A review of the use of high-flow nasal cannula oxygen therapy in hospitalised children at a regional hospital in the Cape Town Metro, South Africa.
High-flow nasal cannula (HFNC) oxygen is a non-invasive alternative to nasal continuous positive airway pressure (CPAP) therapy for infants and children requiring respiratory support. There is a paucity of data to support its use in children, with no published data from sub-Saharan Africa. To describe the outcomes of and adverse events related to HFNC in the first year of its use in a level 2 (L2) general paediatric ward, and to compare these outcomes with those of a historical cohort when this intervention was unavailable. This retrospective descriptive study included children aged <13 years who received HFNC in the first 12 months after its introduction (HFNC-availability group, n=66). Demographic data, clinical characteristics and outcomes (death, treatment failure, length of HFNC and HFNC-related adverse events) were assessed. A comparative description of children who required transfer to level 3 (L3) for any form of respiratory support (other than the available standard low-flow oxygen) during the 12-month period prior to HFNC availability (pre-HFNC group, n=54) was made. All analyses were performed in the paediatric wards, New Somerset Hospital, Cape Town, South Africa. Outcomes were compared using standard descriptive and comparative statistics. The median age of the cohort was 5 months (interquartile range (IQR) 1.9 - 14.6). Sixteen children (13.3%) were malnourished, 10 (8.3%) were HIV-infected, and 30 (25.0%) had been born prematurely. The most common diagnoses were pneumonia, bronchiolitis and asthma. Asthma, anaemia and cardiac abnormalities were the most prevalent underlying comorbidities. Two children died in each group. All 54 children in the pre-HFNC group were transferred to L3; 38 (70.4%) needed CPAP or invasive ventilation. In the HFNC-availability period, 85 children were assessed as needing more than standard low-flow oxygen therapy: of the 19 immediately transferred to L3, 17 (89.4%) received CPAP or invasive ventilation; of the 66 who received HFNC at L2, 16 (24.2%) subsequently required transfer to L3 for CPAP or invasive ventilation. The median duration of HFNC was 46.3 hours (IQR 19.5 - 93.5) overall, and it was 12 hours (IQR 4 - 28) and 58.5 hours (IQR 39.5 - 106) for those who failed or were successfully managed on HFNC, respectively. No HFNC-related serious adverse events were recorded. HFNC is a safe, effective, feasible option for non-invasive ventilation of children with respiratory illnesses in a resource-limited L2 setting. A greater proportion of children with lower respiratory tract infections in the HFNC-availability group than in the pre-HFNC group required support, but the intervention reduced the bed pressure on L3. Improved ways to identify HFNC failures would be beneficial.


The impact of primary health care on malaria morbidity--defining access by disease burden.
Primary care facilities are increasingly becoming the focal point for distribution of malaria intervention strategies, but physical access to these facilities may limit the extent to which communities can be reached. To investigate the impact of travel time to primary care on the incidence of hospitalized malaria episodes in a rural district in Kenya. The incidence of hospitalized malaria in a population under continuous demographic surveillance was recorded over 3 years. The time to travel to the nearest primary health care facility was calculated for every child between birth and 5 years of age and trends in incidence of hospitalized malaria as a function of travel time were evaluated. The incidence of hospitalized malaria more than doubled as travel time to the nearest primary care facility increased from 10 min to 2 h. Good access to primary health facilities may reduce the burden of disease by as much as 66%. Our results highlight both the potential of the primary health care system in reaching those most at risk and reducing the disease burden. Insufficient access is an important risk factor, one that may be inequitably distributed to the poorest households.


Evaluating a decade of exposures to blood and body fluids in an inner-city teaching hospital.
To analyze a decade of hospital staff and student exposures to blood and body fluids (BBF) and to identify risk factors relevant to prevention strategies. Retrospective review of a 1999-2008 data set of BBF exposures. The data, maintained by occupational health staff, detailed the type of exposure, the setting in which the exposure occurred, and the occupational group of the BBF-exposed personnel. Washington DC Veterans Affairs Medical Center (VA-DC), an inner-city tertiary care hospital. All healthcare workers and staff at the VA-DC. Review of database. A review of 10 years of data revealed 564 occupational exposures to BBF, of which 66% were caused by needlesticks and 20% were caused by sharp objects. Exposures occurred most often in the acute care setting (which accounted for 39% of exposures) and the operating room (which accounted for 22%). There was a mean of 4.9 exposures per 10,000 acute care patient-days, 0.5 exposures per 10,000 long-term care patient-days, and 0.35 exposures per 10,000 outpatient visits. Housestaff accounted for the highest number of all exposures (196 [35%]). There were, on average, 15.2 exposures per 100 housestaff full-time equivalents. An average of only 1 exposure per year occurred in the hemodialysis center. Occupational exposures to BBF remain common, but rates vary widely by setting and occupational group. Overall rates are steady across a decade, despite the use of various antiexposure devices and provider education programs. Targeting occupational groups and hospital settings that have been shown to have the highest risk rates should become foundational to future preventative strategies.


Alcohol sales to underage adolescents: an unobtrusive observational field study and evaluation of a police intervention.
The aims of this study were to assess the ease with which adolescents in the United Kingdom are able to buy alcohol, to obtain information concerning vendors' perceptions of alcohol sales to adolescents, and to evaluate a police intervention intended to reduce underage alcohol sales. An unobtrusive naturalistic field study was conducted in two urban locations. Pairs of 13- and 16-year-old boys and girls were trained to attempt the purchase of different types of alcohol (alcopops, beer, cider, wine, spirits) from four different types of retail outlets (corner shops, off-licence, public houses and supermarkets), under the supervision of a researcher and typically a parent. The assessment was repeated, with the omission of the 13-year-old boys, following a police intervention in one of the performance sites, consisting of warning letters and visits to vendors, and the issue of a small number of police cautions. A total of 62 underage confederates in all attempted 470 test purchases in phase 1 and 348 in phase 2. Between the two waves of test purchases a sample (n = 95) of the same vendors was surveyed by telephone. In phase 1, sales resulted from 88.1% of purchase attempts by 16-year-old girls, 77% of attempts by 16-year-old boys, 41.6% of 13-year-old girls and 4.1% of 13-year-old boys. These figures were generally comparable across locations, alcohol types and outlet types. Refusals were more likely when another vendor was present. Eighty per cent of sales to 16-year-olds and 65% of sales to 13-year-old girls were made without challenge. "Prove-It" ID cards were requested in fewer than 12% of purchase attempts in both age groups. Overall, there was no evidence that the police intervention reduced sales of alcohol to 16-year-olds. There was a hint that the intervention may have caused a very short-lasting decrease in sales to 13-year-old girls, but this was contained within an overall increase in sales to this group. Alcohol vendors reported that they rarely encountered underage customers or refused sale though 90% of vendors said that if they became suspicious, they would request ID. Only two vendors believed that they were likely to suffer adverse consequences if they sold alcohol to minors. These data suggest that 16-year-olds, and girls as young as 13, have little difficulty in purchasing alcohol, and that there is little difference between different types of outlets in their willingness to sell alcohol to minors. Vendors perceive little risk in selling alcohol to adolescents. The fact that the police intervention failed to decrease sales suggests that vendors do not change their behaviour in response to the threat of legal action.


Facile deposition of [60]fullerene and carbon nanotubes on ITO electrode by electrochemical oxidative polymerization of ethylenedioxythiophene.
It was found that [60]fullerene encapsulated in p-sulfonatocalix[8]arene and single-walled carbon nanotubes (SWNTs) solubilized by sodium dodecylsulfate can be readily deposited on the ITO electrode by electrochemical oxidative polymerization of ethylenedioxythiophene (EDOT) without chemical modification of these carbon clusters. The driving force for the deposition is an electrostatic interaction between the anionic complexes and the cationic charges of poly(EDOT) formed in the oxidative polymerization process. The surface morphology was thoroughly characterized by scanning electron micrograph: the [60]fullerene/poly(EDOT) film is covered by nano-particles with 20-100 nm diameters whereas the SWNTs/poly(EDOT) film is covered by nanorods with several microm length and ca. 100 nm diameter. The results indicate that the anionic complexes act as nuclei for the polymer growth in the oxidation polymerization. Interestingly, when these modified ITO electrodes were photoirradiated, the appearance of a photocurrent wave was observed. The action spectra showed that the photoexcited energy of [60]fullerene or SWNTs is efficiently collected by the electroconductive poly(EDOT) film and transferred to the ITO electrode.


Associations of physical activity and gross motor skills with executive function in preschool children from low-income South African settings.
Executive function is foundational for cognitive development. Previous research has shown both gross motor skills and physical activity to be related to executive function. However, evidence for these relationships in the preschool years, as well as in low- and middle-income countries is lacking. Therefore, this study aimed to investigate the relationships between components of executive function (inhibition, shifting and working memory) and gross motor skills (locomotor skills and object control skills) in a sample of preschool children from urban and rural low-income settings in South Africa. Results revealed that inhibition and working memory, but not shifting, were associated with gross motor skills. More specifically: inhibition was associated with both locomotor [β = 0.20, p = 0.047] and object control skills [β = 0.24, p = 0.024], whereas working memory was only associated with locomotor skills [β = 0.21, p = 0.039]. Physical activity was not associated with inhibition and shifting but was negatively associated with working memory. These results elaborate a growing evidence base linking executive function and gross motor skills in the early years, and it is the first to look at specific associations of locomotor and object control skills with executive function in the South African context (a low- and middle-income country).


Shaping brain structure: Genetic and phylogenetic axes of macroscale organization of cortical thickness.
The topology of the cerebral cortex has been proposed to provide an important source of constraint for the organization of cognition. In a sample of twins (n = 1113), we determined structural covariance of thickness to be organized along both a posterior-to-anterior and an inferior-to-superior axis. Both organizational axes were present when investigating the genetic correlation of cortical thickness, suggesting a strong genetic component in humans, and had a comparable organization in macaques, demonstrating they are phylogenetically conserved in primates. In both species, the inferior-superior dimension of cortical organization aligned with the predictions of dual-origin theory, and in humans, we found that the posterior-to-anterior axis related to a functional topography describing a continuum of functions from basic processes involved in perception and action to more abstract features of human cognition. Together, our study provides important insights into how functional and evolutionary patterns converge at the level of macroscale cortical structural organization.


Low Interleukin 10 Production at Birth Is a Risk Factor for Atopic Dermatitis in Neonates with Bifidobacterium Colonization.
Altered regulatory immune responses to microbial stimuli and intestinal colonization of beneficial bacteria early in life may contribute to the development of allergic diseases (e.g., atopic dermatitis [AD]). However, few reports have investigated these factors simultaneously. The purpose of this study was to analyze neonatal immune responses to microbial stimuli as well as intestinal colonization of beneficial bacteria, in relation to the development of AD in a birth cohort. Pregnant women were recruited, and their infants were followed up until 7 months of age. Levels of interleukin (IL)-10 released from cord-blood mononuclear cells (CBMCs) stimulated with heat-killed gram-positive bacteria (Bifidobacterium bifidum and Lactobacillus rhamnosus GG) and Lactobacillus-derived peptidoglycan were measured. Fecal Bifidobacterium counts at 4 days and 1 month were quantified using real-time polymerase chain reaction. The development of AD was determined by means of a questionnaire at 7 months of age. The levels of released IL-10 were significantly lower in infants with AD (n = 17) than in infants without AD (n = 53) for all stimuli. In infants with fecal Bifidobacterium, the incidence of AD was inversely associated with the release of IL-10 from cord blood mononuclear cells. Our findings suggest that impaired IL-10 production in response to microbial stimuli at birth may be associated with an increased risk of developing infantile AD, even in infants with early colonization of intestinal bifidobacteria.


Regulation of early tomato fruit development by the diageotropica gene.
The vegetative phenotype of the auxin-resistant diageotropica (dgt) mutant of tomato (Lycopersicon esculentum Mill.) includes reduced gravitropic response, shortened internodes, lack of lateral roots, and retarded vascular development. Here, we report that early fruit development is also dramatically altered by the single-gene dgt lesion. Fruit weight, fruit set, and numbers of locules and seeds are reduced in dgt. In addition, time to flowering and time from anthesis to the onset of fruit ripening are increased by the dgt lesion, whereas ripening is normal. The dgt mutation appears to affect only the early stages of fruit development, irrespective of allele or genetic background. Expression of members of the LeACS (1-aminocyclopropane-1-carboxylic acid synthase, a key regulatory enzyme of ethylene biosynthesis) and LeIAA (Aux/IAA, auxin-responsive) gene families were quantified via real-time reverse transcriptase-polymerase chain reaction in both dgt and wild-type fruits, providing the first analysis of Aux/IAA gene expression in fruit. The dgt lesion affects the expression of only certain members of both the LeACS and LeIAA multigene families. Different subsets of LeIAA gene family members are affected by the dgt mutation in fruits and hypocotyls, indicating that the DGT gene product functions in a developmentally specific manner. The differential expression of subsets of LeIAA and LeACS gene family members as well as the alterations in dgt fruit morphology and growth suggest that the early stages of fruit development in tomato are regulated, at least in part, by auxin- and ethylene-mediated gene expression.


Plastic debris in the open ocean.
There is a rising concern regarding the accumulation of floating plastic debris in the open ocean. However, the magnitude and the fate of this pollution are still open questions. Using data from the Malaspina 2010 circumnavigation, regional surveys, and previously published reports, we show a worldwide distribution of plastic on the surface of the open ocean, mostly accumulating in the convergence zones of each of the five subtropical gyres with comparable density. However, the global load of plastic on the open ocean surface was estimated to be on the order of tens of thousands of tons, far less than expected. Our observations of the size distribution of floating plastic debris point at important size-selective sinks removing millimeter-sized fragments of floating plastic on a large scale. This sink may involve a combination of fast nano-fragmentation of the microplastic into particles of microns or smaller, their transference to the ocean interior by food webs and ballasting processes, and processes yet to be discovered. Resolving the fate of the missing plastic debris is of fundamental importance to determine the nature and significance of the impacts of plastic pollution in the ocean.


Food Handling Behaviors Observed in Consumers When Cooking Poultry and Eggs.
Previous research has shown that many consumers do not follow recommended food safety practices for cooking poultry and eggs, which can lead to exposure to Salmonella and Campylobacter. Past research has been done primarily through surveys and interviews, rather than observations. The objective of this project was to determine through observations whether consumers follow food safety guidelines. Consumers (n = 101) divided among three locations (Manhattan, KS; Kansas City, MO area; and Nashville, TN) were observed as they prepared a baked whole chicken breast, a pan-fried ground turkey patty, a fried egg, and scrambled eggs. The end point temperature for the cooked products was taken (outside the view of consumers) within 30 s after the consumers indicated they were finished cooking. Thermometer use while cooking was low, although marginally higher than that of some previous studies: only 37% of consumers used a thermometer for chicken breasts and only 22% for turkey patties. No one used a thermometer for fried or scrambled eggs. Only 77% of the chicken and 69% of the turkey was cooked to a safe temperature (165°F [74°C]), and 77% of scrambled and 49% of fried eggs reached a safe temperature (160°F [71°C]). Safe hand washing was noted in only 40% of respondents after handling the chicken breast and 44% after handling the ground turkey patty. This value decreased to 15% after handling raw eggs for fried eggs and to 17% for scrambled eggs. These results show that there is a high prevalence of unsafe behaviors (undercooking and poor hand washing technique) when cooking poultry and eggs and a great need for improvement in consumer behavior with poultry and eggs.


Spectral parameters modulation and source localization of blink-related alpha and low-beta oscillations differentiate minimally conscious state from vegetative state/unresponsive wakefulness syndrome.
Recently, the cortical source of blink-related delta oscillations (delta BROs) in resting healthy subjects has been localized in the posterior cingulate cortex/precuneus (PCC/PCu), one of the main core-hubs of the default-mode network. This has been interpreted as the electrophysiological signature of the automatic monitoring of the surrounding environment while subjects are immersed in self-reflecting mental activities. Although delta BROs were directly correlated to the degree of consciousness impairment in patients with disorders of consciousness, they failed to differentiate vegetative state/unresponsive wakefulness syndrome (VS/UWS) from minimally conscious state (MCS). In the present study, we have extended the analysis of BROs to frequency bands other than delta in the attempt to find a biological marker that could support the differential diagnosis between VS/UWS and MCS. Four patients with VS/UWS, 5 patients with MCS, and 12 healthy matched controls (CTRL) underwent standard 19-channels EEG recordings during resting conditions. Three-second-lasting EEG epochs centred on each blink instance were submitted to time-frequency analyses in order to extract the normalized Blink-Related Synchronization/Desynchronization (nBRS/BRD) of three bands of interest (low-alpha, high-alpha and low-beta) in the time-window of 50-550 ms after the blink-peak and to estimate the corresponding cortical sources of electrical activity. VS/UWS nBRS/BRD levels of all three bands were lower than those related to both CTRL and MCS, thus enabling the differential diagnosis between MCS and VS/UWS. Furthermore, MCS showed an intermediate signal intensity on PCC/PCu between CTRL and VS/UWS and a higher signal intensity on the left temporo-parieto-occipital junction and inferior occipito-temporal regions when compared to VS/UWS. This peculiar pattern of activation leads us to hypothesize that resting MCS patients have a bottom-up driven activation of the task positive network and thus are tendentially prone to respond to environmental stimuli, even though in an almost unintentional way.


Repair of clustered DNA lesions. Sequence-specific inhibition of long-patch base excision repair be 8-oxoguanine.
Ionizing radiation induces clustered DNA damage where two or more lesions are located proximal to each other on the same or opposite DNA strands. It has been suggested that individual lesions within a cluster are removed sequentially and that the presence of a vicinal lesion(s) may affect the rate and fidelity of DNA repair. In this study, we addressed the question of how 8-oxoguanine located opposite to normal or reduced abasic sites would affect the repair of these sites by the base excision repair system. We have found that an 8-oxoguanine located opposite to an abasic site does not affect either the efficiency or fidelity of repair synthesis by DNA polymerase beta. In contrast, an 8-oxoguanine located one nucleotide 3'-downstream of the abasic site significantly reduces both strand displacement synthesis supported by DNA polymerase beta or delta and cleavage by flap endonuclease of the generated flap, thus inhibiting the long-patch base excision repair pathway.


TAK-ling IKK activation: "Ub" the judge.
Investigation of the signaling events that lead to the activation of the transcription factor nuclear factor kappaB (NF-kappaB) has been a hotbed for the discovery of previously uncharacterized signaling mechanisms. The important role that nondegradative polyubiquitin chains play in these processes is now well recognized; however, precisely how they orchestrate NF-kappaB signaling is still a matter of much controversy. A recent study has challenged the dogmatic view by demonstrating that interleukin-1beta (IL-1beta), a major proinflammatory cytokine, activates two consecutive pathways, the "RING" and "zinc" pathways, to coordinate early and late activation of NF-kappaB, respectively. This study introduces a paradigm shift in the still-evolving mechanism of regulation of NF-kappaB.


Tibetan medicine Kuan-Jin-Teng exerts anti-arthritic effects on collagen-induced arthritis rats via inhibition the production of pro-inflammatory cytokines and down-regulation of MAPK signaling pathway.
The stems of Tinospora sinensis (Lour.) Merr commonly named "Kuan-Jin-Teng" in Chinese, have been used to treat rheumatoid arthritis as a Tibetan medicine. The effects of the EtOAc fraction of ethanolic extract from the stems of T. sinensis (KJT) on the pro-inflammatory cytokines and MAPK pathway were studied in collagen-induced arthritis (CIA) model. Anti-arthritic activity of KJT was investigated in CIA model. The chemical constituents of KJT were analyzed by LC-MS and HPLC. The CIA model was established with injecting the bovine CII emulsified in Freund's adjuvant in Wistar rats. Several doses of KJT (50.0, 100.0 and 200.0 mg/kg) were administrated via oral gavage to CIA rats daily for 4 weeks. The anti-arthritic activity of KJT was investigated by clinical arthritis scoring, paw swelling inspection and hyperalgesia measurement, as well as radiological and histological analysis in CIA rats. The impacts of KJT on the activation of MAPK pathway, production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) in ankle joints, serum, and spleen in CIA rats were examined by western blot, immunohistochemical staining, ELISA, and quantitative real-time PCR respectively. Lastly, the effects of KJT on production of the nitric oxide (NO) and pro-inflammatory cytokines as well as the regulation of the phosphorylation of p38 and Erk were detected in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells. KJT significantly alleviated the paw swelling, hyperalgesia and arthritic severity, and reduced the synovial tissue proliferation and inflammatory cell infiltration in the CIA rats. Moreover, KJT suppressed the production of TNF-α, IL-1β, and IL-17 in ankle joints, serum, and spleen and reversed the up-regulation of the phosphorylation of p38 and Erk in CIA rats. KJT was also demonstrated to inhibit the production of NO and pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), and phosphorylation of p38 and Erk in LPS-stimulated RAW264.7 cells. These results suggest the mechanisms of KJT performing its anti-arthritis effect may be attributed to inhibiting the production of pro-inflammatory cytokines and down-regulating the MAPK signaling pathway.


Structural basis of LaDR5, a novel agonistic anti-death receptor 5 (DR5) monoclonal antibody, to inhibit DR5/TRAIL complex formation.
As a member of the TNF superfamily, TRAIL could induce human tumor cell apoptosis through its cognate death receptors DR4 or DR5, which can induce formation of the death inducing signaling complex (DISC) and activation of the membrane proximal caspases (caspase-8 or caspase-10) and mitochondrial pathway. Some monoclonal antibodies against DR4 or DR5 have been reported to have anti-tumor activity. In this study, we reported a novel mouse anti-human DR5 monoclonal antibody, named as LaDR5, which could compete with TRAIL to bind DR5 and induce the apoptosis of Jurkat cells in the absence of second cross-linking in vitro. Using computer-guided molecular modeling method, the 3-D structure of LaDR5 Fv fragment was constructed. According to the crystal structure of DR5, the 3-D complex structure of DR5 and LaDR5 was modeled using molecular docking method. Based on distance geometry method and intermolecular hydrogen bonding analysis, the key functional domain in DR5 was predicted and the DR5 mutants were designed. And then, three mutants of DR5 was expressed in prokaryotic system and purified by affinity chromatograph to determine the epitope of DR5 identified by LaDR5, which was consistent with the theoretical results of computer-aided analysis. Our results demonstrated the specific epitope located in DR5 that plays a crucial role in antibody binding and even antineoplastic bioactivity. Meanwhile, revealed structural features of DR5 may be important to design or screen novel drugs agonist DR5.


Golimumab reduces sleep disturbance in patients with active ankylosing spondylitis: results from a randomized, placebo-controlled trial.
To evaluate the effect of golimumab on sleep disturbance in patients with active ankylosing spondylitis (AS). Golimumab was studied in a multicenter, randomized, placebo-controlled study (GO-RAISE). At baseline, 356 patients were randomly assigned in a 1.8:1.8:1 ratio to subcutaneous golimumab 50 mg, 100 mg, or placebo every 4 weeks. Sleep disturbance was assessed using the Jenkins Sleep Evaluation Questionnaire (JSEQ), which was administered at baseline, week 14, and week 24. Treatment effect was evaluated using analysis of variance on the van der Waerden normal scores. Median JSEQ scores at baseline were 9.0 in the placebo group, 10.0 in the 50-mg group, and 11.0 in the 100-mg group, indicating moderate to severe sleep disturbance. Patients who received golimumab showed significantly greater median improvement from baseline in JSEQ scores compared with placebo at week 14 (-3.0 versus 0.0; P < 0.001) and week 24 (-3.0 versus -1.0; P < 0.001). Changes from baseline in JSEQ scores significantly correlated with changes from baseline in Short Form 36 summary scores, Bath AS Functional Index scores, total back pain, night back pain, and Bath AS Disease Activity Index scores. Multiple regression analyses indicated that improvement in the night back pain score was the most consistent predictor of change in JSEQ score or reduction in sleep disturbance. Patients with active AS showed significant sleep disturbance at baseline due to underlying pain associated with AS. Treatment with subcutaneous golimumab every 4 weeks significantly reduced sleep disturbance and improved health-related quality of life.


A wearable patch for continuous monitoring of sweat electrolytes during exertion.
Implementation of wearable sweat sensors for continuous measurement of fluid based biomarkers (including electrolytes, metabolites and proteins) is an attractive alternative to common, yet intrusive and invasive, practices such as urine or blood analysis. Recent years have witnessed several key demonstrations of sweat based electrochemical sensing in wearable formats, however, there are still significant challenges and opportunities in this space for clinical acceptance, and thus mass implementation of these devices. For instance, there are inherent challenges in establishing direct correlations between sweat-based and gold-standard plasma-based biomarker concentrations for clinical decision-making. In addition, the wearable sweat monitoring devices themselves may exacerbate these challenges, as they can significantly alter sweat physiology (example, sweat rate and composition). Reported here is the demonstration of a fully integrated, wireless, wearable and flexible sweat sensing device for non-obtrusive and continuous monitoring of electrolytes during moderate to intense exertion as a metric for hydration status. The focus of this work is twofold: 1- design of a conformable fluidics systems to suit conditions of operation for sweat collection (to minimize sensor lag) with rapid removal of sweat from the sensing site (to minimize effects on sweat physiology). 2- integration of Na+ and K+ ion-selective electrodes (ISEs) with flexible microfluidics and low noise small footprint electronics components to enable wireless, wearable sweat monitoring. While this device is specific to electrolyte analysis during intense perspiration, the lessons in microfluidics and overall system design are likely applicable across a broad range of analytes.


The Chinese rare minnow (Gobiocypris rarus) as an in vivo model for endocrine disruption in freshwater teleosts: a full life-cycle test with diethylstilbestrol.
Chinese rare minnow (Gobiocypris rarus), a freshwater teleost, was exposed to diethylstilbestrol (DES) at 0.05, 0.5, 1 and 5 microg/L from fertilized eggs for up to mature period under flow-through condition. Several endpoints that related to development, reproductive fitness and transgenerational effects were evaluated. It was found that body length and body weight were significantly reduced and vitellogenin (Vtg) levels were significantly increased for fish exposed to DES. Histological examination showed that the sex ratios of F0 fish skewed to female and about 2% of the fish exposed to 0.05 microg/L DES developed testes-ova. The reproductive success, as determined from data on egg production, was reduced in female fish exposed to 0.05, 0.5, 1 and 5 microg/L DES. The lowest-observed-effect concentrations (LOEC) for changes of sex ratios, reproductive success and histology alteration of F0 are 0.05 microg/L. In the offspring, transgenerational effects on egg hatching rate, egg fertilization and Vtg levels of juvenile individuals were not observed. However, survival of F1 generation fry significantly declined. The analysis of sex steroid levels revealed a significant decrease of testosterone (T) in the whole body homogenates (WBH) of male progeny and somewhat elevation of estradiol (E2) in the WBH of female offspring. These findings indicate that exposure to DES causes a variety of developmental, reproductive and transgenerational effects.


Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol.
The effect of the i.p. administration of ethanol on the release of dopamine (DA) and on the output of its main metabolites, dihydroxyphenylacetic acid and homovanillic acid, was estimated in the rat by transcerebral dialysis of two terminal dopaminergic areas, the nucleus accumbens and the dorsal caudate. Low doses of ethanol (0.25-0.5 g/kg i.p.) stimulated DA release specifically in the n. accumbens and elicited pure behavioral stimulation. Higher doses of ethanol (1.0-2.5 g/kg) elicited sedation and hypnosis and stimulated further DA release and dihydroxyphenylacetic acid and homovanillic acid output in the accumbens and, although less, also in the caudate. High doses of ethanol (5 g/kg i.p.) elicited long-lasting hypnosis and sedation and induced a depression followed by stimulation of DA release in the accumbens. DA release in the caudate was stimulated further. Low doses of apomorphine (0.05 mg/kg s.c.) reversed completely the stimulant effect of 0.5 g/kg of ethanol on behavior and on DA release in the accumbens. Moreover, the stimulation of behavior and of DA release in the accumbens elicited by 0.5 g/kg of ethanol were abolished completely by pretreatment with 700 mg/kg of gamma-butyrolactone, an agent which blocks DA firing and DA release. The results indicate that ethanol preferentially stimulates DA transmission in the mesolimbic system probably by activating the firing activity of mesolimbic DA neurons and provide direct evidence that these changes are involved in the motor stimulant effects of ethanol.


The storage stability and concentration of acetoacetate differs between blood fractions.
Plasma concentrations of 3-hydroxybutyrate (3HB) are measured more often than acetoacetate (AcAc) which may be due to the reported storage instability of AcAc. The aims of the study were to compare the storage stability of AcAc in different blood fractions over time (90days) when stored at -80°C and to determine the postprandial concentration of AcAc in whole blood, plasma and red blood cells. Blood was collected from fasting subjects (n=5): whole blood, plasma and red blood cells were isolated and deproteinised in perchloric acid, and supernatants were stored at -80°C until analysis. Postprandial concentrations of AcAc in whole blood, plasma and red blood cells were determined at regular intervals over 420min, after subjects (n=23) had consumed a mixed test meal. Storing deproteinised plasma at -80°C resulted in no significant change in AcAc concentration over 60days. In contrast, whole blood AcAc concentrations significantly decreased by 51% (p=0.018) within 30days. The concentration of AcAc in fasting and postprandial plasma was notably higher than that of whole blood and red blood cells. Our data demonstrates that plasma for AcAc analysis can be stored for longer than previously suggested provided that plasma is deproteinised and stored at -80°C.


How would you feel versus how do you think she would feel? A neuroimaging study of perspective-taking with social emotions.
Perspective-taking is a complex cognitive process involved in social cognition. This positron emission tomography (PET) study investigated by means of a factorial design the interaction between the emotional and the perspective factors. Participants were asked to adopt either their own (first person) perspective or the (third person) perspective of their mothers in response to situations involving social emotions or to neutral situations. The main effect of third-person versus first-person perspective resulted in hemodynamic increase in the medial part of the superior frontal gyrus, the left superior temporal sulcus, the left temporal pole, the posterior cingulate gyrus, and the right inferior parietal lobe. A cluster in the postcentral gyrus was detected in the reverse comparison. The amygdala was selectively activated when subjects were processing social emotions, both related to self and other. Interaction effects were identified in the left temporal pole and in the right postcentral gyrus. These results support our prediction that the frontopolar, the somatosensory cortex, and the right inferior parietal lobe are crucial in the process of self/other distinction. In addition, this study provides important building blocks in our understanding of social emotion processing and human empathy.


Spherical sulfated cellulose adsorbs high-mobility-group box chromosomal protein 1 in vitro and in vivo.
High-mobility-group box chromosomal protein 1 (HMGB1) has recently been identified as a late mediator of various kinds of acute and chronic inflammation. A method for efficiently removing HMGB1 from systemic circulation could be a promising therapy for HMGB1-mediated inflammatory diseases. It is well known that the cationic portion of HMGB1 binds to heparin, which has abundant sulfates in its structure. In this study, we determined whether spherical sulfated cellulose (SC) efficiently adsorbed HMGB1, as well as other inflammatory mediators, in vitro. Then, we investigated the efficacy of hemoperfusion with the SC (SC group) or cellulose beads (control group) at adsorbing endogenous mediators, including HMGB1, in vivo. We have demonstrated that the SC adsorbed significantly larger amounts of HMGB1, interleukin (IL)-4, and IL-8 when compared with cellulose beads, in vitro. Hemoperfusion with the SC for 30 minute, starting 2 hour after an abdominal opening and closure operation, significantly reduced serum HMGB1 levels (p = 0.004) and consistently increased serum IL-10 levels, in vivo. These data suggest the potential benefits of hemoperfusion using the SC in treating HMGB1-mediated inflammatory diseases.


A grading scale for surgically treated patients with spontaneous supratentorial intracerebral hemorrhage: the Surgical Swedish ICH Score.
The authors aimed to develop the first clinical grading scale for patients with surgically treated spontaneous supratentorial intracerebral hemorrhage (ICH). A nationwide multicenter study including 401 ICH patients surgically treated by craniotomy and evacuation of a spontaneous supratentorial ICH was conducted between January 1, 2011, and December 31, 2015. All neurosurgical centers in Sweden were included. All medical records and neuroimaging studies were retrospectively reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the Surgical Swedish ICH [SwICH] Score) was developed using weighting of independent predictors based on strength of association. Factors independently associated with 30-day mortality were Glasgow Coma Scale (GCS) score (p = 0.00015), ICH volume ≥ 50 mL (p = 0.031), patient age ≥ 75 years (p = 0.0056), prior myocardial infarction (MI) (p = 0.00081), and type 2 diabetes (p = 0.0093). The Surgical SwICH Score was the sum of individual points assigned as follows: GCS score 15-13 (0 points), 12-5 (1 point), 4-3 (2 points); age ≥ 75 years (1 point); ICH volume ≥ 50 mL (1 point); type 2 diabetes (1 point); prior MI (1 point). Each increase in the Surgical SwICH Score was associated with a progressively increased 30-day mortality (p = 0.0002). No patient with a Surgical SwICH Score of 0 died, whereas the 30-day mortality rates for patients with Surgical SwICH Scores of 1, 2, 3, and 4 were 5%, 12%, 31%, and 58%, respectively. The Surgical SwICH Score is a predictor of 30-day mortality in patients treated surgically for spontaneous supratentorial ICH. External validation is needed to assess the predictive value as well as the generalizability of the Surgical SwICH Score.


Did government spending cuts to social care for older people lead to an increase in emergency hospital admissions? An ecological study, England 2005-2016.
Government spending on social care in England reduced substantially in real terms following the economic crisis in 2008, meanwhile emergency admissions to hospitals have increased. We aimed to assess the extent to which reductions in social care spend on older people have led to increases in emergency hospital admissions. We used negative binomial regression for panel data to assess the relationship between emergency hospital admissions and government spend on social care for older people. We adjusted for population size and for levels of deprivation and health. Hospitals and adult social care services in England between April 2005 and March 2016. People aged 65 years and over resident in 132 local councils. Primary outcome variable-emergency hospital admissions of adults aged 65 years and over. Secondary outcome measure-emergency hospital admissions for ambulatory care sensitive conditions (ACSCs) of adults aged 65 years and over. We found no significant relationship between the changes in the rate of government spend (£'000 s) on social care for older people within councils and our primary outcome variable, emergency hospital admissions (Incidence rate ratio (IRR) 1.009, 95% CI 0.965 to 1.056) or our secondary outcome measure, admissions for ACSCs (IRR 0.975, 95% CI 0.917 to 1.038). We found no evidence to support the view that reductions in government spend on social care since 2008 have led to increases in emergency hospital admissions in older people. Policy makers may wish to review schemes, such as the Better Care Fund, which are predicated on a relationship between social care provision and emergency hospital admissions of older people.


Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials.
Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces "off" time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. In the open-label study, 92% of 354 patients received monotherapy at post-PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post-PEG-J week 4, mean "off" time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1-4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.


Percutaneous needle biopsy preceding preoperative chemotherapy in the management of massive renal tumors in children.
While the National Wilms' Tumor Study (NWTS) Group in the United States puts an emphasis on accurate staging and histology before any therapy is given for Wilms' tumor, the International Society of Pediatric Oncology (SIOP) in Europe focuses on preoperative therapy and safer surgery. Our current approach combines the benefits of both policies in the management of massive renal tumors in children. In seven consecutive patients we first obtained a percutaneous posterior needle biopsy to obtain adequate tissue for histology, and proceeded with preoperative chemotherapy with vincristine and dactinomycin until tumor shrinkage was sufficient. Tumor removals were feasible and uneventful. At the time of operation, two tumors were found to be totally or almost totally necrotic. In the others, which still included viable tumor, the histology corresponded well to the needle biopsy findings. One case with unfavorable histology and one with rhabdoid sarcoma would have been missed and given suboptimal therapy without the primary needle biopsy. As possible biopsy-related complications, subcapsular intratumoral bleeding was recognized in two patients. We conclude that percutaneous posterior needle biopsy is safe and yields definite, detailed histology in massive renal tumors in children. Preoperative chemotherapy facilitates surgery in these patients.


Predicting the reward value of faces and bodies from social perception.
Social judgments of faces are thought to be underpinned by two perceptual components: valence and dominance. Recent work using a standard key-press task to assess reward value found that these valence and dominance components were both positively related to the reward value of faces. Although bodies play an important role in human social interaction, the perceptual dimensions that underpin social judgments of bodies and their relationship to the reward value of bodies are not yet known. The current study investigated these issues. We replicated previous studies showing that valence and dominance underpin social judgments of faces and that both components are positively related to the reward value of faces. By contrast, social judgments of bodies were underpinned by a single component that reflected aspects of both perceived valence and perceived dominance and was positively correlated with the reward value of bodies. These results highlight differences in how observers process faces and bodies.


Trajectories of male sexual aggression from adolescence through college: A latent class growth analysis.
Approximately 25% of male college students report engaging in some form of sexual coercion by the end of their fourth year of college. White and Smith (2004) found that negative childhood experiences-childhood sexual abuse, childhood physical abuse, and witnessing domestic violence-predicted sexual aggression perpetrated before college, but not during the subsequent college years, a puzzling finding in view of the reasonably consistent rates of sexual aggression from adolescence to the first 2 years of college. The current study takes a person-centered approach to sexual aggression in an attempt to resolve this discrepancy. We examined the possibility of cohesive subgroups of men in terms of their frequency of sexual aggression across the pre-college and college years. A series of latent class growth models were fit to an existing longitudinal dataset of sexual experiences collected across four time points-pre-college through year 3 of college. A four-trajectory model fit the data well, exhibiting significantly better fit than a three-trajectory model. The four trajectories are interpreted as men who perpetrate sexual aggression at (1) low (71.5% of the sample), (2) moderate (21.2%), (3) decreasing (4.2%), and (4) increasing (3.1%) frequencies across time. Negative childhood experiences predicted membership of the decreasing trajectory, relative to the low trajectory, but did not predict membership of the increasing trajectory, explaining the discrepancy uncovered by White and Smith. Implications for primary prevention of sexual aggression are discussed.


Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions.
Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.


A fork head related multigene family is transcribed in Xenopus laevis embryos.
We have isolated and sequenced ten different members of the fork head/HNF-3 multigene family from Xenopus laevis which have been termed Xenopus fork head domain related (XFD) genes 1 to 10. Another four isolated genes (XFD' genes) represent pseudo-allelic variants which arose by an ancient tetraploidization within this species. Whereas all genes of this multigene family exhibit a high degree of sequence homology within the evolutionary conserved fork head domain, sequences outside this module are substantially different. Based upon sequence homologies over the entire coding sequences, XFD-7/7' represent the Xenopus homologs to the rodent hepatocyte nuclear factor HNF-3 alpha, while XFD-3/3' encode the homologs to HNF-3 beta. Here we present an analysis of the temporal transcription pattern of XFD genes 1 to 10 during embryogenesis and in some adult tissues. Eight of these XFD genes are activated during embryonic development, but show different and distinct transcription profiles. The localization of transcripts was determined by whole-mount in situ hybridization. Although transcription of individual XFD genes partially overlaps, each gene is characterized by means of a specific spatial pattern of transcriptional activity.


Sexual risk behavior among youth with perinatal HIV infection in the United States: predictors and implications for intervention development.
Factors associated with initiation of sexual activity among perinatally human immunodeficiency virus (HIV)-infected (PHIV(+)) youth, and the attendant potential for sexual transmission of antiretroviral (ARV) drug-resistant HIV, remain poorly understood. We conducted cross-sectional and longitudinal analyses of PHIV(+) youth aged 10-18 years (mean, 13.5 years) enrolled in the US-based Pediatric HIV/AIDS Cohort Study between 2007 and 2009. Audio computer-assisted self-interviews (ACASI) were used to collect sexual behavior information. Twenty-eight percent (95% confidence interval [CI], 23%-33%) (92/330) of PHIV(+) youth reported sexual intercourse (SI) (median initiation age, 14 years). Sixty-two percent (57/92) of sexually active youth reported unprotected SI. Among youth who did not report history of SI at baseline, ARV nonadherence was associated with sexual initiation during follow-up (adjusted hazard ratio, 2.87; 95% CI, 1.32-6.25). Youth living with a relative other than their biological mother had higher odds of engaging in unprotected SI than those living with a nonrelative. Thirty-three percent of youth disclosed their HIV status to their first sexual partner. Thirty-nine of 92 (42%) sexually active youth had HIV RNA ≥5000 copies/mL after sexual initiation. Viral drug resistance testing, available for 37 of these 39 youth, identified resistance to nucleoside reverse transcriptase inhibitors in 62%, nonnucleoside reverse transcriptase inhibitors in 57%, protease inhibitors in 38%, and all 3 ARV classes in 22%. As PHIV(+) youth become sexually active, many engage in behaviors that place their partners at risk for HIV infection, including infection with drug-resistant virus. Effective interventions to facilitate youth adherence, safe sex practices, and disclosure are urgently needed.


Neuronal networks in children with continuous spikes and waves during slow sleep.
Epileptic encephalopathy with continuous spikes and waves during slow sleep is an age-related disorder characterized by the presence of interictal epileptiform discharges during at least >85% of sleep and cognitive deficits associated with this electroencephalography pattern. The pathophysiological mechanisms of continuous spikes and waves during slow sleep and neuropsychological deficits associated with this condition are still poorly understood. Here, we investigated the haemodynamic changes associated with epileptic activity using simultaneous acquisitions of electroencephalography and functional magnetic resonance imaging in 12 children with symptomatic and cryptogenic continuous spikes and waves during slow sleep. We compared the results of magnetic resonance to electric source analysis carried out using a distributed linear inverse solution at two time points of the averaged epileptic spike. All patients demonstrated highly significant spike-related positive (activations) and negative (deactivations) blood oxygenation-level-dependent changes (P < 0.05, family-wise error corrected). The activations involved bilateral perisylvian region and cingulate gyrus in all cases, bilateral frontal cortex in five, bilateral parietal cortex in one and thalamus in five cases. Electrical source analysis demonstrated a similar involvement of the perisylvian brain regions in all patients, independent of the area of spike generation. The spike-related deactivations were found in structures of the default mode network (precuneus, parietal cortex and medial frontal cortex) in all patients and in caudate nucleus in four. Group analyses emphasized the described individual differences. Despite aetiological heterogeneity, patients with continuous spikes and waves during slow sleep were characterized by activation of the similar neuronal network: perisylvian region, insula and cingulate gyrus. Comparison with the electrical source analysis results suggests that the activations correspond to both initiation and propagation pathways. The deactivations in structures of the default mode network are consistent with the concept of epileptiform activity impacting on normal brain function by inducing repetitive interruptions of neurophysiological function.


The effects of spiritual interventions in patients with cancer: a meta-analysis.
To evaluate the effects of a spiritual intervention in patients with cancer. Databases searched included both international electronic databases (MEDLINE® via PubMed, Cochrane Library CENTRAL, EMBASE, and CINAHL®) as well as Korean electronic databases (KMBASE, KOREAMED, RISS, KISS, and NANET) through December 2013. A meta-analysis was conducted of 15 studies involving 14 controlled trials (7 randomized and 7 nonrandomized) with 889 patients with cancer. Spiritual interventions were compared with a usual care control group or other psychosocial interventions. The weighted average effect size across studies was -0.48 (p = 0.006, I2 = 65%) for spiritual well-being, -0.58 (p = 0.02, I2 = 70%) for meaning of life, -0.87 (p = 0.02, I2 = 87%) for anxiety, and -0.62 (p = 0.001, I2 = 73%) for depression. The findings showed that spiritual interventions had significant but moderate effects on spiritual well-being, meaning of life, and depression. However, the evidence remains weak because of the mixed study design and substantial heterogeneity. Oncology nurses increasingly recognize the significance of the spiritual domain of care. The current study indicates that facilitating spiritual awareness and needs may be a worthwhile nursing intervention for patients with cancer.


Thinking outside our cages.
Researchers seem to be stuck reiterating the now-familiar argument that barren boxes are bad for welfare and that rodents are due ethical consideration. But the prerequisites for real progress are new kinds of arguments, new types of data, and removal of very real practical and cultural obstacles to implementation of meaningful enrichment. We must discover what we have to do to effectively change the practices of people who have care and control of rodents in the laboratory, not just husbandry staff but those who develop the institution's protocols, job descriptions, and resourcing. Researchers are inventers of information, and like any inventor we should experience no satisfaction until our ideas are fully implemented-and we must be an active participant in that process. If we are asking animal caretakers to make deep, paradigmatic changes in their thinking, it is imperative that we in turn develop an emotionally positive understanding of areas important to them. For unless the welfare advocates truly understand the issues such as budgets, biosecurity, and branding, why should the people responsible for those subjects listen to us?


Biological annihilation via the ongoing sixth mass extinction signaled by vertebrate population losses and declines.
The population extinction pulse we describe here shows, from a quantitative viewpoint, that Earth's sixth mass extinction is more severe than perceived when looking exclusively at species extinctions. Therefore, humanity needs to address anthropogenic population extirpation and decimation immediately. That conclusion is based on analyses of the numbers and degrees of range contraction (indicative of population shrinkage and/or population extinctions according to the International Union for Conservation of Nature) using a sample of 27,600 vertebrate species, and on a more detailed analysis documenting the population extinctions between 1900 and 2015 in 177 mammal species. We find that the rate of population loss in terrestrial vertebrates is extremely high-even in "species of low concern." In our sample, comprising nearly half of known vertebrate species, 32% (8,851/27,600) are decreasing; that is, they have decreased in population size and range. In the 177 mammals for which we have detailed data, all have lost 30% or more of their geographic ranges and more than 40% of the species have experienced severe population declines (>80% range shrinkage). Our data indicate that beyond global species extinctions Earth is experiencing a huge episode of population declines and extirpations, which will have negative cascading consequences on ecosystem functioning and services vital to sustaining civilization. We describe this as a "biological annihilation" to highlight the current magnitude of Earth's ongoing sixth major extinction event.


Early results from the infrared astronomical satellite.
For 10 months the Infrared Astronomical Satellite (IRAS) provided astronomers with what might be termed their first view of the infrared sky on a clear, dark night. Without IRAS, atmospheric absorption and the thermal emission from both the atmosphere and Earthbound telescopes make the task of the infrared astronomer comparable to what an optical astronomer would face if required to work only on cloudy afternoons. IRAS observations are serving astronomers in the same manner as the photographic plates of the Palomar Observatory Sky Survey; just as the optical survey has been used by all astronomers for over three decades, as a source of quantitative information about the sky and as a "roadmap" for future observations, the results of IRAS will be studied for years to come. IRAS has demonstrated the power of infrared astronomy from space. Already, from a brief look at a miniscule fraction of the data available, we have learned much about the solar system, about nearby stars, about the Galaxy as a whole and about distant extragalactic systems. Comets are much dustier than previously thought. Solid particles, presumably the remnants of the star-formation process, orbit around Vega and other stars and may provide the raw material for planetary systems. Emission from cool interstellar material has been traced throughout the Galaxy all the way to the galactic poles. Both the clumpiness and breadth of the distribution of this material were previously unsuspected. The far-infrared sky away from the galactic plane has been found to be dominated by spiral galaxies, some of which emit more than 50 percent and as much as 98 percent of their energy in the infrared-an exciting and surprising revelation. The IRAS mission is clearly the pathfinder for future missions that, to a large extent, will be devoted to the discoveries revealed by IRAS.


Efficient molecular screening of Lynch syndrome by specific 3' promoter methylation of the MLH1 or BRAF mutation in colorectal cancer with high-frequency microsatellite instability.
It is sometimes difficult to diagnose Lynch syndrome by the simple but strict clinical criteria, or even by the definitive genetic testing for causative germline mutation of mismatch repair genes. Thus, some practical and efficient screening strategy to select highly possible Lynch syndrome patients is exceedingly desirable. We performed a comprehensive study to evaluate the methylation status of whole MLH1 promoter region by direct bisulfite sequencing of the entire MLH1 promoter regions on Lynch and non-Lynch colorectal cancers (CRCs). Then, we established a convenient assay to detect methylation in key CpG islands responsible for the silencing of MLH1 expression. We studied the methylation status of MLH1 as well as the CpG island methylator phenotype (CIMP) and immunohistochemical analysis of mismatch repair proteins on 16 cases of Lynch CRC and 19 cases of sporadic CRCs with high-frequency microsatellite instability (MSI-H). Sensitivity to detect Lynch syndrome by MLH1 (CCAAT) methylation was 88% and the specificity was 84%. Positive likelihood ratio (PLR) was 5.5 and negative likelihood ratio (NLR) was 0.15. Sensitivity by mutational analysis of BRAF was 100%, specificity was 84%, PLR was 6.3 and NLR was zero. By CIMP analysis; sensitivity was 88%, specificity was 79%, PLR was 4.2, and NLR was 0.16. BRAF mutation or MLH1 methylation analysis combined with MSI testing could be a good alternative to screen Lynch syndrome patients in a cost effective manner. Although the assay for CIMP status also showed acceptable sensitivity and specificity, it may not be practical because of its rather complicated assay.


Maternal negative affect during infancy is linked to disrupted patterns of diurnal cortisol and alpha asymmetry across contexts during childhood.
Maternal negative affect in the early environment is believed to sensitize long-term coping capacities in children. Yet, little work has identified physiological systems associated with coping responses, which may serve as mechanisms for links between early maternal negativity and child outcomes. Using a longitudinal twin sample (N=89), we found that high levels of maternal negative affect during infancy were associated with dysregulation of diurnal cortisol and electroencephalograph (EEG) asymmetry, two physiological systems that may support active approach-oriented coping when children are 7years old. Flattened slopes of diurnal cortisol were also associated with greater numbers of concurrent overanxious behaviors in children. A mediation analysis supported the role of dysregulated diurnal cortisol as a mediator of the link between maternal negative affect in the early environment and childhood risk for anxiety problems.


Population access to rotavirus vaccination in industrialized countries: lessons learnt from current experience.
Four steps are usually necessary before population access to vaccination programmes. Marketing authorization, appropriation by national agencies of the data, recommendation and policy-decision steps on funding and implementation. Using rotavirus vaccination as an illustrative case, this study aims at better understanding picture of population access, and identifying lessons learnt from current experience. Systematic review of national vaccination policies in 20 countries. 12 countries have included rotavirus vaccination in their childhood national vaccination programme, two decided not to include it, decision is pending in three countries, while it has not started in the three remaining countries. Published evaluations and/or advice were available in 16 countries. Many differences in content and outcomes were identified. Rotavirus vaccination implementation across industrialized countries was disparate, leading to unequal population access over time. Comparative analyses of the decision-making process suggest different interpretations of available evidence, raising the need for a similar decision integrated framework, using a structured and systematic approach.


Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm.
Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1-8 μg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-α and IL-6 release and increase in IL-1β. These data provide evidence that MenA inhibitors act as TNF-α and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents.


Reopening California : Seeking Robust, Non-Dominated COVID-19 Exit Strategies.
Amid global scarcity of COVID-19 vaccines and the threat of new variant strains, California and other jurisdictions face the question of when and how to implement and relax COVID-19 Nonpharmaceutical Interventions (NPIs). While policymakers have attempted to balance the health and economic impacts of the pandemic, decentralized decision-making, deep uncertainty, and the lack of widespread use of comprehensive decision support methods can lead to the choice of fragile or inefficient strategies. This paper uses simulation models and the Robust Decision Making (RDM) approach to stress-test California's reopening strategy and other alternatives over a wide range of futures. We find that plans which respond aggressively to initial outbreaks are required to robustly control the pandemic. Further, the best plans adapt to changing circumstances, lowering their stringent requirements to reopen over time or as more constituents are vaccinated. While we use California as an example, our results are particularly relevant for jurisdictions where vaccination roll-out has been slower.


How I manage neonatal thrombocytopenia.
Although neonatal thrombocytopenia (platelet count < 150×10(9) /l) is a common finding in hospital practice, a careful clinical history and examination of the blood film is often sufficient to establish the diagnosis and guide management without the need for further investigations. In preterm neonates, early-onset thrombocytopenia (<72h) is usually secondary to antenatal causes, has a characteristic pattern and resolves without complications or the need for treatment. By contrast, late-onset thrombocytopenia in preterm neonates (>72h) is nearly always due to post-natally acquired bacterial infection and/or necrotizing enterocolitis, which rapidly leads to severe thrombocytopenia (platelet count<50×10(9) /l). Thrombocytopenia is much less common in term neonates and the most important cause is neonatal alloimmune thrombocytopenia (NAIT), which confers a high risk of perinatal intracranial haemorrhage and long-term neurological disability. Prompt diagnosis and transfusion of human platelet antigen-compatible platelets is key to the successful management of NAIT. Recent studies suggest that more than half of neonates with severe thrombocytopenia receive platelet transfusion(s) based on consensus national or local guidelines despite little evidence of benefit. The most pressing problem in management of neonatal thrombocytopenia is identification of safe, effective platelet transfusion therapy and controlled trials are urgently needed.


NADPH oxidase involvement in cellular integrity.
NADPH oxidase activity is involved in plant adaptation and development. The reactive oxygen species sourced by NADPH oxidase activity may contribute to wall strength and protoplast volume adjustment. Root hair bulge apices of the NADPH oxidase mutant rhd2/Atrbohc were more robust than the kjk cellulose synthase mutant, but burst more readily than the wild type (WT). Root epidermal wall appeared impaired in rhd2/Atrbohc, as revealed by the number of protoplasts released by wall-degrading enzymes. Root hair bulges of rhd2/Atrbohc burst more than the WT when challenged in situ with hypo-osmotic low ionic strength medium. Inhibition of NADPH oxidase activity with diphenylene iodonium caused WT to phenocopy the rhd2/Atrbohc bursting in response to hypo-osmotic shock. This implicates RHD2/AtRBOHC in softening the cell wall to permit protoplast expansion. Overall, the results point to a role for RHD2/AtRBOHC in contributing to wall strength.


Role of kinins in pain and hyperalgesia: psychophysical studies in a patient with kininogen deficiency.
1. Bradykinin is considered to be an important mediator of pain and hyperalgesia associated with injury and inflammation. Psychophysical studies were conducted in a patient with complete kininogen deficiency to determine whether the absence of bradykinin was associated with abnormalities in pain sensibility. Pain evoked by heat stimuli to the thenar eminence was tested before and after a localized burn, which has been shown to cause hyperalgesia in normal subjects. In addition, pain evoked by intradermal administration of bradykinin (0.1-10 micrograms) to the forearm and the effects of bradykinin on pain induced by heat stimuli were studied. The patient rated the intensity of pain evoked by all heat stimuli relative to the pain induced by a 3 s 45 degrees C stimulus. 2. The patient's heat pain threshold (45 degrees C) in the glabrous skin was similar to that of age-matched control subjects (n = 5) and to that previously observed in younger control subjects. 3. The burn resulted in a decrease in pain threshold and an increase in pain induced by suprathreshold stimuli. The magnitude of hyperalgesia was within the range observed in the age-matched control subjects and in younger control subjects. Thus, kinins are not essential for the development of hyperalgesia after heat injury. 4. In control subjects, intradermal injections of bradykinin produced pain and hyperalgesia to heat stimuli. In the patient, intradermal bradykinin injections induced minimal pain and no hyperalgesia to heat stimuli. Thus, congenital absence of kininogens may be associated with a deficiency in bradykinin receptors.


Spatial patterns of the vacuolation in subcortical white matter in sporadic Creutzfeldt-Jakob disease (sCJD).
To study the spatial patterns of the vacuolation ("spongiform change") in the subcortical white matter in the "classical" form of sporadic Creutzfeldt-Jakob disease (sCJD). Frontal, parietal, occipital and temporal lobes of 11 cases of sCJD. Spatial patterns were studied across the white matter at the base of the gyri using spatial pattern analysis. In the white matter of all gyri studied, vacuoles were aggregated into clusters, 50 to > 800 microm in diameter and in 22/37 (59%) of gyri, the clusters of vacuoles exhibited a regular distribution across the base of the gyri. In the remaining gyri, the vacuoles were aggregated into large clusters, at least 400 microm or 800 microm in diameter, but without evidence of a regular distribution. In a significant proportion of gyri, the spatial patterns of the vacuolation were similar to those reported previously for spongiform change and prion protein (PrP) deposits in the corresponding grey matter. Degeneration of the white matter and the formation of clusters of vacuoles may occur before the degeneration of the grey matter or could be a consequence of pathology affecting the cortico-cortical pathways.


Carbon and nitrogen gain during the growth of orchid seedlings in nature.
For germination and establishment, orchids depend on carbon (C) and nutrients supplied by mycorrhizal fungi. As adults, the majority of orchids then appear to become autotrophic. To compare the proportional C and nitrogen (N) gain from fungi in mycoheterotrophic seedlings and in adults, here we examined in the field C and N stable isotope compositions in seedlings and adults of orchids associated with ectomycorrhizal and saprotrophic fungi. Using a new highly sensitive approach, we measured the isotope compositions of seedlings and adults of four orchid species belonging to different functional groups: fully and partially mycoheterotrophic orchids associated with narrow or broad sets of ectomycorrhizal fungi, and two adult putatively autotrophic orchids associated exclusively with saprotrophic fungi. Seedlings of orchids associated with ectomycorrhizal fungi were enriched in (13) C and (15) N similarly to fully mycoheterotrophic adults. Seedlings of saprotroph-associated orchids were also enriched in (13) C and (15) N, but unexpectedly their enrichment was significantly lower, making them hardly distinguishable from their respective adult stages and neighbouring autotrophic plants. We conclude that partial mycoheterotrophy among saprotroph-associated orchids cannot be identified unequivocally based on C and N isotope compositions alone. Thus, partial mycoheterotrophy may be much more widely distributed among orchids than hitherto assumed.


Isolation of the bacteriophage lambda receptor from Escherichia coli.
A factor which inactivates the phage lambda can be extracted from Escherichia coli. This factor is a protein and is located in the outer membrane of the bacterial envelope. It is found in extracts of strains which are sensitive to phage lambda, but not in extracts of strains specifically resistant to this phage. We conclude that this factor is the lambda receptor, responsible for the specific adsorption of the phage lambda to E. coli cells. A partial purification of the lambda receptor is described. Inactivation of the phage by purified receptor is shown to be accompanied by the release of deoxyribonucleic acid from the phage.


Strategies for controlling blood pressure among low-income populations in Georgia.
In Georgia an estimated 32% of blacks and 28% of whites have high blood pressure. In 2004 the rate of death from stroke in Georgia was 12% higher than the national average, and blacks in the state have a 1.4 times greater rate of death from stroke than that of whites. The Georgia legislature funds the Stroke and Heart Attack Prevention Program (SHAPP) to provide treatment and medications for indigent Georgians. The median rate of blood pressure (BP) control among SHAPP enrollees is approximately 60%, compared with the national average of 35%. SHAPP was evaluated through interviews with key health care and administrative staff and through focus groups of patients in two clinics. Outcomes for patients were increased knowledge of their BP and improved compliance with taking medication and keeping clinic appointments. Successful components of SHAPP include an easy enrollment process; affordable medication; use of evidence-based, documented protocols and patient tracking systems; routine follow-up of patients; and effective communication between staff and patients. Challenges and recommendations for improvement are identified.


Oxygen consumption using the K2 telemetry system and a metabolic cart.
The purpose of this study was to compare measurements of oxygen consumption (VO2), ventilation (VE), and respiratory rate (RR) between a relatively new portable, telemetry system (K2) and a system that has been shown to be valid and reliable. Duplicate measurements were made at rest and during four levels of exercise in 10 subjects. Heart rate values were comparable for exercise at the same work level during gas collection using the two systems, indicating that the metabolic stresses were similar. Oxygen consumption measurements were significantly lower using the K2 system compared with a metabolic measurement cart (MMC). There was no significant difference in VE, but RR was lower for measurements made with the MMC. Compared with the MMC, the K2 system uses a slightly different formula to calculate VO2 because the content of carbon dioxide in expired air is not measured. To determine differences resulting from the method of calculating VO2, MMC measurements were applied to the formula used by the K2 system, and K2 values were adjusted using the RER values obtained from the MMC. There were no differences between these calculated values and the values obtained directly from either the MMC or the K2 system. Consequently, we concluded that the lower VO2 values obtained with the K2 system were attributed to the method of collecting and analyzing expired air, rather than to the method of calculating VO2.


An on-chip whole blood/plasma separator with bead-packed microchannel on COC polymer.
A disposable on-chip whole blood/plasma separator, which is able to separate plasma from whole human blood by capillary force through a bead-packed microchannel, has been designed, fabricated and characterized in this work. Various sizes of silica beads were slurry-packed through a microchannel using a bump structure which held beads in a defined region. The bead-packed microchannel induces a capillary force which allows plasma to move forward through the bead-packed column more rapidly than red blood cells (RBCs). The blood/plasma separator with bead-packed microchannel has successfully separated plasma from the whole blood without haemolysis of RBCs. The separation method developed in this work can be applied to various on-chip stationary filtrations of RBC for point-of-care clinical diagnostics.


Donated breast milk stored in banks versus breast milk purchased online.
One of my patients asked if she could buy human milk on the Internet to feed her infant if the need arose. Is using donated breast milk from the milk bank safer than buying it online? The World Health Organization and the American Academy of Pediatrics recommend the use of donated breast milk as the first alternative when maternal milk is not available, but the Canadian Paediatric Society does not endorse the sharing of unprocessed human milk. Human breast milk stored in milk banks differs from donor breast milk available via the Internet owing to its rigorous donor-selection process, frequent quality assurance inspections, regulated transport process, and pasteurization in accordance with food preparation guidelines set out by the Canadian Food Inspection Agency. Most samples purchased online contain Gram-negative bacteria or have a total aerobic bacteria count of more than 10(4) colony-forming units per millilitre; they also exhibit higher mean total aerobic bacteria counts, total Gram-negative bacteria counts, coliform bacteria counts, and Staphylococcus spp counts than milk bank samples do. Growth of most bacteria species is associated with the number of days in transit, which suggests poor collection, storage, or shipping practices for milk purchased online.


Processing and characterisation of Mo6S2I8 nanowires.
One-dimensional nanostructures based on the Mo-S-I system have recently aroused a lot of interest as a viable alternative to the ubiquitous carbon nanotube due to their uniform structure and electronic properties for a given composition. Previous research on the Mo(6)S(3)I(6) and Mo(6)S(4.5)I(4.5) stoichiometries has also shown them to be soluble in common solvents like water, acetone or isopropyl alcohol, and to debundle on dilution. Here, the solubility, debundling and composition of Mo(6)S(2)I(8) nanowires are presented. They were found to be most soluble in dimethylformamide, which retained 47 wt% of a 0.08 gl(-1) nanowire (NW) material dispersion as thin NW bundles after one week. Dispersions of 0.8 gl(-1) and 5 gl(-1) even retained 54 wt% and 66 wt%, respectively. However the NW material was completely insoluble in water, and the surface energy of Mo(6)S(2)I(8) NWs was deduced as 67 mJ m(-2), higher than for other Mo-S-I NWs. UV-vis-NIR spectroscopy showed nanowire peaks familiar from Mo(6)S(3)I(6) and Mo(6)S(4.5)I(4.5) spectra around 1.8 and 2.8 eV, as well as unforeseen ultraviolet peaks at 3.5 and 4.4 eV. These chemical differences suggest an alternate, more strongly bonded structure to that seen for Mo(6)S(3)I(6) and Mo(6)S(4.5)I(4.5) NWs. Films deposited from a range of concentrations were investigated using atomic force microscopy (AFM) to determine bundle diameter distributions. The average diameter and the spread in diameters were found to decrease somewhat with decreasing concentration. However extrapolation gave a finite bundle size at infinite dilution, and an extension of the existing debundling model is proposed to take this into account. To confirm the nominal stoichiometry of Mo(6)S(2)I(8), which does not follow the generic Mo(6)S(x)I(9-x) formula of previous stoichiometries, EDX was carried out. The composition of nanowire bundles was found to be Mo(6)S(2.3)I(8.6), supporting the nominal composition.


Presence of Gyriform Air Predicts Unfavorable Outcome in Venous Catheter-Related Cerebral Air Embolism.
This study aimed to investigate the clinical predictors of unfavorable prognosis in patients with venous catheter-related cerebral air embolism. An extensive review of English literature was performed to obtain reports on cerebral air embolism published between January 1982 and July 2014 through PubMed, Journal at Ovid, and Web of Science using the Mesh terms and keywords "cerebral air embolism" and "cerebral gas embolism." Reports not fulfilling the diagnosis of cerebral air embolism and iterant articles were excluded. Demographics, clinical manifestations, and imaging findings were recorded. The air distribution on initial brain computed tomography (CT) was recorded as gyriform air (GF), cavernous sinus bubble, venous sinus bubble, and parenchymal and subarachnoid bubble. The enrolled subjects were further divided into favorable and unfavorable outcome groups for analyses. Of the 33 cases enrolled, 31 had documented follow-up outcomes, including 14 with favorable and 17 with unfavorable prognoses. Patients with unfavorable outcome had older onset age (67.5 ± 15.8 versus 46.7 ± 17.0 years, P < .001), higher frequency of GF on brain CT (58.8% versus 0%, P < .01), initial consciousness disturbance (100% versus 42.9%, P < .001), and hemiparesis (100% versus 42.9%, P < .001), but lower frequency of cardiopulmonary symptoms (5.9% versus 64.3%, P < .01). In patients with central venous catheter-related cerebral air embolism, the retrograde mechanism had a tendency for worse outcomes (43.8% versus 0%, P = .023). In patients with venous catheter-related cerebral air embolism, the presence of GF on brain CT imaging, old age, initial conscious disturbance, and hemiparesis may predict unfavorable outcomes.


Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs.
We calculated the wavelength of the atrial impulse in chronically instrumented conscious dogs by measuring both conduction velocity and refractory period: wavelength = refractory period X conduction velocity. Implantation of multiple stimulating and recording electrodes allowed wavelength determination at four different areas: the right and left parts of Bachmann's bundle and the free walls of the right and left atria. During programmed electrical stimulation, three types of arrhythmias were observed: rapid repetitive responses, atrial flutter, and atrial fibrillation. During normal rhythm, the wavelength of the atrial impulse varied between 14 and 18 cm. Premature beats had a shorter wavelength, depending on the degree of prematurity. Premature beats that evoked rapid repetitive responses showed a critical shortening of the wavelength below 12.3 cm. Episodes of atrial flutter were induced at a wavelength below 9.7 cm, while fibrillation occurred at wavelengths shorter than 7.8 cm. We correlated the induction of these arrhythmias with the values of refractory period, conduction velocity, and wavelength during control and during administration of several drugs. Intravenous administration of acetylcholine shortened the wavelength by 30-40%, mainly because of refractory period shortening. Both propafenone and lidocaine had strong but opposite effects on refractoriness and conduction and, consequently, little effect on the wavelength. Quinidine markedly prolonged the refractory period, but prolongation of wavelength was less because of a simultaneous decrease in conduction velocity. d-Sotalol also increased refractory period, but because it had no appreciable effect on conduction velocity, this drug was the most effective in prolongation of wavelength. Linear discriminant analysis of the data showed that the refractory period and the conduction velocity each were poor parameters to predict the occurrence of the different arrhythmias (predictive value 48% and 38%, respectively). The combination of both properties, however, as expressed in the wavelength, was a more reliable index that predicted the induction of the different arrhythmias correctly in 75% of the cases. We conclude that the wavelength is a useful parameter for evaluating antiarrhythmic drugs.


Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments.
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder affecting approximately 1% of children. ASD is defined by core symptoms in two domains: negative symptoms of impairment in social and communication function, and positive symptoms of restricted and repetitive behaviors. Available treatments are inadequate for treating both core symptoms and associated conditions. Twin studies indicate that ASD susceptibility has a large heritable component. Genetic studies have identified promising leads, with converging insights emerging from single-gene disorders that bear ASD features, with particular interest in mammalian target of rapamycin (mTOR)-linked synaptic plasticity mechanisms. Mouse models of these disorders are revealing not only opportunities to model behavioral perturbations across species, but also evidence of postnatal rescue of brain and behavioral phenotypes. An intense search for ASD biomarkers has consistently pointed to elevated platelet serotonin (5-HT) levels and a surge in brain growth in the first 2 years of life. Following a review of the diversity of ASD phenotypes and its genetic origins and biomarkers, we discuss opportunities for translation of these findings into novel ASD treatments, focusing on mTor- and 5-HT-signaling pathways, and their possible intersection. Paralleling the progress made in understanding the root causes of rare genetic syndromes that affect cognitive development, we anticipate progress in models systems using bona fide ASD-associated molecular changes that have the potential to accelerate the development of ASD diagnostics and therapeutics.


Mild asthma and chronic bronchitis seem to influence functional exercise capacity: a multi-case control study.
In the Genes Environment Interaction in Respiratory Diseases population-based multi-case control study, we investigated whether asthma, chronic bronchitis (CB) and rhinitis were associated with a reduced 6-minute walk distance (6MWD), and whether the 6MWD determinants were similar for subjects with/without respiratory diseases. Cases of asthma (n = 360), CB (n = 120), rhinitis (n = 203) and controls (no respiratory diseases: n = 302) were recruited. The variation in the 6MWD across the groups was analyzed by ANCOVA, adjusting for gender, age, height, weight and comorbidity. The 6MWD determinants were studied by linear regression, and heterogeneity across the cases and controls was investigated. The 6MWD differed across cases and controls (p = 0.01). It was shorter for cases of asthma (-17.1, 95% CI -28.3 to -5.8 m) and CB (-20.7, 95% CI: -36.6 to -4.8 m) than for controls (604 ± 68 m on average), but not for cases of rhinitis. The negative association between age and the 6MWD was significant for cases of CB, but not for the other groups (p = 0.001). Even at the level of severity found in the general population, asthma and CB could influence the 6MWD, which seems to reflect the functional exercise level for daily physical activities. The negative association between ageing and the 6MWD was particularly strong in subjects with CB. Our report adds to the mounting evidence that CB is not a trivial condition, especially in the ageing adult population, and it supports the importance of monitoring functional capacity and of physical reconditioning in mild asthma.


Loss of Furin in β-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to β-Cell Dysfunction.
FURIN is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, but its specific role in pancreatic β-cells is largely unknown. The aim of this study was to determine the role of FURIN in glucose homeostasis. We show that FURIN is highly expressed in human islets, whereas PCs that potentially could provide redundancy are expressed at considerably lower levels. β-cell-specific Furin knockout (βFurKO) mice are glucose intolerant as a result of smaller islets with lower insulin content and abnormal dense-core secretory granule morphology. mRNA expression analysis and differential proteomics on βFurKO islets revealed activation of activating transcription factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βFurKO cells show impaired cleavage or shedding of vacuolar-type ATPase (V-ATPase) subunits Ac45 and prorenin receptor, respectively, and impaired lysosomal acidification. Blocking V-ATPase pharmacologically in β-cells increased mTORC1 activity, suggesting involvement of the V-ATPase proton pump in the phenotype. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation and impaired lysosomal acidification in β-cells lacking Furin, causing β-cell dysfunction.


Barriers and facilitators to the conduct of critical care research in low and lower-middle income countries: A scoping review.
Improvements in health-related outcomes for critically ill adults in low and lower-middle income countries need systematic investments in research capacity and infrastructure. High-quality research has been shown to strengthen health systems; yet, research contributions from these regions remain negligible or absent. We undertook a scoping review to describe barriers and facilitators for the conduct of critical care research. We searched MEDLINE and EMBASE up to December 2021 using a strategy that combined keyword and controlled vocabulary terms. We included original studies that reported on barriers or facilitators to the conduct of critical care research in these settings. Two reviewers independently reviewed titles and abstracts, and where necessary, the full-text to select eligible studies. For each study, reviewers independently extracted data using a standardized data extraction form. Barriers and facilitators were classified along the lines of a previous review and based on additional themes that emerged. Study quality was assessed using appropriate tools. We identified 2693 citations, evaluated 49 studies and identified 6 for inclusion. Of the included studies, four were qualitative, one was a cross-sectional survey and one was reported as an 'analysis'. The total number of participants ranged from 20-100 and included physicians, nurses, allied healthcare workers and researchers. Barriers identified included limited funding, poor institutional & national investment, inadequate access to mentors, absence of training in research methods, limited research support staff, and absence of statistical support. Our review identified potential solutions such as developing a mentorship network, streamlining of regulatory processes, implementing a centralized institutional research agenda, developing a core-outcome dataset and enhancing access to low-cost technology. Our scoping review highlights important barriers to the conduct of critical care research in low and lower-middle income countries, identifies potential solutions, and informs researchers, policymakers and governments on the steps necessary for strengthening research systems.


Physical activity communication between oncology providers and patients with early-stage breast, colon, or prostate cancer.
National guidelines recommend that patients with a cancer diagnosis engage in regular physical activity to reduce cancer-related fatigue, maintain quality of life and physical function, and improve overall prognosis and survival. This study investigates oncology provider communications about physical activity during routine clinic visits with patients with early-stage breast, colon, or prostate cancer. This study used a retrospective chart review for documentation of inquiries or recommendations pertaining to physical activity in clinician notes and after-visit patient summaries. In a 1-month period, 55 oncology providers had 361 encounters (clinic visits) with early-stage cancer patients. Thirty-five percent of these encounters included a provider communication about "physical activity," "exercise," or "activity." Encounters with a medical oncologist resulted in a physical activity communication 55% of the time, whereas encounters with other clinician specialties did so 20% of the time (P < .0001). The likelihood of a physical activity communication increased with patient age (P < .001). When the encounter was with a patient who was being seen for surveillance, chemotherapy, or endocrine treatment, the rate of physical activity communications was significantly higher (46%, 37%, and 58%, respectively) than the rate when the visit was during radiation treatment or surgery (6% and 19%, respectively; P < .0001). This study shows that it is feasible for oncology providers to have physical activity communications during routine clinic visits; however, the frequency of physical activity communications varies among providers. Interventions are needed to remind and encourage all oncology providers to encourage their patients with early-stage cancer to be physically active. .


DNA biosensor based on hybridization refractory mutation system approach for single mismatch detection.
We report on a simple approach to enhance solid-phase hybridization-based single base mismatch discrimination at high ionic strength based on the deliberate insertion of a natural DNA base mismatch in the surface-tethered probe. A large drop in hybridization signal of single base mismatched alleles using the designed probe as compared with the conventional probe, from 80% to less than 25% of the signal obtained with the fully complementary, non-mutation-containing sequence, when using colorimetric detection was further improved to 20% when using electrochemical detection, attributable to a difference of spacing of immobilized probes. Finally, the designed probe was used for the electrochemical detection of the DQA1*05:05 allele amplified from real human blood samples.


Localization of polymorphic N-acetyltransferase (NAT2) in tissues of inbred mice.
Like humans, mice exhibit polymorphism in the N-acetylation of aromatic amines, many of which are toxic and/or carcinogenic. Mice have three N-acetyltransferase (Nat) genes, Nat1, Nat2 and Nat3, and Nat2 is known to be polymorphic. There is a dramatic difference in the acetylation of NAT2 substrates by blood from fast (C57BL/6J) compared with slow acetylator (A/J) mice. However, the acetylation of these substrates by liver cytosols from the two strains is very similar. In order to determine whether the expression of the NAT2 protein corresponded with the activities measured, a polyclonal antipeptide antisera was raised against the C-terminal decapeptide of NAT2 and characterized using recombinant murine NAT2 antigen. Enzyme-linked immunosorbent assays (ELISAs) demonstrated that the anti-NAT2 antiserum bound in a concentration-dependent fashion to recombinant NAT2. Immunochemical analysis of mouse liver cytosols from C57BL/6J or A/J livers indicated that the level of NAT2 protein expressed in the two strains was similar. Immunohistochemical staining of C57BL/6J liver with anti-NAT2 antiserum showed that NAT2 was expressed in hepatocytes throughout the liver although the intensity of staining in the perivenous (centrilobular) region was higher than that in the periportal region. NAT2 was also detected in epithelial cells in the lung, kidney, bladder, small intestine and skin as well as in erythrocytes and lymphocytes in the spleen and hair follicles and sebaceous glands in the skin. Characterization of the distribution of NAT2 will be of value in elucidating the role of polymorphic N-acetylation in protecting the organism from environmental insults as well as in endogenous metabolism.