bluuebunny/crossref_metadata_2025 huggingface dataset:
Closed-Loop Control Performance of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System in a Feasibility Study
Authors: Finan Daniel A. , McCann Thomas W. , Mackowiak Linda , Dassau Eyal , Patek Stephen D. , Kovatchev Boris P. , Doyle Francis J. , Zisser Howard , Anhalt Henry , Venugopalan Ramakrishna
Published: February 2014

Background:

This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System—an automated insulin delivery device—in participants with type 1 diabetes.

Methods:

Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals.

Results:

When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants’ preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis.

Conclusions:

Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.
Average Daily Risk Range (ADRR) in Young Children With Type 1 Diabetes
Authors: Monaghan Maureen , Younge Tamiko B. , McCarter Robert , Cogen Fran R. , Streisand Randi
Published: February 2014

Objective:

The objective was to examine the utility of the average daily risk range (ADRR) in young children with type 1 diabetes.

Methods:

Self-monitored blood glucose (BG) data and A1c values were collected from 134 children (ages 2-6). Other measures of BG variability and diabetes care were calculated using self-monitored BG data. ADRR, A1c, and other glycemic indices were compared to assess their distinctiveness and utility as measures of BG variability and glycemic control.

Results:

Of young children’s ADRR values, 72% were in the “high-risk” range using adult guidelines. ADRR and A1c were highly correlated with indicators of hyperglycemia but only weakly correlated with measures of hypoglycemia. ADRR was moderately correlated with minimum BG value in the past 30 days but not percentage of BG values below 70 mg/dL. A1c was not correlated with either measure of hypoglycemia.

Conclusions:

ADRR values confirm the high degree of BG variability present in young children with type 1 diabetes, particularly as compared with adults. New ADRR risk guidelines are needed for pediatric patients. ADRR and A1c are adequate indicators of hyperglycemia in young children. However, both ADRR and A1c failed to effectively capture hypoglycemia risk in this sample, and neither ADRR nor A1c can take the place of review of raw BG data to evaluate BG variability in young children.
Evaluation of an Algorithm for Retrospective Hypoglycemia Detection Using Professional Continuous Glucose Monitoring Data
Authors: Jensen Morten Hasselstrøm , Mahmoudi Zeinab , Christensen Toke Folke , Tarnow Lise , Seto Edmund , Johansen Mette Dencker , Hejlesen Ole Kristian
Published: February 2014

Background:

People with type 1 diabetes (T1D) are unable to produce insulin and thus rely on exogenous supply to lower their blood glucose. Studies have shown that intensive insulin therapy reduces the risk of late-diabetic complications by lowering average blood glucose. However, the therapy leads to increased incidence of hypoglycemia. Although inaccurate, professional continuous glucose monitoring (PCGM) can be used to identify hypoglycemic events, which can be useful for adjusting glucose-regulating factors. New pattern classification approaches based on identifying hypoglycemic events through retrospective analysis of PCGM data have shown promising results. The aim of this study was to evaluate a new pattern classification approach by comparing the performance with a newly developed PCGM calibration algorithm.

Methods:

Ten male subjects with T1D were recruited and monitored with PCGM and self-monitoring blood glucose during insulin-induced hypoglycemia. A total of 19 hypoglycemic events occurred during the sessions.

Results:

The pattern classification algorithm detected 19/19 hypoglycemic events with 1 false positive, while the PCGM with the new calibration algorithm detected 17/19 events with 2 false positives.

Conclusions:

We can conclude that even after the introduction of new calibration algorithms, the pattern classification approach is still a valuable addition for improving retrospective hypoglycemia detection using PCGM.
Feasibility of Factory Calibration for Subcutaneous Glucose Sensors in Subjects With Diabetes
Authors: Hoss Udo , Budiman Erwin S. , Liu Hanqing , Christiansen Mark P.
Published: February 2014

Background:

Continuous glucose monitoring using subcutaneously inserted sensors currently requires blood glucose tests for sensor calibration. Alternatively, sensors precalibrated during the manufacturing process may eliminate the need for fingerstick calibrations. In this study we evaluated the feasibility of sensor factory calibration in subjects with diabetes.

Methods:

A total of 33 subjects with diabetes were asked to wear 4 sensors in parallel, 2 on the arm and 2 on the abdomen. Sensors from a lot with low in vitro sensitivity coefficient of variation were used in the study. Based on frequent capillary blood glucose measurements, the average glucose sensitivity of each sensor was determined over a 5-day wear time. The in vivo sensitivities were analyzed for inter- and intrasubject variation. Mean absolute relative difference (MARD) calculation and consensus error grid analysis (EGA) were performed using a single calibration factor for all sensors, to simulate factory calibration and compared against conventional finger-stick calibration.

Results:

The sensitivity coefficient of variation between sensors increased from 2.9% in vitro to 6.0% in vivo. No difference in sensor response between subjects ( P = .069) as well as between insertion sites (arm and abdomen) was detected ( P = .104). Applying one calibration factor to all sensors in the study resulted in an MARD of 13.4%, and 83.5% of the values fell in consensus EGA zone A. Multiple fingerstick calibration resulted in an MARD of 12.7% and 84.1% in zone A.

Conclusions:

Feasibility of factory calibration was demonstrated in subjects with diabetes using sensors based on “wired enzyme” technology, resulting in accuracy metrics similar to sensors calibrated with capillary blood glucose.
Validity and Reliability of a Glucometer Against Industry Reference Standards
Authors: Salacinski Amanda J. , Alford Micah , Drevets Kathryn , Hart Sarah , Hunt Brian E.
Published: February 2014

As an appealing alternative to reference glucose analyzers, portable glucometers are recommended for self-monitoring at home, in the field, and in research settings.

Objective:

The purpose was to characterize the accuracy and precision, and bias of glucometers in biomedical research.

Research Design and Methods:

Fifteen young (20-36 years; mean = 24.5), moderately to highly active men (n = 10) and women (n = 5), defined by exercising 2 to 3 times a week for the past 6 months, were given an oral glucose tolerance test (OGTT) after an overnight fast. Participants ingested 50, 75, or 150 grams of glucose over a 5-minute period. The glucometer was compared to a reference instrument.

Results:

The glucometer had 39% of values within 15% of measurements made using the reference instrument ranging from 45.05 to 169.37 mg/dl. There was both a proportional (−0.45 to −0.39) and small fixed (5.06 and 0.90 mg/dl) bias.

Conclusions:

Results of the present study suggest that the glucometer provided poor validity and reliability results compared to the results provided by the reference laboratory analyzer. The portable glucometers should be used for patient management, but not for diagnosis, treatment, or research purposes.
Confusion Regarding Duration of Insulin Action
Authors: Walsh John , Roberts Ruth , Heinemann Lutz
Published: February 2014

People with diabetes on insulin pumps often use a bolus calculator (BC) to obtain insulin dose recommendations. After the first bolus of the day, residual insulin activity, called bolus insulin on board (BOB), must be correctly accounted for to reduce the size of subsequent boluses and minimize the insulin stacking that would otherwise occur. Critical to achieving this calculation is having an appropriate duration of insulin action (DIA) setting in the BC. Unfortunately, the widespread use of inappropriately short DIAs may be causing unrecognized “stacking” of insulin that leads to unexplained hypoglycemic events. Currently, there is no widely accepted definition or value of the DIA for use in a BC. Various shortcomings regarding the selection of an appropriate DIA setting have led to considerable confusion among clinicians and insulin pump users about this important concept. Traditional pharmacological studies used to determine the pharmacodynamic (PD) properties of rapid-acting insulins create a misleading impression that insulin action times (IATs) in daily life vary from 3 to 5 hours and cause IATs to appear more variable than they actually are. These IAT time ranges are not appropriate for use as the DIA time value required to obtain an accurate bolus recommendation from a BC. We highlight the problems that arise when an inappropriately short DIA leads to excessive bolus recommendations, provide a research protocol to accurately measure DIA, and suggest appropriate DIA time recommendations for use in current clinical practice.
Short-Term Thermal-Humidity Shock Affects Point-of-Care Glucose Testing
Authors: Lam Mandy , Louie Richard F. , Curtis Corbin M. , Ferguson William J. , Vy John H. , Truong Anh-Thu , Sumner Stephanie L. , Kost Gerald J.
Published: February 2014

Objective:

The objective was to assess the effects of short-term (≤1 hour) static high temperature and humidity stresses on the performance of point-of-care (POC) glucose test strips and meters.

Background:

Glucose meters are used by medical responders and patients in a variety of settings including hospitals, clinics, homes, and the field. Reagent test strips and instruments are potentially exposed to austere environmental conditions.

Methods:

Glucose test strips and meters were exposed to a mean relative humidity of 83.0% (SD = 8.0%) and temperature of 42°C (107.6°F, SD = 3.2) in a Tenney BTRC environmental chamber. Stressed and unstressed glucose reagent strips and meters were tested with spiked blood samples (n = 40 measurements per time point for each of 4 trials) after 15, 30, 45, and 60 minutes of exposure. Wilcoxon’s signed rank test was applied to compare measurements test strip and meter measurements to isolate and characterize the magnitude of meter versus test strip effects individually.

Results:

Stressed POC meters and test strips produced elevated glucose results, with stressed meter bias as high as 20 mg/dL (17.7% error), and stressed test strip bias as high as 13 mg/dL (12.2% error). The aggregate stress effect on meter and test strips yielded a positive bias as high as 33 mg/dL (30.1% error) after 15 minutes of exposure.

Conclusions:

Short-term exposure (15 minutes) to high temperature and humidity can significantly affect the performance of POC glucose test strips and meters, with measurement biases that potentially affect clinical decision making and patient safety.
Accuracy of a Novel Noninvasive Multisensor Technology to Estimate Glucose in Diabetic Subjects During Dynamic Conditions
Authors: Sobel Sandra I. , Chomentowski Peter J. , Vyas Nisarg , Andre David , Toledo Frederico G. S.
Published: February 2014

Objective:

The purpose of this study was to determine whether an approach of multisensor technology with integrated data analysis in an armband system (SenseWear® Pro Armband, SWA) can provide estimates of plasma glucose concentration in diabetes.

Research Design and Methods:

In all, 41 subjects with diabetes participated. On day 1 subjects underwent an oral glucose tolerance test (OGTT) and on day 2 a 60-minute treadmill test (TT). SWA plasma glucose estimates were compared against reference peripheral venous glucose concentrations. A continuous glucose monitoring device (CGM) was also placed on each subject to serve as a reference for clinical comparison. Pearson coefficient, Clarke error grid (CEG), and mean absolute relative difference (MARD) analyses were used to compare the performance of plasma glucose estimation.

Results:

There were significant correlations between plasma glucose concentrations estimated by the SWA and the reference plasma glucose concentration during the OGTT ( r = .65, P < .05) and the TT ( r = .91, P < .05). CEG analysis revealed that during the OGTT, 93% of plasma glucose concentration readings were in the clinically acceptable zone A+B for the SWA and 95% for the CGM. During the TT, the SWA had 96% of readings in zone A+B, compared to 97% for the CGM. During OGTTs, MARDs for the SWA and CGM were 26% and 18%, respectively. During TTs, MARDs were 16% and 12%, respectively.

Conclusions:

Plasma glucose concentration estimation by the SWA’s noninvasive multisensor approach appears to be feasible and its performance in estimating glucose approaches that of a CGM. The success of this pilot study suggests that multisensor technology holds promising potential for the development of a wearable, noninvasive, painless glucose monitor.
The Impact of Accelerometer and Heart Rate Data on Hypoglycemia Mitigation in Type 1 Diabetes
Authors: Stenerson Matthew , Cameron Fraser , Wilson Darrell M. , Harris Breanne , Payne Shelby , Bequette B. Wayne , Buckingham Bruce A.
Published: February 2014

Background:

Aerobic exercise can lower blood glucose levels and alter insulin sensitivity both during and several hours after exercise, creating challenges for a closed-loop artificial pancreas. Predictive low glucose suspend (PLGS) algorithms are a first step toward an artificial pancreas, but few of these have been successfully applied to exercise. This study incorporates physical activity measurements from a combined accelerometer/heart rate monitor (HRM) to improve the performance of an existing PLGS algorithm at mitigating exercise-associated hypoglycemia in participants with type 1 diabetes.

Methods:

In all, 22 subjects with type 1 diabetes on insulin pump therapy were provided a combined accelerometer/HRM and (if not already using one) a continuous glucose monitor (CGM), then instructed to go about their everyday lives while wearing the devices. After the monitoring period, each subject’s insulin pump, CGM, and accelerometer/HRM were downloaded and the data were used to augment an existing PLGS algorithm to incorporate activity. Using a computer simulator, the accelerometer-augmented algorithm was compared to the HRM-augmented algorithm to determine which was most effective at mitigating hypoglycemia.

Results:

Mean length of monitoring was 4.9 days. Across all subjects, 11 061 CGM readings were recorded during the monitoring period. In the simulator analysis, the PLGS algorithm reduced hypoglycemia by 62%, compared to 71% and 74% reductions for the HRM-augmented and accelerometer-augmented algorithms, respectively; combined accelerometer and HRM augmentation provided a 76% reduction.

Conclusions:

In a simulated setting, the accelerometer-augmented pump suspension algorithm decreases the incidence of exercise-related hypoglycemia by a meaningful amount compared to the PLGS algorithm alone. Results also failed to justify the additional user burden of a HRM.
Drug Development and Potential Regulatory Paths for Insulin Biosimilars
Authors: Minocha Mukul , Gobburu Jogarao
Published: February 2014

Under the Biologics Price Competition and Innovation Act (BPCI Act), a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product. Biosimilar insulins have the potential to reduce ever growing costs associated with insulin treatment by allowing competition. In this article, we describe the current drug development and regulatory paths for biosimilar insulins. Most likely basis of market approval for biosimilar insulins by the US Food and Drug Administration (FDA) and guidance for developing insulin biosimilars by European Medicines Agency (EMA) are discussed in detail. Currently, no product specific biosimilar FDA guidance for insulin biosimilarity assessment exists. We propose efficient and cost-effective drug development and potential regulatory paths based on scientific justification. In addition, novel trial designs for demonstrating interchangeability between the biosimilar and the reference insulin products are presented.
Biosimilar Insulins
Authors: Heinemann Lutz , Hompesch Marcus
Published: February 2014

Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States. Differences in the manufacturing process (none of the insulin manufacturing procedures are 100% identical) can lead to insulins that to some extent may differ from the originator insulin. The key questions are if subtle differences in the structure of the insulins, purity, and so on are clinically relevant and may result in different biological effects. The aim of this article is to introduce and discuss basic aspects that may be of relevance with regard to BI.
Extracellular Matrix Scaffold Technology for Bioartificial Pancreas Engineering
Authors: Salvatori Marcus , Katari Ravi , Patel Timil , Peloso Andrea , Mugweru Jon , Owusu Kofi , Orlando Giuseppe
Published: February 2014

Emergent technologies in regenerative medicine may soon overcome the limitations of conventional diabetes therapies. Collaborative efforts across the subfields of stem cell technology, islet encapsulation, and biomaterial carriers seek to produce a bioengineered pancreas capable of restoring endocrine function in patients with insulin-dependent diabetes. These technologies rely on a robust understanding of the extracellular matrix (ECM), the supportive 3-dimensional network of proteins necessary for cellular attachment, proliferation, and differentiation. Although these functions can be partially approximated by biosynthetic carriers, novel decellularization protocols have allowed researchers to discover the advantages afforded by the native pancreatic ECM. The native ECM has proven to be an optimal platform for recellularization and whole-organ pancreas bioengineering, an exciting new field with the potential to resolve the dire shortage of transplantable organs. This review seeks to contextualize recent findings, discuss current research goals, and identify future challenges of regenerative medicine as it applies to diabetes management.
Matchmaking Promotes Happiness
Authors: Anik Lalin , Norton Michael I.
Published: February 2014

Four studies document and explore the psychology underlying people’s proclivity to connect people to each other—to play “matchmaker.” First, Study 1 shows that chronic matchmaking is associated with higher well-being. Studies 2 and 3 show that matching others on how well they will get along increases happiness and is more intrinsically rewarding than other tasks (e.g., deciding which people would not get along). Study 4 investigates a moderator of the rewarding nature of matchmaking: the type of connection. We show that bridging ties are relatively more attractive than bonding ties: The more unlikely the match, the more rewarding it is. Taken together, these studies provide correlational and causal evidence for the role of matchmaking in promoting happiness.
Safety of dipeptidyl peptidase 4 inhibitors: a perspective review
Authors: Karagiannis Thomas , Boura Panagiota , Tsapas Apostolos
Published: February 2014

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a relatively new class of oral antihyperglycemic agent that enhance insulin secretion by reducing degradation of endogenous glucagon-like peptide 1. Currently, sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved by the US Food and Drug Administration or the European Medicines Agency for use in patients with type 2 diabetes. Their glycemic efficacy has been well documented; however, data regarding their long-term safety are as yet inconclusive. While preclinical studies have indicated a potential cardioprotective effect of DPP-4 inhibitors, current clinical data from cardiovascular safety trials suggest a neutral effect on cardiovascular outcomes. Moreover, postmarketing experience has given rise to concerns about specific adverse events, including pancreatitis and hypersensitivity reactions. This review summarizes available evidence regarding safety of DPP-4 inhibitors. Overall, DPP-4 inhibitors appear to be a safe option for patients with type 2 diabetes. However, close pharmacovigilance is necessary to address the uncertainty regarding pancreas-related adverse events, while their potential impact on cardiovascular outcomes will be further elucidated after completion of more long-term studies.
Aldosterone synthase inhibitors in hypertension: current status and future possibilities
Authors: Hargovan Milan , Ferro Albert
Published: February 2014

The renin-angiotensin aldosterone system is a critical mechanism for controlling blood pressure, and exerts most of its physiological effects through the action of angiotensin II. In addition to increasing blood pressure by increasing vascular resistance, angiotensin II also stimulates aldosterone secretion from the adrenal gland. Aldosterone acts to cause an increase in sodium and water reabsorption, thus elevating blood pressure. Although treatment with angiotensin converting enzyme inhibitors initially lowers circulating aldosterone, with chronic treatment aldosterone levels increase back to baseline, a phenomenon termed aldosterone escape; aldosterone blockade may therefore give added value in the treatment of hypertension. The first mineralocorticoid receptor antagonist developed was spironolactone, but its use has been severely hampered by adverse (notably oestrogenic) effects. The more recently developed mineralocorticoid receptor antagonist eplerenone exhibits a better adverse effect profile, although it is not devoid of effects similar to spironolactone. In addition, aldosterone activates non-genomic receptors that are not inhibited by either eplerenone or spironolactone. It is believed that deleterious organ remodelling is mediated by aldosterone via such non-genomic pathways. A new class of drugs, the aldosterone synthase inhibitors, is currently under development. These may offer a novel therapeutic approach for both lowering blood pressure and preventing the non-genomic effects of aldosterone. Here, we will review the cardiovascular effects of aldosterone and review the drugs available that target this hormone, with a particular focus on the aldosterone synthase inhibitors.
Ecstasy, legal highs and designer drug use: A Canadian perspective
Authors: Hudson Alan L , Lalies Maggie D , Baker Glen B , Wells Kristopher , Aitchison Katherine J
Published: February 2014

Recreational drug use in Canada is not uncommon, but as with most societies, illegal drug use carries harsh penalties resulting in a criminal record when an individual is successfully prosecuted. Popular drugs of use in Canada include ecstasy, cannabis (including some synthetic cannabinoids sold as ‘Spice’ and ‘Incense’) and several emerging psychoactive ‘legal highs’. Surprisingly, Canada is a major manufacturer and exporter of the popular club drug ecstasy, with criminal gangs organising the synthesis and distribution of this club drug worldwide. Over the last 18 months, there has been much interest in and use of alternatives to ecstasy due to contamination of ecstasy during synthesis. One particular contaminant, paramethoxymethamphetamine (PMMA), has resulted in several deaths. Other alternatives include piperazines and mephedrone analogues. With regard to cannabis, some is home grown within people’s properties, but there is also large-scale cultivation in British Columbia where the climate is more temperate. With the introduction of corporate drug screening, there is increasing use of synthetic cannabinoids to avoid detection of marijuana use. This article discusses the problems and trends of synthetic drug use in Canada and reflects on the limited education available to youth in this regard.
Youth and Ethnic Movements and Their Impacts on Party Politics in ECOWAS Member States
Authors: Olaiya Taiwo A.
Published: February 2014

Although they historically played a pivotal role in the fight against colonial rule—as they have in recent attempts to entrench multiparty democratic processes—the role of youth in political parties in West Africa has received less than commensurate attention in studies on democratization. Unlike in advanced democracies where parties are key agents of political socialization and leadership, parties in West Africa are built on ethno-religious foundations. A peculiar character of highly marginalized youth thus becomes inevitable, both in politics and decision-making processes of the state. To assert themselves, the youth have also become agents of destabilization of the democracy they partook to build. Apart from their involvement in political violence, youths are now available as unconscientious “foot soldiers” of ethnic militias and terrorist groups that are constituting increased social problems in West Africa. In this article, we examine how parties and youth have interacted to define the emergence and character of threat to the nascent democracies in contemporary West Africa. The article interrogates how the notions of “youth” and “political participation” have continued to play out in different West African countries within the context of the opportunities and challenges of Africa’s youth bulge on the democratization process. The article observes that the marginalization of West African youths has been part and parcel of history only that their situation has further raised the stake as agent of social disorder in the absence of positive engagement in the recent times.
AIDS-Related Lymphoma
Authors: Hallit Rabih Riad , Afridi Muhammad , Sison Raymund , Szabela Maria Elaine Y. , Bajaj Nikki , Alchaa Roula , Hallit Souheil , Awkar Nelly , Boghossian Jack , Slim Jihad
Published: February 2014

Patients with HIV are at increased risk of malignancy, particularly lymphoma, which is the most common malignancy leading to death. With the advent of highly active antiretroviral therapy (HAART), patients live longer but have a longer duration of antigenic stimulation, increasing the prevalence of AIDS-related lymphoma (ARL) in the population living with HIV. Highly active antiretroviral therapy plays a direct role in preserving the immune system, helping to decrease the incidence of ARL. We present a case of a female patient with HIV (CD4 count of 576 cells/mm3) diagnosed with a stage III-B non-Hodgkin lymphoma in 2009 while off HAART. She was subsequently started on HAART, leading to full resolution of her lymphoma without any chemotherapeutic intervention. She was last seen in the clinic in December 2013 without any evidence of recurrence of her lymphoma. To our knowledge, this is the first case report of a stage III-B non-Hodgkin lymphoma in an HIV-infected patient, which resolved with only HAART.
A genomics approach to identify susceptibilities of breast cancer cells to “fever-range” hyperthermia
Authors: Amaya Clarissa , Kurisetty Vittal , Stiles Jessica , Nyakeriga Alice M , Arumugam Arunkumar , Lakshmanaswamy Rajkumar , Botez Cristian E , Mitchell Dianne C , Bryan Brad A
Published: February 2014

Background

Preclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to “fever range” hyperthermia (increasing the intratumoral temperature to 42-45°C) than normal cells, although it is unknown why cancer cells exhibit this distinctive susceptibility.

Methods

To address this issue, mammary epithelial cells and three malignant breast cancer lines were subjected to hyperthermic shock and microarray, bioinformatics, and network analysis of the global transcription changes was subsequently performed.

Results

Bioinformatics analysis differentiated the gene expression patterns that distinguish the heat shock response of normal cells from malignant breast cancer cells, revealing that the gene expression profiles of mammary epithelial cells are completely distinct from malignant breast cancer lines following this treatment. Using gene network analysis, we identified altered expression of transcripts involved in mitotic regulators, histones, and non-protein coding RNAs as the significant processes that differed between the hyperthermic response of mammary epithelial cells and breast cancer cells. We confirmed our data via qPCR and flow cytometric analysis to demonstrate that hyperthermia specifically disrupts the expression of key mitotic regulators and G2/M phase progression in the breast cancer cells.

Conclusion

These data have identified molecular mechanisms by which breast cancer lines may exhibit enhanced susceptibility to hyperthermic shock.
Estimating recruitment rates for routine use of patient reported outcome measures and the impact on provider comparisons
Authors: Hutchings Andrew , Neuburger Jenny , van der Meulen Jan , Black Nick
Published: February 2014

Background

The routine use of patient reported outcome measures (PROMs) aims to compare providers as regards the clinical need of their patients and their outcome. Simple methods of estimating recruitment rates based on aggregated data may be inaccurate. Our objectives were to: use patient-level linked data to evaluate these estimates; produce revised estimates of national and providers’ recruitment rates; and explore whether or not recruitment bias exists.

Methods

Case study based on patients who were eligible to participate in the English National PROMs Programme for elective surgery (hip and knee replacement, groin hernia repair, varicose vein surgery) using data from pre-operative questionnaires and Hospital Episode Statistics. Data were linked to determine: the eligibility for including operations; eligibility of date of surgery; duplicate questionnaires; cancelled operations; correct assignment to provider. Influence of patient characteristics on recruitment rates were investigated.

Results

National recruitment rates based on aggregated data over-estimated the true rate because of the inclusion of ineligible operations (from 1.9% - 7.0% depending on operation) and operations being cancelled (1.9% - 3.6%). Estimates of national recruitment rates using inclusion criteria based on patient-level linked data were lower than those based on simple methods (eg hip replacement was 73% rather than 78%).

Estimates of provider’s recruitment rates based on aggregated data were also adversely affected by attributing patients to the wrong provider (2.4% - 4.9%). Use of linked data eliminated all estimates of over 100% recruitment, though providers still showed a wide range of rates.

While the principal determinant of recruitment rates was the provider, some patients’ socio-demographic characteristics had an influence on non-recruitment: non-white (Adjusted Odds Ratio 1.25-1.67, depending on operation); most deprived socio-economic group (OR 1.11-1.23); aged over 75 years (OR 1.28-1.79). However, there was no statistically significant association between providers’ recruitment rates and patients’ pre-operative clinical need.

Conclusions

Accurate recruitment rates require the use of linked data to establish consistent inclusion criteria for numerators and denominators. Non-recruitment will bias comparisons of providers’ pre-operative case-mix and may bias comparisons of outcomes if unmeasured confounders are not evenly distributed between providers. It is important, therefore, to strive for high recruitment rates.
Best proximity points of generalized almost ψ-Geraghty contractive non-self-mappings
Authors: Aydi Hassen , Karapınar Erdal , Erhan İnci M , Salimi Peyman
Published: February 2014

In this paper, we introduce the new notion of almost ψ-Geraghty contractive mappings and investigate the existence of a best proximity point for such mappings in complete metric spaces via the weak P-property. We provide an example to validate our best proximity point theorem. The obtained results extend, generalize, and complement some known fixed and best proximity point results from the literature.

MSC:47H10, 54H25, 46J10, 46J15.
Risk factors for cervical HPV infection and genotypes distribution in HIV-infected South Brazilian women
Authors: Rocha-Brischiliari Sheila C , Gimenes Fabrícia , de Abreu André L P , Irie Mary M T , Souza Raquel P , Santana Rosangela G , Gravena Angela A F , de B Carvalho Maria D , Consolaro Marcia E L , Pelloso Sandra M
Published: February 2014

Background

Human Papillomavirus (HPV) infection is particularly burdensome for women infected with human immunodeficiency virus (HIV), which increases their risk of developing cervical lesions and cancer (CC). We conducted a molecular study of the distribution of cervical HPV genotypes and the risk factors for this infection in HIV-infected Brazilian women.

Findings

Cervical and endocervical samples for Papanicolaou screening and HPV detection were collected from 178 HIV-infected women using highly active antiretroviral therapy (HAART) of Maringá city/Brazil. Risk factors were assessed using a standardized questionnaire, and the data regarding to HIV infection from medical records. HPV was detected by polymerase chain reaction (PCR), and genotyping using PCR-restriction fragment length polymorphism analysis. HIV infection was well controlled, but women with a current CD4+ T lymphocyte count between 200–350 cells/mm3 (37.6%) had a two-fold greater risk of HPV infection than those with > 350 cells/mm3 (26.4%). HPV was associated with parity ≥3, hormonal contraceptive use and current smoker. HPV infection occurred with high frequency (46.6%) but a low frequency of cervical abnormalities was detected (7.30%), mainly low-grade squamous intraephitelial cervical lesions (LSIL) (84.6%). A high frequency of multiple HPV infections was detected (23.0%), and the most frequent HPV genotype was HPV-72 (6.7%), followed by −16, -31 and -51 (6.14% each).

Conclusions

We showed that HAART use does not protect HIV-infected women from HPV, but appear to exert some protection against cervical lesions development. This study provides other important information about risk factors and cervical HPV in HIV-infected women, which can contribute to planning protocols.
A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population
Authors: Yang Binyao , Mo Zengnan , Wu Chen , Yang Handong , Yang Xiaobo , He Yunfeng , Gui Lixuan , Zhou Li , Guo Huan , Zhang Xiaomin , Yuan Jing , Dai Xiayun , Li Jun , Qiu Gaokun , Huang Suli , Deng Qifei , Feng Yingying , Guan Lei , Hu Die , Zhang Xiao , Wang Tian , Zhu Jiang , Min Xinwen , Lang Mingjian , Li Dongfeng , Hu Frank B , Lin Dongxin , Wu Tangchun , He Meian
Published: February 2014

Background

Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited.

Methods

A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort.

Results

Briefly, we identified two previously reported UA loci ofSLC2A9(rs11722228, combinedP= 8.98 × 10-31) andABCG2(rs2231142, combinedP= 3.34 × 10-42). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (Pfor interaction = 4.0 × 10-2and 2.0 × 10-2, respectively). The minor allele (T) for rs11722228 inSLC2A9has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 inABCG2had stronger effects on serum UA levels in males than that in females.

Conclusions

Two genetic loci (SLC2A9andABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence thatSLC2A9andABCG2function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender.
Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome
Authors: Schonherz Yael , Davidov Maayan , Knafo Ariel , Zilkha Hadas , Shoval Gal , Zalsman Gil , Frisch Amos , Weizman Abraham , Gothelf Doron
Published: February 2014

Background

22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS.

Methods

The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment.

Results

Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS.

Conclusions

Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.
Stem cells in a three-dimensional scaffold environment
Authors: Meng Xuan , Leslie Patrick , Zhang Yanping , Dong Jiahong
Published: February 2014

Stem cells have emerged as important players in the generation and maintenance of many tissues. However, the accurate in vitro simulation of the native stem cell niche remains difficult due at least in part to the lack of a comprehensive definition of the critical factors of the stem cell niche based on in vivo models. Three-dimensional (3D) cell culture systems have allowed the development of useful models for investigating stem cell physiology particularly with respect to their ability to sense and generate mechanical force in response to their surrounding environment. We review the use of 3D culture systems for stem cell culture and discuss the relationship between stem cells and 3D growth matrices including the roles of the extracellular matrix, scaffolds, soluble factors, cell-cell interactions and shear stress effects within this environment. We also discuss the potential for novel methods that mimic the native stem cell niche in vitro as well as the current associated challenges.
BayMeth: improved DNA methylation quantification for affinity capture sequencing data using a flexible Bayesian approach
Authors: Riebler Andrea , Menigatti Mirco , Song Jenny Z , Statham Aaron L , Stirzaker Clare , Mahmud Nadiya , Mein Charles A , Clark Susan J , Robinson Mark D
Published: February 2014

Affinity capture of DNA methylation combined with high-throughput sequencing strikes a good balance between the high cost of whole genome bisulfite sequencing and the low coverage of methylation arrays. We present BayMeth, an empirical Bayes approach that uses a fully methylated control sample to transform observed read counts into regional methylation levels. In our model, inefficient capture can readily be distinguished from low methylation levels. BayMeth improves on existing methods, allows explicit modeling of copy number variation, and offers computationally efficient analytical mean and variance estimators. BayMeth is available in the Repitools Bioconductor package.
The use of barostratigraphy for identifying and categorizing pressure compartmentalization
Authors: Hall Kevin B. , Williams Kenneth E. , Gevirtz Joel L. , Croy Matt J.
Published: February 2014

Permeability and geologic time are the primary controlling factors for the generation and dissipation of overpressures. With respect to increasing depth, pressure gradients within any layer may increase, decrease, or remain essentially constant. Pore pressure gradients also vary laterally as a response to changes in permeability, which do not always correspond to seismic or correlation surfaces. In some cases, pressure may not respond at all to the presence of a fault, indicating that the fault zone is permeable and that either vertical or lateral fluid flow has allowed pressure to equilibrate across the fault zone. Some faults act as pressure barriers where an overpressured seal does not allow for fluid flow across the fault zone. Barostratigraphy objectively describes the present-day results of the subsurface processes that create overpressures and those that allow abnormal pressures to be maintained and dissipate. Additionally, barostratigraphy provides a formal method to better categorize pressure compartmentalization by providing a framework for the analysis of the stratigraphic nature of subsurface pressure compartments. It is a classification that systematically arranges and partitions subsurface units based on their inherent properties and pressure attributes. These units are identifiable based on observable criteria. They are correlatable, mappable, and useful in identifying the current pressure conditions in all or part of a basin. The prediction of pore pressure at proposed well locations can be optimized by the use of barostratigraphy, which aids in the analysis of subsurface pressure magnitudes and variation, and in basin modeling. Additionally, an understanding of the hydrocarbon distribution in an area (and prospect risking) is enhanced, as is the analysis of seismic velocities and their impact on imaging due to the close relationship between velocity and effective stress.
Predrill pore-pressure prediction and pore pressure and fluid loss monitoring during drilling: A case study for a deepwater subsalt Gulf of Mexico well and discussion on fracture gradient, fluid losses, and wellbore breathing
Authors: Ziegler Fernando Enrique , Jones John F.
Published: February 2014

In this case study, the overburden, pore-pressure, and fracture gradients are calculated for several nearby analog wells and subsequently used to generate a predrill pore-pressure prediction for the deepwater subsalt Gulf of Mexico well, Flying Dutchman, located in Green Canyon 511 no. 1 (OCS-G 22971). Two key analog wells penetrated the lower Miocene and have sufficient data to generate pore-pressure profiles. Subsequently, the predrill pore-pressure prediction is found to be in good agreement with the pore pressure estimated from well logs while drilling. During the drilling phase of the Flying Dutchman well, two zones of significant fluid loss and wellbore breathing were encountered and are evaluated as a means of determining the formation types where they are most likely to occur, as well as their related minimum horizontal stress and fracture gradient.
Duration and Toxicity of Adjuvant Trastuzumab in Older Patients With Early-Stage Breast Cancer: A Population-Based Study
Authors: Vaz-Luis Ines , Keating Nancy L. , Lin Nancy U. , Lii Huichuan , Winer Eric P. , Freedman Rachel A.
Published: February 2014

Purpose

Few data are available regarding adjuvant trastuzumab use in older women with early-stage breast cancer. We examined rates and predictors of adjuvant trastuzumab completion and cardiac events in this population.

Patients and Methods

We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients age ≥ 66 years with stage I to III breast cancer diagnosed between 2005 and 2009 who received trastuzumab. Completion of trastuzumab was defined as receipt of more than 270 days of therapy. We used multivariable logistic regression to examine patient, clinical, and geographic characteristics associated with trastuzumab completion. We also examined rates of hospital admissions for cardiac events.

Results

Among 2,028 women, most (71.2%) were younger than age 76 years and had a comorbidity score of 0 (66.8%); 85.2% received trastuzumab with chemotherapy. Overall, 1,656 women (81.7%) completed trastuzumab. Older patients and those with more comorbidity had lower odds of treatment completion (odds ratio [OR], 0.40 [95% CI, 0.30 to 0.55] for age ≥ 80 years v age 66 to 70 years; OR, 0.65 [95% CI, 0.49 to 0.88] for comorbidity score of 2 v 0). During treatment, 73 patients (3.6%) were hospitalized for cardiac events (2.6% of those who completed trastuzumab v 8.1% of those who did not; P < .001).

Conclusion

Most older patients who initiated adjuvant trastuzumab completed therapy. Age and comorbidity were among factors that were associated with treatment completion, and rates of significant cardiac events were higher in those who did not complete therapy. Further exploration of toxicities and optimal treatments for older women with human epidermal growth factor receptor 2–positive breast cancer are warranted.