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.

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.

Opening a Pandora's Flask on a Prototype Catalytic Direct Arylation Reaction of Pentafluorobenzene: The Ag2CO3/Pd(OAc)2/PPh3 System.

Direct C-H functionalization reactions have opened new avenues in catalysis, removing the need for prefunctionalization of at least one of the substrates. Although C-H functionalization catalyzed by palladium complexes in the presence of a base is generally considered to proceed by the CMD/AMLA-6 mechanism, recent research has shown that silver(I) salts, frequently used as bases, can function as C-H bond activators instead of (or in addition to) palladium(II). In this study, we examine the coupling of pentafluorobenzene 1 to 4-iodotoluene 2a (and its analogues) to form 4-(pentafluorophenyl)toluene 3a catalyzed by palladium(II) acetate with the commonplace PPh3 ligand, silver carbonate as base, and DMF as solvent. By studying the reaction of 1 with Ag2CO3/PPh3 and with isolated silver (triphenylphosphine) carbonate complexes, we show the formation of C-H activation products containing the Ag(C6F5)(PPh3)n unit. However, analysis is complicated by the lability of the Ag-PPh3 bond and the presence of multiple species in the solution. The speciation of palladium(II) is investigated by high-resolution-MAS NMR (chosen for its suitability for suspensions) with a substoichiometric catalyst, demonstrating the formation of an equilibrium mixture of Pd(Ar)(κ1-OAc)(PPh3)2 and [Pd(Ar)(µ-OAc)(PPh3)]2 as resting states (Ar = Ph, 4-tolyl). These two complexes react stoichiometrically with 1 to form coupling products. The catalytic reaction kinetics is investigated by in situ IR spectroscopy revealing a two-term rate law and dependence on [Pdtot/nPPh3]0.5 consistent with the dissociation of an off-cycle palladium dimer. The first term is independent of [1], whereas the second term is first order in [1]. The observed rates are very similar with Pd(PPh3)4, Pd(Ph)(κ1-OAc)(PPh3)2, and [Pd(Ph)(µ-OAc)(PPh3)]2 catalysts. The kinetic isotope effect varied significantly according to conditions. The multiple speciation of both AgI and PdII acts as a warning against specifying the catalytic cycles in detail. Moreover, the rapid dynamic interconversion of AgI species creates a level of complexity that has not been appreciated previously.

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.

Skin cancer in essential thrombocythaemia and polycythaemia vera patients treated with hydroxycarbamide.

Hydroxycarbamide (HC) is used as a cytoreductive treatment in myeloproliferative neoplasms (MPN). Observational studies have raised the possibility that HC contributes to the development of secondary malignancies, including skin tumours in MPN patients. In this retrospective observational study, we report a single-centre experience of 324 HC-treated MPN patients with long-term follow-up, compared to 47 MPN patients not on HC. Thirty-three patients (10.2%) (HC) versus one patient (2.1%) (no HC) developed skin tumours during follow-up (Hazard ratios [HR] 5.70, 95% confidence intervals 0.66-48.09, p = 0.112). However, male gender, age at MPN diagnosis, type of MPN (polycythaemia rubra vera) and previous history of skin cancer were prognostic variables associated with development of skin cancer.

Emergency general surgery: impact of distance and rurality on mortality.

BACKGROUND: There is debate about whether the distance from hospital, or rurality, impacts outcomes in patients admitted under emergency general surgery (EGS). The aim of this study was to determine whether distance from hospital, or rurality, affects the mortality of emergency surgical patients admitted in Scotland. METHODS: This was a retrospective population-level cohort study, including all EGS patients in Scotland aged 16 years or older admitted between 1998 and 2018. A multiple logistic regression model was created with inpatient mortality as the dependent variable, and distance from hospital (in quartiles) as the independent variable of interest, adjusting for age, sex, co-morbidity, deprivation, admission origin, diagnosis category, operative category, and year of admission. A second multiple logistic regression model was created with a six-fold Scottish Urban Rural Classification (SURC) as the independent variable of interest. Subgroup analyses evaluated patients who required operations, emergency laparotomy, and inter-hospital transfer. RESULTS: Data included 1 572 196 EGS admissions. Those living in the farthest distance quartile from hospital had lower odds of mortality than those in the closest quartile (OR 0.829, 95 per cent c.i. 0.798 to 0.861). Patients from the most rural areas (SURC 6) had higher odds of survival than those from the most urban (SURC 1) areas (OR 0.800, 95 per cent c.i. 0.755 to 0.848). Subgroup analysis showed that these effects were not observed for patients who required emergency laparotomy or transfer. CONCLUSION: EGS patients who live some distance from a hospital, or in rural areas, have lower odds of mortality, after adjusting for multiple covariates. Rural and distant patients undergoing emergency laparotomy have no survival advantage, and transferred patients have higher mortality.

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.

Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial.

BACKGROUND: The benefit of fractional exhaled nitric oxide (FeNO) in guiding asthma treatment is uncertain. We evaluated the efficacy of adding FeNO to symptom-guided treatment in children with asthma versus only symptom-guided treatment. METHODS: RAACENO was a multicentre, parallel, randomised, controlled, phase 3 trial done in 35 secondary care centres and 17 primary care recruitment sites (only seven primary care sites managed to recruit patients) in the UK. Patients with a confirmed asthma diagnosis, aged 6-15 years, prescribed inhaled corticosteroids, and who received a course of oral corticosteroids for at least one asthma exacerbation during the 12 months before recruitment were included. Participants were randomly assigned to either FeNO plus symptom-guided treatment (intervention) or symptom-guided treatment alone (standard care) using a 24 h in-house, web-based randomisation system. Participants and the clinical and research teams were not masked to the group allocation. A web-based algorithm gave treatment recommendations based on the Asthma Control Test (ACT) or Childhood ACT (CACT) score; current asthma treatment; adherence to study treatment in the past 3 months; and use of FeNO (in the intervention group). Follow-up occurred at 3-month intervals for 12 months. The primary outcome was any asthma exacerbation treated with oral corticosteroids in the 12 months after randomisation, assessed in the intention-to-treat population. This study is registered with the International Standard Randomised Controlled Trial Registry, ISRCTN67875351. FINDINGS: Between June 22, 2017, and Aug 8, 2019, 535 children were assessed for eligibility, 20 were ineligible and six were excluded post-randomisation. 509 children were recruited and at baseline, the mean age of participants was 10·1 years (SD 2·6), and 308 (60·5%) were male. The median FeNO was 21 ppb (IQR 10-48), mean predicted FEV1 was 89·6% (SD 18·0), and median daily dose of inhaled corticosteroids was 400 µg budesonide equivalent (IQR 400-1000). Asthma was partly or fully controlled in 256 (50·3%) of 509 participants. The primary outcome, which was available for 506 (99%) of 509 participants, occurred in 123 (48·2%) of 255 participants in the intervention group and 129 (51·4%) of 251 in the standard care group, the intention-to-treat adjusted odds ratio (OR) was 0·88 (95% CI 0·61 to 1·27; p=0·49). The adjusted difference in the percentage of participants who received the intervention in whom the primary outcome occurred compared with those who received standard care was -3·1% (-11·9% to 5·6%). In 377 (21·3%) of 1771 assessments, the algorithm recommendation was not followed. Adverse events were reported by 27 (5·3%) of 509 participants (15 in the standard care group and 12 in the intervention group). The most common adverse event was itch after skin prick testing (reported by eight participants in each group). INTERPRETATION: We found that the addition of FeNO to symptom-guided asthma treatment did not lead to reduced exacerbations among children prone to asthma exacerbation. Asthma symptoms remain the only tool for guiding treatment decisions. FUNDING: National Institute for Health Research.

Risk of Recurrent Stillbirth in Subsequent Pregnancies.

OBJECTIVE: To compare the prospective risk of stillbirth between women with and without a stillbirth in their first pregnancy. METHODS: We conducted a cohort study using perinatal data from Finland, Malta, and Scotland. Women who had at least two singleton deliveries were included. The exposed and unexposed cohorts comprised women with a stillbirth and live birth in their first pregnancy, respectively. The risk of stillbirth in any subsequent pregnancy was assessed using a Cox proportional hazards model. Time-to-event analyses were conducted to investigate whether first pregnancy outcome had an effect on time to or the number of pregnancies preceding subsequent stillbirth. RESULTS: The pooled data set included 1,064,564 women, 6,288 (0.59%) with a stillbirth and 1,058,276 with a live birth in a first pregnancy. Compared with women with a live birth, women with a stillbirth in the first pregnancy were more likely to have a subsequent stillbirth (adjusted hazard ratio [aHR] 2.25, 95% CI 1.86-2.72). For women with more than two pregnancies, the difference in risk of subsequent stillbirth between the two groups increased with the number of subsequent pregnancies. Maternal age younger than 25 years or 40 years and older, smoking, low socioeconomic status, not having a partner, pre-existing diabetes, preeclampsia, placental abruption, or delivery of a growth-restricted neonate in a first pregnancy were independently associated with subsequent stillbirth. Compared with women with a live birth in the first pregnancy, women with a stillbirth were more likely to have another pregnancy within 1 year. The absolute risk of stillbirth in a subsequent pregnancy for women with stillbirth and live birth in a first pregnancy were 2.5% and 0.5%, respectively. CONCLUSION: Compared with women with a live birth in a first pregnancy, women with a stillbirth have a higher risk of subsequent stillbirth irrespective of the number and sequence of the pregnancies. Despite high relative risk, the absolute risk of recurrence was low.

Cross-Cultural Differences and Psychometric Properties of the Japanese Actions and Feelings Questionnaire (J-AFQ).

Aims: We aimed to assess the psychometric properties of a Japanese version of the Actions and Feelings Questionnaire (J-AFQ), an 18-item self-report measure of non-verbal emotional communication, as well as to examine its transcultural properties. Methods: The J-AFQ was administered to 500 Japanese adults (age 20-49, 250 male), alongside the Japanese Broad Autism Phenotype Questionnaire (BAPQ-J) and Empathy Quotient (EQ-J). These were compared to a group of 597 British and Irish participants (age 16-18, 148 male). J-AFQ was assessed in terms of validity by confirmatory factor analysis and convergence with BAPQ-J and EQ-J using Pearson correlation. Internal consistency and differential item functioning (DIF) were assessed and compared between Japanese and UK/Irish participants. Results: Reversed worded items (RWIs) showed poor item-total correlations but excluding these left a 13-item version of the J-AFQ with good internal consistency and content validity. Consistent with the English version, J-AFQ scores correlated with EQ and lower BAPQ scores. However, comparing across cultures, J-AFQ scores were significantly lower in the Japanese sample, and there was evidence of important DIF by country in over half of the J-AFQ items Conclusion: Cultural differences in attitudes to self-report, as well as increased acquiescence to RWI's also seen in previous studies, limit the value of the 18-item instrument in Japanese culture. However, the 13-item J-AFQ is a valid and reliable measure of motor empathy, which, alongside the English version, offers promise for research in motor cognition and non-verbal emotional communication across cultures.

Reactivity of a Dinuclear PdI Complex [Pd2(µ-PPh2)(µ2-OAc)(PPh3)2] with PPh3: Implications for Cross-Coupling Catalysis Using the Ubiquitous Pd(OAc)2/nPPh3 Catalyst System.

[PdI 2(µ-PPh2)(µ2-OAc)(PPh3)2] is the reduction product of PdII(OAc)2(PPh3)2, generated by reaction of 'Pd(OAc)2' with two equivalents of PPh3. Here, we report that the reaction of [PdI 2(µ-PPh2)(µ2-OAc)(PPh3)2] with PPh3 results in a nuanced disproportionation reaction, forming [Pd0(PPh3)3] and a phosphinito-bridged PdI-dinuclear complex, namely [PdI 2(µ-PPh2){κ2-P,O-µ-P(O)Ph2}(κ-PPh3)2]. The latter complex is proposed to form by abstraction of an oxygen atom from an acetate ligand at Pd. A mechanism for the formal reduction of a putative PdII disproportionation species to the observed PdI complex is postulated. Upon reaction of the mixture of [Pd0(PPh)3] and [PdI 2(µ-PPh2){κ2-P,O-µ-P(O)Ph2}(κ-PPh3)2] with 2-bromopyridine, the former Pd0 complex undergoes a fast oxidative addition reaction, while the latter dinuclear PdI complex converts slowly to a tripalladium cluster, of the type [Pd3(µ-X)(µ-PPh2)2(PPh3)3]X, with an overall 4/3 oxidation state per Pd. Our findings reveal complexity associated with the precatalyst activation step for the ubiquitous 'Pd(OAc)2'/nPPh3 catalyst system, with implications for cross-coupling catalysis.

Reproductive Pattern of Parous Women and the Risk of Cancer in Later Life.

We assessed the risk of any and site-specific cancers in a case-control study of parous women living in northeast Scotland in relation to: total number of pregnancies, cumulative time pregnant, age at first delivery and interpregnancy interval. We analysed 6430 women with cancer and 6430 age-matched controls. After adjustment for confounders, women with increasing number of pregnancies had similar odds of cancer diagnosis as women with only one pregnancy. The adjusted odds of cancer diagnosis were no higher in women with cumulative pregnancy time 50-150 weeks compared to those pregnant ≤ 50 weeks. Compared with women who had their first delivery at or before 20 years of age, the adjusted odds ratio (AOR) among those aged 21-25 years was 0.81, 95% CI 0.74, 0.88; 26-30 years AOR 0.77, 95% CI 0.69, 0.86; >30 years AOR 0.63, 95% CI 0.55, 0.73. After adjustment, the odds of having any cancer were higher in women who had an inter-pregnancy interval >3 years compared to those with no subsequent pregnancy (AOR 1.17, 95% CI 1.05, 1.30). Older age at first pregnancy was associated with increased risk of breast and gastrointestinal cancer, and reduced risk of invasive cervical, carcinoma in situ of the cervix and respiratory cancer.

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.

Emergency general surgery: Impact of hospital and surgeon admission case volume on mortality.

BACKGROUND: Emergency general surgery (EGS) is a high-volume and high-risk surgical service. Interhospital variation in EGS outcomes exists, but there is disagreement in the literature as to whether hospital admission volume affects in-hospital mortality. Scotland collects high-quality data on all admitted patients, whether managed operatively or nonoperatively. Our aim was to determine the relationship between hospital admission volume and in-hospital mortality of EGS patients in Scotland. Second, to investigate whether surgeon admission volume affects mortality. METHODS: This national population-level cohort study included EGS patients aged 16 years and older, who were admitted to a Scottish hospital between 2014 and 2018 (inclusive). A logistic regression model was created, with in-hospital mortality as the dependent variable, and admission volume of hospital per year as a continuous covariate of interest, adjusted for age, sex, comorbidity, deprivation, surgeon admission volume, surgeon operative rate, transfer status, diagnosis, and operation category. RESULTS: There were 376,076 admissions to 25 hospitals, which met our inclusion criteria. The EGS hospital admission rate per year had no effect on in-hospital mortality (odds ratio [OR], 1.000; 95% confidence interval [CI], 1.000-1.000). Higher average surgeon monthly admission volume increased the odds of in-hospital mortality (>35 admissions: OR, 1.139; 95% CI, 1.038-1.250; 25-35 admissions: OR, 1.091; 95% CI, 1.004-1.185; <25 admissions was the referent). CONCLUSION: In Scotland, in contrast to other settings, EGS hospital admission volume did not influence in-hospital mortality. The finding of an association between individual surgeons' case volume and in-hospital mortality warrants further investigation. LEVEL OF EVIDENCE: Care management, Level IV.

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.

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.

Laparoscopic supracervical hysterectomy compared with second-generation endometrial ablation for heavy menstrual bleeding: the HEALTH RCT.

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem that affects many British women. When initial medical treatment is unsuccessful, the National Institute for Health and Care Excellence recommends surgical options such as endometrial ablation (EA) or hysterectomy. Although clinically and economically more effective than EA, total hysterectomy necessitates a longer hospital stay and is associated with slower recovery and a higher risk of complications. Improvements in endoscopic equipment and training have made laparoscopic supracervical hysterectomy (LASH) accessible to most gynaecologists. This operation could preserve the advantages of total hysterectomy and reduce the risk of complications. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of LASH with second-generation EA in women with HMB. DESIGN: A parallel-group, multicentre, randomised controlled trial. Allocation was by remote web-based randomisation (1 : 1 ratio). Surgeons and participants were not blinded to the allocated procedure. SETTING: Thirty-one UK secondary and tertiary hospitals. PARTICIPANTS: Women aged < 50 years with HMB. Exclusion criteria included plans to conceive; endometrial atypia; abnormal cytology; uterine cavity size > 11 cm; any fibroids > 3 cm; contraindications to laparoscopic surgery; previous EA; and inability to give informed consent or complete trial paperwork. INTERVENTIONS: LASH compared with second-generation EA. MAIN OUTCOME MEASURES: Co-primary clinical outcome measures were (1) patient satisfaction and (2) Menorrhagia Multi-Attribute Quality-of-Life Scale (MMAS) score at 15 months post randomisation. The primary economic outcome was incremental cost (NHS perspective) per quality-adjusted life-year (QALY) gained. RESULTS: A total of 330 participants were randomised to each group (total n = 660). Women randomised to LASH were more likely to be satisfied with their treatment than those randomised to EA (97.1% vs. 87.1%) [adjusted difference in proportions 0.10, 95% confidence interval (CI) 0.05 to 0.15; adjusted odds ratio (OR) from ordinal logistic regression (OLR) 2.53, 95% CI 1.83 to 3.48; p < 0.001]. Women randomised to LASH were also more likely to have the best possible MMAS score of 100 (68.7% vs. 54.5%) (adjusted difference in proportions 0.13, 95% CI 0.04 to 0.23; adjusted OR from OLR 1.87, 95% CI 1.31 to 2.67; p = 0.001). Serious adverse event rates were low and similar in both groups (4.5% vs. 3.6%). There was a significant difference in adjusted mean costs between LASH (£2886) and EA (£1282) at 15 months, but no significant difference in QALYs. Based on an extrapolation of expected differences in cost and QALYs out to 10 years, LASH cost an additional £1362 for an average QALY gain of 0.11, equating to an incremental cost-effectiveness ratio of £12,314 per QALY. Probabilities of cost-effectiveness were 53%, 71% and 80% at cost-effectiveness thresholds of £13,000, £20,000 and £30,000 per QALY gained, respectively. LIMITATIONS: Follow-up data beyond 15 months post randomisation are not available to inform cost-effectiveness. CONCLUSION: LASH is superior to EA in terms of clinical effectiveness. EA is less costly in the short term, but expected higher retreatment rates mean that LASH could be considered cost-effective by 10 years post procedure. FUTURE WORK: Retreatment rates, satisfaction and quality-of-life scores at 10-year follow-up will help to inform long-term cost-effectiveness. TRIAI REGISTRATION: Current Controlled Trials ISRCTN49013893. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 53. See the NIHR Journals Library website for further project information.

Almost 1.5 million women in England and Wales suffer from heavy periods. Initial treatment involves tablets or a medicated coil inserted within the womb. Sometimes these treatments do not work and many women need an operation, either endometrial ablation (EA) (removing the lining of the womb) or a full hysterectomy (complete removal of the womb). Previous studies have shown that a full hysterectomy is better at relieving symptoms, but the risk of complications during surgery is higher and patients take longer to recover fully. A newer operation, laparoscopic (keyhole) supracervical hysterectomy, or 'LASH', removes only the part of the womb that causes periods and preserves the cervix or neck of the womb. Women who have LASH can expect fewer complications, earlier discharge from hospital and quicker recovery time. In this study, we compared EA with LASH by asking women who had either procedure how they felt about it 1 year after their operation. Regardless of which operation they had, most women were very satisfied and felt that their symptoms were better. However, the results were much better for those who had the LASH operation, although these women stayed in hospital for longer and took more time to recover. There was no difference in complications from either surgery, although nearly 1 in 20 women who had an EA returned within 1 year to have their wombs removed in a second operation. Although LASH led to a greater improvement in symptoms and levels of satisfaction, it was more expensive in terms of costs incurred by both the health service and society. Given that some women who had an EA are likely to need a second operation in the future, LASH surgery may provide better value for money in the long term.

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.