Engaging Users in the Behavior Change Process With Digitalized Motivational Interviewing and Gamification: Development and Feasibility Testing of the Precious App.
Most adults do not engage in sufficient physical activity to maintain good health. Smartphone apps are increasingly used to support physical activity but typically focus on tracking behaviors with no support for the complex process of behavior change. Tracking features do not engage all users, and apps could better reach their targets by engaging users in reflecting their reasons, capabilities, and opportunities to change. Motivational interviewing supports this active engagement in self-reflection and self-regulation by fostering psychological needs proposed by the self-determination theory (ie, autonomy, competence, and relatedness). However, it is unknown whether digitalized motivational interviewing in a smartphone app engages users in this process. This study aimed to describe the theory- and evidence-based development of the Precious app and to examine how digitalized motivational interviewing using a smartphone app engages users in the behavior change process. Specifically, we aimed to determine if use of the Precious app elicits change talk in participants and how they perceive autonomy support in the app. A multidisciplinary team built the Precious app to support engagement in the behavior change process. The Precious app targets reflective processes with motivational interviewing and spontaneous processes with gamified tools, and builds on the principles of self-determination theory and control theory by using 7 relational techniques and 12 behavior change techniques. The feasibility of the app was tested among 12 adults, who were asked to interact with the prototype and think aloud. Semistructured interviews allowed participants to extend their statements. Participants' interactions with the app were video recorded, transcribed, and analyzed with deductive thematic analysis to identify the theoretical themes related to autonomy support and change talk. Participants valued the autonomy supportive features in the Precious app (eg, freedom to pursue personally relevant goals and receive tailored feedback). We identified the following five themes based on the theory-based theme autonomy support: valuing the chance to choose, concern about lack of autonomy, expecting controlling features, autonomous goals, and autonomy supportive feedback. The motivational interviewing features actively engaged participants in reflecting their outcome goals and reasons for activity, producing several types of change talk and very little sustain talk. The types of change talk identified were desire, need, reasons, ability, commitment, and taking steps toward change. The Precious app takes a unique approach to engage users in the behavior change process by targeting both reflective and spontaneous processes. It allows motivational interviewing in a mobile form, supports psychological needs with relational techniques, and targets intrinsic motivation with gamified elements. The motivational interviewing approach shows promise, but the impact of its interactive features and tailored feedback needs to be studied over time. The Precious app is undergoing testing in a series of n-of-1 randomized controlled trials.


Analysis of Physical Collisions in Elite National Rugby League Match Play.
To investigate the impact forces of collision events during both attack and defense in elite rugby league match play and to compare the collision profiles between playing positions. 26 elite rugby league players. Player collisions were recorded using an integrated accelerometer in global positioning system units (SPI-Pro X, GPSports). Impact forces of collisions in attack (hit-ups) and defense (tackles) were analyzed from 359 files from outside backs (n = 78), adjustables (n = 97), wide-running forwards (n = 136), and hit-up forwards (n = 48) over 1 National Rugby League season. Hit-up forwards were involved in 0.8 collisions/min, significantly more than all other positional groups (wide-running forwards P = .050, adjustables P = .042, and outside backs P = .000). Outside backs experienced 25% fewer collisions per minute than hit-up forwards. Hit-up forwards experienced a collision within the 2 highest classifications of force (≥ 10 g) every 2.5 min of match play compared with 1 every 5 and 9 min for adjustables and outside backs, respectively. Hit-up forwards performed 0.5 tackles per minute of match play, 5 times that of outside backs (ES = 1.90; 95% CI [0.26,3.16]), and 0.2 hit-ups per minute of match play, twice as many as adjustables. During a rugby league match, players are exposed to a significant number of collision events. Positional differences exist, with hit-up and wide-running forwards experiencing greater collision events than adjustables and outside backs. Although these results may be unique to the individual team's defensive- and attacking-play strategies, they are indicative of the significant collision profiles in professional rugby league.


Socioecological indicators of senior financial exploitation: an application of data science to 8,800 substantiated mistreatment cases.
Senior financial exploitation (FE) is prevalent and harmful. Its often insidious nature and co-occurrence with other forms of mistreatment make detection and substantiation challenging. A secondary data analysis of N = 8,800 Adult Protective Services substantiated senior mistreatment cases, using machine learning algorithms, was conducted to determine when pure FE versus hybrid FE was occurring. FE represented N = 2514 (29%) of the cases with 78% being pure FE. Victim suicidal ideation and threatening behaviors, injuries, drug paraphernalia, contentious relationships, caregiver stress, and burnout and victims needing assistance were most important for differentiating FE vs non-FE-related mistreatment. The inability to afford housing, medications, food, and medical care as well as victims suffering from intellectual disability disorder(s) predicted hybrid FE. This study distinguishes socioecological factors strongly associated with the presence of FE during protective service investigations. These findings support existing and new indicators of FE and could inform protective service investigation practices.


Finding Waldo: Learning about Users from their Interactions.
Visual analytics is inherently a collaboration between human and computer. However, in current visual analytics systems, the computer has limited means of knowing about its users and their analysis processes. While existing research has shown that a user's interactions with a system reflect a large amount of the user's reasoning process, there has been limited advancement in developing automated, real-time techniques that mine interactions to learn about the user. In this paper, we demonstrate that we can accurately predict a user's task performance and infer some user personality traits by using machine learning techniques to analyze interaction data. Specifically, we conduct an experiment in which participants perform a visual search task, and apply well-known machine learning algorithms to three encodings of the users' interaction data. We achieve, depending on algorithm and encoding, between 62% and 83% accuracy at predicting whether each user will be fast or slow at completing the task. Beyond predicting performance, we demonstrate that using the same techniques, we can infer aspects of the user's personality factors, including locus of control, extraversion, and neuroticism. Further analyses show that strong results can be attained with limited observation time: in one case 95% of the final accuracy is gained after a quarter of the average task completion time. Overall, our findings show that interactions can provide information to the computer about its human collaborator, and establish a foundation for realizing mixed-initiative visual analytics systems.


Derivation and characterisation of the human embryonic stem cell line, OxF1.
OxF1 is a human embryonic stem cell line derived from a surplus embryo donated through the Oxford IVF clinic. The cells have a stable 46 XX karyotype and show expression of Oct 4, Nanog and TRA-1-60. Embryoid bodies differentiate into cells that represent all three germ layers as demonstrated by immunohistochemical localisation of beta III tubulin, nestin, desmin, smooth muscle actin, Gata 6 and cytokeratin 18. Directed differentiation through haematopoiesis has been demonstrated.


Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary microRNAs.
The importance of microRNAs (miRNAs) in biological and disease processes necessitates a better understanding of the mechanisms that regulate miRNA abundance. We showed that the activities of the mitogen-activated protein kinase (MAPK) p38 and its downstream effector kinase MAPK-activated protein kinase 2 (MK2) were necessary for the efficient processing of a subset of primary miRNAs (pri-miRNAs). Through yeast two-hybrid screening, we identified p68 (also known as DDX5), a key component of the Drosha complex that processes pri-miRNAs, as an MK2-interacting protein, and we found that MK2 phosphorylated p68 at Ser(197) in cells. In wild-type mouse embryonic fibroblasts (MEFs) treated with a p38 inhibitor or in MK2-deficient (MK2(-/-)) MEFs, expression of a phosphomimetic mutant p68 fully restored pri-miRNA processing, suggesting that MK2-mediated phosphorylation of p68 was essential for this process. We found that, whereas p68 was present in the nuclei of wild-type MEFs, it was found mostly in the cytoplasm of MK2(-/-) MEFs. Nuclear localization of p68 depended on MK2-mediated phosphorylation of Ser(197). In addition, inhibition of p38 MAPK promoted the growth of wild-type MEFs and breast cancer MCF7 cells by enhancing the abundance of c-Myc through suppression of the biogenesis of the miRNA miR-145, which targets c-Myc. Because pri-miRNA processing occurs in the nucleus, our findings suggest that the p38 MAPK-MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear localization of p68.


A novel combination of TaqMan RT-PCR and a suspension microarray assay for the detection and species identification of pestiviruses.
The genus pestivirus contains four recognized species: classical swine fever virus, border disease virus, bovine viral diarrhoea virus types 1 and 2. All are economically important and globally distributed but classical swine fever is the most serious, concerning losses and control measures. It affects both domestic pigs and wild boars. Outbreaks of this disease in domestic pigs call for the most serious measures of disease control, including a stamping out policy in Europe. Since all the members of the pestivirus genus can infect swine, differential diagnosis using traditional methods poses some problems. Antibody tests may lack specificity due to cross-reactions, antigen capture ELISAs may have low sensitivity, and virus isolation may take several days or even longer time to complete. PCR-based tests overcome these problems for the most part, but in general lack the multiplexing capability to detect and differentiate all the pestiviruses simultaneously. The assay platform described here addresses all of these issues by combining the advantages of real-time PCR with the multiplexing capability of microarray technology. The platform includes a TaqMan real-time PCR designed for the universal detection of pestiviruses and a microarray assay that can use the amplicons produced in the real-time PCR to identify the specific pestivirus.


The effects of oral xylitol administration on bone density in rat femur.
To examine the effects of oral xylitol administration on rat femur bone density, 36 four-week-old male Wistar rats divided into three groups were fed CE-2 diet (control, n = 12) alone or supplemented with 10% (n = 12) or 20% (n = 12) dietary xylitol for 40 days. Biochemical, morphological, and histological analyses were performed. The 10% and 20% xylitol groups showed higher levels of both serum Ca and alkaline phosphatase activity and lower levels of serum tartrate-resistant acid phosphatase than the control group. Although no significant differences in the three-dimensional bone structure or trabecular bone structure of the femur were observed, both xylitol groups showed significantly higher bone density than the control group. Compared to the control group, the 10% and 20% xylitol groups showed an increase in trabeculae. Thus, oral administration of xylitol appears to affect bone metabolism, leading to increased bone density in rat femur.


Bradykinin-induced modulation of calcium signals in rat dorsal root ganglion neurons in vitro.
We used combined patch-clamp-microfluorimetric recordings to examine the effects of bradykinin on [Ca2+]i transients and the Ca2+ current (ICa) in rat dorsal root ganglion neurons in vitro. Bradykinin increased [Ca2+]i in approximately 20% of dorsal root ganglion cells examined and inhibited the ICa in approximately 65% of dorsal root ganglion cells. Bradykinin also inhibited the ICa when [Ca2+]i was buffered with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid or when Ba2+ was the charge carrier. When ICa's of increasing duration were elicited in these neurons, [Ca2+]i transients were produced that increased in amplitude but eventually approached an asymptote at longer voltage steps. Similarly, the amplitude of the [Ca2+]i transient also approached an asymptote in current-clamp recordings when cells were induced to fire a large number of action potentials. The bradykinin-induced inhibition of the amplitude of the [Ca2+]i transient was more pronounced at shorter voltage steps. At pulse durations that produced asymptotic [Ca2+]i signals, bradykinin no longer decreased the amplitude of the rise in [Ca2+]i, although it still reduced the ICa. In current-clamp recordings, bradykinin also reduced the [Ca2+]i signal that accompanied the generation of action potentials, but again bradykinin was more effective for shorter spike trains. Bradykinin also depolarized the majority of neurons (65%). The reduction in [Ca2+]i produced by bradykinin in sensory neurons may be an important factor contributing to bradykinin-induced excitation of primary sensory afferents.


Correlation between atmospheric backscattering and meteorological visual range.
On the basis of our present knowledge of the distribution of natural haze particles in the atmosphere, the relation between backscatter intensity and the visual range, or the extinction coefficient, has been analyzed. It can be shown that the various processes which cause the changes in visibility (increasing particle number, changes in particle size distribution, etc.) result in rather different backscatter conditions. Only by a combination of such processes is it possible to explain a relation between backscatter and extinction coefficient as it can be derived from experimental data. It therefore becomes clear that such a relation cannot be a unique one and that it will change from one situation to another.


Oxyuricassis ekstromi n. sp. (Oxyurida: Pharyngodonidae) from Lasiancistrus saetiger (Siluriform: Loricariidae) from the Eastern Amazon.
Oxyuricassis ekstromi n. sp. is the third species of the genus described from the intestine of Lasiancistrus saetiger Armbruster in Brazil. This species can be easily differentiated from its congeners by the presence of a tooth-like sclerotized piece that occupies half of the stoma and absence of spine projections on the tail of both males and females. Also, males of the new species lack caudal alae present in Oxyuricassis coronatus and Oxyuricassis hexaspinatus. Additionally, we observed a different number and pattern of the distribution of cloacal papilla; males of O. coronatus and O. hexaspinatus have 1 pair of pre-cloacal and 2 pairs of post-cloacal papillae; while the new species has 1 pre-cloacal and 3 post-cloacal pairs of papillae.


Explaining Counterfeit Alcohol Purchases in Russia.
Alcohol is a common target of counterfeiting in Russia. Counterfeit alcohol is defined here as the manufacture, distribution, unauthorized placement (forgery) of protected commodity trademarks, and infringement of the exclusive rights of the registered trademark holders of alcoholic beverages. It is often argued that the expansion of the counterfeit product market is due to the steady demand of economically disadvantaged people for low-priced goods. The situation becomes more complicated once deceptive and nondeceptive forms of counterfeiting are taken into account. This study aimed to identify markers of risky behavior associated with the purchase of counterfeit alcohol in Russia. The analysis relied on consumer self-reports of alcohol use and purchase collected nationwide by the Russia Longitudinal Monitoring Survey (RLMS-HSE) in 2012 to 2014. I used a generalized linear mixed-model logistic regression to identify predictors of risky behavior by consumers who purchased counterfeit alcohol, either knowingly or unknowingly, during the 30 days preceding the survey. Purchases of counterfeit alcohol declined slightly from 2012 to 2014, mainly due to a decrease in consumers mistakenly purchasing counterfeit products. Predictors of counterfeit alcohol purchases differed between consumers who knowingly and unknowingly purchased counterfeit products. Nondeceptive purchase of counterfeit alcohol was related primarily to an indifference to alcohol brands. Consumers with social networks that include drinkers of nonbeverage alcohol and producers of homemade alcohol were highly likely to consume counterfeit alcohol deliberately. Problem drinking was significantly associated with a higher risk of both deceptive and nondeceptive purchases of counterfeit alcohol. Poverty largely contributed to nondeceptive counterfeiting. The literature has overestimated the impact of low prices on counterfeit alcohol consumption. Problem drinking and membership in social networks of consumers of surrogate alcohol (i.e., nonbeverage) are more influential in explaining why people purchase counterfeit alcohol. Further research on these 2 factors is needed to more fully understand the purchase and consumption of counterfeit alcoholic beverages.


Analysis of the occurrence and risk assessment of polar pesticides in the Llobregat River Basin (NE Spain).
Contamination of surface waters by pesticides continues to be the focus of concern for water authorities due to the growing evidence of their deleterious effects on aquatic life. In this context, the present work investigates the occurrence of 16 selected pesticides belonging to the classes of triazines, phenylureas, organophosphates, chloroacetanilides and thiocarbamates in surface waters from the Llobregat River (NE Spain) and some of its tributaries (Anoia and Rubí) and assesses their potential impact on the aquatic organisms by applying a recently developed index, the Short-term Pesticide Risk Index for the Surface Water System (PRISW-1), which takes into account the pesticides concentrations and their overall toxicity against three aquatic organisms (algae, Daphnia, and fish). Chemical analysis, performed by means of a fully automated method based on isotope dilution on-line solid phase extraction-liquid chromatography-electrospray-tandem mass spectrometry (on-line SPE-LC-ESI-MS/MS), revealed diuron and diazinon as the most ubiquitous and abundant compounds with levels up to 818 and 132 ng L(-1), respectively. Total pesticide concentrations, which in only 1 out of 66 samples surpassed 500 ng L(-1), were higher in the tributaries than in the river but their contribution in terms of mass-loads to the overall pesticide pollution of the Llobregat River was relatively small. Contamination increased downstream of the river and was clearly influenced by rainfall and hence river flow. Application of the PRISW-1 index indicated that, although pesticides levels fulfilled the European Union Environmental Quality Standards (EQS) for surface waters, the existing pesticide contamination poses a low to high ecotoxicological risk for aquatic organisms, that algae and macro-invertebrates are at higher risk than fish, and that the organophosphates diazinon and malathion and the phenylurea diuron are the major contributors to the overall toxicity and therefore the most problematic compounds.


Copy number alterations and neoplasia-specific mutations in MELK, PDCD1LG2, TLN1, and PAX5 at 9p in different neoplasias.
Genetic alterations affecting 9p are commonly present in many cancer types and many cancer-related genes are located in this chromosomal region. We sequenced all of the genes located in a 32Mb region of 9p by targeted next generation sequencing (NGS) in 96 patients with different cancer types, including acute lymphoblastic leukemia, bone malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, fibrosarcoma, Ewing's sarcoma, and lung carcinoma. Copy number alterations (CNA), and mutations were studied from the NGS data. We detected a deletion at the CDKN2A locus as being the most frequent genetic alteration in all cancer types. In addition to this locus, NGS also identified other small regions of copy number loss and gain. However, different cancer types did not reveal any statistically significant differences with regard to CNA frequency or type. Of the 191 genes within the target region, two novel recurrent mutations were found in the MELK and PDCD1LG2 genes. The most commonly mutated gene in sarcomas was TLN1 (8%) and PAX5 in ALL (9%). Mutations in PAX5, and RUSC2, were seen exclusively in ALL patients and those in KIAA1432, CA9, TLN1, and MELK only in sarcomas (MFH, FS, EFT). Thus using targeted NGS of the 9p region, in addition to commonly deleted CDKN2A locus, we were able to identify a number of small deletions and gains, as well as novel recurrent mutations in different cancer types. © 2014 Wiley Periodicals, Inc.


Similar controls on calcification under ocean acidification across unrelated coral reef taxa.
Ocean acidification (OA) is a major threat to marine ecosystems, particularly coral reefs which are heavily reliant on calcareous species. OA decreases seawater pH and calcium carbonate saturation state (Ω), and increases the concentration of dissolved inorganic carbon (DIC). Intense scientific effort has attempted to determine the mechanisms via which ocean acidification (OA) influences calcification, led by early hypotheses that calcium carbonate saturation state (Ω) is the main driver. We grew corals and coralline algae for 8-21 weeks, under treatments where the seawater parameters Ω, pH, and DIC were manipulated to examine their differential effects on calcification rates and calcifying fluid chemistry (Ωcf , pHcf , and DICcf ). Here, using long duration experiments, we provide geochemical evidence that differing physiological controls on carbonate chemistry at the site of calcification, rather than seawater Ω, are the main determinants of calcification. We found that changes in seawater pH and DIC rather than Ω had the greatest effects on calcification and calcifying fluid chemistry, though the effects of seawater carbonate chemistry were limited. Our results demonstrate the capacity of organisms from taxa with vastly different calcification mechanisms to regulate their internal chemistry under extreme chemical conditions. These findings provide an explanation for the resistance of some species to OA, while also demonstrating how changes in seawater DIC and pH under OA influence calcification of key coral reef taxa.


Comparative outcomes of predominant facility-level use of ferumoxytol versus other intravenous iron formulations in incident hemodialysis patients.
Ferumoxytol was first approved for clinical use in 2009 solely based on data from trial comparisons with oral iron on biochemical anemia efficacy end points. To compare the rates of important patient outcomes (infection, cardiovascular events and death) between facilities predominantly using ferumoxytol versus iron sucrose (IS) or ferric gluconate (FG) in patients with end-stage renal disease (ESRD)-initiating hemodialysis (HD). Using the United States Renal Data System, we identified all HD facilities that switched (almost) all patients from IS/FG to ferumoxytol (July 2009-December 2011). Each switching facility was matched with three facilities that continued IS/FG use. All incident ESRD patients subsequently initiating HD in these centers were studied and assigned their facility exposure. They were followed for all-cause mortality, cardiovascular hospitalization/death or infectious hospitalization/death. Follow-up ended at kidney transplantation, switch to peritoneal dialysis, transfer to another facility, facility switch to another iron formulation and end of database (31 December 2011). Cox proportional hazards regression was then used to estimate adjusted hazard ratios [HR (95% confidence intervals)]. In July 2009-December 2011, 278 HD centers switched to ferumoxytol; 265 units (95.3%) were matched with 3 units each that continued to use IS/FG. Subsequently, 14 206 patients initiated HD, 3752 (26.4%) in ferumoxytol and 10 454 (73.6%) in IS/FG centers; their characteristics were very similar. During 6433 person-years, 1929 all-cause, 726 cardiovascular and 191 infectious deaths occurred. Patients in ferumoxytol (versus IS/FG) facilities experienced similar all-cause [0.95 (0.85-1.07)], cardiovascular [0.99 (0.83-1.19)] and infectious mortality [0.88 (0.61-1.25)]. Among 5513 Medicare (Parts A + B) beneficiaries, cardiovascular events [myocardial infarction, stroke and cardiovascular death; 1.05 (0.79-1.39)] and infectious events [hospitalization/death; 0.96 (0.85-1.08)] did not differ between the iron exposure groups. In incident HD patients, ferumoxytol showed similar short- to mid-term safety profiles with regard to cardiovascular, infectious and mortality outcomes compared with the more commonly used intravenous iron formulations IS and FG.


Sequential Therapy with Saratin, Bevacizumab and Ilomastat to Prolong Bleb Function following Glaucoma Filtration Surgery in a Rabbit Model.
To determine if sequential treatment with Bevacizumab (Avastin), a monoclonal, VEGF antibody that blocks angiogenesis; Saratin, a 12 kD polypeptide with anti-inflammatory and anti-thrombotic properties; and Ilomastat, a matrix metalloproteinase (MMP) inhibitor, prolongs bleb life following glaucoma filtration surgery (GFS) in a rabbit model. Thirty-two New Zealand White rabbits (eight rabbits per group) underwent GFS in the left eye. Group 1 received a perioperative injection of both Saratin and Bevacizumab, and later, subconjuctival injections of Ilomastat on days 8 and 15. Group 2 received only Saratin perioperatively, and also received Ilomastat injections on days 8 and 15. Group 3, the negative control, received a single perioperative injection of Balanced Saline Solution (BSS) along with post-operative BSS injections on days 8 and 15. Group 4, the positive control, received topical treatment with Mitomycin-C (MMC) at the time of surgery with no further treatment. Blebs were evaluated by an observer masked to treatment every third day. Histology was obtained on two eyes in each group on post-op day twelve as well as all eyes following bleb failure. Eyes in group 1 had a mean bleb survival time of 29 ± 2.7 days, whereas those in group 2 that received the experimental treatment without Bevacizumab had a mean survival time of 25.5 ± 2.7 days. An ANOVA test showed that the Saratin/Ilomastat/Bevacizumab group demonstrated a significant prolongation of bleb survival compared to the BSS control-mean survival time of 19.7 ±2.7 days-(p = 0.0252) and was not significantly different from the MMC positive control group (p = 0.4238)-mean survival time of 32.5 ± 3.3. From tissue histology at day 12, the four different groups showed marked differences in the cellularity and capsule fibrosis. The MMC eyes showed minimal cellularity, were avascular and had minimal fibrous tissue. BSS group showed high cellularity, moderate to high fibrosis, and thicker and more defined capsules than either of the treatment groups and the positive control. Both the Saratin/Ilomastat/Bevacizumab and Saratin/Ilomastat only eyes showed moderate cellularity with minimal fibrosis, with less cellularity and fibrosis present in the triple treatment group. Sequential therapy with multiple agents, including Bevacizumab, prolonged bleb function following GFS in the rabbit model and were significantly better than the negative BSS control. The experimental group did not show the same surface tissue histological thinning and side effects associated with MMC treatment.


Americans' conflicting views about the public health system, and how to shore up support.
This analysis of national opinion polls shows that a majority of Americans support increased spending on public health in general and that they see public health interventions as saving money in the long term. At the same time, many do not favor increased federal spending in a number of areas that public health officials deem important. In addition, polls show striking partisan differences, with Republicans much less supportive than Democrats of additional spending on public health. This split may have political implications for the public health component of the new health reform law if there is a change in party control of one or more houses of Congress after the November 2010 elections. As a result, in order to sustain public support for increased spending, it will be critically important to give examples of cost savings from public health programs and to highlight how they have reduced mortality from major chronic illnesses, such as cancer, heart disease, and HIV/AIDS.


Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension.
In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.


Pediatric Hospital Discharges to Home Health and Postacute Facility Care: A National Study.
Acute care hospitals are challenged to provide efficient, high-quality care to children who have medically complex conditions and may require weeks or months for recovery. Although the use of home health care (HHC) and facility-based postacute care (PAC) after discharge is well documented for adults, to our knowledge, little is known for children. To assess the national prevalence of, characteristics of children discharged to, and variation in use across states of HHC and PAC for children. Retrospective analysis of 2,423,031 US acute care hospital discharges in 2012 for patients ages 0 to 21 years from the nationally representative Agency for Healthcare Research and Quality Kids' Inpatient Database. Discharges to HHC (eg, visiting or private-duty home nursing) and PAC (eg, rehabilitation facility) were identified from Centers for Medicare and Medicaid Services Discharge Status Codes. We compared children's characteristics (eg, race/ethnicity and number of chronic conditions) by discharge type using generalized linear regression. The median age of participants was 3 years (interquartile range, 0-13 years), and 45.6% were female. Of 2,423,031 US acute care hospital discharges in 2012 for patients ages 0 to 21 years, 122,673 discharges (5.1%) were to HHC and 26,282 (1.1%) were to PAC facilities. Neonatal care was the most common reason (44.5%, n = 54,589) for acute care hospitalization with discharge to HHC. Nonneonatal respiratory, musculoskeletal, and trauma-related problems, collectively, were the most common reasons for discharge to PAC (42.9%, n = 11,275). When compared with PAC, more discharges to HHC had no chronic condition (34.4% vs 18.0%, P < .001) and fewer discharges to HHC had 4 or more chronic conditions (22.5% vs 37.7%, P < .001). In multivariable analysis, Hispanic children were less likely to use PAC (0.8% vs 1.1%; odds ratio [OR], 0.9 [95% CI, 0.8-0.9]) or HHC (3.3% vs 5.5%; OR, 0.8 [95% CI, 0.7-0.8]) compared with other children. Children with 4 or more chronic conditions compared with no chronic conditions had a higher likelihood of HHC use (11.0% vs 4.4%; OR, 2.9 [95% CI, 2.8-3.0]) and PAC (3.9% vs 0.8%; OR, 4.5 [95% CI, 4.3-4.9]). After case-mix adjustment, there was significant (P < .001) variation across states in HHC (range, 0.4%-24.5%) and PAC (range, 0.4%-4.9%) use. Home health care and PAC use after discharge for hospitalized children is infrequent, even for children with multiple chronic conditions. It varies significantly by race/ethnicity and across states. Further investigation is needed to assess reasons for this variation and to determine for which children HHC and PAC are most effective.


Do schools moderate the genetic determinants of smoking?
This paper uses data from the National Longitudinal Study of Adolescent Health to examine the extent to which school-level social and institutional factors moderate genetic tendencies to smoke cigarettes. Our analysis relies on a sub-sample of 1,198 sibling and twin pairs nested within 84 schools. We develop a multilevel modeling extension of regression-based quantitative genetic techniques to calculate school-specific heritability estimates. We show that smoking onset (h2 = .51) and daily smoking (h2 = .58) are both genetically influenced. Whereas the genetic influence on smoking onset is consistent across schools, we show that schools moderate the heritability of daily smoking. The heritability of daily smoking is the highest within schools in which the most popular students are also smokers and reduced within schools in which the majority of the students are non-Hispanic and white. These findings make important contributions to the literature on gene-environment interactions.


Engineered biocompatible nanoparticles for in vivo imaging applications.
Iron-platinum alloy nanoparticles (FePt NPs) are extremely promising candidates for the next generation of contrast agents for magnetic resonance (MR) diagnostic imaging and MR-guided interventions, including hyperthermic ablation of solid cancers. FePt has high Curie temperature, saturation magnetic moment, magneto-crystalline anisotropy, and chemical stability. We describe the synthesis and characterization of a family of biocompatible FePt NPs suitable for biomedical applications, showing and discussing that FePt NPs can exhibit low cytotoxicity. The importance of engineering the interface of strongly magnetic NPs using a coating allowing free aqueous permeation is demonstrated to be an essential parameter in the design of new generations of diagnostic and therapeutic MRI contrast agents. We report effective cell internalization of FePt NPs and demonstrate that they can be used for cellular imaging and in vivo MRI applications. This opens the way for several future applications of FePt NPs, including regenerative medicine and stem cell therapy in addition to enhanced MR diagnostic imaging.


Linear scaling multireference singles and doubles configuration interaction.
A linear scaling multireference singles and doubles configuration interaction (MRSDCI) method has been developed. By using localized bases to span the occupied and virtual subspace, local truncation schemes can be applied in tandem with integral screening to reduce the various bottlenecks in a MRSDCI calculation. Among these, the evaluation of electron repulsion integrals and their subsequent transformation, together with the diagonalization of the large CI Hamiltonian matrix, correspond to the most computationally intensive steps in a MRSDCI calculation. We show that linear scaling is possible within each step. The scaling of the method with system size is explored with a system of linear alkane chains and we proceed to demonstrate this method can produce smooth potential energy surfaces via calculating the dissociation of trans-6-dodecene (C(12)H(24)) along the central C[Double Bond]C bond.


Coupled-cavity surface-emitting lasers: spectral and polarization threshold characteristics and electrooptic switching.
We study spectral and polarization threshold characteristics of coupled-cavity Vertical-Surface-Emitting Lasers (CC-VCSEL) on the base of a simple matrix approach. We show that strong wavelength discrimination can be achieved in CC-VCSELs by slightly detuning the cavities. However, polarization discrimination is not provided by the coupled-cavity design. We also consider the case of reverse-biasing one of the cavities, i.e. using it as a modulator via linear and/or quadratic electrooptic effect. Such a CC-VCSEL can act as a voltage-controlled polarization or wavelength switching device that is decoupled from the laser design and can be optimized for high modulation speed. We also show that using QD stack instead of quantum wells in the top cavity would lead to significant reduction of the driving electrical field.


Direct antithrombins: mechanisms, trials, and role in contemporary interventional medicine.
Direct thrombin inhibitors have several potential advantages over indirect thrombin inhibitors such as heparin. Bivalirudin, a bivalent direct thrombin inhibitor, is most commonly used in clinical practice and has a proven role in contemporary interventional medicine with elective percutaneous coronary intervention (PCI) as well as in patients with non-ST-elevation acute coronary syndrome (NSTEACS). Results from well-controlled clinical trials have shown that bivalirudin is associated with an approximate 50% reduction in major bleeding while having similar effects on incidence of death and myocardial infarction (MI) compared with herapin or enoxaparin and glycoprotein IIb/IIIa inhibitors. Bivalirudin has been successfully used in off- and on-pump cardiac surgery. Argatroban is the most evaluated among the univalent direct thrombin inhibitors inhibiting only the catalytic site of thrombin. It has been associated with similar rates of major bleeding compared with heparin in patients with acute MI receiving either streptokinase or alteplase with no effects on clinical endpoints. In a meta-analysis of 11 randomised trials where direct thrombin inhibitors (hirudin, bivalirudin, argatroban, efegatan or inogatran) were compared with unfractionated heparin in >35,000 patients with ST-elevation MI (STEMI) or NSTEACS there was no mortality difference between treatment groups but the incidence of MI at 30 days was significantly reduced in patients treated with direct thrombin inhibitors compared with heparin (4.7% vs 5.3%; p < 0.004). The role of direct thrombin inhibitors in both primary angioplasty for STEMI and angioplasty after fibrinolytic therapy needs to be established. Overall, the efficacy and improved safety profile make bivalirudin an attractive first-line anticoagulant for elective PCI and in patients with NSTEACS undergoing an invasive strategy.


Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles.
Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" β-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.


Tracking the processes behind conscious perception: a review of event-related potential correlates of visual consciousness.
Event-related potential (ERP) studies have attempted to discover the processes that underlie conscious visual perception by contrasting ERPs produced by stimuli that are consciously perceived with those that are not. Variability of the proposed ERP correlates of consciousness is considerable: the earliest proposed ERP correlate of consciousness (P1) coincides with sensory processes and the last one (P3) marks postperceptual processes. A negative difference wave called visual awareness negativity (VAN), typically observed around 200 ms after stimulus onset in occipitotemporal sites, gains strong support for reflecting the processes that correlate with, and possibly enable, aware visual perception. Research suggests that the early parts of conscious processing can proceed independently of top-down attention, although top-down attention may modulate visual processing even before consciousness. Evidence implies that the contents of consciousness are provided by interactions in the ventral stream, but indispensable contributions from dorsal regions influence already low-level visual responses.


Genetics, inheritance and strategies for prevention in populations at high risk of colorectal cancer (CRC).
Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the "pro drug"sulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months , the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600 mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and polyp removal, 48 recruits developed CRC. Of these, 18 received aspirin and 30 received AP; the HR for CRC for aspirin was 0.63 (CI 0.35-1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect: IRR 0.56 (CI 0.32-0.99, p = 0.05). For those who took aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19-0.86 p = 0.02) and the IRR, 0.37 (CI 0.18-0.78 p = 0.008). Combined analysis of all LS cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42-1.00, p = 0.05 and IRR was 0.59 (CI 0.39-0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26-0.79 p = 0.005,) and IRR was 0.42 (CI 0.25-0.72, p = 0.001). Adverse events in the aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or ulcers in the aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend aspirin to all Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses.


How You Move Is What I See: Planning an Action Biases a Partner's Visual Search.
Activating action representations can modulate perceptual processing of action-relevant dimensions, indicative of a common-coding of perception and action. When two or more agents work together in joint action, individual agents often need to consider not only their own actions and their effects on the world, but also predict the actions of a co-acting partner. If in these situations the action of a partner is represented in a functionally equivalent way to the agent's own actions, one may also expect interaction effects between action and perception across jointly acting individuals. The present study investigated whether the action of a co-acting partner may modulate an agent's perception. The "performer" prepared a grasping or pointing movement toward a physical target while the "searcher" performed a visual search task. The performer's planned action impaired the searcher's perceptual performance when the search target dimension was relevant to the performer's movement execution. These results demonstrate an action-induced modulation of perceptual processes across participants and indicate that agents represent their partner's action by employing the same perceptual system they use to represent an own action. We suggest that task representations in joint action operate along multiple levels of a cross-brain predictive coding system, which provides agents with information about a partner's actions when they coordinate to reach a common goal.


Distributed Bayesian Computation and Self-Organized Learning in Sheets of Spiking Neurons with Local Lateral Inhibition.
During the last decade, Bayesian probability theory has emerged as a framework in cognitive science and neuroscience for describing perception, reasoning and learning of mammals. However, our understanding of how probabilistic computations could be organized in the brain, and how the observed connectivity structure of cortical microcircuits supports these calculations, is rudimentary at best. In this study, we investigate statistical inference and self-organized learning in a spatially extended spiking network model, that accommodates both local competitive and large-scale associative aspects of neural information processing, under a unified Bayesian account. Specifically, we show how the spiking dynamics of a recurrent network with lateral excitation and local inhibition in response to distributed spiking input, can be understood as sampling from a variational posterior distribution of a well-defined implicit probabilistic model. This interpretation further permits a rigorous analytical treatment of experience-dependent plasticity on the network level. Using machine learning theory, we derive update rules for neuron and synapse parameters which equate with Hebbian synaptic and homeostatic intrinsic plasticity rules in a neural implementation. In computer simulations, we demonstrate that the interplay of these plasticity rules leads to the emergence of probabilistic local experts that form distributed assemblies of similarly tuned cells communicating through lateral excitatory connections. The resulting sparse distributed spike code of a well-adapted network carries compressed information on salient input features combined with prior experience on correlations among them. Our theory predicts that the emergence of such efficient representations benefits from network architectures in which the range of local inhibition matches the spatial extent of pyramidal cells that share common afferent input.


Enhanced platelet cyclic AMP response to prostaglandin E1 in essential hypertension.
Platelets provide an accessible and homogeneous cellular system for investigative studies on hypertension. Hypertension-associated abnormalities of cyclic adenosine 3',5'-monophosphate (AMP) metabolism were studied in human platelets. Platelets from hypertensive subjects had an enhanced cyclic AMP accumulation response to prostaglandin E1 (twofold increase in prostaglandin E1 sensitivity). The degree of adenylate cyclase activation in response to both prostaglandin E1 (receptor-mediated) and forskolin (non-receptor-mediated) was greater in hypertensive than normotensive subjects, and prostaglandin E1-stimulated and forskolin-stimulated adenylate cyclase activity correlated directly (r = 0.71, p less than 0.001, n = 26). This finding suggests that the catalytic subunit of the enzyme is the rate-limiting step of this hormonal information transduction. Platelets from hypertensive subjects were more sensitive to epinephrine-induced inhibition of the stimulatory effects of prostaglandin E1 on both cyclic AMP accumulation (fourfold) and activation of cyclic AMP-dependent protein kinase. These findings suggest that the enhanced cyclic AMP metabolic response to prostaglandin E1 in platelets from subjects with established essential hypertension may function as a negative feedback mechanism to protect the cells against calcium overload and to reduce their stimulated participation in hemostatic and thrombotic processes.


Effects of extracellular calcium on cholesteatoma migration and adhesion in vitro.
Cholesteatoma matrix and tympanic epithelia share the unique property of en mass migratory locomotion in vitro. Although this migratory behavior is not well understood, it is thought to be a major contributor to the pathogenesis and pathophysiology of cholesteatoma disease. We have surmised that en mass migration depends on tight calcium-dependent intercellular and substrate cellular adhesions. The purpose of this investigation was to determine the effects of a diminished extracellular calcium level on cholesteatoma migration and adhesion. Cholesteatoma matrixes obtained intraoperatively from patients undergoing mastoidectomies for chronic ear disease were cut into small fragments and grown in culture. When cultured specimens were exposed to low-calcium medium (0.14 mmol/L calcium), a greater than 10-fold reduction in the rate of migration was observed when compared with control values (1.8 mmol/L calcium). This reduction of migration returned to normal within 48 hours after extracellular calcium was replenished. Substrate cellular adhesion was also significantly reduced when cholesteatoma cells were grown in low-calcium medium. These observations were further supported by histomorphologic findings. Our findings suggest that calcium-dependent intercellular and substrate cellular adhesions are essential for cholesteatoma migration and adhesion. These studies further our understanding of the pathophysiology of cholesteatoma disease and may provide clues on how to better treat patients with this disease.


Experiences of a proactive IR(ME)R inspection in radiotherapy.
The Ionizing Radiation (Medical Exposure) Regulations 2000, IR(ME)R, apply to the safety of the patient referred for a medical exposure to ionizing radiation. In Scotland, the Scottish Executive (Department of Health) is responsible for carrying out inspections of compliance with these regulations. IR(ME)R specifically addresses issues concerned with Employer's duties, responsibilities of the Practitioner, Operator and Referrer, justification of individual medical exposures for diagnosis and treatment, optimization of all procedures, clinical audit and adequate training of all duty holders. A proactive IR(ME)R inspection of the Clinical Oncology Department, Raigmore Hospital, Inverness, was carried out in November 2001 by inspectors based at the Department of Health, London, and seconded by the Scottish Executive, Department of Health. The aim of the inspection was to assess the degree of compliance with the regulations. In this case study the experiences of a proactive inspection are described in detail and some of the important elements of implementing IR(ME)R in a department that operates an ISO 9000-2000 Quality Management System addressed. The identification of IR(ME)R Duty Holders' responsibilities is one important aspect which may be inadequately described by the existing Quality Management System documentation. Other key elements of the inspection include the methods of authorizing the justification, the importance of the treatment prescription sheets in the demonstration of compliance with IR(ME)R, patient identification and pregnancy questions and dose recording procedures. The integration of the standard operating procedures as described in Schedule 1 of the regulations is also important. Where the existing Quality Management System documentation is written to include the IR(ME)R requirements of duty holder's responsibilities and the allocation of all the important tasks, then there is no need to re-badge these documents for IR(ME)R purposes. IR(ME)R encourages departments to focus on the safety of the patient and to document good practice. In order to comply, departments will have to show evidence of optimization of their procedures and must address the clinical governance issues associated with delivery of treatment.


Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor.
We have previously shown that carbon monoxide (CO) inhalation at a low concentration provides protection against cold ischemia-reperfusion (I/R) injury after kidney transplantation. As vascular endothelial growth factor (VEGF) may promote the recovery process of impaired vascular endothelial cells during I/R injury, we examined whether protective effects of CO involved VEGF induction and its upstream hypoxia-inducible factor (HIF)-1 activation. Lewis rat kidney graft, preserved in University of Wisconsin at 4 degrees C for 24 hr, was orthotopically transplanted into syngeneic recipient. Recipients were continuously maintained in air or exposed to CO (250 ppm) for 1 hr before and 24 hr after transplant. Prolonged cold preservation resulted in progressive impairment of kidney graft function with early inflammatory responses. Carbon monoxide significantly protected kidney grafts from cold I/R injury, improved renal function and enhanced recipient survival. Real-time reverse transcriptase-polymerase chain reaction revealed upregulation of HIF-1alpha and VEGF in the CO-treated kidney grafts as early as 1 hr after reperfusion. Western blot showed CO significantly upregulated VEGF expression 1 to 3 hr after kidney transplantation. Considerably more VEGF-positive cells were observed mainly in tubular epithelial cells in CO-treated, but not air-exposed, kidney grafts at 3 hr after reperfusion. YC-1, HIF-1alpha inhibitor, completely abrogated the actions of CO on VEGF induction and reversed the protective effects afforded by CO. Nitric oxide production in the grafts was increased by CO, however, abolished by YC-1. These results demonstrate that the protective effect of CO against renal cold I/R injury may involve VEGF upregulation through its upstream signal, HIF-1 activation.


Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide.
Prostate cancer is the most common noncutaneous malignancy of American men. Although it can be initially treated with androgen deprivation therapy, tumors that relapse become resistant to future hormonal manipulation. We previously found that the multidrug resistance protein (MRP), MRP1, is overexpressed in advanced stage and grade human prostate cancer and is negatively regulated by p53. In this study, we sought to determine whether the cellular accumulation of the antiandrogen flutamide, a drug commonly used in the treatment of prostate cancer, is affected by MRP1 expression. There were significant differences between the wild-type and MRP1-overexpressing cells in efflux and accumulation of flutamide and hydroxyflutamide, its active metabolite. In contrast, transport of dihydrotestosterone was not affected by MRP1. Treating the cells with leukotriene D4, a known MRP1 substrate, or VX-710, an MRP1 modulator, restored flutamide and hydroxyflutamide accumulation. Finally, intracellular glutathione depletion with buthionine sulfoximine or energy depletion using 2-deoxy-D-glucose/sodium azide restored flutamide accumulation to that of parental cells while incubating the cells at 4 degrees C abolished MRP1-mediated transport. In summary, these studies indicate that flutamide and hydroxyflutamide but not dihydrotestosterone are transported by MRP1 and that these findings may contribute to our understanding of resistance to hormone refractory prostate cancer.


The true costs of participatory sanitation: Evidence from community-led total sanitation studies in Ghana and Ethiopia.
Evidence on sanitation and hygiene program costs is used for many purposes. The few studies that report costs use top-down costing methods that are inaccurate and inappropriate. Community-led total sanitation (CLTS) is a participatory behavior-change approach that presents difficulties for cost analysis. We used implementation tracking and bottom-up, activity-based costing to assess the process, program costs, and local investments for four CLTS interventions in Ghana and Ethiopia. Data collection included implementation checklists, surveys, and financial records review. Financial costs and value-of-time spent on CLTS by different actors were assessed. Results are disaggregated by intervention, cost category, actor, geographic area, and project month. The average household size was 4.0 people in Ghana, and 5.8 people in Ethiopia. The program cost of CLTS was $30.34-$81.56 per household targeted in Ghana, and $14.15-$19.21 in Ethiopia. Most program costs were from training for three of four interventions. Local investments ranged from $7.93-$22.36 per household targeted in Ghana, and $2.35-$3.41 in Ethiopia. This is the first study to present comprehensive, disaggregated costs of a sanitation and hygiene behavior-change intervention. The findings can be used to inform policy and finance decisions, plan program scale-up, perform cost-effectiveness and benefit studies, and compare different interventions. The costing method is applicable to other public health behavior-change programs.


Engineering the optical response of the titanium-MIL-125 metal-organic framework through ligand functionalization.
Herein we discuss band gap modification of MIL-125, a TiO2/1,4-benzenedicarboxylate (bdc) metal-organic framework (MOF). Through a combination of synthesis and computation, we elucidated the electronic structure of MIL-125 with aminated linkers. The band gap decrease observed when the monoaminated bdc-NH2 linker was used arises from donation of the N 2p electrons to the aromatic linking unit, resulting in a red-shifted band above the valence-band edge of MIL-125. We further explored in silico MIL-125 with the diaminated linker bdc-(NH2)2 and other functional groups (-OH, -CH3, -Cl) as alternative substitutions to control the optical response. The bdc-(NH2)2 linking unit was predicted to lower the band gap of MIL-125 to 1.28 eV, and this was confirmed through the targeted synthesis of the bdc-(NH2)2-based MIL-125. This study illustrates the possibility of tuning the optical response of MOFs through rational functionalization of the linking unit, and the strength of combined synthetic/computational approaches for targeting functionalized hybrid materials.


Implementation of a COVID-19 cohort area resulted in no surface or air contamination in surrounding areas in one academic emergency department.
As a result of the COVID-19 pandemic and highly contagious nature of SARS-CoV-2, emergency departments (EDs) have been forced to implement new measures and protocols to minimize the spread of the disease within their departments. The primary objective of this study was to determine if the implementation of a designated COVID-19 cohort area (hot zone) within a busy ED mitigated the dissemination of SARS-CoV-2 throughout the rest of the department. In an ED of a tertiary academic medical center, with 64,000 annual visits, an eight room pod was designated for known COVID-19 or individuals with high suspicion for infection. There was a single entry and exit for donning and doffing personal protective equipment (PPE). Health care workers (HCW) changed gowns and gloves between patients, but maintained their N-95 mask and face shield, cleaning the shield with a germicidal wipe between patients. Staffing assignments designated nurses and technicians to remain in this area for 4 h, where physicians regularly moved between the hot zone and rest of the ED. Fifteen surface samples and four air samples were taken to evaluate SARS-CoV-2 contamination levels and the effectiveness of infection control practices. Samples were collected outside of patient rooms in 3 primary ED patient care areas, the reception area, the primary nurses station, inside the cohort area, and the PPE donning and doffing areas immediately adjacent. Samples were recovered and analyzed for the presence of the E gene of SARS-CoV-2 using RT-PCR. SARS-CoV-2 was not detected on any surface samples, including in and around the cohort area. All air samples outside the COVID-19 hot zone were negative for SARS-CoV-2, but air samples within the cohort area had a low level of viral contamination. A designated COVID-19 cohort area resulted in no air or surface contamination outside of the hot zone, and only minimal air, but no surface contamination, within the hot zone.


Advanced decision support system for older adults.
Decision support systems are rapidly becoming part of today's healthcare delivery. The paradigm has shifted from traditional and manual recording to computer-based electronic records and, further, to handheld devices as versatile and innovative healthcare monitoring systems. The current study focuses on interpreting multiple physical signs and early warning for hospitalized older adults so that severe consequences can be minimized. Data from a total of 30 patients have been collated in New Zealand Hospitals under local and national ethics approvals. The system records blood pressure, heart rate (pulse), oxygen saturation (SpO2), ear temperature and blood glucose levels from hospitalized patients and transfers this information to a web-based software application for remote monitoring and further interpretation. Ultimately, this system is aimed to achieve a high level of agreement with clinicians' interpretation when assessing specific physical signs such as bradycardia, tachycardia, hypertension, hypotension, hypoxemia, fever and hypothermia and to generate early warnings.


Current state of immunotherapy for non-small cell lung cancer.
Lung cancer is the leading cause of cancer mortality and non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers. Platinum-based doublet chemotherapy is the standard first-line treatment for metastatic NSCLC when genomic testing reveals no targetable alteration such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) or ROS1 translocation/re-arrangements. But, chemotherapy produces response rates ranging only between 15-30%. For patients whose disease progresses on first-line chemotherapy, second-line therapy historically consists of taxane-based salvage chemotherapy with a response rate of less than 25%. Recently, immunotherapy with checkpoint inhibitor agents have demonstrated responses in advanced NSCLC, with some patients exhibiting durable responses after discontinuing therapy. In 2015, two immune checkpoint inhibitors targeting programmed cell death-1 (PD-1), nivolumab and pembrolizumab were approved for second-line therapy of NSCLC. In 2016, another checkpoint inhibitor targeting program death-ligand 1 (PD-L1), atezolizumab was approved for the same indication. Moreover, pembrolizumab also received approval in 2016 for first-line NSCLC treatment in patients with high PD-L1 expressing tumors. Immunotherapy for NSCLC has therefore, recently evolved into a true treatment modality with the acceptance of PD-1 and PD-L1 inhibitors as the new standard of care for second-line treatment. However, it is still at the discretion of the treating physician whether to use PD-1 or PD-L1 inhibitor as data to compare these two pathways is lacking. Focus is now also on exploring their role in the adjuvant and consolidation settings for NSCLC as well as on exploring novel combinations combining these agents with chemotherapy or radiation. Research is also needed in the development of predictive and prognostic biomarkers for these agents. While vaccine therapy trials in NSCLC have so far failed to show significant clinical benefit, the demonstration of enhanced immune response in these trials suggest the vaccine therapy needs additional evaluation in combination with other therapeutic modalities especially checkpoint inhibition.


The avrRxo1 gene from the rice pathogen Xanthomonas oryzae pv. oryzicola confers a nonhost defense reaction on maize with resistance gene Rxo1.
Maize lines that contain the single dominant gene Rxo1 exhibit a rapid hypersensitive response (HR) after infiltration with the rice bacterial streak pathogen Xanthomonas oryzae pv. oryzicola, but not with the rice bacterial blight pathogen X. oryzae pv. oryzae. The avirulence effector gene that corresponds to Rxo1, designated avrRxo1, was identified in an X. oryzae pv. oryzicola genomic library. When introduced into X. oryzae pv. oryzae, clones containing avrRxo1 induced an HR on maize with Rxo1, but not on maize without Rxo1. The avrRxo1 gene is 1,266 bp long and shows no significant homology to any database sequences. When expressed in an X. oryzae pv. oryzae hrpC mutant that is deficient in the type III secretion system, avrRxo1 did not elicit the HR, indicating that the avrRxo1-Rxo1 interaction is dependent on type III secretion. Transient expression of avrRxo1 in onion cells after biolistic delivery revealed that the protein product was associated with the plasma membrane. Transient expression in maize lines carrying Rxo1 resulted in cell death, suggesting that AvrRxo1 functions from inside maize cells to elicit Rxo1-dependent pathogen recognition.


[Role of omega-3 polyunsaturated fatty acids in diet of patients with rheumatic diseases].
The beneficial effects of omega-3 polyunsaturated fatty acids have been widely described in the literature in particular those on cardiovascular system. In the last decade there has been an increased interest in the role of these nutrients in the reduction of articular inflammation as well as in the improvement of clinical symptoms in subjects affected by rheumatic diseases, in particular rheumatoid arthritis (RA). Nutritional supplementation with omega-3 may represent an additional therapy to the traditional pharmacological treatment due to the anti-inflammatory properties which characterize this class of lipids: production of alternative eicosanoids, reduction of inflammatory cytokines, reduction of T-lymphocytes activation, reduction of catabolic enzymes activity. The encouraging results of dietetic therapy based on omega-3 in RA are leading researchers to test their effectiveness on patients with other rheumatic conditions such as systemic lupus erythematosus and ankylosing spondylitis. Nutritional therapy based on food rich in omega-3 or on supplementation with fish oil capsules, proved to be a valid support to he treatment of chronic inflammatory rheumatic diseases.


Complementary distribution of glutamatergic cerebellar and GABAergic basal ganglia afferents to the rat motor thalamic nuclei.
Motor thalamic nuclei, ventral anterior (VA), ventral lateral (VL) and ventral medial (VM) nuclei, receive massive glutamatergic and GABAergic afferents from the cerebellum and basal ganglia, respectively. In the present study, these afferents were characterized with immunoreactivities for glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular glutamate transporter (VGluT)2, and examined by combining immunocytochemistry with the anterograde axonal labeling and neuronal depletion methods in the rat brain. VGluT2 immunoreactivity was intense in the caudodorsal portion of the VA-VL, whereas GAD67 immunoreactivity was abundant in the VM and rostroventral portion of the VA-VL. The rostroventral VA-VL and VM contained two types of GAD67-immunopositive varicosities (large and small), but the caudodorsal VA-VL comprised small ones alone. VGluT2-immunopositive varicosities were much larger in the caudodorsal VA-VL than those in the rostroventral VA-VL and VM. When anterograde tracers were injected into the basal ganglia output nuclei, the vast majority of labeled axon varicosities were large and distributed in the rostroventral VA-VL and VM, showing immunoreactivity for GAD67, but not for VGluT2. Only the large GAD67-immunopositive varicosities were mostly abolished by kainic acid depletion of substantia nigra neurons. In contrast, large to giant axon varicosities derived from the deep cerebellar nuclei were distributed mostly in the caudodorsal VA-VL, displaying VGluT2 immunoreactivity. The VGluT2-positive varicosities disappeared from the core portion of the caudodorsal VA-VL by depletion of cerebellar nucleus neurons. Thus, complementary distributions of large VGluT2- and GAD67-positive terminals in the motor thalamic nuclei are considered to reflect glutamatergic cerebellar and GABAergic basal ganglia afferents, respectively.


Variation in excess all-cause mortality by age, sex, and province during the first wave of the COVID-19 pandemic in Italy.
Although previous evidence suggests that the infection fatality rate from COVID-19 varies by age and sex, and that transmission intensity varies geographically within countries, no study has yet explored the age-sex-space distribution of excess mortality associated with the COVID pandemic. By applying the principles of small-area estimation to existing model formulations for excess mortality, this study develops a novel method for assessing excess mortality across small populations and assesses the pattern of COVID excess mortality by province, year, week, age group, and sex in Italy from March through May 2020. We estimate that 53,200 excess deaths occurred across Italy during this time period, compared to just 35,500 deaths where COVID-19 was registered as the underlying cause of death. Out of the total excess mortality burden, 97% of excess deaths occurred among adults over age 60, and 68% of excess deaths were concentrated among adults over age 80. The burden of excess mortality was unevenly distributed across the country, with just three of Italy's 107 provinces accounting for 32% of all excess mortality. This method for estimating excess mortality can be adapted to other countries where COVID-19 diagnostic capacity is still insufficient, and could be incorporated into public health rapid response systems.


Patellar fractures in adults.
Patellar fracture is a common injury caused by excessive tension through the extensor mechanism or a direct blow. The intact patella increases the leverage and efficiency of the extensor mechanism and articulates with the femoral trochlea. Patellar fractures can lead to stiffness, extension weakness, and patellofemoral arthritis. Nonsurgical management is indicated for nondisplaced fractures with an intact extensor mechanism. Surgical fixation is recommended for fractures that either disrupt the extensor mechanism or demonstrate >2 to 3 mm step-off and >1 to 4 mm of displacement. Anatomic reduction and fixation with a tension-band technique is associated with the best outcomes; however, symptomatic hardware is a frequent complication. Open fractures are associated with more complications than closed fractures. These complications can be mitigated with timely débridement, irrigation, and internal fixation.


Efficacy of aquatic therapy for multiple sclerosis: a systematic review.
Multiple sclerosis (MS) is a chronic, inflammatory, progressive, disabling autoimmune disease affecting the central nervous system. Symptoms and signs of MS vary widely and patients may lose their ability to walk. To date the benefits of aquatic therapy often used for rehabilitation in MS patients have not been reviewed. The aim of this study was to systematically review the current state of aquatic treatment for persons with MS (hydrotherapy, aquatic therapy, aquatic exercises, spa therapy) and to evaluate the scientific evidence supporting the benefits of this therapeutic option. The databases PubMed, Scopus, WoS and PEDro were searched to identify relevant reports published from January 1, 2011 to April 30, 2016. Of 306 articles identified, only 10 fulfilled the inclusion criteria: 5 randomized controlled, 2 simple randomized quasi-experimental, 1 semi-experimental, 1 blind controlled pilot and 1 pilot. Evidence that aquatic treatment improves quality of life in affected patients was very good in two studies, good in four, fair in two and weak in two.


Mechanisms of the oxygen reduction reaction on B- and/or N-doped carbon nanomaterials with curvature and edge effects.
Despite recent increased research interest in hetero-atom (B and/or N) doping effects on the oxygen reduction reaction (ORR) performance of carbon nanomaterials, microscopic understanding of active catalytic sites and effects of B and/or N doping has not been conclusively reached. Here, through comparative first-principles simulations between BN codoping and isolated B or N doping in both graphene nanoribbons (GNRs) and carbon nanotubes (CNTs), we not only identify active sites in these doped carbon nanomaterials, but elucidate the underlying mechanism of ORR processes. While the distortion of C-C bonds in CNTs leads to strong binding of O2, spin density distribution along the edges plays a key role in enhancing the adsorption strength of O2 on GNRs. The effective adsorption of O2 facilitates the following elementary reduction reactions. Based on thermodynamic analyses, O2 adsorption as well as the electron and proton transfer to O atom are identified as key rate-determining steps. For CNTs, a good linear scaling is found between the adsorption energies of key intermediate products and that of atomic O, and thus the latter serves as a good descriptor for ORR activities. Further, N-doped high-quality CNTs are shown to exhibit best performance. For GNRs, due to edge effects, the linear relationship is broken, which promotes the catalytic activities in the BN codoping case. These findings resolve the long-standing controversy on the synergetic effects of B and N codoping, which deepens our understanding of the reaction mechanism. This work might further facilitate the optimization of the doping strategies for high-efficiency carbon-based ORR catalysts.


Hypoglycemia, functional brain failure, and brain death.
Hypoglycemia commonly causes brain fuel deprivation, resulting in functional brain failure, which can be corrected by raising plasma glucose concentrations. Rarely, profound hypoglycemia causes brain death that is not the result of fuel deprivation per se. In this issue of the JCI, Suh and colleagues use cell culture and in vivo rodent studies of glucose deprivation and marked hypoglycemia and provide evidence that hypoglycemic brain neuronal death is in fact increased by neuronal NADPH oxidase activation during glucose reperfusion (see the related article beginning on page 910). This finding suggests that, at least in the setting of profound hypoglycemia, therapeutic hyperglycemia should be avoided.


Telephone Usage and Cochlear Implant: Auditory Training Benefits.
Introduction Difficulties with telephone use by adult users of cochlear implants (CIs) are reported as a limitation in daily life. Studies to improve the speech understanding of CI users on the telephone are scarce in the Brazilian scientific literature. Objective To develop and evaluate the effectiveness of a training program of auditory abilities on the telephone for an adult CI user. Resumed Report The subject was a 55-year-old woman with a degree in accounting who used a CI for 24 months. The program consisted of three stages: pretraining evaluation, eight sessions of advanced auditory abilities training, and post-training evaluation. Auditory abilities with CI were evaluated before and after training in three conditions: sound field, telephone with the speech processor in the microphone function, and telephone with the speech processor in the telecoil function. Speech recognition was assessed by three different lists: one with monosyllabic and dissyllabic words, another with nonsense syllables, and another one with sentences. The Client Oriented Scale of Improvement (COSI) was used to assess whether the needs established by the CI user in everyday telephone use situations improved after training. The auditory abilities training resulted in a relevant improvement in the percentage of correct answers in speech tests both in the telephone use conditions and in the sound field condition. Conclusion The results obtained with the COSI inventory indicated a performance improvement in all situations presented at the beginning of the program.


Ossification of Posterior Longitudinal Ligament of Cervical Spine Among Omani Patients Referred for CT Scan at a Tertiary Care Hospital in Oman.
We sought to evaluate the proportion of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine and associated factors among Omani patients. We reviewed the cervical spine computed tomography (CT) scans of all patients referred to the Radiology Department, Sultan Qaboos University Hospital, from 2011 to 2017. Descriptive statistics were employed to determine the proportion of OPLL. We used the chi-square test to determine the association of age, gender, and diabetes mellitus with OPLL. A total of 843 patients aged ≥ 20 years were included in the study. The proportion of OPLL was 2.7% and was more frequent in men (3.2%) than women (1.9%). The male to female ratio of OPLL was 1.7:1.0. OPLL occurrence was significantly more in non-diabetic patients (p < 0.001). No significant association was found between OPLL with gender (p = 0.281) and age (p = 0.878). The observed proportion of OPLL in this single-center study is relatively low, but the finding is important as the condition can eventually lead to debilitating neurologic outcomes affecting the patient's quality of life. OPLL occurrence was significantly more in non-diabetic patients, which necessitate further research on OPLL in a larger sample across Oman.


Negative regulation of neuromedin U mRNA expression in the rat pars tuberalis by melatonin.
The pars tuberalis (PT) is part of the anterior pituitary gland surrounding the median eminence as a thin cell layer. The characteristics of PT differ from those of the pars distalis (PD), such as cell composition and gene expression, suggesting that the PT has a unique physiological function compared to the PD. Because the PT highly expresses melatonin receptor type 1, it is considered a mediator of seasonal and/or circadian signals of melatonin. Expression of neuromedin U (NMU) that is known to regulate energy balance has been previously reported in the rat PT; however, the regulatory mechanism of NMU mRNA expression and secretion in the PT are still obscure. In this study, we examined both the diurnal change of NMU mRNA expression in the rat PT and the effects of melatonin on NMU in vivo. In situ hybridization and quantitative PCR analysis of laser microdissected PT samples revealed that NMU mRNA expression in the PT has diurnal variation that is high during the light phase and low during the dark phase. Furthermore, melatonin administration significantly suppressed NMU mRNA expression in the PT in vivo. On the other hand, 48 h fasting did not have an effect on PT-NMU mRNA expression, and the diurnal change of NMU mRNA expression was maintained. We also found the highest expression of neuromedin U receptor type 2 (NMUR2) mRNA in the third ventricle ependymal cell layer, followed by the arcuate nucleus and the spinal cord. These results suggest that NMU mRNA expression in the PT is downregulated by melatonin during the dark phase and shows diurnal change. Considering that NMU mRNA in the PT showed the highest expression level in the brain, PT-NMU may act on NMUR2 in the brain, especially in the third ventricle ependymal cell layer, with a circadian rhythm.


Colour coding for blood collection tube closures - a call for harmonisation.
At least one in 10 patients experience adverse events while receiving hospital care. Many of the errors are related to laboratory diagnostics. Efforts to reduce laboratory errors over recent decades have primarily focused on the measurement process while pre- and post-analytical errors including errors in sampling, reporting and decision-making have received much less attention. Proper sampling and additives to the samples are essential. Tubes and additives are identified not only in writing on the tubes but also by the colour of the tube closures. Unfortunately these colours have not been standardised, running the risk of error when tubes from one manufacturer are replaced by the tubes from another manufacturer that use different colour coding. EFLM therefore supports the worldwide harmonisation of the colour coding for blood collection tube closures and labels in order to reduce the risk of pre-analytical errors and improve the patient safety.


Autonomous differentiation of dorsal axial structures from an animal cap cleavage stage blastomere in Xenopus.
Dorsal or ventral blastomeres of the 16- and 32-cell stage animal hemisphere were labeled with a lineage dye and transplanted into the position of a ventral, vegetal midline blastomere. The donor blastomeres normally give rise to substantial amounts of head structures and central nervous system, whereas the blastomere which they replaced normally gives rise to trunk mesoderm and endoderm. The clones derived from the transplanted ventral blastomeres were found in tissues appropriate for their new position, whereas those derived from the transplanted dorsal blastomeres were found in tissues appropriate for their original position. The transplanted dorsal clones usually migrated into the host's primary axis (D1.1, 92%; D1.1.1, 69%; D1.1.2, 100%), and in many cases they also induced and populated a secondary axis (D1.1, 43%; D1.1.1, 67%; D1.1.2, 63%). Bilateral deletion of the dorsal blastomeres resulted in partial deficits of dorsal axial structures in the majority of cases, whereas deletions of ventral midline blastomeres did not. When the dorsal blastomeres were cultured as explants they elongated. Notochord and cement glands frequently differentiated in these explants. These studies show that the progeny of the dorsal, midline, animal blastomeres: (1) follow their normal lineage program to populate dorsal axial structures after the blastomere is transplanted to the opposite pole of the embryo; (2) induce and contribute to a secondary axis from their transplanted position in many embryos; (3) are important for the normal formation of the entire length of the dorsal axis; and (4) autonomously differentiate in the absence of exogenous growth factor signals. These data indicate that by the 16-cell stage, these blastomeres have received instructions regarding their fate, and they are intrinsically capable of carrying out some of their developmental program.


Neural Model of Coding Stimulus Orientation and Adaptation.
The coding of line orientation in the visual system has been investigated extensively. During the prolonged viewing of a stimulus, the perceived orientation continuously changes (normalization effect). Also, the orientation of the adapting stimulus and the background stimuli influence the perceived orientation of the subsequently displayed stimulus: tilt after-effect (TAE) or tilt illusion (TI). The neural mechanisms of these effects are not fully understood. The proposed model includes many local analyzers, each consisting of two sets of neurons. The first set has two independent cardinal detectors (CDs), whose responses depend on stimulus orientation. The second set has many orientation detectors (OD) tuned to different orientations of the stimulus. The ODs sum up the responses of the two CDs with respective weightings and output a preferred orientation depending on the ratio of CD responses. It is suggested that during prolonged viewing, the responses of the CDs decrease: the greater the excitation of the detector, the more rapid the decrease in its response. Thereby, the ratio of CD responses changes during the adaptation, causing the normalization effect and the TAE. The CDs of the different local analyzers laterally inhibit each other and cause the TI. We show that the properties of this model are consistent with both psychophysical and neurophysiological findings related to the properties of orientation perception, and we investigate how these mechanisms can affect the orientation's sensitivity.


Computed Tomography-Derived Radiomic Metrics Can Identify Responders to Immunotherapy in Ovarian Cancer.
To determine if radiomic measures of tumor heterogeneity derived from baseline contrast-enhanced computed tomography (CE-CT) are associated with durable clinical benefit and time to off-treatment in patients with recurrent ovarian cancer (OC) enrolled in prospective immunotherapeutic trials. This retrospective study included 75 patients with recurrent OC who were enrolled in prospective immunotherapeutic trials (n = 74) or treated off-label (n = 1) and had baseline CE-CT scans. Disease burden (total tumor volume, number of disease sites), radiomic measures of intertumor heterogeneity (cluster-site entropy, cluster-site dissimilarity), and intratumor heterogeneity of the largest lesion (Haralick texture features) were computed. Associations of clinical, conventional imaging, and radiomic measures with durable clinical benefit and time to off-treatment were examined. In univariable analysis, fewer disease sites, lower intertumor heterogeneity (lower cluster-site entropy, lower cluster-site dissimilarity), and lower intratumor heterogeneity of the largest lesion (higher energy) were significantly associated with durable clinical benefit (P ≤ .031). More disease sites, presence of pleural disease and/or distant metastases, higher intertumor heterogeneity (higher cluster-site entropy, higher cluster-site dissimilarity), and higher intratumor heterogeneity of the largest lesion (higher Contrastlargest-lesion) were significantly associated with shorter time to off-treatment (P ≤ .034). In multivariable analysis, higher Energylargest-lesion (indicator of lower intratumor heterogeneity; P = .006; odds ratio, 1.41) and fewer disease sites (P = .003; odds ratio, 1.64) remained significant indicators of durable clinical benefit (multivariable model C-index, 0.821). Higher cluster-site dissimilarity (indicator of higher intertumor heterogeneity) was a modest but single independent indicator of shorter time to off-treatment (P = .004; hazard ratio, 1.19; C-index, 0.6). Fewer disease sites and lower intra- and intertumor heterogeneity modeled from the baseline CE-CT may indicate better response of OC to immunotherapy.


Lymphocytosis as a predictor of poor response to treatment of hepatitis C.
Identification of factors predicting response to therapy is critical in the management of hepatitis C. This study assessed significance of lymphocytosis as a predictor of sustained virological response (SVR). Retrospective analysis of lymphocytosis and its correlation with virologic response was performed in 110 subjects with chronic HCV infection, who underwent interferon based therapy. Lymphocytosis was defined as ratio of lymphocytes to neutrophils (L/N) above 0.6. L/N ratios were calculated to avoid the impact of hypersplenism and constitutional leukopenia seen in African Americans (AA). At baseline, L/N of HCV subjects (0.86) as compared to Hepatitis B controls (0.56) was significantly higher (P < 0.01). More AA HCV subjects (81.8%) had lymphocytosis at baseline when compared to Caucasian Americans subjects with HCV (37.9%) or AA controls (39.4%). Nonresponders had a higher frequency of lymphocytosis at baseline compared to subjects that achieved SVR (61.4% vs. 36.0%, p<0.05). More HCV subjects without lymphocytosis at baseline achieved SVR (33.3%) compared to HCV subjects with lymphocytosis (15%). At week 12 of therapy, nonresponders had higher L/N (1.02 vs. 0.86) and frequency of lymphocytosis (73% vs. 48%) compared to subjects that achieved SVR (p<0.05 for both). Only 17.2% of subjects with lymphocytosis at 12 weeks achieved SVR compared to 37.5% without lymphocytosis (p < 0.05). All responders exhibited significant normalization of lymphocytosis after treatment. HCV induces lymphocytosis, especially in AA, and is associated with lower rate of SVR. Furthermore, lymphocytosis may serve as an inexpensive pre-treatment tool to predict poor virologic response to HCV therapy.


Derivation of new reference tables for human heart weights in light of increasing body mass index.
As body weights and body mass indices have increased over time, we questioned the validity of correlating heart weight with body weight and whether tables from previous decades remain relevant. We investigated this by collecting details of heart weight, body weight, height, gender and age from 384 autopsy cases with no obvious heart or lung disease. Heart weights, body weights and heights showed a normal distribution for both genders. Heart weight correlated slightly better with body surface area than body weight and we present new reference charts derived from these data. The correlation between heart weight and body weight has changed little, despite increases in body weight and body mass index. As life expectancy is increasing, we investigated the effect of age on heart weight and demonstrated a small increase in heart weight relative to body surface area for both genders, in contrast to a previous study.


Checking for completeness of 24-h urine collection using para-amino benzoic acid not necessary in the Observing Protein and Energy Nutrition study.
The orally administered para-amino benzoic acid (PABA) is known to have near 100% excretion in urine and is used as a measure of 24-h urine collection completeness (referred to as PABAcheck). The purpose was to examine the effect of including urine collections deemed incomplete based on PABAcheck in a dietary measurement error study. The Observing Protein and Energy Nutrition (OPEN) study was conducted in 1999-2000 and included 484 men and women aged 40-69 years. A food frequency questionnaire and 24-h dietary recalls were evaluated using recovery biomarkers that included urinary nitrogen and potassium from two 24-h urine collections. Statistical modeling determined the measurement error properties of dietary assessment instruments. In the original analyses, PABAcheck was used as a measure of complete urine collection; incomplete collections were either excluded or adjusted to acceptable levels. The OPEN data were reanalyzed including all urine collections and by using criteria based on self-reported missing voids to assess the differences. Means and coefficients of variation for biomarker-based protein and potassium intakes, and measurement error model-based correlations and attenuation factors were similar regardless of whether PABAcheck or missed voids were considered. PABAcheck may not be required in large population-based biomarker studies. However, until there are more analyses evaluating the necessity of a PABAcheck, it is recommended that PABA be given to all participants, but not necessarily analyzed. Then, PABAcheck could be used selectively as a marker of completeness among the collections in which low levels of biomarker are detected or for which noncompliance is suspected.


Science centers: a potential for learning.
The past decade has witnessed a proliferation of science-technology centers, or public places for informal learning about science and technology. Science centers are the only institutions that can provide the general public with participatory exhibits and experiences, together with an accurate scientific interpretation of the materials that are involved. The dramatic rise in attendance and the enthusiasm of repeat visitors to science centers reflect a strong public demand for exhibits designed to help the visitor develop a better understanding of the contemporary scientific issues of society.


Long-term effect of the self-management comprehensive coping strategy program on quality of life in patients with breast cancer treated with high-dose chemotherapy.
This study aims to examine the effectiveness of a self-management multimodal comprehensive coping strategy program (CCSP) on quality of life (QOL) among breast cancer patients 1 year after treatment. Patients (n = 110) with stage II, III, or IV breast cancer scheduled to receive high dose chemotherapy and autologous hematopoietic stem cell transplantation were randomized to either CCSP treatment or control group. The CCSP intervention was taught 2 week before hospital admission with reinforcement at specified times during treatment and 3 months after discharge. The CCSP components included educational information, cognitive restructuring, coping skills enhancement, and relaxation with guided imagery. Instruments administered at baseline included the following: Quality of Life Index-Cancer Version (QOLI-CV), State-Trait Anxiety Inventory, Beck Depression Inventory, and Coping Strategies Questionnaire. At 1-year follow-up, patients (n = 73) completed and returned the follow-up QOLI-CV. Patients were mainly ≥ 40 years of age, married, Caucasian, and diagnosed with advanced breast cancer. A model measuring effectiveness of CCSP on QOL (total and subscale) at 1-year follow-up showed that the CCSP group (n = 38) had significant improvement in overall QOL (p < 0.01), health and functioning (p < 0.05), and socioeconomic (p < 0.05) and psychological/spiritual well-being (p < 0.01) compared with the control group (n = 35). The CCSP patients frequently used the CCSP to manage psychological (51%) and sleep problems (60%). The CCSP improved QOL for patients at 1-year follow-up. Patients overwhelmingly reported that CCSP was beneficial. The CCSP as an effective coping intervention has potential as a self-management program for breast cancer survivors.


Diminished Ovarian Reserve Predisposes to Premature Luteinizing Hormone Surges in Gonadotropin-Releasing Hormone Antagonist Cycles in In vitro Fertilization.
A premature luteinizing hormone (LH) surge, in in vitro fertilization (IVF) cycles with gonadotropin-releasing hormone (GnRH)-antagonist downregulation, leads to cycle cancellation. Currently, risk factors for the development of premature LH surge remain unknown. The aim of the study was to determine the incidence and identify the contributing factors for premature LH surge in IVF cycles with GnRH antagonist suppression. This was a retrospective cohort study. IVF-embryo transfer program at a fertility and research center. The study included all patients undergoing IVF from December 1, 2014, to November 30, 2018, in whom GnRH-antagonist (cetrorelix 0.25 mg/d) flexible protocol was used. The primary outcome measure was the identification of premature LH surges (documented by a 2.5-fold increase in LH from the baseline above a threshold of 17 mIU/mL) with or without a decrease in E2 and appearance of free fluid on ultrasound. Premature LH surges occurred in 15 (2.16%) of 692 patients undergoing IVF with GnRH-antagonist suppression. Patients with premature surges had significantly lower ovarian reserve as compared to the controls (as seen from their higher age group, higher day 2 follicle-stimulating hormone (FSH), lower antral follicle counts, and lower anti-Müllerian hormone). Premature LH surge in a GnRH-antagonist cycle can lead to cycle cancellation and disappointment. Although this is a rare event, the incidence is higher in patients with diminished ovarian reserve. Further studies are needed to determine if giving the human chorionic gonadotropin trigger a day earlier or giving higher doses of GnRH-antagonist can benefit such cases.