Lifestyle modification and metformin as long-term treatment options for obese adolescents: study protocol.
Childhood obesity is a serious health concern affecting over 155 million children in developed countries worldwide. Childhood obesity is associated with significantly increased risk for development of type 2 diabetes, cardiovascular disease and psychosocial functioning problems (i.e., depression and decreased quality of life). The two major strategies for management of obesity and associated metabolic abnormalities are lifestyle modification and pharmacologic therapy. This paper will provide the background rationale and methods of the REACH childhood obesity treatment program. The REACH study is a 2-year multidisciplinary, family-based, childhood obesity treatment program. Seventy-two obese adolescents (aged 10-16 years) and their parents are being recruited to participate in this randomized placebo controlled trial. Participants are randomized to receive either metformin or placebo, and are then randomized to a moderate or a vigorous intensity supervised exercise program for the first 12-weeks. After the 12-week exercise program, participants engage in weekly exercise sessions with an exercise facilitator at a local community center. Participants engage in treatment sessions with a dietitian and social worker monthly for the first year, and then every three months for the second year. The primary outcome measure is change in body mass index and the secondary outcome measures are changes in body composition, risk factors for type 2 diabetes and cardiovascular disease, changes in diet, physical activity, and psychosocial well-being (e.g., quality of life). It is hypothesized that participants who take metformin and engage in vigorous intensity exercise will show the greatest improvements in body mass index. In addition, it is hypothesized that participants who adhere to the REACH program will show improvements in body composition, physical activity, diet, psychosocial functioning and risk factor profiles for type 2 diabetes and cardiovascular disease. These improvements are expected to be maintained over the 2-year program. The findings from this study will advance the knowledge regarding the long-term efficacy and sustainability of interventions for childhood obesity. ClinicalTrials.gov number NCT00934570.


Risk factors for breast cancer in women undergoing mammography.
To determine risk factors for carcinoma of the breast, we compared women with cancer on screening and diagnostic mammography with those in whom cancer was not detected. For 39 months, medical histories were collected by mammography technologists on 3492 women having routine screenings or diagnostic mammograms at our institution. Potential risk factors of women with biopsy-proved breast cancer were compared with those in women who had normal findings on mammograms or negative biopsy results (control subjects). Of the 3492 women, 49 had biopsy-proved breast cancer. There were 3361 patients in the control group, including those women with normal findings on mammograms (3294) and those with negative biopsy results (67). Eighty-two women had incomplete questionnaires or were lost to follow up. Nearly all of the patients with breast cancer were postmenopausal compared with 68% of the control subjects. The mean length of lactation for breast cancer patients was significantly less than for control subjects: 5.6 vs 7.5 weeks (p = .015). This was true also for the postmenopausal patients: 8.1 vs 6.1 weeks (p = .041). Postmenopausal breast cancer patients had menstruated significantly more years (p = .016) than the postmenopausal control subjects: 34 vs 31 years, although the mean age at menarche was not different. When corrected for age, there was no significant difference in the total duration of menstruation in the postmenopausal cancer patients compared with the postmenopausal control subjects. Postmenopausal breast cancer patients had a significantly greater (p = .021) average body weight than postmenopausal control subjects: 71.7 vs 66.7 kg, although body weight was the same when all patients were considered. Similar results were found when Quetelet's index for obesity (weight in kg/height in cm2) (p = .004) was calculated for postmenopausal patients: 28 for cancer patients and 26 for control subjects. There was no significant difference in height between the cancer patients and control subjects when all patients or just the postmenopausal patients were considered. History of oral contraceptive use was significantly less common among postmenopausal breast cancer patients than among postmenopausal control subjects: 9% vs 20%. Patients with breast cancer had lower parity than the control subjects. In our series of patients, women in whom breast cancer was detected on mammography lactated less, showed no significant difference in years of menstruation when corrected for age, had a greater average body weight, used oral contraceptives less often, and had fewer children than women in whom no cancer was detected on mammography.


Renal impairment and clinical outcomes of Clostridium difficile infection in two randomized trials.
Patients with chronic kidney disease (CKD) have increased risk for Clostridium difficile infection (CDI) and for subsequent mortality. We determined the effect of CKD on response to treatment for CDI. This is a post hoc analysis of two randomized controlled phase 3 trials that enrolled patients with CDI. Patients received either fidaxomicin 200 mg b.i.d. or vancomycin 125 mg q.i.d. for 10 days. Univariate and multivariate analyses compared end points by treatment received and CKD stage. At baseline, 27, 21, and 9% of the patients had stage 2 (60-89 ml/min/1.73 m(2)), stage 3 (30-59), and stage 4 or higher (<30) CKD. Cure rates were similar for normal (91%) and stage 2 CKD (92%), but declined to 80% for stage 3 and to 75% for stage 4 CKD (p < 0.001 for trend). Time to resolution of diarrhea (TTROD) increased with stage 3 and stage 4 CKD. CDI recurrence rates 4 weeks after treatment were 16, 20, 27, and 24% for normal, stage 2, stage 3, and stage 4 or higher CKD, respectively. Mortality increased with CKD stage. In multivariate analyses, stage 3 or higher CKD correlated with lower odds of cure, greater chance of recurrence, and lower odds of sustained response 28 days after treatment. Initial cure rates were similar in the vancomycin or fidaxomicin groups; however, the rate of recurrence was higher following vancomycin treatment independent of renal function. The presence of immunosuppression did not alter this effect. Progressive CKD is associated with increased TTROD, lower cure rates, and higher recurrence rates with treatment of CDI.


Tuberculosis in a 2.5-month-old infant: congenital or acquired dilemma?
Infants may develop congenital tuberculosis from an infectious mother or acquire the disease postnatally by contact with an infectious adult. Delayed diagnosis is common, especially in infants under 1 year of age, and, if unrecognised, there is an increased risk of death. A 2.5-month-old boy presented with respiratory distress, small inhomogeneous opacities in both lungs and hepatosplenomegaly mimicking sepsis. He had received BCG vaccination and there was no history of contact with tuberculosis (TB). He had had fever since 1 month of age for which there had been several outpatient visits. Gastric aspirate cartridge-based nucleic acid amplification test (CBNAAT) confirmed TB and sonological evaluation demonstrated multiple granulomata in the liver and spleen, and a liver biopsy supported TB. He responded well to 12 months of anti-tuberculous treatment. The mother's tuberculin test, chest radiograph and endometrial biopsy showed no evidence of TB. There was no history of tuberculous contact with close family members. Despite the lack of proof of current tuberculous TB infection in the mother, it is likely that the infant had congenital TB.


Portsmouth physiological and operative severity score for the Enumeration of Mortality and morbidity scoring system in general surgical practice and identifying risk factors for poor outcome.
Estimation of the outcome is paramount in disease stratification and subsequent management in severely ill surgical patients. Risk scoring helps us quantify the prospects of adverse outcome in a patient. Portsmouth-Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (P-POSSUM) the world over has proved itself as a worthy scoring system and the present study was done to evaluate the feasibility of P-POSSUM as a risk scoring system as a tool in efficacious prediction of mortality and morbidity in our demographic profile. Validity of P-POSSUM was assessed prospectively in fifty major general surgeries performed at our hospital from May 2011 to October 2012. Data were collected to obtain P-POSSUM score, and statistical analysis was performed. Majority (72%) of patients was male and mean age was 40.24 ± 18.6 years. Seventy-eight percentage procedures were emergency laparotomies commonly performed for perforation peritonitis. Mean physiological score was 17.56 ± 7.6, and operative score was 17.76 ± 4.5 (total score = 35.3 ± 10.4). The ratio of observed to expected mortality rate was 0.86 and morbidity rate was 0.78. P-POSSUM accurately predicted both mortality and morbidity in patients who underwent major surgical procedures in our setup. Thus, it helped us in identifying patients who required preferential attention and aggressive management. Widespread application of this tool can result in better distribution of care among high-risk surgical patients.


Long-term treatment with a Chinese herbal formula, Sheng-Mai-San, improves cardiac contractile function in aged rats: the role of Ca(2+) homeostasis.
A Chinese herbal formula Sheng-Mai-Yin (SMY), the liquid dosage form of Sheng-Mai-San, has been used clinically for treating heart failure, particularly in aged patients. To investigate the effect of SMY treatment on the contractile function of aged hearts, we first examined cardiac hemodynamics in aged rats. To define the mechanism involved in the enhancement of cardiac function, we investigated the effect of SMY treatment on Ca(2+) homeostasis in ventricular cardiomyocytes isolated from aged rats. Ca(2+) release was assessed by measurements of changes in cardiac Ca(2+) transients and Ca(2+) sparks, using laser scanning confocal microscopy. The functional status of Ca(2+)-release regulators, including L-type Ca(2+) channels, sarcoplasmic reticulum (SR) Ca(2+)-adenosine triphosphatase (ATPase), and ryanodine receptors (RyRs), was also assessed. The results indicated that SMY treatment (2 g/kg per day for 30 doses within 6 weeks, intragastically) significantly improved hemodynamic parameters in aged rats. SMY treatment markedly increased the amplitude and shortened the duration of Ca(2+) transients in aged cardiomyocytes, and reversed the age-related increase in frequency, decrease in amplitude, and changes in spatiotemporal properties of Ca(2+) sparks in cardiomyocytes. In addition, SMY treatment increased the L-type Ca(2+) current density, SR Ca(2+) content, and SR Ca(2+)-ATPase expression, and decreased the sensitivity of RyRs to Ca(2+), all of which are causally related to increases in the amplitude of Ca(2+) transients and the size of Ca(2+) sparks. In conclusion, the improvement in cardiac contractile function afforded by SMY treatment in aged rats is likely mediated by an increase in Ca(2+) release from the SR through L-type Ca(2+) current-activated RyRs.


Fluorescence microscopy as a tool for in situ life detection.
The identification of extant and, in some cases, extinct bacterial life is most convincingly and efficiently performed with modern high-resolution microscopy. Epifluorescence microscopy of microbial autofluorescence or in conjunction with fluorescent dyes is among the most useful of these techniques. We explored fluorescent labeling and imaging of bacteria in rock and soil in the context of in situ life detection for planetary exploration. The goals were two-fold: to target non-Earth-centric biosignatures with the greatest possible sensitivity and to develop labeling procedures amenable to robotic implementation with technologies that are currently space qualified. A wide panel of commercially available dyes that target specific biosignature molecules was screened, and those with desirable properties (i.e., minimal binding to minerals, strong autofluorescence contrast, no need for wash steps) were identified. We also explored the potential of semiconductor quantum dots (QDs) as bacterial and space probes. A specific instrument for space implementation is suggested and discussed.


Generation and analysis of transcriptomic resources for a model system on the rise: the sea anemone Aiptasia pallida and its dinoflagellate endosymbiont.
The most diverse marine ecosystems, coral reefs, depend upon a functional symbiosis between cnidarian hosts and unicellular dinoflagellate algae. The molecular mechanisms underlying the establishment, maintenance, and breakdown of the symbiotic partnership are, however, not well understood. Efforts to dissect these questions have been slow, as corals are notoriously difficult to work with. In order to expedite this field of research, we generated and analyzed a collection of expressed sequence tags (ESTs) from the sea anemone Aiptasia pallida and its dinoflagellate symbiont (Symbiodinium sp.), a system that is gaining popularity as a model to study cellular, molecular, and genomic questions related to cnidarian-dinoflagellate symbioses. A set of 4,925 unique sequences (UniSeqs) comprising 1,427 clusters of 2 or more ESTs (contigs) and 3,498 unclustered ESTs (singletons) was generated by analyzing 10,285 high-quality ESTs from a mixed host/symbiont cDNA library. Using a BLAST-based approach to predict which unique sequences derived from the host versus symbiont genomes, we found that the contribution of the symbiont genome to the transcriptome was surprisingly small (1.6-6.4%). This may reflect low levels of gene expression in the symbionts, low coverage of alveolate genes in the sequence databases, a small number of symbiont cells relative to the total cellular content of the anemones, or failure to adequately lyse symbiont cells. Furthermore, we were able to identify groups of genes that are known or likely to play a role in cnidarian-dinoflagellate symbioses, including oxidative stress pathways that emerged as a prominent biological feature of this transcriptome. All ESTs and UniSeqs along with annotation results and other tools have been made accessible through the implementation of a publicly accessible database named AiptasiaBase. We have established the first large-scale transcriptomic resource for Aiptasia pallida and its dinoflagellate symbiont. These data provide researchers with tools to study questions related to cnidarian-dinoflagellate symbioses on a molecular, cellular, and genomic level. This groundwork represents a crucial step towards the establishment of a tractable model system that can be utilized to better understand cnidarian-dinoflagellate symbioses. With the advent of next-generation sequencing methods, the transcriptomic inventory of A. pallida and its symbiont, and thus the extent of AiptasiaBase, should expand dramatically in the near future.


Glucuronide transport across the endoplasmic reticulum membrane is inhibited by epigallocatechin gallate and other green tea polyphenols.
Toxic endogenous or exogenous compounds can be inactivated by various conjugation reactions. Glucuronidation (i.e. conjugation with glucuronate) is especially important due to the large number of drugs and chemical carcinogens that are detoxified through this pathway. Stable and harmless glucuronides can be reactivated by enzymatic hydrolysis thus inhibitors of glucuronidase activity reduce the risk of chemical carcinogenesis. The aim of this study was to reveal whether this mechanism contributes to the anti-cancer effect of green tea flavanols, which has been shown in various animal models. Therefore, we investigated the effect of these polyphenols on deglucuronidation in rat liver microsomes and in Hepa 1c1c7 mouse hepatoma cells, using 4-methylumbelliferyl glucuronide as model substrate. Tea flavanols inhibited beta-glucuronidase in intact vesicles, where glucuronide transport across the microsomal membrane is rate-limiting, but were almost ineffective in permeabilized vesicles. Epigallocatechin gallate, the major green tea flavanol was shown to have a concentration-dependent inhibitory effect on both beta-glucuronidase activity and glucuronide transport in native vesicles. Epigallocatechin gallate also inhibited beta-glucuronidase activity in native Hepa 1c1c7 mouse hepatoma cells, while failed to affect the enzyme in alamethicin-permeabilized cells, where the endoplasmic membrane barrier was eliminated. Our findings indicate that tea flavanols inhibit deglucuronidation in the endoplasmic reticulum at the glucuronide transport stage. This phenomenon might potentially contribute to the cancer-preventing dietary or pharmacological effect attributed to these catechins.


Hepatitis C cross-genotype immunity and implications for vaccine development.
While about a quarter of individuals clear their primary hepatitis C (HCV) infections spontaneously, clearance (spontaneous or treatment-induced) does not confer sterilizing immunity against a future infection. Since successful treatment does not prevent future infections either, an effective vaccine is highly desirable in preventing HCV (re)infection. However, development of an effective vaccine has been complicated by the diversity of HCV genotypes, and complexities in HCV immunological responses. Smaller studies on humans and chimpanzees reported seemingly opposing results regarding cross-neutralizing antibodies. We report a lack of cross-genotype immunity in the largest cohort of people to date. In the adjusted Cox proportional hazards model, reinfection with a heterologous HCV genotype (adjusted Hazard Ratio [aHR]: 0.45, 95% CI: 0.25-0.84) was associated with a 55% lower likelihood of re-clearance. Among those who cleared their first infection spontaneously, the likelihood of re-clearance was 49% lower (aHR: 0.51, 95% CI: 0.27-0.94) when reinfected with a heterologous HCV genotype. These findings indicate that immunity against a particular HCV genotype does not offer expanded immunity to protect against subsequent infections with a different HCV genotype. A prophylactic HCV vaccine boosted with multiple HCV genotype may offer a broader and more effective protection.


Hearing status in patients with rheumatoid arthritis.
Rheumatoid arthritis is thought to induce conductive hearing loss and/or sensorineural hearing loss. This study evaluated the function of the middle ear and cochlea, and the related factors. Pure tone audiometry, speech reception thresholds, speech discrimination scores, tympanometry, acoustic reflexes, and distortion product otoacoustic emissions were assessed in rheumatoid arthritis patients and healthy volunteers. Pure tone audiometry results revealed a higher bone conduction threshold in the rheumatoid arthritis group, but there was no significant difference when evaluated according to the sensorineural hearing loss definition. Distortion product otoacoustic emissions related prevalence of conductive or mixed hearing loss, tympanometry values, acoustic reflexes, and speech discrimination scores were not significantly different between the two groups. Sensorineural hearing loss was significantly more prevalent in patients who used azathioprine, cyclosporine and etanercept. Higher bone conduction thresholds in some frequencies were detected in rheumatoid arthritis patients that were not clinically significant. Sensorineural hearing loss is significantly more prevalent in refractory rheumatoid arthritis patients.


Effects of 6-Hydroxyflavone on Osteoblast Differentiation in MC3T3-E1 Cells.
Osteoblast differentiation plays an essential role in bone integrity. Isoflavones and some flavonoids are reported to have osteogenic activity and potentially possess the ability to treat osteoporosis. However, limited information concerning the osteogenic characteristics of hydroxyflavones is available. This study investigates the effects of various hydroxyflavones on osteoblast differentiation in MC3T3-E1 cells. The results showed that 6-hydroxyflavone (6-OH-F) and 7-hydroxyflavone (7-OH-F) stimulated ALP activity. However, baicalein and luteolin inhibited ALP activity and flavone showed no effect. Up to 50 μ M of each compound was used for cytotoxic effects study; flavone, 6-OH-F, and 7-OH-F had no cytotoxicity on MC3T3-E1 cells. Moreover, 6-OH-F activated AKT and serine/threonine kinases (also known as protein kinase B or PKB), extracellular signal-regulated kinases (ERK 1/2), and the c-Jun N-terminal kinase (JNK) signaling pathways. On the other hand, 7-OH-F promoted osteoblast differentiation mainly by activating ERK 1/ 2 signaling pathways. Finally, after 5 weeks of 6-OH-F induction, MC3T3-E1 cells showed a significant increase in the calcein staining intensity relative to merely visible mineralization observed in cells cultured in the osteogenic medium only. These results suggested that 6-OH-F could activate AKT, ERK 1/2, and JNK signaling pathways to effectively promote osteoblastic differentiation.


Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism.
Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a-/-) mice lacking all functional Cyp3a genes. Cyp3a-/- mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a-/- mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems.


Cortical networks for working memory and executive functions sustain the conscious resting state in man.
The cortical anatomy of the conscious resting state (REST) was investigated using a meta-analysis of nine positron emission tomography (PET) activation protocols that dealt with different cognitive tasks but shared REST as a common control state. During REST, subjects were in darkness and silence, and were instructed to relax, refrain from moving, and avoid systematic thoughts. Each protocol contrasted REST to a different cognitive task consisting either of language, mental imagery, mental calculation, reasoning, finger movement, or spatial working memory, using either auditory, visual or no stimulus delivery, and requiring either vocal, motor or no output. A total of 63 subjects and 370 spatially normalized PET scans were entered in the meta-analysis. Conjunction analysis revealed a network of brain areas jointly activated during conscious REST as compared to the nine cognitive tasks, including the bilateral angular gyrus, the left anterior precuneus and posterior cingulate cortex, the left medial frontal and anterior cingulate cortex, the left superior and medial frontal sulcus, and the left inferior frontal cortex. These results suggest that brain activity during conscious REST is sustained by a large scale network of heteromodal associative parietal and frontal cortical areas, that can be further hierarchically organized in an episodic working memory parieto-frontal network, driven in part by emotions, working under the supervision of an executive left prefrontal network.


Clinical course of thrombocytopenia in patients treated with imatinib mesylate for accelerated phase chronic myelogenous leukemia.
We studied 28 patients with accelerated phase chronic myelogenous leukemia (CML) who were enrolled on the Novartis expanded access study 114. Diagnosis of accelerated phase CML was based on karyotypic evolution (n = 9) and hematologic criteria (n = 18). All patients were begun on 600 mg/day of imatinib mesylate. Dose reductions to 400 mg/day and then 300 mg/day were prescribed for an absolute neutrophil count (ANC) of <0.5/microl or a platelet count of <20,000/microl. Twenty-seven of the 28 patients continued treatment for a median of 34 weeks. Eleven patients developed thrombocytopenia following an average of 8.4 +/- 1.4 weeks of therapy. The onset of thrombocytopenia was associated with disease progression in one patient and a decline in bone marrow megakaryocytes in the other 10. Nine patients recovered to a platelet count of >20,000/microl after an average of 19.7 +/- 1.8 weeks. Patients who developed thrombocytopenia had a longer duration of disease (9.39 vs. 4.35 years; P < 0.01) and were more likely to be diagnosed with accelerated phase CML by hematologic criteria. Hematologic responses in patients with and without thrombocytopenia were comparable; however, 31.3% of patients without thrombocytopenia had a complete cytogenetic response compared to none of those with thrombocytopenia. Grade III-IV thrombocytopenia is common in accelerated phase CML and may be a marker for the inability to achieve cytogenetic response using single agent imatinib mesylate.


Novel index for predicting mortality during the first 24 hours after traumatic brain injury.
Failure of cerebral autoregulation and subsequent hypoperfusion is common during the acute phase of traumatic brain injury (TBI). The cerebrovascular pressure-reactivity index (PRx) indirectly reflects cerebral autoregulation and has been used to derive optimal cerebral perfusion pressure (CPP). This study provides a method for the use of a combination of PRx, CPP, and intracranial pressure (ICP) to better evaluate the extent of cerebral hypoperfusion during the first 24 hours after TBI, allowing for a more accurate prediction of mortality risk. Continuous ICP and arterial blood pressure (ABP) signals acquired from 295 TBI patients during the first 24 hours after admission were retrospectively analyzed. The CPP at the lowest PRx was determined as the optimal CPP (CPPopt). The duration of a severe hypoperfusion event (dHP) was defined as the cumulative time that the PRx was > 0.2 and the CPP was < 70 mm Hg with the addition of intracranial hypertension (ICP > 20 or > 22 mm Hg). The outcome was determined as 6-month mortality. The cumulative duration of PRx > 0.2 and CPP < 70 mm Hg exhibited a significant association with mortality (p < 0.001). When utilized with basic clinical information available during the first 24 hours after admission (i.e., Glasgow Coma Scale score, age, and mean ICP), a dHP > 25 minutes yielded a significant predictive capacity for mortality (p < 0.05, area under the curve [AUC] = 0.75). The parameter was particularly predictive of mortality for patients with a mean ICP > 20 or > 22 mm Hg (AUC = 0.81 and 0.87, respectively). A short duration (25 minutes) of severe hypoperfusion, evaluated as lowered CPP during worsened cerebrovascular reactivity during the 1st day after TBI, is highly indicative of mortality.


Consumption of Combustible and Smokeless Tobacco - United States, 2000-2015.
Combustible and smokeless tobacco use causes adverse health outcomes, including cardiovascular disease and multiple types of cancer (1,2). Standard approaches for measuring tobacco use include self-reported surveys of use and consumption estimates based on tobacco excise tax data (3,4). To provide the most recently available tobacco consumption estimates in the United States, CDC used federal excise tax data to estimate total and per capita consumption during 2000-2015 for combustible tobacco (cigarettes, roll-your-own tobacco, pipe tobacco, small cigars, and large cigars) and smokeless tobacco (chewing tobacco and dry snuff). During this period, total combustible tobacco consumption decreased 33.5%, or 43.7% per capita. Although total cigarette consumption decreased 38.7%, cigarettes remained the most commonly used combustible tobacco product. Total noncigarette combustible tobacco (i.e., cigars, roll-your-own, and pipe tobacco) consumption increased 117.1%, or 83.8% per capita during 2000-2015. Total consumption of smokeless tobacco increased 23.1%, or 4.2% per capita. Notably, total cigarette consumption was 267.0 billion cigarettes in 2015 compared with 262.7 billion in 2014. These findings indicate that although cigarette smoking declined overall during 2000-2015, and each year from 2000 to 2014, the number of cigarettes consumed in 2015 was higher than in 2014, and the first time annual cigarette consumption was higher than the previous year since 1973. Moreover, the consumption of other combustible and smokeless tobacco products remains substantial. Implementation of proven tobacco prevention interventions (5) is warranted to further reduce tobacco use in the United States.


The effects of endurance exercise on dystrophic mdx mice. I. Contractile and histochemical properties of intact muscles.
Genetically normal (C57BL/10) and dystrophic (mdx) mice underwent a 15 week endurance swimming programme (2 hours per day, 5 days per week) where animals were weighted (5% body weight) during most sessions. No significant changes were seen in the contractile properties or morphology of muscles from control mice following the exercise protocol. In contrast, the soleus muscles of exercised mdx mice displayed higher normalized tensions, and the extensor digitorum longus (EDL) exhibited longer half-relaxation times compared with sedentary mdx mice. Both the EDL and soleus muscles of mdx mice exhibited increased resistance to fatigue after endurance exercise. Sedentary mdx mice exhibited increased proportions of type I (slow oxidative) fibres in the soleus and type IIA (fast, oxidative glycolytic) fibres in the EDL compared with animals of the normal strain. In both the EDL and soleus muscles of mdx mice an even greater proportion of type I fibres was apparent following the training programme. The endurance exercise was beneficial to the mdx mice, enhancing the regeneration of function of their muscles by increasing the proportion of oxidative fibres and reducing muscle fatiguability.


Area modulation grating for sinusoidal structure illumination on phase-measuring profilometry.
Sinusoidal structured illumination is used widely in three-dimensional (3-D) sensing and machine vision. Phase algorithms, for example, in phase-measuring profilometry, are inherently free of errors only with perfect sinusoidal fringe projection. But it is difficult to produce a perfect sinusoidal grating. We propose a new concept, area modulation, to improve the sinusoidality of structured illumination. A binary-coded picture is made up of many micrometer units. An aperture is open in every micrometer unit, and its area is determined by the value of the sinusoidal function. When such a grating is projected onto an object surface, the image of the grating becomes sinusoidal because of the convolution function of an optical system. We have designed and manufactured an area modulation grating for sinusoidal structure illumination using a large-scale integration technique. The area modulation grating has been used in the high-precision phase-measuring profilometry system, and the phase errors caused by the area modulation grating are reduced to 0.1%. The grating guaranteed the entire measuring accuracy to a 1% equivalent wavelength. The experimental results proved that area modulation grating would be of significant help in improving the phase-measurement accuracy of the 3-D sensing system.


A multi-algorithm, multi-timescale method for cell simulation.
Many important problems in cell biology require the dense nonlinear interactions between functional modules to be considered. The importance of computer simulation in understanding cellular processes is now widely accepted, and a variety of simulation algorithms useful for studying certain subsystems have been designed. Many of these are already widely used, and a large number of models constructed on these existing formalisms are available. A significant computational challenge is how we can integrate such sub-cellular models running on different types of algorithms to construct higher order models. A modular, object-oriented simulation meta-algorithm based on a discrete-event scheduler and Hermite polynomial interpolation has been developed and implemented. It is shown that this new method can efficiently handle many components driven by different algorithms and different timescales. The utility of this simulation framework is demonstrated further with a 'composite' heat-shock response model that combines the Gillespie-Gibson stochastic algorithm and deterministic differential equations. Dramatic improvements in performance were obtained without significant accuracy drawbacks. A multi-timescale demonstration of coupled harmonic oscillators is also shown.


Recent advances in our understanding of receptor binding, viral fusion and cell entry of hepatitis C virus: new targets for the design of antiviral agents.
Improvements to antiviral therapies for the treatment of hepatitis C virus (HCV) infections will require the use of multiple drugs that target viral proteins essential for replication. The discovery of anti-HCV compounds has been severely hampered by the lack of cell culture replication systems. Since the late 1990s, the advent of sub-genomic replicons that model the intracellular events leading to HCV genome replication have enabled the discovery of HCV protease and polymerase inhibitors, but did not allow the study of HCV entry or entry inhibitors. More recently, retroviral pseudotyping of the viral glycoproteins and the development of a cell culture-based system that recapitulates the entire HCV replication cycle were achieved. These new experimental systems have enabled a rapid advance in our knowledge of how HCV glycoproteins, E1 and E2, mediate receptor binding and viral entry. These systems have facilitated the discovery of a range of viral receptors. Evidence is emerging that CD81, scavenger receptor class B type I, claudin-1 and the low-density lipoprotein receptor are involved in viral entry. In addition, DC-SIGN and L-SIGN may function to internalize virus into dendritic or endothelial cells, facilitating the transport of virions to sites of infection such as the liver. This review focuses on the interaction between the HCV glycoproteins and cellular receptors, and our current understanding of the viral entry pathway. In addition, key questions on the role that these receptors play in viral entry are raised and potential avenues for the discovery of new antiviral agents are highlighted.


Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice.
In Drosophila, the trithorax-group and the Polycomb-group genes are necessary to maintain the expression of the homeobox genes in the appropriate segments. Loss-of-function mutations in those groups of genes lead to misexpression of the homeotic genes resulting in segmental homeotic transformations. Recently, mouse homologues of the Polycomb-group genes were identified including M33, the murine counterpart of Polycomb. In this report, M33 was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its function during development. Homozygous M33 (-/-) mice show greatly retarded growth, homeotic transformations of the axial skeleton, sternal and limb malformations and a failure to expand in vitro of several cell types including lymphocytes and fibroblasts. In addition, M33 null mutant mice show an aggravation of the skeletal malformations when treated to RA at embryonic day 7.5, leading to the hypothesis that, during development, the M33 gene might play a role in defining access to retinoic acid response elements localised in the regulatory regions of several Hox genes.


Induction of bladder sphincter dyssynergia by kappa-2 opioid receptor agonists in the female rat.
The nonselective kappa opioid receptor agonist ethylketocyclazocine suppresses external urethral sphincter (EUS) reflexes in cats. We examined the role of spinal kappa-opioid receptor subtypes in the control of EUS function in rats using selective kappa-1 (U-50,488) or kappa-2 (GR-89,696) opiate receptor agonists. Urethane anesthetized female rats were catheterized through the bladder dome for cystometry. EUS function was assessed electromyographically. Drugs were administered intrathecally or intravenously. Micturition in rats is accompanied at different times by tonic (continuous) EUS spike activity and by phasic bursts of spikes separated by pauses. GR-89,696 (0.05 to 5 microg intrathecally) caused a dose dependent decrease in the number of bursts per micturition without affecting spike frequency within individual bursts or during periods of tonic activity. It resulted in decreased voiding efficiency and at high doses dyssynergia and overflow incontinence. The nonselective opiate receptor antagonist naloxone (1 mg/kg intravenously) blocked GR-89,696 effects. U-50,488H (0.05 to 15 microg intrathecally) caused no change in cystometric parameters or in EUS-electromyography. Efficient voiding in rats depends on a spinal pattern generator causing EUS motor neuron firing to occur in bursts, resulting in rapid urethral contraction and relaxation. Intrathecal kappa-2-opiate receptor agonists suppress this pattern generator, decreasing the number of bursts occurring during each micturition without decreasing motor neuron spike frequency during individual bursts or during tonic spike activity associated with urethral closure. Resultant dyssynergia leads to decreased voiding efficiency. The relevance of kappa-2 opioid receptors should be explored in higher species, especially regarding spinal cord injury induced dyssynergia.


Elevated growth temperatures alter hydraulic characteristics in trembling aspen (Populus tremuloides) seedlings: implications for tree drought tolerance.
Although climate change will alter both soil water availability and evaporative demand, our understanding of how future climate conditions will alter tree hydraulic architecture is limited. Here, we demonstrate that growth at elevated temperatures (ambient +5 °C) affects hydraulic traits in seedlings of the deciduous boreal tree species Populus tremuloides, with the strength of the effect varying with the plant organ studied. Temperature altered the partitioning of hydraulic resistance, with greater resistance attributed to stems and less to roots in warm-grown seedlings (P < 0.02), and a 46% (but marginally significant, P = 0.08) increase in whole plant conductance at elevated temperature. Vulnerability to cavitation was greater in leaves grown at high than at ambient temperatures, but vulnerability in stems was similar between treatments. A soil-plant-atmosphere (SPA) model suggests that these coordinated changes in hydraulic physiology would lead to more frequent drought stress and reduced water-use efficiency in aspen that develop at warmer temperatures. Tissue-specific trade-offs in hydraulic traits in response to high growth temperatures would be difficult to detect when relying solely on whole plant measurements, but may have large-scale ecological implications for plant water use, carbon cycling and, possibly, plant drought survival.


Results of salvage abdominoperineal resection for recurrent anal carcinoma following combined chemoradiation therapy.
Combined chemotherapy and radiation therapy is the standard treatment for epidermoid carcinoma of the anal canal. Failures are often not associated with distant recurrence and are therefore potentially amenable to salvage abdominoperineal resection. The aim of this study was to review our experience with abdominoperineal resection following failure of chemoradiation therapy for epidermoid carcinoma of the anus. Between 1980 and 1998, 17 patients underwent salvage abdominoperineal resection following failure of chemoradiation therapy. Four patients were excluded from survival analysis because resection was performed with palliative intent. Survival curves were based on the method of Kaplan and Meier, and univariate analysis of predictive variables was performed using the log-rank test. Twelve patients underwent abdominoperineal resection for persistent disease and five patients for recurrent disease. No operative deaths occurred, but local complications including perineal wound infection and wound breakdown was seen in 8 of 17 patients and 6 of 17 patients, respectively. Patients undergoing omental flap reconstruction (n = 3) or no pelvic reconstruction (n = 5) had a higher incidence of perineal breakdown compared to those undergoing muscle flap reconstruction (n = 9) (P <0.05). The median follow-up time for the patients operated on with curative intent was 53 months. The 5-year actuarial survival was 47%. Potential prognostic factors that were not found to have an impact on survival included margin status of resection, sphincter invasion, and degree of differentiation. Only pathologic tumor size greater than 5.0 cm (P <0.001) and age over 55 years (P <0.05) adversely affected survival. Selected patients with recurrent or persistent anal carcinoma following chemoradiation therapy can be offered salvage abdominoperineal resection. This operation is associated with a high incidence of local wound complications, and muscle flap reconstruction should be considered when possible. Prolonged survival can be achieved in some patients following salvage resection for epidermoid carcinoma of the anal canal.


Feasibility and Complications between Phacoemulsification and Manual Small Incision Surgery in Subluxated Cataract.
Purpose. To compare the feasibility of cataract surgery with implantation of endocapsular supporting devices and intraocular lens (IOL) in subluxated cataract in phacoemulsification and manual small incision cataract surgery (MSICS). Design. Prospective randomized intervention case series consisting of 60 eyes with visually significant subluxated cataract. Method. The patients were randomly distributed between the two groups equally. The main outcome measure was implantation of in-the-bag IOL, requirement of additional procedure and complications, if any. Results. Capsular bag retention in subluxated lenses is possible in 90% cases in phacoemulsification versus 76.67% cases in MSICS (P = 0.16). Both groups, achieved similar best corrected visual acuity (P = 0.73), although additional procedures, intraoperative, and postoperative complications were more common in MSICS. Conclusions. Achieving intact capsulorhexis and nuclear rotation in MSICS may be difficult in cases with large nucleus size and severe subluxation, but subluxated cataracts can be effectively managed by both phacoemuslification and MSICS.


[Fluoride intake through consumption of water from municipal network in the INMA-Gipuzkoa cohort].
To estimate fluoride intake through consumption of water from the municipal network in pregnant women and their children from the INMA-Gipuzkoa cohort and to compare these intakes with recommended levels. In Euskadi (Spain), fluoridation of drinking water is compulsory in water supplies for more than 30,000 inhabitants. 575 pregnant women (recruitment, 2006-2008) and 424 4-year-old children (follow-up, 2010-2012) have been included. Fluoride levels in drinking water were obtained from the water consumption information system of the Basque Country (EKUIS). Water consumption habits and socioeconomic variables were obtained by questionnaire. 74.9% and 87.7% of women and children consumed water from the municipal network. Average fluoride levels in fluoridated water were 0.805 (SD: 0.194) mg/L during baseline recruitment and 0.843 (SD: 0.080) mg/L during follow up, at 4 years old of the children. Average and 95th percentile of fluoride intake were 0.015 and 0.026mg/kg per day in women and 0.033 and 0.059mg/kg per day in children. Considering only fluoride provided by drinking water, 8.71% of children living in fluoridated areas exceeded intake level recommended by the European Food Safety Authority, consisting in 0.05mg/kg per day. The results show that ingested levels of fluoride through consumption of municipal water can exceed the recommended levels in children and encourages further studies that will help in fluoridation policies of drinking water in the future.


Transcriptomic Analysis Reveals Prognostic Molecular Signatures of Stage I Melanoma.
Previously identified transcriptomic signatures have been based on primary and metastatic melanomas with relatively few American Joint Committee on Cancer (AJCC) stage I tumors, given difficulties in sampling small tumors. The advent of adjuvant therapies has highlighted the need for better prognostic and predictive biomarkers, especially for AJCC stage I and stage II disease. A total of 687 primary melanoma transcriptomes were generated from the Leeds Melanoma Cohort (LMC). The prognostic value of existing signatures across all the AJCC stages was tested. Unsupervised clustering was performed, and the prognostic value of the resultant signature was compared with that of sentinel node biopsy (SNB) and tested as a biomarker in three published immunotherapy datasets. Previous Lund and The Cancer Genome Atlas signatures predicted outcome in the LMC dataset (P = 10-8 to 10-4) but showed a significant interaction with AJCC stage (P = 0.04) and did not predict outcome in stage I tumors (P = 0.3-0.7). Consensus-based classification of the LMC dataset identified six classes that predicted outcome, notably in stage I disease. LMC class was a similar indicator of prognosis when compared with SNB, and it added prognostic value to the genes reported by Gerami and colleagues. One particular LMC class consistently predicted poor outcome in patients receiving immunotherapy in two of three tested datasets. Biological characterization of this class revealed high JUN and AXL expression and evidence of epithelial-to-mesenchymal transition. A transcriptomic signature of primary melanoma was identified with prognostic value, including in stage I melanoma and in patients undergoing immunotherapy.


Lack of replication for the myosin-18B association with mathematical ability in independent cohorts.
Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin-18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome-wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin-18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities.


Emotional awareness deficits in inpatients of a psychosomatic ward: a comparison of two different measures of alexithymia.
The TAS 20 has demonstrated strong psychometric properties in a broad variety of studies in healthy populations. Much less work has been done in clinical contexts exploring the validity of the TAS 20 as a measure of the cognitive processing of emotions. The TAS 20, a self-report scale, tends to correlate with self-reported negative affect, but in a clinical context it is important to be able to differentiate between negative affect and the cognitive processing of emotion. We therefore used the TAS 20 and a performance measure, the Levels of Emotional Awareness Scale (LEAS), which in previous studies demonstrated no overlap with measures of negative affect, to explore the ability of the two measures to detect deficits in emotional awareness in a clinical sample. Data from inpatients of a psychosomatic ward were collected at onset (N = 394) and at the end of multimodal psychodynamic treatment (N = 249). The sample consisted of six diagnostic groups (depression; anxiety and compulsive-obsessive disorders, adjustment disorders, somatoform disorders, psychological factors related to somatic disorders, eating disorders). Changes in the TAS 20 and LEAS were compared at the two time points controlling for the effects of gender, age, educational level, and associations with self-reported negative affect. In contrast to the LEAS, the TAS 20 correlated with negative affect at the onset and the end of treatment. The scores of the TAS 20 decreased with treatment in all diagnostic groups but the change in the TAS 20 was not statistically significant when negative affect was controlled. In contrast, LEAS scores increased with treatment in the groups with somatoform disorders and psychological factors related to somatic disorders, and this change was independent of negative affect. The LEAS captured a change in emotional awareness due to treatment, whereas the TAS 20 captured a change in negative affect. The LEAS appears to be a more specific measure of change in emotional awareness in clinical contexts than the TAS 20.


Effect of synthetic aβ peptide oligomers and fluorinated solvents on Kv1.3 channel properties and membrane conductance.
The impact of synthetic amyloid β (1-42) (Aβ(1-42)) oligomers on biophysical properties of voltage-gated potassium channels Kv 1.3 and lipid bilayer membranes (BLMs) was quantified for protocols using hexafluoroisopropanol (HFIP) or sodium hydroxide (NaOH) as solvents prior to initiating the oligomer formation. Regardless of the solvent used Aβ(1-42) samples contained oligomers that reacted with the conformation-specific antibodies A11 and OC and had similar size distributions as determined by dynamic light scattering. Patch-clamp recordings of the potassium currents showed that synthetic Aβ(1-42) oligomers accelerate the activation and inactivation kinetics of Kv 1.3 current with no significant effect on current amplitude. In contrast to oligomeric samples, freshly prepared, presumably monomeric, Aβ(1-42) solutions had no effect on Kv 1.3 channel properties. Aβ(1-42) oligomers had no effect on the steady-state current (at -80 mV) recorded from Kv 1.3-expressing cells but increased the conductance of artificial BLMs in a dose-dependent fashion. Formation of amyloid channels, however, was not observed due to conditions of the experiments. To exclude the effects of HFIP (used to dissolve lyophilized Aβ(1-42) peptide), and trifluoroacetic acid (TFA) (used during Aβ(1-42) synthesis), we determined concentrations of these fluorinated compounds in the stock Aβ(1-42) solutions by (19)F NMR. After extensive evaporation, the concentration of HFIP in the 100× stock Aβ(1-42) solutions was ∼1.7 μM. The concentration of residual TFA in the 70× stock Aβ(1-42) solutions was ∼20 μM. Even at the stock concentrations neither HFIP nor TFA alone had any effect on potassium currents or BLMs. The Aβ(1-42) oligomers prepared with HFIP as solvent, however, were more potent in the electrophysiological tests, suggesting that fluorinated compounds, such as HFIP or structurally-related inhalational anesthetics, may affect Aβ(1-42) aggregation and potentially enhance ability of oligomers to modulate voltage-gated ion channels and biological membrane properties.


Development of the larval migration inhibition test for comparative analysis of ivermectin sensitivity in cyathostomin populations.
Cyathostomins are the most prevalent parasitic pathogens of equids worldwide. These nematodes have been controlled using broad-spectrum anthelmintics; however, cyathostomin resistance to each anthelmintic class has been reported and populations insensitive to more than one class are relatively commonplace. The faecal egg count reduction test (FECRT) is considered the most suitable method for screening anthelmintic sensitivity in horses, but is subject to variation and is relatively time-consuming to perform. Here, we describe a larval migration inhibition test (LMIT) to assess ivermectin (IVM) sensitivity in cyathostomin populations. This test measures the paralysing effect of IVM on the ability of third stage larvae (L3) to migrate through a pore mesh. When L3 from a single faecal sample were examined on multiple occasions, variation in migration was observed: this was associated with the length of time that the L3 had been stored before testing but the association was not significant. Half maximal effective concentration (EC50) values were then obtained for cyathostomin L3 from six populations of horses or donkeys that showed varying sensitivity to IVM in previous FECRTs. Larvae from populations indicated as IVM resistant by FECRT displayed significantly higher EC50 values in the LMIT than L3 from populations classified as IVM sensitive or L3 from populations that had not been previously exposed to IVM or had limited prior exposure. The analysis also showed that EC50 values obtained using L3 from animals in which IVM faecal egg count reduction (FECR) levels had been recorded as <95% were significantly higher than EC50 values obtained using L3 from animals for which FECR was measured as >95%. For one of the populations, time that had elapsed since IVM administration had an effect on the EC50 value obtained, with a longer time since treatment associated with lower EC50 values. These results indicate that the LMIT has value in discriminating IVM sensitivity amongst cyathostomin populations, but several factors were identified that need to be taken into account when executing the test and interpreting the derived data.


Induction of renal 20-hydroxyeicosatetraenoic acid by clofibrate attenuates high-fat diet-induced hypertension in rats.
This study compared renal hemodynamics, the expression of CYP4A isoforms [the enzymes for 20-hydroxyeicosatetraenoic acid (20-HETE) production], and tubular sodium transporters in male rats fed a high-fat (HF) or control diet for 10 weeks. We also studied the effect of treatment with clofibrate, a CYP4A inducer, on sodium retention and renal function and on CYP4A expression in HF rats. HF rats had higher blood pressure (BP), renal plasma flow, and glomerular filtration rate (GFR), but no significant change in renal vascular resistance. Reverse transcription-polymerase chain reaction analysis showed that CYP4A1 and CYP4A8 expression was significantly decreased in the renal cortex of HF rats. Western blot analysis showed up-regulation of expression of the alpha-subunit of the epithelial sodium channel (alpha-ENaC), the beta-subunit of the epithelial sodium channel (beta-ENaC), sodium/hydrogen exchanger (NHE)-3, and the renal outer medulla K(+) channel (ROMK) in HF rats, whereas expression of the gamma-subunit of the epithelial sodium channel and the alpha1-subunit of Na(+)-K(+)-ATPase remained unchanged. Thus, HF treatment caused the reduction of renal CYP4A1 and CYP4A8 expression, whereas the increases in alpha-ENaC, beta-ENaC, NHE-3, and ROMK expression in renal tubules may have contributed sodium retention and hypertension in HF rats. Furthermore, clofibrate treatment (240 mg/kg/day) caused the decrease of BP and GFR and the attenuation of cumulative sodium balance in HF rats. The attenuation of sodium retention by clofibrate treatment is linked to decreased expression of NHE-3 in renal cortex. Clofibrate induction of CYP4A expression occurred in proximal tubules and in the thick ascending limb of the loop of Henle but not in renal microvessels. This induction correlated with the expression of peroxisome proliferator-activated receptor (PPARalpha) in renal tubules. Therefore, these results suggest that the effects of clofibrate on sodium retention and blood pressure regulation in HF rats may be due to the induction of renal tubular 20-HETE production through the PPARalpha pathway.


Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.
Several blood pressure guidelines recommend low sodium intake (<2.3 g/day, 100 mmol, 5.8 g/day of salt) for the entire population, on the premise that reductions in sodium intake, irrespective of the levels, will lower blood pressure, and, in turn, reduce cardiovascular disease occurrence. These guidelines have been developed without effective interventions to achieve sustained low sodium intake in free-living individuals, without a feasible method to estimate sodium intake reliably in individuals, and without high-quality evidence that low sodium intake reduces cardiovascular events (compared with moderate intake). In this review, we examine whether the recommendation for low sodium intake, reached by current guideline panels, is supported by robust evidence. Our review provides a counterpoint to the current recommendation for low sodium intake and suggests that a specific low sodium intake target (e.g. <2.3 g/day) for individuals may be unfeasible, of uncertain effect on other dietary factors and of unproven effectiveness in reducing cardiovascular disease. We contend that current evidence, despite methodological limitations, suggests that most of the world's population consume a moderate range of dietary sodium (2.3-4.6g/day; 1-2 teaspoons of salt) that is not associated with increased cardiovascular risk, and that the risk of cardiovascular disease increases when sodium intakes exceed 5 g/day. While current evidence has limitations, and there are differences of opinion in interpretation of existing evidence, it is reasonable, based upon observational studies, to suggest a population-level mean target of <5 g/day in populations with mean sodium intake of >5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality.


A quantitative, non-destructive methodology for habitat characterisation and benthic monitoring at offshore renewable energy developments.
Following governments' policies to tackle global climate change, the development of offshore renewable energy sites is likely to increase substantially over coming years. All such developments interact with the seabed to some degree and so a key need exists for suitable methodology to monitor the impacts of large-scale Marine Renewable Energy Installations (MREIs). Many of these will be situated on mixed or rocky substrata, where conventional methods to characterise the habitat are unsuitable. Traditional destructive sampling is also inappropriate in conservation terms, particularly as safety zones around (MREIs) could function as Marine Protected Areas, with positive benefits for biodiversity. Here we describe a technique developed to effectively monitor the impact of MREIs and report the results of its field testing, enabling large areas to be surveyed accurately and cost-effectively. The methodology is based on a high-definition video camera, plus LED lights and laser scale markers, mounted on a "flying array" that maintains itself above the seabed grounded by a length of chain, thus causing minimal damage. Samples are taken by slow-speed tows of the gear behind a boat (200 m transects). The HD video and randomly selected frame grabs are analysed to quantify species distribution. The equipment was tested over two years in Lyme Bay, UK (25 m depth), then subsequently successfully deployed in demanding conditions at the deep (>50 m) high-energy Wave Hub site off Cornwall, UK, and a potential tidal stream energy site in Guernsey, Channel Islands (1.5 ms⁻¹ current), the first time remote samples from such a habitat have been achieved. The next stage in the monitoring development process is described, involving the use of Remote Operated Vehicles to survey the seabed post-deployment of MREI devices. The complete methodology provides the first quantitative, relatively non-destructive method for monitoring mixed-substrate benthic communities beneath MPAs and MREIs pre- and post-device deployment.


A randomized controlled trial of a pharmacist consultation program for family physicians and their elderly patients.
Pharmacists can improve patient outcomes in institutional and pharmacy settings, but little is known about their effectiveness as consultants to primary care physicians. We examined whether an intervention by a specially trained pharmacist could reduce the number of daily medication units taken by elderly patients, as well as costs and health care use. We conducted a randomized controlled trial in family practices in 24 sites in Ontario. We randomly allocated 48 randomly selected family physicians (69.6% participation rate) to the intervention or the control arm, along with 889 (69.5% participation rate) of their randomly selected community-dwelling, elderly patients who were taking 5 or more medications daily. In the intervention group, pharmacists conducted face-to-face medication reviews with the patients and then gave written recommendations to the physicians to resolve any drug-related problems. Process outcomes included the number of drug-related problems identified among the senior citizens in the intervention arm and the proportion of recommendations implemented by the physicians. After 5 months, seniors in the intervention and control groups were taking a mean of 12.4 and 12.2 medication units per day respectively (p = 0.50). There were no statistically significant differences in health care use or costs between groups. A mean of 2.5 drug-related problems per senior was identified in the intervention arm. Physicians implemented or attempted to implement 72.3% (790/1093) of the recommendations. The intervention did not have a significant effect on patient outcomes. However, physicians were receptive to the recommendations to resolve drug-related problems, suggesting that collaboration between physicians and pharmacists is feasible.


Effect of calcium pre-rinse and fluoride dentifrice on enamel and on dental plaque formed in situ.
The aim of this in situ double-blind randomised crossover study was to investigate the effect of calcium (Ca) pre-rinse on the composition of plaque and on enamel prior to the use of fluoride (F) dentifrice. During four phases (14 days each) of this study, 10 volunteers had agreed to wear dental appliances containing two healthy bovine enamel blocks. A fresh solution containing 20% weight/volume (w/v) sucrose was dripped on the enamel blocks ex vivo for 5 min three times a day. Subsequently, the appliances were replaced in the mouth, and the volunteers rinsed their mouth with 10 mL of a Ca (150 mmol/L) or a placebo rinse (1 min). In sequence, a slurry (1:3 w/v) of F (1030 ppm) or placebo dentifrice was dripped onto the blocks ex vivo for 1 min. During this time, the volunteers brushed their teeth with the respective dentifrice. The appliances were replaced in the mouth, and the volunteers rinsed their mouth with water. The plaque formed on the blocks was analysed for F and Ca. The enamel demineralisation as well as the incorporation of F on enamel was evaluated by cross-sectional microhardness and alkali-soluble F analysis, respectively. Data were tested using analysis of variance (P < 0.05). The Ca pre-rinse prior to the use of the F dentifrice led to a three- and sixfold increase in the plaque F and Ca concentrations, respectively. It also did not have any additive effect on the F content on the enamel and the demineralisation of the enamel, in comparison with the use of F dentifrice alone. A Ca lactate rinse used prior to the F dentifrice was able to change the mineral content in the plaque, but it was unable to prevent enamel demineralisation.


The effect of nonsurgical periodontal treatment on serum and gingival crevicular fluid markers in patients with atherosclerosis.
The aim of this study is to compare patients with atherosclerosis and chronic periodontitis and patients who are systemically healthy and chronic periodontitis using alteration of adrenomedullin (ADM), chemokine (C-C motif) ligand 28 (CCL-28), white blood cell levels, platelet levels, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein, creatinine, and fibrinogen. Totally, 40 patients were involved in study; a test group of 20 patients with atherosclerosis-chronic periodontitis and a control group of 20 patients who were nonatherosclerosis-chronic periodontitis. Nonsurgical periodontal treatment was offered to all patients, in whom systemic markers of atherosclerosis were measured in serum; ADM and CCL-28 biomarkers were measured in gingival crevicular fluid. Systemic markers of atherosclerosis, ADM, and CCL-28 levels have changed significantly in the test group compared to the control group after nonsurgical periodontal treatment. Treatment of local inflammation and reduction of systemic inflammatory markers are believed to lower the diagnostic criteria for atherosclerosis as well. It is possible to conclude that nonsurgical periodontal treatment of chronic periodontitis, which is a risk factor for atherosclerosis, has a positive effect on the atherosclerosis prognosis.


Effects of auricular electrical stimulation on vagal activity in healthy men: evidence from a three-armed randomized trial.
The activity of the VN (vagus nerve) is negatively associated with risk factors such as stress and smoking, morbidity and mortality. In contrast, it is also a target of therapeutic intervention. VN stimulation is used in depression and epilepsy. Because of its high invasivity and exclusive application to therapy-resistant patients, there is interest in less invasive methods affecting the VN. Several studies examining acupuncture report beneficial effects on vagal activity. However, findings are inconsistent, and applied methods are heterogeneous resulting in difficulties in interpretation. The purpose of the present study was evaluation of the effects of acupuncture on vagal activity in a three-armed randomized trial while controlling several disturbing factors. Fourteen healthy men participated in random order in four examinations: a control condition without intervention, a condition with placebo, manual acupuncture and electroacupuncture. Acupuncture was conducted on the concha of the ear, as there is neuroanatomical evidence for vagal afferents. Each examination took place once, with a week's time between examinations. RSA(TR) (respiratory sinus arrhythmia adjusted for tidal volume) indicating vagal activity was measured continuously. The study was conducted partially blind in accordance with recommendations. After controlling for respiration,condition-specific pain sensation, individual differences in belief of acupuncture effectiveness and time effects not attributable to the interventions, electroacupuncture but not manual acupuncture was found to have a positive effect on RSA(TR). The results underline the potential role of auricular electrical stimulation to induce an increase in vagal activity, and it therefore might be used as preventive or adjuvant therapeutic intervention promoting health.


Nutrition care-related practices and factors affecting nutritional intakes in hospital patients at risk of pressure ulcers.
Malnutrition is common in hospitals and is a risk factor for pressure ulcers. Nutrition care practices relating to the identification and treatment of malnutrition have not been assessed in patients at risk of pressure ulcers. The present study describes nutrition care practices and factors affecting nutritional intakes in this patient group. The study was conducted in four wards at two hospitals in Queensland, Australia. Adult patients at risk of pressure ulcers as a result of restricted mobility were observed for 24 h to determine their daily oral intake and practices such as nutrition screening, documentation and intervention. Independent samples t-tests and chi-squared tests were used to analyse dietary intake and nutrition care-related data. Predictors of receiving a dietitian referral were identified using logistic regression analyses. Two hundred and forty-one patients participated in the present study. The observed nutritional screening rate was 59% (142 patients). Weight and height were documented in 71% and 34% of cases. Sixty-nine patients (29%) received a dietitian referral. Predictors of receiving a dietitian referral included lower body mass index and longer length of stay. On average, patients consumed 73% and 72% of the energy and protein provided, respectively. Between 22% and 38% of patients consumed <50% of food provided at main meals. Nutrition care practices including malnutrition risk screening and documentation of nutritional parameters appear to be inadequate in patients at risk of pressure ulcers. A significant proportion of these patients eat inadequately at main meals, further increasing their risk of malnutrition and pressure ulcers.


Male breast cancer precursor lesions: analysis of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program.
In men, data regarding breast cancer carcinogenesis are limited. The aim of our study was to describe the presence of precursor lesions adjacent to invasive male breast cancer, in order to increase our understanding of carcinogenesis in these patients. Central pathology review was performed for 1328 male breast cancer patients, registered in the retrospective joint analysis of the International Male Breast Cancer Program, which included the presence and type of breast cancer precursor lesions. In a subset, invasive breast cancer was compared with the adjacent precursor lesion by immunohistochemistry (n=83) or targeted next generation sequencing (n=7). Additionally, we correlated the presence of ductal carcinoma in situ with outcome. A substantial proportion (46.2%) of patients with invasive breast cancer also had an adjacent precursor lesion, mainly ductal carcinoma in situ (97.9%). The presence of lobular carcinoma in situ and columnar cell-like lesions were very low (<1%). In the subset of invasive breast cancer cases with adjacent ductal carcinoma in situ (n=83), a complete concordance was observed between the estrogen receptor, progesterone receptor, and HER2 status of both components. Next generation sequencing on a subset of cases with invasive breast cancer and adjacent ductal carcinoma in situ (n=4) showed identical genomic aberrations, including PIK3CA, GATA3, TP53, and MAP2K4 mutations. Next generation sequencing on a subset of cases with invasive breast cancer and an adjacent columnar cell-like lesion showed genomic concordance in two out of three patients. A multivariate Cox model for survival showed a trend that the presence of ductal carcinoma in situ was associated with a better overall survival, in particular in the Luminal B HER2+ subgroup. In conclusion, ductal carcinoma in situ is the most commonly observed precursor lesion in male breast cancer and its presence seems to be associated with a better outcome, in particular in Luminal B HER2+ cases. The rate of lobular carcinoma in situ and columnar cell-like lesions adjacent to male breast cancer is very low, but our findings support the role of columnar cell-like lesions as a precursor of male breast cancer.


Preparation and properties of nanoscale containers for biomedical application in drug delivery: preliminary studies with kynurenic acid.
The main purpose of this study was to facilitate the delivery of kynurenic acid (KYNA) across the blood-brain barrier (BBB) by applying micelles as nanoscale containers. Non-ionic amphiphilic molecules were used for preparation of spherical micelles for delivery of kynurenic acid in aqueous solution in physiological condition. It was established that Triton X 100 and Lutensol AP 20 non-ionic surfactants are able to produce stable nanocontainers for delivery of kynurenic acid molecules. The incorporation of KYNA molecules was investigated by dynamic light scattering and the size of micelles were calculated between 5 and 10 nm in 150 mM NaCl and pH 7.5-7.6 solutions. Encapsulated kynurenic acid showed a significantly higher blood-brain barrier permeability compared with non-encapsulated kynurenic acid. The in vivo experiments showed that the encapsulated kynurenic acid is able to display effects within the central nervous system, even after its peripheral administration.


Electro-optic technique to study biaxiality of liquid crystals with positive dielectric anisotropy: the case of a bent-core material.
We propose that, for materials having positive dielectric anisotropy, the biaxiality can be clearly verified or excluded by measuring the transmitted light intensity as a function of electric field. If the material is biaxial and is observed in homeotropically aligned cells, the schlieren texture should not disappear (transmitted intensity is not zero) even at very high fields, since the field does not affect the distribution of the second director normal to the main director. On the other hand, if the material is uniaxial the transmitted intensity should decrease with increasing field and a perfect homeotropic texture can be achieved at high fields. We have studied a bent-core compound in which a uniaxial-biaxial nematic (N_{u}-N_{b}) transition has been reported. This material has a positive dielectric anisotropy at low frequencies, so we could apply the technique described above. Our studies indicate that the material is uniaxial in the entire nematic range.


Anemia in hemodialysis patients: variables affecting this outcome predictor.
Despite the prevalent use of recombinant human erythropoietin (rhEPO), anemia is a frequent finding in hemodialysis patients. The goal of this study was to evaluate the impact of anemia on patient survival and characterize the determinants of hematopoiesis that may be amenable to therapeutic manipulation to enhance rhEPO responsiveness and reduce death risk. Patient characteristics and laboratory data were collected for 21,899 patients receiving hemodialysis three times per week in dialysis centers throughout the United States in 1993. Hemoglobin concentrations (Hb) < or =80 g/L were associated with a twofold increase in the odds of death (odds ratio = 2.01; P = 0.001) when compared with Hb 100 to 110 g/L. No improvement in the odds of death was afforded for Hb >110 g/L. Using multiple linear regression, variables of rhEPO administration (rhEPO dose and percentage of treatments that rhEPO was administered), variables of iron status (serum iron, transferrin saturation, and ferritin), variables of nutritional status (serum albumin and creatinine concentration), and the dose of dialysis (urea reduction ratio) were found to be significantly associated with hemoglobin concentration (P < 0.001). Age, race, and gender were also found to be significantly associated with hemoglobin concentrations (P < 0.001). From this report, the following conclusions may be made. (1) Anemia may be predictive of an increased risk of mortality in some hemodialysis patients. (2) Hemoglobin concentrations > 110 g/L are not associated with further improvements in the odds of death. (3) Laboratory surrogates of iron stores, nutritional status, and the delivered dose of dialysis are predictive of hemoglobin concentration. Whether manipulation of the factors that improve anemia will also enhance the survival of patients on hemodialysis is unknown and should be evaluated by prospective, interventional studies.


Dental metal-induced innate reactivity in keratinocytes.
Gold, nickel, copper and mercury, i.e. four metals frequently used in dental applications, were explored for their capacity to induce innate immune activation in keratinocytes (KC). Due to their anatomical location the latter epithelial cells are key in primary local irritative responses of skin and mucosa. Fresh foreskin-derived keratinocytes and skin and gingiva KC cell lines were studied for IL-8 release as a most sensitive parameter for NF-kB activation. First, we verified that viral-defense mediating TLR3 is a key innate immune receptor in both skin- and mucosa derived keratinocytes. Second, we found that, in line with our earlier finding that ionized gold can mimic viral dsRNA in triggering TLR3, gold is very effective in KC activation. It would appear that epithelial TLR3 can play a key role in both skin- and mucosa localized irritation reactivities to gold. Subsequently we found that not only gold, but also nickel, copper and mercury salts can activate innate immune reactivity in keratinocytes, although the pathways involved remain unclear. Although current alloys have been optimized for minimal leakage of metal ions, secondary factors such as mechanical friction and acidity may still facilitate such leakage. Subsequently, these metal ions may create local irritation, itching and swelling by triggering innate immune reactions, potentially also facilitating the development of metal specific adaptive immunity.


TEM study of PM2.5 emitted from coal and tire combustion in a thermal power station.
The research presented here was conducted within the scope of an experiment investigating technical feasibility and environmental impacts of tire combustion in a coal-fired power station. Previous work has shown that combustion of a coal+tire blend rather than pure coal increased bulk emissions of various elements (e.g., Zn, As, Sb, Pb). The aim of this study is to characterize the chemical and structural properties of emitted single particles with dimensions <2.5 microm (PM2.5). This transmission electron microscope (TEM)-based study revealed that, in addition to phases typical of coal fly ash (e.g., aluminum-silicate glass, mullite), the emitted PM2.5 contains amorphous selenium particles and three types of crystalline metal sulfates never reported before from stack emissions. Anglesite, PbSO4, is ubiquitous in the PM2.5 derived from both fuels and contains nearly all Pb present in the PM. Gunningite, ZnSO4-H2O, is the main host for Zn and only occurs in the PM derived from the coal+tire blend, whereas yavapaiite, KFe3+(SO4)2, is present only when pure coal was combusted. We conclude that these metal sulfates precipitated from the flue gas, may be globally abundant aerosols, and have, through hydration or dissolution, a major environmental and health impact.


Is an effective immune intervention for Alzheimer's disease in prospect?
Alzheimer's disease is characterized in part by abnormal deposits in the brain of the peptide beta amyloid (Abeta), in the form of plaques. Recent work with a transgenic model of Abeta deposition has uncovered a remarkable capacity of antibodies to prevent or clear these deposits. These experiments offer the attractive possibility, albeit some way in the future, of using antibodies as a therapy in Alzheimer's disease.


Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry.
Mass cytometry enables high-dimensional, single-cell analysis of cell type and state. In mass cytometry, rare earth metals are used as reporters on antibodies. Analysis of metal abundances using the mass cytometer allows determination of marker expression in individual cells. Mass cytometry has previously been applied only to cell suspensions. To gain spatial information, we have coupled immunohistochemical and immunocytochemical methods with high-resolution laser ablation to CyTOF mass cytometry. This approach enables the simultaneous imaging of 32 proteins and protein modifications at subcellular resolution; with the availability of additional isotopes, measurement of over 100 markers will be possible. We applied imaging mass cytometry to human breast cancer samples, allowing delineation of cell subpopulations and cell-cell interactions and highlighting tumor heterogeneity. Imaging mass cytometry complements existing imaging approaches. It will enable basic studies of tissue heterogeneity and function and support the transition of medicine toward individualized molecularly targeted diagnosis and therapies.


Symbiotic nitrogen fixation in the fungus gardens of leaf-cutter ants.
Bacteria-mediated acquisition of atmospheric N2 serves as a critical source of nitrogen in terrestrial ecosystems. Here we reveal that symbiotic nitrogen fixation facilitates the cultivation of specialized fungal crops by leaf-cutter ants. By using acetylene reduction and stable isotope experiments, we demonstrated that N2 fixation occurred in the fungus gardens of eight leaf-cutter ant species and, further, that this fixed nitrogen was incorporated into ant biomass. Symbiotic N2-fixing bacteria were consistently isolated from the fungus gardens of 80 leaf-cutter ant colonies collected in Argentina, Costa Rica, and Panama. The discovery of N2 fixation within the leaf-cutter ant-microbe symbiosis reveals a previously unrecognized nitrogen source in neotropical ecosystems.


Urinary fluoride excretion in 6- to 7-year-olds ingesting milk containing 0.5 or 0.9 mg fluoride.
Effectiveness of 0.5 mg fluoride (F) milk ingestion in preventing caries has been termed only 'moderate'. In this 3-arm partial cross-over intervention, 32 children aged 6-7 years in a non-F area were recruited and urinary F excretion (UFE) measured before and after ingestion of 0.5 or 0.9 mg F milk. Maintaining customary dietary and oral hygiene habits, children underwent a 2-week 'wash-in' with non-F milk, providing a 24-hour urine sample on day 4 of non-F (baseline) and F milk ingestion containing either (i) 0.5 mg or (ii) 0.9 mg F (intervention). A comparative group of thirteen 6- to 7-year-olds living in fluoridated areas provided a 24-hour urine sample on day 4 of daily non-F milk ingestion, following a 2-week non-F milk wash-in. Valid urine samples were analysed for F and UFE estimated from corrected 24-hour urine volume and F concentration. For the 24 test children providing 2 valid urine samples, mean (95% CI) change in corrected 24-hour UFE was 0.130 (0.049, 0.211) and 0.153 (0.062, 0.245) mg/day for 0.5 mg (p < 0.007) and 0.9 mg F (p < 0.001) groups, respectively. Post-intervention, mean (SD) corrected 24-hour UFE was 0.437 (0.153) mg/day and 0.420 (0.188) mg/day for the 0.5 and 0.9 mg F groups, respectively, which were lower than the WHO provisional standards (0.48-0.60 mg F/day). F milk consumption significantly increased UFE; however, the F content of 0.5 and 0.9 mg F milk may be too low to achieve WHO provisional UFE standards concomitant with optimal F exposure in children aged ≥6 years.


Comparative Transcriptomic Analyses of Three Species of Placobdella (Rhynchobdellida: Glossiphoniidae) Confirms a Single Origin of Blood Feeding in Leeches.
One of the recalcitrant questions regarding the evolutionary history of clitellate annelids involves the feeding preference of the common ancestor of extant rhynchobdellid (proboscis bearing) and arhynchobdellid (jaw bearing) leeches. Whereas early evidence, based on morphological data, pointed towards independent acquisitions of blood feeding in the 2 orders, molecular-based phylogenetic data suggest that the ancestor of modern leeches was a sanguivore. Here, we use a comparative transcriptomic approach in order to increase our understanding of the diversity of anticoagulation factors for 3 species of the genus Placobdella, for which comparative data have been lacking, and inspect these in light of archetypal anticoagulant data for both arhynchobdellid and other rhynchobdellid species. Notwithstanding the varying levels of host specificity displayed by the 3 different species of Placobdella, transcriptomic profiles with respect to anticoagulation factors were largely similar -this despite the fact that Placobdella kwetlumye only retains a single pair of salivary glands, as opposed to the 2 pairs more common in the genus. Results show that 9 different anticoagulant proteins and an additional 5 putative antihemostasis proteins are expressed in salivary secretions of the 3 species. In particular, an ortholog of the archetypal, single-copy, anticoagulant hirudin (not previously available as comparative data for rhynchobdellids) is present in at least 2 of 3 species examined, corroborating the notion of a single origin of blood feeding in the ancestral leech.


Silicon-zinc interactions and potential roles for dietary zinc and copper in minimizing silica urolithiasis in rats.
Two 8-wk experiments were conducted with Sprague-Dawley weanling rats to determine whether interactions occurring between Zn and Si, or a nutritional deficiency of either Cu or Zn, affect silica urolith formation. In Exp. 1, concentrations of 0, 540, and 2,700 mg of Si/kg of diet from tetraethylorthosilicate were used with dietary Zn concentrations of 4, 12, and 500 mg/kg of diet in a 3 x 3 factorial arrangement. In Exp. 2, copper at 1 or 5 mg/kg of diet and Zn at 4, 12, and 500 mg/kg of diet were used in a 2 x 3 factorial arrangement. All diets in Exp. 2 contained 2,700 mg of Si/kg. Silica uroliths occurred in all treatments providing, 2,700 mg of Si/kg of diet. There was a trend (P = .17) toward a reduction of silica urolith incidence with increasing concentrations of dietary Zn in Exp. 1. In Exp. 2, a deficiency of Zn, and a Cu deficiency exacerbated by 500 mg of Zn/kg of diet, increased (P < .05) silica urolith formation. An antagonism between Si and Zn, as demonstrated previously in the rat, may not be of a sufficient magnitude to be applicable to the prevention of silica urolithiasis. The data further demonstrate that Zn deficiency and, to a lesser extent, Cu deficiency contributed to silica urolith formation in rats fed diets having a high content of absorbable Si. However, 540 mg of Si/kg of diet may potentiate the metabolic activity of Zn, as indicated by a 23% Si-mediated weight gain response in Zn-deficient rats.


Transcript imaging of the development of human T helper cells using oligonucleotide arrays.
Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells at the site of inflammation. Understanding the genetic program that controls the functional properties of T helper type 1 (Th1) versus T helper type 2 (Th2) cells may provide insight into the pathophysiology of inflammatory diseases. We compared the gene-expression profiles of human Th1 and Th2 cells using high-density oligonucleotide arrays with the capacity to display transcript levels of 6,000 human genes. Here we analyse the data sets derived from five independent experiments using statistical algorithms. This approach resulted in the identification of 215 differentially expressed genes, encoding proteins involved in transcriptional regulation, apoptosis, proteolysis, and cell adhesion and migration. A subset of these genes was further upregulated by exposure of differentiated Th1 cells to interleukin-12 (IL-12), as confirmed by kinetic PCR analysis, indicating that IL-12 modulates the effector functions of Th1 cells in the absence of antigenic stimulation. Functional assays and in vivo expression of selected genes have validated the biological relevance of our study. Our results provide new insight into the transcriptional program controlling the functional diversity of subsets of T helper cells.


The quality of life when a partner has substance use problems: a scoping review.
To examine the existing body of knowledge on quality of life (QoL) in partners of people with substance use problems (PP-SUPs) to provide a synthesized summary of the evidence and identify gaps in our knowledge on the QoL of PP-SUPs. A systematic scoping review was performed. Publications indexed in EMBASE, Medline, PsycINFO, CINAHL, SocINDEX, and CENTRAL were searched for original, empirical, peer-reviewed, full-length research papers that examined QoL in PP-SUPs. Research papers identified through a manual search of key references and known references by co-authors were also included. A total of 3070 abstracts were screened, 41 full-text papers examined, and nine were found to meet the inclusion criteria. Eligibility was determined in two steps by four and two independent researchers, respectively. The main findings were explored by content analysis. Eight of the nine included studies had quantitative designs, one had a mixed methods design, and no qualitative studies were found. Three studies were conducted exclusively among PP-SUPs, whereas the others included various subgroups. A majority of participants were women, and no study was conducted exclusively among men. Nearly half of the studies reported on whether there were minor children in the PP-SUPs' household. The studies used established and generic QoL instruments based on different conceptual and theoretical perspectives on QoL. A majority of the studies found lower QoL in PP-SUPs than in general population, with substance use by the person with a SUP having the most impact on QoL of all evaluated factors. Two studies reported that gender was associated with QoL, with poor QoL being associated with being a male partner and vice versa for female partners. Further research is needed to examine QoL in PP-SUPs exclusively. A variety of QoL instruments covering various, but limited, dimensions of the concept have been used in previous studies of PP-SUPs. Thus, obtaining a comprehensive understanding of PP-SUPs' QoL is challenging. Both qualitative and large-scale quantitative designs should be used in research on QoL in PP-SUPs, particularly among those with a parenting role.


The McGill Brisbane Symptom Score in relation to survival in pancreatic adenocarcinoma: a validation study.
The McGill Brisbane Symptom Score (MBSS) is a clinical score for pancreatic cancer patients upon initial presentation that takes into account four variables (weight loss, abdominal pain, jaundice, and history of smoking) to stratify them into two MBSS intensity categories. Several studies have suggested that these categories are strongly associated with eventual survival in patients with resectable (rPCa) and unresectable (uPCa) pancreatic cancer. This study aimed to validate the MBSS in a cohort of patients with pancreatic cancer from a single institution. Survival time by resection status and MBSS intensity category were analyzed among 633 patients from our institution between 2001 and 2010. Hazard ratios for death using Cox proportional hazards models, with age as the timescale, adjustment for sex and year of diagnosis, and stratified by adjuvant chemotherapy status were estimated. Median survival time was the longest in patients with low-intensity MBSS and rPCa (817 days), whereas the shortest survival time was found among patients with uPCa regardless of MBSS status (144-147 days). After consideration of age and chemotherapy status, high-intensity MBSS was associated with poorer survival for both rPCa (HR 1.64; 95 % CI 1.07-2.52) and uPCa (HR 1.35; 95 % CI 1.06-1.72). Preoperative MBSS intensity is a useful prognostic indicator of survival in resectable as well as unresectable pancreatic cancer.


The comparative effectiveness of NRTI-sparing dual regimens in emulated trials using observational data from the Swiss HIV Cohort Study.
Nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) cause side effects in some patients, prompting the use of either partly or fully NRTI-sparing regimens. We used data from the Swiss HIV Cohort Study to estimate the effectiveness of two new dolutegravir dual regimens relative to the alternative NRTI-sparing dual regimens that our clinicians used previously. We emulated two trials by propensity score matching case patients on the dolutegravir regimen with control patients on an alternative regimen. We analysed the case control sets using a Bayesian Cox model and estimated effectiveness as the percentage still on their trial regimen without virological failure at 48 weeks. In a comparison of partly NRTI-sparing regimens, 58 cases treated with dolutegravir were matched to 17 controls treated with boosted darunavir (both with lamivudine or emtricitabine). The estimated difference in effectiveness was 15% (95% credible interval [CrI] 2-33) and 12% (95% CrI 0-26) in two sequential analyses 1 year apart. In a comparison of fully NRTI-sparing regimens, 54 cases treated with dolutegravir were matched to 32 controls treated with raltegravir (both with boosted darunavir). The estimated difference in effectiveness was 9% (95% CrI -1-21) and 5% (95% CrI -4-15) in the two sequential analyses. Estimates of relative effectiveness suggest that both dolutegravir regimens are not inferior to these alternative regimens. All four regimens seem suitable for patients needing an NRTI-sparing regimen: there were few virological failures and few treatment changes due to toxicity.


Host and bacterial factors associated with Haemophilus influenzae type b disease in Minnesota children vaccinated with type b polysaccharide vaccine.
Host and bacterial factors were evaluated among 86 Minnesota children with Haemophilus influenzae type b disease detected by active surveillance after introduction of type b polysaccharide vaccine in the state. Children were 2-6 y of age. Thirty-three (38%) had been vaccinated. There was no significant difference between the frequency of low serum concentrations of IgM, IgA, IgG, or IgG2 in the vaccinated and nonvaccinated subjects (13% vs. 8%, P = .5). The presence of the Gm immunoglobulin allotype phenotype (1,3,17;23;5,13,21), previously associated with a lower relative risk of vaccine failure in children from other states, was associated with a fourfold decrease in the relative risk of vaccine failure in Minnesota (P less than .07). Haemophilus isolates from 58 of the children were available for clonal characterization by multilocus electrophoresis and outer membrane protein subtyping. There were no significant differences between the clone distribution of the strains causing disease in vaccinated and nonvaccinated patients, and nearly all disease-producing clones in Minnesota also are known to cause disease in other areas of the country. Thus, vaccine failure in Minnesota is infrequently associated with hypogammaglobulinemia or with infection by unusual clones of a H. influenzae type b. Also, the Gm phenotype associated with protection against vaccine failure in other areas of the USA appears to be protective in Minnesota.


Reduction of friction and wear by grooves applied on the nanoscale polished surface in boundary lubrication conditions.
The evolution of a friction surface geometry with initially directed microscale grooves on a nanoscale polished surface in ring-on-block sliding contact is studied experimentally. Reduced wear and friction is observed when the orientation of grooves coincides with the direction of sliding. A new compressive-vacuum hypothesis of friction force nature under a condition of boundary lubrication is proposed, which successfully explains the observed phenomena. Grooves supply lubricant into the contact zone and facilitate its devacuumization, which lead to substantial reduction of surface wear. The obtained results enable developing optimized roughness profiles of friction surfaces to create high-performance durable friction units.


A Convolutional Autoencoder-based Explainable Clustering Approach for Resting-State EEG Analysis.
Machine learning methods have frequently been applied to electroencephalography (EEG) data. However, while supervised EEG classification is well-developed, relatively few studies have clustered EEG, which is problematic given the potential for clustering EEG to identify novel subtypes or patterns of dynamics that could improve our understanding of neuropsychiatric disorders. There are established methods for clustering EEG using manually extracted features that reduce the richness of the feature space for clustering, but only a couple studies have sought to use deep learning-based approaches with automated feature learning to cluster EEG. Those studies involve separately training an autoencoder and then performing clustering on the extracted features, and the separation of those steps can lead to poor quality clustering. In this study, we propose an explainable convolutional autoencoder-based approach that combines model training with clustering to yield high quality clusters. We apply the approach within the context of schizophrenia (SZ), identifying 8 EEG states characterized by varying levels of δ activity. We also find that individuals who spend more time outside of the dominant state tend to have increased negative symptom severity. Our approach represents a significant step forward for clustering resting-state EEG data and has the potential to lead to novel findings across a variety of neurological and neuropsychological disorders in future years.