The effect of end-ischaemic normothermic machine perfusion on donor hepatic artery endothelial integrity.

BACKGROUND: Ex vivo normothermic machine liver perfusion (NMLP) involves artificial cannulation of vessels and generation of flow pressures. This could lead to shear stress-induced endothelial damage, predisposing to vascular complications, or improved preservation of donor artery quality. This study aims to assess the spatial donor hepatic artery (HA) endothelial quality downstream of the cannulation site after end-ischaemic NMLP. METHODS: Remnant HA segments from the coeliac trunk up to the gastroduodenal artery branching were obtained after NMLP (n = 15) and after static cold storage (SCS) preservation (n = 15). Specimens were fixed in 10% neutral buffered formalin and sectioned at pre-determined anatomical sites downstream of the coeliac trunk. CD31 immunohistostaining was used to assess endothelial integrity by a 5-point ordinal scale (grade 0: intact endothelial lining, grade 5: complete denudation). Endothelial integrity after SCS was used as a control for the state of the endothelium at commencement of NMP. RESULTS: In the SCS specimens, regardless of the anatomical site, near complete endothelial denudation was present throughout the HA (median scores 4.5-5). After NMLP, significantly less endothelial loss in the distal HA was present compared to SCS grafts (NMLP vs. SCS: median grade 3 vs. 4.5; p = 0.042). In NMLP specimens, near complete endothelial denudation was present at the cannulation site in all cases (median grade: 5), with significantly less loss of the endothelial lining the further from the cannulation site (proximal vs. distal, median grade 5 vs. 3; p = 0.005). CONCLUSION: Loss of endothelial lining throughout the HA after SCS and at the cannulation site after NMLP suggests extensive damage related to surgical handling and preservation injury. Gradual improved endothelial lining along more distal sites of the HA after NMLP indicates potential for re-endothelialisation. The regenerative effect of NMLP on artery quality seems to occur to a greater extent further from the cannulation site. Therefore, arterial cannulation for machine perfusion of liver grafts should ideally be as proximal as possible on the coeliac trunk or aortic patch, while the site of anastomosis should preferentially be attempted distal on the common HA.

Pharmaceutical industry-led partnerships focused on addressing the global burden of non-communicable diseases: a review of Access Accelerated.

OBJECTIVE: In spite of the increasing number of global health partnerships led by biopharmaceutical companies, there is a paucity of information on the number, type, and role of partners. This paper aims to analyze partnerships carrying out company programs included in Access Accelerated, a new industry initiative, focused on addressing the global non-communicable disease burden. STUDY DESIGN: Document review and content analysis. METHODS: We extracted data on the number, type, and role of partners from 63 company programs reported into the Access Observatory, a public platform for reporting on access-to-medicines programs, in 2017. We did a descriptive analysis of the proportion of partners by sector, institution, and location. We used the Fischer's exact test to analyze the relationship between the program strategies, disease focus, and countries with the type of program partners. Based on our empirical findings, we developed a typology of program partnerships, according to which we categorized each of the 63 programs. RESULTS: Programs worked with three partners on average, the majority of which were local governmental or non-governmental organizations (70%). Most programs focused on health service strengthening (83%), community awareness and linkage to care (81%), and health service delivery (60%). Twenty-six of the 63 programs (41%) worked with the local Ministries of Health while 25 (40%) partnered with disease-specific organizations, 21 (33%) with hospitals, and 16 (25%) with academic institutions. Partnering with the Ministries of Health was significantly associated with the use of a health service strengthening program strategy (P = 0.02). Partnering with a hospital (P = 0.004) or private sector partner (P = 0.0009) was significantly associated with a program disease focus on cancer. Seventy-nine percent of the programs were solely funded by pharmaceutical companies. According to our program typology, 40 (63%) programs partnered directly or indirectly with multiple implementing organizations, which delivered the program directly to beneficiaries. CONCLUSION: Pharmaceutical companies play a leading role in funding Access Accelerated programs with local governmental or non-governmental organizations mainly involved in program implementation. A detailed and transparent reporting of the role of local stakeholders in agenda setting, planning, and coordination of programs is needed to ensure public trust and accountability of programs led by pharmaceutical companies. More research is needed to identify the partnerships that are particularly suitable to promote efficient implementation, evaluation, and reporting depending on the nature of the program and context.

A perspective on global access to insulin: a descriptive study of the market, trade flows and prices.

AIM: To describe the global insulin market. METHODS: Market intelligence data, United Nations Commodity Trade Statistics for insulin trade, the International Medical Products Price Guide for prices of human insulin and additional web searches were used as data sources. These sources were combined to gain further insight into possible links among market, trade flows and prices. Descriptive statistics and Spearman's rank order correlation were used for the analysis. RESULTS: A total of 34 insulin manufacturers were identified. Most countries and territories are reliant on a limited number of supplying countries. The overall median (interquartile range) government procurement price for a 10-ml, 100-IU/ml vial during the period 1996-2013 equivalent was US$4.3 (US$ 3.8-4.8), with median prices in Africa (US$ 4.7) and low- (US$ 6.9) and low- to middle- (US$ 4.7) income countries being higher over this period. The relationships between price and quantity of insulin (Spearman's r=0.046; P>0.1) and number of import links (Spearman's r=0.032; P>0.1) were weak. The links between price and percentage of total insulin from a country where a 'big three' manufacturer produces insulin (Spearman's r=0.294; P<0.05) and total insulin from the main import link (Spearman's r=-0.392; P<0.05) were stronger. CONCLUSIONS: This research shows the high variability of insulin prices and the reliance on a few sources, both companies and countries, for global supply. In addressing access to insulin, countries need to use existing price data to negotiate prices, and mechanisms need to be developed to foster competition and security of supply of insulin, given the limited number of truly global producers.

Liver Transplantation Using Grafts From Donors After Circulatory Death: A Propensity Score-Matched Study From a Single Center.

The use of livers from donation after circulatory death (DCD) is increasing, but concerns exist regarding outcomes following use of grafts from "marginal" donors. To compare outcomes in transplants using DCD and donation after brain death (DBD), propensity score matching was performed for 973 patients with chronic liver disease and/or malignancy who underwent primary whole-liver transplant between 2004 and 2014 at University Hospitals Birmingham NHS Foundation Trust. Primary end points were overall graft and patient survival. Secondary end points included postoperative, biliary and vascular complications. Over 10 years, 234 transplants were carried out using DCD grafts. Of the 187 matched DCDs, 82.9% were classified as marginal per British Transplantation Society guidelines. Kaplan-Meier analysis of graft and patient survival found no significant differences for either outcome between the paired DCD and DBD patients (p = 0.162 and p = 0.519, respectively). Aspartate aminotransferase was significantly higher in DCD recipients until 48 h after transplant (p < 0.001). The incidences of acute kidney injury and ischemic cholangiopathy were greater in DCD recipients (32.6% vs. 15% [p < 0.001] and 9.1% vs. 1.1% [p < 0.001], respectively). With appropriate recipient selection, the use of DCDs, including those deemed marginal, can be safe and can produce outcomes comparable to those seen using DBD grafts in similar recipients.

Transplantation of Declined Liver Allografts Following Normothermic Ex-Situ Evaluation.

The demand for liver transplantation (LT) exceeds supply, with rising waiting list mortality. Utilization of high-risk organs is low and a substantial number of procured livers are discarded. We report the first series of five transplants with rejected livers following viability assessment by normothermic machine perfusion of the liver (NMP-L). The evaluation protocol consisted of perfusate lactate, bile production, vascular flows, and liver appearance. All livers were exposed to a variable period of static cold storage prior to commencing NMP-L. Four organs were recovered from donors after circulatory death and rejected due to prolonged donor warm ischemic times; one liver from a brain-death donor was declined for high liver function tests (LFTs). The median (range) total graft preservation time was 798 (range 724-951) min. The transplant procedure was uneventful in every recipient, with immediate function in all grafts. The median in-hospital stay was 10 (range 6-14) days. At present, all recipients are well, with normalized LFTs at median follow-up of 7 (range 6-19) months. Viability assessment of high-risk grafts using NMP-L provides specific information on liver function and can permit their transplantation while minimizing the recipient risk of primary graft nonfunction. This novel approach may increase organ availability for LT.

Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study.

BACKGROUND: Approximately 40% of hormone receptor-positive, HER2-negative breast cancers (BCs) are associated with activating mutations of the phosphatidylinositol 3-kinase (PI3K) pathway. Pictilisib, a potent and highly specific class I pan-PI3K inhibitor, demonstrated preclinical activity in BC cell lines and may potentiate the effect of taxanes, benefiting patients with or without aberrant activation of the PI3K pathway. PEGGY (NCT01740336), a randomised, placebo-controlled phase II trial, examined whether pictilisib augments the anti-tumour activity of paclitaxel in patients with hormone receptor-positive, HER2-negative locally recurrent or metastatic BC (mBC). We report results from the protocol-specified interim analysis. PATIENTS AND METHODS: One hundred and eighty-three eligible patients were randomised (1:1) to receive paclitaxel (90 mg/m2 weekly for 3 weeks in every 28-day cycle) with either 260 mg pictilisib or placebo (daily on days 1-5 every week). The primary end point was progression-free survival (PFS) in the intention-to-treat (ITT) population and patients with PIK3CA-mutated tumours. Secondary end points included overall response rate (ORR), duration of response, and safety. RESULTS: In the ITT population, the median PFS was 8.2 months with pictilisib (n = 91) versus 7.8 months with placebo (n = 92) [hazard ratio (HR) for progression or death, 0.95; 95% confidence interval (CI) 0.62-1.46; P = 0.83]. In patients with PIK3CA-mutated tumours, the median PFS was 7.3 months for pictilisib (n = 32) versus 5.8 months with placebo (n = 30) (HR, 1.06; 95% CI 0.52-2.12; P = 0.88). ORR was similar between treatment arms. The safety profile of pictilisib was consistent with previous reports, with no new safety signals. Proportions of patients with grade ≥3 adverse events (AEs), serious AEs, and dose reductions/discontinuations due to AEs were higher with pictilisib. CONCLUSIONS: PEGGY did not meet its primary end point, revealing no significant benefit from adding pictilisib to paclitaxel for patients with hormone receptor-positive, HER2-negative locally recurrent or mBC. CLINICAL TRIAL NUMBER: NCT01740336.

Identification of Eye-Specific Domains and Their Relation to Callosal Connections in Primary Visual Cortex of Long Evans Rats.

Ocular dominance columns (ODCs) exist in many primates and carnivores, but it is believed that they do not exist in rodents. Using a combination of transneuronal tracing, in situ hybridization for Zif268 and electrophysiological recordings, we show that inputs from both eyes are largely segregated in the binocular region of V1 in Long Evans rats. We also show that, interposed between this binocular region and the lateral border of V1, there lies a strip of cortex that is strongly dominated by the contralateral eye. Finally, we show that callosal connections colocalize primarily with ipsilateral eye domains in the binocular region and with contralateral eye input in the lateral cortical strip, mirroring the relationship between patchy callosal connections and specific sets of ODCs described previously in the cat. Our results suggest that development of cortical modular architecture is more conserved among rodents, carnivores, and primates than previously thought.

Creating the optimal workspace for hospital staff using human centred design.

We were tasked with creating best possible non-clinical workspace solutions for approximately 450 hospital staff across 11 departments encompassing medical, nursing, allied health, administrative and other support staff. We used a Human-Centred Design process, involving 'Hear, Create and Deliver' stages. We used observations, contextual enquiry and role-specific workshops to understand needs, key interactions and drivers of behaviour. Co-design workshops were then used to explore and prototype-test concepts for the final design. With extensive employee engagement and design process expertise, an innovative solution was created that focussed on meeting the functional workspace needs of a diverse group of staff requiring a range of different spaces, incorporating space constraints and equity. This project demonstrated the strength of engaging employees in an expert-led Human-Centred Design process. We believe this is a successful blueprint process for other institutions to embrace when facing similar workspace design challenges.

How do the EMA and FDA decide which anticancer drugs make it to the market? A comparative qualitative study on decision makers' views.

BACKGROUND: The process leading to a regulatory outcome is guided by factors both related and unrelated to the data package, defined in this analysis as 'formal and informal factors', respectively. The aim of this qualitative study was to analyse which formal and informal factors drive the decision-making process of the European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulators with regard to anticancer drugs, using in-depth semi-structured interviews with regulators of the two agencies. METHODS: In line with the theory and practice of qualitative research, no set sample size was defined a priori. Respondent enrolment continued until saturation and redundancy were reached. Data were collected through means of in-depth semi-structured interviews conducted either in a face-to-face setting or via Skype(®) with each regulator. The interviews were audio-recorded and verbatim transcribed. The analysis was manually carried out on the transcribed text. Data were independently coded and categorized by two researchers. Interpretation of the findings emerged through a process of triangulation between the two. RESULTS: Seven EMA and six FDA regulators, who had extensive experience with making decisions about anticancer medicines, were interviewed between April and June 2012. There is an open dialogue between the FDA and EMA, with the two moving closer and exchanging information, not opinions. Differences in decision-making between the agencies may be due to a different evaluation of end points. Different interaction modalities with industry and patients represent an additional source of divergence with a potential impact on decision-making. The key message of our respondents was that the agencies manage uncertainty in a different way: unlike the EMA, the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments. CONCLUSIONS: Although formal factors are the main drivers for regulatory decisions, the influence of informal factors plays an important role in the drug evaluation process.

Upper gastrointestinal training in the UK and Ireland: a Roux Group Study.

INTRODUCTION: Surgical training programmes in the United Kingdom and Ireland (UK&I) are in a state of flux. This study aims to report the contemporary opinions of trainee and consultant surgeons on the current upper gastrointestinal (UGI) training model in the UK&I. METHODS: A questionnaire was developed and distributed via national UGI societies. Questions pertained to demographics, current training evaluation, perceived requirements and availability. RESULTS: A total of 241 responses were received with representation from all UK&I postgraduate training regions. The biggest discrepancies between rotation demand and national availability related to advanced/therapeutic endoscopy and robotic surgery, with 91.7% of respondents stating they would welcome greater geographical flexibility in training. The median suggested academic targets were 3-5 publications (trainee vs consultant <3 vs 3-5, p<0.001); <3 presentations (<3 vs 3-5, p=0.002); and 3-5 audits/quality improvement projects (<3 vs 3-5, p<0.001). Current operative requirements were considered achievable (87.6%) but inadequate for day one consultant practice (74.7%). Reassuringly, 76.3% deemed there was role for on-the-job operative training following consultant appointment. Proficiency in diagnostic endoscopy was considered a minimum requirement for Certificate of Completion of Training (CCT) yet the majority regarded therapeutic endoscopy competency as non-essential. The median numbers of index UGI operations suggested were comparable with the current curriculum requirements. Post-CCT fellowships were not considered necessary; however, the majority (73.6%) recognised their advantage. CONCLUSIONS: Current CCT requirements are largely consistent with the opinions of the UGI community. Areas for improvement include flexibility in geographical working and increasing national provisions for high-quality endoscopy training.

Measurement of long-term outcome in patients with cervical spondylotic myelopathy treated surgically.

PURPOSE: The Myelopathy Disability Index and the Neck Disability Index are widely used to assess outcome in cervical spine surgery. Short Form (SF) 36 is a generic measure of health which can be used to measure health gains across a wide variety of conditions. The aim of the current study is to assess long-term outcomes using these measures in a cohort of patients with cervical spondylotic myelopathy (CSM). METHODS: Cohort study with prospective data collection. Patients with CSM being offered decompressive surgery were asked to complete a set of generic and condition-specific outcome measures. This was repeated post-operatively at 3, 12, 24 and 60 months. SF-36 was used as a generic outcome measure and the Myelopathy Index, Neck Disability Score and visual analogue scores for arm, neck and hand pain, paraesthesia and dysthaesia were used as condition-specific outcome measures. RESULTS: Significant improvements in all outcome measures were seen in 70% of the cohort. For SF-36, pre-operative scores were lower than age-matched controls in all domains and significant improvements were seen 3 months following surgery. This improvement in outcome was maintained at 5 years follow-up in approximately two-thirds of those with initial improvement. CONCLUSION: We have used generic and condition-specific outcome measures of health and shown that in patients with CSM treated surgically, up to 70% can expect improvement in their quality of life. These outcome measures are easy to collect and provide objective evidence of changes in quality of life and disability and can help quantify the potential health gains that can be achieved.

Evaluation of the impact of PEPFAR transition on retention in care in South Africa's Western Cape Province.

BACKGROUND: Research on the impact of the US President's Emergency Plan for AIDS Relief (PEPFAR) transition in South Africa (SA) in 2012 found varying results in retention in care (RIC) of people living with HIV (PLWH). OBJECTIVES: To investigate the factors that impacted RIC during the PEPFAR transition in Western Cape Province, SA, in 2012. METHODS: We used aggregate data from 61 facilities supported by four non-governmental organisations from 2007 to 2015. The main outcome was RIC 12 months after antiretroviral therapy initiation for two periods - during PEPFAR and post PEPFAR. We used adjusted quantile regression to estimate the effect of the PEPFAR pull-out on RIC. RESULTS: Regression models (50th quantile) for 12-month RIC showed a 4.0% (95% CI -7.7 - -0.4%) decline in RIC post-direct service. Facilities supported by Anova/Kheth'impilo fared worst post PEFPAR, with a decline in RIC of -4.9% (95% CI -8.8 - -1.0%), while TB, HIV/AIDS, Treatment Support, and Integrated Therapy (that'sit) fared best (3.6% increase in RIC; 95% CI: -0.2 - 7.3%). There was a decrease in RIC when comparing urban with rural areas (-7.8%; 95% CI -12.8 - -2.9%). City of Cape Town combined with Western Cape Government health facilities showed a substantial decrease (-6.1%; 95% CI -10.6 - -1.7%), while community health clinic (v. central day clinics) declined (-6.4; 95% CI -10.6 - -2.1%) in RIC. We observed no RIC difference by facility size and a slight increase when two or more human resources transitioned from PEPFAR to the government. CONCLUSION: When PEPFAR funding decreased in 2012, there was a decrease in RIC. To ensure the continuity of HIV care when a major funder withdraws sufficient and stable transition resources, investment in organisations that understand the local context, joint planning and co-ordination are required.

Practical measurement of affordability: an application to medicines.

OBJECTIVE: To develop two practical methods for measuring the affordability of medicines in developing countries. METHODS: The proposed methods--catastrophic and impoverishment methods--rely on easily accessible aggregated expenditure data and take into account a country's income distribution and absolute level of income. The catastrophic method quantifies the proportion of the population whose resources would be catastrophically reduced by spending on a given medicine; the impoverishment method estimates the proportion of the population that would be pushed below the poverty line by procuring a given medicine. These methods are illustrated by calculating the affordability of glibenclamide, an antidiabetic drug, in India and Indonesia. The results were validated by comparing them with the results obtained by using household micro data for India and Indonesia. FINDINGS: When accurate aggregate data are available, the proposed methods offer a practical way to obtain informative and accurate estimates of affordability. Their results are very similar to those obtained with household micro data analysis and are easily compared across countries. CONCLUSION: The catastrophic and impoverishment methods, based on macro data, can provide a suitable estimate of medicine affordability when the household level micro data needed to carry out more sophisticated studies are not available. Their usefulness depends on the availability of accurate aggregated data.

Prospective study of outcome of foramen magnum decompressions in patients with syrinx and non-syrinx associated Chiari malformations.

OBJECTIVE: To assess the outcome in patients with syrinx and non-syrinx associated Chiari malformations undergoing Foramen Magnum Decompression (FMD). METHODS: Sixty-one patients undergoing FMD for Chiari malformations were prospectively studied with disease specific, generic (SF 36) and subjective (patient reported) outcomes. Of these, 34 patients had objective outcome data including SF36, visual analogue pain scores, Neck and Myelopathy disability indices and the Hospital anxiety and depression score. SF 36 scores were compared to normative data. Data were collected pre-operatively, at 3 months and during long-term follow up (12-60 months). RESULTS: Patient reported improvements in headache and neck pain post-operatively was reported in both syrinx and non-syrinx associated patients. Visual Analogue scores showed improvements in arm pain, paresthesia and hand tingling at 3 months in the syrinx group only. Non-syrinx patients showed significant improvements post-operatively in the Neck disability index and the SF-36 domains for physical function, role physical and bodily pain. Comparison with SF-36 normative data indicates that patients still have significantly impaired quality of life 12 months post-operatively. CONCLUSION: FMD is able to relieve symptoms and improve quality of life in patients with both syrinx and non-syrinx associated Chiari malformations. In syrinx patients we observed symptomatic improvement in limb symptoms as well as radiological resolution of the syrinx. The use of SF-36 allows the health gain associated with FMD to be quantified. SF 36 is not adequate as a stand alone measure of outcome in this complex disorder and we advocate the concurrent use of disease specific measures and post-operative imaging of the syrinx.

Out of hours magnetic resonance imaging for suspected cauda equina syndrome: lessons from a comparative study across two centres.

BACKGROUND: Cauda equina syndrome, a rare but disabling spinal surgical emergency, requires prompt investigation, ideally using magnetic resonance imaging as patients may require decompressive surgery. Out of hours access to magnetic resonance imaging is only routinely available in major trauma centres and neurosurgical units. Patients in regional hospitals with suspected cauda equina syndrome may require transfer for diagnostic imaging. We retrospectively studied the proportion of patients referred with suspected cauda equina syndrome who required out of hours transfer for magnetic resonance imaging and decompressive surgery. MATERIALS ANDS METHODS: Retrospective cohort study of patients referred using online referral platforms with suspected acute cauda equina syndrome and transferred out of hours between 6pm to 8am on weekdays and all day on weekends to two of the largest neurosurgical units in the UK in Birmingham and Cambridge. RESULTS: A total of 441 patients were referred across both sites with a suspicion of acute cauda equina syndrome; 339 patients were transferred for diagnostic scans and only 16 of them (4.7%) were positive for cauda equina compression, necessitating prompt decompressive surgery. Of the patients with negative magnetic resonance scans, 50% had their discharge or transfer back to referring hospitals delayed by more than 24 hours. CONCLUSIONS: Over 95% of patients who were transferred for imaging did not undergo emergency decompression. The authors propose a greater role for the provision of out of hours magnetic resonance imaging in all hospitals admitting emergency patients to streamline management.

Medicine prices, availability, and affordability in 36 developing and middle-income countries: a secondary analysis.

BACKGROUND: WHO and Health Action International (HAI) have developed a standardised method for surveying medicine prices, availability, affordability, and price components in low-income and middle-income countries. Here, we present a secondary analysis of medicine availability in 45 national and subnational surveys done using the WHO/HAI methodology. METHODS: Data from 45 WHO/HAI surveys in 36 countries were adjusted for inflation or deflation and purchasing power parity. International reference prices from open international procurements for generic products were used as comparators. Results are presented for 15 medicines included in at least 80% of surveys and four individual medicines. FINDINGS: Average public sector availability of generic medicines ranged from 29.4% to 54.4% across WHO regions. Median government procurement prices for 15 generic medicines were 1.11 times corresponding international reference prices, although purchasing efficiency ranged from 0.09 to 5.37 times international reference prices. Low procurement prices did not always translate into low patient prices. Private sector patients paid 9-25 times international reference prices for lowest-priced generic products and over 20 times international reference prices for originator products across WHO regions. Treatments for acute and chronic illness were largely unaffordable in many countries. In the private sector, wholesale mark-ups ranged from 2% to 380%, whereas retail mark-ups ranged from 10% to 552%. In countries where value added tax was applied to medicines, the amount charged varied from 4% to 15%. INTERPRETATION: Overall, public and private sector prices for originator and generic medicines were substantially higher than would be expected if purchasing and distribution were efficient and mark-ups were reasonable. Policy options such as promoting generic medicines and alternative financing mechanisms are needed to increase availability, reduce prices, and improve affordability.

A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial.

BACKGROUND: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. METHODS: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). RESULTS: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. CONCLUSIONS: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.

A comparative analysis of asthma treatment guidelines and Essential Medicine Lists in sub-Saharan Africa.

INTRODUCTION: Asthma is a chronic condition affecting between 300 and 400 million people worldwide. Studies have shown that asthma symptoms can be controlled by the daily use of inhaled corticosteroids (ICS). The management of asthma varies in different settings.METHODS: Asthma management in 13 sub-Saharan African countries was compared to the 2018 Global Initiative for Asthma (GINA) guidelines and the 20th WHO model list of essential medicines (2019). A table with predefined criteria extracted from the international guidelines was used to analyse the content and compare the different treatment guidelines using an Excel spreadsheet.RESULTS: There are variations in the way asthma is diagnosed and treated in different countries. Countries with older treatment guidelines do not have a stepwise approach to assessing severity as stipulated by GINA. Of the 13 countries, only 46% have inhaled ICS at the primary level, 38% have ICS at the secondary level and 16% do not specify.CONCLUSION: The management of asthma varies widely between different countries in sub-Saharan Africa. The noticed variations in approach to care can be explored as an opportunity to harness resources to produce similar and updated guidelines, resulting in uniformity of care across different countries.

Metabolic syndrome and prostate cancer: a review.

Androgen deprivation therapy is widely used in a number of different settings in the treatment of prostate cancer. This overview will look at the current evidence for the potential development of metabolic syndrome and cardiovascular disease as a consequence of this therapy, and highlight strategies aimed at their prevention. The relationship between metabolic syndrome and prostate cancer development will also be examined.

A gene expression profiling approach assessing celecoxib in a randomized controlled trial in prostate cancer.

BACKGROUND: We performed a pilot study, looking at the COX-2 inhibitor celecoxib, on newly diagnosed prostate cancer patients in the neo-adjuvant setting using DNA microarray analysis. PATIENTS AND METHODS: This was a single-blinded, randomized controlled phase II presurgical (radical prostatectomy) 28-day trial of celecoxib versus no drug in patients with localized T1-2 N0 M0 prostate cancer. cDNA microarray analysis was carried out on prostate cancer biopsies taken from freshly obtained radical prostatectomy samples. Results were confirmed by qPCR analysis of a selection of genes. RESULTS: Multiple genes were differentially expressed in response to celecoxib treatment. Statistical analysis of microarray data indicated 24 genes were up-regulated and 4 genes down-regulated as a consequence of celecoxib treatment. Gene changes e.g. survivin, SRP72kDa, were associated with promoting apoptotic cell death, enhancement of antioxidant processes and tumour suppressor function (p73 and cyclin B1 up-regulation). CONCLUSION: Celecoxib at 400 mg b.i.d. for 4 weeks perioperatively gave rise to changes in gene expression in prostate cancer tissue consistent with enhancement of apoptosis and tumour suppressor function. Given the short time interval for the duration of this study, the data are encouraging and provide a good rationale for conducting further trials of celecoxib in prostate cancer.