CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Registry-derived stage (RD-Stage) for capturing cancer stage at diagnosis for endometrial cancer.

BACKGROUND: Capture of cancer stage at diagnosis is important yet poorly reported by health services to population-based cancer registries. In this paper we describe current completeness of stage information for endometrial cancer available in Australian cancer registries; and develop and validate a set of rules to enable cancer registry medical coders to calculate stage using data available to them (registry-derived stage or 'RD-Stage'). METHODOLOGY: Rules for deriving RD-stage (Endometrial carcinoma) were developed using the American Joint Commission on Cancer (AJCC) TNM (tumour, nodes, metastasis) Staging System (8th Edition). An expert working group comprising cancer specialists responsible for delivering cancer care, epidemiologists and medical coders reviewed and endorsed the rules. Baseline completeness of data fields required to calculate RD-Stage, and calculation of the proportion of cases for whom an RD stage could be assigned, was assessed across each Australian jurisdiction. RD-Stage (Endometrial cancer) was calculated by Victorian Cancer Registry (VCR) medical coders and compared with clinical stage recorded by the patient's treating clinician and captured in the National Gynae-Oncology Registry (NGOR). RESULTS: The necessary data completeness level for calculating RD-Stage (Endometrial carcinoma) across various Australian jurisdictions varied from 0 to 89%. Three jurisdictions captured degree of spread of cancer, rendering RD-Stage unable to be calculated. RD-Stage (Endometrial carcinoma) could not be derived for 64/485 (13%) cases and was not captured for 44/485 (9%) cases in NGOR. At stage category level (I, II, III, IV), there was concordance between RD-Stage and NGOR captured stage in 393/410 (96%) of cases (95.8%, Kendall's coefficient = 0.95). CONCLUSION: A lack of consistency in data captured by, and data sources reporting to, population-based cancer registries meant that it was not possible to provide national endometrial carcinoma stage data at diagnosis. In a sample of Victorian cases, where surgical pathology was available, there was very good concordance between RD-Stage (Endometrial carcinoma) and clinician-recorded stage data available from NGOR. RD-Stage offers promise in capturing endometrial cancer stage at diagnosis for population epidemiological purposes when it is not provided by health services, but requires more extensive validation.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Safety of emergency, elective and day case operating during the winter period at East Suffolk and North Essex NHS Foundation Trust: lessons from the outcomes of 4,254 surgical patients from the first COVID-19 wave.

BACKGROUND: There is limited evidence on perioperative outcomes of surgical patients during the COVID-19 pandemic to inform continued operating into the winter period. METHODS: We retrospectively analysed the rate of 30-day COVID-19 transmission and mortality of all surgical patients in the three hospitals in our trust in the East of England during the first lockdown in March 2020. All patients who underwent a swab were swabbed on or 24 hours prior to admission. RESULTS: There were 4,254 patients and an overall 30-day mortality of 0.99%. The excess surgical mortality in our region was 0.29%. There were 39 patients who were COVID-19 positive within 30 days of admission, 12 of whom died. All 12 were emergency admissions with a length of stay longer than 24 hours. There were three deaths among those who underwent day case surgery, one of whom was COVID-19 negative, and the other two were not swabbed but not suspected to have COVID-19. There were two COVID-19 positive elective cases and none in day case elective or emergency surgery. There were no COVID-19 positive deaths in elective or day case surgery. CONCLUSIONS: There was a low rate of COVID-19 transmission and mortality in elective and day case operations. Our data have allowed us to guide patients in the consent process and provided the evidence base to restart elective and day case operating with precautions and regular review. A number of regions will be similarly affected and should perform a review of their data for the winter period and beyond.

Lasmiditan for acute treatment of migraine.

Lasmiditan, a selective 5-HT1F receptor agonist, is a harbinger for the novel ditan class of medications for acute migraine treatment. Lasmiditan activates 5-HT1F receptors on presynaptic trigeminal nerve terminals, which impedes the release of calcitonin gene-related peptide (CGRP) from trigeminal nerve endings and thereby suppresses activation of the trigeminovascular system. Notably, lasmiditan does not result in vasoconstriction, making lasmiditan a migraine-specific acute treatment option for those with cardiovascular risk factors. However, lasmiditan does have centrally mediated side effects. This review will discuss the background of lasmiditan development, its preclinical pharmacology, safety, drug interactions and indications for use.

Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.

Methodological approaches to situational analysis in global mental health: a scoping review.

Global inequity in access to and availability of essential mental health services is well recognized. The mental health treatment gap is approximately 50% in all countries, with up to 90% of people in the lowest-income countries lacking access to required mental health services. Increased investment in global mental health (GMH) has increased innovation in mental health service delivery in LMICs. Situational analyses in areas where mental health services and systems are poorly developed and resourced are essential when planning for research and implementation, however, little guidance is available to inform methodological approaches to conducting these types of studies. This scoping review provides an analysis of methodological approaches to situational analysis in GMH, including an assessment of the extent to which situational analyses include equity in study designs. It is intended as a resource that identifies current gaps and areas for future development in GMH. Formative research, including situational analysis, is an essential first step in conducting robust implementation research, an essential area of study in GMH that will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in low- and middle-income countries (LMICs). While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions.

Lower risk of invasive meningococcal disease during pregnancy: national prospective surveillance in England, 2011-2014.

OBJECTIVE: To describe cases of invasive meningococcal disease (IMD) in women of childbearing age and to estimate the disease incidence and relative risk of IMD in pregnant compared with non-pregnant women. DESIGN: Prospective enhanced national surveillance for IMD. SETTING: England. POPULATION: Women of reproductive age (15-44 years) with laboratory-confirmed IMD. METHODS: Public Health England conducts enhanced national surveillance for IMD in England. Laboratory-confirmed cases are followed up with postal questionnaires to general practitioners. All cases confirmed in women of reproductive age from 1 January 2011 to 31 December 2014 were included. MAIN OUTCOME MEASURES: Annual IMD incidence and relative risk of IMD in pregnant compared with non-pregnant women of reproductive age. RESULTS: During the 4-year surveillance period, there were 1502 cases of IMD in females across England; of these, 310 (20.6%) cases were in women of reproductive age, including four women who were pregnant at the time of IMD confirmation (1.3%). Serogroup distribution of IMD cases in women of childbearing age was similar to the overall distribution. The four cases in otherwise healthy pregnant women were confirmed across all trimesters and all survived; one case in the first trimester had a septic miscarriage. The incidence of IMD was lower in pregnant than in non-pregnant women (0.16 compared with 0.76 per 100 000 pregnant and non-pregnant years, respectively), giving a lower risk of IMD in pregnant women (incidence rate ratio, IRR, 0.21; 95% confidence interval, 0.06-0.54). CONCLUSIONS: Pregnant women are nearly five times less likely to develop IMD compared with non-pregnant women, but the infection can be severe. TWEETABLE ABSTRACT: The risk of meningococcal disease is lower in pregnant women compared with non-pregnant women; the infection can occur across all trimesters and can be severe.

Real-world Outcomes and Factors Predicting Survival and Completion of Radium 223 in Metastatic Castrate-resistant Prostate Cancer.

AIMS: To analyse outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with radium 223 (Ra-223) across the Yorkshire and Humber Cancer Network. MATERIALS AND METHODS: A regional, multicentre, retrospective cohort study of 189 men undergoing Ra-223 for mCRPC between March 2014 and April 2017 was undertaken. Factors predicting overall survival and completion of planned treatment were assessed. RESULTS: The median overall survival for the entire cohort was 10.5 months. Those completing five to six cycles of Ra-223 had a higher overall survival of 18.6 months. On multivariable analysis, four factors remained independent significant predictors of overall survival: age (P = 0.005, hazard ratio 1.07 [1.02-1.12]); number of cycles of Ra-223: 5-6 versus 1-4 (P ≤ 0.001, hazard ratio 0.10 [0.005-0.20]); baseline alkaline phosphatase (P = 0.044, hazard ratio 1.06 [1.002-1.12]); neutrophil-to-lymphocyte ratio (P = 0.033, hazard ratio 1.19 [1.01-1.40]). Baseline performance status 0 versus 2 (P = 0.026, odds ratio 0.080 [0.001-0.74]) and higher baseline haemoglobin (P = 0.028, odds ratio 1.04 [1.004-1.074]) were independent predictors of the completion of five to six cycles of Ra-223. CONCLUSIONS: Younger age, completion of five to six cycles of Ra-223, lower alkaline phosphatase and neutrophil-to-lymphocyte ratio are predictors of overall survival. This is the first study to report neutrophil-to-lymphocyte ratio as an independent predictor of overall survival in a Ra-223 cohort. Good performance status and higher baseline haemoglobin predict the completion of five to six cycles of Ra-223.

Screening for cognitive impairment in SLE using the Self-Administered Gerocognitive Exam.

Objective Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can affect the central nervous system in multiple ways, including causing cognitive dysfunction. Cognitive dysfunction is a common complaint of SLE patients yet diagnosis is challenging, time consuming, and costly. This study evaluated the Self-Administered Gerocognitive Exam (SAGE) as a screening test for cognitive impairment in a cohort of SLE patients. Methods A total of 118 SLE patients completed the SAGE. Providers completed the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI). SAGE scores were grouped into normal (>16) and abnormal (≤16) categories. Univariate and multivariate analyses were performed. Results Of the 118 participants, 21(18%) scored ≤16 on the SAGE instrument. In univariate analysis, race, ethnicity, household income, and SLICC-DI scores were associated with the SAGE ( p < 0.05). In multivariable analysis, abnormal SAGE score was independently associated with higher SLICC-DI score (odds ratio (OR) = 1.44, 95% confidence intervals 1.04-1.99, p = 0.03)), Hispanic ethnicity (OR = 43.4, 95% CI 3.1-601, p = 0.005), and lower household income (OR = 11.9 for ≤$15,000 vs >$50,000, 95% CI 2.45-57, p = 0.002). Conclusions In SLE patients, this study demonstrates an independent relationship between neurocognitive impairment (as measured by the SAGE) and higher lupus-related damage, as measured by the SLICC-DI, and lower household income. Abnormal SAGE scores were also associated with Hispanic ethnicity. A language barrier could explain this because the SAGE instrument was conducted in English only. The SAGE was feasible to measure in the clinic setting.

Australian multicentre study of current real-world prophylaxis practice in severe and moderate haemophilia A and B.

INTRODUCTION: With the emergence of novel treatment products for haemophilia and an increasing focus on the benefits of pharmacokinetic driven individualized prophylaxis, robust national data with regard to current patterns of factor consumption and adherence are required. AIM: To characterize current Australian practice with regard to use of prophylactic clotting factor infusions in patients with moderate or severe haemophilia A (HA) and haemophilia B (HB). METHODS: This was a retrospective, non-interventional study utilizing Australian Bleeding Disorder Registry (ABDR) data collected over a 12 month period. Registered and consented patients with moderate or severe HA or HB without inhibitors were included. RESULTS: A total of 718 HA (551 severe, 167 moderate) and 166 HB (87 severe, 79 moderate) patients were included. Regular prophylaxis was prescribed in 453 patients (82%) with severe HA, 42 patients (25%) with moderate HA, 66 patients (75%) with severe HB and 11 patients (14%) with moderate HB. Near universal prophylaxis was achieved in the paediatric subgroup. The mean weekly dose of factor VIII in severe HA was 84 international units/kg/wk (IU/kg/wk) vs 71 IU/kg/wk of factor IX in severe HB. Most patients on prophylaxis were treated ≥3 times/wk (HA) or 2 times/wk (HB). Non-adherence peaked in the 20-29 year age group. Older individuals on regular prophylaxis used more factor than was expected for their prescribed regimen. CONCLUSION: Prophylaxis rates in severe haemophilia are comparable with other developed nations. The benefit of a national registry is demonstrable. Furthermore research into the underlying reasons for non-compliance in young adults with haemophilia is required.

Quality of life in bipolar disorder: towards a dynamic understanding.

BACKGROUND: Although quality of life (QoL) is receiving increasing attention in bipolar disorder (BD) research and practice, little is known about its naturalistic trajectory. The dual aims of this study were to prospectively investigate: (a) the trajectory of QoL under guideline-driven treatment and (b) the dynamic relationship between mood symptoms and QoL. METHODS: In total, 362 patients with BD receiving guideline-driven treatment were prospectively followed at 3-month intervals for up to 5 years. Mental (Mental Component Score - MCS) and physical (Physical Component Score - PCS) QoL were measured using the self-report SF-36. Clinician-rated symptom data were recorded for mania and depression. Multilevel modelling was used to analyse MCS and PCS over time, QoL trajectories predicted by time-lagged symptoms, and symptom trajectories predicted by time-lagged QoL. RESULTS: MCS exhibited a positive trajectory, while PCS worsened over time. Investigation of temporal relationships between QoL and symptoms suggested bidirectional effects: earlier depressive symptoms were negatively associated with mental QoL, and earlier manic symptoms were negatively associated with physical QoL. Importantly, earlier MCS and PCS were both negatively associated with downstream symptoms of mania and depression. CONCLUSIONS: The present investigation illustrates real-world outcomes for QoL under guideline-driven BD treatment: improvements in mental QoL and decrements in physical QoL were observed. The data permitted investigation of dynamic interactions between QoL and symptoms, generating novel evidence for bidirectional effects and encouraging further research into this important interplay. Investigation of relevant time-varying covariates (e.g. medications) was beyond scope. Future research should investigate possible determinants of QoL and the interplay between symptoms and wellbeing/satisfaction-centric measures of QoL.

A cadaveric study showing the anatomical variations in the branches of the dorsalis pedis artery at the level of the ankle joint and its clinical implication in ankle arthroscopy.

Introduction Pseudoaneurysm formation following ankle arthroscopy is a rare but potentially catastrophic complication. The placement of anterior ankle portals carries inherent risk to the superficial and deep peroneal nerves, as well as to the dorsalis pedis artery. Anatomical variations in the dorsalis pedis and the presence of branches at the joint line may increase the risk of vascular injury and pseudoaneurysm formation during arthroscopy. There is limited anatomical evidence available regarding the branches of the dorsalis pedis artery, which occur at the point at which they cross the ankle joint. Objectives The objective of the study was to describe the frequency and direction of branches of the dorsalis pedis crossing the ankle joint. Materials and Methods Nineteen cadaveric feet were carefully dissected to explore the course of the dorsalis pedis artery, noting in particular the branching pattern at the joint line. Results Eleven of the nineteen feet had a branch of the dorsalis pedis artery that crossed the level of the ankle joint. Out of these, six were lateral, four medial and one bilateral. Eight of the eleven specimens had one branch at, or just before, the level of the joint. Two specimens had two branches and one had three branches crossing the ankle, which were all in the same direction, crossing laterally to the main trunk of the dorsalis pedis. Conclusions Our study demonstrated high rates of branching of the dorsalis pedis artery at the level of the ankle joint. The role of these branches in pseudoaneurysm formation during anterior hindfoot surgery remains unclear.

Surgical outcomes and sleep endoscopy for children with sleep-disordered breathing and hypotonia.

OBJECTIVE: To study the efficacy of surgical management for obstructive sleep apnea (OSA) syndrome in children with hypotonia, and to identify common anatomic sites of airway obstruction. METHODS: Retrospective chart review of polysomnographic parameters and quality of life instrument scores for seventy eight children with hypotonia who underwent surgical intervention for sleep-disordered breathing at two tertiary children's hospitals, and analysis of drug-induced sleep endoscopy data using a previously validated scoring system. RESULTS: Children undergoing surgical intervention had baseline severe OSA with a statistically significant improvement in apnea-hypopnea index from 23.6 to 11.1 after surgery, but persistent severe OSA. OSA-18 sleep-related quality of life measurement and overall quality of life score showed statistically and clinically significant improvements, from 72.0 to 43.4 and from 5.3 to 7.6 respectively. Sleep endoscopy showed an average obstructive score of 7.2/15 (n = 39), with multi-level obstruction in 49% of children. Greater than 50% obstruction was observed at the tongue base in 64% of patients, velum in 46%, lateral pharyngeal wall in 38%, supraglottis in 38%, and adenoid in 23%. CONCLUSION: OSA syndrome is challenging to treat in hypotonic children. Severe residual OSA is common after surgical intervention, but improvement in quality of life is clinically and statistically significant. The tongue base is the most common site of persistent airway obstruction. Drug-induced sleep endoscopy can identify sites of airway obstruction and may aid in surgical planning for high-risk patients.

Clinical Characteristics and prognostic analysis of Triple-negative Breast Cancer: Single institute experience.

BACKGROUND: Triple-negative breast cancer (TNBC) is a poor prognostic subset of breast cancer that lacks the benefit of specific targeted therapy. MATERIALS AND METHODS: A prospective study of the clinical profile of triple negative breast cancer cases at a tertiary referral centre. The duration of the study period was 26 months and the median follow up period was ten months. A total of 111 invasive breast cancer patients were evaluated from 1st August 2009 to 31st October 2011. We examined TNBC patients with respect to clinicopathological parameters, adjuvant chemotherapy regimens and relapse free survival. RESULTS: In our study, patients were young (median age at presentation, 47yrs), premenopausal (54%), tumour size was discordant with lymph node positivity, the histology was predominantly intraductal carcinoma (90%), histological grade higher than two (90%). Relapses were early and preferential visceral (32%) and CNS metastasises (11.7%). 91% of patients were eligible for adjuvant therapy but only 80% of the patients could complete full course of adjuvant chemotherapy. Anthracycline-based regimens (43%), sequential anthracycline and taxane-based regimen (24%) and other regimes like CMF (13%) were used as adjuvant chemotherapy in eligible TNBC patients. Median relapse free survival in patients following adjuvant chemotherapy was around 10 months at last follow-up. CONCLUSIONS: Patients with TNBC have aggressive clinicopathological characteristics with early and higher rate of disease relapse and therefore derive inadequate benefit from current adjuvant chemotherapy. So, new treatment strategies in adjuvant chemotherapy for TNBC are needed.

Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease.

AIM: To evaluate the long-term efficacy, safety and tolerability of dapagliflozin versus placebo added to usual care in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). METHODS: Data were pooled from two phase III studies (NCT01031680 and NCT01042977) in high-risk patients (N = 1887) with T2DM and CVD treated with dapagliflozin (10 mg/day) or placebo. Patients completing the double-blind treatment studies (24 weeks) entered one or two sequential double-blind, long-term (LT) extensions of 28 (LT1; n = 1649) and 52 (LT2; n = 568) weeks. RESULTS: Baseline and CVD characteristics were similar in the two groups. Patients entering LT1 and LT2 on dapagliflozin maintained a greater mean reduction in glycated haemoglobin (HbA1c) versus placebo at 52 weeks [LT1, -0.58% (95% confidence interval -0.68, -0.49)] and 104 weeks [LT2, -0.35% (95% confidence interval -0.59, -0.12)]. Mean body weight and systolic blood pressure (SBP) reductions versus placebo were maintained in patients entering LT1 (52 weeks; -2.23 kg and -3.25 mmHg, respectively) and LT2 (104 weeks; -3.16 kg and -2.03 mmHg, respectively). Patients on dapagliflozin had a better three-item composite endpoint of clinical benefit (glycaemia, weight and SBP) compared with placebo at week 24 (LT1, 10.1% vs. 1.1%) and week 104 (LT2, 6.7% vs. 1.4%). Genital and urinary tract infections were more frequent with dapagliflozin than with placebo. Events of hypoglycaemia, renal impairment/failure and volume depletion were similar between groups. CONCLUSIONS: The long-term efficacy of dapagliflozin to maintain reductions in HbA1c, SBP and body weight over 2 years, together with its tolerability profile, make dapagliflozin an appropriate option in high-risk patients with T2DM and CVD.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Conservative management of aortic arch injury following penetrating trauma.

Aortic arch injuries following penetrating trauma are typically lethal events with high mortality rates. Traditionally, the standard of care for patients presenting with penetrating injury and aortic involvement has included surgical intervention. We report the case of a 31-year-old man who was managed non-operatively after sustaining multiple stab wounds to the left chest and presenting with mid aortic arch injury.