Comparison of two exploratory data analysis methods for fMRI: unsupervised clustering versus independent component analysis.
Exploratory data-driven methods such as unsupervised clustering and independent component analysis (ICA) are considered to be hypothesis-generating procedures, and are complementary to the hypothesis-led statistical inferential methods in functional magnetic resonance imaging (fMRI). In this paper, we present a comparison between unsupervised clustering and ICA in a systematic fMRI study. The comparative results were evaluated by 1) task-related activation maps, 2) associated time-courses, and 3) receiver operating characteristic analysis. For the fMRI data, a comparative quantitative evaluation between the three clustering techniques, self-organizing map, "neural gas" network, and fuzzy clustering based on deterministic annealing, and the three ICA methods, FastICA, Infomax and topographic ICA was performed. The ICA methods proved to extract features relatively well for a small number of independent components but are limited to the linear mixture assumption. The unsupervised Clustering outperforms ICA in terms of classification results but requires a longer processing time than the ICA methods.


SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress.
SIRT1, an NAD-dependent deacetylase, plays a role in regulation of autophagy. SIRT1 increases mitochondrial function and reduces oxidative stress, and has been linked to age-related reactive oxygen species (ROS) generation, which is highly dependent on mitochondrial metabolism. H2O2 induces oxidative stress and autophagic cell death through interference with Beclin 1 and the mTOR signaling pathways. We evaluated connections between SIRT1 activity and induction of autophagy in murine (m) and human (h) embryonic stem cells (ESCs) upon ROS challenge. Exogenous H2 O2 (1 mM) induced apoptosis and autophagy in wild-type (WT) and Sirt1-/- mESCs. High concentrations of H2O2 (1 mM) induced more apoptosis in Sirt1-/-, than in WT mESCs. However, addition of 3-methyladenine, a widely used autophagy inhibitor, in combination with H2O2 induced more cell death in WT than in Sirt1-/- mESCs. Decreased induction of autophagy in Sirt1-/- mESCs was demonstrated by decreased conversion of LC3-I to LC3-II, lowered expression of Beclin-1, and decreased LC3 punctae and LysoTracker staining. H2O2 induced autophagy with loss of mitochondrial membrane potential and disruption of mitochondrial dynamics in Sirt1-/- mESCs. Increased phosphorylation of P70/85-S6 kinase and ribosomal S6 was noted in Sirt1-/- mESCs, suggesting that SIRT1 regulates the mTOR pathway. Consistent with effects in mESCs, inhibition of SIRT1 using Lentivirus-mediated SIRT1 shRNA in hESCs demonstrated that knockdown of SIRT1 decreased H2O2-induced autophagy. This suggests a role for SIRT1 in regulating autophagy and mitochondria function in ESCs upon oxidative stress, effects mediated at least in part by the class III PI3K/Beclin 1 and mTOR pathways.


Many-level multilevel structural equation modeling: An efficient evaluation strategy.
Structural equation models are increasingly used for clustered or multilevel data in cases where mixed regression is too inflexible. However, when there are many levels of nesting, these models can become difficult to estimate. We introduce a novel evaluation strategy, Rampart, that applies an orthogonal rotation to the parts of a model that conform to commonly met requirements. This rotation dramatically simplifies fit evaluation in a way that becomes more potent as the size of the data set increases. We validate and evaluate the implementation using a 3-level latent regression simulation study. Then we analyze data from a state-wide child behavioral health measure administered by the Oklahoma Department of Human Services. We demonstrate the efficiency of Rampart compared to other similar software using a latent factor model with a 5-level decomposition of latent variance. Rampart is implemented in OpenMx, a free and open source software.


Pure-tone anomalies. I. Pitch-intensity effects and diplacusis in normal ears.
Pitch-intensity functions were obtained in both ears of five normal-hearing subjects, together with measurements of binaural diplacusis as a function of intensity. The results show that pitch-intensity functions are often significantly different in the two ears of a given subject at a given frequency. Furthermore, for each subject and frequency condition tested, an intensity existed for which no significant diplacusis was found. For these conditions, therefore, binaural diplacusis as a function of intensity could be accounted for by the interaural differences in pitch-intensity functions. Forward-masking patterns (FMP's) as a function of intensity were also obtained in both ears of several subjects. The FMP's were compared with pitch-intensity functions, obtained for the same conditions, for evidence of a covariation in the direction of shifts in masking patterns as a function of intensity with the direction of pitch shifts as a function of intensity. No convincing evidence of such a covariation was found. The implications of the results of these experiments are discussed relative to the question of temporal versus tonotopic coding of pure-tone pitch.


Tumour front inflammation and necrosis are independent prognostic predictors in high-grade urothelial carcinoma of the bladder.
Inflammation and necrosis have been associated with prognosis in multiple epithelial malignancies. Our objective was to evaluate inflammation and necrosis in a cohort of patients with high-grade urothelial carcinomas of the bladder to determine their association with pathological parameters and their prognostic effect on relapse-free and disease-specific survival. A retrospective cohort that underwent radical cystectomy for urothelial carcinomas (n=235) was evaluated for invasive front and central inflammation using the Klintrup-Makinen assessment method. Necrosis was scored using a four-point scale. The relationship of inflammation and necrosis with stage, nodal status, carcinoma in situ, tumour size, margin status and vascular space invasion and the impact on relapse-free and disease-specific survival were calculated using appropriate statistical tests. On multivariate analysis, invasive front inflammation (p=0.003) and necrosis (p=0.000) were independent predictors of relapse-free survival. Both invasive front inflammation (p=0.009) and necrosis (p=0.002) again were independent predictors of disease-specific survival. For pathological features, low invasive front inflammation was associated with lymphovascular space invasion (p=0.008), a positive soft tissue margin (p=0.028) and carcinoma in situ (p=0.042). Necrosis was statistically associated with tumours >3 cm in size (p=0.013) and carcinoma in situ (p<0.001). Necrosis and invasive front inflammation are additional histological variables with independent prognostic relevance in high-grade urothelial carcinoma of the bladder.


In vitro cytotoxicity screening of wild plant extracts from Saudi Arabia on human breast adenocarcinoma cells.
This study investigated the in vitro anticancer activities of a total of 14 wild angiosperms collected in Saudi Arabia. The cytotoxic activity of each extract was assessed against human breast adenocarcinoma (MCF-7) cell lines by using the MTT assay. Among the plants screened, the potential cytotoxic activity exhibited by the extract of Lavandula dentata (Lamiaceae) was identified, and we analyzed its anticancer potential by testing antiproliferative and apoptotic activity. Our results clearly show that ethanolic extract of L. dentata exhibits promising cytotoxic activity with an IC50 value of 39 μg/mL. Analysis of cell morphological changes, DNA fragmentation and apoptosis (using an Annexin V assay) also confirmed the apoptotic effect of L. dentata extract, and thus, our data call for further investigations to determine the active chemical constituent(s) and their mechanisms of inducing apoptosis.


The hypoferremic response to acute inflammation is maintained in thalassemia mice even under parenteral iron loading.
Hepcidin controls iron homeostasis by inducing the degradation of the iron efflux protein, ferroportin (FPN1), and subsequently reducing serum iron levels. Hepcidin expression is influenced by multiple factors, including iron stores, ineffective erythropoiesis, and inflammation. However, the interactions between these factors under thalassemic condition remain unclear. This study aimed to determine the hypoferremic and transcriptional responses of iron homeostasis to acute inflammatory induction by lipopolysaccharide (LPS) in thalassemic (Hbbth3 /+) mice with/without parenteral iron loading with iron dextran. Wild type and Hbbth3 /+ mice were intramuscularly injected with 5 mg of iron dextran once daily for two consecutive days. After a 2-week equilibration, acute inflammation was induced by an intraperitoneal injection of a single dose of 1 µg/g body weight of LPS. Control groups for both iron loading and acute inflammation received equal volume(s) of saline solution. Blood and tissue samples were collected at 6 hours after LPS (or saline) injection. Iron parameters and mRNA expression of hepcidin as well as genes involved in iron transport and metabolism in wild type and Hbbth3 /+ mice were analyzed and compared by Kruskal-Wallis test with pairwise Mann-Whitney U test. We found the inductive effects of LPS on liver IL-6 mRNA expression to be more pronounced under parenteral iron loading. Upon LPS administration, splenic erythroferrone (ERFE) mRNA levels were reduced only in iron-treated mice, whereas, liver bone morphogenetic protein 6 (BMP6) mRNA levels were decreased under both control and parenteral iron loading conditions. Despite the altered expression of the aforementioned hepcidin regulators, the stimulatory effect of LPS on hepcidin mRNA expression was blunt in iron-treated Hbbth3 /+ mice. Contrary to the blunted hepcidin response, LPS treatment suppressed FPN1 mRNA expression in the liver, spleen, and duodenum, as well as reduced serum iron levels of Hbbth3 /+ mice with parenteral iron loading. Our study suggests that a hypoferremic response to LPS-induced acute inflammation is maintained in thalassemic mice with parenteral iron loading in a hepcidin-independent manner.


Association of nucleotide polymorphisms within the O-antigen gene cluster of Escherichia coli O26, O45, O103, O111, O121, and O145 with serogroups and genetic subtypes.
Shiga toxin-producing Escherichia coli (STEC) strains are important food-borne pathogens capable of causing hemolytic-uremic syndrome. STEC O157:H7 strains cause the majority of severe disease in the United States; however, there is a growing concern for the amount and severity of illness attributable to non-O157 STEC. Recently, the Food Safety and Inspection Service (FSIS) published the intent to regulate the presence of STEC belonging to serogroups O26, O45, O103, O111, O121, and O145 in nonintact beef products. To ensure the effective control of these bacteria, sensitive and specific tests for their detection will be needed. In this study, we identified single nucleotide polymorphisms (SNPs) in the O-antigen gene cluster that could be used to detect STEC strains of the above-described serogroups. Using comparative DNA sequence analysis, we identified 22 potentially informative SNPs among 164 STEC and non-STEC strains of the above-described serogroups and designed matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) assays to test the STEC allele frequencies in an independent panel of bacterial strains. We found at least one SNP that was specific to each serogroup and also differentiated between STEC and non-STEC strains. Differences in the DNA sequence of the O-antigen gene cluster corresponded well with differences in the virulence gene profiles and provided evidence of different lineages for STEC and non-STEC strains. The SNPs discovered in this study can be used to develop tests that will not only accurately identify O26, O45, O103, O111, O121, and O145 strains but also predict whether strains detected in the above-described serogroups contain Shiga toxin-encoding genes.


Job satisfaction and stress levels among anaesthesiologists of south India.
Stress being high among practicing anaesthesiologists has effects on the quality of life. Methods to mitigate the stress have to be ensured to achieve job satisfaction. A survey was conducted through a questionnaire to know the various aspects of job satisfaction and job stress. The results of the data obtained were analyzed. An anaesthetists work area may vary from a small private hospital to a large tertiary centre.Depending on the number of anaesthetists in a particular hospital, the working hours and on call duties would be distributed. Overworked anaesthetists are prone to burnout due to sleep deprivation. This could lead to fatigue related error. Lesser the number of anaesthetists would mean less support from colleagues in the event of complications. Having a good rapport with surgical colleagues also helps to prevent stress.Anaesthesiologists should have adequate monitors to avoid error in judgement. Chronic stress has serious health hazards. Keeping updated with latest developments in our field helps to improve the quality of care provided. Anaesthetists should also receive the recognition and remuneration due to them. To improve the quality of care provided to a patient,anaesthesiologists must cope with job stress. An anaesthetist must enjoy the work rather than be burdened by it.


From Scheme to System (Part 2): Findings from Ten Countries on the Policy Evolution of Results-Based Financing in Health Systems.
Abstract- This article presents the enablers and barriers to the scaling-up of results-based financing (RBF) programs. It draws on the Alliance for Health Policy and Systems Research's multicountry program of research Taking Results Based Financing From Scheme to System, which compared the scale-up of RBF interventions over four phases-generation, adoption, institutionalization, and expansion-across ten countries. Comparing country experiences reveals broad lessons on scale up of RBF for each of the scale-up phases. Though the coming together of global, national, and regional contextual factors was key to the development of pilot projects, national factors were important to scale up these pilots to national programs, including a political context favoring results and transparency, the presence of enabling policies and institutions, and the presence of policy entrepreneurs at the national level. The third transition, from program to policy, was enabled by the availability of domestic financial resources, legislative and financing arrangements to enhance health facility autonomy, and technical and political leadership within and beyond the Ministry of Health. The article provides lessons learned on RBF policy evolution, emphasizing the importance of phase-specific groups of actors, the need to tailor advocacy messages to enable scale-up, the influence of political feasibility on policy content, and policy processes to build national ownership and enable health system strengthening.


Surface photochemistry of pesticides: an approach using diffuse reflectance and chromatography techniques.
The photochemistry of pesticides triadimenol and triadimefon was studied on cellulose and beta-cyclodextrin (beta-CD) in controlled and natural conditions, using diffuse reflectance techniques and chromatographic analysis. The photochemistry of triadimenol occurs from the chlorophenoxyl moiety, while the photodegradation of triadimefon also involves the carbonyl group. The formation of 4-chlorophenoxyl radical is one of the major reaction pathways for both pesticides and leads to 4-chlorophenol. Triadimenol also undergoes photooxidation and dechlorination, leading to triadimefon and dechlorinated triadimenol, respectively. The other main reaction process of triadimefon involves alpha-cleavage from the carbonyl group, leading to decarbonylated compounds. Triadimenol undergoes photodegradation at 254 nm but was found to be stable at 313 nm, while triadimefon degradates in both conditions. Both pesticides undergo photochemical decomposition under solar radiation, being the initial degradation of rate per unit area of triadimefon 1 order of magnitude higher than the observed for triadimenol in both supports. The degradation rates of the pesticides were somewhat lower in beta-CD than on cellulose. Photoproduct distribution of triadimenol and triadimefon is similar for the different irradiation conditions, indicating an intramolecular energy transfer from the chlorophenoxyl moiety to the carbonyl group in the latter pesticide.


The hospital organization of the future.
The future of hospital Nuclear Medicine is triggered by the hospital organisation itself. In general, the hospital organisation of the present requires substantial changes in order to be competitive, economical, and abreast of the rapid progresses in medical developments and patient management. It also must be flexible to changes in health politics. In this special report an organisational hospital structure is outlined which may help encounter the challenging hospital future. Some hospitals have already implemented convincing changes, whereas others are far behind.


Sex-Based Disparities in the Hourly Earnings of Surgeons in the Fee-for-Service System in Ontario, Canada.
Sex-based income disparities are well documented in medicine and most pronounced in surgery. These disparities are commonly attributed to differences in hours worked. One proposed solution to close the earnings gap is a fee-for-service payment system, which is theoretically free of bias. However, it is unclear whether a sex-based earnings gap persists in a fee-for-service system when earnings are measured on the basis of hours worked. To determine whether male and female surgeons have similar earnings for each hour spent operating in a fee-for-service system. This cross-sectional, population-based study used administrative databases from a fee-for-service, single-payer health system in Ontario, Canada. Surgeons who submitted claims for surgical procedures performed between January 1, 2014, and December 31, 2016, were included. Data analysis took place from February 2018 to December 2018. Surgeon sex. This study compared earnings per hour spent operating between male and female surgeons and earnings stratified by surgical specialty in a matched analysis. We explored factors potentially associated with earnings disparities, including differences in procedure duration and type between male and female surgeons and hourly earnings for procedures performed primarily on male vs female patients. We identified 1 508 471 surgical procedures claimed by 3275 surgeons. Female surgeons had practiced fewer years than male surgeons (median [interquartile range], 8.4 [2.9-16.6] vs 14.7 [5.9-25.7] years; P < .001), and the largest proportion of female surgeons practiced gynecology (400 of 819 female surgeons [48.8%]). Hourly earnings for female surgeons were 24% lower than for male surgeons (relative rate, 0.76 [95% CI, 0.74-0.79]; P < .001). This disparity persisted after adjusting for specialty and in matched analysis stratified by specialty, with the largest mean differences in cardiothoracic surgery (in US dollars: $59.64/hour) and orthopedic surgery ($55.45/hour). There were no differences in time taken by male and female surgeons to perform common procedures; however, female surgeons more commonly performed procedures with the lowest hourly earnings. Even within a fee-for-service system, male and female surgeons do not have equal earnings for equal hours spent working, suggesting that the opportunity to perform the most lucrative surgical procedures is greater for men than women. These findings call for a comprehensive analysis of drivers of sex-based earning disparities, including referral patterns, and highlight the need for systems-level solutions.


Indolo[3,2-b]indole-based crystalline hole-transporting material for highly efficient perovskite solar cells.
We have designed and synthesized fluorinated indolo[3,2-b]indole (IDID) derivatives as crystalline hole-transporting materials (HTM) for perovskite solar cells. The fluorinated IDID backbone enables a tight molecular arrangement stacked by strong π-π interactions, leading to a higher hole mobility than that of the current HTM standard, p,p-spiro-OMeTAD, with a spherical shape and amorphous morphology. Moreover, the photoluminescence quenching in a perovskite/HTM film is more effective at the interface of the perovskite with IDIDF as compared to that of p,p-spiro-OMeTAD. As a consequence, the device fabricated using IDIDF shows superior photovoltaic properties compared to that using p,p-spiro-OMeTAD, exhibiting an optimal performance of 19%. Thus, this remarkable result demonstrates IDID core-based materials as a new class of HTMs for highly efficient perovskite solar cells.


The Efficacy and Safety of First-line Chemotherapy in Advanced Esophagogastric Cancer: A Network Meta-analysis.
A globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA). Medline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs). The NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, n = 10 249) and 29 direct comparisons for PFS (34 studies, n = 7795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HR = 0.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HR = 0.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HR = 0.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HR = 0.61, 95% CrI = 0.38 to 0.99), FI (combined HR = 0.62, 95% CrI = 0.38 to 0.99), and FOx (combined HR = 0.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx. Based on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.


Efficient multi-fidelity computation of blood coagulation under flow.
Clot formation is a crucial process that prevents bleeding, but can lead to severe disorders when imbalanced. This process is regulated by the coagulation cascade, a biochemical network that controls the enzyme thrombin, which converts soluble fibrinogen into the fibrin fibers that constitute clots. Coagulation cascade models are typically complex and involve dozens of partial differential equations (PDEs) representing various chemical species' transport, reaction kinetics, and diffusion. Solving these PDE systems computationally is challenging, due to their large size and multi-scale nature. We propose a multi-fidelity strategy to increase the efficiency of coagulation cascade simulations. Leveraging the slower dynamics of molecular diffusion, we transform the governing PDEs into ordinary differential equations (ODEs) representing the evolution of species concentrations versus blood residence time. We then Taylor-expand the ODE solution around the zero-diffusivity limit to obtain spatiotemporal maps of species concentrations in terms of the statistical moments of residence time, [Formula: see text], and provide the governing PDEs for [Formula: see text]. This strategy replaces a high-fidelity system of N PDEs representing the coagulation cascade of N chemical species by N ODEs and p PDEs governing the residence time statistical moments. The multi-fidelity order (p) allows balancing accuracy and computational cost providing a speedup of over N/p compared to high-fidelity models. Moreover, this cost becomes independent of the number of chemical species in the large computational meshes typical of the arterial and cardiac chamber simulations. Using a coagulation network with N = 9 and an idealized aneurysm geometry with a pulsatile flow as a benchmark, we demonstrate favorable accuracy for low-order models of p = 1 and p = 2. The thrombin concentration in these models departs from the high-fidelity solution by under 20% (p = 1) and 2% (p = 2) after 20 cardiac cycles. These multi-fidelity models could enable new coagulation analyses in complex flow scenarios and extensive reaction networks. Furthermore, it could be generalized to advance our understanding of other reacting systems affected by flow.


Contribution of fast and slow conducting myelinated axons to single-peak compound action potentials in rat spinal cord white matter preparations.
Unlike recordings derived from optic nerve or corpus callosum, compound action potentials (CAPs) recorded from rodent spinal cord white matter (WM) have a characteristic single-peak shape despite the heterogeneity of axonal populations. Using a double sucrose gap technique, we analyzed the CAPs recorded from dorsal, lateral, and ventral WM from mature rat spinal cord. The CAP decay was significantly prolonged with increasing stimulus intensities suggesting a recruitment of higher threshold, slower conducting axons. At 3.5 mm conduction distance, a hidden higher threshold, slower conducting component responsible for prolongation of CAP decay was uncovered in 22 of 25 of dorsal WM strips by analyzing the stimulus-response relationships and a normalization-subtraction procedure. This component had a peak conduction velocity (CV) of 5.0 ± 0.2 (SE) m/s as compared with 9.3 ± 0.5 m/s for the lower threshold peak (P < 0.0001). Oxygen-glucose deprivation (OGD), along with its known effects on CAP amplitude, significantly (P < 0.015) shortened the CAP decay. The hidden higher threshold, slower conducting component showed greater sensitivity to OGD compared with the lower threshold, faster conducting component, suggesting a differential sensitivity of axonal populations of spinal cord WM. At longer conduction distances and lower temperatures (9.8 mm, 22-24°C), the slower peak could be directly visualized in CAPs at higher stimulation intensities. A detailed analysis of single-peak CAPs to identify their fast and slow conducting components may be of particular importance for studies of axonal physiology and pathophysiology in small animals where the conduction distance is not sufficiently long to separate the CAP peaks.


Uptake and effects of copper in rat liver mitochondria.
The rate and extent of Cu2+ uptake by rat liver mitochondria was measured under various conditions. 1. The uptake is both greater and faster without an energy supply. 2. The uptake, when occuring in ionic media, has a biphasic character, that is it always slows down after an initial burst, and then re-accelerates. 3. Uptake of Cu2+ in the presence of energy initiates K+ uptake from K+-containing media with accompanying swelling and respiratory stimulation. Depending on the amounts of Cu2+ added and the K+ concentration, an inhibition of respiration later ensues. 4. Chelation of the Cu2+ by substrates (notably glutamate) decreases the effects. 5. Prior exposure to Cu2+ decreases or prevents energy-dependent Ca2+ uptake.


An SIR-type epidemiological model that integrates social distancing as a dynamic law based on point prevalence and socio-behavioral factors.
Modeling human behavior within mathematical models of infectious diseases is a key component to understand and control disease spread. We present a mathematical compartmental model of Susceptible-Infectious-Removed to compare the infected curves given by four different functional forms describing the transmission rate. These depend on the distance that individuals keep on average to others in their daily lives. We assume that this distance varies according to the balance between two opposite thrives: the self-protecting reaction of individuals upon the presence of disease to increase social distancing and their necessity to return to a culturally dependent natural social distance that occurs in the absence of disease. We present simulations to compare results for different society types on point prevalence, the peak size of a first epidemic outbreak and the time of occurrence of that peak, for four different transmission rate functional forms and parameters of interest related to distancing behavior, such as: the reaction velocity of a society to change social distance during an epidemic. We observe the vulnerability to disease spread of close contact societies, and also show that certain social distancing behavior may provoke a small peak of a first epidemic outbreak, but at the expense of it occurring early after the epidemic onset, observing differences in this regard between society types. We also discuss the appearance of temporal oscillations of the four different transmission rates, their differences, and how this oscillatory behavior is impacted through social distancing; breaking the unimodality of the actives-curve produced by the classical SIR-model.


Identification of modifiable factors that affect the genetic diversity of the transmitted HIV-1 population.
Our previous studies have shown that the majority of African women were infected with multiple HIV-1 genetic variants, while in the remaining women only a single viral genotype was detected early in infection. Infection with multiple viral variants was associated with higher plasma HIV-1 RNA levels and faster CD4 T-cell decline. Socio-behavioral characteristics, use of hormonal contraceptives, and the presence of sexually transmitted diseases were prospectively assessed at approximately monthly intervals around the time of HIV-1 acquisition in female sex workers in Kenya. We assessed the relationship between these factors and HIV-1 genetic complexity early in infection. One hundred and fifty-six women were included in this analysis, of whom 89 had multiple viral genotypes and 67 had a single genotype at primary infection. Women with multiple variants were more likely to have a genital tract infection [odds ratio (OR), 4.7; 95% confidence interval (CI), 1.4-18.1] or to be using hormonal contraceptives (OR, 2.7; 95% CI, 1.3-5.6) at the time of their infection than those with a single variant. In multivariate analyses, these factors were independent predictors of early HIV-1 genetic complexity, and the presence of multiple viral variants early in infection remained significantly associated with a higher steady state plasma HIV-1 RNA level. The presence of genital tract infections and hormonal contraceptive use at the time of transmission were associated with the acquisition of multiple HIV-1 variants.


Ankle and foot tuberculosis: a diagnostic dilemma.
To know the biological behavior of ankle and foot tuberculosis (AFTB) and to know the reasons for delay in diagnosis and treatment of AFTB in our population. Patients with non-healing ulcers/sinuses/swellings in the ankle and foot region are the subjects of present study. Detailed clinical history, physical examination and relevant investigations were done in all cases. Pus/wound discharge for acid fast bacillus (AFB) study and biopsy from wound margin/sinus tract was taken in all the cases. During the period from July 2007-June 2012, 20 cases of AFTB were treated. Out of them five cases were difficult to diagnose and a mean period of 6 month to 5year was elapsed before final diagnosis was established. Out of these five cases - three cases were diabetic with ulcers and sinuses in the heel and ankle region. One case was wrongly diagnosed as angiodysplasia with A-V malformation of foot and diagnosis was delayed for 5 year. In one case of rheumatoid arthritis with abscess in ankle joint, the diagnosis was delayed for 1year. AFTB is very rare condition. AFTB is suspected in cases with long standing pain/swelling/discharging sinus in the foot and thorough investigations is must to differentiate from other foot diseases. Diagnosis is delayed due to lack of clinical suspicion and non-confirmatory biopsy reports. Early diagnosis and ATT for 9-18 months is must in all cases of AFTB to prevent joint involvement and other complications.


Measuring cognitive change in Alzheimer's disease clinical drug trials.
In the following paper the cognitive measures used in clinical trials of drugs for Alzheimer's disease are reviewed. The potential benefits of employing innovative tests that map cognitive domains poorly indexed by traditional measures such as the ADAS-cog are considered. Finally, issues pertaining to the cognitive breadth of any proposed new instrument are discussed, as well as the clinical relevance of cognitive change.


Place of birth effects on self-reported discrimination: Variations by type of discrimination.
Researchers have suggested that perceptions of discrimination may vary depending on place of birth and the length of time spent living in the U.S., variables related to acculturation. However, the existing literature provides a mixed picture, with data suggesting that the effects of acculturation on perceptions of discrimination vary by race and other sociodemographic factors. This study evaluated the role of place of birth (POB: defined as U.S.-born vs. foreign-born), age at immigration, and length of residence in the U.S. on self-reported discrimination in a sample of urban-dwelling Asian and Black adults (n= 1454). Analyses examined POB effects on different types of discrimination including race-related stigmatization, exclusion, threat, and workplace discrimination. Sociodemographic variables (including age, gender, employment status and education level) were tested as potential moderators of the relationship between POB and discrimination. The results revealed a significant main effect for POB on discrimination, with U.S.-born individuals reporting significantly more discrimination than foreign-born individuals, although the effect was reduced when sociodemographic variables were controlled. Across the sample, POB effects were seen only for race-related stigmatization and exclusion, not for threat and workplace discrimination. With the exception of limited effects for gender, sociodemographic variables did not moderate these effects. Younger age at immigration and greater years of residence in the U.S. were also positively associated with higher levels of perceived discrimination. These findings suggest increasing acculturation may shape the experience and perception of racial and ethnic discrimination.


Feng Chen's work on translational and clinical imaging.
Dr. Feng Chen is a chief medical doctor and the vice chairman of the Department of Radiology in Zhong Da Hospital at Southeast University, Nanjing, China and a senior researcher in the Department of Radiology at the Catholic University of Leuven, Belgium. His main areas of interest are translational imaging research including stroke, tumor angiogenesis, assessment of therapeutic response in solid tumors, and magnetic resonance contrast media. Dr. Feng Chen has published 44 scientific papers in peer-reviewed international journals. He and his colleagues have developed an imaging platform which includes animal models, animal preparations and multiparametric magnetic resonance imaging (MRI) protocols for translational animal imaging research using clinical machines. His MRI findings on rodent stroke are considered to "serve as a model for future laboratory investigations of treatment of acute stroke and unify the approaches developed for clinical studies". He and his colleagues have introduced a novel liver tumor model in rodents, in which a series of studies concerning the antitumor activity of vascular disrupting agents have been successively conducted and assessed by in vivo MRI, especially by diffusion weighted imaging as an imaging biomarker. His goal is to provide valuable references for clinical practice and to contribute to the translation of animal imaging research into patient applications.


Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.
To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.


Automatic Generation of Labeled Data for Video-Based Human Pose Analysis via NLP applied to YouTube Subtitles.
With recent advancements in computer vision as well as machine learning (ML), video-based at-home exercise evaluation systems have become a popular topic of current research. However, performance depends heavily on the amount of available training data. Since labeled datasets specific to exercising are rare, we propose a method that makes use of the abundance of fitness videos available online. Specifically, we utilize the advantage that videos often not only show the exercises, but also provide language as an additional source of information. With push-ups as an example, we show that through the analysis of subtitle data using natural language processing (NLP), it is possible to create a labeled (irrelevant, relevant correct, relevant incorrect) dataset containing relevant information for pose analysis. In particular, we show that irrelevant clips (n = 332) have significantly different joint visibility values compared to relevant clips (n = 298). Inspecting cluster centroids also show different poses for the different classes.


Cord blood cytokine levels in neonates born to mothers with prolonged premature rupture of membranes and its relationship with morbidity and mortality.
The purpose of this study was to determine cord blood cytokine levels and their relationship with morbidity and mortality in neonates with prolonged, premature rupture of membranes (PPROM). Forty two premature neonates of 29-35 weeks gestational age with PPROM exceeding 24 hours were considered as the PPROM group and simultaneously, 41 premature neonates without PPROM were considered as the control group. All the neonates were admitted to the Neonatology Unit for further evaluation of subsequent complications such as early neonatal sepsis, pneumonia, intraventicular haemorrhage (IVH), respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC) and chronic lung disease (CLD). Cord blood and mothers' blood samples were obtained during delivery in both groups and tested for IL-6, IL-8 and TNF-alpha levels. Twenty one percent of patients with PPROM had histological chorioamnionitis. The risk for developing early neonatal sepsis increased significantly in neonates whose mothers had histological chorioamnionitis (p < 0.05). There was a statistically significant relationship between PPROM and risk of developing NEC (p < 0.05); no significant increase was seen as regards early neonatal sepsis, IVH, RDS, pneumonia, or BPD. The mean IL-8 levels in cord blood and mothers' serum were significantly higher in the PPROM group (p < 0.001, p< 0.005). In addition, IL-6 levels found in mothers' serum were significantly higher than those found in the control group (p < 0.01). However, levels in cord blood were similar (p > 0.05). TNF-alpha levels were similar in both groups (p > 0.05). Neonates who developed NEC had higher IL-8 levels in their cord blood when compared to those without NEC (p < 0.05). In conclusion, the presence of PPROM increases the risk of chorioamnionitis. In addition, PPROM increases the risk of NEC, and patients who developed NEC had significantly higher cord blood IL-8 values. We may conclude that patients with PPROM and higher IL-8 levels in cord blood might be considered as at possible risk of NEC.


Aqueous humor and serum IgE antibody in experimental ocular Onchocerca infection of guinea pigs.
Infection of inbred Strain 2 guinea pigs by subcutaneous or intradermal injection of fresh or cryopreserved living Onchocerca lienalis microfilariae, followed by a challenge intracorneal infection of microfilariae, resulted in serum and aqueous IgE antibody and in significant corneal inflammation. Systemic or intraocular infections given separately were not sufficient to elicit IgE antibody or ocular inflammation. When intravenous transfer of pooled spleen cell suspensions from systemically infected donors to normal syngeneic recipients was substituted for the course of systemic infections, a subsequent intracorneal challenge of cell transfer recipients with microfilariae produced serum and aqueous IgE antibody. Administration of diethylcarbamazine citrate to infected animals following the intracorneal challenge resulted in increased serum IgE antibody and in increased corneal inflammation.


Isolation of erythropoietin-sensitive cells from Friend virus-infected marrow cultures: characteristics of the erythropoietin response.
Murine erythroid precursor cells, stimulated to proliferate in vitro in the absence of added erythropoietin (EP) by the anemia strain of Friend virus (FVA), will subsequently respond to EP by complete erythrocyte differentiation. If not exposed to EP, the erythroid cells divide for about 120 hr in culture, and they maintain the potential for full differentiation in response to EP added at any time during the period from 72 to 120 hr. Between 96 and 120 hr of culture without added EP, the EP-sensitive erythroid precursor cells that have formed discrete erythroid bursts can be isolated in relatively large numbers from such cultures by plucking with a Pasteur pipette. The addition of EP initiates the final stages of erythroid differentiation, including heme synthesis in 70%-80% of these isolated cells. With respect to homogeneity of the precursor cells, quantity of EP-responsive cells obtainable, and uniformity of EP responsiveness, this system is uniquely favorable for biochemical studies of the late differentiation effects of EP. The overall changes in gene expression accompanying EP-induced terminal differentiation were examined by two-dimensional gel electrophoresis of proteins labeled for a short time with radioactive amino acids. Several new proteins are synthesized in these erythroid cells during terminal differentiation, but the number is a very small percentage of the total number of proteins being made. Thus, in this system, the effect of EP is to initiate expression of a small group of genes, including those for globins, spectrin, and other proteins involved in the final stages of erythroid differentiation.


Component Composition and Biological Activity of Oleo-Gum Resin from Boswellia serrata (Burseraceae).
The review summarizes the published data on identification of biologically active compounds (BACs) and the pharmacological potential of various components of oleo-gum resin from the Indian frankincense Boswellia serrata Roxb. ex Colebr. Boswellia oleo-gum resin contains a wide range of BACs from the classes of mono-, sesqui-, di-, and triterpenes. Numerous in vivo and in vitro studies demonstrated their anti-inflammatory and antiproliferative effects. Boswellic acids (BAs), which belong to the tetra- and pentacyclic triterpenoid classes, showed the highest anti-inflammatory activity. The frankincense resin is traditionally used in Ayurvedic and Unani medicine and can provide a promising source to design drugs effective in treating musculoskeletal disorders.


A remarkable new target gene for the dioxin receptor: The Vav3 proto-oncogene links AhR to adhesion and migration.
The dioxin receptor (AhR) is possibly the best characterized xenobiotic receptor because of its essential role in mediating the harmful effects of highly toxic environmental pollutants. Despite the fact that AhR-dependent toxicity is a major environmental concern, compelling evidence has recently been produced unveiling novel and remarkable endogenous functions of AhR in cell physiology and tissue homeostasis. Adding to its role in cell proliferation and differentiation, AhR is also involved in the control of cell adhesion and migration, both highly relevant tasks in development and in disease states such as cancer. Interestingly, the effect of AhR on cell migration is cell-type specific because it can sustain or slow down cell motility. Here, I will comment on our recent report showing that AhR is a positive regulator of fibroblast cells migration. Besides characterizing the phenotype of such mesenchymal cells, the most important single finding of our study is that AhR uses the cytoskeleton regulator and oncogen Vav3 to signal through small Rho GTPases, ultimately leading to the physiological control of cell adhesion and migration. These data reveal that AhR activity is required to maintain signaling pathways governing normal cell function and open the question of whether AhR plays a role in cell migration during development and in pathological conditions such as tumor metastasis.


Monoclonal antibodies to the large glycoproteins of respiratory syncytial virus: possible evidence for several functional antigenic sites.
Employing different routes of immunization and different adjuvants, a large number of hybridomas were produced that secreted monoclonal antibodies (MAbs) against the large envelope glycoprotein (GP90) and the fusion glycoprotein (GP70) of respiratory syncytial virus (RSV). The antigenic specificity of the MAbs was established by immunoblot analysis and radioimmunoprecipitation. Three hybridomas secreting anti-GP90 MAbs were established from mice immunized by intraperitoneal injection of purified RSV in Freund's complete adjuvant. MAbs from these hybridomas did not neutralize viral infectivity. Three other hybridomas established from mice immunized by intraperitoneal inoculation of purified RSV with Bordetella pertussis produced anti-GP90 MAbs that neutralized the virus with or without complement. Similarly three other hybridomas established from mice immunized by infection with RSV via intranasal instillation of the virus produced anti-GP90 MAb that neutralized the virus in the presence and absence of complement. On the other hand, most anti-GP70 MAbs exhibited no neutralizing activity in the absence of complement, although many had low levels of neutralizing activity in the presence of complement, regardless of the type of immunization or the isotype of immunoglobulin. These observations suggest that there may be multiple antigenic sites on GP90, some of which involve a region of the molecule that functions in viral neutralization.


4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis.
Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE. Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice. Our results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro. Our work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.


Development of a multi-component gastroretentive expandable drug delivery system (GREDDS) for personalized administration of metformin.
Efficacy and compliance of type II diabetes treatment would greatly benefit from dosage forms providing controlled release of metformin in the upper gastrointestinal tract. In this respect, the feasibility of a new system ensuring stomach-retention and personalized release of this drug at its absorption window for multiple days was investigated. The system proposed comprised of a drug-containing core and a viscoelastic umbrella-like skeleton, which were manufactured by melt-casting and 3D printing. Prototypes, alone or upon assembly and insertion into commercially-available capsules, were characterized for key parameters: thermo-mechanical properties, accelerated stability, degradation, drug release, deployment performance and resistance to simulated gastric contractions. Each part of the system was successfully manufactured using purposely-selected materials and the performance of final prototypes matched the desired one. This included: i) easy folding of the skeleton against the core in the collapsed administered shape, ii) rapid recovery of the cumbersome configuration at the target site, even upon storage and iii) prolonged release of metformin. Composition, geometry and performance of the system developed in this work were deemed acceptable for stomach retention and prolonged as well as customizable release of metformin at its absorption window, laying promising bases for further development steps.


Immunohistochemical localization of a calcium pump and calbindin-D28k in the oviduct of the laying hen.
The localization of a plasma membrane calcium pump in the oviduct of the laying hen was investigated by immunohistochemical techniques, utilizing a monoclonal antibody (5F10) produced against the human erythrocyte calcium pump. This antibody was shown to react with an epitope of the pump in oviductal tissue, and prominent staining was observed on the microvilli of the tubular gland cells of the hen shell gland (uterus) and the isthmus. The Ca2+ pump was not detectable in the infundibulum or the magnum. Calbindin-D28k, also localized by immunohistochemical means, was observed to be present in the tubular gland cells of the shell gland and the distal isthmus (adjacent to shell gland) but not in either the proximal isthmus (adjacent to the magnum), the magnum or the infundibulum. The localization of the Ca2+ pump in the oviduct corresponds to known sites of mineral deposition during egg shell formation. The distribution of calbindin-D28k differed, co-localizing with the Ca2+ pump in the shell gland and distal isthmus but not in the proximal isthmus. This might reflect a greater rate of active Ca2+ secretion in the distal isthmus and shell gland as compared to the proximal isthmus.


Validation of Abbreviated Four- and Eight-Item Versions of the PTSD Checklist for DSM-5 in a Traumatically Injured Sample.
Rates of posttraumatic stress disorder (PTSD) are three times higher in traumatically injured populations than the general population, yet limited brief, valid measures for assessing PTSD symptom severity exist. The PTSD Checklist for DSM-5 (PCL-5) is a valid, efficient measure of symptom severity, but its completion is time consuming. Subsequently, abbreviated four- and eight-item versions were developed using the Mini-International Neuropsychiatric Interview-7 PTSD module and validated in Veteran samples. This study aimed to validate these abbreviated versions using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), the gold standard for PTSD diagnosis, in a traumatically injured civilian population. Participants were 251 traumatically injured adults (Mage = 42.52 years; 69.3% male; 50.2% Caucasian) recruited from a Level 1 trauma center inpatient unit; 32.3% and 17.9% of participants experienced a motor vehicle crash or gunshot wound, respectively. The CAPS-5 and PCL-5 were administered approximately 6.5 months postinjury. We examined whether compared to the full PCL-5, the abbreviated versions would adequately differentiate between participants with and without a CAPS-5 PTSD diagnosis. The abbreviated versions were highly correlated with the total scale and showed good-to-excellent internal consistency. The diagnostic utility of the abbreviated measures was comparable to that of the total scale regarding sensitivity, suggesting they may be useful as abbreviated screening tools; however, the total scale functioned better regarding specificity. The abbreviated versions of the PCL-5 may be useful screening instruments in the long-term care of traumatic injury survivors and may be more likely to be implemented across routine clinical and research contexts.


Effects of CO2 enrichment on the photosynthetic light response of sun and shade leaves of canopy sweetgum (Liquidambar styraciflua) in a forest ecosystem.
To investigate whether sun and shade leaves respond differently to CO2 enrichment, we examined photosynthetic light response of sun and shade leaves in canopy sweetgum (Liquidambar styraciflua L.) trees growing at ambient and elevated (ambient + 200 microliters per liter) atmospheric CO2 in the Brookhaven National Laboratory/Duke University Free Air CO2 Enrichment (FACE) experiment. The sweetgum trees were naturally established in a 15-year-old forest dominated by loblolly pine (Pinus taeda L.). Measurements were made in early June and late August 1997 during the first full year of CO2 fumigation in the Duke Forest FACE experiment. Sun leaves had a 68% greater leaf mass per unit area, 63% more leaf N per unit leaf area, 27% more chlorophyll per unit leaf area and 77% greater light-saturated photosynthetic rates than shade leaves. Elevated CO2 strongly stimulated light-saturated photosynthetic rates of sun and shade leaves in June and August; however, the relative photosynthetic enhancement by elevated CO2 for sun leaves was more than double the relative enhancement of shade leaves. Elevated CO2 stimulated apparent quantum yield by 30%, but there was no interaction between CO2 and leaf position. Daytime leaf-level carbon gain extrapolated from photosynthetic light response curves indicated that sun leaves were enhanced 98% by elevated CO2, whereas shade leaves were enhanced 41%. Elevated CO2 did not significantly affect leaf N per unit area in sun or shade leaves during either measurement period. Thus, the greater CO2 enhancement of light-saturated photosynthesis in sun leaves than in shade leaves was probably a result of a greater amount of nitrogen per unit leaf area in sun leaves. A full understanding of the effects of increasing atmospheric CO2 concentrations on forest ecosystems must take account of the complex nature of the light environment through the canopy and how light interacts with CO2 to affect photosynthesis.


Raphe-spinal neurons display an age-dependent differential capacity for neurite outgrowth compared to other brainstem-spinal populations.
Functional regeneration of brainstem-spinal pathways occurs in the developing chick when the spinal cord is severed prior to embryonic day (E) 13. Functional spinal cord regeneration is not observed in animals injured after E13. This developmental transition from a permissive to a restrictive repair period may be due to the formation of an extrinsic inhibitory environment preventing axonal growth, and/or an intrinsic inability of mature neurons to regenerate. Here, we investigated the capacity of specific populations of brainstem-spinal projection neurons to regrow neurites in vitro from young (E8) versus mature (E17) brainstem explants. A crystal of carbocyanine dye (DiI) was implanted in ovo into the E5 cervical spinal cord to retrogradely label brainstem-spinal projection neurons. Three or 12 days later, discrete regions of the brainstem containing DiI-labeled neurons were dissected to produce explant cultures grown in serum-free media on laminin substrates. The subsequent redistribution of DiI into regenerating processes permitted the study of in vitro neurite outgrowth from identified brainstem-spinal neurons. When explanted on E8, i.e., an age when brainstem-spinal neurons are normally elongating through the spinal cord and are capable of in vivo functional regeneration, robust neurite outgrowth was observed from all brainstem populations, including rubro-, reticulo-, vestibulo-, and raphe-spinal neurons. In contrast, when explanted on E17, robust neurite outgrowth was seen only from raphe-spinal neurons. Neurite outgrowth from raphe-spinal neurons was 5-hydroxy-tryptamine immunoreactive. This study demonstrates that in growth factor-free environments with permissive growth substrates, neurite outgrowth from brainstem-spinal neurons is dependent on both neuronal age and phenotype.


Analyzing Predictors of Control Measures and Psychosocial Problems Associated with COVID-19 Pandemic: Evidence from Eight Countries.
COVID-19 has harshly impacted communities globally. This study provides relevant information for creating equitable policy interventions to combat the spread of COVID-19. This study aims to predict the knowledge, attitude, and practice (KAP) of the COVID-19 pandemic at a global level to determine control measures and psychosocial problems. A cross-sectional survey was conducted from July to October 2020 using an online questionnaire. Questionnaires were initially distributed to academicians worldwide. These participants distributed the survey among their social, professional, and personal groups. Responses were collected and analyzed from 67 countries, with a sample size of 3031. Finally, based on the number of respondents, eight countries, including Bangladesh, China, Japan, Malaysia, Mexico, Pakistan, the United States, and Zambia were rigorously analyzed. Specifically, questionnaire responses related to COVID-19 accessibility, behavior, knowledge, opinion, psychological health, and susceptibility were collected and analyzed. As per our analysis, age groups were found to be a primary determinant of behavior, knowledge, opinion, psychological health, and susceptibility scores. Gender was the second most influential determinant for all metrics except information about COVID-19 accessibility, for which education was the second most important determinant. Respondent profession was the third most important metric for all scores. Our findings suggest that health authorities must promote health educations, implement related policies to disseminate COVID-19-awareness that can prevent and control the spread of COVID-19 infection.


Systematic review of behaviour change techniques to promote participation in physical activity among people with dementia.
The objective of this study was to systematically review the evidence for the potential promise of behaviour change techniques (BCTs) to increase physical activity among people with dementia (PWD). PsychINFO, MEDLINE, CINAHL, and the Cochrane Central Register of Controlled Trials databases were searched 01/01/2000-01/12/2016. Randomized controlled/quasi-randomized trials were included if they recruited people diagnosed/suspected to have dementia, used at least one BCT in the intervention arm, and had at least one follow-up measure of physical activity/adherence. Studies were appraised using the Cochrane Collaboration Risk of Bias Tool, and BCTs were coded using Michie et al., 2013, Annals of Behavioral Medicine, 46, 81. taxonomy. Intervention findings were narratively synthesized as either 'very promising', 'quite promising', or 'non-promising', and BCTs were judged as having potential promise if they featured in at least twice as many very/quite promising than non-promising interventions (as per Gardner et al., 2016, Health Psychology Review, 10, 89). Nineteen articles from nine trials reported physical activity findings on behavioural outcomes (two very promising, one quite promising, and two non-promising) or intervention adherence (one quite promising and four non-promising). Thirteen BCTs were used across the interventions. While no BCT had potential promise to increase intervention adherence, three BCTs had potential promise for improving physical activity behaviour outcomes: goal setting (behaviour), social support (unspecified), and using a credible source. Three BCTs have potential promise for use in future interventions to increase physical activity among PWD. Statement of contribution What is already known on this subject? While physical activity is a key lifestyle factor to enhance and maintain health and wellbeing amongst the general population, adults rarely participate in sufficient levels to obtain these benefits. Systematic reviews suggest that specific behaviour change techniques can increase physical activity, although one review suggested that self-regulatory techniques may be counterproductive when promoting physical activity among older people. Until now, no systematic review has been conducted to assess which behaviour change techniques may be associated with greater participation in physical activity among people with dementia. What does this study add? Interventions showed mixed promise for increasing physical activity and little effect on participant adherence. Goal setting (behaviour), social support (unspecified), and using a credible source are promising approaches. No technique showed promise for increasing adherence to physical activity interventions among people with dementia.


Effects of short-term exposure to particulate matter air pollution on cognitive performance.
This paper assesses the effect of short-term exposure to particulate matter (PM) air pollution on human cognitive performance via a double cross over experimental design. Two distinct experiments were performed, both of which exposed subjects to low and high concentrations of PM. Firstly, subjects completed a series of cognitive tests after being exposed to low ambient indoor PM concentrations and elevated PM concentrations generated via candle burning, which is a well-known source of PM. Secondly, a different cohort underwent cognitive tests after being exposed to low ambient indoor PM concentrations and elevated ambient outdoor PM concentrations via commuting on or next to roads. Three tests were used to assess cognitive performance: Mini-Mental State Examination (MMSE), the Stroop Color and Word test, and Ruff 2 & 7 test. The results from the MMSE test showed a statistically robust decline in cognitive function after exposure to both the candle burning and outdoor commuting compared to ambient indoor conditions. The similarity in the results between the two experiments suggests that PM exposure is the cause of the short-term cognitive decline observed in both. The outdoor commuting experiment also showed a statistically significant short-term cognitive decline in automatic detection speed from the Ruff 2 and 7 selective attention test. The other cognitive tests, for both the candle and commuting experiments, showed no statistically significant difference between the high and low PM exposure conditions. The findings from this study are potentially far reaching; they suggest that elevated PM pollution levels significantly affect short term cognition. This implies average human cognitive ability will vary from city to city and country to country as a function of PM air pollution exposure.


Localization and expression of zonula occludins-1 in the rabbit corneal epithelium following exposure to benzalkonium chloride.
Preservatives are a major component of the ophthalmic preparations in multi-dose bottles. The purpose of this study was to investigate the acute effect of benzalkonium chloride (BAC), a common preservative used in ophthalmic preparations, on the localization and expression of zonula occludens (ZO)-1 in the rabbit corneal epithelium in vivo. BAC at 0.005%, 0.01%, or 0.02% was topically applied to one eye each of albino rabbits at 5 min intervals for a total of 3 times. The contralateral untreated eyes served as controls. The following clinical indications were evaluated: Schirmer test, tear break-up time (BUT), fluorescein and rose Bengal staining. The structure of central cornea was examined by in vivo confocal microscopy, and the corneal barrier function was evaluated by measurement of corneal transepithelial electrical resistance and permeability to carboxy fluorescein. Whole mount corneas were analyzed by using fluorescence confocal microscopy for the presence of ZO-1, 2, occludin, claudin-1, Ki67 and cell apoptosis in the epithelium. The expression of ZO-1 in the corneal epithelium was also examined by western blot and reverse transcription-polymerase chain reaction analyses. Exposure to BAC resulted in higher rose Bengal staining scores while no significant changes in BUT, Schirmer and corneal florescein scores. It also induced corneal epithelial cell damage, dispersion of ZO-1 and ZO-2 from their normal locus at the superficial layer and disruption of epithelial barrier function. However, the amounts of ZO-1 mRNA and protein in the corneal epithelium were not affected by BAC treatment. Exposure to BAC can quickly impair the corneal epithelium without tear deficiency. BAC disrupts the tight junctions of corneal epithelium between superficial cells in the rabbit corneal epithelium in vivo.


Pelvic floor muscle retraining for pediatric voiding dysfunction using interactive computer games.
We evaluated a new noninvasive outpatient method of pelvic muscle retraining in children using computer game assisted biofeedback. All patients in whom voiding dysfunction was confirmed by history, uroflowmetry-electromyography and voiding cystourethrography were enrolled in a pelvic floor muscle retraining program. Patients received a pretreatment, mid treatment and posttreatment survey instrument documenting subjective improvement, including the frequency of diurnal enuresis, nocturnal enuresis, constipation and encopresis. Pretreatment and posttreatment simultaneous uroflowmetry surface electrode electromyography was performed and post-void residual urine volume was determined in all patients. A total of 8 boys and 33 girls 5 to 11 years old (mean age 7.2) completed therapy and were available for evaluation. These patients completed 2 to 11 (average 6) hourly treatment sessions. Followup was 3 to 15 months (average 7). At the midterm evaluation improvement in nocturnal enuresis was reported by 57% of the patients, diurnal enuresis by 84%, constipation by 83% and encopresis by 91%. End treatment evaluation revealed improvement in nocturnal enuresis by 90% of patients, diurnal enuresis by 89%, constipation by 100% and encopresis by 100%. Uroflowmetry-electromyography patterns improved in 42% of the patients and post-void residual urine decreased in 57%. Comparison of initial to end recorded millivoltage pelvic floor muscle values demonstrated that 56% of the patients had lower resting tone at the beginning of the session after completing therapy and 78% had improved contracting tone after performing Kegel exercises, as proved by increased microvoltage values. Initial uroflowmetry-electromyography revealed certain categories of cases, including a flattened voiding curve with a hyperactive pelvic floor and low post-void residual urine in 40%, a flattened voiding curve with a hyperactive pelvic floor and high post-void residual urine in 40%, a staccato voiding curve with a hyperactive pelvic floor and low post-void residual urine in 3%, and a staccato voiding curve with a hyperactive pelvic floor and high post-void residual urine in 17%. Of the girls 91% presented with the classic spinning top deformity on voiding cystourethrography. A total of 22 patients presented with a significant history of recurrent urinary tract infections, and infection developed in 3 during treatment and followup. Vesicoureteral reflux in 14 patients resolved during treatment in 3, reimplantation was performed in 1 and 10 are still being observed. A program of conservative medical management with computer game assisted pelvic floor muscle retraining resulted in significant subjective improvement in continence, constipation and encopresis as well as objective improvement in uroflowmetry-electromyography, post-void residual urine volume and the microvoltage value of pelvic floor muscles in the majority of patients with dysfunctional voiding.


The impact of prior aortic surgery on outcomes after multibranched endovascular aortic aneurysm repair.
The purpose of this study was to evaluate the impact of prior aortic surgery on outcomes after multibranched endovascular aneurysm repair (MBEVAR) of thoracoabdominal aortic aneurysms (TAAAs) and pararenal aortic aneurysms (PRAAs). From July 2005 to October 2016, there were 153 patients who underwent elective endovascular repair of TAAA and PRAA using multibranched stent grafts. Data on demographics, procedural details, and outcomes were collected prospectively. The mean age was 73 ± 8 years, and 113 of 153 (74%) were men. Mean aneurysm diameter was 67 ± 9 mm. Before MBEVAR, 68 of 153 (44%) patients had undergone a prior aortic surgery; 49 of 68 (72%) had prior open aortic surgery, 15 of 68 (22%) had prior endovascular aortic surgery, and 4 of 68 (6%) had both. There were no significant differences in age, sex, preoperative aneurysm diameter, or medical comorbidities (coronary artery disease, lung disease, diabetes mellitus, or hypertension) in patients with previous aortic surgery compared with those without. Patients with previous aortic surgery had higher fluoroscopy times (131 ± 59 vs 118 ± 54 minutes; P = .18) and procedural times (370 ± 101 vs 345 ± 118 minutes; P = .27) during MBEVAR, but these differences did not reach statistical significance. Patients without previous aortic intervention had higher rates of postoperative paraplegia (9/85 [11%]) vs (0/68 [0%]; P = .005) compared with those with previous aortic surgery. Of 153 patients, 3 (2%) had a postoperative stroke, and this was not different between the two groups. Median follow-up time was 2.5 years (interquartile range, 1.0-4.5 years) and did not differ between those with and those without previous aortic surgery. Kaplan-Meier estimated 5-year freedom from aneurysm-related mortality and overall mortality was 90% and 48%, respectively, and did not differ between the two groups. There was also no difference in branch vessel occlusion between the two groups. A high proportion of patients undergoing MBEVAR for TAAA or PRAA have already undergone prior open or endovascular aortic procedures, but this does not appear to increase the complication rate or affect midterm clinical outcomes. Patients with prior aortic surgery who undergo MBEVAR have lower rates of paraplegia compared with those without prior surgery, which may be due to effective recruitment of collateral circulation.


Effects of stacked quantitative resistances to downy mildew in lettuce do not simply add up.
In a stacking study of eight resistance QTLs in lettuce against downy mildew, only three out of ten double combinations showed an increased resistance effect under field conditions. Complete race nonspecific resistance to lettuce downy mildew, as observed for the nonhost wild lettuce species Lactuca saligna, is desired in lettuce cultivation. Genetic dissection of L. saligna's complete resistance has revealed several quantitative loci (QTL) for resistance with field infection reductions of 30-50 %. To test the effect of stacking these QTL, we analyzed interactions between homozygous L. saligna CGN05271 chromosome segments introgressed into the genetic background of L. sativa cv. Olof. Eight different backcross inbred lines (BILs) with single introgressions of 30-70 cM and selected predominately for quantitative resistance in field situations were intercrossed. Ten developed homozygous lines with stacked introgression segments (double combinations) were evaluated for resistance in the field. Seven double combinations showed a similar infection as the individual most resistant parental BIL, revealing epistatic interactions with 'less-than-additive' effects. Three double combinations showed an increased resistance level compared to their parental BILs and their interactions were additive, 'less-than-additive' epistatic and 'more-than-additive' epistatic, respectively. The additive interaction reduced field infection by 73 %. The double combination with a 'more-than-additive' epistatic effect, derived from a combination between a susceptible and a resistant BIL with 0 and 30 % infection reduction, respectively, showed an average field infection reduction of 52 %. For the latter line, an attempt to genetically dissect its underlying epistatic loci by substitution mapping did not result in smaller mapping intervals as none of the 22 substitution lines reached a similar high resistance level. Implications for breeding and the inheritance of L. saligna's complete resistance are discussed.


Plasmonic Magnesium Nanoparticles Are Efficient Nanoheaters.
Understanding and guiding light at the nanoscale can significantly impact society, for instance, by facilitating the development of efficient, sustainable, and/or cost-effective technologies. One emergent branch of nanotechnology exploits the conversion of light into heat, where heat is subsequently harnessed for various applications including therapeutics, heat-driven chemistries, and solar heating. Gold nanoparticles are overwhelmingly the most common material for plasmon-assisted photothermal applications; yet magnesium nanoparticles present a compelling alternative due to their low cost and superior biocompatibility. Herein, we measured the heat generated and quantified the photothermal efficiency of the gold and magnesium nanoparticle suspensions. Photothermal transduction experiments and optical and thermal simulations of different sizes and shapes of gold and magnesium nanoparticles showed that magnesium is more efficient at converting light into heat compared to gold at near-infrared wavelengths, thus demonstrating that magnesium nanoparticles are a promising new class of inexpensive, biodegradable photothermal platforms.


Improved test-retest reliability of R2* and susceptibility quantification using multi-shot multi-echo 3D EPI.
This study aimed to evaluate the potential of 3D echo-planar imaging (EPI) for improving the reliability of T2*-weighted (T2*w) data and quantification of R2* decay rate and susceptibility (χ) compared to conventional gradient echo (GRE)-based acquisition. Eight healthy subjects in a wide age range were recruited. Each subject received repeated scans for both GRE and EPI acquisitions with an isotropic 1 mm resolution at 3 T. Maps of R2* and χ were quantified and compared using their inter-scan difference to evaluate the test-retest reliability. Inter-protocol differences of R2* and χ between GRE and EPI were also measured voxel by voxel and in selected ROIs to test the consistency between the two acquisition methods. The quantifications of R2* and χ using EPI protocols showed increased test-retest reliability with higher EPI factors up to 5 as performed in the experiment and were consistent with those based on GRE. This result suggested multi-shot multi-echo 3D EPI can be a useful alternative acquisition method for T2*w MRI and quantification of R2* and χ with reduced scan time, improved test-retest reliability and similar accuracy compared to commonly used 3D GRE.


Sanitization of Chicken Frames by a Combination of Hydrogen Peroxide and UV Light To Reduce Contamination of Derived Edible Products.
Chicken carcass frames are used to obtain mechanically separated chicken (MSC) for use in other further processed food products. Previous foodborne disease outbreaks involving Salmonella-contaminated MSC have demonstrated the potential for the human pathogen to be transmitted to consumers via MSC. The current study evaluated the efficacy of multiple treatments applied to the surfaces of chicken carcass frames to reduce microbial loads on noninoculated frames and frames inoculated with a cocktail of Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium. Inoculated or noninoculated frames were left untreated (control) or were subjected to treatment using a prototype sanitization apparatus. Treatments consisted of (i) a sterile water rinse, (ii) a water rinse followed by 5 s of UV-C light application, or (iii) an advanced oxidation process (AOP) combining 5 or 7% (v/v) hydrogen peroxide (H2O2) with UV-C light. Treatment with 7% H2O2 and UV-C light reduced numbers of aerobic bacteria by up to 1.5 log CFU per frame (P < 0.05); reductions in aerobic bacteria subjected to other treatments did not statistically differ from one another (initial mean load on nontreated frames: 3.6 ± 0.1 log CFU per frame). Salmonella numbers (mean load on inoculated, nontreated control was 5.6 ± 0.2 log CFU per frame) were maximally reduced by AOP application in comparison with other treatments. No difference in Salmonella reductions obtained by 5% H2O2 (1.1 log CFU per frame) was detected compared with that obtained following 7% H2O2 use (1.0 log CFU per frame). The AOP treatment for sanitization of chicken carcass frames reduces microbial contamination on chicken carcass frames that are subsequently used for manufacture of MSC.


A risk score as part of an evidence-based approach to the selection of corneal replacement surgery.
There is currently no standardized methodology that permits preoperative prediction of the surgical technique or drug regimen for corneal grafting most likely to succeed for an individual patient. A score factor related to the chance of successful penetrating keratoplasty (PK) may assist in standardization of graft outcome reporting and evidence-based management. The Risk Score (RS) is based on factors shown to reduce the probability of 1-year survival of conventional PK in increments, using published Australian Corneal Graft Registry data. To asses its validity, Kaplan-Meier survival curves from 156 corneal replacement surgeries, stratified by preoperative RS, were used to derive the probability of survival at 1 year for donor PK, with or without systemic immunosuppression, and for synthetic PK with the AlphaCor artificial cornea. The probability of survival was then plotted against RS for each regimen, producing a family of curves. The mean RS for immunosuppressed cases was higher than for nonimmunosuppressed cases. The AlphaCor group had the highest scores. AlphaCor survival is little affected by the factors that affect the risk of graft survival, whereas the probability of donor graft survival, immunosuppressed or not, is inversely related to RS. This study was designed to test a method that allows objective comparison of outcomes of different methods of corneal replacement for different risk categories. Analysis of this small dataset supports the validity of the concept and suggests that the Risk Score is a useful descriptive statistic. With a sufficient sample size, statistically significant evidence of the optimum management method for an individual patient with a particular risk profile could be determined such that a prospective patient's preoperative RS could be used to assist management decisions. In particular, data allowing separation of different immunosuppression regimes would be useful. Functional outcomes such as visual acuity would be more significant clinically than the survival end point used in this study and the system also could be adapted to different follow-up periods.


KLIC-Score Does Not Predict Failure After Early Prosthetic Joint Infection: An External Validation with 153 Knees and 130 Hips.
A preoperative risk score, the KLIC-score (chronic renal failure [K], liver cirrhosis [L], indication of the index surgery [I], cemented prosthesis [C] and C-reactive protein >115 mg/L), has been developed to predict the risk of treatment failure after early prosthetic joint infection (PJI). This study aimed to validate the KLIC-score for the debridement, antibiotics, and implant retention (DAIR) procedure and one-stage revisions in a Northern European cohort. Revisions due to early PJI of the hip or knee between 1 January 2008 and 12 September 2021 were identified retrospectively. The primary outcome was early failure, which was considered when the patient needed an unscheduled surgery, the patient died, or the patient was prescribed long-term suppressive antibiotics. To examine the association between KLIC-score and failure risk, univariable logistic regression with the area under curves (AUCs) was used. In addition, models were calibrated to assess prognostic ability and clinical utility was examined with decision-curve-analyses. An increase in KLIC-score had a moderate predictive value for early failure after DAIR (Odds ratio [OR] 1.45, confidence interval [CI] 1.13 to 1.90). For one-stage revision, it was only slightly predictive of failure (OR 1.20, CI 0.93 to 1.56). After 60 days, the AUC for DAIR was 0.63 (CI 0.55 to 0.72) and 0.56 (CI 0.46 to 0.66) for one-stage revisions, indicating poor discriminative ability. The decision curve analyses revealed that the model did not offer a remarkabe net benefit across a range of threshold probabilities. We demonstrated that the KLIC-score is not a reliable predictor of early failure after early PJI in a Northern European cohort. Using the model to guide treatment decisions does not provide any additional clinical utility beyond the baseline strategies.


[Effects of digoxin on ventricular arrhythmias in patients with mitral valve defects].
A study was undertaken to examine 55 (27 females and 28 males) patients aged 25 to 74 years who had ventricular arrhythmias. Twenty five patients were diagnosed as having mitral valvular disease concurrent with predominant stenosis, 30 presented with prevalent mitral dysfunction. Twenty eight patients showed Stages I to IIA circulatory failure, and 27 had Stages IIB to III heart failure. All the patients displayed perpetual ciliary arrhythmia of various duration. More frequent and severe ventricular arrhythmias were recorded in mitral valvular disease patients with predominant mitral dysfunction than in those with stenoses. When the plasma digoxin concentration was less than 1.1 ng/ml in patients with a low end-diastolic volume and initial signs of circulatory failure, the agent produced an antiarrhythmic effects on ventricular arrhythmias in many cases, in mitral valvular disease patients with predominant stenosis in particular. The arrhythmogenic effect of digoxin was found in 47.6% patients with prevalent mitral dysfunction concurrent with Stages IIB-III circulatory failure. The agent may show arrhythmogenic action in mitral valvular disease patients with prevalent mitral dysfunction who had larger cardiac volumes and plasma digoxin concentrations of no more than 1.6 ng/ml in the absence of clinical signs of digitalis intoxication.


The Topographic Design of River Channels for Form-Process Linkages.
Scientists and engineers design river topography for a wide variety of uses, such as experimentation, site remediation, dam mitigation, flood management, and river restoration. A recent advancement has been the notion of topographical design to yield specific fluvial mechanisms in conjunction with natural or environmental flow releases. For example, the flow convergence routing mechanism, whereby shear stress and spatially convergent flow migrate or jump from the topographic high (riffle) to the low point (pool) from low to high discharge, is thought to be a key process able to maintain undular relief in gravel bedded rivers. This paper develops an approach to creating riffle-pool topography with a form-process linkage to the flow convergence routing mechanism using an adjustable, quasi equilibrium synthetic channel model. The link from form to process is made through conceptualizing form-process relationships for riffle-pool couplets into geomorphic covariance structures (GCSs) that are then quantitatively embedded in a synthetic channel model. Herein, GCSs were used to parameterize a geometric model to create five straight, synthetic river channels with varying combinations of bed and width undulations. Shear stress and flow direction predictions from 2D hydrodynamic modeling were used to determine if scenarios recreated aspects of the flow convergence routing mechanism. Results show that the creation of riffle-pool couplets that experience flow convergence in straight channels requires GCSs with covarying bed and width undulations in their topography as supported in the literature. This shows that GCSs are a useful way to translate conceptualizations of form-process linkages into quantitative models of channel form.


Combating autophagy is a strategy to increase cytotoxic effects of novel ALK inhibitor entrectinib in neuroblastoma cells.
Neuroblastoma (NB) is a threatening childhood malignancy. Its prognosis is affected by several morphological, and biological characteristics, including the constitutive expression of ALK tyrosine kinase. In this study we examined the therapeutic potential of a novel ALK inhibitor, entrectinib, in obliterating NB tumor cells. Entrectinib showed the growth-inhibitory effects on NB cells with a 50% inhibitory concentration range of 0.03-5 μM. In the ALK-dependent cells, entrectinib mediated G1-arrest, which was associated with modified expression of multiple cell-cycle regulators. Down-regulation of Ki-67, and attenuated phosphorylation of ERK1/2, and STAT3, correlated with observed antiproliferative capacity of entrectinib. Initial cytostatic activity of entrectinib was followed by concentration-dependent apoptotic cell death, and Caspase-3 activation. However, we delineated a reduced sensitivity of ALK mutated NB cells to entrectinib, and demonstrated strong activation of autophagy in SH-SY5YF1174L NB cell line. Abrogation of autophagy by chloroquine increased significantly the toxicity of entrectinib, as confirmed by enhanced death rate, and PARP protein cleavage in SH-SY5YF1174L cells. In aggregate, our data show that entrectinib inhibits proliferation, and induces G1-arrest, and apoptosis in NB cells. We propose entrectinib for further consideration in treatment of NB, and recommend pharmacological inhibition of autophagy to be explored for a combined therapeutic approach in NB patients that might develop resistance to entrectinib.


Identification of antimicrobial activity among FDA-approved drugs for combating Mycobacterium abscessus and Mycobacterium chelonae.
Rapidly growing mycobacteria have long been neglected in drug discovery efforts and this neglect is reflected in the paucity of therapeutic options available for diseases resulting from these infections. The purpose of this work is to identify new candidate drugs for treating non-tuberculous mycobacteria (NTM) by testing FDA-approved drugs for antimicrobial activity against Mycobacterium abscessus and Mycobacterium chelonae, two emerging NTM drug-resistant pathogens. In this study, we screened 1040 FDA-approved drugs against M. abscessus and M. chelonae. Of the drugs screened, 32 compounds exhibited significant antimicrobial activity, with an MIC ≤ 8 mg/L, against M. chelonae, while only 7 compounds showed such activity against M. abscessus. Notably, neostigmine bromide and cinnarizine exhibited highly significant antimicrobial activity against M. chelonae, but had little potency against M. abscessus. Metronidazole and puromycin were the only drugs that acted equipotently against both strains, in decreasing order of effectiveness. The dearth of identified compounds active against M. abscessus exemplifies its ability to resist drugs as well as the resilience of rapidly growing NTM. Repurposing of approved drugs is a viable alternative to de novo drug discovery and development.


A community-based trial of transdermal antihypertensive therapy with clonidine (Catapres-TTS).
The effectiveness of transdermally administered clonidine using Catapres-TTS patches applied once a week was assessed in the control of mild to moderate hypertension by 16 general practitioners in 135 subjects. Following two weeks on placebo patches, subjects with mean seated diastolic pressures 90 to 104 mmHg were titrated to one, two or three patches and blood pressure responses measured at monthly intervals for three months. Satisfactory response of blood pressure to 90 mmHg or lower was obtained in 85% of patients who completed the maintenance phase; in 20 patients whose blood pressure responses did not reach 90 mmHg, a significantly higher blood pressure (mean 158/103 mmHg) occurred at entry into the trial (145/96 mmHg). Withdrawal from the trial was mainly for reasons of inadequate blood pressure control (15%) or localised skin reactions (15%). Dryness of the mouth was the only systemic side effect encountered with significant frequency and resulted in the withdrawal of three patients. Localised skin reactions were encountered in 51% of subjects, in the majority these were mild and subjects elected to continue with transdermal clonidine because of the convenience of once a week administration. Severe or generalised skin reactions were not encountered. Serum biochemical measurements, including serum lipid levels, remained unaltered. Transdermal clonidine therapy provided satisfactory blood pressure control in the majority of subjects and apart from the localised skin reactions which were largely of nuisance value, proved safe and acceptable to patients.


The inverse scattering problem for orthotropic media in polarization-sensitive optical coherence tomography.
In this paper we provide for a first time, to our knowledge, a mathematical model for imaging an anisotropic, orthotropic medium with polarization-sensitive optical coherence tomography. The imaging problem is formulated as an inverse scattering problem in three dimensions for reconstructing the electrical susceptibility of the medium using Maxwell's equations. Our reconstruction method is based on the second-order Born-approximation of the electric field.


Sudden Respiratory Failure due to Tracheobronchomalacia by Relapsing Polychondritis, Successfully Rescued by Multiple Metallic Stenting and Tracheostomy.
Relapsing polychondritis (RP) is a rare systemic autoimmune disease that affects cartilaginous structures. RP causes tracheobronchomalacia (TBM) by affecting the bronchial cartilage. TBM is a fatal condition characterized by excessive weakening of the walls of the trachea and bronchi. We herein report a case of a 73-year-old man who experienced sudden respiratory failure due to TBM caused by RP. Immunosuppressive treatment did not improve his respiratory failure. Multiple metallic stentings dramatically improved his severe airway symptoms. When the airway condition becomes lethal in RP patients, then metallic stenting can be a useful treatment option.


[Specific features of DNA isolation for polymerase chain reaction in extrapulmonary tuberculosis].
While testing samples by the polymerase chain reaction (PCR), a procedure for DNA isolation is advisable adapted for different types of materials; thorough DNA purification is of the greatest importance in testing blood-containing samples, deep sample lysis is of particular importance for osseous tissue samples. A differential approach to isolating DNA from clinical samples allows the efficiency of PCR to be enhanced.


Efficacy of normal saline solution versus heparin solution for maintaining patency of peripheral intravenous catheters in children.
Literature reports support the use of normal saline solution for maintaining patency of peripheral intermittent intravenous infusion devices (PIID) in the adult population; however, there are limited data regarding this policy in the pediatric population. The purpose of this study was to establish the effects of heparin flush and saline solution flush solutions in maintaining patency of infusion devices in the pediatric population, and to establish cost-saving implications related to both procedures. The specific aims of the study included the following: (1) to determine the efficacy of normal saline solution flush for peripheral i.v. access devices for the pediatric population, and (2) to establish cost-saving implications related to normal saline solution versus heparin flush for PIIDs in terms of pharmacy costs and costs related to nursing time. The study was a prospective, randomized, double-blind controlled trial of flushing solutions. The control group (n = 77) received 3 ml of a 10 units heparin/ml normal saline solution i.v. flush. The experimental group (n = 73) received 3 ml of normal saline solution only for the i.v. flush. Routine hospital procedure for flushing was followed during the study period. Descriptive and correlation statistics were used to analyze the data; chi 2, t test, and analysis of variance were calculated. There were no significant differences between the two groups for demographics or complications. Annual cost savings were computed for both procedures with an estimated annual savings of nursing time and unit cost of solutions equaling $27,594. The savings per procedure was estimated at $9.45. This study provided support for the efficacy of normal saline solution as an alternative to heparin solutions for the maintenance of peripheral i.v. devices. Implications include elimination of risks associated with heparin (drug incompatibilities, thrombosis syndrome, hypersensitivity reactions, local tissue damage, and iatrogenic hemorrhage); decreased potential for infection associated with breaks in the integrity of the i.v. system; substantial money savings as a result of the change to normal saline solution realized by the patient and the institution; and decreased nursing time. By simplifying the procedure, nurses have more time to provide aspects of nursing care to patients.


Effect of nitric oxide on circular muscle of the canine small intestine.
1. Experiments were designed to determine in circular muscle of the canine jejunum whether exogenous nitric oxide (NO) mimics the non-adrenergic, non-cholinergic inhibitory junction potential (NANC IJP), and whether changes in the availability of endogenous NO affects IJP amplitude. 2. Mechanical and intracellular electrical activity were recorded simultaneously from circular muscle of the canine jejunum. Electrical field stimulation evoked NANC IJPs and inhibited spontaneous contractions. 3. Infusions of NO solutions evoked immediate dose-dependent and transient hyperpolarizations and transiently inhibited spontaneous contractions. NO-evoked hyperpolarizations were unaffected by atropine, propranolol, phentolamine and tetrodotoxin. 4. The maximum IJP amplitude and the maximum amplitude of NO-evoked hyperpolarization were similar. 5. NG-Mono-methyl-L-arginine (L-NMMA), which inhibits synthesis of NO from L-arginine, reduced IJP amplitudes but did not reduce the response to exogenous NO. L-Arginine, but not D-arginine, reversed the effect of L-NMMA on IJP amplitude. 6. Oxyhaemoglobin, which binds and inactivates NO, reduced IJP amplitude and abolished the response to exogenous NO. 7. Exogenous NO mimicked the effects of NANC inhibitory input. Reducing the availability of endogenous NO reduced NANC inhibitory input. 8. It was concluded that NO mediates NANC neural inhibition and may act as a NANC inhibitory neurotransmitter in the canine jejunum.


Enhancing learning through an interprofessional project competition.
This article describes the process of using an interprofessional team project to address one of the most commonly occurring challenges in health care delivery--medication reconciliation. We describe the planning and execution of the process and the lessons learned from the experience. The intent of this article is to document the significance of each process and the importance of each member involved in the process, and to act as a guideline for institutions planning similar interprofessional team project experiences for students.