Proper understanding of recurrent stress urinary incontinence treatment in women (PURSUIT): a randomised controlled trial of endoscopic and surgical treatment.

BACKGROUND: Women with stress urinary incontinence (SUI) experience urine leakage with physical activity. Currently, the interventional treatments for SUI are surgical, or endoscopic bulking injection(s). However, these procedures are not always successful, and symptoms can persist or come back after treatment, categorised as recurrent SUI. There are longstanding symptoms and distress associated with a failed primary treatment, and currently, there is no consensus on how best to treat women with recurrent, or persistent, SUI. METHODS: A two-arm trial, set in at least 20 National Health Service (NHS) urology and urogynaecology referral units in the UK, randomising 250 adult women with recurrent or persistent SUI 1:1 to receive either an endoscopic intervention (endoscopic bulking injections) or a standard NHS surgical intervention, currently colposuspension, autologous fascial sling or artificial urinary sphincter. The aim of the trial is to determine whether surgical treatment is superior to endoscopic bulking injections in terms of symptom severity at 1 year after randomisation. This primary outcome will be measured using the patient-reported International Consultation on Incontinence Questionnaire - Urinary Incontinence - Short Form (ICIQ-UI-SF). Secondary outcomes include assessment of longer-term clinical impact, improvement of symptoms, safety, operative assessments, sexual function, cost-effectiveness and an evaluation of patients' and clinicians' views and experiences of the interventions. DISCUSSION: There is a lack of high-quality, randomised, scientific evidence for which treatment is best for women presenting with recurrent SUI. The PURSUIT study will benefit healthcare professionals and patients and provide robust evidence to guide further treatment and improve symptoms and quality of life for women with this condition. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) registry ISRCTN12201059. Registered on 09 January 2020.

Cost-effectiveness of Interventions for Chronic Fatigue Syndrome or Myalgic Encephalomyelitis: A Systematic Review of Economic Evaluations.

INTRODUCTION: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has profound quality of life and economic consequences for individuals, their family, formal services and wider society. Little is known about which therapeutic interventions are more cost-effective. OBJECTIVE: A systematic review was carried out to identify and critically appraise the evidence on the cost-effectiveness of CFS/ME interventions. METHODS: The review protocol was prespecified (PROSPERO: CRD42018118731). Searches were carried out across two databases-MEDLINE (1946-2020) and EMBASE (1974-2020). Additional studies were identified by searching reference lists. Only peer-reviewed journal articles of full economic evaluations examining CFS/ME interventions were included. Trial- and/or model-based economic evaluations were eligible. Data extraction and screening were carried out independently by two reviewers. The methodological quality of the economic evaluation and trial were assessed using the Consensus Health Economic Criteria checklist (CHEC-list) and Risk of Bias-2 (RoB-2) tool, respectively. A narrative synthesis was used to summarise the economic evidence for interventions for adults and children in primary and secondary care settings. RESULTS: Ten economic evaluations, all based on data derived from randomised controlled trials, met our eligibility criteria. Cognitive behavioural therapy (CBT) was evaluated across five studies, making it the most commonly evaluated intervention. There was evidence from three trials to support CBT as a cost-effective treatment option for adults; however, findings on CBT were not uniform, suggesting that cost-effectiveness may be context-specific. A wide array of other interventions were evaluated in adults, including limited evidence from two trials supporting the cost effectiveness of graded exercise therapy (GET). Just one study assessed intervention options for children. Our review highlighted the importance of informal care costs and productivity losses in the evaluation of CFS/ME interventions. CONCLUSIONS: We identified a limited patchwork of evidence on the cost-effectiveness of interventions for CFS/ME. Evidence supports CBT as a cost-effective treatment option for adults; however, cost-effectiveness may depend on the duration and frequency of sessions. Limited evidence supports the cost effectiveness of GET. Key weaknesses in the literature included small sample sizes and short duration of follow-up. Further research is needed on pharmacological interventions and therapies for children.

Systematic review of the methods used in economic evaluations of targeted physical activity and sedentary behaviour interventions.

The burden of noncommunicable diseases (NCD) on health systems worldwide is substantial. Physical inactivity and sedentary behaviour are major risk factors for NCD. Previous attempts to understand the value for money of preventative interventions targeting physically inactive individuals have proved to be challenging due to key methodological challenges associated with the conduct of economic evaluations in public health. A systematic review was carried out across six databases (Medline, SPORTSDiscus, EconLit, PsychINFO, NHS EED, HTA) along with supplementary searches. The review examines how economic evaluations published between 2009-March 2017 have addressed methodological challenges with the aim of bringing to light examples of good practice for future studies. Fifteen economic evaluations from four high-income countries were retrieved; there is a dearth of studies targeting sedentary behaviour as an independent risk factor from physical activity. Comparability of studies from the healthcare and societal perspectives were limited due to analysts' choice in cost categories, valuation technique and time horizon differing substantially. The scarcity of and inconsistencies across economic evaluations for these two behaviours have exposed a mismatch between calls for more preventative action to tackle NCD and the lack of information available on how resources may be optimally allocated in practice. Consequently, this paper offers a table of recommendations on how future studies can be improved.

Donor brain death inhibits tolerance induction in miniature swine recipients of fully MHC-disparate pulmonary allografts.

We have previously shown that a short course of high-dose tacrolimus induces long-term tolerance to fully mismatched lung allografts procured from healthy MHC-inbred miniature swine. Here, we investigate whether donor brain death affects tolerance induction. Four recipient swine were transplanted with fully mismatched lung grafts from donors that were rendered brain dead and mechanically ventilated for 4 h before procurement (Group 1). These recipients were compared to two control groups (Group 2: 4 h of donor ventilation without brain death [n = 5]; and Group 3: no donor brain death with <1 h of ventilation [n = 6]). All recipients were treated with a 12-day course of tacrolimus. In contrast to both groups of control animals, the swine transplanted with lung allografts from brain dead donors all rejected their grafts by postoperative day 45 and showed persistent responsiveness to donor antigen by MLR. Several additional swine underwent brain death induction and/or mechanical ventilation alone to determine the effects of these procedures on the expression of proinflammatory molecules. Significant increases in serum concentrations of IL-1, TNF-α and IL-10 were seen after brain death. Upregulation of IL-1 and IL-6 gene expression was also observed.

Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine.

The ability of transient immunosuppression with a combination of a non-depleting anti-CD4 (NDCD4) antibody and cyclosporine (CyA) to abrogate immune reactivity to both adeno-associated viral vector (AAV) and its transgene product was evaluated. This combination of immunosuppressants resulted in a 20-fold reduction in the resulting anti-AAV8 antibody titres, to levels in naïve mice, following intravenous administration of 2 × 10(12) AAV8 vector particles per kg to immunocompetent mice. This allowed efficient transduction upon secondary challenge with vector pseudotyped with the same capsid. Persistent tolerance did not result, however, as an anti-AAV8 antibody response was elicited upon rechallenge with AAV8 without immunosuppression. The route of vector administration, vector dose, AAV serotype or the concomitant administration of adenoviral vector appeared to have little impact on the ability of the NDCD4 antibody and CyA combination to moderate the primary humoral response to AAV capsid proteins. The combination of NDCD4 and CyA also abrogated the humoral response to the transgene product, that otherwise invariably would occur, following intramuscular injection of AAV5, leading to stable transgene expression. These observations could significantly improve the prospects of using rAAV vectors for chronic disorders by allowing for repeated vector administration and avoiding the development of antibodies to the transgene product.

Liver histopathology of the sharptooth catfish Clarias gariepinus as a biomarker of aquatic pollution.

This paper reports on a comparative perspective of liver histopathological data of the sharptooth catfish Clarias gariepinus. The data was collected from a spectrum of relatively un-impacted and isolated, to polluted, eutrophic freshwater ecosystems. Results were compared between regional areas, by combining data from freshwater systems which has a similar pollution status and/or is located within the same geographical region. Measurements included necropsy observations, semi-quantitative liver histopathology (Liver Index), and selected biometrical indices. The aim was to establish whether the results of these measurements would differ between, and/or reflect the pollution status of, the different freshwater aquatic ecosystems. The histopathological analysis showed a higher prevalence of toxicopathic non-neoplastic, and pre-neoplastic alterations in C. gariepinus from the polluted sites. We also found a significant difference between the Liver Index, hepatosomatic index, and condition factor values of fish inhabiting impoundments known to be polluted, compared to the same species from the selected reference sites. Fish from polluted sites also had more macroscopic liver abnormalities. The results suggest that the liver histopathology of this bio-indicator fish species could be a useful biomarker of freshwater aquatic pollution.

Hepatitis B surface antigen fusions delivered by DNA vaccination elicit CTL responses to human papillomavirus oncoproteins associated with tumor protection.

We describe the construction and evaluation of a recombinant hepatitis B surface antigen (HBsAg)-vectored DNA vaccine encoding the E7 and E6 tumor-associated oncoproteins of human papillomavirus (HPV) type 16. We show the induction of effector and memory cytotoxic T lymphocyte responses to E7 and E6 class I-restricted epitopes after a single immunization, which were associated with tumor prevention and therapy. The findings vindicate the use of a HBsAg-based DNA vaccine as a vehicle to elicit responses to co-encoded tumor antigens, and have specific implications for the development of a therapeutic vaccine for HPV-associated squamous carcinomas.

The indirect alloresponse impairs the induction but not maintenance of tolerance to MHC class I-disparate allografts.

We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I-mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor-derived or control third-party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T-cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney-heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney-heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long-term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.

Enhancing transduction of the liver by adeno-associated viral vectors.

A number of distinct factors acting at different stages of the adeno-associated virus vector (AAV)-mediated gene transfer process were found to influence murine hepatocyte transduction. Foremost among these was the viral capsid protein. Self-complementary (sc) AAV pseudotyped with capsid from serotype 8 or rh.10 mediated fourfold greater hepatocyte transduction for a given vector dose when compared with vector packaged with AAV7 capsid. An almost linear relationship between vector dose and transgene expression was noted for all serotypes with vector doses as low as 1 x 10(7) vg per mouse (4 x 10(8) vg kg(-1)) mediating therapeutic levels of human FIX (hFIX) expression. Gender significantly influenced scAAV-mediated transgene expression, with twofold higher levels of expression observed in male compared with female mice. Pretreatment of mice with the proteasome inhibitor bortezomib increased scAAV-mediated hFIX expression from 4+/-0.6 to 9+/-2 microg ml(-1) in female mice, although the effect of this agent was less profound in males. Exposure of mice to adenovirus 10-20 weeks after gene transfer with AAV vectors augmented AAV transgene expression twofold by increasing the level of proviral mRNA. Hence, optimization of individual steps in the AAV gene transfer process can further enhance the potency of AAV-mediated transgene expression, thus increasing the probability of successful gene therapy.

The transition from medical student to doctor: perceptions of final year students and preregistration house officers related to expected learning outcomes.

In this prospective qualitative study over 12 months, we evaluated the educational and clinical effectiveness of a new final year undergraduate programme in a London medical school (Guy's, King's and St Thomas'). A stratified sample of 17/360 final year students were interviewed four times, and the content was assessed against 32 amalgamated learning outcomes identified in 1997 in The New Doctor. At the beginning of the preregistration year, eight of the learning outcomes were already met, 10 partly, eight remained to be attained and for six, insufficient evidence existed. Preregistration house officers who have been through the final year student house officer programme expressed competence in many of the outcomes of the General Medical Council's New Doctor. The study identified areas such as prescribing where further developments are needed and will help in planning the new foundation programme.

A prospective, within-patient comparison between metal butterfly needles and Teflon cannulae in subcutaneous infusion of drugs to terminally ill hospice patients.

We performed a prospective study of hospice in-patients requiring a syringe driver (SD), to determine the site duration and tolerability of metal butterfly needles compared to Teflon cannulae. Using patients as their own control, prescribed medications were divided equally between two SDs (Graseby MS16a), for delivery over 24 h. A butterfly infusion (Flosafer, 25 gauge) was connected to one SD and a Teflon cannula (Abbocath-T, 24 gauge), to the second. These were inserted subcutaneously (s.c.) on opposite sides of the body at comparable sites; oedematous, broken or painful sites were excluded. SD sites were examined at 4-hourly intervals. The study was terminated when both devices had required resiting. Needle and cannula times were compared using the Wilcoxon signed rank test. Thirty patients entered the study, 13 males and 17 females, mean age (standard deviation): 70 (11) years. Thirteen patients completed the study. Nine patients died and eight patients discontinued the study before both needle and cannula had been resited. All 30 patients are included in the analysis. The time from insertion to resiting of the cannula was significantly longer than the needle: P < 0.0002, median (range) 93.5 (22.8-263.5) h versus 42.8 (7.5-162.3) h, respectively. The cost of the needle versus cannula is 1.93 Pounds versus 2.51 Pounds, respectively. Teflon cannulae have a median life span twice that of metal butterfly needles and are a cost-effective alternative for administration of medications by s.c. infusion in terminally ill patients.

Pre-registration house officers in general practice: the views of GP trainers.

BACKGROUND: Recent changes have led to an upsurge of interest in pre-registration rotations in general practice. In 1998, a national pilot programme of >40 new rotations incorporating general practice was implemented. OBJECTIVE: The aim of this study was to explore the experiences of GPs involved in the four pilot rotations established in South Thames region. METHODS: Semi-structured interviews were conducted with trainers and partners. RESULTS: The supervisory workload for pre-registration house officers (PRHOs) was much greater than that required by registrars. All GPs felt that increased remuneration was important for the future viability of the scheme. The majority of GPs remained supportive of the scheme, although a minority were concerned about the value of the experience gained by PRHOs. There were a few instances in which inadequacies in patient management had to be dealt with subsequently by trainers. The supervisory implications of such events will need to be addressed. CONCLUSION: This significant development in medical education has important implications for GPs and their patients which need further exploration through long-term evaluations.

The doctor-patient relationship: from undergraduate assumptions to pre-registration reality.

OBJECTIVES: To describe the ways in which the doctor-patient relationship experienced by newly qualified pre-registration house officers (PRHOs) differed from their undergraduate expectations. DESIGN: Qualitative study in which in-depth semistructured interviews were carried out with each PRHO within 4-6 weeks of the start of their first job. SETTING: Three teaching hospitals, three district general hospitals and four general practices in south-east England. PARTICIPANTS: 24 newly qualified PRHOs. RESULTS: A number of differences were identified by PRHOs. These were caused in part by the impact of factors such as the shortage of time, which could lead to emotional 'blunting'. Some PRHOs were changing their ideas about what constitutes a 'good' doctor, and were redefining the meaning of a 'professional' relationship. The relationships of PRHOs with patients were also affected by the attitudes of their senior colleagues. For example, where PRHOs tried to maintain a patient-centred relationship, they could be identified by colleagues as working too slowly. PRHOs working in general practice were able to utilize and improve their communication skills with patients, but found it difficult to transfer these skills back into the hospital setting. CONCLUSIONS: Despite receiving substantial undergraduate education on how best to communicate with patients, a variety of factors conspired to prevent hospital-based PRHOs from utilizing this information. Building on these findings, a number of recommendations are made to help improve practice.

The clinical and educational experiences of pre-registration house officers in general practice.

AIMS: To describe aspects of the clinical experience and educational supervision gained by pre-registration house officers (PRHOs) in general practice, and to relate these to the current General Medical Council (GMC) aims for general clinical training in general practice. DESIGN: Qualitative evaluation, part of which involved semistructured interviews with 12 PRHOs who were experiencing a general practice rotation. Interviews were conducted at the beginning and the end of the pre-registration year, and following return to hospital work after completion of the general practice placement. SETTINGS: Three teaching hospitals, two district general hospitals and six general practices in south-east England. PARTICIPANTS: 12 PRHOs who were involved in rotations incorporating a general practice placement. RESULTS: To varying degrees, the GMC aims for training in general practice were met for all the participants. All PRHOs recognized the value of the clinical experience and educational supervision they received in general practice. They particularly valued aspects such as having an individual training programme based on their own needs, and the interlinking of theory and practice, which aided learning. Most felt that having responsibility for their own patients acted as an important incentive for learning, and in general, PRHOs appreciated having the time to learn which general practice allowed. CONCLUSIONS: For the majority of PRHOs, the time spent in general practice was seen as a positive clinical and educational experience. In a variety of ways, the general practice placement encouraged PRHOs to develop the self-directed learning skills seen as essential to the lifelong learning advocated by the GMC. A number of recommendations are made to help improve the integration of the hospital and general practice components of these rotations.

Pre-registration house officer rotations incorporating general practice: does the order of rotation matter?

CONTEXT: In relation to pre-registration house officer (PRHO) rotations incorporating general practice, previous research has recommended that where possible, no PRHO should undertake general practice as the first placement, because of the difficulties encountered. It was recognized that logistically, this could make such schemes almost unworkable. Within the context of a larger qualitative evaluation comparing how 24 PRHOs learned in hospital and general practice settings, the issue of rotation order was explored. METHODS: In-depth semistructured interviews were conducted with the 12 PRHOs who were involved in general practice rotations. They were interviewed at the beginning and end of the PRHO year, and following their return to hospital work after the general practice placement. RESULTS: Each rotation order had both advantages and disadvantages, with no particular rotation order being obviously better or worse for the PRHOs involved. CONCLUSIONS: This small qualitative evaluation has highlighted a number of advantages and disadvantages specific to each rotation order, and makes some practical recommendations to help alleviate the problems encountered. It is important that future evaluations of similar schemes consider this issue, as there are conflicting reports about the significance of the rotation order.

PRHOs in primary care: what is happening out there?

Preregistration house officer (PRHO) placements in general practice were introduced throughout Britain in August 1998. This paper describes an evaluation of PRHOs in primary care rotations in South Thames during 1998-99. There are important messages for both educational supervisors and undergraduates considering a PRHO in primary care rotation.

Pre-registration rotations into general practice: the concerns of pre-registration house officers and the views of hospital consultants.

AIMS: To explore the concerns of pre-registration house officers (PRHOs) and the views of hospital consultants in relation to pre-registration rotations with a general practice component. METHOD: As part of a larger qualitative study evaluating how a group of 24 PRHOs learn in hospital and primary care settings, face-to-face semistructured interviews were conducted with the PRHOs, and semistructured telephone interviews with the PRHOs' educational supervisors were carried out. RESULTS: The interviews with the PRHOs highlighted their concerns about how consultants might view PRHO rotations into general practice. However, the majority of consultants interviewed recognized and valued specific aspects of the experience to be gained by PRHOs in general practice, including the relationship between primary and secondary care; communications skills; specific clinical skills, and an understanding of the natural course of illnesses. The experience was seen as valuable for PRHOs considering either a general practice or a hospital career. Of the 17 consultants, 10 were also confident that 4-month placements in surgery and medicine would give PRHOs adequate experience in either specialty, providing the placements were sufficiently busy. CONCLUSIONS: Medical school deans and medical students considering PRHO rotations with a general practice component can be encouraged by the fact that, in this small study, the majority of hospital consultants interviewed valued the specific experience offered by these rotations, and felt that adequate medical and surgical experience could be gained in busy 4-month hospital placements.

Changes in chalazal cell walls and in the peroxidase enzymes of the crease region during grain development in barley.

In an investigation of the role of peroxidase enzymes in the differentiation of the tissues of the crease region of barley, plants of winter barley cv. Halcyon were grown from anthesis onwards in controlled conditions at a constant temperature of 16 degrees C. Four ears were harvested at 2-d intervals from 6 d after anthesis (daa) until 50 daa. Grains from mid-ear were used for (i) fresh and dry weight determinations, (ii) extraction of crease tissue for the determination of peroxidase activity and for the separation of isozymes of peroxidase by isoelectric focusing (IEF) and (iii) detection of lignin and suberin in the tissues of the crease using autofluorescence and cytochemistry. Peroxidase activity was located histochemically in the crease tissue of cv. Chariot. Scanning electron microscopy studies were carried out on developing grains of cv. Blenheim. Maximum grain water content was achieved at 14 daa. Lignin and suberin were detected in the walls of the chalazal cells from 18 daa onwards. No changes in the staining of chalazal cell walls were detected at the end of grain filling (32 daa), but loss of autofluorescence and staining were observed at 42 daa, just prior to the final, rapid phase of grain dehydration. Peroxidase activity per fresh weight of crease tissue was high at 6 daa and low at 22 daa. It was also low between 32 and 40 daa, but it rose again from 42 daa onwards. IEF demonstrated that both anionic and cationic isozymes of peroxidase were present in crease tissue, the pattern of bands showing some marked changes during the course of grain development.