Describing nonequilibrium soft matter with mean field game theory.

We demonstrate that combining an emerging approach to game theory with self-consistent mean field theory provides realistic treatments of diblock copolymer phase evolution. We especially examine order-order phase transformations upon quenched temperature change involving hexagonal cylinders, lamellae, and the gyroid. Our findings demonstrate that (i) the game theoretical dynamics produce realistic trajectories for the evolution of the local compositions, (ii) the predicted small-angle scattering follows experimentally observed trends, (iii) nucleation and growth is active when the system is quenched far from the critical point, and (iv) epitaxial growth is manifest. To our knowledge, the methodology presented provides the first merger of mean field game theory and statistical mechanics for soft matter systems, giving a new inroad to studying polymer dynamics.

Jammed Limit of Bijel Structure Formation.

Over the past decade, methods to control microstructure in heterogeneous mixtures by arresting spinodal decomposition via the addition of colloidal particles have led to an entirely new class of bicontinuous materials known as bijels. Herein, we present a new model for the development of these materials that yields to both numerical and analytical evaluation. This model reveals that a single dimensionless parameter that captures both chemical and environmental variables dictates the dynamics and ultimate structure formed in bijels. We demonstrate that this parameter must fall within a fixed range in order for jamming to occur during spinodal decomposition, as well as show that known experimental trends for the characteristic domain sizes and time scales for formation are recovered by this model.

Eigenvector Centrality is a Metric of Elastomer Modulus, Heterogeneity, and Damage.

We present an application of eigenvector centrality to encode the connectivity of polymer networks resolved at the micro- and meso-scopic length scales. This method captures the relative importance of different nodes within the network structure and provides a route toward the development of a statistical mechanics model that correlates connectivity with mechanical response. This scheme may be informed by analytical and semi-analytical models for the network structure, or through direct experimental examination. It may be used to predict the reduction in mechanical performance for heterogeneous materials subjected to specific modes of damage. Here, we develop the method and demonstrate that it leads to the prediction of established trends in elastomers. We also apply the model to the case of a self-healing polymer network reported in the literature, extracting insight about the fraction of bonds broken and re-formed during strain and recovery.

Examining the role of fluctuations in the early stages of homogenous polymer crystallization with simulation and statistical learning.

We propose a relationship between the dynamics in the amorphous and crystalline domains during polymer crystallization: the fluctuations of ordering-rate about a material-specific value in the amorphous phase drive those fluctuations associated with the increase in percent crystallinity. This suggests a differential equation that satisfies the three experimentally observed time regimes for the rate of crystal growth. To test this postulated expression, we applied a suite of statistical learning tools to molecular dynamics simulations to extract the relevant phenomenology. This study shows that the proposed relationship holds in the early time regime. It illustrates the effectiveness of soft computing tools in the analysis of coarse-grained simulations in which patterns exist, but may not easily yield to strict quantitative evaluation. This ability assists us in characterizing the critical early time molecular arrangement during the primary nucleation phase of polymer melt crystallization. In addition to supporting the validity of the proposed kinetics expression, the simulations show that (i) the classical nucleation and growth mechanism is active in the early stages of ordering; (ii) the number of nuclei and their masses grow linearly during this early time regime; and (iii) a fixed inter-nuclei distance is established.

A 9-year retrospective evaluation of 102 pressure ulcer reconstructions.

OBJECTIVE: Several pressure ulcer (PU) risk factors including paralysis and age greater than 70 have been identified, while others such as nutrition are debated. The object of this study is to identify perioperative risk factors that may predict improved outcomes and reduced complications in primary and recurrent PU reconstructions. METHOD: A retrospective chart review of patients treated surgically for PUs from 2004 to 2013 at the University of Toledo Medical Center, Toledo, Ohio, US, was completed. Data collected included ulcer and medical history, as well as risk factors, complications and postoperative outcome. Data were statistically analysed for perioperative variances between primary and recurrent ulcers and closure status. RESULTS: A total of 49 patients with 102 reconstructions were reviewed. Spinal cord injured patients accounted for 90% receiving flap coverage of ulcers. Numerous differences between primary and recurrent ulcers were identified, including ulcer location, patient nutritional status, wound infection, postoperative course and recurrence. Multivariate analysis revealed a flap reconstruction prediction model using creatinine, haematocrit, haemoglobin, and prealbumin that is able to successfully predict closure outcome in 83.6% of cases. CONCLUSION: Many factors play a role in the development, course and treatment of PUs. It is vital to understand the role of patient risk factors in the development of PUs, to direct subsequent management and reconstruction, and to prevent future recurrences. DECLARATION OF INTEREST: The authors have no conflicts of interest to disclose.

Flattening of Dendrimers from Solutions onto Charged Surfaces.

The adsorption of dendrimers onto charged surfaces plays a role in many emerging applications. Numerous studies found in the literature report that dendrimers flatten at these interfaces. Here, we provide a simple scaling theory that describes the height of the adsorbed layer, the fraction of segments within the dendrimer that touch the surface, and the total number of dendrimers adsorbed as a function of generation of growth, surface charge density, and concentration. We demonstrate that these predictions agree well with extensive molecular dynamics simulations. Combined, the simulations and scaling argument indicate that simultaneous adsorption and compression at the interface take place.

The escape of a charged dendrimer from an oppositely charged planar surface.

Many of the envisioned applications of dendrimers revolve around placing these molecules at and removing them from charged interfaces. Herein, we provide a prescription for the conditions needed to release a charged dendrimer from an oppositely charged flat substrate. Identifying an effective segment step length that reflects the intramolecular repulsions due to excluded volume and electrostatics, as well as the dendrimer's branching, provides the essential concept leading to an analytical prediction for the boundary between captured and free molecules. We find that this effective step length obeys trends similar to those predicted for linear chains, but is modified by the dendrimer's connectivity. Moreover, the boundary predicted for the capture of linear chains holds for dendrimers once this effective step length is employed. Monte Carlo computer simulations of coarse-grained model dendrimers escaping from charged surfaces validate these findings. The simulations consider generations 2 through 6 with a range of lengths between the branch points, as well as a range of solution ionic strengths and surface charge densities.

Dendrimers as synthetic gene vectors: cell membrane attachment.

We present molecular-level simulations of dendrimer/DNA complexes in the presence of a model cell membrane. We determine the required conditions for the complex to arrive intact at the membrane, and the lifetime of the complex as it resides attached to the membrane. Our simulations directly pertain to critical issues arising in emerging gene delivery therapeutic applications, where a molecular carrier is required to deliver DNA segments to the interior of living cells.

An outbreak of Cryptosporidium hominis infection at an Illinois recreational waterpark.

Cryptosporidium has become increasingly recognized as a pathogen responsible for outbreaks of diarrhoeal illness in both immunocompetent and immunocompromised persons. In August 2001, an Illinois hospital reported a cryptosporidiosis cluster potentially linked to a local waterpark. There were 358 case-patients identified. We conducted community-based and waterpark-based case-control studies to examine potential sources of the outbreak. We collected stool specimens from ill persons and pool water samples for microscopy and molecular analysis. Laboratory-confirmed case-patients (n=77) were more likely to have attended the waterpark [odds ratio (OR) 16.0, 95% confidence interval (CI) 3.8-66.8], had pool water in the mouth (OR 6.0, 95% CI 1.3-26.8), and swallowed pool water (OR 4.5, 95% CI 1.5-13.3) than age-matched controls. Cryptosporidium was found in stool specimens and pool water samples. The chlorine resistance of oocysts, frequent swimming exposures, high bather densities, heavy usage by diaper-aged children, and increased recognition and reporting of outbreaks are likely to have contributed to the increasing trend in number of swimming pool-associated outbreaks of cryptosporidiosis. Recommendations for disease prevention include alteration of pool design to separate toddler pool filtration systems from other pools. Implementation of education programmes could reduce the risk of faecal contamination and disease transmission.

Hospitalized valvular heart disease in patients on renal transplant waiting list: incidence, clinical correlates and outcomes.

BACKGROUND: Patients with ESRD are at increased risk for heart valve calcification. It has not been established whether hospitalized valvular heart disease (VHD) is a substantial barrier to renal transplantation (RT) after transplant listing, or whether VHD progresses after RT. METHODS: Using data from the USRDS, we studied 35,215 patients with ESRD enrolled on the renal transplant waiting list from July 1994 to June 1997. Cox non-proportional hazards regression models were used to calculate adjusted, time-dependent hazard ratios (HR) for RT and VHD. RESULTS: In comparison to maintenance dialysis (2.2/1,000 person years), RT was independently associated with a lower hazard for hospitalization for VHD (0.7/1,000 person years, HR 0.28, 95% confidence interval 0.17 - 0.47). Renal transplant recipients had much lower rates of VHD after transplant than before (rate ratio (RR) 0.49, 95% Cl 0.47 - 0.52). Patients with VHD were significantly less likely to receive RT (adjusted rate for RT 0.38, 95% CI 0.20 - 0.45) but patients who received valve replacement surgeries (VRS) were not affected (adjusted rate for RT 1.10, 95% CI 0.52 - 2.32, not significant). CONCLUSIONS: VHD is an uncommon but serious barrier to RT after listing, while VRS is not a significant barrier to RT. Established VHD does not appear to worsen after RT. Clinicians should consider giving increased attention to the detection and treatment of VHD during the pre-transplant evaluation.

Altered expression and localization of PKC eta in human breast tumors.

Protein kinase C (PKC) eta is a PKC isoform whose upregulation is associated with differentiation in many epithelial tissues, including the rat mammary gland. The purpose of this study was to examine whether PKC eta is altered, in expression or localization, in human breast cancer. Paraffin sections of 49 in situ breast lesions, 29 invasive breast tumors, and nine normal breast biopsies were examined for PKC eta expression by immunohistochemistry. Adjacent regions of normal epithelium, and in situ lesions that were present adjacent to invasive lesions were also analyzed. In normal epithelium, regardless of the presence of adjacent in situ or invasive lesions, PKC eta was present in the cytoplasm of the luminal epithelium, and increased in areas of normal lobular development, similar to normal rat mammary gland. PKC eta staining intensity was homogeneous in normal lobules, but heterogeneous in in situ and invasive lesions, being focally increased in cells with aberrant nuclear morphology. In situ lesions were similar to adjacent normal epithelium in average staining intensity, regardless of whether invasion was also present. However, the invasive lesions themselves were significantly decreased in staining intensity compared to adjacent in situ lesions. In addition, 75% of invasive breast cancer lesions showed decreased staining relative to adjacent normal epithelium, compared to 37% of in situ lesions. The invasive tumors which possessed high PKC eta staining were associated with positive lymph node status. These results demonstrate that quantitative and qualitative alterations in PKC eta occur in human breast cancers.

The impact of renal transplantation on the incidence of congestive heart failure in patients with end-stage renal disease due to diabetes.

BACKGROUND: Patients with end stage renal disease (ESRD) are at increased risk for cardiovascular disease. We hypothesized that the clinical incidence of congestive heart failure (CHF) would be lessened after successful renal transplantation, as many of the metabolic and intravascular volume abnormalities associated with dialysis-dependent ESRD would resolve. METHODS: Using data from the USRDS, we studied 11,369 patients with ESRD due to diabetes enrolled on the renal and renal-pancreas transplant waiting list from 1 July 1994-30 June 1997. Cox non-proportional hazards regression models were used to calculate adjusted, time-dependent hazard ratios (HR) for time to the most recent hospitalization for CHF (including acute myocardial infarction, unstable angina, or other CHF, ICD9 Code 428.x) for a given patient in the study period, controlling for both demographics and comorbidities in the medical evidence form (HCFA 2728). RESULTS: In comparison to maintenance dialysis, renal transplantation was independently associated with a lower risk for CHF (HR 0.64, 95% confidence interval, 0.54-0.77) in a model including age, gender, race, and year of first dialysis, but not in a model including comorbidities from the medical evidence form, although the sample was much smaller. CONCLUSIONS: Patients with ESRD due to diabetes on the renal transplant waiting list were much less likely to be hospitalized for congestive heart failure after renal transplantation, despite post transplant complications due to immunosuppression.

Human immunodeficiency virus/acquired immunodeficiency syndrome-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival in the pre highly active antiretroviral therapy era.

BACKGROUND: The patient characteristics and course of HlV/AIDS-associated nephropathy (HIVAN) are presented for a national sample of end-stage renal disease (ESRD). METHODS: 375,152 patients in the United States Renal Data System were initiated on ESRD therapy between 1 January 1992 and 30 June 1997 and analyzed in an historical cohort study of HIVAN. RESULTS: Of the study population, 3653 (0.97%) had HIVAN. Among patients with HIVAN, 87.8% were African American. HIVAN had the strongest association with African American race compared to other causes of renal failure except sickle cell anemia in logistic regression analysis (odds ratio 12.20, 95% confidence interval (CI) 10.57-14.07). In a separate logistic regression analysis, HIVAN was associated with male gender, decreased age (39.32 +/- 8.51 vs. 60.97 +/- 16.43 years, p<0.01 by Student's t-test), weight, body mass index, hemoglobin, albumin, decreased rate of pre-dialysis erythropoietin use, increased creatinine, decreased hypertension and increased rate of no medical insurance. The geographic distribution of HIVAN was similar to the distribution of HIV cases nationally. Two-year all cause unadjusted survival was 36% for HIVAN vs. 64% for all other patients with ESRD. HIVAN was associated with decreased patient survival in Cox regression analysis (hazard ratio for mortality 5.74, 95% CI, 5.40-6.10). CONCLUSIONS: HIVAN had the strongest association with African American race of all causes of renal failure among patients on maintenance dialysis. HIVAN was associated with decreased patient survival after initiation of dialysis, which may be associated with poorer medical condition at initiation of dialysis.

Risk factors for hospitalizations resulting from pulmonary embolism after renal transplantation in the United States.

BACKGROUND: Risk factors for pulmonary embolism (PE) have been identified in the general population but have not been studied in a national population of renal transplant recipients. METHODS: Therefore, 33,479 renal transplant recipients in the United States Renal Data System from 1 July 1994-30 June 1997 were analyzed in a historical cohort study of hospitalized PE (ICD9 Code 415.1x). HCFA form 2728 was used for comorbidities. RESULTS: Renal transplant recipients had an incidence of PE of 2.26 hospitalizations per 1000 patient years at risk. In multivariate analysis, polycystic kidney disease (adjusted odds ratio, 4.44, 95% confidence interval, 2.31-8.53), older recipient age, higher recipient weight, cadaveric donation, history of ischemic heart disease, and decreased serum albumin were associated with increased risk of PE. Body mass index and hemoglobin were not significant. Kidney-pancreas transplantation was also not significant. In Cox Regression analysis PE was associated with increased mortality (hazard ratio 2.06, 95% CI 1.34-3.18). CONCLUSIONS: The most important risk factors for PE in this population were polycystic kidney disease, advanced age and increased weight. The reasons for the increased risk of polycystic kidney disease remain to be determined but were independent of hematocrit level at initiation of end stage renal disease, and may result from venous compression. Prospective studies of anatomical and hemostatic changes after renal transplantation in recipients with polycystic kidney disease are warranted.

Molecular mechanisms of polymer crystallization from solution.

Our simulations of polymer crystallization from solutions show that (1) entropic barriers control the selection of the initial lamellar thickness, (2) growth at the crystalline interface is chain adsorption followed by crystallographic registry, and (3) lamellar thickening is a highly cooperative process requiring the mobility of all chains in the crystal. These results, especially the latter, challenge the conventional Lauritzen-Hoffman theory and its generalizations.

Involvement of proteasome alpha-subunit PSMA7 in hepatitis C virus internal ribosome entry site-mediated translation.

Ribozymes are small catalytic RNA molecules that can be engineered to enzymatically cleave RNA transcripts in a sequence-specific fashion and thereby inhibit expression and function of the corresponding gene product. With their simple structures and site-specific cleavage activity, they have been exploited as potential therapeutic agents in a variety of human disorders, including hepatitis C virus (HCV) infection. We have designed a hairpin ribozyme (Rz3'X) targeting the HCV minus-strand replication intermediate at position 40 within the 3'X tail. Surprisingly, Rz3'X was found to induce ganciclovir (GCV)-resistant colonies in a bicistronic cellular reporter system with HCV internal ribosome entry site (IRES)-dependent translation of herpes simplex virus thymidine kinase (TK). Rz3'X-transduced GCV-resistant HeLa reporter cells showed substantially reduced IRES-mediated HCV core protein translation compared with control vector-transduced cells. Since these reporter systems do not contain the HCV 3'X tail sequences, the results indicate that Rz3'X probably exerted an inhibitory effect on HCV IRES activity fortuitously through another gene target. A novel technique of ribozyme cleavage-based target gene identification (cleavage-specific amplification of cDNA ends) (M. Krüger, C. Beger, P. J. Welch, J. R. Barber, and F. Wong-Staal, Nucleic Acids Res. 29:e94, 2001) revealed that human 20S proteasome alpha-subunit PSMA7 mRNA was a target RNA recognized and cleaved by Rz3'X. We then showed that additional ribozymes directed against PSMA7 RNA inhibited HCV IRES activity in two assay systems: GCV resistance in the HeLa IRES TK reporter cell system and a transient transfection assay performed with a bicistronic Renilla-HCV IRES-firefly luciferase reporter in Huh7 cells. In contrast, ribozymes were inactive against IRES of encephalomyocarditis virus and human rhinovirus. Additionally, proteasome inhibitor MG132 exerted a dose-dependent inhibitory effect on HCV IRES-mediated translation but not on cap-dependent translation. These data suggest a principal role for PSMA7 in regulating HCV IRES activity, a function essential for HCV replication.

C-SPACE (cleavage-specific amplification of cDNA ends): a novel method of ribozyme-mediated gene identification.

A hairpin ribozyme, RzCR2A, directed against position 323 of the hepatitis C virus 5'-untranslated region (HCV 5'-UTR) was used to establish and validate a novel method for the detection of cellular target molecules for hairpin ribozymes, termed C-SPACE (cleavage-specific amplification of cDNA ends). For C-SPACE, HeLa mRNA containing the transcript of interest was subjected to in vitro cleavage by RzCR2A in parallel with a control ribozyme, followed by reverse transcription using a modified SMART cDNA amplification method and cleavage-specific PCR analysis. C-SPACE allowed identification of the RzCR2A target transcript from a mixture containing the entire cellular mRNA while only requiring knowledge of the ribozyme binding sequence for amplification. In a similar approach, C-SPACE was used successfully to identify human 20S proteasome alpha-subunit PSMA7 mRNA as the cellular target RNA of Rz3'X, a ribozyme originally designed to cleave the negative strand HCV 3'-UTR. Rz3'X was found to substantially inhibit HCV internal ribosome entry site (IRES) activity and PSMA7 was subsequently confirmed to be involved in HCV IRES-mediated translation. Thereby, C-SPACE was validated as a powerful tool to rapidly identify unknown target RNAs recognized and cleaved by hairpin ribozymes.

Analyzing process variation in chart review using a networked spreadsheet application in the Walter Reed Army Medical Center Nephrology Clinic.

The role of reviewer variation in interpreting outcomes of outpatient clinic chart reviews has been poorly studied. The present study used results collected from a network-based spreadsheet application (Microsoft Excel), which is widely available throughout the Army Medical Department, for chart reviews. Data were collected from January 1998 to August 2000, and 2,308 charts of 1,127 patients were reviewed. Results showed a significant improvement in documentation of contact with the referring provider from 1998 to 2000 (55.9% in 1998, 81.6% in 1999, and 80.6% in 2000; p < 0.01 by chi 2 for both). The percentage of charts for new consultations with inadequately controlled blood pressure managed appropriately improved from 73.7% in 1999 to 89.2% in 2000 (p < 0.01 by chi 2). These results persisted in logistic regression analysis controlling for different reviewers. In conclusion, widely available office automation tools allow the systematic analysis of chart review data with the potential to improve practice patterns.

Hospitalizations for fractures after renal transplantation in the United States.

PURPOSE: To investigate the incidence, risk factors, and associated mortality of fractures in renal transplant recipients. METHODS: Retrospective registry study of 33,479 patients in the United States Renal Data System (USRDS) who received kidney transplants between 1 July 1994 and 30 June 1997. Associations with hospitalizations for a primary discharge diagnosis of fractures (all causes) were assessed. RESULTS: Renal transplant recipients had an adjusted incidence ratio for fractures of 4.59 (95% confidence interval 3.29 to 6.31). In multivariate analysis, recipients with prevalent fractures, as well as recipients who were Caucasian, women, in the lower quartiles of recipient weight (<95.9 kg), had end stage renal disease caused by diabetes, and had prolonged pretransplant dialysis were at increased risk for hospitalization because of fractures after transplantation. Recipients hospitalized for hip fractures had decreased all-cause survival (hazard ratio for mortality 1.60, 95% CI 1.13 to 2.26) in Cox Regression analysis. CONCLUSIONS: In the early post-transplant course (<3 years), renal transplant recipients had a greater incidence of fractures than the general population, which were associated with decreased patient survival. Preventive efforts should focus on recipients with the risk factors identified in this analysis, most of which can be easily obtained through history and physical examination.

Effects of angiotensin-converting enzyme inhibitor and steroid therapy on proteinuria in FSGS: a retrospective study in a single clinic.

We retrospectively evaluated the response to steroids (S) +/- angioten-sin-converting enzyme inhibitors (ACEI) vs. ACEI in nephrotic patients with FSGS seen in our clinic from 1992 - 1999. Of 48 patients with biopsy-proven FSGS, 30 had pre-therapy and follow-up evaluations of proteinuria. Of these, 22 were nephrotic (> or = 3 g protein/24 h). Twelve/22 were treated with S and 10/22 with ACEI +/- HMG-CoA reductase inhibitor (statin) alone. 92% of S patients received ACEI during follow-up, 83% concurrently with steroid treatment. The two cohorts (S vs. ACEI) were not different in age (34 +/- 12 vs. 33 +/- 12), sex (75% vs. 78% male), or ethnicity (83% vs. 83% African American). Mean follow-up time was 16 (range 4 - 61 months) vs. 23 months (range 6 - 56 months). Mean S dose was 70 mg qd (range 60 - 100 mg), with mean treatment duration of 4 months. Nephrotic patients were compared with regard to degree of proteinuria at follow-up. There were no complete remissions (proteinuria < or = 200 mg/24 h) in either group. There was no difference in partial remissions (> 200 mg to < 3 g proteinuria/24 h) between the two groups - 5/12 vs. 6/10 (p = 0.434). There was no difference in the proportion of patients progressing to ESRD. Although proteinuria decreased significantly with time in both groups, there was no significant treatment effect. There was no significant time or treatment effect on serum creatinine. Mean arterial pressure and serum cholesterol were not significantly different between the groups. Thus, treatment with S +/- ACEI is no more effective in reducing proteinuria in FSGS than treatment with ACEI alone.