Patient Perception of Cough in Interstitial Lung Disease; Impact of Cough Hypersensitivity.

INTRODUCTION: Cough is common in interstitial lung disease (ILD) and is associated with disease progression, yet its mechanisms are understudied. We investigated cough hypersensitivity features and impact in ILD. METHODS: Participants with ILD and cough (n = 195) completed a multiple choice and free text questionnaire on cough sensations/triggers and impacts. RESULTS: The majority of participants were male (54%), aged > 65 (64%), with idiopathic pulmonary fibrosis (IPF, 75%). Common cough triggers were body position (74%), physical activity (72%), and talking (62%). Common laryngeal sensations were globus (43%), and itch/tickle (42%). Cough impacted everyday life in 55%, and all activities in 31%, causing exhaustion (59%), social embarrassment (70%), urinary incontinence (46% females), and syncope/pre-syncope (12%). The total number of cough-provoking sensations/triggers correlated with impacts; ρ = 0.73, p < 0.001. CONCLUSION: Cough hypersensitivity symptoms are prevalent in ILD and detrimentally affect quality of life. Further studies investigating mechanisms of cough hypersensitivity and targeted pharmacotherapy are warranted.

Migrant status and risk of compulsory admission at first diagnosis of psychotic disorder: a population-based cohort study in Sweden.

BACKGROUND: Minority ethnic and migrant groups face an elevated risk of compulsory admission for mental illness. There are overlapping cultural, socio-demographic, and structural explanations for this risk that require further investigation. METHODS: By linking Swedish national register data, we established a cohort of persons first diagnosed with a psychotic disorder between 2001 and 2016. We used multilevel mixed-effects logistic modelling to investigate variation in compulsory admission at first diagnosis of psychosis across migrant and Swedish-born groups with individual and neighbourhood-level covariates. RESULTS: Our cohort included 12 000 individuals, with 1298 (10.8%) admitted compulsorily. In an unadjusted model, being a migrant [odds ratio (OR) 1.48; 95% confidence interval (CI) 1.26-1.73] or child of a migrant (OR 1.27; 95% CI 1.10-1.47) increased risk of compulsory admission. However after multivariable modelling, region-of-origin provided a better fit to the data than migrant status; excess risk of compulsory admission was elevated for individuals from sub-Saharan African (OR 1.94; 95% CI 1.51-2.49), Middle Eastern and North African (OR 1.46; 95% CI 1.17-1.81), non-Nordic European (OR 1.27; 95% CI 1.01-1.61), and mixed Swedish-Nordic backgrounds (OR 1.33; 95% CI 1.03-1.72). Risk of compulsory admission was greater in more densely populated neighbourhoods [OR per standard deviation (s.d.) increase in the exposure: 1.12, 95% CI 1.06-1.18], an effect that appeared to be driven by own-region migrant density (OR per s.d. increase in exposure: 1.12; 95% CI 1.02-1.24). CONCLUSIONS: Inequalities in the risk of compulsory admission by migrant status, region-of-origin, urban living and own-region migrant density highlight discernible factors which raise barriers to equitable care and provide potential targets for intervention.

Identifying critical source areas using multiple methods for effective diffuse pollution mitigation.

Diffuse pollution from agriculture constitutes a key pressure on the water quality of freshwaters and is frequently the cause of ecological degradation. The problem of diffuse pollution can be conceptualised with a source-mobilisation-pathway (or delivery)-impact model, whereby the combination of high source risk and strong connected pathways leads to 'critical source areas' (CSAs). These areas are where most diffuse pollution will originate, and hence are the optimal places to implement mitigation measures. However, identifying the locations of these areas is a key problem across different spatial scales within catchments. A number of approaches are frequently used for this assessment, although comparisons of these assessments are rarely carried out. We evaluate the CSAs identified via traditional walkover surveys supported by three different approaches, highlighting their benefits and disadvantages. These include a custom designed smartphone app; a desktop geographic information system (GIS) and terrain analysis-based SCIMAP (Sensitive Catchment Integrated Modelling and Analysis Platform) approach; and the use of a high spatial resolution drone dataset as an improved input data for SCIMAP modelling. Each of these methods captures the locations of the CSAs, revealing similarities and differences in the prioritisation of CSA features. The differences are due to the temporal and spatial resolution of the three methods such as the use of static land cover information, the ability to capture small scale features, such as gateways and the incomplete catchment coverage of the walkover survey. The relative costs and output resolutions of the three methods indicate that they are suitable for application at different catchment scales in conjunction with other methods. Based on the results in this paper, it is recommended that a multi-evidence-based approach to diffuse pollution management is taken across catchment spatial scales, incorporating local knowledge from the walkover with the different data resolutions of the SCIMAP approach.

A cloud based tool for knowledge exchange on local scale flood risk.

There is an emerging and urgent need for new approaches for the management of environmental challenges such as flood hazard in the broad context of sustainability. This requires a new way of working which bridges disciplines and organisations, and that breaks down science-culture boundaries. With this, there is growing recognition that the appropriate involvement of local communities in catchment management decisions can result in multiple benefits. However, new tools are required to connect organisations and communities. The growth of cloud based technologies offers a novel way to facilitate this process of exchange of information in environmental science and management; however, stakeholders need to be engaged with as part of the development process from the beginning rather than being presented with a final product at the end. Here we present the development of a pilot Local Environmental Virtual Observatory Flooding Tool. The aim was to develop a cloud based learning platform for stakeholders, bringing together fragmented data, models and visualisation tools that will enable these stakeholders to make scientifically informed environmental management decisions at the local scale. It has been developed by engaging with different stakeholder groups in three catchment case studies in the UK and a panel of national experts in relevant topic areas. However, these case study catchments are typical of many northern latitude catchments. The tool was designed to communicate flood risk in locally impacted communities whilst engaging with landowners/farmers about the risk of runoff from the farmed landscape. It has been developed iteratively to reflect the needs, interests and capabilities of a wide range of stakeholders. The pilot tool combines cloud based services, local catchment datasets, a hydrological model and bespoke visualisation tools to explore real time hydrometric data and the impact of flood risk caused by future land use changes. The novel aspects of the pilot tool are; the co-evolution of tools on a cloud based platform with stakeholders, policy and scientists; encouraging different science disciplines to work together; a wealth of information that is accessible and understandable to a range of stakeholders; and provides a framework for how to approach the development of such a cloud based tool in the future. Above all, stakeholders saw the tool and the potential of cloud technologies as an effective means to taking a whole systems approach to solving environmental issues. This sense of community ownership is essential in order to facilitate future appropriate and acceptable land use management decisions to be co-developed by local catchment communities. The development processes and the resulting pilot tool could be applied to local catchments globally to facilitate bottom up catchment management approaches.

Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Dissolved organic nutrient uptake by riverine phytoplankton varies along a gradient of nutrient enrichment.

The concentration of dissolved organic matter (DOM) in freshwaters is increasing in large areas of the world. In addition to carbon, DOM contains nitrogen and phosphorus and there is growing concern that these organic nutrients may be bioavailable and contribute to eutrophication. However, relatively few studies have assessed the potential for dissolved organic nitrogen (DON) or dissolved organic phosphorus (DOP) compounds to be bioavailable to natural river phytoplankton communities at different locations or times. Temporal and spatial variations in uptake, relative to environmental characteristics were examined at six riverine sites in two contrasting catchments in the UK. This study also examined how the uptake by riverine phytoplankton of four DON and four DOP compounds commonly found in rivers, varied with concentration. Total nitrogen (TN) and phosphorus (TP) concentrations, the proportion of inorganic nutrient species, and nutrient limitation varied temporally and spatially, as did the potential for DON and DOP uptake. All eight of the DOM compounds tested were bioavailable, but to different extents. Organic nutrient use depended on the concentration of the organic compound supplied, with simple compounds (urea and glucose-6-phosphate) supporting algal growth even at very low concentrations. DON use was negatively correlated with the TN and ammonia concentration and DOP use was negatively correlated with soluble reactive phosphorus (SRP) and dissolved organic carbon (DOC) concentration. The evidence indicates that DOM in rivers has been overlooked as a potential source of nutrients to phytoplankton and therefore as an agent of eutrophication.

Aqueous humor myocilin protein levels in normal, genetic carriers, and glaucoma Beagles.

OBJECTIVE: The gene (myocilin: MYOC) has been attributed to be involved in over 6% of inherited types of human glaucoma, the highest correlation for any gene to date. This study determines myocilin protein levels in the aqueous humor (AH) of normal laboratory quality, genetic carrier (offspring of normal laboratory quality and POAG Beagles), and primary open angle glaucoma (POAG) Beagles. MATERIALS AND METHODS: Eighteen dogs were used and classified as either normal, carrier or having mild, moderate or advanced POAG. A 0.1 mL sample of AH was drawn from the anterior chamber of each dog in the study and frozen on dry ice. A modified Coomassie stain and Western blot, using a polyclonal rabbit antihuman myocilin antibody (Santa Cruz Biotechnologies, Santa Cruz, CA), was run on each sample to compare the myocilin levels. A purified human trabecular meshwork excreted myocilin protein sample was used as a control (Alcon Research Laboratories, Fort Worth, TX) and its band/densitometry measurement was defined as one unit of myocilin for comparisons. RESULTS: Comparisons of AH myocilin levels differed among normal laboratory quality, genetic carrier, and POAG Beagles at different stages of the disease. In the normal laboratory, Beagles the AH myocilin measured 0.817 +/- 0.075 units (mean +/- SEM); in the carrier Beagles the AH myocilin was 3.117 +/- 0.290 units. As POAG progressed, myocilin protein levels also increased to 6.097 +/- 0.810, 8.844 +/- 1.079, and 17.228 +/- 1.198 units in the early, moderate, and advanced forms, respectively. Overall comparisons between normal, carrier and all POAG Beagles combined showed significant differences (P < 0.0010). Individual comparisons between normal and carrier eyes showed significant differences (P < 0.0193). Comparisons between normal and all POAG eyes also showed significant differences (P < 0.0426). CONCLUSION: This study shows myocilin protein is present in normal Beagles, markedly increased in POAG Beagles, and mildly increased in genetic carrier Beagles. There is a strong correlation between amounts of AH myocilin protein and the presence and severity of POAG. The exact role of AH myocilin levels in the genesis of ocular hypertension remains unresolved, but myocilin may adversely affect AH outflow.

Myocilin protein levels in the aqueous humor of the glaucomas in selected canine breeds.

OBJECTIVE: To compare aqueous humor myocilin protein levels in dogs with the primary glaucomas to those with the secondary glaucomas, primary cataracts, and diabetic cataracts. MATERIALS AND METHODS: Four groups were selected, based on diagnosis by the attending veterinary ophthalmologists and included: primary glaucoma (primary open-angle glaucoma (POAG) and primary closed angle glaucoma (PCAG); n = 155); secondary glaucoma (n = 94); primary (presumed inherited) cataract (n = 142), and diabetic cataract (n = 83). A total of 474 samples (187 males, 263 females, 24 unreported) with average ages of 117 months for the males and 101 months for the females were analyzed. Myocilin protein was measured using the Coomassie staining and Western blot methods relative to a myocilin control. RESULTS: Differences were seen between nonglaucomatous (cataractous) and glaucomatous dogs with myocilin levels in glaucomatous eyes being many times higher than those in the cataractous dogs. Primary glaucomatous dogs were found to have an aqueous humor myocilin protein level of 17.30 +/- 1.03 units. Secondary glaucomas had the highest level of myocilin in the aqueous humor with 19.27 +/- 1.41 units. Diabetic cataractous dogs had the lowest levels of myocilin reported with 6.60 +/- 0.88 (mean +/- SEM) units. Normal (cataractous) dogs had a myocilin level in the aqueous humor of 8.05 +/- 0.86 units. CONCLUSION: Aqueous humor protein levels were elevated, relative to the myocilin control, in both the primary and secondary glaucoma groups compared to the cataract and diabetic cataract groups. Like in the Beagle POAG, aqueous humor myocilin protein levels are increased. Further studies are indicated to investigate the exact role of the aqueous humor myocilin protein in the genesis in increased IOP in these primary glaucomatous breeds.

A variant epidermal growth factor receptor protein is similarly expressed in benign hyperplastic and carcinomatous prostatic tissues in black and white men.

BACKGROUND AND OBJECTIVE: Anti-epidermal growth factor receptor strategies are now established in cancer treatment We have recently described the presence of EGFRvIII (a variant EGFR) in prostatic tumours from UK white men and this is now a target for anti-prostate cancer treatments. However, there has been no report on the expression of this abnormal protein in black men. MATERIALS AND METHODS: We determined EGFRvIII expression in sections of normal, benign hyperplastic (BPH) and carcinomatous (CaP) prostatic archival tissues from Nigerian men and UK white men using streptavidin immunohistochemical techniques. The EGFRvIII immunoreactivity was scored visually using a semi-quantitative method and the results compared statistically. RESULTS: EGFRvIII expression increased with increasing malignancy in both study populations (CaP > BPH > Normal p, <0.0001). Furthermore, EGFRvIII expression was similar in both BPH and CaP tissues in black and white men (p, 0.86 and 0.31 respectively). CONCLUSION: These results demonstrate that EGFRvIII immunoreactivity in prostatic tumours in black men is similar to that in white men. Anti-cancer treatments directed at the EGFRvIII should be equally effective in men from both subpopulations.

Phytoplankton community responses in a shallow lake following lanthanum-bentonite application.

The release of phosphorus (P) from bed sediments to the overlying water can delay the recovery of lakes for decades following reductions in catchment contributions, preventing water quality targets being met within timeframes set out by environmental legislation (e.g. EU Water Framework Directive: WFD). Therefore supplementary solutions for restoring lakes have been explored, including the capping of sediment P sources using a lanthanum (La)-modified bentonite clay to reduce internal P loading and enhance the recovery process. Here we present results from Loch Flemington where the first long-term field trial documenting responses of phytoplankton community structure and abundance, and the UK WFD phytoplankton metric to a La-bentonite application was performed. A Before-After-Control-Impact (BACI) analysis was used to distinguish natural variability from treatment effect and confirmed significant reductions in the magnitude of summer cyanobacterial blooms in Loch Flemington, relative to the control site, following La-bentonite application. However this initial cyanobacterial response was not sustained beyond two years after application, which implied that the reduction in internal P loading was short-lived; several possible explanations for this are discussed. One reason is that this ecological quality indicator is sensitive to inter-annual variability in weather patterns, particularly summer rainfall and water temperature. Over the monitoring period, the phytoplankton community structure of Loch Flemington became less dominated by cyanobacteria and more functionally diverse. This resulted in continual improvements in the phytoplankton compositional and abundance metrics, which were not observed at the control site, and may suggest an ecological response to the sustained reduction in filterable reactive phosphorus (FRP) concentration following La-bentonite application. Overall, phytoplankton classification indicated that the lake moved from poor to moderate ecological status but did not reach the proxy water quality target (i.e. WFD Good Ecological Status) within four years of the application. As for many other shallow lakes, the effective control of internal P loading in Loch Flemington will require further implementation of both in-lake and catchment-based measures. Our work emphasizes the need for appropriate experimental design and long-term monitoring programmes, to ascertain the efficacy of intervention measures in delivering environmental improvements at the field scale.

NMR structure of the sea urchin (Strongylocentrotus purpuratus) metallothionein MTA.

The three-dimensional structure of [(113)Cd7]-metallothionein-A (MTA) of the sea urchin Strongylocentrotus purpuratus was determined by homonuclear(1)H NMR experiments and heteronuclear [(1)H, (113)Cd]-correlation spectroscopy. MTA is composed of two globular domains, an N-terminal four-metal domain of the amino acid residues 1 to 36 and a Cd4Cys11cluster, and a C-terminal three-metal domain including the amino acid residues 37 to 65 and a Cd3Cys9cluster. The structure resembles the known mammalian and crustacean metallothioneins, but has a significantly different connectivity pattern of the Cys-metal co-ordination bonds and concomitantly contains novel local folds of some polypeptide backbone segments. These differences can be related to variations of the Cys sequence positions and thus emphasize the special role of the cysteine residues in defining the structure of metallothioneins, both on the level of the domain architecture and the topology of the metal-thiolate clusters.

Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma.

The cellular pathways involved in the pathogenesis of hormone resistance remain unclear. Studies evaluating the role of changes in human androgen receptor (hAR) expression in the progression of prostatic tumors have been inconclusive. Androgenic influence over prostatic growth is mediated via the regulation of interactions between stromal and epithelial cells. We hypothesized that neoplastic transformation of the prostate would be associated with alterations in hAR expression in the adjacent stroma. Using immunohistochemical techniques, we determined hAR positivity in the epithelium and adjacent stroma of sections from 17 benign and 39 malignant prostatic glands. We found that whereas the expression of the receptor decreased in both cellular compartments as the tissues dedifferentiated, the depletion was more pronounced in the stromal nuclei (P<0.0001). However, in sections from both untreated and hormone-resistant prostate cancer tissues, although heterogeneity of hAR expression in malignant epithelia was increased, there appeared to be a unique field effect around the cancerous prostate glands that resulted in a decreased expression of the receptor in the adjacent benign glands and its total loss in the surrounding stroma. The loss of hAR in the stroma adjacent to malignant prostatic epithelium may play an important role in prostate cancer progression. Furthermore, the similarity of the lack of stromal hAR expression in newly diagnosed and hormone-resistant prostate cancer (P = 0.85) may be an indication that the mechanisms responsible for the acquisition of hormone independence are established early in the malignant transformation process.

HLA-DR and DQ DNA polymorphisms in subjects of Asian Indian and white Caucasian origin.

There is a close correspondence between serologically defined DR types and DR beta chain restriction fragment length polymorphisms (RFLPs). There is also an association between DR types and DQ alpha and DQ beta RFLPs because of linkage disequilibrium. We present the results of an analysis of DR beta, DQ alpha and DQ beta RFLPs in Asian Indians and white Caucasian subjects. DR beta RFLPs were similar in the two groups. Clearly distinguishable DR beta patterns were observed for DR1, 2, 3, 4, 5, 7 and w10. The DR beta patterns associated with DR3 were, however, also found with w6. The DR7 DR beta patterns were also found with w9. For DR specificities 1, 3, 4, 5, 7 and w10, the associated DQ alpha and DQ beta RFLPs were similar in both racial groups, but for DR2, however, marked differences were found. The DR2-positive white Caucasian subjects all possessed a single DQ alpha/DQ beta combination whereas the DQ alpha/DQ beta patterns in DR2-positive Asian Indians showed considerable heterogeneity. The pattern seen in white subjects was present in only a minority of Asians. DR-DQ relationships clearly vary in different racial groups. RFLP analysis of HLA-linked diseases in different populations should prove to be an important technique in identifying the primary genetic factor(s) in these disorders.

Discordant expression of the G syndrome in monozygotic twins.

We present clinical manifestations of monozygotic male twins with different degrees of expression of the G syndrome. Monozygosity was confirmed using DNA mini-satellite "fingerprint" analysis. The findings in these twins suggest that expression of the G syndrome can be strongly influenced by the prenatal developmental environment.

Tubulovillous adenoma arising 30 years after ileocystoplasty.

The possibility of recurrent colonic metaplasia occurring as a complication of pelvic ileal pouches after ileo-rectal anastomosis has been raised. Several reports have documented malignant bladder tumours developing in patients many years after an ileocystoplasty. The case of a 50 year old man, who developed a tubulovillous adenoma in the ileal patch 30 years after an ileocystoplasty had been performed to enlarge a tuberculous shrunken bladder, is reported. The adjacent small intestinal mucosa showed features suggestive of colonic metaplasia.

Reactions in rabbit Fallopian tube after plastic reconstruction. I. Gross pathology, tubal patency, and pregnancy.

PIP: Rabbit tubal repair surgery was aseptic with Nembutal and ether anesthesia. Both tubes were cut at the uterotubal junction, a .61 mm thick polyethylene splint was inserted, sutured to the myometrium, and the junction sutured. At 2, 6, 10, 16, and 24 weeks the splint was removed through an incision. After a dye test for patency, 1 tube was removed and the rabbit was mated 1 week later. Results were 30% distorted placement of tube, 30% fibrose tubes (especially after 16 weeks), 47% adhesion (particularly after 6 weeks), some infection, and 55% positive dye flow test. 3 out of 7 rabbits delivered, all in those of the 2-week group that had no adhesions. 2 of the pregnancies occurred in rabbits with no dye passage.^ieng

Reactions in the rabbit Fallopian tube after plastic reconstruction. II. Histopathology.

PIP: In this histological study of tubal repair in rabbits, both fallopian tubes were cut at the uterotubal junction, a .61 mm thick polyethylene splint was inserted, sutured to the myometrium, and the junction sutured. At 2, 6, 10, 16, and 24 weeks the splint was removed through an incision. After a dye test for patency, 1 tube was removed and the rabbit mated 1 week later. Histological stains used included hematoxylin and eosin for detail, periodic acid (Schiff) for secretion, and Herovici for collagen. The normally folded epithelium remained flat. There were few mitoses but many basophilic cells and polymorphonuclear leucocytes appeared in the 2- and 6-week groups. Fibrous replacement of muscle seemed to prevent pregnancy, but absence of folded ciliated epithelium permitted pregnancy in 3 rabbits.^ieng

Preoperative esophageal transit studies are a useful predictor of dysphagia after fundoplication.

Fundoplication performed for gastroesophageal reflux disease may be complicated by postoperative dysphagia despite successful reduction in reflux symptoms. This is more likely in those patients with reflux who have concurrent esophageal dysmotility. The aim of this study was to establish whether esophageal transit studies using a technetium-99m jello bolus (jello esophageal transit) could detect the presence of motility disorders preoperatively and hence predict surgical outcome. Transit studies in 33 healthy volunteers yielded a normal range of 2 to 24 seconds using ninety-fifth percentile distribution. In the second phase of the study, 26 patients accepted for laparoscopic fundoplication were enrolled: jello esophageal transit, manometry, and endoscopy were attempted preoperatively in all subjects. A clinical dysphagia score was assigned from a questionnaire. Six months after surgery, five patients had dysphagia and of these four were found to have abnormal preoperative jello esophageal transit, for a sensitivity of 80%. Of the 21 patients who had no dysphagia after surgery, 20 patients had normal preoperative jello esophageal transit, showing a specificity of 95%. This esophageal transit study is noninvasive, reliable, and sensitive. When performed prior to fundoplication, it appears to be of significant value in detecting a subtle functional motility disorder that predisposes to postoperative dysphagia. Jello esophageal transit may assist the surgeon in planning treatment of gastroesophageal reflux disease.

Further characterization of storage-related alterations in immunoreactivity of archival tissue sections and its implications for collaborative multicenter immunohistochemical studies.

Storage of unstained paraffin slides may lead to the deterioration of specimens and failure to detect cellular proteins immunohistochemically. Although the implication of age-induced alterations on multicenter immunohistochemical studies would be considerable, they have not been investigated previously. The current study was undertaken to examine the effect of this factor further and to explore new ways of overcoming the resultant shortcomings. The authors now report on the immunodetection of a host of antigens in similarly preserved unstained serial paraffin slides obtained from three centers using a panel of eight antibodies. Staining of recently prepared sections from the authors' centers resulted in similar strong patterns in seven of eight antibodies, with one antibody demonstrating variable immunoreactivity. However, storage of unstained paraffin sections at room temperature resulted in a variable but progressive decrease in expression of several tissue antigens. Although the loss in antigenicity was proportional to the length of storage, the effect was reversible if super antibody concentrations were used. The authors conclude that recently prepared paraffin sections from centers with similar fixation protocols have similar immunoreactivity and are suitable for use in comparative multicenter studies. However, in view of the delays that may attend tissue transportation during these projects, the authors suggest that test systems should be checked for age-induced antigen degradation by incubating sections with higher antibody concentrations.

Using diagnoses to describe populations and predict costs.

The Diagnostic Cost Group Hierarchical Condition Category (DCG/HCC) payment models summarize the health care problems and predict the future health care costs of populations. These models use the diagnoses generated during patient encounters with the medical delivery system to infer which medical problems are present. Patient demographics and diagnostic profiles are, in turn, used to predict costs. We describe the logic, structure, coefficients and performance of DCG/HCC models, as developed and validated on three important data bases (privately insured, Medicaid, and Medicare) with more than 1 million people each.