Sapphire Fabry-Perot interferometer for high-temperature pressure sensing.

An adhesive-free encapsulation sapphire Fabry-Perot interferometer (FPI) is proposed and demonstrated for high-temperature pressure measurements. The sapphire FPI sensor is packaged by zirconia ferrules and a zirconia sleeve, which is easy to be configured and low in cost. Owing to this packaging technology, the sapphire FPI sensor presents good stability and high temperature resistance. The pressure and temperature properties of the sapphire FPI sensor are investigated within a temperature range from -50∘C to 1200°C and a pressure range from 0.4 to 4.0 MPa. Experimental results show the FPI has a temperature sensitivity of 23 pm/°C and still works as the temperature is up to 1200°C. Meanwhile, the wavelength shift of the sapphire FPI versus the applied pressure is linear at each tested temperature. The pressure sensitivity is measured to be 1.20 nm/MPa at 1200°C, and the linear response shows the proposed sensor has good repeatability within 0.4-4.0 MPa. Such a sapphire FPI sensor has potential applications in engineering areas, such as the oil industry and gas boilers.

High temperature strain sensing with alumina ceramic derived fiber based Fabry-Perot interferometer.

A Fabry-Perot interferometer (FPI) based on an alumina ceramic derived fiber (CDF) is proposed and demonstrated for high temperature strain sensing. The strain sensor is constructed by splicing a piece of CDF between two standard single-mode fibers (SMFs). The strain properties of the sensor are investigated from room temperature to 1200 °C. Experimental results show that the wavelength shift of the CDF-FPI presents a linear relationship with the tensile strain at both room temperature and high temperature with up to 1000 °C. The strain sensitivity is calculated to be 1.5 pm/µÉ› at 900 °C, and the linear response is repeatable within 0-3000 µÉ›. Moreover, for each applied force at 1000 °C, the wavelength shift versus time shows the stability of the developed CDF-FPI sensor within 0-2000 µÉ›. The obtained results show that such a CDF-FPI has potential application in various engineering areas, such as aeronautics, metallurgy, and gas boiler.

Crystallization-induced refractive index modulation on sapphire-derived fiber for ultrahigh temperature sensing.

We have demonstrated crystallization-induced refractive index (RI) modulation on sapphire-derived fiber (SDF) showing superheat resistance and developed the SDF based Fabry-Perot interferometers (FPIs) for ultrahigh temperature sensing. The SDF is a special fiber with high concentration of alumina to silica in the fiber core region. Reheating and cooling the SDF by arc discharge generates mullite particles in the core region, which achieves RI modulation up to ~0.015. Such crystallized region in the SDF is explored as mirrors for FPI, showing a good linear response to temperature with sensitivity of ~13.2 pm/°C. Benefiting from superheat resistance of the crystallized SDF being mirrors, the developed SDF-FPI sensor is capable to withstand high temperature up to 1600°C, which is the highest working temperature for amorphous fiber. Moreover, the SDF-FPI sensor exhibits 6-hour stability at 1200°C. The crystallized SDF-FPIs with compactness, wide temperature working range, high sensitivity, and robustness show great potential application in harsh environment such as turbine engines, power plants, petrochemical, gas industry, etc.

Prevalence and clinical distribution of multidrug-resistant bacteria (3537 isolates) in a tertiary Chinese hospital (January 2012-December 2013).

OBJECTIVE: Multidrug-resistant organisms (MDROs) have become a widespread serious problem in recent years. Our objective was to determine the prevalence and clinical distribution of MDROs in a tertiary care hospital in China from January 1, 2012 to December 31, 2013. METHODS: The strains were cultured according to standard methods; bacterial identification and susceptibility testing were detected by Vitek 2 system. The prevalence and clinical distribution of extended-spectrum ß-lactamases (ESBLs)-producing enterobacteriaceae, carbapenem-resistant enterobacteriaceae (CRE), multiple-drug/pan-drug resistant P. aeruginosa (MDR/PDR-PA), carbapenem-resistant A. baumannii (CR-AB), methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) were analyzed by WHONET 5.6. RESULTS: A total of 3537 (33.4%) MDROs were found among 10,594 microbial isolates. ESBLs producing E. coli (ESBLs-ECO) (1153 cases) were the most frequent MDROs, followed by CR-AB (827 cases). The proportion of acquired resistance of A. baumannii (48.9%) accounted for the highest in all the MDROs. These MDROs were mainly isolated from respiratory (70.3%) and secretions (12.7%). Various types of intensive care unit (ICU) and surgery were the main source departments. The proportion of CRE and VRE were relatively few. CRE was most isolated from respiratory tract and closed body cavity fluid, while the distribution of VRE was relatively dispersed. CONCLUSION: High prevalence of MDROs has emerged in our hospital, particular in various ICU and surgical department. The effective way to prevent the further spread of MDROs is to strengthen the protection of respiratory tract and surgical wounds.

Control of an outbreak due to orthopedic infections caused by Enterobacteriaceae producing IMP-4 or IMP-8 carbapenemases.

OBJECTIVE: To investigate control of an outbreak due to orthopedic infections caused by Enterobacteriaceae producing IMP carbapenemases. METHODS: The sporadic orthopedic infections with Enterobacteriaceae producing carbapenemase (CPE) were retrospectively analyzed in a Chinese tertiary care hospital from November 2010 to September 2012. RESULTS: The CPE were isolated from four distinct orthopedic patients, three patients infected with Enterobacter cloacae while the other with Klebsiella oxytoca. All strains were resistant to almost all the conventional antimicrobial. The strains produced IMP-4 type detected in the two early patients, while other strains could produce IMP-8 type. All of the four patients had ever undergoing invasive surgical procedure, and three of them were given fluoroquinolones for anti-infection treatment while the other patients was treated with meropenem. Ultimately, all patients were cured and discharged, without outbreak of nosocomial infection caused by CPE. CONCLUSION: Our study shows that strict infection control plays an important role in limiting dissemination of Enterobacteriaceae producing IMP carbapenemase. In addition, reasonable supporting treatment and disinfection protection seems to be more effective for the infection of strains.

Relationship between RUNX3 methylation and hepatocellular carcinoma in Asian populations: a systematic review.

Runt-related transcription factor 3 (RUNX3) is a potential tumor suppressor that is frequently hypermethylated in hepatocellular carcinoma (HCC). The present meta-analysis of case-control studies was carried out to determine whether RUNX3 hypermethylation is associated with HCC. The PubMed, Embase, and Chinese National Knowledge Infrastructure databases were searched for all relevant studies published between May 2000 and May 2012. A total of 11 studies were identified, and 8 studies involving 491 patients with HCC and 409 patients without tumors were found to satisfy the inclusion criteria for the meta-analysis. All tissue samples were from Asian populations. There was significant heterogeneity between the studies. Over the entire sample, the odds ratio (OR) of RUNX3 promoter methylation was 18.5 [95% confidence interval (CI), 11.6-29.6] for HCC tissues relative to control tissues. The ORs of RUNX3 methylation were 16.6 (95%CI = 6.5-42.4) for tumor tissues relative to tumor-adjacent tissues in patients with HCC, 67.3 (95%CI = 13.0-348.5) for tumor tissues from patients with HCC relative to liver tissues from patients with non-neoplastic liver diseases, and 3.26 (95%CI = 1.54-6.90) for tissues from patients with hepatitis C virus (HCV)- related HCC relative to liver tissues from patients with HCC unrelated to HCV. There was no association between RUNX3 methylation and age, gender, pathological stage, or hepatitis B virus infection in HCC tissues. Methylation of the RUNX3 promoter strongly correlated with HCC in Asian populations, especially in individuals with HCV-related HCC, and may be a useful marker for HCC diagnosis in these populations.

SWI/SNF family mutations in advanced NSCLC: genetic characteristics and immune checkpoint inhibitors' therapeutic implication.

BACKGROUND: SWItch/Sucrose NonFermentable (SWI/SNF) mutations have garnered increasing attention because of their association with unfavorable prognosis. However, the genetic landscape of SWI/SNF family mutations in Chinese non-small-cell lung cancer (NSCLC) is poorly understood. In addition, the optimal treatment strategy has not yet been determined. PATIENTS AND METHODS: We collected sequencing data on 2027 lung tumor samples from multiple centers in China to comprehensively analyze the genomic characteristics of the SWI/SNF family within the Chinese NSCLC population. Meanwhile, 519 patients with NSCLC from Sun Yat-sen University Cancer Center were enrolled to investigate the potential implications of immunotherapy on patients with SWI/SNF mutations and to identify beneficial subpopulations. We also validated our findings in multiple publicly available cohorts. RESULTS: Approximately 15% of Chinese patients with lung cancer harbored mutations in the SWI/SNF chromatin remodeling complex, which were mutually exclusive to the EGFR mutations. Patients with SWI/SNFmut NSCLC who received first-line chemoimmunotherapy had better survival outcomes than those who received chemotherapy alone (median progression-free survival: 8.70 versus 6.93 months; P = 0.028). This finding was also confirmed by external validation using the POPLAR/OAK cohort. SWI/SNFmut NSCLC is frequently characterized by high tumor mutational burden and concurrent TP53 or STK11/KEAP mutations. Further analysis indicated that TP53 and STK11/KEAP1 mutations could be stratifying factors in facilitating personalized immunotherapy and guiding patient selection. CONCLUSIONS: This study provides a step forward in understanding the genetic and immunological characterization of SWI/SNF genetic alterations. Moreover, our study reveals substantial benefits of immunotherapy over chemotherapy for SWI/SNF-mutant patients, especially the SWI/SNFmut and TP53mut subgroups.

Clinical applications of preoperative perforator planning using CT angiography in the anterolateral thigh perforator flap transplantation.

AIM: To evaluate the reliability and utility of preoperative perforator planning using computed tomography angiography (CTA) in anterolateral thigh perforator flap (ALTPF) transplantation. MATERIALS AND METHODS: Thirty-two consecutive patients who underwent extremity reconstruction using the ALTPF were retrospectively reviewed from 2008 to 2012. These patients were divided into two groups. In group I (n = 16), suitable perforators were designed based on four criteria using CTA. These were used for the operation and compared with the intraoperative findings. In group II (n = 16), all patients underwent operation using conventional methods without preoperative perforator planning. The surgical results of all patients were evaluated for flap complications, alteration of the donor site, donor site morbidity, and the incidence of reoperation. RESULTS: In group I, there were no statistically significant differences between the parameters, including the calibre and location of the origin (perpendicular and horizontal distance from the origin of the perforator to both the superior lateral border of the patella and the lateral region of the thigh) of all planning perforators and the operative measurement results (p-values were 0.3, 0.422, and 0.129, respectively). The types were consistent with the operative findings; the rate of the septocutaneous type was 31.25% (5/16), and the rate of the musculocutaneous type was 68.75% (11/16). The use of preoperative perforator planning in group I was associated with a significant reduction in flap complications (p = 0.009) compared with group II. There was no difference between the two groups in alteration of the donor site, donor site morbidity, or the incidence of reoperation (p-values were 0.225, 0.225, and 0.33, respectively). CONCLUSION: Preoperative perforator planning using CTA in ALTPF transplantation is a reliable and useful method resulting in safer operation with optimal outcome.

HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes.

Prostate cancer is one of the most commonly diagnosed male malignancies. Genome wide association studies have revealed HNF1b to be a major risk gene for prostate cancer susceptibility. We examined the mechanisms of involvement of HNF1b in prostate cancer development. We integrated data from Gene Expression Omnibus prostate cancer genes from the Dragon Database of Genes Implicated in Prostate Cancer, and used meta-analysis data to generate a panel of HNF1b-associated prostate cancer risk genes. An RT-PCR was used to assess expression levels in DU145, PC3, LNCaP, and RWEP-1 cells. Twelve genes (BAG1, DDR1, ERBB4, ESR1, HSPD1, IGFBP2, IGFBP5, NR4A1, PAWR, PIK3CG, RAP2A, and TPD52) were found to be associated with both HNF1b and prostate cancer risk. Six of them (BAG1, ERBB4, ESR1, HSPD1, NR4A1, and PIK3CG) were mapped to the KEGG pathway, and submitted to further gene expression assessment. HNF1b, NR4A1, and HSPD1 were found to be highly expressed in the LNCaP androgenic hormone-dependent cell line. Compared to expression levels in wild-type prostate cancer cells, NR4A1, HSPD1, ERBB4, and ESR1 expression levels were also found to be significantly increased in the HNF1b-transfected cells. We conclude that the mechanism of action of HNF1b in prostate cancer involves modulation of the association between androgenic hormone and prostate cancer cells. Gene-gene interaction and coordination should be taken into account to determine relationships between specific loci and diseases.

[Comparison of safety of total laparoscopic versus laparoscopic-assisted radical gastrectomy for distal gastric cancer in older patients].

Objective: To compare the effectiveness of total laparoscopic versus laparoscopic-assisted distal gastrectomy and investigate the safety and replicability of total laparoscopic distal gastrectomy in older patients. Methods: This was a retrospective cohort study. The inclusion criteria were as follows: (1) age ≥65 years; (2) malignant gastric tumor diagnosed pathologically preoperatively; (3) Eastern Cooperative Oncology Group performance status score 0-1; (4) Grade I-III American Society of Anesthesiologists physical status; (5) preoperative clinical tumor stage I-III; (6) total laparoscopic or laparoscopic-assisted distal gastrectomy performed; and (7) gastrointestinal tract reconstruction using uncut Roux-en-Y or Billroth-II+Braun procedure. Patients who had received neoadjuvant therapy, undergone conversion to open surgery, or had serious comorbidities or incomplete data were excluded. The clinical data of 129 patients who met the above criteria and had undergone laparoscopic surgery for gastric cancer from January 2012 to December 2021 in the Gastrointestinal Cancer Center in the Beijing Cancer Hospital were analyzed. According to the operation method, the patients were divided into total laparoscopic group and laparoscopic-assisted group. Variables studied comprised: (1) surgical procedure and postoperative recovery; (2) postoperative pathological findings; and (3) postoperative complications. Measurement data with skewed distribution are represented as mean(quartile 1, quartile 3). Comparisons between groups were evaluated using the Mann-Whitney U test. Results: After propensity score matching in a 1:1 ratio, there were 40 patients in the total laparoscopic distal gastrectomy group and 40 in the laparoscopic-assisted distal gastrectomy group. Baseline characteristics did not differ significantly between the two groups (all P>0.05).Compared with the laparoscopic-assisted group, the total laparoscopic group had shorter main incisions (4.1±1.0 cm vs. 8.5±2.8 cm, t=9.375, P<0.001), time to fluid intake [4.0 (3.0, 4.8) days vs. 5.0 (4.0, 6.0) days, Z=2.167, P=0.030], and duration of indwelling abdominal drainage catheter [6.0 (6.0, 7.0) days vs. 7.0 (6.0, 8.0) days, Z=2.323, P=0.020]. Numerical Rating Scale scores on postoperative days 1 and 2 were higher in the total laparoscopic than the laparoscopic-assisted group [2.5 (1.0, 3.0) vs. 1.5 (1.0, 2.0), Z=1.980, P=0.048; 2.0 (1.0, 3.0) vs. 1.0 (1.0, 2.0), Z=2.334, P=0.020, respectively]. However, there were no significant differences between the groups in operation time, intraoperative blood loss, white blood cell count, hemoglobin concentration, or albumin concentration on postoperative day 1, time to ambulation, mean time to bowel movement, postoperative admission to the intensive care unit, length of postoperative hospital stay, or Numerical Rating Scale scores on postoperative day 3 (all P>0.05). There were also no significant differences between the two groups in maximum tumor diameter, pathological tumor type, total number of lymph nodes dissected, or total number of positive lymph nodes (all P>0.05). The incidence of postoperative complications was 15.0% (6/40) in the total laparoscopic group and the laparoscopic-assisted group; these differences are not significant (χ2<0.001, P>0.999). Conclusions: Compared with laparoscopic-assisted radical gastrectomy for distal gastric cancer, total laparoscopic surgery has the advantages of shorter incision, shorter time to fluid intake, and shorter duration of indwelling abdominal drainage catheter in older patients (age ≥65 years). Total laparoscopic radical gastrectomy for distal gastric cancer does not increase the risk of postoperative complications and could therefore be performed more frequently.

Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy, Libmeldy (atidarsagene autotemcel), was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis. RESULTS: Data was collected through a moderator-assisted online 60-min survey and 30-min semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n = 10), France (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 20), juvenile (n = 11) or borderline late infantile/juvenile (n = 1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child's initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms of MLD and provide added context to help elevate the index of suspicion of disease. Distinctions between caregiver descriptions of late infantile and juvenile MLD in symptom onset and disease course were also identified. CONCLUSIONS: This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.

Novel insights into heat tolerance using metabolomic and high-throughput sequencing analysis in dairy cows rumen fluid.

Heat stress influences rumen fermentative processes with effects on the physiology and production of dairy cows. However, the underlying relationship between rumen microbiota and its associated metabolism with heat tolerance in cows have not been extensively described yet. Therefore, the main objective of this study was to investigate differential heat resistance in Holstein cows using rumen bacterial and metabolome analyses. We performed both principal component analysis and membership function analysis to select seven heat-tolerant (HT) and seven heat-sensitive (HS) cows. Under heat stress conditions, the HT cows had a significantly (P < 0.05) higher propionic acid content than the HS cows; while measures of the respiratory rate, acetic, and butyric acid in the HT cows were significantly (P < 0.05) lower compared with the HS cows. Also, the HT cows showed lower (P < 0.01) rectal temperature and acetic acid to propionic acid ratio than the HS group of cows. Omics sequencing revealed that the relative abundances of Muribaculaceae, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, Rikenellaceae_RC9_gut_group, Succiniclasticum, Ruminococcaceae_NK4A214_group and Christensenellaceae_R-7_group were significantly (P < 0.01) higher in the HT cows; whereas Prevotellaceae, Prevotella_1, Ruminococcaceae_UCG-014, and Shuttleworthia were significantly (P < 0.01) lower in HT cows compared to HS cows. Substances mainly involved in carbohydrate metabolism, including glycerol, mannitol, and maltose, showed significantly higher content in the HT cows (P < 0.05) compared to that in the HS cows. Simultaneously, distinct metabolites were significantly correlated with differential bacteria, suggesting that glycerol, mannitol, and maltose could serve as potential biomarkers for determining heat resistance that require further study. Overall, distinct changes in the rumen microbiota and metabolomics in the HT cows may be associated with a better adaptability to heat stress. These findings suggest their use as diagnostic tools of heat tolerance in dairy cattle breeding schemes.

[The efficacy of the improved tongue base suspension surgery combined with UPPP in the treatment of severe OSA].

Objective:This study was designed to show the preliminary efficacy and safety of the improved tongue base suspension surgery in severe obstructive sleep apnea(OSA) patients classified as Friedman Ⅱand Friedman Ⅲ. Method:The severe OSA patients diagnosed by PSG as Friedman Ⅱ type and Ⅲ type underwent surgery treatment. The tongue base of the patient was implanted with titanium plate and fixed on the chin of mandible. The UPPP surgery was performed with reference to H-UPPP. After surgery, the patients were followed up, PSG was re-examined and the change of various subjective and objective indicators of rehabilitation and adverse reactions were observed and recorded.Result: One hundred and two patients with severe OSA who were not tolerant or unwilling to use CPAP treatment were treated by the above surgical method. All the patients underwent surgery successfully and generally recovered about 1 month after the surgery without obvious tongue base pain, foreign body sensation or other discomfort. Eating and speaking function were as usual, the wound was healed well, and no serious infection or rejection was observed. The main postoperative adverse reactionwas tension line fracture(3 cases). Sixty-seven patients completed follow-up. At 3 to 6 months after surgery, the AHI, ESS sleepiness score and snore index were lower than those before surgery, while LSaO2and CT 90% were higher than those before surgery(P<0.01). The AHI before surgery was 60.5± 22.4, and the average AHI after surgery was 27.8± 22.4. The effective rate of the surgery was 71.6% and the success rate was 58.2%. The AHI has dropped by an average of 54.0%, and snore improved by 63.9%. Conclusion: After preliminary clinical observation, the study suggests that the improved tongue base suspension with UPPP has satisfactory curative effect and feasibility for the treatment of severe OSA patients classified as Friedman Ⅱ type and Ⅲ type.

[The surgical treatments and clinical characteristics of snoring with epiglottis collapse].

Objective:The aim of this study is to summary the characteristics of sleep breath disorder patients with epiglottis collapse and find out the way to treat them with surgery.Method:This is a retrospective study. There were eighteen patients who complained of snoring and somnolence, as well as had undergone DISE. Eight of them were diagnosed as epiglottis collapse. We analysis the clinical features, surgical treatments and prognosis of these eight patents, and compare their BMI, shape of epiglottis and AHI with the patients without epiglottis collapse. Result: Patients with epiglottis collapse usually complained of breathless during sleeping. The shape of their epiglottis was mainly flat and wide, as the cure of the upper margin of their epiglottises shows significant difference with those who are without epiglottis collapse(P=0.03,0.04).DISE is the diagnosis examination. The primary surgical treatment is Epiglottoplasty. Conclusion: It's not uncommon to see epiglottis collapse clinically. Whenever we meet the particular clinical manifestation,the diagnose of epiglottis collapse should be taken into consideration. DISE is the diagnosis examination. Epiglottoplasty can treat them to some degree.

Preschool healthcare utilisation related to home oxygen status.

OBJECTIVE: To determine, in prematurely born children who had bronchopulmonary dysplasia (BPD), if respiratory morbidity, healthcare utilisation, and cost of care during the preschool years were influenced by use of supplementary oxygen at home after discharge from the neonatal intensive care unit. DESIGN: Observational study. SETTING: Four tertiary neonatal intensive care units. PATIENTS: 190 children, median gestational age 27 weeks (range 22-31), 70 of whom received supplementary oxygen when discharged home. INTERVENTIONS: Review of hospital and general practitioner records together with a parent completed respiratory questionnaire. MAIN OUTCOME MEASURES: Healthcare utilisation, cost of care, cough, wheeze, and use of an inhaler. RESULTS: Seventy children had supplementary oxygen at home (home oxygen group), but only one had a continuous requirement for home oxygen beyond 2 years of age. There were no significant differences in the gestational age or birth weight of the home oxygen group compared with the rest of the cohort. However, between 2 and 4 years of age inclusive, the home oxygen group had more outpatient attendances (p = 0.0021) and specialist attendances (p = 0.0023), and, for respiratory problems, required more prescriptions (p<0.0001). Their total cost of care was higher (p<0.0001). In addition, more of the home oxygen group wheezed more than once a week (p = 0.0486) and were more likely to use an inhaler (p<0.0001). CONCLUSIONS: Children with BPD who have supplementary oxygen at home after discharge have increased respiratory morbidity and healthcare utilisation in the preschool years.

Generalisability in economic evaluation studies in healthcare: a review and case studies.

OBJECTIVES: To review, and to develop further, the methods used to assess and to increase the generalisability of economic evaluation studies. DATA SOURCES: Electronic databases. REVIEW METHODS: Methodological studies relating to economic evaluation in healthcare were searched. This included electronic searches of a range of databases, including PREMEDLINE, MEDLINE, EMBASE and EconLit, and manual searches of key journals. The case studies of a decision analytic model involved highlighting specific features of previously published economic studies related to generalisability and location-related variability. The case-study involving the secondary analysis of cost-effectiveness analyses was based on the secondary analysis of three economic studies using data from randomised trials. RESULTS: The factor most frequently cited as generating variability in economic results between locations was the unit costs associated with particular resources. In the context of studies based on the analysis of patient-level data, regression analysis has been advocated as a means of looking at variability in economic results across locations. These methods have generally accepted that some components of resource use and outcomes are exchangeable across locations. Recent studies have also explored, in cost-effectiveness analysis, the use of tests of heterogeneity similar to those used in clinical evaluation in trials. The decision analytic model has been the main means by which cost-effectiveness has been adapted from trial to non-trial locations. Most models have focused on changes to the cost side of the analysis, but it is clear that the effectiveness side may also need to be adapted between locations. There have been weaknesses in some aspects of the reporting in applied cost-effectiveness studies. These may limit decision-makers' ability to judge the relevance of a study to their specific situations. The case study demonstrated the potential value of multilevel modelling (MLM). Where clustering exists by location (e.g. centre or country), MLM can facilitate correct estimates of the uncertainty in cost-effectiveness results, and also a means of estimating location-specific cost-effectiveness. The review of applied economic studies based on decision analytic models showed that few studies were explicit about their target decision-maker(s)/jurisdictions. The studies in the review generally made more effort to ensure that their cost inputs were specific to their target jurisdiction than their effectiveness parameters. Standard sensitivity analysis was the main way of dealing with uncertainty in the models, although few studies looked explicitly at variability between locations. The modelling case study illustrated how effectiveness and cost data can be made location-specific. In particular, on the effectiveness side, the example showed the separation of location-specific baseline events and pooled estimates of relative treatment effect, where the latter are assumed exchangeable across locations. CONCLUSIONS: A large number of factors are mentioned in the literature that might be expected to generate variation in the cost-effectiveness of healthcare interventions across locations. Several papers have demonstrated differences in the volume and cost of resource use between locations, but few studies have looked at variability in outcomes. In applied trial-based cost-effectiveness studies, few studies provide sufficient evidence for decision-makers to establish the relevance or to adjust the results of the study to their location of interest. Very few studies utilised statistical methods formally to assess the variability in results between locations. In applied economic studies based on decision models, most studies either stated their target decision-maker/jurisdiction or provided sufficient information from which this could be inferred. There was a greater tendency to ensure that cost inputs were specific to the target jurisdiction than clinical parameters. Methods to assess generalisability and variability in economic evaluation studies have been discussed extensively in the literature relating to both trial-based and modelling studies. Regression-based methods are likely to offer a systematic approach to quantifying variability in patient-level data. In particular, MLM has the potential to facilitate estimates of cost-effectiveness, which both reflect the variation in costs and outcomes between locations and also enable the consistency of cost-effectiveness estimates between locations to be assessed directly. Decision analytic models will retain an important role in adapting the results of cost-effectiveness studies between locations. Recommendations for further research include: the development of methods of evidence synthesis which model the exchangeability of data across locations and allow for the additional uncertainty in this process; assessment of alternative approaches to specifying multilevel models to the analysis of cost-effectiveness data alongside multilocation randomised trials; identification of a range of appropriate covariates relating to locations (e.g. hospitals) in multilevel models; and further assessment of the role of econometric methods (e.g. selection models) for cost-effectiveness analysis alongside observational datasets, and to increase the generalisability of randomised trials.

Regional and molecular separation of the four bioactivities of 'tribulin'.

The endocoid tribulin has four known bioactivities: monoamine oxidase A and B inhibitory activities (MAO-AI and MAO-BI) and peripheral and central benzodiazepine receptor binding inhibitory activities (PBR-I and CBR-I). Analysis of the four bioactivities in rat tissue reveals regional dissociation. Most notably liver was particularly rich in PBR-I yet contained no detectable MAO-AI. In addition we have succeeded in separating the four activities from human urine. MAO-AI and MAO-BI have greater retention on charcoal than PBR-I and CBR-I when eluted step-wise with aqueous methanol. MAO-AI can be separated from MAO-BI and in addition PBR-I can be separated from CBR-I by step aqueous methanol elution from Amberlite XAD-4. Hence we present two lines of evidence that, contrary to the original view, tribulin is composed of a number of distinct molecular components.