The outcome of pregnancies in women with cystic fibrosis--single centre experience 1998-2011.

OBJECTIVE: To describe the maternal and fetal outcomes of pregnancies in women with cystic fibrosis. DESIGN: Retrospective study. SETTING: Single obstetric hospital and adult cystic fibrosis centre. METHODS: Retrospective case-note review of pregnant women with cystic fibrosis referred for antenatal care and delivery. MAIN OUTCOME MEASURES: Maternal and fetal outcomes, mode of delivery, lung function and pregnancy complications. RESULTS: Forty-eight pregnancies were studied in 41 women. There were two miscarriages, 44 singleton pregnancies and two sets of twins. All babies were liveborn and survived. The mean gestational age at delivery was 35.9 ± 3.3 weeks. There were no fetal abnormalities or terminations of pregnancy. The median birthweight centile was 31.9 (interquartile range 14.9-55.6). Twenty-five (52.1%) of the women had pancreatic insufficiency and 17 (35.4%) required insulin. There was a positive correlation between booking predicted forced expiratory volume in 1 second (FEV(1) ) and gestational age at delivery (P < 0.01). Women with FEV(1) ≤60% were more likely to deliver earlier and by caesarean section compared with women with FEV(1) >60% (35.0 ± 3.2 weeks versus 37.1 ± 3.0 weeks; P = 0.02 and 75.0% versus 25.0%; P = 0.01). Three of the seven women with an FEV(1) <40% died within 18 months of delivery. Four of the eight women with FEV(1) 40-50% died between 2 and 8 years after delivery. CONCLUSION: Pregnancy for women with cystic fibrosis is possible and results in favourable maternal and fetal outcomes, but the incidence of preterm delivery and caesarean section is increased. Women with pre-existing poor lung function should be counselled antenatally to ensure that they understand the implications of their shortened life-expectancy and parenthood.

Education Team Time Out in Oncologic Visceral Surgery Optimizes Surgical Resident Training and Team Communication-Results of a Prospective Trial.

BACKGROUND: Surgical education is highly dependent on intraoperative communication. Trainers must know the trainee's training level to ensure high-quality surgical training. A systematic preoperative dialogue (Educational Team Time Out, ETO) was established to discuss the steps of each surgical procedure. METHODS: Over 6 months, ETO was performed within a time limit of 3 minutes. Digital surveys on the utility of ETO and its impact on performance were conducted immediately after surgery and at the end of the study period among the staff of the participating disciplines (trainer, trainee, surgical nursing staff, anaesthesiologists, and medical students). The number of surgical substeps performed was recorded and compared with the equivalent period one year earlier. RESULTS: ETO was performed in 64 of the 103 eligible operations (62%). Liver resection (n = 37) was the most frequent procedure, followed by left-sided colorectal surgery (n = 12), partial pancreaticoduodenectomy (n = 6), right-sided hemicolectomies (n = 5), and thyroidectomies (n = 4). Anaesthesiologists most frequently reported that ETO had a direct impact on their work during surgery (90.9%). The influence scores were 46.8% for trainees, 8.8% for trainers, 53.3% for surgical nursing staff and 66.6% for medical students. During the implementation of ETO, a trend towards more assisted substeps in oncologic visceral surgery was seen compared to the corresponding period one year earlier (51% vs.40%; p = 0.11). CONCLUSION: ETO leads to improved intraoperative communication and more performed substeps during complex procedures, which increases motivation and practical training. This concept can easily be implemented in all surgical specialties to improve surgical education.

Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study.

BACKGROUND: Making trials more patient-centred improves recruitment and retention, patient satisfaction and makes research accessible to a more representative population. We aimed to understand the factors that influence participation and engagement in clinical trials in cystic fibrosis (CF) trials to guide the rational design and delivery of patient-centred trials. METHODS: We used a Delphi process, supported by extensive literature review and 3 workshops, to determine which factors stakeholders think exert significant influence in participation and engagement in CF trials. Panellists were recruited from across the UK and the study was administered online. RESULTS: We had representation from 19 CF centres; 28 people with CF (pwCF), 26 parents and 30 healthcare professionals (HCPs). Panels were presented with a shortlist of 104 factors and asked which they thought influence participation and engagement in CF trials. After 3 iterations, 43 statements met consensus for pwCF, 48 for the parents and 69 for the HCPs. CONCLUSIONS: We identified many targets to make trials more patient-centred. Whilst some require an overhaul of trial delivery, many are relatively easy to implement. We outline a list of 'dos and don'ts' for sponsors and research teams including: focus on good communication; recognise that lack of time is the greatest barrier to trial participation so minimise the frequency and length of visits; help participants fit trials around busy lives; remember trial participation can be a major life-event and support participants accordingly; and don't underestimate the impact of simple strategies e.g. on-site access to Wifi and cups of tea.

Tenofovir-associated renal and bone toxicity.

OBJECTIVES: The aims of the study were to describe the clinical presentation and renal and bone abnormalities in a case series of HIV-infected patients receiving treatment with tenofovir (TDF), and to recommend appropriate screening for toxicity related to TDF. METHODS: Patients were identified from referrals to a specialist HIV renal clinic. Patients were included if treatment with TDF was assessed as the primary cause of the renal function impairment and clinical data were available prior to and following discontinuation of TDF treatment. Data were collected from case note review and clinic databases. RESULTS: Twenty-two patients (1.6% of all those who received TDF) were identified with TDF-associated renal toxicity. All had normal serum creatinine prior to TDF therapy. All presented with proteinuria. On stopping TDF, renal function improved. Eight patients had confirmed Fanconi syndrome. Twelve patients presented with bone pain and osteomalacia was confirmed on an isotope bone scan in seven of these patients. The findings (in those patients tested) of tubular proteinuria, reduced tubular transport maximum of phosphate (TmP), and glycosuria were all consistent with the proximal tubule being the site of toxicity. CONCLUSION: Renal toxicity remains a concern in patients treated with TDF. Clinical presentation may be with renal dysfunction, Fanconi syndrome or osteomalacia. Our investigations suggest proximal tubular toxicity as a common pathogenic mechanism.

Prevalence of incontinence and incontinence-specific quality of life impairment in women with cystic fibrosis.

AIMS: Cystic fibrosis (CF) is the commonest autosomal recessive disorder in Caucasians. With advancing medical technology, the life expectancy has more than double in the last twenty years. This has led to new unforeseen health problems like urinary incontinence. The aim was to establish the prevalence, symptomatic typology, and quality of life impact of incontinence in a population of women with CF. METHODS: Women were recruited from two London tertiary referral centres for CF. They were asked to fill in a self- completed anonymous King's Health Questionnaire (KHQ) for assessment of symptoms and quality of life Impairment. Their age was also noted. Descriptive statistics are reported. Correlation was assessed using Pearson's Product Moment Correlation Coefficient (r). RESULTS: One hundred and forty six women were approached for enrolment. 98(67%) consented to take part in study. Their mean age was 28. Seventy three (74%) reported symptoms of urinary incontinence, which in all cases was perceived as stress urinary incontinence. Of these 44(60%) reported mild stress incontinence, 16(22%) moderate stress incontinence and 13(18%) severe stress incontinence. Continent and incontinent women perceived their general health to be similarly poor (mean score 40 vs 44 points). Strong positive correiations were found between age and stress urinary incontinence severity (r=0.742; P <0.001) and between age and total King's Health Questionnaire score (r=0.828; P <0.001). CONCLUSIONS: Women with CF have a higher prevalence of stress urinary incontinence than the general population, with both the prevalence and associated quality of life impairment increasing with age.

A comparison of the prevalence of urinary incontinence in girls with cystic fibrosis, asthma, and healthy controls.

Urinary incontinence (UI) is recognized as a significant problem in adult females with cystic fibrosis and can often have a marked impact on day-to-day activities. The prevalence and severity of UI in the pediatric cystic fibrosis (CF) female population is less clear and there are no comparative data with healthy children or children with other respiratory disorders. An anonymous self-completed semi-structured questionnaire was used to study the prevalence rates of UI in girls with CF aged between 11 and 17 and compared it to age-matched asthmatic and healthy girls. The prevalence of UI in girls with CF was significantly higher (17/51, 33%) than the asthmatic (4/25, 16%) and healthy girls (2/27, 7%) (P = 0.02). It may manifest as early as 11 years of age and is associated with increasing lung disease. Surprisingly it is perceived as a relatively minor problem in terms of the distress it causes. Pediatric CF clinics should be routinely addressing UI as a potential problem in all girls from the age of 11 years.

Reduced bone mineral density in HIV-positive individuals.

A total of 105 HIV-positive patients underwent dual-energy X-ray absorbtiometry (DEXA) scan to assess bone mineral density (BMD). The prevalence of reduced BMD was found to be 71% and was higher in patients who had ever been treated with protease inhibitors (PI). Our results suggest a possible association between PI and reduced BMD, and further complicate the debate regarding when to commence treatment of HIV and with what agents to start.

Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. Royal Free Centre for HIV Medicine.

OBJECTIVE: To describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed. METHODS: We studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log10 copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen. RESULTS: Overall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm3 in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm3 per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (-0.66, P = 0.0002). CONCLUSION: Patients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption.

Immunological, virological and clinical response to highly active antiretroviral therapy treatment regimens in a complete clinic population. Royal Free Centre for HIV Medicine.

BACKGROUND: Highly active antiretroviral therapy (HAART) is now widely used in clinical practice and gives rise to a range of immunological, virological and clinical responses. OBJECTIVES: To describe the immunological, virological and clinical response to HAART and to examine the frequency of modification of the HAART regimen among patients from a single treatment centre. METHODS: Kaplan-Meier estimation and incidence rates were used to describe responses to HAART (a protease inhibitor or non-nucleoside drug in addition to at least two nucleoside analogues) among 421 patients from the Royal Free Hospital in London. RESULTS: The median CD4 cell count at starting HAART was 186 x 10(6) cells/l [interquartile range (IQR) 76-310] and viral load was 5.13 log10 copies/ml (IQR 4.66-5.56). At 6 months after starting HAART, 51.1% of patients were estimated to have experienced a 100 x 10(6) cells/l increase in CD4 cell count; the median time for viral load to fall below 400 copies/ml was 3.7 months (95% confidence interval 3.2-4.4). At 6 months after the first viral load was < 400 copies/ml, 16.4% of patients were estimated to have failed on the basis of a single viral load > 400 copies/ml and 12.4% were estimated to have failed if the more stringent definition of two viral loads above the limit of detection was used. Compared with the pre-HAART era, the incidence of death among patients on HAART was one sixth of that level; new AIDS-defining illnesses was one seventh; and hospital admissions was one fifth. In total, 141 patients (33.5%) stopped at least one of the antiretroviral agents included as part of their HAART regimen; the occurrence of side effects was the most common reason (n = 63; 44.7%). CONCLUSION: A good response occurred to an initial HAART regimen. There was a high rate of virological relapse, which varied considerably according to the definition of failure used. Even so, the rates of clinical progression and hospital admissions observed to date were low. Further follow-up of these patients is required to determine their long-term immunological, virological and clinical outcome.

Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre.

OBJECTIVE: To describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic. SUBJECTS: A total of 556 patients who started HAART at the Royal Free Hospital were included in analyses. Modification was defined as stopping or switching any antiretrovirals in the regimen, whereas discontinuation was defined as the simultaneous stopping of all antiretrovirals included in the initial regimen. Reasons were classified as immunological/virological failure (IVF) and toxicities and patient choice/poor compliance (TPC). RESULTS: The median CD4 count at starting HAART was 171 x 10(6) cells/l and viral load 5.07 log copies/ml. During a median follow-up of 14.2 months, 247 patients (44.4%) modified their HAART regimen, 72 due to IVF (29.1%) and 159 due to TPC (64.4%) and a total of 148 patients (26.6%) discontinued HAART. Older patients were less likely to modify HAART [relative hazard (RH), 0.73 per 10 years; P = 0.0008], as were previously treatment-naive patients (RH, 0.65; P = 0.0050), those in a clinical trial (RH, 0.64; P = 0.027) and those who started nelfinavir (RH, 0.57; P = 0.035). Patients who started with four or more drugs (RH, 2.21, P < 0.0001), who included ritonavir in the initial regimen (RH, 1.41; P = 0.035) or who had higher viral loads during follow-up (RH per log increase, 1.51; P < 0.0001) were more likely to modify HAART. CONCLUSIONS: There was a high rate of modification and discontinuation of HAART regimens in the first 12 months, particularly due to toxicities, patient choice or poor compliance.

In vivo HIV-1 replicative capacity in early and advanced infection.

OBJECTIVE: Previous studies on patients treated with potent antiretroviral therapy have shown that viral clearance rates do not tend to change between early and advanced HIV-1 infection. Our objective was to investigate whether the other major aspect of virus dynamics, viral replicative capacity, does change. In vitro work has indicated that the viral replicative, capacity increases but in vivo evidence has been lacking. METHODS: As an in vivo measure of the viral replicative capacity, we studied the rate of rebound of plasma HIV RNA level during a 1-week therapy interruption in previously untreated patients who had received 2 weeks of antiretroviral therapy. RESULTS: Such therapy in five previously drug-naive patients with high CD4 lymphocyte counts (mean, 611 x 10(6)/l) and five patients with low counts (mean, 49 x 10(6)/l) led to a mean 2.2 log10 copies/ml decrease in plasma HIV-1 levels (from 5-6 log10 copies/ml) in 2 weeks. This was similar in the two groups. Interruption of therapy for the ensuing week resulted in a stable HIV-1 level for approximately 2 days followed by a rebound towards pretherapy level, which was much more marked in the patients with low CD4 cell counts (estimated mean rise 2.22 log10 versus 1.06 log10 copies/ml; P < 0.02). After restarting therapy, HIV RNA levels returned to pre-interruption levels. CONCLUSIONS: These findings need confirmation, but the ability of HIV-1 to replicate in vivo appears to increase during HIV-1 infection. This increased replicative capacity, for which there are several potential explanations, may be the cause of gradual CD4 lymphocyte depletion.

Research bronchoscopies do not adversely affect HIV-infected individuals' future health-care decisions.

STUDY OBJECTIVES: Asymptomatic HIV-infected individuals are increasingly recruited for studies involving invasive procedures such as bronchoscopy. We sought to determine the response to and outcome of a request for a research bronchoscopy in HIV-positive individuals with no respiratory disease, and whether this would adversely affect future decisions to have a medically indicated bronchoscopy. DESIGN AND SETTING: Prospective, semistructured, questionnaire-based study in a London teaching hospital HIV outpatient clinic. PARTICIPANTS: One hundred and seven consecutive HIV-infected eligible individuals. Thirty-one healthy volunteers served as a control group for the subjective response to bronchoscopy. MAIN OUTCOME MEASURES: Subjects' attitudes and responses to requests for bronchoscopy and subsequent behavior when they required medically indicated bronchoscopy. RESULTS: Seventy-five patients (70%) agreed to the procedure in principle, predominantly for altruistic reasons. Thirty-nine subjects underwent bronchoscopy. Five percent found it worse than expected; and 79% agreed to another research bronchoscopy (performed in 11 subjects approximately 2 years later). All patients said they would undergo bronchoscopy again for diagnostic purposes (required in seven during the study). When compared to a healthy volunteer population within the same study, postbronchoscopy symptoms were similar in frequency although somewhat different in nature. Subjects felt that a clear explanation of what was involved enhanced their participation in this research. CONCLUSIONS: Invasive research procedures such as bronchoscopy can be performed and are repeatable in a healthy HIV-infected population. Performance of procedures for research purposes does not appear to adversely affect future health-care decisions.

Demographic, clinical and social factors associated with human immunodeficiency virus infection and other sexually transmitted diseases in a cohort of women from the United Kingdom and Ireland. MRC Collaborative Study of women with HIV.

BACKGROUND: Clinical experience suggests many women with HIV infection have experienced no other sexually transmitted diseases (STD). Our objective was to test the hypothesis that a substantial proportion of women with HIV infection in the United Kingdom and Ireland have experienced no other diagnosed STD and to describe the demographic, clinical and social factors associated with the occurrence of other STD in a cohort of HIV infected women. METHOD: Analysis of cross-sectional baseline data from a prospective study of 505 women with diagnosed HIV infection. The setting was 15 HIV treatment centres in the United Kingdom and Ireland. The main outcome measures were occurrence of other STD diagnosed for the first time before and after HIV diagnosis. Data were obtained from interview with women and clinic notes. We particularly focused on occurrence of gonorrhoea, chlamydia and trichomoniasis after HIV diagnosis, as these are the STD most likely to reflect recent unprotected sexual intercourse. RESULTS: The women were mainly infected via heterosexual sex (n = 304), and injection drug use (n = 174). 151 were black Africans. A total of 250 (49.5%) women reported never having been diagnosed with an STD apart from HIV, 255 (50.5%) women had ever experienced an STD besides HIV, including 109 (21.6%) who had their first other STD diagnosed after HIV. Twenty-five (5%) women reported having had chlamydia, gonorrhoea or trichomoniasis diagnosed for the first time after HIV diagnosis, possibly reflecting unprotected sexual intercourse since HIV diagnosis. In all 301 (60%) women reported having had sex with a man in the 6 months prior to entry to the study. Of these, 168 (58%) reported using condoms 'always', 66(23%) 'sometimes' and 56 (19%) 'never'. CONCLUSIONS: Half the women in this study reported having never experienced any other diagnosed STD besides HIV. However, after HIV diagnosis most women remain sexually active and at least 5% had an STD diagnosed which reflect unprotected sexual intercourse.

Inhibition of gastric K+/H+-ATPase by acid-activated 2-((2-pyridylmethyl)sulphinyl)benzimidazole products.

The inhibitory effects of timoprazole- and omeprazole-derived metabolites were studied in different in vitro test systems in order to characterize the metabolites of substituted benzimidazoles originating from acid activation. Acidification of timoprazole and omeprazole to pH 1.0 markedly increased the inhibitory potency on gastric K+/H+-ATPase. The timoprazole-derived tetracyclic thiol and radical were found to be equally or more potent on the K+/H+-ATPase than the mother compounds dissolved at pH 1.0. Kinetic studies with omeprazole sulphide revealed a competitive inhibition of the K+/H+-ATPase with respect to K+. The mercaptan dithiothreitol reversed the inhibitory effect of omeprazole, acidified timoprazole and the timoprazole-derived radical in the parietal cell and K+/H+-ATPase preparation. In contrast, the inhibitory effect of omeprazole sulphide and the timoprazole-derived thiol could not be reversed by dithiothreitol. Wash-out experiments indicated that acidified timoprazole and the tetracyclic compounds interact irreversibly with the K+/H+-ATPase, which contrasts with the properties of timoprazole in the parietal cell preparation. It is concluded from these data that neither the tetracyclic compounds nor the sulphide act as the 'active principle' of substituted benzimidazoles in the parietal cell preparion.

Do women with HIV infection consult with their GPs?

In a cohort of 106 HIV-positive women, 86 (81%) were registered with a general practitioner (GP) and 71 (83%) had a GP who was aware of their HIV status. GPs were primarily consulted for perceived non-HIV-related problems and prescriptions. This is encouraging. However, primary and secondary care services should aim to increase the proportions of HIV-positive individuals with access to primary care.

Do people attending a same day testing clinic discuss their need for a HIV test with their GP?

In the United Kingdom, people with HIV infection present with advanced disease and general practitioners (GPs) are currently an underused resource for HIV testing. We describe the reasons for using an open-access clinic rather than primary care for testing for HIV. People attending the clinic were asked to complete a questionnaire asking about GP registration, access, and whether HIV testing was discussed in primary care. Despite access to GPs, HIV testing in primary care was rarely discussed. If HIV testing is to move to a general practice setting, GPs could address the issues, such as the recording of sensitive information in notes, future life insurance, and confidentiality, which this report identifies as the main barriers for using primary care.

Are we training junior doctors to respond to major incidents? A survey of doctors in the Wessex region.

OBJECTIVE: To assess the current status of awareness and training of junior medical staff in the Wessex region in the event of a "conventional" major incident. METHODS: A telephone questionnaire of specialist registrars (SpRs) (or equivalent, for example, staff grade) in six core specialties was performed in all the 11 acute hospitals in the Wessex region on the same evening. This group was selected to represent a sample of the most senior medical staff "on site" at each hospital. RESULTS: 56 of 64 (87.5%) SpRs participated. Nine of the 56 (16%) SpRs questioned had previously been involved in a major incident, and 18 (32%) had experienced some form of major incident training exercise. Subgroup analysis of the specialties showed that although there were no significant differences in numbers of training experiences between specialties, only one of nine (11%) orthopaedic SpRs had ever been involved in a training exercise. Twenty five of the 56 (45%) SpRs felt that they were confident of their role in the event of an incident. CONCLUSION: Most middle grade staff in Wessex were not confident of their role in the event of a major incident. Most SpRs questioned had never attended a major incident training exercise.

Social effects of integrated classrooms and resource room/regular class placements on elementary students with learning disabilities.

The social status of elementary students with learning disabilities (LD) served by the Integrated Classroom Model (ICM) was compared to the social status of elementary students with learning disabilities served in a regular class with resource room support. The ICM serves elementary special education and non-special-education students (1:2) together as one class. The comparison group was composed of students with learning disabilities who received special education services outside of their regular classroom for a portion of their school day. Social status was determined by assessing interpersonal relationships among students, using a peer rating method. The results of analyses of various dimensions suggest that while special education students in both programs have significantly lower social status on average than their non-special-education peers, the children in the ICM have a better opportunity to blend successfully into the classroom than the children who go out to a resource room.