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.

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.

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.

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 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.

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.

Inhaled corticosteroids for asthma therapy: patient compliance, devices, and inhalation technique.

BACKGROUND: Patient compliance, inhalation devices, and inhalation techniques influence the effectiveness of inhaled medications. METHODS: This article presents the results of a systematic literature review of studies measuring compliance with inhaled corticosteroids, measuring inhalation technique with different inhalation devices, and estimating the proportion of inhaled drug that is deposited in the lung. RESULTS: Overall, patients took the recommended doses of inhaled medication on 20 to 73% of days. Frequency of efficient inhalation technique ranged from 46 to 59% of patients. Education programs have been shown to improve compliance and inhalation techniques. The lung deposition achieved with different inhalers depends on particle size as well as inhaler technique. CONCLUSION: This review demonstrates that multiple factors may come between a prescription of an inhaled corticosteroid and the arrival of that medicine at its target organ, the lung.

Outcome of illegitimate conceptions in a black population.

PIP: Field interviews were conducted to gather data on pregnancy wastage and illegitimacy among 990 urban black women in a North Carolina Standard Metropolitan Statistical Area. The sample range in age from 15-39, was at least gravida 1, and was at the poverty level (based on relationship of family size to income). 90% of births were illegitimate with little influence from economic status or income, but higher educational levels were associated with a greater percentage of conceptions resulting in illegitimate live births. The older the women, the lower was the proportion of illegitimate conceptions resulting in illegitimate births. In groups aged 15-24, and 30-39, there was a positive relationship between education and percentage of illegitimate live births, possibly due to general good health, awareness of health facilities for the more educated, and a reluctance to view abortion as acceptable. In this group aged 25-29, higher education was negatively related to illegitimate births, possibly explained by the relatively better health of this group, regardless of knowledge or availability of health care, and their tendency to view abortion as acceptable. Only 4% saw having children as a handicap to getting married. Only 9.7% of all conceptions which were terminated could have been via abortion, which is indicative of the corresponding attitudinal survey where 77% of the sample were opposed to abortion under any circumstances.^ieng

Nurse management of patients with minor illnesses in general practice: multicentre, randomised controlled trial.

OBJECTIVE: To assess the acceptability and safety of a minor illness service led by practice nurses in general practice. DESIGN: Multicentre, randomised controlled trial. SETTING: 5 general practices in south east London and Kent representing semi-rural, suburban, and urban settings. PARTICIPANTS: 1815 patients requesting and offered same day appointments by receptionists. INTERVENTION: Patients were assigned to treatment by either a specially trained nurse or a general practitioner. Patients seen by a nurse were referred to a general practitioner when appropriate. MAIN OUTCOME MEASURES: The general satisfaction of the patients as measured by the consultation satisfaction questionnaire. Other outcome measures included the length of the consultation, number of prescriptions written, rates of referral to general practitioners, patient's reported health status, patient's anticipated behaviour in seeking health care in future, and number of patients who returned to the surgery, visits to accident and emergency, and out of hours calls to doctors. RESULTS: Patients were very satisfied with both nurses and doctors, but they were significantly more satisfied with their consultations with nurses (mean (SD) score of satisfaction 78.6 (16. 0) of 100 points for nurses v 76.4 (17.8) for doctors; 95% confidence interval for difference between means -4.07 to -0.38). Consultations with nurses took about 10 minutes compared with about 8 minutes for consultations with doctors. Nurses and doctors wrote prescriptions for a similar proportion of patients (nurses 481/736 (65.4%) v doctors 518/816 (63.5%)). 577/790 (73%) patients seen by nurses were managed without any input from doctors. CONCLUSION: Practice nurses seem to offer an effective service for patients with minor illnesses who request same day appointments.

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.

Home care information systems: strategies for the future.

As market reform of the US health care system propels home care providers onto center stage, savvy home care leaders are quietly preparing a new information technology strategy to cope with the challenges that lie ahead.

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.