Esophagogastric junction morphology assessment by high resolution manometry in obese patients candidate to bariatric surgery.
Obesity is a strong independent risk factor of gastroesophageal reflux disease (GERD) symptoms and hiatal hernia development. Pure restrictive bariatric surgery should not be indicated in case of hiatal hernia and GERD. However it is unclear what is the real incidence of disruption of esophagogastric junction (EGJ) in patients candidate to bariatric surgery. Actually, high resolution manometry (HRM) can provide accurate information about EGJ morphology. Aim of this study was to describe the EGJ morphology determined by HRM in obese patients candidate to bariatric surgery and to verify if different EGJ morphologies are associated to GERD-related symptoms presence. All patients underwent a standardized questionnaire for symptom presence and severity, upper endoscopy, high resolution manometry (HRM). EGJ was classified as: Type I, no separation between the lower esophageal sphincter (LES) and crural diaphragm (CD); Type II, minimal separation (>1 and < 2 cm); Type III, >2 cm separation. One hundred thirty-eight obese (BMI>35) subjects were studied. Ninety-eight obese patients referred at least one GERD-related symptom, whereas 40 subjects were symptom-free. According to HRM features, EGJ Type I morphology was documented in 51 (36.9%) patients, Type II in 48 (34.8%) and Type III in 39 (28.3%). EGJ Type III subjects were more frequently associated to Symptoms than EGJ Type I (38/39, 97.4%, vs. 21/59, 41.1% p < 0.001). Obese subjects candidate to bariatric surgery have a high risk of disruption of EGJ morphology. In particular, obese patients with hiatal hernia often refer pre-operative presence of GERD symptoms. Testing obese patients with HRM before undergoing bariatric surgery, especially for restrictive procedures, can be useful for assessing presence of hiatal hernia.


Emergency department of a university hospital: who is admitted and who is transferred?
Our main aim was to describe the path of patients seen in our emergency department (ED) and either admitted or transferred and to compare the characteristics of patients hospitalized in our hospital with those of transferred patients. Our secondary aim was to compare the receipts linked to patient hospital stays. All patients seen in the ED of our hospital and ill enough to be either admitted or transferred were prospectively enrolled during 2 consecutive weeks. Information was obtained from the hospital discharge report and from local medical databases. The characteristics of the patients and receipts were compared according to their path. Among the 251 patients included in the study, 9% were transferred directly from the ED to another hospital. Among admitted patients, two-thirds were admitted to the short-stay unit (SSU). Schematically, patients transferred from the ED are more likely to be men around 50 years of age with few comorbidities, requiring surgery with relatively short hospital stays. Patients transferred from the SSU were more likely to be women around 67 years of age with severe comorbidities requiring medical care and longer stays. The mean receipt per day was two to three times greater for patients transferred from the ED as compared with patients hospitalized in our hospital. The mean receipt per day for patients transferred from the SSU also tended to be higher. Our results show that patients requiring shorter care are transferred, whereas more severe patients are hospitalized on site. Hospitals will need solutions to optimize their receipts while fulfilling their public missions such as continuity of care.


All-fiber laser pump reflector based on a femtosecond-written inner cladding Bragg grating.
We report on the writing of chirped cladding Bragg gratings using 400 nm femtosecond pulses and the phase-mask inscription technique in the pure silica inner cladding of the gain fiber. The usefulness of such a fiber component is demonstrated as a pump reflector in a cladding-pumped all-fiber laser. A reflectivity of 53% for the residual pump power guided in the highly multimode 125 μm fiber's cladding is achieved, allowing for significant pump recycling in the fiber laser cavity which therefore optimizes the overall laser performances. As proof of concept, adding this pump reflector at the output of a 25 W erbium-doped fiber laser operating near 1.6 μm increased its slope efficiency according to the launched pump power from 17% to 23%, with the beneficial effect of reducing by 25% the optimal gain fiber length. This new, to the best of our knowledge, fiber laser component would have a great impact on the efficiency and cost of high-power cladding-pumped fiber laser systems.


Diosmin improved cognitive deficit and amplified brain electrical activity in the rat model of traumatic brain injury.
Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities in humans. Clinically, it is essential to limit the progress of cognitive impairment after TBI. It is reported that diosmin has a neuroprotective effect that can limit the progress of the impairment. The aim of this study was to evaluate the effects of diosmin on neurological score, memory, tumor necrosis factor-α (TNF-α) level and long-term potentiation in hippocampal dentate gyrus after the injury. A total of ninety six adult male Wistar rats were used as test subjects in this study. The animals were randomly assigned into one of the following three groups (n=32/group): Sham, TBI and diosmin (100mg/kg, p.o for seven consecutive days before TBI induction). TBI was induced into the animals by Marmarou's method. Briefly, a 200g weight was dropped from a 1m height through a free-falling tube onto the head of the anesthetized rats. The veterinary coma scale scores, memory and long-term potentiation in TBI group showed significant decrease at different times after the onset of TBI when compared with Sham (p<0.001). The TNF-α level in the hippocampus of the TBI group of animals was significantly higher than that found in the test subjects from the Sham group (p<0.001). The pre-treatment of the TBI group with diosmin significantly improved their neurological scores, memory and long-term potentiation (p<0.001) when compared with the TBI group. The TNF-α level in hippocampus of the diosmin group was significantly lower than the TBI group (p<0.001). Based on the results of the present study, pre-treatment with diosmin has protective effects against TBI-induced memory and long-term potentiation impairment. The effects of diosmin may be mediated through a decrement in the TNF-α concentration of hippocampus as a pro-inflammatory cytokine.


Randomized window of opportunity trial evaluating high-dose vitamin D in breast cancer patients.
Epidemiologic and preclinical data suggest a potential role for vitamin D in breast cancer treatment and prevention. However, results of prospective randomized trials are inconsistent. The objective of this study was to assess the effects of high-dose cholecalciferol (vitamin D3) on breast tumour proliferation and apoptosis. We conducted a prospective, randomized, phase 2, double-blinded pre-surgical window of opportunity trial. Newly diagnosed breast cancer patients were randomized to receive 40,000 IU of vitamin D3 per day or placebo for 2 to 6 weeks prior to breast surgery. The primary outcome was the relative change in proliferation (Ki67) and apoptosis (cleaved caspase 3 apoptotic assay [CC3]) in primary breast cancer cells pre and post treatment. Of 83 patients randomized, 80 completed the study (43 (53.8%) vitamin D and 37 (46.3%) placebo). Mean duration of drug intake was 19 days (range 9-28 days). There were no significant differences between the control arm and the vitamin D arm in percent changes of either Ki67 index (1.6% vs. 16.7%, p = 0.25) or CC3 (- 55.9% vs. - 45.9%, p = 0.28). Serum 25-hydroxyvitamin D (25-OHD) levels were 3 times higher in the vitamin D arm (62 nmol/L vs. 246 nmol/L, p < 0.001). Adverse effects were minimal and all classified as grade 1. Despite significantly higher levels of serum 25-OHD in the vitamin D-treated group, this was not associated with any significant effects on tumour proliferation or apoptosis. These findings are consistent with the lack of benefit observed in prospective prevention trials. Trial registration clinicaltrials.gov NCT01948128.


Does patient experience of multimorbidity predict self-management and health outcomes in a prospective study in primary care?
There is a need to better understand the mechanisms which lead to poor outcomes in patients with multimorbidity, especially those factors that might be amenable to intervention. This research aims to explore what factors predict self-management behaviour and health outcomes in patients with multimorbidity in primary care in the UK. A prospective study design was used. Questionnaires were mailed out to 1460 patients with multimorbidity. Patients were asked to complete a range of self-report measures including measures of multimorbidity, measures of their experience of multimorbidity and service delivery and outcomes (three measures of self-management: behaviours, Self-monitoring and Insight and medication adherence; and a measure of self-reported health). In total, 36% (n = 499) of patients responded to the baseline survey and 80% of those respondents completed follow-up. Self-management behaviour at 4 months was predicted by illness perceptions around the consequences of individual conditions. Self-monitoring and Insight at 4 months was predicted by patient experience of 'Hassles' in health services. Self-reported medication adherence at 4 months was predicted by health status, Self-monitoring and Insight and 'Hassles' in health services. Perceived health status at 4 months was predicted by age and patient experience of multimorbidity. This research shows that different factors, particularly around patients' experiences of health care and control over their treatment, impact on various types of self-management. Patient experience of multimorbidity was not a critical predictor of self-management but did predict health status in the short term. The findings can help to develop and target interventions that might improve outcomes in patients with multimorbidity.


Rapid formation of size-controlled three dimensional hetero-cell aggregates using micro-rotation flow for spheroid study.
Spheroids that are formed from aggregated cells have enhanced biological function compared to individual cells. In particular, hetero-spheroids composed of different types of cells, such as hepatocytes and endothelial cells, express tissue specific functions at a high level, which is advantageous for more precise drug screening and biological research. In this study, we propose rapid formation of size-controlled three-dimensional hetero-cell aggregates consisting of hepatocytes and endothelial cells using micro-rotation flow. Based on previous data, these aggregates are expected to ultimately become hetero-spheroids. The hepatocytes are coated with collagen gel films less than 200 nm thick, which were experimentally verified to increase adhesion strength between hepatocytes and endothelial cells. Gel-coated hepatocytes and endothelial cells are collected in an array by micro-rotational flow, thereby forming hetero-cell aggregates within 2 min. This array allowed the size of the three-dimensional cell aggregates to be hydrodynamically controlled, with standard deviations of less than 19%, by varying the cell density of the medium without altering the device geometry. Endothelial cells were successfully and uniformly dispersed in the aggregates. The proposed microfluidic device, with its capability of rapidly forming size-controlled hetero-cell aggregates, will offer an efficient experimental platform for future hetero-spheroid study that will contribute to drug screening and regenerative medicine.


Surface properties of extracellular malaria parasites: electrophoretic and lectin-binding characteristics.
The surface charge and lectin-binding capacity of isolated malaria parasites and host erythrocytes were analyzed and compared by chromatographic, electrophoretic, and cytochemical methods. Results indicated that at physiological pH values both freshly prepared and glutaraldehyde-fixed parasites and erythrocytes possess a net negative surface charge. Both cell types were strongly bound to cation-exchange resins and underwent cathode-directed electrophoretic migration. The isoelectric points for erythrocyte-free parasites and uninfected erythrocytes were approximately 3.0 and 4.0, respectively. The different effects of selective enzymatic digestion and solvent extraction on the electrophoretic mobilities of free parasites and erythrocytes suggested that the chemical constituents responsibile for the net negative surface charges on each type of cell are different. The surface charge of the free parasites seemed mainly to be a function of ionized phospholipids rather than of the ionogenic sialic acid moieties, which are the major contributors to the negative charge on erythrocytes. Results of lectin-binding studies indicated that specific glycosidimoieties (i.e., glucose, galactose, mannose, and n-acetyglucosamine), common to the erythrocyte surface, were either absent or in low concentration at the parasite's surface. These observations suggest that the normally intracellular malaria parasites have surface characteristics, differing from those of the host cell, characterized by a scarcity of lectin-binding receptors and sialic acid residues and by the major contribution of lipids to their surface charge.


Symptoms of anxiety, depression and self-care behaviors during the COVID-19 pandemic in the general population.
The COVID-19 pandemic can have important psychosocial consequences in the population. To determine the levels of anxiety, depression and self-care symptoms during the COVID-19 pandemic in the general population. Online survey distributed over three weeks using a non-probability sampling. The PHQ-9 Patient Health Questionnaire, the GAD-7 Generalized Anxiety Disorder Scale and Visual analog scale for self-care behaviors were used. Between-group (anxiety and depression) descriptive and comparison analyses were carried out. Out of 1508 included participants, 20.8% had symptoms of severe anxiety, while 27.5% showed symptoms of severe depression. Being a woman, being single, having no children, having medical comorbidities and a history of mental health care were risk factors for developing symptoms of anxiety and depression; 66 to 80 % of the population complied with self-care recommendations. A need for receiving mental health care was identified in our study population. A larger number of individuals with moderate to severe anxiety and depression symptoms were observed than in other pandemics. COVID-19 pandemic psychological effects are considered an emerging public health problem, and implementation of programs for their care is therefore recommended.


Psychological variables impacting weight gain rapidity in adolescents hospitalized for eating disorders.
This prospective study examined whether psychological variables related to the transdiagnostic theory of eating disorders measured at admission predicted length of time to reach 85 per cent of ideal body weight (IBW) among underweight adolescents hospitalized for an eating disorder. Thirty-three girls (aged 12-17) weighing below 85 per cent of IBW, admitted to an inpatient and/or partial hospitalization eating disorder programme completed self-report measures at admission. Cox regression tested whether scores on admission measures predicted time to reach 85 per cent of IBW. After controlling for IBW at admission, higher self-esteem and lower perfectionism predicted shorter time to reach 85 per cent of IBW, with emotion regulation as a marginally significant predictor. Self-esteem and perfectionism may be predictors of responsiveness to weight-gain efforts during hospitalization. Further studies are necessary to determine whether these variables might be appropriate targets for intervention to promote weight gain in underweight girls with eating disorders.


Mapping the Molecular Basis and Markers of Papillary Thyroid Carcinoma Progression and Metastasis Using Global Transcriptome and microRNA Profiling.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). In a subgroup of patients with PTC, the disease progresses to an invasive stage or in some cases to distant organ metastasis. At present, there is an unmet clinical and diagnostic need for early identification of patients with PTC who are at risk of disease progression or metastasis. In this study, we report several molecular leads and potential biomarker candidates of PTC metastasis for further translational research. The study design was based on comparisons of PTC in three different groups using cross-sectional sampling: Group 1, PTC localized to the thyroid (n = 20); Group 2, PTC with extrathyroidal progression (n = 22); and Group 3, PTC with distant organ metastasis (n = 20). Global transcriptome and microRNAs (miRNA) analyses were conducted using an initial screening set comprising nine formalin-fixed paraffin-embedded PTC samples obtained from three independent patients per study group. The findings were subsequently validated by quantitative real-time polymerase chain reaction (qRT-PCR) using the abovementioned independent patient sample set (n = 62). Comparative analyses of differentially expressed miRNAs showed that miR-193-3p, miR-182-5p, and miR-3607-3p were novel miRNAs associated with PTC metastasis. These potential miRNA biomarkers were associated with TC metastasis and miRNA-target gene associations, which may provide important clinicopathological information on metastasis. Our findings provide new molecular leads for further translational biomarker research, which could facilitate the identification of patients at risk of PTC disease progression or metastasis.


A novel approach for the selective determination of tryptophan in blood serum in the presence of tyrosine based on the electrochemical reduction of oxidation product of tryptophan formed in situ on graphite electrode.
In this study, a novel method was proposed for the selective determination of tryptophan (TRP) in blood serum in the presence of tyrosine. This method is based on the electrochemical reduction of 2-amino-3-(5-oxo-3,5-dihydro-2H-indol-3-yl)-propionic acid (5-O-3,5DH-TRP) formed by the oxidation of TRP on the electrochemically treated pencil graphite (ETPG) electrode surface at a suitable potential value. The parameters affecting the TRP determination were deeply investigated. The optimal pH value was determined as 3. The highest reduction current intensity was obtained at the accumulation potential and time values of +0.95 V and 120 s, respectively. The reduction peak current values of 5-O-3,5DH-TRP versus TRP concentration at the ETPG electrode showed linearity in the range from 0.5 μM to 50.0 μM (R(2)=0.9962) with a detection limit of 0.05 μM (S/N=3). The reduction peak intensity of 5-O-3,5DH-TRP on the ETPG electrode showed no significant change in the presence of different interfering substances. The analytical application of the proposed novel method was successfully tested by using human blood serum samples.


Potential Role of Rebamipide in Osteoclast Differentiation and Mandibular Condylar Cartilage Homeostasis.
Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease that involves changes in subchondral bone and progressive degradation of cartilage. Currently, rebamipide, a gastroprotective drug, is administered to protect gastric mucosa and accelerate ulcer healing. Recent studies have shown that rebamipide also attenuates cartilage degeneration by suppressing oxidative damage and inducing homeostasis of the extracellular matrix of articular chondrocytes. Regarding the latter, reduced expression of cathepsin K, NFATc1, c-Src, and integrin β3, and increased expression of nuclear factor-kappa B, have been found to be mediated by the transcription factor, receptor activator of nuclear factor kappa-B ligand (RANKL). Treatment with rebamipide was also found to activate, mitogen-activated protein kinases such as p38, ERK, and JNK to reduce osteoclast differentiation. Taken together, these results strongly indicate that rebamipide mediates inhibitory effects on cartilage degradation and osteoclastogenesis in TMJ-OA. Here, we highlight recent evidence regarding the potential for rebamipide to affect osteoclast differentiation and TMJ-OA pathogenesis. We also discuss the potential role of rebamipide to serve as a new strategy for the treatment of TMJ-OA.


Cost-effectiveness of prophylactic cranial irradiation with hippocampal avoidance in limited stage small cell lung cancer.
Prophylactic cranial irradiation (PCI) in limited stage small cell lung cancer (LS-SCLC) prevents brain metastases and improves survival, with the potential for neurocognitive toxicity. RTOG0933 demonstrated that hippocampal avoidance (HA) during whole brain radiotherapy preserves neurocognition. This study's objective was to evaluate the cost-effectiveness of HA-PCI in LS-SCLC through decision analysis. A Markov model was developed to simulate the clinical course of LS-SCLC who received HA-PCI or conventional PCI (C-PCI). A willingness-to-pay threshold of $100,000/QALY was used. Incremental cost effectiveness ratio was calculated (ICER). Sensitivity analyses were performed to determine the parameter thresholds and to assess the robustness of the model. In the base case scenario, HA-PCI is more cost-effective than C-PCI, with an ICER of $47,107/QALY. HA-PCI was preferred over C-PCI provided that the risk of developing brain metastases was not increased by at least 14%, or if neurocognitive dysfunction rates were reduced by at least 40%. HA-PCI was the cost-effective strategy in 68% of tested iterations in probabilistic sensitivity analysis. This study demonstrates that HA-PCI is more cost-effective than C-PCI in LS-SCLC. Our results support the use of HA-PCI in this patient population, should results from RTOG0933 be confirmed by the ongoing NRGCC003 trial.


Whole-genome sequencing approaches for conservation biology: Advantages, limitations and practical recommendations.
Whole-genome resequencing (WGR) is a powerful method for addressing fundamental evolutionary biology questions that have not been fully resolved using traditional methods. WGR includes four approaches: the sequencing of individuals to a high depth of coverage with either unresolved or resolved haplotypes, the sequencing of population genomes to a high depth by mixing equimolar amounts of unlabelled-individual DNA (Pool-seq) and the sequencing of multiple individuals from a population to a low depth (lcWGR). These techniques require the availability of a reference genome. This, along with the still high cost of shotgun sequencing and the large demand for computing resources and storage, has limited their implementation in nonmodel species with scarce genomic resources and in fields such as conservation biology. Our goal here is to describe the various WGR methods, their pros and cons and potential applications in conservation biology. WGR offers an unprecedented marker density and surveys a wide diversity of genetic variations not limited to single nucleotide polymorphisms (e.g., structural variants and mutations in regulatory elements), increasing their power for the detection of signatures of selection and local adaptation as well as for the identification of the genetic basis of phenotypic traits and diseases. Currently, though, no single WGR approach fulfils all requirements of conservation genetics, and each method has its own limitations and sources of potential bias. We discuss proposed ways to minimize such biases. We envision a not distant future where the analysis of whole genomes becomes a routine task in many nonmodel species and fields including conservation biology.


Operational temperature regulates anodic biofilm growth and the development of electrogenic activity.
The operational temperature of microbial fuel cell reactors influences biofilm development, and this has an impact on anodic biocatalytic activity. In this study, we compared three microbial fuel cell (MFC) reactors acclimated at 10°C, 20°C and 35°C to investigate the effect on biomass development, methanogenesis and electrogenic activity over time. The start-up time was inversely influenced by temperature, but the amount of biomass accumulation increased with increased temperatures, the 10°C, 20°C and 35°C acclimated biofilms resulted in 0.57, 0.82 and 5.43 g biomass (volatile suspended solids) per litre respectively at 56 weeks of operation. Biofilm build-up on the 35°C anode was further demonstrated by scanning electron microscopy, which showed large aggregations of biomass accumulating on the anode when compared to 10°C and 20°C biofilms. Biomass accumulation had a direct impact on biocatalytic performance, with the maximum power at 35°C after 60 weeks of operation being 2.14 W m(-3) and power densities for the 10°C and 20°C reactors being and 4.29 W m(-3). Methanogenic activity was also shown to be higher at 35°C, with a rate of 10.1 mmol CH(4) biofilm per gram of volatile suspended solid (VSS) per day, compared to 0.28 mmol CH(4) per gram of VSS per day produced at 20°C. These results demonstrate that higher MFC operating temperatures could be detrimental to the biocatalytic performance of electrochemically active bacteria in anodic biofilms due to biomass accumulation with enhanced development of non-electrogenic communities (e.g. methanogens and fermenters), meaning that, over time, psychro- or mesophilic operation can have beneficial effects for the development of electrogenically active populations in the reactor.


Functionalized carbon nanotubes for probing and modulating molecular functions.
Carbon nanotubes (CNTs) entered the domain of biological research a few years ago, creating a significant amount of interest due to their extraordinary physicochemical properties. The integration of CNT-based strategies with biology necessitates a multidisciplinary approach that requires competences in the diverse fields of chemistry, physics, and life sciences. In the biomedical domain CNTs are extensively explored as novel drug delivery systems for therapy and diagnosis. Additionally, CNTs can also be designed as new tools for modulation of molecular functions, by directly affecting various biological processes or by interaction with bioactive molecules. The aim of this review is to discuss how CNTs can be exploited as new probes for molecular functions. The different sections illustrate various applications of CNTs, including gene silencing, surface cell interactions via glycoproteins, biosensing, intracellular drug delivery using an atomic force microscopy tip-based nanoinjector, modulation of antibody/antigen interaction and enzyme activity, and blocking of ion channels.


Maternal emotional availability at bedtime predicts infant sleep quality.
In the present study, linkages were examined between parental behaviors (maternal practices) at bedtime, emotional availability of mothering at bedtime, and infant sleep quality in a cross-sectional sample of families with infants between 1 and 24 months of age. Observations of maternal behaviors and maternal emotional availability were conducted independently by 2 sets of trained observers who were blind to data being coded by the other. With infant age statistically controlled, specific maternal behaviors at bedtime were unrelated to infant sleep disruptions at bedtime and during the night. By contrast, emotional availability of mothering at bedtime was significantly and inversely related to infant sleep disruption, and, although these links were stronger for younger infants, they were significant for older infants as well. Maternal emotional availability was also inversely linked with mothers' ratings of whether their infants had sleep difficulties. These findings demonstrate that parents' emotional availability at bedtimes may be as important, if not more important, than bedtime practices in predicting infant sleep quality. Results support the theoretical premise that parents' emotional availability to children in sleep contexts promotes feelings of safety and security and, as a result, better-regulated child sleep.


Perception of orthodontic treatment need among Swedish children, adolescents and young adults.
Perceptions of orthodontic treatment need and perceptions of dental aesthetics was investigated among subjects ages 10, 15 and 19. A total of 489 subjects completed a questionnaire after inspecting 10 photographs in the Aesthetic Component scale of the Index of Orthodontic Treatment Need to (i) reveal the lower limit for orthodontic treatment need and (ii) rate their dental aesthetics by selecting the most similar photo. The mean lower limit for orthodontic treatment need was significantly higher (and closer to literature-based standards) among subjects, age 10 (4.2 ± 1.5), than among subjects, age 15 (3.6 ± 1.2) (p = .0009), and subjects, age 19 (3.5 ± 1.2) (p = .00002). Among subjects ages 15 and 19, the lower limit for orthodontic treatment need was lower in groups with (i) self-perceived orthodontic treatment need (p = .002 and .001, respectively) and (ii) previous orthodontic treatment (p = .005 and .035, respectively). Self-perceived orthodontic treatment need was present in more than one-third of subjects, age 19, who had previously received orthodontic treatment. Subjects of foreign origin reported that their dental aesthetics were worse (p = .002) and those same subjects, age 19, set the lower limit for orthodontic treatment lower (p = .047) than Swedes, age 19. The lower limit for orthodontic treatment need among subjects, age 10, was higher - compared to subjects, ages 15 and 19 - and closer to literature-based standards. Subjects with self-perceived orthodontic treatment need, subjects with previous orthodontic treatment, and subjects age 19 of foreign origin, have higher aesthetic demands.


The impact of an incentive on the use of an online self-directed wellness and self-management program.
Those who pay for health care are increasingly looking for strategies to influence individuals to take a more active role in managing their health. Incenting health plan members and/or employees to participate in wellness programs is a widely used approach. In this study, we examine financial incentives to health plan members to participate in an online self-management/wellness program-US $20 for completing the patient activation measure (PAM) and an additional US $40 for completing 8 learning modules. We examined whether the characteristics of plan members differed by the degree to which they responded to the incentives. Further, we examined whether participation in the wellness program was associated with improvements in PAM scores and changes in health care utilization. This retrospective study compared demographic characteristics and change in PAM scores and health utilization for 144,625 health plan members in 2011. Four groups were compared: (1) those who were offered the incentives but chose not to participate (n=128,634), (2) those who received the initial incentive (PAM only) but did not complete 8 topics (n=7099), (3) those who received both incentives (completing 8 topics but no more) (n=2693), and (4) those who received both incentives and continued using the online program beyond what was required by the incentives (n=6249). The vast majority of health plan members did not participate in the program (88.91%, 128,634/144,675). Of those who participated, only 7099 of 16,041 (44.25%) completed the PAM for the first incentive, 2693 (16.79%) completed 8 topics for the second incentive, and 6249 (38.96%) received both incentives and continued using the program beyond the incentive requirements. Nonparticipants were more likely to be men and to have lower health risk scores on average than the other three groups of participants (P<.001). In multivariate regression models, those who used the online program (8 topics or beyond) increased their PAM score by approximately 1 point more than those who only took the PAM and did not use the wellness program (P<.03). In addition, emergency department visits were lower for all groups who responded to any level of the incentive as compared to those who did not (P<.01). No differences were found in other types of utilization. The incentive was not sufficient to spark most health plan members to use the wellness program. However, the fact that many program participants went beyond the incentive in their use of the online wellness program suggests that the users of the online program found value in using it, and it was their own internal motivation that stimulated this additional use. Providing an incentive for program participation may be an effective pathway for working with less activated patients, particularly if the program is tailored to the needs of the less activated.


Effect of implementation of a Bragg reflector in the photonic band structure of the Suzuki-phase photonic crystal lattice.
We investigate the change of the photonic band structure of the Suzuki-phase photonic crystal lattice when the horizontal mirror symmetry is broken by an underlying Bragg reflector. The structure consists of an InP photonic crystal slab including four InAsP quantum wells, a SiO(2) bonding layer, and a bottom high index contrast Si/SiO(2) Bragg mirror deposited on a Si wafer. Angle- and polarization-resolved photoluminescence spectroscopy has been used for measuring the photonic band structure and for investigating the coupling to a polarized plane wave in the far field. A drastic change in the k-space photonic dispersion between the structure with and without Bragg reflector is measured. An important enhancement on the photoluminescence emission up to seven times has been obtained for a nearly flat photonic band, which is characteristic of the Suzuki-phase lattice.


A novel triple-regulated oncolytic adenovirus carrying p53 gene exerts potent antitumor efficacy on common human solid cancers.
Conditionally replicating adenoviruses (CRAd) can replicate specifically in cancer cells and lyse them. The CRAds were widely used in the preclinical and clinical studies of cancer therapy. We hypothesize that more precisely regulated replication of CRAds may further improve the vector safety profile and enhance its antitumor efficacy. Here, a triple-regulated CRAd carrying p53 gene expression cassette, SG600-p53, was engineered. In SG600-p53, the E1a gene with a deletion of 24 nucleotides within CR2 region is controlled under the human telomerase reverse transcriptase (hTERT) promoter, the E1b gene expression is directed by the hypoxia response element (HRE), whereas the p53 gene is controlled by the cytomegalovirus promoter. The precise triple-regulation endows SG600-p53 with enhanced antitumor potential and improved safety profile. The tumor-selective replication of this virus and its antitumor efficacy were characterized in several tumor cell lines in vitro and in xenograft models of human non-small cell lung cancer in nude mice. With the selective replication and oncolysis, it was found by ELISA assay that SG600-p53 expressed p53 efficiently in cancer cells. In NCI-H1299 tumor xenograft models, SG600-p53 displayed a tumor-selective killing capacity. At a dose of 2 x 10(9) plaque-forming units, SG600-p53 could completely inhibit the tumor growth and more effective than replication-defective Ad-p53. Histopathologic examination revealed that SG600-p53 administration resulted in cancer cell apoptosis. We concluded that the triple-regulated SG600-p53, as a more potent and safer antitumor therapeutic, could provide a new strategy for cancer biotherapy.


Internet appointment has more advantages than traditional appointment in the nursing service of dry eye patients.
Dry eye disease is one of the most common eye diseases. Clinical studies have found that meibomian gland expression can effectively improve the function of meibomian glands in patients with meibomian gland dysfunction. Compared with traditional appointments, Internet appointment has advantages in treating dry eye disease. A cross-sectional study was conducted to collect 300 patients with dry eye disease through an online questionnaire. Using Pearson chi-squared test, associations between the clinical parameters and appointment mode were analyzed. Spearman-rho test was executed to compare clinical data and appointment mode for correlation analysis and relationship between score of advantages of Internet booking (SOAIB), evaluation of the effectiveness of the Internet booking (EEIB), waiting in line for medical treatment (WMT). Univariate logistic regression analysis calculated the odds ratio (OR) of appointment mode for potential correlation factors. By using Pearson chi-squared test, SOAIB (P = .005), EEIB (P = .029) and WMT (P = .041) was significantly correlated with the appointment mode. Spearman correlation coefficient displayed that appointment mode was significantly correlated with EEIB (ρ = -0.126, P = .029) and WMT (ρ = 0.118, P = .041). Univariate logistic regression and concludes that EEIB (OR = 0.183, 95%CI: 0.033-1.004, P = .05), WMT (OR = 2.543, 95%CI: 1.013-6.384, P = .047) have a clear correlation with appointment mode. Spearman correlation coefficient displayed that SOAIB was significantly correlated with EEIB (ρ = -0.247, P < .001) and WMT (ρ = 0.157, P = .006). Internet appointment can effectively reduce the waiting time for dry eye disease treatment by meibomian gland expression. Effectiveness evaluation of Internet appointments is significantly higher than traditional appointments.


An Arf-like small G protein, ARL-8, promotes the axonal transport of presynaptic cargoes by suppressing vesicle aggregation.
Presynaptic assembly requires the packaging of requisite proteins into vesicular cargoes in the cell soma, their long-distance microtubule-dependent transport down the axon, and, finally, their reconstitution into functional complexes at prespecified sites. Despite the identification of several molecules that contribute to these events, the regulatory mechanisms defining such discrete states remain elusive. We report the characterization of an Arf-like small G protein, ARL-8, required during this process. arl-8 mutants prematurely accumulate presynaptic cargoes within the proximal axon of several neuronal classes, with a corresponding failure to assemble presynapses distally. This proximal accumulation requires the activity of several molecules known to catalyze presynaptic assembly. Dynamic imaging studies reveal that arl-8 mutant vesicles exhibit an increased tendency to form immotile aggregates during transport. Together, these results suggest that arl-8 promotes a trafficking identity for presynaptic cargoes, facilitating their efficient transport by repressing premature self-association.


Induction of sister chromatid exchanges and cell division delays in human lymphocytes by microsomal activation of benzene.
Metabolic activation of benzene by rat liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system (S-9 mix) induced sister chromatid exchanges (SCEs) and cell division delays in cultured human lymphocytes. There were optimal concentrations of S-9 mix for the conversion of benzene into the active metabolites that exerted these cytotoxic effects. Reduced glutathione prevented the induction of SCEs by benzene plus S-9 mix in a dose-dependent manner. Reduced glutathione (3 mM) also prevented the induction of SCEs by catechol or hydroquinone, active metabolites of benzene and potent inducers of SCEs, strongly suggesting that glutathione did not simply inhibit the activity of S-9 mix to activate benzene but actually prevented the production of DNA lesions by the active metabolites. Pulse treatment of cells with benzene plus S-9 mix produced the largest number of SCEs when administered at 40 hr of culture (fixed at 72 hr) but did not induce SCEs when administered immediately after the beginning of culture. This indicates that induced DNA lesions that could lead to formation of SCEs are removed in time.


Chromatic compensation of programmable Fresnel lenses.
Two proposals to compensate chromatic aberration of a programmable phase Fresnel lens displayed on a liquid crystal device and working under polychromatic illumination are presented. They are based on multiplexing a set of lenses, designed with a common focal length for different wavelengths, and a multicolor filter that makes each sublens work almost monochromatically. One proposal uses spatial multiplexing with mosaic aperture. The other uses a rotating scheme, a color filter against an array of lens sectors, and hybrid spatial-time integration. The central order focalization has a unique location at the focal plane. We have drastically reduced the transversal chromatic aberration of the polychromatic point spread function by properly adjusting the pupil size of each sublens. Depth of focus curves have been made coincident too for the selected wavelengths.


Improved Gait symmetry with spinal cord transcutaneous stimulation in individuals with spinal cord injury.
A previous study by our group showed preliminary results showcasing the usage of optimal and individualized spinal cord transcutaneous stimulation (scTS) parameters during overground gait training to facilitate more repeatable gait kinematics profiles for one participant with an incomplete spinal cord injury (SCI). The goal of this study was to use the combined targeted scTS and training to improve spatial and temporal parameters to achieve a symmetrical gait profile after completing activity-based training (ABT) (stepping and stand training) and exoskeleton training with and without scTS. Our data indicates that stimulation with optimal and individualized parameters can lead to more effective, stable and symmetric gait patterns in participants with varied levels of SCI.Clinical Relevance- This analysis will enable us to better understand the combined effect of exercise based training and tonic scTS on improving the quality and symmetry of gait pattern in participants with incomplete SCI.


Gaps in the Lexicon Restrict Communication.
Across languages, words carve up the world of experience in different ways. For example, English lacks an equivalent to the Chinese superordinate noun tiáowèipǐn, which is loosely translated as "ingredients used to season food while cooking." Do such differences matter? A conventional label may offer a uniquely effective way of communicating. On the other hand, lexical gaps may be easily bridged by the compositional power of language. After all, most of the ideas we want to express do not map onto simple lexical forms. We conducted a referential Director/Matcher communication task with adult speakers of Chinese and English. Directors provided a clue that Matchers used to select words from a word grid. The three target words corresponded to a superordinate term (e.g., beverages) in either Chinese or English but not both. We found that Matchers were more accurate at choosing the target words when their language lexicalized the target category. This advantage was driven entirely by the Directors' use/non-use of the intended superordinate term. The presence of a conventional superordinate had no measurable effect on speakers' within- or between-category similarity ratings. These results show that the ability to rely on a conventional term is surprisingly important despite the flexibility languages offer to communicate about non-lexicalized categories.


In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner.
The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-γ or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals. This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells.


Laser-induced alveolar bone changes during orthodontic movement: a histological study on rodents.
The aim of this study was to assess by light microscopy changes in alveolar bone during orthodontic movement in rats. Orthodontic movement causes both removal and deposition of bone tissue. The use of laser phototherapy (LPT) is considered an enhancement factor for bone repair. Thirty Wistar rats were divided into two groups (n = 15) and subdivided according to animal death (7,13, and 19 days). Half of the animals in each group were treated with LPT during orthodontic movement. After animal death, specimens were processed and underwent histological and semi-quantitative analyses (HE and Sirius red). LPT-irradiated specimens showed significantly higher numbers of osteoclasts when compared with controls at both 7 (p = 0.015) and 19 (p = 0.007) days, as well as significant increases in the number of osteoblasts (p = 0.015) between days 7 and 13. The amount of collagen matrix was significantly reduced between days 7 and 13 at both pressure and tension sites in controls (p = 0.015) but not in LPT-treated animals. LPT-treated subjects showed significantly greater deposition of collagen matrix at the pressure site at both the thirteenth (p = 0.007) and nineteenth days (p = 0.001). At the tension site, a significant increase in the amount of collagen matrix was observed in non-irradiated specimens (p = 0.048) between days 7 and 19. LPT caused significant histological changes in the alveolar bone during induced tooth movement, including alterations in the number of both osteoclasts and osteoblasts and in collagen deposition in both pressure and tension areas.


A rat model of Charcot-Marie-Tooth disease 1A recapitulates disease variability and supplies biomarkers of axonal loss in patients.
Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peripheral myelin protein 22 gene causes the most frequent subform Charcot-Marie-Tooth 1A. Patients develop a slowly progressive dysmyelinating and demyelinating peripheral neuropathy and distally pronounced muscle atrophy. The amount of axonal loss determines disease severity. Although patients share an identical monogenetic defect, the disease progression is strikingly variable and the impending disease course can not be predicted in individual patients. Despite promising experimental data, recent therapy trials have failed. Established clinical outcome measures are thought to be too insensitive to detect amelioration within trials. Surrogate biomarkers of disease severity in Charcot-Marie-Tooth 1A are thus urgently needed. Peripheral myelin protein 22 transgenic rats harbouring additional copies of the peripheral myelin protein 22 gene ('Charcot-Marie-Tooth rats'), which were kept on an outbred background mimic disease hallmarks and phenocopy the variable disease severity of patients with Charcot-Marie-Tooth 1A. Hence, we used the Charcot-Marie-Tooth rat to dissect prospective and surrogate markers of disease severity derived from sciatic nerve and skin tissue messenger RNA extracts. Gene set enrichment analysis of sciatic nerve transcriptomes revealed that dysregulation of lipid metabolism associated genes such as peroxisome proliferator-activated receptor gamma constitutes a modifier of present and future disease severity. Importantly, we directly validated disease severity markers from the Charcot-Marie-Tooth rats in 46 patients with Charcot-Marie-Tooth 1A. Our data suggest that the combination of age and cutaneous messenger RNA levels of glutathione S-transferase theta 2 and cathepsin A composes a strong indicator of disease severity in patients with Charcot-Marie-Tooth 1A, as quantified by the Charcot-Marie-Tooth Neuropathy Score. This translational approach, utilizing a transgenic animal model, demonstrates that transcriptional analysis of skin biopsy is suitable to identify biomarkers of Charcot-Marie-Tooth 1A.


Guided tissue regeneration with bioabsorbable and expanded polytetrafluoroethylene barrier membranes in the treatment of naturally occurring periodontal defects in dogs.
The purpose of the present study was to evaluate the healing events and compare the effects of guided tissue regeneration (GTR) using 3 different membranes: a weakly cross-linked bioabsorbable bovine collagen membrane; a strongly cross-linked bioabsorbable bovine collagen membrane; and a non-resorbable ePTFE membrane. Twenty adult female beagle dogs with naturally occurring periodontitis were subjected to periodontal probing and scaling. In both right and left mandibular quadrants, mucoperiosteal flaps were raised, and after debridement, the roots of experimental premolar teeth received apical reference notches. The following treatments were randomly assigned: 1) gingival flap curettage (GFC) + ePTFE membrane, control membrane; 2) GFC + slightly cross-linked collagen membrane, 1st test membrane; and 3) GFC + strongly cross-linked collagen membrane, 2nd test membrane. The flaps were sutured in such a manner that the membranes were completely covered. All dogs received a soft diet for a 2-week period and an oral hygiene program until time of sacrifice. The animals were randomly scheduled for sacrifice at 2, 4, 12, and 24 weeks. The ePTFE membranes still in place were removed at 6 weeks. The jaws were dissected and specimens prepared for descriptive histology and histomorphometry. The early resorption of the 1st test membrane was achieved at 4 weeks, and the 2nd test membrane at 12 weeks, both with normal inflammatory reaction. Measurements of epithelium, connective tissue attachment, new bone, and neocementum were compared within an animal (paired t test). Analyses were performed on data at 4, 12, and 24 weeks post-healing; little differences were found between these periods. Limited connective tissue repair was favored by the placement of all the membranes (about 20%), with no statistically significant difference. These findings indicate that bioabsorbable collagen membranes with different cross-linking and ePTFE barriers promote similar new attachment in GTR procedures on naturally occurring periodontal defects in dogs.


[Tropical African neuromyelopathies: 61 studied cases in the Ivory Coast].
Sixty one cases of tropical myeloneuropathies (TNM) from Abidjan, Ivory Coast, are reported. The mean age of patients was 35 years. The socioeconomic level was often very low and puerperality was a common initiating factor. Several clinical forms are noted: pure pyramidal (16 cases), pure ataxic (11 cases), sensory motor polyneuritis (8 cases), combined sclerosis of the spinal cord (1 case), ataxic polyneuritis (25 cases). In fact the extent of the pathobiological process was more severe as shown by slowings of peripheral motor nerve conduction velocities, prolonged central conduction time determined after cortical and spinal stimulations, and a severe sensory axonal impairment on nerve biopsies. These changes were observed with varying degrees in all clinical forms. As long as the etiological factors of TMN are not known (preventing from the possibility to split this disease in several entities) it is preferable to speak about one global disorder and not isolated various clinical forms (e.g. particulary: tropical spastic paraplegia). HTLV-I retrovirus seems to play a limited role in the etiology of TMN in Ivory Coast (1 positive case).


Anesthesia complications of pediatric radiation therapy.
Complications of anesthesia for pediatric radiation therapy are imperative for both radiation oncologists and anesthesiologists to clinically assess and manage. We performed the first systematic review to date addressing this important issue. A systematic search of PubMed and EMBASE was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches were not restricted based on publication date. Nine original investigations were identified, analyzed, and collated for this report. General anesthesia has proven superior to conscious sedation with regard to maintaining satisfactory procedural sedation while maintaining low respiratory and cardiovascular complication rates. Although agents such as ketamine (complication rates approaching 23%-24%) have been used in the past, other agents such as propofol and volatile anesthetics have lower complication rates because of improved drug side effect profiles (0.01%-3.5%). Most common complications are respiratory-based (eg, airway obstruction, broncho/laryngospasm, desaturation, apnea), followed by those that are cardiovascular-based (eg, tachy/bradycardia, arrhythmias, hypotension) and nausea/vomiting. Though procedure duration and anesthetic dose can be associated with higher complication risks, prior or concurrent chemotherapy does not confer added risks other than neutropenia-related sepsis. Other potential complications include those with vascular access devices, observed in up to 20% to 25%, with peripherally inserted central catheters having the highest rates of vascular complications and port catheters the lowest. Rates of anesthetic complications encountered in pediatric radiation therapy are similar, if not lower, than rates reported in controlled operating room settings, implying that anesthesia for pediatric radiation therapy is safe, with low complication rates periprocedurally. Propofol infusion and oxygen delivery via nasal cannula offer the lowest immediate anesthetic complication rates and are hence most recommended for use. Though the long-term neurocognitive consequences of multiple anesthetics in pediatric patients have yet to be clearly defined, health care providers should be cognizant of the potentially serious implications.


A case report of malignant hyperthermia in a dental clinic operating room.
A healthy 5-year-old boy presented for arch bar placement under general anesthesia in an operating room in a dental school. The patient had previously undergone general anesthesia without complication, and no family history of anesthetic problems were reported. Halothane mask induction, intravenous catheter placement, and nasal intubation proceeded uneventfully without the aid of a muscle relaxant. Halfway through the procedure, signs and symptoms of malignant hyperthermia, including muscle rigidity, hypercarbia, tachypnea, and tachycardia were noted. Immediate treatment, including discontinuation of the triggering agent, dantrolene administration, and cooling measures were applied, and once stable, the child was transferred to Columbus Children's Hospital for further management. The patient experienced no postoperative complications. Further discussion regarding the pathophysiology and management of malignant hyperthermia is provided.


Quantitative measurement of delta 9-tetrahydrocannabinol and two major metabolites in physiological specimens using capillary column gas chromatography negative ion chemical ionization mass spectrometry.
delta 9-Tetrahydrocannabinol and two of its metabolites, 11-hydroxy-delta 9-tetrahydrocannabinol and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol, can be measured in a single 1-ml sample of blood, plasma, or urine by a new assay which combines a relatively rapid extraction procedure with capillary column gas chromatography and negative ion chemical ionization mass spectrometry. Deuterium-labeled analogs of each cannabinoid are added to the physiological specimen as internal standards. Two extracts are obtained from each sample: a neutral fraction containing delta 9-tetrahydrocannabinol and 11-hydroxy-delta 9-tetrahydrocannabinol, and an acid fraction containing 11-nor-9-carboxy-delta 9-tetrahydrocannabinol. The neutral fraction is derivatized by treatment with trifluoroacetic anhydride; the acid fraction is first treated with BF3-methanol followed by reaction with trifluoroacetic anhydride. Under electron-capture chemical ionization conditions the derivatized delta 9-tetrahydrocannabinol and 11-nor-9-carboxy-delta 9-tetrahydrocannabinol give abundant molecular anions ideally suited for selected ion monitoring. The negative ion chemical ionization spectrum of the HO-THC-trifluoroacetate shows no molecular anion. Consequently, quantitation of the hydroxy metabolite is achieved by monitoring a fragment ion formed by loss of CF3CO2 from its molecular anion. The limits of reliable measurement are judged to be 0.1 ng ml-1 for 11-nor-9-carboxy-delta 9-tetrahydrocannabinol, 0.2 ng ml-1 for delta 9-tetrahydrocannabinol and 0.5 ng ml-1 for 11-hydroxy-delta 9-tetrahydrocannabinol. Four examples are given of the application of the assay to the analysis of specimens of medico-legal importance.


Barrierless tautomerization of Criegee intermediates via acid catalysis.
The tautomerization of Criegee intermediates via a 1,4 β-hydrogen atom transfer to yield a vinyl hydroperoxide has been examined in the absence and presence of carboxylic acids. Electronic structure calculations indicate that the organic acids catalyze the tautomerization reaction to such an extent that it becomes a barrierless process. In contrast, water produces only a nominal catalytic effect. Since organic acids are present in parts-per-billion concentrations in the troposphere, the present results suggest that the acid-catalyzed tautomerization, which can also result in formation of hydroxyl radicals, may be a significant pathway for Criegee intermediates.


Weakness on the intensive care unit.
Patients who are recovering from critical illness may be weak and difficult to wean from ventilatory support as a complication of their underlying disorder, intercurrent events or treatment given during prolonged intensive care. These patients are difficult to assess because of the severity of their weakness and any accompanying encephalopathy. It is essential to undertake a meticulous review, including assessment of any septic, hypoxic or metabolic derangements and a detailed look at the dosage and duration of medication including antibiotics, neuromuscular junction blocking agents and sedation. If a primary underlying neurological cause or an intercurrent event have been excluded, the likeliest cause of weakness is one of the neuromuscular complications of critical care such as: critical care polyneuropathy, an acute axonal neuropathy which develops in patients with preceding sepsis or multi-organ failure; the use of neuromuscular junction blocking agents or steroids; and critical illness myopathy, which is the most common cause of critical care related weakness.


Multi-Institutional Assessment and Crowdsourcing Evaluation of Deep Learning for Automated Classification of Breast Density.
We developed deep learning algorithms to automatically assess BI-RADS breast density. Using a large multi-institution patient cohort of 108,230 digital screening mammograms from the Digital Mammographic Imaging Screening Trial, we investigated the effect of data, model, and training parameters on overall model performance and provided crowdsourcing evaluation from the attendees of the ACR 2019 Annual Meeting. Our best-performing algorithm achieved good agreement with radiologists who were qualified interpreters of mammograms, with a four-class κ of 0.667. When training was performed with randomly sampled images from the data set versus sampling equal number of images from each density category, the model predictions were biased away from the low-prevalence categories such as extremely dense breasts. The net result was an increase in sensitivity and a decrease in specificity for predicting dense breasts for equal class compared with random sampling. We also found that the performance of the model degrades when we evaluate on digital mammography data formats that differ from the one that we trained on, emphasizing the importance of multi-institutional training sets. Lastly, we showed that crowdsourced annotations, including those from attendees who routinely read mammograms, had higher agreement with our algorithm than with the original interpreting radiologists. We demonstrated the possible parameters that can influence the performance of the model and how crowdsourcing can be used for evaluation. This study was performed in tandem with the development of the ACR AI-LAB, a platform for democratizing artificial intelligence.


Williams syndrome and happiness.
Williams syndrome is a genetic disorder resulting in a variety of medical and developmental features, one of which is a frequent outward presentation of substantial happiness. In this paper we describe the unique expression of happiness in people with Williams syndrome, with several anecdotes and a frame by frame conversational analysis. We then discuss this happiness in the context of other dimensions of the impact of Williams syndrome, especially anxiety. We conclude with a discussion of the role of genetics in emotions.


Development of bioorthogonal reactions and their applications in bioconjugation.
Biomolecule labeling using chemical probes with specific biological activities has played important roles for the elucidation of complicated biological processes. Selective bioconjugation strategies are highly-demanded in the construction of various small-molecule probes to explore complex biological systems. Bioorthogonal reactions that undergo fast and selective ligation under bio-compatible conditions have found diverse applications in the development of new bioconjugation strategies. The development of new bioorthogonal reactions in the past decade has been summarized with comments on their potentials as bioconjugation method in the construction of various biological probes for investigating their target biomolecules. For the applications of bioorthogonal reactions in the site-selective biomolecule conjugation, examples have been presented on the bioconjugation of protein, glycan, nucleic acids and lipids.


Light dosimetry: effects of dehydration and thermal damage on the optical properties of the human aorta.
The influences of dehydration and thermal damage on in vitro optical properties of human aorta were studied. The absorption coefficient increased by 20-50%, especially in the visible range when at least 40% of total tissue weight was lost as a result of dehydration. The reduced scattering coefficient increased by 10-45% in the visible and 30% to over 150% in the near IR after the tissue samples were heated in a constant temperature water bath at 100 degrees C for 300 +/- 10 s. This study implies that dehydration and protein coagulation during photothermal treatment of tissue are important factors altering optical properties of tissue.


Sources of the slow-growing pigmented water bacteria.
The group of organisms often labelled as "slow-growing pigmented water bacteria" may include various species of the Xanthomonas, Cytophoga, Pseudomonas, Aeromonas and Flavobacterium genera. Due to their slow growth, this group is usually overlooked in the average clinical laboratory since the pigmented colonies are most easily noted on membrane filter pads or on surface streaked agar plates, but only after 5-15 days of incubation at room temperature. Although present at low levels in free-flowing domestic water supplies (less than 1 per ml), they can be easily isolated by swabbing sink faucets, drinking fountain heads, surgical scrub sink heads and aerators, dental chair spray units, and from the air water interface in humidifiers, nebulizers, water baths, and reservoirs where the water may remain static for weeks. Although not considered primary pathogens, several strains have been implicated in infections in nurseries and among patients in intensive care units. Contamination control in critical research and patient care areas demands scrupulous sanitation practices, regular cleaning and decontamination of all equipment, and the use of bacteria-free water whenever possible.


Cell Biology Symposium: genetics of feed efficiency in dairy and beef cattle.
Increasing food production for the growing human population off a constraining land base will require greater efficiency of production. Genetic improvement of feed efficiency in cattle, which is cumulative and permanent, is one likely vehicle to achieving efficiency gains. The objective of this review is to summarize genetic parameters for feed efficiency traits in dairy and beef cattle and also to address some of the misconceptions associated with feed efficiency in these sectors, as well as discuss the potential use of feed efficiency in breeding programs. A meta-analysis of up to 39 scientific publications in growing cattle clearly showed that genetic variation in feed efficiency exists with a pooled heritability for residual feed intake (RFI) and feed conversion efficiency of 0.33 ± 0.01 (range of 0.07 to 0.62) and 0.23 ± 0.01 (range of 0.06 to 0.46), respectively. Heritability estimates for feed efficiency in cows were lower; a meta-analysis of up to 11 estimates revealed heritability estimates for gross feed efficiency and RFI of 0.06 ± 0.010 and 0.04 ± 0.008, respectively. Meta-analysis of genetic correlations between feed intake, feed efficiency and other performance traits are presented, and selection index theory is used to calculate the proportion of genetic variation in feed intake that can be explained by easy to measure, and often already collected, data. A large proportion of the genetic variation in feed intake could be explained in both growing animals and lactating animals using up to 5 predictor traits, including BW, growth rate, milk yield, body composition, and linear type traits reflecting body size and muscularity. Knowledge of genetic merit for feed intake can be used, along with estimates of genetic merit for energy sinks, to calculate genetic merit for feed efficiency. Therefore, the marginal benefit of collecting actual feed intake data, using the genetic parameters used in this study, appears to be low. There is now sufficient information available to develop a road map on how best to direct research to ensure long-term food security for a growing human population. Gaps in knowledge are identified here, and possibilities to address these gaps are discussed.


Asymmetric synthesis of both enantiomers of arteludovicinolide A.
The first total synthesis of either enantiomer of Arteludovicinolide A and their biological evaluation is reported, featuring a new strategy for the asymmetric construction of γ-butyrolactones with stereogenic side chains in the 4-position. Starting from the renewable resource methyl 2-furoate, the sesquiterpene lactone was synthesized in 9 steps and 4.8% overall yield via an asymmetric cyclopropanation and two diastereoselective nucleophile additions making use of a donor-acceptor-cyclopropane-lactonization cascade. At noncytotoxic concentrations (≤10 μM) (+)-1 was found to have a 15 times higher anti-inflammatory activity (4.87 ± 1.1 μM) than previously reported for concentrations of ≥45 μM.


Pharmacists promote rational use of antibiotic prophylaxis in Type I incision operations via application of drug use evaluation.
Drug use evaluation (DUE) criteria were established to assess the rational use of antibiotic prophylaxis (RUAP) in Type I incision operations (TOIO) during peri-operation period and to enhance pharmacists' responsibilities for antibiotic stewardship. The criteria were set with a threshold based on a literature review and discussions with multidisciplinary experts. Patients who received TOIO from July 2008 to June 2012 were enrolled in the study. The percentage of prescriptions adhering to all items of criteria was 10% at baseline. According to DUEs and interviews by pharmacists, the percentages of prescriptions adhering to all items of criteria of DUE-1, DUE-3, DUE-5, and DUE-8 were 13.3, 20.0, 50.0 and 66.7%, respectively. The study showed that the most common inappropriate therapies were no indications for prophylaxis antibiotic use and inappropriate choices of antibiotics. Pharmacists finally disseminated DUE criteria and reports to prescribe and improve RUAP in TOIO at the hospital through the Drug and Therapeutics Committee (DTC). The study demonstrated that application of pharmacist- directed DUE is a useful strategy to detect, supervise and help correct challenges encountered during antibiotic prophylaxis in TOIO.


Host methylation predicts SARS-CoV-2 infection and clinical outcome.
Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2-4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. We customized Illumina's Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g. IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections.


Requirements for successful mitochondrial transplantation.
Maintenance of mitochondrial oxidative phosphorylation capacity and other mitochondrial functions are essential for the prevention of mitochondrial dysfunction-related diseases such as neurodegenerative, cardiovascular, and liver diseases. To date, no well-known treatment modality has been developed to prevent or reduce mitochondrial dysfunction. However, a novel approach that transplants fully functional mitochondria directly into defective cells has recently caught the attention of scientists. In this review, we provide an overview of the cell/tissue source of the mitochondria to prompt cell regeneration or tissue repair in vitro and in vivo applications. The animal and human models entail that effective procedures should be used in the isolation and confirmation of mitochondrial membrane potential and function. We believe that these procedures for mitochondrial transplantation for tissue or cell culture will confirm intact, viable, and free from contamination isolated mitochondria from the appropriate sources.


Promiscuous drugs compared to selective drugs (promiscuity can be a virtue).
The word selectivity describes a drug's ability to affect a particular cell population in preference to others. As part of the current state of art in the search for new therapeutic agents, the property of selectivity is a mode of action thought to have a high degree of desirability. Consequently there is a growing activity in this area of research. Selectivity is generally a worthy property in a drug because a drug having high selectivity may have a dramatic effect when there is a single agent that can be targeted against the appropriate molecular-driver involved in the pathogenesis of a disease. An example is chronic myeloid leukemia (CML). CML has a specific chromosomal abnormality, the Philadelphia chromosome, that results in a single gene that produces an abnormal protein. There is a burgeoning understanding of the cellular mechanisms that control the etiology and pathogeneses of diseases. This understanding both enables and motivates the development of drugs that induce a specific action in a selected cell population; i.e., a targeted treatment. Consequently, drugs that can target distinct molecular targets involved in pathologic/pathogenetic processes, or signal-transduction pathways, are being developed. However, in most cases, diseases involve multiple abnormalities. A disease may be associated with more than one dysfunctional protein and these may be out-of-balance with each other. Likewise a drug might strongly target a protein that shares a similar active domain with other proteins. A drug may also target pleiotropic cytokines, or other proteins that have multi-physiological functions. In this way multiple normal cellular pathways can be simultaneously influenced. Long term experience with drugs supposedly designed for only a single target, but which unavoidably involve other functional effects, is uncovering the fact that molecular targeting is not medically flawless. We contend that an ideal drug may be one whose efficacy is based not on the inhibition of a single target, but rather on the rebalancing of the several proteins or events, that contribute to the etiology, pathogeneses, and progression of diseases, i.e., in effect a promiscuous drug. Ideally, if this could be done at minimum drug concentration, side effects could be minimized. Corollaries to this argument are that the growing fervor for researching truly selective drugs may be imprudent when considering the totality of responses; and that the expensive screening techniques used to discover these, may be both medically and financially inefficient.


Gait Variability to Phenotype Common Orthopedic Gait Impairments Using Wearable Sensors.
Mobility impairments are a common symptom of age-related degenerative diseases. Gait features can discriminate those with mobility disorders from healthy individuals, yet phenotyping specific pathologies remains challenging. This study aims to identify if gait parameters derived from two foot-mounted inertial measurement units (IMU) during the 6 min walk test (6MWT) can phenotype mobility impairment from different pathologies (Lumbar spinal stenosis (LSS)-neurogenic diseases, and knee osteoarthritis (KOA)-structural joint disease). Bilateral foot-mounted IMU data during the 6MWT were collected from patients with LSS and KOA and matched healthy controls (N = 30, 10 for each group). Eleven gait parameters representing four domains (pace, rhythm, asymmetry, variability) were derived for each minute of the 6MWT. In the entire 6MWT, gait parameters in all four domains distinguished between controls and both disease groups; however, the disease groups demonstrated no statistical differences, with a trend toward higher stride length variability in the LSS group (p = 0.057). Additional minute-by-minute comparisons identified stride length variability as a statistically significant marker between disease groups during the middle portion of 6WMT (3rd min: p ≤ 0.05; 4th min: p = 0.06). These findings demonstrate that gait variability measures are a potential biomarker to phenotype mobility impairment from different pathologies. Increased gait variability indicates loss of gait rhythmicity, a common feature in neurologic impairment of locomotor control, thus reflecting the underlying mechanism for the gait impairment in LSS. Findings from this work also identify the middle portion of the 6MWT as a potential window to detect subtle gait differences between individuals with different origins of gait impairment.


HEPATIC GLYCOGEN DEPLETION IN AMPHIUMA DURING INDUCED ANOXIA.
Giant salamanders, Amphiuma means, measuring 240 to 280 millimeters from snout to vent, tolerate induced anoxia for 6 hours. After 3 hours of anoxia, hepatic glycogen units are reduced in size and concentration; after 6 hours the glycogen units are almost completely depleted. Greater development and changes in the density of the endoplasmic reticulum indicate that this structure participates in the mobilization of glycogen from the cell.


Suicide rates in rural Tamil Nadu, South India: verbal autopsy of 39 000 deaths in 1997-98.
In India, death registration is not complete, especially in rural areas. Chiefly for other purposes special efforts were made to identify all deaths that occurred during 1997-98 in rural areas of one of the districts in Tamil Nadu, South India, and the verbal autopsy was done. Trained non-medical field interviewers interviewed surviving spouses, close associates or neighbours, and wrote the verbal autopsy reports in the local language (Tamil). The reports were reviewed independently by two physicians to arrive at the probable underlying cause of death. About 5% of the data were randomly selected for re-interview. The verbal autopsy was done for 38 836 deaths. Injuries accounted for 18.5% of the total deaths. About half of these were suicides. The average annual suicide rate for men and women were 71 and 53/100 000, respectively. Three-fourths of all suicides were in the socially and economically productive age-group of 15-44 years. At ages 15-24 years the female suicide rate of 109/100 000 exceeded the male rate of 78/100 000; suicide was responsible for 49% of all deaths in women and 38% of all deaths in men at these ages. This is the second largest study to date that has used verbal autopsy to estimate mortality rates in India. Suicides accounted for 9% of total deaths, and the ratio of male to female suicide was 1: 0.72. The overall (male + female) annual suicide rate was 62/100 000 population. The female suicide rate at ages 15-24 years was higher than the male rate in that age-group and other female age-groups. About 50% of suicides were by self-poisoning, one-third by hanging and one-eighth by self-immolation.


Derivation and characterization of Dicer- and microRNA-deficient human cells.
We have used genome editing to generate inactivating deletion mutations in all three copies of the dicer (hdcr) gene present in the human cell line 293T. As previously shown in murine ES cells lacking Dicer function, hDcr-deficient 293T cells are severely impaired for the production of mature microRNAs (miRNAs). Nevertheless, RNA-induced silencing complexes (RISCs) present in these hDcr-deficient cells are readily programmed by transfected, synthetic miRNA duplexes to repress mRNAs bearing either fully or partially complementary targets, including targets bearing incomplete seed homology to the introduced miRNA. Using these hDcr-deficient 293T cells, we demonstrate that human pre-miRNA processing can be effectively rescued by ectopic expression of the Drosophila Dicer 1 protein, but only in the presence of the PB isoform of Loquacious (Loqs-PB), the fly homolog of the hDcr cofactor TRBP. In contrast, Drosophila Dicer 2, even in the presence of its cofactors Loqs-PD and R2D2, was unable to support human pre-miRNA processing. Interestingly, although ectopic Drosophila Dicer 1/Loqs-PB or hDcr both rescued pre-miRNA processing effectively in these hDcr-deficient cells, there were significant differences in the ratio of the miRNA isoforms that were produced, especially in the case of miR-30 family members, and we also noted differences in the relative expression level of miRNAs vs. passenger strands for a subset of human miRNAs. These data demonstrate that the mechanisms underlying the accurate processing of pre-miRNAs are largely, but not entirely, conserved between mammalian and insect cells.


CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells.
It has been shown that excess stress to the endoplasmic reticulum (ER) triggers apoptosis, but the mechanisms underlying these processes remain unclear. We and others have reported previously that DR5 expression is up-regulated in thapsigargin (THG)-treated human cancer cells. Here, we provide evidence that CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. In human colon cancer HCT116 cells, knockdown of DR5 by siRNA blocked THG-induced Bax conformational change along with caspase-3 activation and cell death. Moreover, inhibition of CHOP expression attenuated DR5 up-regulation and apoptosis induced by THG, whereas ectopic expression of DR5 restored the sensitivity of CHOP siRNA-transfected cells to THG-induced apoptosis. In addition to HCT116 cells, inhibition of CHOP or DR5 induction also attenuated THG-induced cell death in other cancer cell lines including LNCaP, A2780S, and DU145, indicating that CHOP and DR5 are critical for ER stress-mediated apoptosis in human carcinoma cells. Furthermore, we identified a potential CHOP-binding site in the 5'-flanking region of the DR5 gene. Mutation of this site abrogated the enhanced reporter activity in response to THG treatment. Together, our findings suggest that CHOP regulates ER stress-induced apoptosis, at least in part, through enhancing DR5 expression in some types of human cancer cells.


Monthly application of 10 per cent moxidectin and 2.5 per cent imidacloprid spot-on to prevent relapses in generalised demodicosis: a pilot study.
Canine generalised demodicosis (GD) can be difficult to cure, with some dogs requiring life-long treatment. The aim of this pilot study was to evaluate the effectiveness of monthly 10 per cent moxidectin/2.5 per cent imidacloprid spot-on in maintaining long-term (12 months) clinical and parasitological remission in dogs with relapsing GD. Fourteen dogs were included: 10 with juvenile-onset GD (JOGD) and four with adult-onset GD (AOGD). All dogs had been treated previously and relapsed (1-4 times). Each dog was treated again with either milbemycin oxime 2 mg/kg or ivermectin 400 μg/kg orally once daily, until two consecutive negative skin scrapings at one-month intervals (total 4-7 months of treatment). After treatment discontinuation, 10 per cent moxidectin/2.5 per cent imidacloprid spot-on was applied monthly for 12 months. Dogs were rechecked after 1, 2, 3, 6 and 12 months, and multiple skin scrapings were taken. Twelve dogs completed the study and were clinically normal and parasitologically negative at each recheck (four dogs with AOGD and eight with JOGD). One dog died suddenly for unrelated reasons, and one dog relapsed. Results of this pilot study suggest that monthly application of 10 per cent moxidectin/2.5 per cent imidacloprid spot-on may be effective as maintenance therapy in relapsing cases of GD.


Bridging the gap in ageing: Translating policies into practice in Malaysian Primary Care.
Population ageing is poised to become a major challenge to the health system as Malaysia progresses to becoming a developed nation by 2020. This article aims to review the various ageing policy frameworks available globally; compare aged care policies and health services in Malaysia with Australia; and discuss various issues and challenges in translating these policies into practice in the Malaysian primary care system. Fundamental solutions identified to bridge the gap include restructuring of the health care system, development of comprehensive benefit packages for older people under the national health financing scheme, training of the primary care workforce, effective use of electronic medical records and clinical guidelines; and empowering older people and their caregivers with knowledge, skills and positive attitudes to ageing and self care. Ultimately, family medicine specialists must become the agents for change to lead multidisciplinary teams and work with various agencies to ensure that better coordination, continuity and quality of care are eventually delivered to older patients across time and settings.


[Peripheral arterial disease of the lower limbs : from diagnosis to treatment].
Peripheral arterial disease of the lower limbs (PAD) is a widespread disease whose diagnosis and treatment are still inadequate, despite several available current national and international recommendations. Screening for PAD is recommended in patients presenting with lower limb symptoms (claudication) and in those at risk. For all patients with PAD, initial management measures include treatment of cardiovascular risk factors, lifestyle modification, exercise training and antithrombotic therapy, at least for any symptomatic PAD. Revascularization is discussed on a case-by-case basis, depending on the stage of the disease, in a multidisciplinary setting. A diagnostic algorithm for PAD is presented, together with the basic principles of comprehensive disease management.


Handball players have superior shoulder proprioception: a prospective controlled study.
Proper proprioceptive and neuromuscular control is crucial for the overhead athlete's performance. The aim of the present study was to evaluate the shoulder joint position sense (JPS) levels in overhead throwing athletes. The secondary aim was to confront the proprioceptive abilities with glenohumeral adaptive changes and pathologies among athletes. Ninety professional handball players and 32 healthy volunteers were recruited. JPS levels were measured by an electronic goniometer and expressed as values of an active reproduction of the joint position (ARJP) and as error of ARJP (EARJP) in 3 different reference positions for each movement (abduction and flexion at 60°, 90°, and 120°; internal [IR] and external rotation [ER] at 30°, 45°, and 60°). Side-to-side differences revealed significantly better values of EARJP for the throwing shoulders in abduction at 90° and 120°, flexion at 90° and 120°, IR at 60°, and ER at 30° and 60° compared with the nonthrowing shoulders. Handball players showed significantly better proprioceptive levels in their throwing shoulder compared to the dominant shoulder of the control group in abduction at 90° (P = .037) and 120° (P = .001), flexion at 120° (P = .035), IR at 60° (P = .045), and in ER at 60° (P = .012). Handball players present superior shoulder JPS in their dominant throwing shoulder at high range of motion angles when compared to a nonathlete population and to their own nondominant shoulder.


Breaking and Connecting: Highly Hazy and Transparent Regenerated Networked-Nanofibrous Cellulose Films via Combination of Hydrolysis and Crosslinking.
High optical transparency combined with high optical haze are essential requirements for optoelectronic substrates. Light scattering caused by haze is responsible for increasing light harvesting in photon-absorbing active materials, hence increasing efficiencies. A trade-off between transparency and haze is common in solar substrates with high transparency (~90%) and low optical haze (~20%), or vice versa. In this study, we report a novel, highly transparent film fabricated from regenerated cellulose after controlled acid-hydrolysis of microcrystalline cellulose (MCC). The developed networked-nanofibrous cellulose was chemically crosslinked with glutaraldehyde (GA) and vacuum-cured to facilitate the fabrication of mechanically stable films. The effects of crosslinker concentration, crosslinking time, and curing temperature were investigated. Optimum conditions for fabrication unveils high optical transparency (~94%) and high haze (~60%), using 25% GA for 24 hr with a curing temperature of 25 °C; therefore, conveying an optimal substrate for optoelectronics applications. The high haze arises primarily from the crystalline, networked crystals of cellulose II structure formed within the regenerated cellulose upon hydrolysis. Moreover, the developed crosslinked film presents high thermal stability, water resistance, and good mechanical resilience. This high-performance crosslinked cellulose film can be considered a potential material for new environmentally-friendly optical substrates.


Similar sponge-associated bacteria can be acquired via both vertical and horizontal transmission.
Marine sponges host diverse communities of microorganisms that are often vertically transmitted from mother to oocyte or embryo. Horizontal transmission has often been proposed to co-occur in marine sponges, but the mechanism is poorly understood. To assess the impact of the mode of transmission on the microbial assemblages of sponges, we analysed the microbiota in sympatric sponges that have previously been reported to acquire bacteria via either vertical (Corticium candelabrum and Crambe crambe) or horizontal transmission (Petrosia ficiformis). The comparative study was performed by polymerase chain reaction-denaturing gradient gel electrophoresis and pyrosequencing of barcoded PCR-amplified 16S rRNA gene fragments. We found that P. ficiformis and C. candelabrum each harbour their own species-specific bacteria, but they are similar to other high-microbial-abundance sponges, while the low-microbial-abundance sponge C. crambe hosts microbiota of a very different phylogenetic signature. In addition, nearly 50% of the reads obtained from P. ficiformis were most closely related to bacteria that were previously reported to be vertically transmitted in other sponges and comprised vertical-horizontal transmission phylogenetic clusters (VHT clusters). Therefore, our results provide evidence for the hypothesis that similar sponge-associated bacteria can be acquired via both vertical and horizontal transmission.


Associations among locus coeruleus catecholamines, tau pathology, and memory in aging.
The locus coeruleus (LC) is the brain's major source of the neuromodulator norepinephrine, and is also profoundly vulnerable to the development of Alzheimer's disease (AD)-related tau pathology. Norepinephrine plays a role in neuroprotective functions that may reduce AD progression, and also underlies optimal memory performance. Successful maintenance of LC neurochemical function represents a candidate mechanism of protection against the propagation of AD-related pathology and may facilitate the preservation of memory performance despite pathology. Using [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure catecholamine synthesis capacity in LC regions of interest, we examined relationships among LC neurochemical function, AD-related pathology, and memory performance in cognitively normal older adults (n = 49). Participants underwent [11C]Pittsburgh compound B and [18F]Flortaucipir PET to quantify β-amyloid (n = 49) and tau burden (n = 42) respectively. In individuals with substantial β-amyloid, higher LC [18F]FMT net tracer influx (Kivis) was associated with lower temporal tau. Longitudinal tau-PET analyses in a subset of our sample (n = 30) support these findings to reveal reduced temporal tau accumulation in the context of higher LC [18F]FMT Kivis. Higher LC catecholamine synthesis capacity was positively correlated with self-reported cognitive engagement and physical activity across the lifespan, established predictors of successful aging measured with the Lifetime Experiences Questionnaire. LC catecholamine synthesis capacity moderated tau's negative effect on memory, such that higher LC catecholamine synthesis capacity was associated with better-than-expected memory performance given an individual's tau burden. These PET findings provide insight into the neurochemical mechanisms of AD vulnerability and cognitive resilience in the living human brain.


Intravenous voriconazole after toxic oral administration.
In a male patient with rhinocerebral invasive aspergillosis, prolonged high-dosage oral administration of voriconazole led to hepatotoxicity combined with a severe cutaneous reaction while intravenous administration in the same patient did not. High concentrations in the portal blood precipitate liver enzyme abnormalities, and therefore, oral administration of voriconazole may have a hepatotoxicity profile different from that of intravenous (i.v.) administration. Intravenously administered voriconazole might still be an option after oral-voriconazole-induced toxicity has resolved.


ZIF-1-mediated degradation of endogenous and heterologous zinc finger proteins in the C. elegans germ line.
Rapid and conditional protein depletion is the gold standard genetic tool for deciphering the molecular basis of developmental processes. Previously, we showed that by conditionally expressing the E3 ligase substrate adaptor ZIF-1 in Caenorhabditis elegans somatic cells, proteins tagged with the first CCCH Zn finger (ZF1) domain from the germline regulator PIE-1 degrade rapidly, resulting in loss-of-function phenotypes. The described role of ZIF-1 is to clear PIE-1 and several other CCCH Zn finger proteins from early somatic cells, helping to enrich them in germline precursor cells. Here, we show that proteins tagged with the PIE-1 ZF1 domain are subsequently cleared from primordial germ cells in embryos and from undifferentiated germ cells in larvae and adults by ZIF-1. We harness germline ZIF-1 activity to degrade a ZF1-tagged heterologous protein from PGCs and show that its depletion produces phenotypes equivalent to those of a null mutation. Our findings reveal that ZIF-1 switches roles from degrading CCCH Zn finger proteins in somatic cells to clearing them from undifferentiated germ cells, and that ZIF-1 activity can be harnessed as a new genetic tool to study the early germ line.


Prescription patterns of Chinese herbal products for patients with fractures in Taiwan: A nationwide population-based study.
Traditional Chinese medicine (TCM) has been used in the treatment of fracture for thousands of years. However, large-scale surveys examing the utilization of Chinese herbal products (CHPs) for treating fractures and their related symptoms are lacking. This study aimed to investigate the prescription patterns of CHPs among patients with fractures in Taiwan. The TCM usage in patients with fractures was analyzed using a sample of one million individuals randomly selected from the National Health Insurance Research Database who were newly diagnosis with fractures in 2001-2008, with a followed-up period through 2010. We identified 115,327 patients who were newly diagnosed with fractures in the study population. Among them, 4.97% (n=5731) adjunctively utilized TCM for fracture treatment. TCM users were mostly young or middle-aged, female, and resided in highly urbanized areas. With regard to the comorbidities of fractures, TCM users had a lower prevalence of coronary artery disease, chronic obstructive lung disease, diabetes mellitus, hypertension and stroke than non-TCM users, except for osteoporosis. Shu-jing-huo-xue-tang was the most frequently prescribed Chinese herbal formula, while Rhizoma Drynariae (Gu-sui-bu) was the most common single herb for patients with fractures. The CHPs were found to cover not only bone healing but also fracture-related symptoms. TCM users had lower medical expenditure for hospitalization for the first six months after incident fractures than non-TCM users (1749±2650 versus 2274±3159 US dollars, p<0.0001). Our study identified the TCM utilization for patients with fractures in Taiwan. Integration of TCM treatment reduced the medical costs for hospitalization. Further basic research and clinical studies to investigate the mechanism and clinical efficacies of CHPs are warranted.


Food sanitation practices in restaurants of Ramallah and Al-Bireh district of Palestine.
Safe handling of food in restaurants is a basic element in the reduction of foodborne illness. We investigated knowledge and practices about food safety by food-handlers in restaurants in Ramallah and Al-Bireh district of Palestine. A high proportion of workers in the restaurants had no previous experience in other restaurants and 63.4% had received no training on food sanitation and safety. Most of the restaurants in the refugee camps, villages and towns had only 1 worker. Restaurants lacked basic conditions for food sanitation and safety, such as hot water in most and cleaning materials in some. Many workers had poor personal hygiene practices. Training is needed for restaurant owners and staff to improve food handling practices and standards.