially critically ill ones with congenital defects, may benefit from early splinting to preserve function and development. Neonates are the most challenging patients to make a perfect-fit splint for, and 3D printing may offer a potential solution.

A Dichotomy in Cross-Coupling Site Selectivity in a Dihalogenated Heteroarene: Influence of Mononuclear Pd, Pd Clusters, and Pd Nanoparticles-the Case for Exploiting Pd Catalyst Speciation.

Site-selective dihalogenated heteroarene cross-coupling with organometallic reagents usually occurs at the halogen proximal to the heteroatom, enabled by intrinsic relative electrophilicity, particularly in strongly polarized systems. An archetypical example is the Suzuki-Miyaura cross-coupling (SMCC) of 2,4-dibromopyridine with organoboron species, which typically exhibit C2-arylation site-selectivity using mononuclear Pd (pre)catalysts. Given that Pd speciation, particularly aggregation, is known to lead to the formation of catalytically competent multinuclear Pdn species, the influence of these species on cross-coupling site-selectivity remains largely unknown. Herein, we disclose that multinuclear Pd species, in the form of Pd3-type clusters and nanoparticles, switch arylation site-selectivity from C2 to C4, in 2,4-dibromopyridine cross-couplings with both organoboronic acids (SMCC reactions) and Grignard reagents (Kumada-type reactions). The Pd/ligand ratio and the presence of suitable stabilizing salts were found to be critically important in switching the site-selectivity. More generally, this study provides experimental evidence that aggregated Pd catalyst species not only are catalytically competent but also alter reaction outcomes through changes in product selectivity.

Maintaining musculoskeletal health using a behavioural therapy approach: a population-based randomised controlled trial (the MAmMOTH Study).

OBJECTIVE: Cognitive-behavioural therapy (CBT) has been shown to be effective in the management of chronic widespread pain (CWP); we now test whether it can prevent onset among adults at high risk. METHODS: A population-based randomised controlled prevention trial, with recruitment through UK general practices. A mailed screening questionnaire identified adults at high risk of CWP. Participants received either usual care (UC) or a short course of telephone CBT (tCBT). The primary outcome was CWP onset at 12 months assessed by mailed questionnaire. There were seven secondary outcomes including quality of life (EuroQol Questionnaire-five dimensions-five levels/EQ-5D-5L) used as part of a health economic assessment. RESULTS: 996 participants were randomised and included in the intention-to-treat analysis of which 825 provided primary outcome data. The median age of participants was 59 years; 59% were women. At 12 months there was no difference in the onset of CWP (tCBT: 18.0% vs UC: 17.5%; OR 1.05; 95% CI 0.75 to 1.48). Participants who received tCBT were more likely to report better quality of life (EQ-5D-5L utility score mean difference 0.024 (95% CI 0.009 to 0.040)); and had 0.023 (95% CI 0.007 to 0.039) more quality-adjusted life-years at an additional cost of £42.30 (95% CI -£451.19 to £597.90), yielding an incremental cost-effectiveness ratio of £1828. Most secondary outcomes showed significant benefit for the intervention. CONCLUSIONS: A short course of tCBT did not prevent onset of CWP in adults at high risk, but improved quality of life and was cost-effective. A low-cost, short-duration intervention benefits persons at risk of CWP. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02668003).

The Ambulance Cardiac Chest Pain Evaluation in Scotland Study (ACCESS): A Prospective Cohort Study.

STUDY OBJECTIVE: To determine whether risk stratification in the out-of-hospital setting could identify patients with chest pain who are at low and high risk to avoid admission or aid direct transfer to cardiac centers. METHODS: Paramedics prospectively enrolled patients with suspected acute coronary syndrome without diagnostic ST-segment elevation on the ECG. The History, ECG, Age and Risk Factors (HEAR) score was recorded contemporaneously, and out-of-hospital samples were obtained to measure cardiac Troponin I (cTnI) level on a point-of-care device, to allow calculation of the History, ECG, Age, Risk Factors, and Troponin (HEART) score. HEAR and HEART scores less than or equal to 3 and greater than or equal to 7 were defined as low and high risk for major adverse cardiac events at 30 days. RESULTS: Of 1,054 patients (64 years [SD 15 years]; 42% women), 284 (27%) experienced a major adverse cardiac event at 30 days. The HEAR score was calculated in all patients, with point-of-care cTnI testing available in 357 (34%). A HEAR score less than or equal to 3 identified 32% of patients (334/1,054) as low risk, with a sensitivity of 84.9% (95% confidence interval [CI] 80.7% to 89%), whereas a score greater than or equal to 7 identified just 3% of patients (30/1,054) as high risk, with a specificity of 98.7% (95% CI 97.9% to 99.5%). A point-of-care HEART score less than or equal to 3 identified a similar proportion as low risk (30%), with a sensitivity of 87.0% (95% CI 80.7% to 93.4%), whereas a score greater than or equal to 7 identified 14% as high risk, with a specificity of 94.8% (95% CI 92.0% to 97.5%). CONCLUSION: Paramedics can use the HEAR score to discriminate risk, but even when used in combination with out-of-hospital point-of-care cTnI testing, the HEART score does not safely rule out major adverse cardiac events, and only a small proportion of patients are identified as high risk.

Screen detection is a survival predictor independent of pathological grade in colorectal cancer. A prospective cohort study.

INTRODUCTION: Patients with screened detected colorectal cancer (CRC) have a better survival than patients referred with symptoms. This may be because of cancers being identified in a younger population and at an earlier stage. In this study, we assess whether screened detected CRC has an improved outcome after controlling for key pathological and patient factors known to influence prognosis. METHOD: This is a cohort study of all CRC patients diagnosed in NHS Grampian. Patients aged 51-75 years old between June 2007 and July 2017 were included. Data were obtained from a prospectively maintained regional pathology database and outcomes from ISD records. All-cause mortality rates at 1 and 5 years were examined. A Cox proportional hazards regression model was used to estimate the effect of screening status, age, gender, Duke stage, tumour location, extramural venous invasion (EMVI) status and lymph node ratio (LNR) on overall survival. RESULTS: Of 1618 CRC cases, 449 (27.8%) were screened and 1169 (72.2%) were symptomatic. Screened CRC patients had improved survival compared to non-screened CRC at 1 year (88.9% vs 83.9% p < 0.001) and 5-years (42.5% vs 36.2%; p < 0.001). On multivariable analysis of patients who had no neoadjuvant therapy (n = 1272), screening had better survival (HR 0.57; 95% CI 0.44-0.74; p < 0.001). EMVI (HR 2.22; CI 1.76 to 2.79; p < 0.001) and tumour location were found to affect outcome. CONCLUSION: Patients referred through screening had improved survival compared with symptomatic patients. Further research could be targeted to determine if screened CRC cases are pathologically different to symptomatic cancers or if the screening cohort is inherently more healthy.

Laparoscopic supracervical hysterectomy versus endometrial ablation for women with heavy menstrual bleeding (HEALTH): a parallel-group, open-label, randomised controlled trial.

BACKGROUND: Heavy menstrual bleeding affects 25% of women in the UK, many of whom require surgery to treat it. Hysterectomy is effective but has more complications than endometrial ablation, which is less invasive but ultimately leads to hysterectomy in 20% of women. We compared laparoscopic supracervical hysterectomy with endometrial ablation in women seeking surgical treatment for heavy menstrual bleeding. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial in 31 hospitals in the UK, women younger than 50 years who were referred to a gynaecologist for surgical treatment of heavy menstrual bleeding and who were eligible for endometrial ablation were randomly allocated (1:1) to either laparoscopic supracervical hysterectomy or second generation endometrial ablation. Women were randomly assigned by either an interactive voice response telephone system or an internet-based application with a minimisation algorithm based on centre and age group (<40 years vs ≥40 years). Laparoscopic supracervical hysterectomy involves laparoscopic (keyhole) surgery to remove the upper part of the uterus (the body) containing the endometrium. Endometrial ablation aims to treat heavy menstrual bleeding by destroying the endometrium, which is responsible for heavy periods. The co-primary clinical outcomes were patient satisfaction and condition-specific quality of life, measured with the menorrhagia multi-attribute quality of life scale (MMAS), assessed at 15 months after randomisation. Our analysis was based on the intention-to-treat principle. The trial was registered with the ISRCTN registry, number ISRCTN49013893. FINDINGS: Between May 21, 2014, and March 28, 2017, we enrolled and randomly assigned 660 women (330 in each group). 616 (93%) of 660 women were operated on within the study period, 588 (95%) of whom received the allocated procedure and 28 (5%) of whom had an alternative surgery. At 15 months after randomisation, more women allocated to laparoscopic supracervical hysterectomy were satisfied with their operation compared with those in the endometrial ablation group (270 [97%] of 278 women vs 244 [87%] of 280 women; adjusted percentage difference 9·8, 95% CI 5·1-14·5; adjusted odds ratio [OR] 2·53, 95% CI 1·83-3·48; p<0·0001). Women randomly assigned to laparoscopic supracervical hysterectomy were also more likely to have the best possible MMAS score of 100 than women assigned to endometrial ablation (180 [69%] of 262 women vs 146 [54%] of 268 women; adjusted percentage difference 13·3, 95% CI 3·8-22·8; adjusted OR 1·87, 95% CI 1·31-2·67; p=0·00058). 14 (5%) of 309 women in the laparoscopic supracervical hysterectomy group and 11 (4%) of 307 women in the endometrial ablation group had at least one serious adverse event (adjusted OR 1·30, 95% CI 0·56-3·02; p=0·54). INTERPRETATION: Laparoscopic supracervical hysterectomy is superior to endometrial ablation in terms of clinical effectiveness and has a similar proportion of complications, but takes longer to perform and is associated with a longer recovery. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Interventions for treating people with symptoms of bladder pain syndrome: a network meta-analysis.

BACKGROUND: Bladder pain syndrome (BPS), which includes the condition of interstitial cystitis, is a poorly understood clinical condition for which patients present with varying symptoms. Management of BPS is challenging for both patients and practitioners. At present, there is no universally accepted diagnosis and diverse causes have been proposed. This is reflected in wide-ranging treatment options, used alone or in combination, with limited evidence. A network meta-analysis (NMA) simultaneously comparing multiple treatments may help to determine the best treatment options for patients with BPS. OBJECTIVES: To conduct a network meta-analysis to assess the effects of interventions for treating people with symptoms of bladder pain syndrome (BPS). SEARCH METHODS: We searched the Cochrane Incontinence Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and handsearched journals and conference proceedings (searched 11 May 2018) and the reference lists of relevant articles. We conducted a further search on 5 June 2019, which yielded four small studies that were screened for eligibility but were not incorporated into the review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of interventions for treating adults with BPS. All types of interventions (including conservative, pharmacological and surgical) were eligible. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of included studies using Cochrane's 'Risk of bias' tool. Primary outcomes were the number of people cured or improved, pain, frequency and nocturia. For each outcome, random-effects NMA models were fitted using WinBUGS 1.4. We monitored median odds ratios (ORs) for binary outcomes and mean differences (MDs) for continuous outcomes with 95% credible intervals (Crls). We compared results of the NMA with direct evidence from pairwise meta-analysis of head-to-head trials. We used the CINeMA tool to assess the certainty of evidence for selected treatment categories. MAIN RESULTS: We included 81 RCTs involving 4674 people with a median of 38 participants (range 10 to 369) per RCT. Most trials compared treatment against control; few trials compared two active treatments. There were 65 different active treatments, and some comparisons were informed by direct evidence from only one trial. To simplify, treatments were grouped into 31 treatment categories by mode of action. Most studies were judged to have unclear or high risk of bias for most domains, particularly for selection and detection bias. Overall, the NMA suggested that six (proportion cured/improved), one (pain), one (frequency) and zero (nocturia) treatment categories were effective compared with control, but there was great uncertainty around estimates of effect. Due to the large number of intervention comparisons in this review, we focus on three interventions: antidepressants, pentosan polysulfate (PPS) and neuromuscular blockade. We selected these interventions on the basis that they are given 'strong recommendations' in the EAU Guidelines for management of BPS (EAU Guidelines 2019). We found very low-certainty evidence suggesting that antidepressants were associated with greater likelihood of cure or improvement compared with control (OR 5.91, 95% CrI 1.12 to 37.56), but it was uncertain whether they reduced pain (MD -1.27, 95% CrI -3.25 to 0.71; low-certainty evidence), daytime frequency (MD -2.41, 95% CrI -6.85 to 2.05; very low-certainty evidence) or nocturia (MD 0.01, 95% CrI -2.53 to 2.50; very low-certainty evidence). There was no evidence that PPS had improved cure/improvement rates (OR 0.14, 95% CrI 0.40 to 3.35; very low-certainty evidence) or reduced pain (MD 0.42, 95% CrI -1.04 to 1.91; low-certainty evidence), frequency (MD -0.37, 95% CrI -5.00 to 3.44; very low-certainty evidence) or nocturia (MD -1.20, 95% CrI -3.62 to 1.28; very low-certainty evidence). There was evidence that neuromuscular blockade resulted in greater cure or improvement (OR 5.80, 95% CrI 2.08 to 18.30) but no evidence that it improved pain (MD -0.33, 95% CrI -1.71 to 1.03), frequency (MD -0.91, 95% CrI -3.24, 1.29) or nocturia (MD -0.04, 95% CrI -1.35 to 1.27). The certainty of this evidence was always very low. AUTHORS' CONCLUSIONS: We are uncertain whether some treatments may be effective in treating patients with BPS because the certainty of evidence was generally low or very low. Data were available for a relatively large number of trials, but most had small sample sizes and effects of treatments often could not be estimated with precision. An NMA was successfully conducted, but limited numbers of small trials for each treatment category hampered our ability to fully exploit the advantages of this analysis. Larger, more focused trials are needed to improve the current evidence base.

Pharmacist services for non-hospitalised patients.

BACKGROUND: This review focuses on non-dispensing services from pharmacists, i.e. pharmacists in community, primary or ambulatory-care settings, to non-hospitalised patients, and is an update of a previously-published Cochrane Review. OBJECTIVES: To examine the effect of pharmacists' non-dispensing services on non-hospitalised patient outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases and two trial registers in March 2015, together with reference checking and contact with study authors to identify additional studies. We included non-English language publications. We ran top-up searches in January 2018 and have added potentially eligible studies to 'Studies awaiting classification'. SELECTION CRITERIA: Randomised trials of pharmacist services compared with the delivery of usual care or equivalent/similar services with the same objective delivered by other health professionals. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures of Cochrane and the Effective Practice and Organisation of Care Group. Two review authors independently checked studies for inclusion, extracted data and assessed risks of bias. We evaluated the overall certainty of evidence using GRADE. MAIN RESULTS: We included 116 trials comprising 111 trials (39,729 participants) comparing pharmacist interventions with usual care and five trials (2122 participants) comparing pharmacist services with services from other healthcare professionals. Of the 116 trials, 76 were included in meta-analyses. The 40 remaining trials were not included in the meta-analyses because they each reported unique outcome measures which could not be combined. Most trials targeted chronic conditions and were conducted in a range of settings, mostly community pharmacies and hospital outpatient clinics, and were mainly but not exclusively conducted in high-income countries. Most trials had a low risk of reporting bias and about 25%-30% were at high risk of bias for performance, detection, and attrition. Selection bias was unclear for about half of the included studies.Compared with usual care, we are uncertain whether pharmacist services reduce the percentage of patients outside the glycated haemoglobin target range (5 trials, N = 558, odds ratio (OR) 0.29, 95% confidence interval (CI) 0.04 to 2.22; very low-certainty evidence). Pharmacist services may reduce the percentage of patients whose blood pressure is outside the target range (18 trials, N = 4107, OR 0.40, 95% CI 0.29 to 0.55; low-certainty evidence) and probably lead to little or no difference in hospital attendance or admissions (14 trials, N = 3631, OR 0.85, 95% CI 0.65 to 1.11; moderate-certainty evidence). Pharmacist services may make little or no difference to adverse drug effects (3 trials, N = 590, OR 1.65, 95% CI 0.84 to 3.24) and may slightly improve physical functioning (7 trials, N = 1329, mean difference (MD) 5.84, 95% CI 1.21 to 10.48; low-certainty evidence). Pharmacist services may make little or no difference to mortality (9 trials, N = 1980, OR 0.79, 95% CI 0.56 to 1.12, low-certaintly evidence).Of the five studies that compared services delivered by pharmacists with other health professionals, no studies evaluated the impact of the intervention on the percentage of patients outside blood pressure or glycated haemoglobin target range, hospital attendance and admission, adverse drug effects, or physical functioning. AUTHORS' CONCLUSIONS: The results demonstrate that pharmacist services have varying effects on patient outcomes compared with usual care. We found no studies comparing services delivered by pharmacists with other healthcare professionals that evaluated the impact of the intervention on the six main outcome measures. The results need to be interpreted cautiously because there was major heterogeneity in study populations, types of interventions delivered and reported outcomes.There was considerable heterogeneity within many of the meta-analyses, as well as considerable variation in the risks of bias.

Clinical response of pigment epithelial detachment associated with neovascular age-related macular degeneration in switching treatment from Ranibizumab to Aflibercept.

BACKGROUND: To study the clinical outcomes of pigment epithelial detachment (PED) associated with neovascular age-related macular degeneration (nAMD) in patients switched from Ranibizumab to Aflibercept. METHODS: Retrospective non-comparative case series. 50 eyes with active nAMD and fovea involving PED of ≥100 µm measured manually using the caliper on the OCT, initially treated with intravitreal Ranibizumab (0.5 mg/0.05 ml) and later switched to Aflibercept (2.0 mg/0.05 ml). The outcome measures of best corrected visual acuity (BCVA), PED height, PED width and number of injections were measured at baseline and at time point of switch, 4 months, 1 year and at last follow up visit post-switch. Three paired t-tests and Pearson's correlations were calculated to analyze variables at switch and change in variables at 1 year. RESULTS: After switch to Aflibercept, the improvement of BCVA was 1.84 (p = 0.11), 1.74 (p = 0.21) and 1.16 (p = 0.45) letters, the change in PED height was - 65.6µm (p < 0.001), - 50.64µm (p = 0.007) and - 68.48µm (p < 0.001) and the change in PED width was - 36.6µm (p = 0.514), + 29.7µm (p = 0.922) and + 118.4µm (p = 0.210) at 4 months, 1 year and the last visit respectively. There was a moderate negative correlation between reduction in PED height at 1 year after switch and PED height at the time of switch to Aflibercept (r = - 0.474, p < 0.05). CONCLUSION: The improvement in BCVA and change in PED width was not statistically significant however the reduction in PED height was significant after switching treatment to Aflibercept. The change in BCVA at 1 year after switch was not correlated with any of the analyzed anatomical characteristics of PED.

The prevalence of sarcopaenia in a vascular surgical patient cohort and its impact on outcome.

BACKGROUND: Sarcopaenia, loss of lean muscle mass and quality, has prognostic significance and can be used to guide the management of oncology patients.1 However, there is limited research into the prevalence and effect of sarcopaenia in vascular populations. We aim to investigate the prevalence of this measure of physiological reserve in a vascular patient group. METHODS: All patients admitted to a tertiary vascular unit in a single year were considered for the study. Patients with an abdominal CT scan (available for analysis) within 12 months of admission were included. Patient data were extracted from electronic patient records and hospital case notes. CT scans were analysed at L3 vertebral body to calculate body composition indices, as previously described.1 Sarcopaenia was defined as skeletal muscle index of <41 cm2/m2 in female patients and non-obese males and <53 cm2/m2 in obese males. Outcome at 3-years was ascertained. RESULTS: Of 314 patients, 129 (41.1%) were sarcopaenic. Female patients were more likely to be sarcopaenic (p < 0.0001). The prevalence of sarcopaenia increased with age (p < 0.001). Rates of sarcopaenia didn't differ between occlusive and aneurysmal diagnoses. In a potentially unique finding in vascular literature to date, mortality and non-home discharge were not significantly different between the groups. On multivariate analysis, sarcopaenia was not significantly associated with earlier death (p = 0.55). CONCLUSIONS: Sarcopaenia is highly prevalent in vascular surgical patients. In our analysis, sarcopaenia was not independently associated with mortality. Potentially the associated cardiovascular risk of patients with end stage vascular disease may negate the additional risk of altered body composition.

Psychological preparation and postoperative outcomes for adults undergoing surgery under general anaesthesia.

BACKGROUND: In a review and meta-analysis conducted in 1993, psychological preparation was found to be beneficial for a range of outcome variables including pain, behavioural recovery, length of stay and negative affect. Since this review, more detailed bibliographic searching has become possible, additional studies testing psychological preparation for surgery have been completed and hospital procedures have changed. The present review examines whether psychological preparation (procedural information, sensory information, cognitive intervention, relaxation, hypnosis and emotion-focused intervention) has impact on the outcomes of postoperative pain, behavioural recovery, length of stay and negative affect. OBJECTIVES: To review the effects of psychological preparation on postoperative outcomes in adults undergoing elective surgery under general anaesthetic. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL 2014, Issue 5), MEDLINE (OVID SP) (1950 to May 2014), EMBASE (OVID SP) (1982 to May 2014), PsycINFO (OVID SP) (1982 to May 2014), CINAHL (EBESCOhost) (1980 to May 2014), Dissertation Abstracts (to May 2014) and Web of Science (1946 to May 2014). We searched reference lists of relevant studies and contacted authors to identify unpublished studies. We reran the searches in July 2015 and placed the 38 studies of interest in the `awaiting classification' section of this review. SELECTION CRITERIA: We included randomized controlled trials of adult participants (aged 16 or older) undergoing elective surgery under general anaesthesia. We excluded studies focusing on patient groups with clinically diagnosed psychological morbidity. We did not limit the search by language or publication status. We included studies testing a preoperative psychological intervention that included at least one of these seven techniques: procedural information; sensory information; behavioural instruction; cognitive intervention; relaxation techniques; hypnosis; emotion-focused intervention. We included studies that examined any one of our postoperative outcome measures (pain, behavioural recovery, length of stay, negative affect) within one month post-surgery. DATA COLLECTION AND ANALYSIS: One author checked titles and abstracts to exclude obviously irrelevant studies. We obtained full reports of apparently relevant studies; two authors fully screened these. Two authors independently extracted data and resolved discrepancies by discussion.Where possible we used random-effects meta-analyses to combine the results from individual studies. For length of stay we pooled mean differences. For pain and negative affect we used a standardized effect size (the standardized mean difference (SMD), or Hedges' g) to combine data from different outcome measures. If data were not available in a form suitable for meta-analysis we performed a narrative review. MAIN RESULTS: Searches identified 5116 unique papers; we retrieved 827 for full screening. In this review, we included 105 studies from 115 papers, in which 10,302 participants were randomized. Mainly as a result of updating the search in July 2015, 38 papers are awaiting classification. Sixty-one of the 105 studies measured the outcome pain, 14 behavioural recovery, 58 length of stay and 49 negative affect. Participants underwent a wide range of surgical procedures, and a range of psychological components were used in interventions, frequently in combination. In the 105 studies, appropriate data were provided for the meta-analysis of 38 studies measuring the outcome postoperative pain (2713 participants), 36 for length of stay (3313 participants) and 31 for negative affect (2496 participants). We narratively reviewed the remaining studies (including the 14 studies with 1441 participants addressing behavioural recovery). When pooling the results for all types of intervention there was low quality evidence that psychological preparation techniques were associated with lower postoperative pain (SMD -0.20, 95% confidence interval (CI) -0.35 to -0.06), length of stay (mean difference -0.52 days, 95% CI -0.82 to -0.22) and negative affect (SMD -0.35, 95% CI -0.54 to -0.16) compared with controls. Results tended to be similar for all categories of intervention, although there was no evidence that behavioural instruction reduced the outcome pain. However, caution must be exercised when interpreting the results because of heterogeneity in the types of surgery, interventions and outcomes. Narratively reviewed evidence for the outcome behavioural recovery provided very low quality evidence that psychological preparation, in particular behavioural instruction, may have potential to improve behavioural recovery outcomes, but no clear conclusions could be reached.Generally, the evidence suffered from poor reporting, meaning that few studies could be classified as having low risk of bias. Overall,we rated the quality of evidence for each outcome as 'low' because of the high level of heterogeneity in meta-analysed studies and the unclear risk of bias. In addition, for the outcome behavioural recovery, too few studies used robust measures and reported suitable data for meta-analysis, so we rated the quality of evidence as `very low'. AUTHORS' CONCLUSIONS: The evidence suggested that psychological preparation may be beneficial for the outcomes postoperative pain, behavioural recovery, negative affect and length of stay, and is unlikely to be harmful. However, at present, the strength of evidence is insufficient to reach firm conclusions on the role of psychological preparation for surgery. Further analyses are needed to explore the heterogeneity in the data, to identify more specifically when intervention techniques are of benefit. As the current evidence quality is low or very low, there is a need for well-conducted and clearly reported research.

Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis.

BACKGROUND: Seasonal/perennial allergic conjunctivitis is the most common allergic conjunctivitis, usually with acute manifestations when a person is exposed to allergens and with typical signs and symptoms including itching, redness, and tearing. The clinical signs and symptoms of allergic conjunctivitis are mediated by the release of histamine by mast cells. Histamine antagonists (also called antihistamines) inhibit the action of histamine by blocking histamine H1 receptors, antagonising the vasoconstrictor, and to a lesser extent, the vasodilator effects of histamine. Mast cell stabilisers inhibit degranulation and consequently the release of histamine by interrupting the normal chain of intracellular signals. Topical treatments include eye drops with antihistamines, mast cell stabilisers, non-steroidal anti-inflammatory drugs, combinations of the previous treatments, and corticosteroids. Standard treatment is based on topical antihistamines alone or topical mast cell stabilisers alone or a combination of treatments. There is clinical uncertainty about the relative efficacy and safety of topical treatment. OBJECTIVES: The objective of this review was to assess the effects of topical antihistamines and mast cell stabilisers, alone or in combination, for use in treating seasonal and perennial allergic conjunctivitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 July 2014. We also searched the reference lists of review articles and relevant trial reports for details of further relevant publications. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing topical antihistamine and mast cell stabilisers, alone or in combination, with placebo, no treatment or to any other antihistamine or mast cell stabiliser, or both, that examined people with seasonal or perennial allergic conjunctivitis, or both. The primary outcome was any participant-reported evaluation (by questionnaire) of severity of four main ocular symptoms: itching, irritation, watering eye (tearing), and photophobia (dislike of light), both separately and, if possible, by an overall symptom score. We considered any follow-up time between one week and one year. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Disagreements were resolved by discussion among review authors and the involvement of a third review author. We followed standard methodological approaches used by Cochrane. MAIN RESULTS: We identified 30 trials with a total of 4344 participants randomised, with 17 different drugs or treatment comparisons. The following antihistamines and mast cell stabilisers were evaluated in at least one RCT: nedocromil sodium or sodium cromoglycate, olopatadine, ketotifen, azelastine, emedastine, levocabastine (or levocabastine), mequitazine, bepotastine besilate, combination of antazoline and tetryzoline, combination of levocabastine and pemirolast potassium. The most common comparison was azelastine versus placebo (nine studies).We observed a large variability in reporting outcomes. The quality of the studies and reporting was variable, but overall the risk of bias was low. Trials evaluated only short-term effects, with a range of treatment of one to eight weeks. Meta-analysis was only possible in one comparison (olopatadine versus ketotifen). There was some evidence to support that topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo. There were no reported serious adverse events related to the use of topical antihistamine and mast cell stabilisers treatment. AUTHORS' CONCLUSIONS: It seems that all reported topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo in the short term. However, there is no long-term data on their efficacy. Direct comparisons of different antihistamines and mast cell stabilisers need to be interpreted with caution. Overall, topical antihistamines and mast cell stabilisers appear to be safe and well tolerated. We observed a large variability in outcomes reported. Poor quality of reporting challenged the synthesis of evidence.

Vitrectomy with internal limiting membrane peeling versus no peeling for idiopathic full-thickness macular hole.

OBJECTIVE: To determine whether internal limiting membrane (ILM) peeling improves anatomic and functional outcomes of full-thickness macular hole (FTMH) surgery when compared with the no-peeling technique. DESIGN: Systematic review and individual participant data (IPD) meta-analysis undertaken under the auspices of the Cochrane Eyes and Vision Group. Only randomized controlled trials (RCTs) were included. PARTICIPANTS AND CONTROLS: Patients with idiopathic stage 2, 3, and 4 FTMH undergoing vitrectomy with or without ILM peeling. INTERVENTION: Macular hole surgery, including vitrectomy and gas endotamponade with or without ILM peeling. MAIN OUTCOME MEASURES: Primary outcome was best-corrected distance visual acuity (BCdVA) at 6 months postoperatively. Secondary outcomes were BCdVA at 3 and 12 months; best-corrected near visual acuity (BCnVA) at 3, 6, and 12 months; primary (after a single surgery) and final (after >1 surgery) macular hole closure; need for additional surgical interventions; intraoperative and postoperative complications; patient-reported outcomes (PROs) (EuroQol-5D and Vision Function Questionnaire-25 scores at 6 months); and cost-effectiveness. RESULTS: Four RCTs were identified and included in the review. All RCTs were included in the meta-analysis; IPD were obtained from 3 of the 4 RCTs. No evidence of a difference in BCdVA at 6 months was detected (mean difference, -0.04; 95% confidence interval [CI], -0.12 to 0.03; P=0.27); however, there was evidence of a difference in BCdVA at 3 months favoring ILM peeling (mean difference, -0.09; 95% CI, -0.17 to-0.02; P=0.02). There was evidence of an effect favoring ILM peeling with regard to primary (odds ratio [OR], 9.27; 95% CI, 4.98-17.24; P<0.00001) and final macular hole closure (OR, 3.99; 95% CI, 1.63-9.75; P=0.02) and less requirement for additional surgery (OR, 0.11; 95% CI, 0.05-0.23; P<0.00001), with no evidence of a difference between groups with regard to intraoperative or postoperative complications or PROs. The ILM peeling was found to be highly cost-effective. CONCLUSIONS: Available evidence supports ILM peeling as the treatment of choice for patients with idiopathic stage 2, 3, and 4 FTMH.

A comparison of three methods of assessing differential item functioning (DIF) in the Hospital Anxiety Depression Scale: ordinal logistic regression, Rasch analysis and the Mantel chi-square procedure.

PURPOSE: It is important for clinical practice and research that measurement scales of well-being and quality of life exhibit only minimal differential item functioning (DIF). DIF occurs where different groups of people endorse items in a scale to different extents after being matched by the intended scale attribute. We investigate the equivalence or otherwise of common methods of assessing DIF. METHOD: Three methods of measuring age- and sex-related DIF (ordinal logistic regression, Rasch analysis and Mantel χ(2) procedure) were applied to Hospital Anxiety Depression Scale (HADS) data pertaining to a sample of 1,068 patients consulting primary care practitioners. RESULTS: Three items were flagged by all three approaches as having either age- or sex-related DIF with a consistent direction of effect; a further three items identified did not meet stricter criteria for important DIF using at least one method. When applying strict criteria for significant DIF, ordinal logistic regression was slightly less sensitive. CONCLUSIONS: Ordinal logistic regression, Rasch analysis and contingency table methods yielded consistent results when identifying DIF in the HADS depression and HADS anxiety scales. Regardless of methods applied, investigators should use a combination of statistical significance, magnitude of the DIF effect and investigator judgement when interpreting the results.

A survey of factors influencing career preference in new-entrant and exiting medical students from four UK medical schools.

BACKGROUND: Workforce planning is a central issue for service provision and has consequences for medical education. Much work has been examined the career intentions, career preferences and career destinations of UK medical graduates but there is little published about medical students career intentions. How soon do medical students formulate careers intentions? How much do these intentions and preferences change during medical school? If they do change, what are the determining factors? Our aim was to compare medical students' career preferences upon entry into and exit from undergraduate medical degree programmes. METHODS: This was a cross-sectional questionnaire survey. Two cohorts [2009-10, 2010-11] of first and final year medical students at the four Scottish graduating medical schools took part in career preference questionnaire surveys. Questions were asked about demographic factors, career preferences and influencing factors. RESULTS: The response rate was 80.9% [2682/3285]. Significant differences were found across the four schools, most obviously in terms of student origin [Scotland, rest of UK or overseas], age group, and specialty preferences in Year 1 and Year 5. Year 1 and Year 5 students' specialty preferences also differed within each school and, while there were some common patterns, each medical school had a different profile of students' career preferences on exit. When the analysis was adjusted for demographic and job-related preferences, specialty preferences differed by gender, and wish for work-life balance and intellectual satisfaction. CONCLUSIONS: This is the first multi-centre study exploring students' career preferences and preference influences upon entry into and exit from undergraduate medical degree programmes. We found various factors influenced career preference, confirming prior findings. What this study adds is that, while acknowledging student intake differs by medical school, medical school itself seems to influence career preference. Comparisons across medical school populations must therefore control for differences in input [the students] as well as context and process [the medical school] when looking at output [e.g., performance]. A robust, longitudinal study is required to explore how medical students' career preferences change as they progress through medical school and training to understand the influence of the learning environment on training choice and outcomes.

Evidence for Suzuki-Miyaura cross-couplings catalyzed by ligated Pd3-clusters: from cradle to grave.

Pdn clusters offer unique selectivity and exploitable reactivity in catalysis. Understanding the behavior of Pdn clusters is thus critical for catalysis, applied synthetic organic chemistry and greener outcomes for precious Pd. The Pd3 cluster, [Pd3(µ-Cl)(µ-PPh2)2(PPh3)3][Cl] (denoted as Pd3Cl2), which exhibits distinctive reactivity, was synthesized and immobilized on a phosphine-functionalized polystyrene resin (denoted as immob-Pd3Cl2). The resultant material served as a tool to study closely the role of Pd3 clusters in a prototypical Suzuki-Miyaura cross-coupling of 4-fluoro-1-bromobenzene and 4-methoxyphenyl boronic acid at varying low Pd ppm concentrations (24, 45, and 68 ppm). Advanced heterogeneity tests such as Hg poisoning and the three-phase test showed that leached mononuclear or nanoparticulate Pd are unlikely to be the major active catalyst species under the reaction conditions tested. EXAFS/XANES analysis from (pre)catalyst and filtered catalysts during and after catalysis has shown the intactness of the triangular structure of the Pd3X2 cluster, with exchange of chloride (X) by bromide during catalytic turnover of bromoarene substrate. This finding is further corroborated by treatment of immob-Pd3Cl2 after catalyzing the Suzuki-Miyaura reaction with excess PPh3, which releases the cluster from the polymer support and so permits direct observation of [Pd3(µ-Br)(µ-PPh2)2(PPh3)3]+ ions by ESI-MS. No evidence is seen for a proposed intermediate in which the bridging halogen on the Pd3 motif is replaced by an aryl group from the organoboronic acid, i.e. formed by a transmetallation-first process. Our findings taken together indicate that the 'Pd3X2' motif is an active catalyst species, which is stabilized by being immobilized, providing a more robust Pd3 cluster catalyst system. Non-immobilized Pd3Cl2 is less stable, as is followed by stepwise XAFS of the non-immobilized Pd3Cl2, which gradually changes to a species consistent with 'Pdx(PPh3)y' type material. Our findings have far-reaching future implications for Pd3 cluster involvement in catalysis, showing that immobilization of Pd3 cluster species offers advantages for rigorous mechanistic examination and applied chemistries.