Tezepelumab decreases airway epithelial IL-33 and T2-inflammation in response to viral stimulation in patients with asthma.

BACKGROUND: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti-TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known. AIM: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNß, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge. METHODS: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2- and pro-inflammatory cytokines, IFNß IFNλ, and viral load were analyzed by RT-qPCR and multiplex ELISA before and after stimulation. RESULTS: IL-33 expression in unstimulated BECs and IL-33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL-33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)-induced IL-4, IL-13, and IL-17A release from BECs was also reduced with tezepelumab whereas IFNß and IFNλ expression and viral load were unchanged. CONCLUSION: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL-33 and T2 cytokines to viral challenge without affecting anti-viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses.

Loss of function of the gdpP protein leads to joint ß-lactam/glycopeptide tolerance in Staphylococcus aureus.

The genetic basis of tolerance to inhibitors of peptidoglycan biosynthesis in Staphylococcus aureus was investigated by generating tolerant mutants in vitro and characterizing them by comparative genome sequencing. Two independently selected tolerant mutants harbored nonsynonymous mutations in gdpP, a gene encoding a putative membrane-located signaling protein. Insertional inactivation of gdpP also conferred tolerance. Our findings further implicate altered signal transduction as a route to antibiotic tolerance in S. aureus.

Barriers to research implementation by community nurses.

This article presents the community findings from a study of nurses in community and acute settings using Funk et al's Barriers to Research Utilization Scale (Barriers) (Funk et al, 1991a), which aimed to identify the main barriers to implementing research in practice. The Barriers questionnaire was sent to all nurses working in three community trusts in Yorkshire (n=2327), and practice nurses in one Yorkshire health authority (n=190). A 51.5% response rate gave a sample of 1297 nurses. The top two barriers were reported to be lack of time and resources. There were significant differences between sub-samples, e.g. older women perceived more barriers than younger colleagues, and practice nurses had particular problems with the cooperation of GPs. Factor analysis generated four new factors different from those found by Funk et al (1991a) (shown in brackets): benefits (nurse characteristics); quality (research characteristics); accessibility (presentation of the research characteristics) and resources (setting characteristics). Recommendations include developing nurses' critical appraisal skills so that, given more time and adequate resources, research findings might be judiciously implemented in practice.

Structural investigation of the active site in bacteriorhodopsin: geometric constraints on the roles of Asp-85 and Asp-212 in the proton-pumping mechanism from solid state NMR.

Constraints on the proximity of the carboxyl carbons of the Asp-85 and Asp-212 side chains to the 14-carbon of the retinal chromophore have been established for the bR(555), bR(568), and M(412) states of bacteriorhodopsin (bR) using solid-state NMR spectroscopy. These distances were examined via (13)C-(13)C magnetization exchange, which was observed in two-dimensional RF-driven recoupling (RFDR) and spin diffusion experiments. A comparison of relative RFDR cross-peak intensities with simulations of the NMR experiments yields distance measurements of 4.4 +/- 0.6 and 4.8 +/- 1.0 A for the [4-(13)C]Asp-212 to [14-(13)C]retinal distances in bR(568) and M(412), respectively. The spin diffusion data are consistent with these results and indicate that the Asp-212 to 14-C-retinal distance increases by 16 +/- 10% upon conversion to the M-state. The absence of cross-peaks from [14-(13)C]retinal to [4-(13)C]Asp-85 in all states and between any [4-(13)C]Asp residue and [14-(13)C]retinal in bR(555) indicates that these distances exceed 6.0 A. For bR(568), the NMR distance constraints are in agreement with the results from recent diffraction studies on intact membranes, while for the M state the NMR results agree with theoretical simulations employing two bound waters in the region of the Asp-85 and Asp-212 residues. The structural information provided by NMR should prove useful for refining the current understanding of the role of aspartic acid residues in the proton-pumping mechanism of bR.

What determines the choice of procedure in stress incontinence surgery? The use of multilevel modeling.

The purpose of this study was to identify the determinants of choice of surgical procedure (anterior colporrhaphy, colposuspension, or needle suspension) to treat stress incontinence in women. We used multilevel modeling of data on 271 patients in 18 hospitals in England in 1993-94. Patient-related factors included sociodemographic details, anatomical diagnosis, symptom severity, symptom impact, previous treatment, parity, comorbidity, and general health status. Surgeon-related factors were specialty, grade, and annual volume of procedures undertaken. Hospital teaching status was considered. Some patient-related factors were associated with choice of procedure: women with a concomitant genital prolapse, with a history of high parity, and with no previous nonsurgical treatment were more likely to undergo an anterior colporrhaphy than a colposuspension or needle suspension (although this finding could be confounded by surgical specialty). In addition, women were more likely to be treated by colposuspension if their surgeon specialized in incontinence surgery (measured by annual volume of cases). Finally, being treated by needle suspension depended on there being a consultant surgeon familiar with the procedure at the hospital attended. While choice of surgical procedure depends partly on the patient's anatomical diagnosis, it is also dependent on the specialty of the surgeon whom she consults and the hospital that she attends. This variability, in turn, could have implications for the patient (as the relative effectiveness of the different procedures is unknown) and for the purchasers of care (as the relative cost-effectiveness of procedures is also unknown).

Impact of surgery for stress incontinence on the social lives of women.

OBJECTIVE: To assess the feasibility of collecting disease-specific and generic data on the impact of surgery on the social lives of women with stress incontinence; to describe the social impact of surgery in a representative group; and to determine the effect of timing on the assessment of outcome. DESIGN: Longitudinal study; questionnaires before and three, six, and twelve months after surgery. SETTING: Eighteen hospitals in North Thames region. PARTICIPANTS: Four hundred and forty-two women undergoing surgery for stress incontinence between January 1993 and June 1994. MAIN OUTCOME MEASURES: Post-operative recovery time, stress incontinence symptom impact index, activities of daily living, and cost of protection. RESULTS: Post-operative recovery was uneventful for most women, but three months after surgery 24% of those in paid employment beforehand were still on sick or unpaid leave. Most women (75%) reported that stress incontinence had less adverse impact on their lives three months after surgery, though 18% reported no change, and 7% felt life was worse. The likelihood of improvement was similar regardless of whether pre-operative urodynamic studies had been conducted. The extent of improvement was dependent on pre-operative severity. Similar findings were obtained six and twelve months after surgery. After an initial slight but nonsignificant deterioration in their ability to carry out activities of daily living, women gained a slight benefit from surgery (proportion with no or only slight limitation rose from 72% to 82%; P=0.0001). The mean cost of protection (pads and towels) fell from 8.59 pound sterling a month before surgery to 2.99 pound sterling a month one year after surgery, by which time 68% of women were not using protection. In contrast, 11% were still spending over 10 pound sterling a month. CONCLUSIONS: It is possible to collect standard data on the impact of surgery on social functioning and, thus, provide women with better information on likely outcomes. The benefits of pre-operative urodynamic investigations need to be assessed. The stability of the outcome measures over the first post-operative year suggest that outcomes need to be assessed only once and at any time from three to twelve months after the operation.

Surgical training: an objective assessment of recent changes for a single health board.

The reduction in doctors' hours and the introduction of specialist training have reduced general surgical training by 60%. This study assessed the implications for a single health board. A questionnaire listing 13 representative operations was sent to 44 trainees and 52 trainers to determine the number of operations a trainee should perform. The total number of operations required for training was compared against the total actually performed across the health board. Operating times for five representative operations were audited prospectively. Trainers and trainees recommended a similar and conservative number of operations. The total number of operations available for training (4913) was 38% less than the number recommended (7946). Trainees required 50-75% more operating time than consultants. To increase the proportion of operations undertaken by trainees from the current 30% to 70% would require an extra 270 theatre days (of pounds 1.3m) yearly. The minimum number of operations required for training must be defined and the proportion of supervised operations undertaken by trainees substantially increased. Service and financial implications will have to be addressed. Action is needed urgently, as the first trainees will become consultants in less than five years.

Ventilatory function in British adults after asthma or wheezing illness at ages 0-35.

The impact of past and current asthma on ventilatory function was assessed among young adults born in Britain March 3-9, 1958 who had been followed from birth to ages 7, 11, 16, 23, and 33 yr. We compared 1,060 subjects with a history of asthma, wheezy bronchitis, or wheezing with 275 control subjects with no history of chest illness. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured at 34-35 yr of age before and 20 min after inhalation of 400 micrograms salbutamol, and adjusted for sex, height, and smoking by multiple regression. Among 551 cases reporting no wheeze in the year before examination, ventilatory function after salbutamol did not differ significantly from the controls, except for FEV1 in 192 subjects with transient wheezing before age 7 (p < 0.05). Among 509 cases reporting wheeze in the past year, FEV1 and FEV1/FVC ratio were reduced to a greater extent in those with an earlier age of onset of wheeze (p < 0.001 for trend in each case). These relative reductions were greater if wheezing had persisted through childhood and adolescence, and were only partially reversed by inhalation of salbutamol. Progressive pulmonary changes related to chronic asthma may be an important mechanism underlying the association between childhood chest illnesses and chronic respiratory disease in adult life.

Sociodemographic and symptomatic characteristics of women undergoing stress incontinence surgery in the UK.

OBJECTIVES: To: (i) describe the sociodemographic characteristics of women undergoing surgery for stress incontinence in the UK and the ways in which they differ from women of a similar age in the general population: (ii) the severity and impact of their symptoms and their expectations of surgery and: (iii) their general state of health. PATIENTS AND METHODS: A prospective cohort study was carried out on 442 women undergoing surgery for stress incontinence in 18 hospitals in the North Thames region between January 1993 and June 1994. Sociodemographic factors, stress incontinence severity, symptom impact scores, and general health status were measured. RESULTS: Women undergoing surgery for stress incontinence were similar to their peers in the general population apart from being more likely to have smoked (61.4 against 51.1%), to have subsequently given up (39.5 and 25.3%) and to be of higher parity (> or = 4; 19.7 and 12.0%). Most women (81.6%) reported moderate to very severe stress incontinence. The impact of symptoms was correlated positively with severity (P < 0.001) after accounting for its positive correlation with mental health status (P < 0.005), socioeconomic status (P < 0.05) and its negative correlation with age (P < 0.02). Many women also suffered from other urinary symptoms including urgency (76%) and frequency (42.3%). Apart from their urinary problems, women were in good health (77% reported no or only mild coexistent conditions). However, a very high proportion (34.2%) had previously undergone a hysterectomy. CONCLUSIONS: These results suggest that women undergoing stress incontinence surgery are remarkably similar to their peers, apart from their primary condition. The effect that stress incontinence has on women's lives depends not only on the severity of the problem but also on other factors. The high rate of previous hysterectomy warrants further study.

Comparative assessment of surgical training using objective criteria.

The aims of the study were to develop and validate an objective method of assessing the operative experience of surgical trainees. Data were retrieved from a prospectively recorded computer database of operating activity in a single surgical unit over a three-year period. Operations were weighted using intermediate equivalent (IE) values. The number of operations performed (caseload), IE workload, consultant involvement and a subjective assessment of operative ability by consultant was obtained for each of 3 SHO IIIs and 7 SHO Is. The total caseload correlated poorly with subjective grading. The total workload correlated well with the subjective assessment of the SHO IIIs and, excluding minor operations, with the SHO Is. SHO IIIs' workload consisted of a higher number of more complex procedures than SHO Is' and for both types of trainee the degree of complexity increased during the tenure of each one year post. A consultant was the assistant in 50 per cent of the intermediate and major operations performed by the SHO Is in the first quarter of each one year post dropping to 30 per cent in the remaining three-quarters. In conclusion an objective assessment was easily obtained and interpreted. Similar data from other surgical units are required to place this work in perspective and to allow formulation of guidelines.

Training in surgical outpatients.

The consultants in this department, where the trainees are predominantly SHOs, organise their outpatient clinics such that one consultant sees mainly new patients (A), another mainly follow-up patients (C) and the third a mixture (B). A prospective audit was conducted to assess the impact of these different arrangements on training. Details of the training received were recorded at 32 consecutive clinics. A training episode (TE) occurred if the trainee and consultant jointly reviewed, or directly discussed, the patient in the clinic. A total of 550 patients attended and trainees were involved with 254 (46 per cent). A TE occurred in only 88 (16 per cent). The 235 (43 per cent) new patients produced 66 (28 per cent) TE and the 315 follow-up patients 22 (7 per cent) TE. Seventeen of 46 (37 per cent) procedures were a TE. The TE for the individual consultants were (new and follow-up): A 0, 8 (7 per cent); B 19 (22 per cent), 7 (8 per cent); C 47 (57 per cent), 7 (6 per cent). Outpatient training was greatly influenced by clinic organisation. Follow-up patients, who often have complex problems, rarely generate a TE. Training in surgical outpatients has not received the same attention as operative training and this deficiency needs to be addressed.

An objective assessment of surgical training.

The aim of this study was to determine the feasibility of assessing surgical training from routine, prospectively collected data and to establish whether weighted workload assessed surgical training more objectively than caseload (case counting). The surgeons in this surgical unit prospectively documented details of all operations and endoscopic procedures (caseload) on a database. Over a six-month period the workload was calculated by weighting the caseload using Intermediate Equivalent (IE) values. Some 1827 procedures were documented. The three consultants performed 796 (44 per cent) procedures, the senior registrar (SR) 137 (7.5 per cent), the registrar 241 (13 per cent) and the three senior house officers (SHO) 644 (35 per cent). The consultant was first assistant in 185 (66 per cent) procedures performed by the SHOs, in 52 (61 per cent) by the registrar in 9 (13 per cent) by the SR. When assessed by caseload one SHO (as a representative example) performed 224 procedures compared to 137 by the SR. The IE workloads were 156 and 166 respectively. This better reflected the greater complexity of the operations performed by the SR. This study has shown that details of surgical training can be easily retrieved from existing administrative databases. This can be used to document the number and type of operations performed by a trainee and the degree of consultant supervision. The degree of surgical training is better assessed by weighted workload rather than caseload.

Written discharge advice sheets reduce visits to the general practitioner.

A prospective audit of early post-operative morbidity in patients who would not normally receive routine outpatient review was undertaken. One-hundred-and forty-seven (92 per cent) of 162 patients invited returned for assessment. Thirty-five patients (24 per cent) had complications. These were of a minor nature with infected wounds being most numerous. Much of this morbidity appeared avoidable if the patients had received appropriate advice whilst in hospital. Also noted was the surprising frequency with which patients required to consult their general practitioner (GP) for guidance regarding an otherwise uncomplicated convalescence. Written advice sheets for the patients were drawn up and the study repeated. One-hundred-and-fifty (93 per cent) of 162 patients attended including 11 (7.3 per cent) who did not receive an advice sheet. Twenty-five (16.7 per cent) had complications. Although the overall complication rate was not significantly different there were significantly fewer wound infections in the second group (6 (4 per cent) versus 15 (10 per cent); p < 0.05). The number of GP visits was also reduced (24 (16.3 per cent) versus 13 (8.7 per cent); p < 0.05). Written post-operative advice sheets should be given to all patients following minor surgery.

Structural model for the beta-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide.

Amyloids are a class of noncrystalline, yet ordered, protein aggregates. A new approach was used to provide the initial structural data on an amyloid fibril--comprising a peptide (beta 34-42) from the C-terminus of the beta-amyloid protein--based on measurement of intramolecular 13C-13C distances and 13C chemical shifts by solid-state 13C NMR and individual amide absorption frequencies by isotope-edited infrared spectroscopy. Intermolecular orientation and alignment within the amyloid sheet was determined by fitting models to observed intermolecular 13C-13C couplings. Although the structural model we present is defined to relatively low resolution, it nevertheless shows a pleated antiparallel beta-sheet characterized by a specific intermolecular alignment.

Effect of ambient levels of smoke and sulphur dioxide on the health of a national sample of 23 year old subjects in 1981.

BACKGROUND: There is concern that, despite the fall in air pollution levels since the 1950s, there may still be adverse effects at current levels. A study was carried out to investigate the association between air pollution and respiratory symptoms in 23 year old subjects in 1981. METHODS: Data on cough, phlegm, and wheeze were available on 11,552 members of the 1958 national birth cohort. Counties in the UK were ranked by annual average level of black smoke and sulphur dioxide (SO2), and then divided into five groups. The subject's county of residence determined their categorisation of pollution exposure. The association between air pollution exposure and respiratory symptoms was examined by logistic regression, adjusting for social class, sex, and smoking. RESULTS: The ranges of the air pollution groups were 2.0-13.0, 13.1-18.7, 19.6-20.8, 21.0-25.8, and 26.1-55.1 micrograms/m3 for black smoke, and 7.0-36.4, 36.7-42.7, 43.0-50.5, 52.0-59.3, and 60.9-87.7 micrograms/m3 for SO2. The overall prevalences of cough, phlegm, wheezing since age 16, and wheezing in the past year were 13.3%, 10.3%, 9.4%, and 4.4%, respectively. Phlegm symptoms increased with increasing smoke levels with evidence of a plateau. Cough and wheeze were not associated with black smoke; no symptom was associated with SO2. In the subgroup with wheeze at ages 16-23 there was no effect of smoke level on phlegm. CONCLUSIONS: Low ambient levels of black smoke were associated with decreased prevalence of phlegm symptoms in young adults in the UK in 1981. The effect was evident below the current EC guideline of 34-51 micrograms/m3 annual black smoke. In 1991 the annual mean smoke level for each county ranged from 3.4 to 26.5 micrograms/m3, spanning all but the last exposure group used here. This is consistent with the existence of adverse and possibly chronic effects at current levels.

Intraprofessional teamwork in district nursing: in whose interest?

The purpose of this paper is to examine intraprofessional teamworking between district nurses. Data from an exploratory study, conducted in the United Kingdom, of 130 home visits of 16 district nurses describes intraprofessional relationships in community nursing teams. Participant observation and in-depth interviews were the methods of data collection. The findings suggest that the professional culture of community nursing has led to the development of organizational rules which, in a quest to avoid conflict between team members, potentially militate against patient choice. The data presented here explore three areas of the nurses' practice: committing services, changing care and working unsocial hours.

Nursing treatment of patients with chronic leg ulcers in the community.

A descriptive survey of current reported practice by 146 community nurses for their nursing treatment of leg ulcers was undertaken. Sixty-four per cent of nurses reported they would apply compression bandages to only venous ulcers; in only 23% of cases could the products described achieve an adequate level of compression. A variety of modern wound dressings were used by the nurses; 89% of nurses reported using a combination of different products layered over the ulcer. There is no evidence that this has any beneficial effect and could therefore be a potential waste of money, as well as contributing to allergic skin reactions. It would be useful if primary-health-care teams and Family Health Service Authority information pharmacists formulated protocols based upon effective treatments for patients with chronic leg ulcers.