Aluminum-Induced photoluminescence red shifts in core-shell GaAs/Al(x)Ga(1-x)As nanowires.
We report a new phenomenon related to Al-induced carrier confinement at the interface in core-shell GaAs/Al(x)Ga(1-x)As nanowires grown using metal-organic vapor phase epitaxy with Au as catalyst. All Al(x)Ga(1-x)As shells strongly passivated the GaAs nanowires, but surprisingly the peak photoluminescence (PL) position and the intensity from the core were found to be a strong function of Al composition in the shell at low temperatures. Large and systematic red shifts of up to ~66 nm and broadening in the PL emission from the GaAs core were observed when the Al composition in the shell exceeded 3%. On the contrary, the phenomenon was observed to be considerably weaker at the room temperature. Cross-sectional transmission electron microscopy reveals Al segregation in the shell along six Al-rich radial bands displaying a 3-fold symmetry. Time-resolved PL measurements suggest the presence of indirect electron-hole transitions at the interface at higher Al composition. We discuss all possibilities including a simple shell-core-shell model using simulations where the density of interface traps increases with the Al content, thus creating a strong local electron confinement. The carrier confinement at the interface is most likely related to Al inhomogeneity and/or Al-induced traps. Our results suggest that a low Al composition in the shell is desirable in order to achieve ideal passivation in GaAs nanowires.


Neurophysiological responses to music and vibroacoustic stimuli in Rett syndrome.
People with Rett syndrome (RTT) have severe communicative difficulties. They have as well an immature brainstem that implies dysfunction of the autonomic nervous system. Music plays an important role in their life, is often used as a motivating tool in a variety of situations and activities, and caregivers are often clear about people with RTTs favourites. The aim of this study was to investigate physiological and emotional responses related to six different musical stimuli in people with RTT. The study included 29 participants with RTT who were referred to the Swedish Rett Center for medical brainstem assessment during the period 2006-2007. 11 children with a typical developmental pattern were used as comparison. A repeated measures design was used, and physiological data were collected from a neurophysiological brainstem assessment. The continuous dependent variables measured were Cardiac Vagal Tone (CVT), Cardiac Sensitivity to Baroreflex (CSB), Mean Arterial Blood Pressure (MAP) and the Coefficient of Variation of Mean Arterial Blood Pressure (MAP-CV). These parameters were used to categorise brainstem responses as parasympathetic (calming) response, sympathetic (activating) response, arousal (alerting) response and unclear response. The results showed that all participants responded to the musical stimuli, but not always in the expected way. It was noticeable that both people with and without RTT responded with an arousal to all musical stimuli to begin with. Even though the initial expressions sometimes changed after some time due to poor control functions of their brainstem, the present results are consistent with the possibility that the RTT participants' normal responses to music are intact. These findings may explain why music is so important for individuals with RTT throughout life.


Sedentary activity associated with metabolic syndrome independent of physical activity.
This study examined the association between objectively measured sedentary activity and metabolic syndrome among older adults. Data were from 1,367 men and women, aged ≥ 60 years who participated in the 2003-2006 National Health and Nutrition Examination Survey (NHANES). Sedentary time during waking hours was measured by an accelerometer (<100 counts per minute). A sedentary bout was defined as a period of time >5 min. A sedentary break was defined as an interruption in sedentary time (≥ 100 counts per minute). Metabolic syndrome was defined according to the Adult Treatment Panel (ATP) III criteria. On average, people spent 9.5 h (65% of wear time) as sedentary. Compared with people without metabolic syndrome, people with metabolic syndrome spent a greater percentage of time as sedentary (67.3 vs. 62.2%), had longer average sedentary bouts (17.7 vs. 16.7 min), had lower intensity during sedentary time (14.8 vs. 15.8 average counts per minute), and had fewer sedentary breaks (82.3 vs. 86.7), adjusted for age and sex (all P < 0.01). A higher percentage of time sedentary and fewer sedentary breaks were associated with a significantly greater likelihood of metabolic syndrome after adjustment for age, sex, ethnicity, education, alcohol consumption, smoking, BMI, diabetes, heart disease, and physical activity. The association between intensity during sedentary time and metabolic syndrome was borderline significant. The proportion of sedentary time was strongly related to metabolic risk, independent of physical activity. Current results suggest older people may benefit from reducing total sedentary time and avoiding prolonged periods of sedentary time by increasing the number of breaks during sedentary time.


Variation in riparian consumer diet composition and differential bioaccumulation by prey influence the risk of exposure to elements from a recently remediated fly ash spill.
Emerging aquatic insects play a key role in transporting aquatic nutrients and contaminants to riparian consumers. However, little is known about how within- and between-year variation in the diet or patterns of element bioaccumulation in emerging insect taxa may influence the risk of exposure to wildlife. During 2 breeding seasons, the composition of the diet of tree swallows (Tachycineta bicolor) was examined at several colonies that were exposed to element contamination from a remediated coal fly ash spill to determine how variation in the diet influenced the risk of exposure to elements. The proportion of the diet that consisted of insects with an aquatic larval stage was positively related to concentrations of As, Fe, Se, and Tl in the samples. The proportion of the diet that consisted of Chironomidae (midges) was positively related to exposure to these elements at most colonies within and between years. Ephemeroptera (mayflies) contained higher concentrations of Se than midges, including 17 samples with concentrations of Se above 5 µg/g dry mass, the threshold of toxicological concern for birds. This was even the case at colonies several kilometers downstream from the spill. The results indicate that greater consideration should be given to the pattern of element bioaccumulation among different prey taxa and their relative importance in the diet to better assess the risk of contaminant exposure.


Cyanotryptophans as Novel Fluorescent Probes for Studying Protein Conformational Changes and DNA-Protein Interaction.
Described herein are the syntheses and photophysical characterization of three novel cyanotryptophans, and their efficient incorporation into proteins as fluorescent probes. Photophysical characteristics indicated that each was significantly brighter and red-shifted in fluorescence emission relative to tryptophan. Each analogue was used to activate a suppressor tRNA transcript and was incorporated with good efficiency into two different positions (Trp22 and Trp74) of Escherichia coli dihydrofolate reductase (ecDHFR). The Trp analogues could be monitored selectively in the presence of multiple native Trp residues in DHFR. 6-CNTrp (A) formed an efficient Förster resonance energy transfer (FRET) pair with l-(7-hydroxycoumarin-4-yl)ethylglycine (HCO, D) at position 17. Further, 6-CNTrp (A) was incorporated into two DNA binding proteins, including the Klenow fragment of DNA polymerase I and an RNA recognition motif (RRM2) of heterogeneous nuclear ribonucleoprotein L-like (hnRNP LL). Using these proteins, we demonstrated the use of FRET involving A as a fluorescence donor and benzo[g]quinazoline-2,4-(1H,3H)-dione 2'-deoxyriboside (Tf) or 4-aminobenzo[g]quinazoline-2-one 2'-deoxyriboside (Cf) as fluorescent acceptors to study the binding interaction of the Klenow fragment with duplex DNA oligomers (labeled with Tf), or the domain-specific association between hnRNP LL and the BCL2 i-motif DNA (labeled with Cf). Thus, the non-natural amino acid could be used as a FRET partner for studying protein-nucleic acid interactions. Together, these findings demonstrate the potential utility of 6-CNTrp (A) as a fluorescence donor for the study of protein conformational events.


Pathway, in silico and tissue-specific expression quantitative analyses of oesophageal squamous cell carcinoma genome-wide association studies data.
Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants. We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P = .75E-14). Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs.


Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib.
Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A2 (PLA2) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA2. Recently, varespladib was also found to inhibit snake venom PLA2 and PLA2-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA2-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA2-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA2-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA2 and PLA2-like toxins.


Phylogenetic analysis of the ecology and evolution of mammalian sleep.
The amount of time asleep varies greatly in mammals, from 3 h in the donkey to 20 h in the armadillo. Previous comparative studies have suggested several functional explanations for interspecific variation in both the total time spent asleep and in rapid-eye movement (REM) or "quiet" (non-REM) sleep. In support of specific functional benefits of sleep, these studies reported correlations between time in specific sleep states (NREM or REM) and brain size, metabolic rate, and developmental variables. Here we show that estimates of sleep duration are significantly influenced by the laboratory conditions under which data are collected and that, when analyses are limited to data collected under more standardized procedures, traditional functional explanations for interspecific variation in sleep durations are no longer supported. Specifically, we find that basal metabolic rate correlates negatively rather than positively with sleep quotas, and that neither adult nor neonatal brain mass correlates positively with REM or NREM sleep times. These results contradict hypotheses that invoke energy conservation, cognition, and development as drivers of sleep variation. Instead, the negative correlations of both sleep states with basal metabolic rate and diet are consistent with trade-offs between sleep and foraging time. In terms of predation risk, both REM and NREM sleep quotas are reduced when animals sleep in more exposed sites, whereas species that sleep socially sleep less. Together with the fact that REM and NREM sleep quotas correlate strongly with each other, these results suggest that variation in sleep primarily reflects ecological constraints acting on total sleep time, rather than the independent responses of each sleep state to specific selection pressures. We propose that, within this ecological framework, interspecific variation in sleep duration might be compensated by variation in the physiological intensity of sleep.


A gene phylogeny of the red algae (Rhodophyta) based on plastid rbcL.
A phylogeny for the Rhodophyta has been inferred by parsimony analysis of plastid rbcL sequences representing 81 species, 68 genera, 38 families, and 17 orders of red algae; rbcL encodes the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. Levels of sequence divergence among species, genera, and families are high in red algae, typically much greater than those reported for flowering plants. The Rhodophyta traditionally consists of one class, Rhodophyceae, and two subclasses, Bangiophycidae and Florideophycidae. The Bangiophycidae with three orders (Porphyridiales, Compsopogonales, and Bangiales) appears to be polyphyletic, and the Florideophycidae with 17 orders is monophyletic in this study. The current classification of the Florideophycidae based on ultrastructure of pit connections is supported. With the exception of the Rhodogorgonales, which appears to be misplaced, orders with one or two pit-plug cap layers (Hildenbrandiales, Corallinales, Acrochaetiales, Palmanales, Batrachospermales, and Nemaliales) terminate long branches of basal position within Florideophycidae in the most parsimonious rbcL tree. Orders that lack typical cap layers but possess a cap membrane are resolved as a monophyletic clade sister to the Ahnfeltiales. The large order Gigartinales, which is distributed among five rbcL clades, is polyphyletic. Families that possess typical carrageenan in their cell walls are resolved as a terminal clade containing two family complexes centered around the Solieriaceae and Gigartinaceae.


Variation in M protein production among Streptococcus pyogenes strains according to emm genotype.
M protein is an important virulence determinant in Streptococcus pyogenes, but the amounts of M protein in various strains of the species remain to be elucidated. To assess the amount of M protein in strains of each emm genotype, dot blot analysis was performed on 141 clinically isolated strains. Among the cell membrane-associated proteins, M protein was present in greater quantities in the emm1, 3, and 6 strains than in the other emm strains. In addition three strains, one each of the emm1, 3, and 6 types, showed prolific M protein production (M protein-high producers). These three emm genotypes are frequently isolated in clinical practice. Sequencing of the csrRS gene, one of the two-component signal transduction systems implicated in virulence, was performed on 25 strains bearing different amounts of M protein. CsrS mutations, in contrast to CsrR protein, were detected in 11 strains. The M protein-high producer strain of emm1 type carried two amino acid substitutions, whereas the other three emm1 strains carried only one substitution each. The M protein-high producer expressed its emm gene more strongly than the corresponding M protein-low producer did according to TaqMan RT-PCR. These observations suggest that the accumulation of amino acid substitutions in CsrS protein may contribute, at least in part, to the large amount of M protein production seen in several emm genotypes.


Expression of tumor suppressor REIC/Dkk-3 by a newly improved adenovirus vector with insertion of a hTERT promoter at the 3'-side of the transgene.
Reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3) overexpression, induced using an adenovirus (Ad)-REIC, has been revealed to have a dramatic therapeutic effect on multiple types of cancer. To achieve an improved therapeutic effect from Ad-REIC on cancer, our group previously developed an enhanced gene expression system, the C-TSC cassette [cytomegalovirus (CMV)-RU5' located upstream (C); another promoter unit composed of triple tandem promoters, human telomerase reverse transcriptase (hTERT), simian virus 40 and CMV, located downstream of the cDNA (TSC); plus a polyadenylation (polyA) signal]. When applied to the conventional Ad-REIC, this novel system induced the development of an enhanced product, Ad-C-TSC-REIC, which exhibited a noticeable anticancer effect. However, there were difficulties in terms of Ad-C-TSC-REIC productivity in HEK293 cells, which are a widely used donor cell line for viral production. Productivity of Ad-C-TSC-REIC was significantly reduced compared with the conventional Ad-REIC, as the Ad-C-TSC-REIC had a significantly higher ability to induce apoptotic cell death of not only various types of cancer cell, but also HEK293 cells. The present study aimed to overcome this problem by modifying the C-TSC structure, resulting in an improved candidate: A C-T cassette (C: CMV-RU5' located upstream; T: another promoter unit composed of a single hTERT promoter, located downstream of the cDNA plus a polyA signal), which demonstrated gene expression comparable to that of the C-TSC system. The improved adenovirus REIC/Dkk-3 product with the C-T cassette, named Ad-C-T-REIC, exhibited a higher expression level of REIC/Dkk3, similar to that of Ad-C-TSC-REIC. Notably, the vector mitigated the cell death of donor HEK293 cells, resulting in a higher rate of production of its adenovirus. These results indicated that Ad-C-T-REIC has the potential to be a useful tool for application in cancer gene therapy.


The Interaction of REM Fragmentation and Night-Time Arousal Modulates Sleep-Dependent Emotional Memory Consolidation.
The sleep-to-forget, sleep-to-remember (SFSR) hypothesis states that the neurobiological environment provided by rapid-eye movement (REM)-rich sleep decouples the content of an emotional memory from its attendant emotional arousal. This decoupling allows divergent attenuation and enhancement effects (i.e., erosion of the memory's emotional tone and simultaneous strengthening of its content). However, support for this proposal is mixed. An alternative account suggests there might be convergent attenuation and enhancement (i.e., elevated emotional arousal is positively coupled with enhanced emotional memory). We tested predictions emerging from the SFSR hypothesis using (a) individuals diagnosed with post-traumatic stress disorder (PTSD; n = 21), (b) trauma-exposed non-PTSD individuals (n = 19), and (c) healthy controls (n = 20). We included PTSD-diagnosed individuals because they typically experience altered REM sleep, impaired emotional memory, and heightened emotional arousal in response to threatening stimuli. Participants were assessed before and after both an 8-h period of polysomnographically monitored sleep and an 8-h period of waking activity. The assessment included exposure to negatively valenced, positively valenced, and neutral pictures before the 8-h delay, and a recognition task afterward. We measured emotional arousal by recording psychophysiological responses to the pictures, both pre- and post-delay. Results indicated no significant between-group differences in emotional memory accuracy or arousal. However, after a sleep-filled delay, pictures of all categories were recognized with equal accuracy, whereas after a wake-filled delay, negative pictures were recognized preferentially. Furthermore, the findings demonstrated that a sleep-filled delay was associated with attenuated emotional arousal to pictures of all categories, whereas a wake-filled delay was associated with a rise in emotional arousal across the day. Intriguingly, poorer recognition accuracy for valenced (but not neutral) pictures was predicted by an interaction of increased REM fragmentation and increased emotional arousal. In summary, we found some support for the SFSR hypothesis in the way it describes the REM- and arousal-based mechanisms that process emotional material. We also, however, found disconfirming evidence regarding the outcome of that process (i.e., sleep did not favor consolidation of emotional over neutral memory), and we demonstrated a convergence between attenuation of emotional arousal and weakening of emotional content relative to neutral content.


Risk of Major Cardiovascular Events in People with Down Syndrome.
Improved medical care over more than five decades has markedly increased life expectancy, from 12 years to approximately 60 years, in people with Down syndrome (DS). With increased survival into late adulthood, there is now a greater need for the medical care of people with DS to prevent and treat aging-related disorders. In the wider population, acquired cardiovascular diseases such as stroke and coronary heart disease are common with increasing age, but the risks of these diseases in people with DS are unknown. There are no population-level data on the incidence of acquired major cerebrovascular and coronary diseases in DS, and no data examining how cardiovascular comorbidities or risk factors in DS might impact on cardiovascular event incidence. Such data would be also valuable to inform health care planning for people with DS. Our objective was therefore to conduct a population-level matched cohort study to quantify the risk of incident major cardiovascular events in DS. A population-level matched cohort study compared the risk of incident cardiovascular events between hospitalized patients with and without DS, adjusting for sex, and vascular risk factors. The sample was derived from hospitalization data within the Australian state of Victoria from 1993-2010. For each DS admission, 4 exact age-matched non-DS admissions were randomly selected from all hospitalizations within a week of the relevant DS admission to form the comparison cohort. There were 4,081 people with DS and 16,324 without DS, with a total of 212,539 person-years of observation. Compared to the group without DS, there was a higher prevalence in the DS group of congenital heart disease, cardiac arrhythmia, dementia, pulmonary hypertension, diabetes and sleep apnea, and a lower prevalence of ever-smoking. DS was associated with a greater risk of incident cerebrovascular events (Risk Ratio, RR 2.70, 95% CI 2.08, 3.53) especially among females (RR 3.31, 95% CI 2.21, 4.94) and patients aged ≤ 50 years old. The association of DS with ischemic strokes was substantially attenuated on adjustment for cardioembolic risk (RR 1.93, 95% CI 1.04, 3.20), but unaffected by adjustment for atherosclerotic risk. DS was associated with a 40-70% reduced risk of any coronary event in males (RR 0.58, 95% CI 0.40, 0.84) but not in females (RR 1.14, 95% CI 0.73, 1.77). DS is associated with a high risk of stroke, expressed across all ages. Ischemic stroke risk in DS appears mostly driven by cardioembolic risk. The greater risk of hemorrhagic stroke and lower risk of coronary events (in males) in DS remain unexplained.


Acceptance and User Experiences of a Wearable Device for the Management of Hospitalized Patients in COVID-19-Designated Wards in Ho Chi Minh City, Vietnam: Action Learning Project.
Wearable devices have been used extensively both inside and outside of the hospital setting. During the COVID-19 pandemic, in some contexts, there was an increased need to remotely monitor pulse and saturated oxygen for patients due to the lack of staff and bedside monitors. A prototype of a remote monitoring system using wearable pulse oximeter devices was implemented at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, from August to December 2021. The aim of this work was to support the ongoing implementation of the remote monitoring system. We used an action learning approach with rapid pragmatic methods, including informal discussions and observations as well as a feedback survey form designed based on the technology acceptance model to assess the use and acceptability of the system. Based on these results, we facilitated a meeting using user-centered design principles to explore user needs and ideas about its development in more detail. In total, 21 users filled in the feedback form. The mean technology acceptance model scores ranged from 3.5 (for perceived ease of use) to 4.4 (for attitude) with behavioral intention (3.8) and perceived usefulness (4.2) scoring in between. Those working as nurses scored higher on perceived usefulness, attitude, and behavioral intention than did physicians. Based on informal discussions, we realized there was a mismatch between how we (ie, the research team) and the ward teams perceived the use and wider purpose of the technology. Designing and implementing the devices to be more nurse-centric from their introduction could have helped to increase their efficiency and use during the complex pandemic period.


A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: Part I-patient perspectives.
Despite the well-acknowledged problem of poor adherence to antipsychotic (AP) medication, long-acting injectables (LAIs) that could improve adherence are underused in Canada. Attitudes concerning LAIs among patients and psychiatrists may contribute to this underuse. Our objective was to investigate perceptions of and attitudes toward LAIs among patients in Canada. Focus groups were conducted with 34 patients with a diagnosis of schizophrenia spectrum psychoses in 4 Canadian provinces. The focus groups inquired about experiences with and attitudes toward LAI APs. The sessions were audiotaped and transcribed verbatim, and transcripts were coded using a combination of deductive and inductive methods. Four themes emerged: awareness of and knowledge about LAIs; perceptions about LAIs; cost and convenience considerations; and issues arising from the coercive context under which LAIs were often prescribed. Nine patients had never heard about LAIs, and some others reported not having understood what was discussed with them regarding LAIs. Patients had typically heard about LAIs in either a context of coercion or of medication nonadherence. Patients had positive and negative perceptions concerning LAIs. The positive perceptions centred on relapse prevention and reduced effort in ensuring adherence, and the negative perceptions centred on financial costs and the inconvenience of appointments to receive injections. To enhance LAI usage, some of the issues that need to be addressed are the inadequacy of information given to patients, the element of coercion involved in LAI introduction, the pragmatic barriers to LAI uptake by patients, and negative subjective perceptions about LAIs.


DNA helicases Sgs1 and BLM promote DNA double-strand break resection.
A key cellular response to DNA double-strand breaks (DSBs) is 5'-to-3' DSB resection by nucleases to generate regions of ssDNA that then trigger cell cycle checkpoint signaling and DSB repair by homologous recombination (HR). Here, we reveal that in the absence of exonuclease Exo1 activity, deletion or mutation of the Saccharomyces cerevisiae RecQ-family helicase, Sgs1, causes pronounced hypersensitivity to DSB-inducing agents. Moreover, we establish that this reflects severely compromised DSB resection, deficient DNA damage signaling, and strongly impaired HR-mediated repair. Furthermore, we show that the mammalian Sgs1 ortholog, BLM--whose deficiency causes cancer predisposition and infertility in people--also functions in parallel with Exo1 to promote DSB resection, DSB signaling and resistance to DSB-generating agents. Collectively, these data establish evolutionarily conserved roles for the BLM and Sgs1 helicases in DSB processing, signaling, and repair.


Regulation of connective tissue collagenase production: stimulators from adult and fetal epidermal cells.
We have examined the ability of primary adult rabbit skin cells to regulate collagenase production in vitro. Dermal cells constitutively produce collagenase in culture, and enzyme production by these cells can be influenced by epithelial cells. Co-culture with skin epidermal cells resulted in more enzyme production by dermal cells, whereas co-culture with corneal epithelial cells yielded less enzyme activity. Connective tissue cells from a different source, cornea, also produced collagenase when co-cultured with skin epidermal cells, although the stromal cells alone made no enzyme. The drug cytochalasin B had very little influence on collagenase production by dermal cells, either alone or in co-culture with epidermal cells, but did significantly potentiate enzyme production by corneal stromal cells responding to epidermal effector molecules. Epidermal-cell-conditioned medium from both fetal and adult rabbit skin was a potent source of stimulators (apparent mol wt 20,500 and 55,000) of connective-tissue-cell collagenase production. Stimulator production by epidermal cultures was cell density dependent. Optimal production of stimulators occurred in adult cultures containing 10(6) epidermal cells/ml of medium, and in fetal cultures containing 10(5) cells/ml. Inhibitors of connective tissue cell enzyme production were not detected in conditioned medium from either adult or fetal epidermal cells.


The Canadian birth place study: examining maternity care provider attitudes and interprofessional conflict around planned home birth.
Available birth settings have diversified in Canada since the integration of regulated midwifery. Midwives are required to offer eligible women choice of birth place; and 25-30% of midwifery clients plan home births. Canadian provincial health ministries have instituted reimbursement schema and regulatory guidelines to ensure access to midwives in all settings. Evidence from well-designed Canadian cohort studies demonstrate the safety and efficacy of midwife-attended home birth. However, national rates of planned home birth remain low, and many maternity providers do not support choice of birth place. In this national, mixed-methods study, our team administered a cross-sectional survey, and developed a 17 item Provider Attitudes to Planned Home Birth Scale (PAPHB-m) to assess attitudes towards home birth among maternity providers. We entered care provider type into a linear regression model, with the PAPHB-m score as the outcome variable. Using Students' t tests and ANOVA for categorical variables and correlational analysis (Pearson's r) for continuous variables, we conducted provider-specific bivariate analyses of all socio-demographic, education, and practice variables (n=90) that were in both the midwife and physician surveys. Median favourability scores on the PAPHB-m scale were very low among obstetricians (33.0), moderately low for family physicians (38.0) and very high for midwives (80.0), and 84% of the variance in attitudes could be accounted for by care provider type. Amount of exposure to planned home birth during midwifery or medical education and practice was significantly associated with favourability scores. Concerns about perinatal loss and lawsuits, discomfort with inter-professional consultations, and preference for the familiarity of the hospital correlated with less favourable attitudes to home birth. Among all providers, favourability scores were linked to beliefs about the evidence on safety of home birth, and confidence in their own ability to manage obstetric emergencies at a home birth. Increasing the knowledge base among all maternity providers about planned home birth may increase favourability. Key learning competencies include criteria for birth site selection, management of obstetric emergencies at planned home births, critical appraisal of literature on safety of home birth, and inter-professional communication and collaboration when women are transferred from home to hospital.


Mueller-matrix ellipsometry using the division-of-amplitude photopolarimeter: a study of depolarization effects.
A fully automated Mueller-matrix ellipsometer with a division-of-amplitude photopolarimeter as the polarization-state detector is described. This device achieves Mueller-matrix ellipsometry by measuring the Stokes parameters of reflected light as a function of the fast axis C of a quarter-wave retarder, which, in combination with a fixed linear polarizer, determines the polarization state of incident light. The reflected Stokes parameters were Fourier analyzed to give the 16 elements of the Mueller matrix. We investigated depolarization of polarized light on reflection from rough, heterogeneous, and anisotropic surfaces by obtaining measurements on rolled aluminum and plant leaves. The results demonstrate (1) a variation of degree of polarization of reflected light with the input polarization state, (2) the precision with which the measured matrices describe the depolarization results, (3) effects of surface anisotropy (rolling direction) on depolarization and cross polarization by reflection from aluminum surfaces, and (4) large values and differences in the depolarization effects from conifer and deciduous leaves. Depolarization of light reflected by the aluminum surfaces was most sensitive to the angle between the plane of incidence and the rolling direction when the incident Stokes parameters S(1), S(2), and S(3) were equal.


Development of a model to predict antidepressant treatment response for depression among Veterans.
Only a limited number of patients with major depressive disorder (MDD) respond to a first course of antidepressant medication (ADM). We investigated the feasibility of creating a baseline model to determine which of these would be among patients beginning ADM treatment in the US Veterans Health Administration (VHA). A 2018-2020 national sample of n = 660 VHA patients receiving ADM treatment for MDD completed an extensive baseline self-report assessment near the beginning of treatment and a 3-month self-report follow-up assessment. Using baseline self-report data along with administrative and geospatial data, an ensemble machine learning method was used to develop a model for 3-month treatment response defined by the Quick Inventory of Depression Symptomatology Self-Report and a modified Sheehan Disability Scale. The model was developed in a 70% training sample and tested in the remaining 30% test sample. In total, 35.7% of patients responded to treatment. The prediction model had an area under the ROC curve (s.e.) of 0.66 (0.04) in the test sample. A strong gradient in probability (s.e.) of treatment response was found across three subsamples of the test sample using training sample thresholds for high [45.6% (5.5)], intermediate [34.5% (7.6)], and low [11.1% (4.9)] probabilities of response. Baseline symptom severity, comorbidity, treatment characteristics (expectations, history, and aspects of current treatment), and protective/resilience factors were the most important predictors. Although these results are promising, parallel models to predict response to alternative treatments based on data collected before initiating treatment would be needed for such models to help guide treatment selection.


Widespread transcription of a Qa region gene in adult mice.
The mouse MHC class I family includes genes encoded in four regions: H-2K, H-2D, Qa and Tla. While K/D genes are well characterized, relatively little is known about Qa or Tla genes. We have studied the transcription of a B10.P Qa region gene. DNA sequence comparisons of the transmembrane region, supported by Southern blot analysis of cosmid and genomic DNAs from BALB/c and C57BL/10, demonstrate the lambda 3a gene corresponds to Q4p. In both Northern blots and RNA protection experiments using probes derived from the 3' noncoding region, we found that Q4, like the H-2K and H-2D genes, is widely transcribed in B10.P tissues. These data demonstrate for the first time widespread transcription of a Qa gene.


A preclinical evaluation of antimycin a as a potential antilung cancer stem cell agent.
Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs) as the major contributor to these clinical challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP) method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs), was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA), was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, β -catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress β -catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate β -catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.


American College of Gastroenterology guideline: management of acute pancreatitis.
This guideline presents recommendations for the management of patients with acute pancreatitis (AP). During the past decade, there have been new understandings and developments in the diagnosis, etiology, and early and late management of the disease. As the diagnosis of AP is most often established by clinical symptoms and laboratory testing, contrast-enhanced computed tomography (CECT) and/or magnetic resonance imaging (MRI) of the pancreas should be reserved for patients in whom the diagnosis is unclear or who fail to improve clinically. Hemodynamic status should be assessed immediately upon presentation and resuscitative measures begun as needed. Patients with organ failure and/or the systemic inflammatory response syndrome (SIRS) should be admitted to an intensive care unit or intermediary care setting whenever possible. Aggressive hydration should be provided to all patients, unless cardiovascular and/or renal comorbidites preclude it. Early aggressive intravenous hydration is most beneficial within the first 12-24 h, and may have little benefit beyond. Patients with AP and concurrent acute cholangitis should undergo endoscopic retrograde cholangiopancreatography (ERCP) within 24 h of admission. Pancreatic duct stents and/or postprocedure rectal nonsteroidal anti-inflammatory drug (NSAID) suppositories should be utilized to lower the risk of severe post-ERCP pancreatitis in high-risk patients. Routine use of prophylactic antibiotics in patients with severe AP and/or sterile necrosis is not recommended. In patients with infected necrosis, antibiotics known to penetrate pancreatic necrosis may be useful in delaying intervention, thus decreasing morbidity and mortality. In mild AP, oral feedings can be started immediately if there is no nausea and vomiting. In severe AP, enteral nutrition is recommended to prevent infectious complications, whereas parenteral nutrition should be avoided. Asymptomatic pancreatic and/or extrapancreatic necrosis and/or pseudocysts do not warrant intervention regardless of size, location, and/or extension. In stable patients with infected necrosis, surgical, radiologic, and/or endoscopic drainage should be delayed, preferably for 4 weeks, to allow the development of a wall around the necrosis.


Stonin 2: an adaptor-like protein that interacts with components of the endocytic machinery.
Endocytosis of cell surface proteins is mediated by a complex molecular machinery that assembles on the inner surface of the plasma membrane. Here, we report the identification of two ubiquitously expressed human proteins, stonin 1 and stonin 2, related to components of the endocytic machinery. The human stonins are homologous to the Drosophila melanogaster stoned B protein and exhibit a modular structure consisting of an NH(2)-terminal proline-rich domain, a central region of homology specific to the stonins, and a COOH-terminal region homologous to the mu subunits of adaptor protein (AP) complexes. Stonin 2, but not stonin 1, interacts with the endocytic machinery proteins Eps15, Eps15R, and intersectin 1. These interactions occur via two NPF motifs in the proline-rich domain of stonin 2 and Eps15 homology domains of Eps15, Eps15R, and intersectin 1. Stonin 2 also interacts indirectly with the adaptor protein complex, AP-2. In addition, stonin 2 binds to the C2B domains of synaptotagmins I and II. Overexpression of GFP-stonin 2 interferes with recruitment of AP-2 to the plasma membrane and impairs internalization of the transferrin, epidermal growth factor, and low density lipoprotein receptors. These observations suggest that stonin 2 is a novel component of the general endocytic machinery.


Growing self-organizing surface map: learning a surface topology from a point cloud.
The growing self-organizing surface map (GSOSM) is a novel map model that learns a folded surface immersed in a 3D space. Starting from a dense point cloud, the surface is reconstructed through an incremental mesh composed of approximately equilateral triangles. Unlike other models such as neural meshes (NM), the GSOSM builds a surface topology while accepting any sequence of sample presentation. The GSOSM model introduces a novel connection learning rule called competitive connection Hebbian learning (CCHL), which produces a complete triangulation. GSOSM reconstructions are accurate and often free of false or overlapping faces. This letter presents and discusses the GSOSM model. It also presents and analyzes a set of results and compares GSOSM with some other models.


Health Alliance for Prudent Prescribing, Yield and Use of Antimicrobial Drugs in the Treatment of Respiratory Tract Infections (HAPPY AUDIT).
Excessive and inappropriate use of antibiotics is considered to be the most important reason for development of bacterial resistance to antibiotics. As antibiotic resistance may spread across borders, high prevalence countries may serve as a source of bacterial resistance for countries with a low prevalence. Therefore, bacterial resistance is an important issue with a potential serious impact on all countries. The majority of respiratory tract infections (RTIs) are treated in general practice. Most infections are caused by virus and antibiotics are therefore unlikely to have any clinical benefit. Several intervention initiatives have been taken to reduce the inappropriate use of antibiotics in primary health care, but the effectiveness of these interventions is only modest. Only few studies have been designed to determine the effectiveness of multifaceted strategies in countries with different practice setting. The aim of this study is to evaluate the impact of a multifaceted intervention targeting general practitioners (GPs) and patients in six countries with different prevalence of antibiotic resistance: Two Nordic countries (Denmark and Sweden), two Baltic Countries (Lithuania and Kaliningrad-Russia) and two Hispano-American countries (Spain and Argentina). HAPPY AUDIT was initiated in 2008 and the project is still ongoing. The project includes 15 partners from 9 countries. GPs participating in HAPPY AUDIT will be audited by the Audit Project Odense (APO) method. The APO method will be used at a multinational level involving GPs from six countries with different cultural background and different organisation of primary health care. Research on the effect of the intervention will be performed by analysing audit registrations carried out before and after the intervention. The intervention includes training courses on management of RTIs, dissemination of clinical guidelines with recommendations for diagnosis and treatment, posters for the waiting room, brochures to patients and implementation of point of care tests (Strep A and CRP) to be used in the GPs'surgeries. To ensure public awareness of the risk of resistant bacteria, media campaigns targeting both professionals and the public will be developed and the results will be published and widely disseminated at a Working Conference hosted by the World Association of Family Doctors (WONCA-Europe) at the end of the project period. HAPPY AUDIT is an EU-financed project with the aim of contributing to the battle against antibiotic resistance through quality improvement of GPs' diagnosis and treatment of RTIs through development of intervention programmes targeting GPs, parents of young children and healthy adults. It is hypothesized that the use of multifaceted strategies combining active intervention by GPs will be effective in reducing prescribing of unnecessary antibiotics for RTIs and improving the use of appropriate antibiotics in suspected bacterial infections.


A zero dimensional model of lithium-sulfur batteries during charge and discharge.
Lithium-sulfur cells present an attractive alternative to Li-ion batteries due to their large energy density, safety, and possible low cost. Their successful commercialisation is dependent on improving their performance, but also on acquiring sufficient understanding of the underlying mechanisms to allow for the development of predictive models for operational cells. To address the latter, we present a zero dimensional model that predicts many of the features observed in the behaviour of a lithium-sulfur cell during charge and discharge. The model accounts for two electrochemical reactions via the Nernst formulation, power limitations through Butler-Volmer kinetics, and precipitation/dissolution of one species, including nucleation. It is shown that the flat shape of the low voltage plateau typical of the lithium-sulfur cell discharge is caused by precipitation. During charge, it is predicted that the dissolution can act as a bottleneck, because for large enough currents the amount that dissolves becomes limited. This results in reduced charge capacity and an earlier onset of the high plateau reaction, such that the two voltage plateaus merge. By including these effects, the model improves on the existing zero dimensional models, while requiring considerably fewer input parameters and computational resources than one dimensional models. The model also predicts that, due to precipitation, the customary way of experimentally obtaining the open circuit voltage from a low rate discharge might not be suitable for lithium-sulfur. This model can provide the basis for mechanistic studies, identification of dominant effects in a real cell, predictions of operational behaviour under realistic loads, and control algorithms for applications.


Genetic and spectrally distinct in vivo imaging: embryonic stem cells and mice with widespread expression of a monomeric red fluorescent protein.
DsRed the red fluorescent protein (RFP) isolated from Discosoma sp. coral holds much promise as a genetically and spectrally distinct alternative to green fluorescent protein (GFP) for application in mice. Widespread use of DsRed has been hampered by several issues resulting in the inability to establish and maintain lines of red fluorescent protein expressing embryonic stem cells and mice. This has been attributed to the non-viability, or toxicity, of the protein, probably as a result of its obligate tetramerization. A mutagenesis approach directing the stepwise evolution of DsRed has produced mRFP1, the first true monomer. mRFP1 currently represents an attractive autofluorescent reporter for use in heterologous systems. We have used embryonic stem cell-mediated transgenesis to evaluate mRFP1 in embryonic stem cells and mice. We find that mRFP1 exhibits the most spatially homogenous expression when compared to the native (tetrameric) and variant dimeric forms of DsRed. High levels of mRFP1 expression do not affect cell morphology, developmental potential or viability and fertility of animals. High levels of widespread mRFP1 expression are maintained in a constitutive manner in embryonic stem cells in culture and in transgenic animals. We have used various optical imaging modalities to visualize mRFP1 expressing cells in culture, in embryos and adult mice. Moreover co-visualization of red, green and cyan fluorescent cells within a sample is easily achieved without the need for specialized methodologies, such as spectral deconvolution or linear unmixing. Fluorescent proteins with excitation and/or emission profiles in the red part of the visible spectrum represent distinct partners, or longer wavelength substitutes for GFP. Not only do DsRed-based RFPs provide a genetically and spectrally distinct addition to the available repertoire of autoflorescent proteins, but by virtue of their spectral properties they permit deeper tissue imaging. Our work in generating CAG::mRFP1 transgenic ES cells and mice demonstrates the developmental neutrality of mRFP1 in an organismal context. It paves the way for the use of DsRed-based monomeric RFPs in transgenic and gene targeted approaches which often necessitate spatially and/or temporally restricted reporter expression. Moreover animals of the CAG::mRFP1 transgenic strain serve as a source of RFP tagged tissue for the derivation of cell lines and explant, transplant and embryo chimera experiments.


Ocean Warming and CO₂-Induced Acidification Impact the Lipid Content of a Marine Predatory Gastropod.
Ocean warming and acidification are current global environmental challenges impacting aquatic organisms. A shift in conditions outside the optimal environmental range for marine species is likely to generate stress that could impact metabolic activity, with consequences for the biosynthesis of marine lipids. The aim of this study was to investigate differences in the lipid content of Dicathais orbita exposed to current and predicted future climate change scenarios. The whelks were exposed to a combination of temperature and CO₂-induced acidification treatments in controlled flowthrough seawater mesocosms for 35 days. Under current conditions, D. orbita foot tissue has an average of 6 mg lipid/g tissue, but at predicted future ocean temperatures, the total lipid content dropped significantly, to almost half. The fatty acid composition is dominated by polyunsaturated fatty acids (PUFA 52%) with an n-3:6 fatty acid ratio of almost 2, which remains unchanged under future ocean conditions. However, we detected an interactive effect of temperature and pCO₂ on the % PUFAs and n-3 and n-6 fatty acids were significantly reduced by elevated water temperature, while both the saturated and monounsaturated fatty acids were significantly reduced under increased pCO₂ acidifying conditions. The present study indicates the potential for relatively small predicted changes in ocean conditions to reduce lipid reserves and alter the fatty acid composition of a predatory marine mollusc. This has potential implications for the growth and survivorship of whelks under future conditions, but only minimal implications for human consumption of D. orbita as nutritional seafood are predicted.


Handoffs and transitions in critical care (HATRICC): protocol for a mixed methods study of operating room to intensive care unit handoffs.
Operating room to intensive care unit handoffs are high-risk events for critically ill patients. Studies in selected patient populations show that standardizing operating room to intensive care unit handoffs improves information exchange and decreases errors. To adapt these findings to mixed surgical populations, we propose to study the implementation of a standardized operating room to intensive care unit handoff process in two intensive care units currently without an existing standard process. The Handoffs and Transitions in Critical Care (HATRICC) study is a hybrid effectiveness- implementation trial of operating room to intensive care unit handoffs. We will use mixed methods to conduct a needs assessment of the current handoff process, adapt published handoff processes, and implement a new standardized handoff process in two academic intensive care units. Needs assessment: We will use non-participant observation to observe the current handoff process. Focus groups, interviews, and surveys of clinicians will elicit participants' impressions about the current process. Adaptation and implementation: We will adapt published standardized handoff processes using the needs assessment findings. We will use small group simulation to test the new process' feasibility. After simulation, we will incorporate the new handoff process into the clinical work of all providers in the study units. Using the same methods employed in the needs assessment phase, we will evaluate use of the new handoff process. The primary effectiveness outcome is the number of information omissions per handoff episode as compared to the pre-intervention period. Additional intervention outcomes include patient intensive care unit length of stay and intensive care unit mortality. The primary implementation outcome is acceptability of the new process. Additional implementation outcomes include feasibility, fidelity and sustainability. The HATRICC study will examine the effectiveness and implementation of a standardized operating room to intensive care unit handoff process. Findings from this study have the potential to improve healthcare communication and outcomes for critically ill patients. ClinicalTrials.gov identifier: NCT02267174. Date of registration October 16, 2014.


A sublimation heat engine.
Heat engines are based on the physical realization of a thermodynamic cycle, most famously the liquid-vapour Rankine cycle used for steam engines. Here we present a sublimation heat engine, which can convert temperature differences into mechanical work via the Leidenfrost effect. Through controlled experiments, quantified by a hydrodynamic model, we show that levitating dry-ice blocks rotate on hot turbine-like surfaces at a rate controlled by the turbine geometry, temperature difference and solid material properties. The rotational motion of the dry-ice loads is converted into electric power by coupling to a magnetic coil system. We extend our concept to liquid loads, generalizing the realization of the new engine to both sublimation and the instantaneous vapourization of liquids. Our results support the feasibility of low-friction in situ energy harvesting from both liquids and ices. Our concept is potentially relevant in challenging situations such as deep drilling, outer space exploration or micro-mechanical manipulation.


Do cognitive, physiological, and psychosocial risk and promotive factors predict desistance from delinquency in males?
Relatively few studies have examined cognitive, physiological, and psychosocial promotive and risk factors that can be linked to desistance from delinquency in community samples. This paper reports on a sample of boys first studied at age 7 and then followed up yearly to age 20. Around age 16, most of the boys received a range of cognitive tests; at that time, information regarding their resting heart rate and skin conductance activity in response to aversive stimuli was also collected. Several psychosocial and two cognitive measures distinguished delinquents from nondelinquents around age 16. Among the promotive factors associated with low delinquency were good housing quality, low community crime (parent and youth report), verbal IQ, delayed verbal memory, and sustained attention. Predictive analyses discriminating between desisters and persisters in delinquency between ages 17 and 20 showed that all of the significant predictors were either child or peer risk factors. None of the cognitive, physiological, parenting, or community factors significantly predicted desistance from delinquency. In addition, no promotive factors were significantly related to desistance. The final set of analyses compared persisters, desisters, and nondelinquents in terms of their adult adjustment. Desisters were similar to persisters in that desisters continued to display serious problems in anxiety, failure to graduate from high school, no post high school education, being a nonstudent and unemployed, daily cigarette use, and weekly marijuana use. Desisters scored low on depression and weekly heavy drinking and in these respects were indistinguishable from nondelinquents and better off than persisters.


Effects of dalcetrapib in patients with a recent acute coronary syndrome.
In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).


Long-term satisfaction and predictors of use of intracorporeal injections for post-prostatectomy erectile dysfunction.
Intracorporeal injections have low use rates and high discontinuation rates. We examined factors associated with intracorporeal injection use, long-term satisfaction with intracorporeal injection and reasons for discontinuation in men treated with radical prostatectomy. Between October 2000 and September 2003, 731 men who underwent open radical retropubic prostatectomy were enrolled in a prospective outcomes study. The 8-year followup evaluation included the UCLA-PCI, and a survey capturing intracorporeal injection use, satisfaction and reasons for discontinuation. Logistic regression was used to determine associations between intracorporeal injection use and preoperative variables. The 8-year self-assessment was completed by 368 (50.4%) men. Of these men 140 (38%) indicated prior or current intracorporeal injection use, with only 34 using intracorporeal injection at 8 years. Overall, 44% of the men were satisfied with intracorporeal injections. Reasons for discontinuation included dislike (47%), pain (33%), return of erection (19%), inefficacy (14%) and no partner (6%). Men trying intracorporeal injections had greater preoperative UCLA-PCI sexual function scores (75.2 vs 65.62, p = 0.00005) as well as greater decreases in this score at 3 months (p = 0.0002) and 2 years (p = 0.003). Higher preoperative sexual function scores were independently associated with the use of intracorporeal injections in a model adjusted for age, marital status, nerve sparing status and body mass index (OR 1.021, 95% CI 1.008-1.035). Men pursuing intracorporeal injections have better baseline erectile function and experience greater deterioration in erectile function during the early postoperative period. Despite the high efficacy of injections, many men discontinue intracorporeal injections due to dislike or discomfort. Satisfaction rates for intracorporeal injections indicate their long-term role in restoring sexual function in men with post-prostatectomy erectile dysfunction.


Aqua-(5,10,15,20-tetra-phenyl-porphyrin-ato-κ(4) N)cadmium(II)-18-crown-6 (1/1).
The title compound, [Cd(C44H28N4)(H2O)]·(C12H24O6), was made by the reaction of the [Cd(TPP)] with an excess of 18-crown-6 in chloro-benzene (where TPP is tetra-phenyl-porphyrinate). The Cd(II) cation is chelated by a TPP anion and coordinated by a water mol-ecule in a distorted N4O square-pyramidal geometry, the Cd(II) cation being displaced by 0.7533 (9) Å from the mean plane of four N atoms of TPP anion. The porphyrin core presents a significant distortion, the maximum atomic deviation from the 24-atom mean plane is 0.1517 (2) Å. The 18-crown-6 mol-ecule is linked with the Cd(II) complex via classical O-H⋯O hydrogen bonds. In the crystal, weak C-H⋯π inter-actions link the complex and 18-crown-6 mol-ecules into a three-dimensional supra-molecular architecture.


Solution structure of the fifth and sixth transmembrane segments of the mitochondrial oxoglutarate carrier.
The structures of the fifth and sixth transmembrane segments of the bovine mitochondrial oxoglutarate carrier (OGC) and of the hydrophilic loop that connects them were studied by CD and NMR spectroscopies. Peptides F215-R246, W279-K305 and P257-L278 were synthesized and structurally characterized. CD data showed that at high concentrations of TFE and SDS all peptides assume alpha-helical structures. (1)H-NMR spectra of the three peptides in TFE/water were fully assigned and the secondary structures of the peptides were obtained from nuclear Overhauser effects, (3)J(aH-NH) coupling constants and alphaH chemical shifts. The three-dimensional solution structures of the peptides were generated by distance geometry calculations. A well-defined alpha-helix was found in the region L220-V243 of peptide F215-R246 (TMS-V), in the region P284-M303 of peptide W279-K305 (TMS-VI) and in the region N261-F275 of peptide P257-L278 (hydrophilic loop). The helix L220-V243 exhibited a sharp kink at P239, while a little bend around P291 was observed in the helical region P284-M303. Fluorescence studies performed on peptide W279-K305, alone and together with other transmembrane segments of OGC, showed that the W279 fluorescence was quenched upon addition of peptide F215-R246, but not of peptides K21-K46, R78-R108 and P117-A149 suggesting a specific interaction between TMS-V and TMS-VI of OGC.


Comparative performance of biomarkers of alcohol consumption in a population sample of working-aged men in Russia: the Izhevsk Family Study.
To assess the performance of a range of biomarkers of alcohol consumption in a heavy-drinking population of working-aged Russian men. Cross-sectional study of men originally sampled at random from a population register. Izhevsk, a Russian city with a population of 650 000 people. A total of 1023 men aged 27-59 years living in Izhevsk who took part in a health check examination in 2008-2009. Self-reported alcohol consumption, hazardous drinking behaviours, socio-economic position, anthropometric measurements plus blood levels of alcohol biomarkers [carbohydrate-deficient transferrin (CDT, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and mean cell volume of erythrocytes (MCV)] and hepatitis B and C status. In the year before interview there was a high prevalence of high-risk alcohol consumption indicated by consumption of non-beverage alcohols (5%), problem drinking behaviours (4.4%) and alcohol consumption exceeding an average 40 g per day (12.6%). All biomarkers were associated strongly with total beverage alcohol consumption even after adjustment for confounders. CDT performed best as an alcohol biomarker, with a sensitivity of 67% and specificity of 71% for detecting an average consumption of more than 40 g per day versus less. For all biomarkers sensitivity was considerably lower than specificity. Hazardous drinking patterns per se were not well detected by any of the biomarkers, all with sensitivity below 60%. In a Russian population with high levels of alcohol consumption, carbohydrate-deficient transferrin (CDT) might be the most sensitive and specific biomarker for detecting ethanol consumption above 40 g/day. A biomarker reflecting hazardous drinking patterns has yet to be established.


Drosophila bunched integrates opposing DPP and EGF signals to set the operculum boundary.
The Drosophila BMP homolog DPP can function as a morphogen, inducing multiple cell fates across a developmental field. However, it is unknown how graded levels of extracellular DPP are interpreted to organize a sharp boundary between different fates. Here we show that opposing DPP and EGF signals set the boundary for an ovarian follicle cell fate. First, DPP regulates gene expression in the follicle cells that will create the operculum of the eggshell. DPP induces expression of the enhancer trap reporter A359 and represses expression of bunched, which encodes a protein similar to the mammalian transcription factor TSC-22. Second, DPP signaling indirectly regulates A359 expression in these cells by downregulating expression of bunched. Reduced bunched function restores A359 expression in cells that lack the Smad protein MAD; ectopic expression of BUNCHED suppresses A359 expression in this region. Importantly, reduction of bunched function leads to an expansion of the operculum and loss of the collar at its boundary. Third, EGF signaling upregulates expression of bunched. We previously demonstrated that the bunched expression pattern requires the EGF receptor ligand GURKEN. Here we show that activated EGF receptor is sufficient to induce ectopic bunched expression. Thus, the balance of DPP and EGF signals sets the boundary of bunched expression. We propose that the juxtaposition of cells with high and low BUNCHED activity organizes a sharp boundary for the operculum fate.


ASAF: altered spontaneous activity fingerprinting in Alzheimer's disease based on multisite fMRI.
Several monocentric studies have noted alterations in spontaneous brain activity in Alzheimer's disease (AD), although there is no consensus on the altered amplitude of low-frequency fluctuations in AD patients. The main aim of the present study was to identify a reliable and reproducible abnormal brain activity pattern in AD. The amplitude of local brain activity (AM), which can provide fast mapping of spontaneous brain activity across the whole brain, was evaluated based on multisite rs-fMRI data for 688 subjects (215 normal controls (NCs), 221 amnestic mild cognitive impairment (aMCI) 252 AD). Two-sample t-tests were used to detect group differences between AD patients and NCs from the same site. Differences in the AM maps were statistically analyzed via the Stouffer's meta-analysis. Consistent regions of lower spontaneous brain activity in the default mode network and increased activity in the bilateral hippocampus/parahippocampus, thalamus, caudate nucleus, orbital part of the middle frontal gyrus and left fusiform were observed in the AD patients compared with those in NCs. Significant correlations (P < 0.05, Bonferroni corrected) between the normalized amplitude index and Mini-Mental State Examination scores were found in the identified brain regions, which indicates that the altered brain activity was associated with cognitive decline in the patients. Multivariate analysis and leave-one-site-out cross-validation led to a 78.49% prediction accuracy for single-patient classification. The altered activity patterns of the identified brain regions were largely correlated with the FDG-PET results from another independent study. These results emphasized the impaired brain activity to provide a robust and reproducible imaging signature of AD.


GWASdb v2: an update database for human genetic variants identified by genome-wide association studies.
Genome-wide association studies (GWASs), now as a routine approach to study single-nucleotide polymorphism (SNP)-trait association, have uncovered over ten thousand significant trait/disease associated SNPs (TASs). Here, we updated GWASdb (GWASdb v2, http://jjwanglab.org/gwasdb) which provides comprehensive data curation and knowledge integration for GWAS TASs. These updates include: (i) Up to August 2015, we collected 2479 unique publications from PubMed and other resources; (ii) We further curated moderate SNP-trait associations (P-value < 1.0 × 10(-3)) from each original publication, and generated a total of 252,530 unique TASs in all GWASdb v2 collected studies; (iii) We manually mapped 1610 GWAS traits to 501 Human Phenotype Ontology (HPO) terms, 435 Disease Ontology (DO) terms and 228 Disease Ontology Lite (DOLite) terms. For each ontology term, we also predicted the putative causal genes; (iv) We curated the detailed sub-populations and related sample size for each study; (v) Importantly, we performed extensive function annotation for each TAS by incorporating gene-based information, ENCODE ChIP-seq assays, eQTL, population haplotype, functional prediction across multiple biological domains, evolutionary signals and disease-related annotation; (vi) Additionally, we compiled a SNP-drug response association dataset for 650 pharmacogenetic studies involving 257 drugs in this update; (vii) Last, we improved the user interface of website.


Comparative and Functional Screening of Three Species Traditionally used as Antidepressants: Valeriana officinalis L., Valeriana jatamansi Jones ex Roxb. and Nardostachys jatamansi (D.Don) DC.
The essential oils (EOs) of three Caprifoliaceae species, the Eurasiatic Valeriana officinalis (Vo), the Himalayan Valeriana jatamansi (Vj) and Nardostachys jatamansi (Nj), are traditionally used to treat neurological disorders. Roots/rhizomes micromorphology, DNA barcoding and EOs phytochemical characterization were carried out, while biological effects on the nervous system were assessed by acetylcholinesterase (AChE) inhibitory activity and microelectrode arrays (MEA). Nj showed the highest inhibitory activity on AChE (IC50 67.15 μg/mL) followed by Vo (IC50 127.30 μg/mL) and Vj (IC50 246.84 μg/mL). MEA analyses on rat cortical neurons, carried out by recording mean firing rate (MFR) and mean bursting rate (MBR), revealed stronger inhibition by Nj (IC50 18.8 and 11.1 μg/mL) and Vo (16.5 and 22.5 μg/mL), compared with Vj (68.5 and 89.3 μg/mL). These results could be related to different EO compositions, since sesquiterpenes and monoterpenes significantly contribute to the observed effects, but the presence of oxygenated compounds such as aldehydes and ketones is a discriminating factor in determining the order of potency. Our multidisciplinary approach represents an important tool to avoid the adulteration of herbal drugs and permits the evaluation of the effectiveness of EOs that could be used for a wide range of therapeutic applications.


Dynamics of fatty acid vesicles in response to pH stimuli.
We investigate the dynamics of decanoic acid/decanoate (DA) vesicles in response to pH stimuli. Two types of dynamic processes induced by the micro-injection of NaOH solutions are sequentially observed: deformations and topological transitions. In the deformation stage, DA vesicles show a series of shape deformations, i.e., prolate-oblate-stomatocyte-sphere. In the topological transition stage, spherical DA vesicles follow either of the two pathways, pore formation and vesicle fusion. The pH stimuli modify a critical aggregation concentration of DA molecules, which causes the solubilization of DA molecules in the outer leaflet of the vesicle bilayers. This solubilization decreases the outer surface area of the vesicle, thereby increasing surface tension. A kinetic model based on area difference elasticity theory can accurately describe the dynamics of DA vesicles triggered by pH stimuli.


RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins.
The S100 protein family comprises at least 25 members which, with the exception of S100G, act as Ca2+-sensor proteins that participate in Ca2+ signal transduction by interacting with target proteins thereby modifying their activities. S100 proteins are expressed in vertebrates exclusively, display a cell-specific distribution, and regulate a large variety of intracellular activities. Some S100 proteins are released by a non-classical pathway and exert regulatory effects on several cell types. The receptor for advanced glycation end products (RAGE) has been shown to transduce extracellular effects of S100B, S100A4, S100A6, S100A11, S100A12, S100A13 and S100P. However, some S100 proteins can signal by engaging RAGE as well as non-RAGE receptors. Immune cells (i.e., monocytes/macrophages/microglia, neutrophils and lymphocytes), activated endothelial and vascular smooth muscle cells, neurons, astrocytes, chondrocytes and pancreatic tumor cells are the cell types reported to respond to certain S100 proteins via RAGE engagement. In general, relatively high concentrations of S100 proteins are required for activation of RAGE in responsive cells. S100B is unique in that it can engage RAGE in neurons at low and high concentrations with trophic and toxic effects, respectively, and S100A4 stimulates matrix metalloproteinase 13 release from chondrocytes at nanomolar doses in a RAGE-mediated manner. Oligomerization of S100 proteins under the non-reducing, high-Ca2+ conditions found extracellularly appears to play a relevant role in RAGE activation, and binding of at least S100A12 and S100B results in RAGE oligomerization. Thus, S100/RAGE interactions might have important consequences during development and in tissue homeostasis as well as in inflammatory, degenerative and tumor processes.


Return to Sports and Physical Activities After First Metatarsophalangeal Joint Arthrodesis in Young Patients.
Arthrodesis of the first metatarsophalangeal (MTP) joint has been shown to be effective in alleviating pain and correcting deformity in hallux rigidus. However, outcomes in specific sports and physical activities remain unclear. The aim of this study was to assess sports and physical activities in young patients following first MTP joint arthrodesis and to compare these results with clinical outcomes. Patients between ages 18 and 55 years who underwent MTP arthrodesis were identified by review of a prospective registry. Fifty of 73 eligible patients (68%) were reached for follow-up at a mean of 5.1 (range, 2.2-10.2) years with a mean age at surgery of 49.7 (range, 23-55) years. Physical activity was evaluated with a previously developed sports-specific, patient-administered questionnaire. Clinical outcomes were evaluated with the Foot and Ankle Outcome Score (FAOS). Patients participated in 22 different sports and physical activities. The most common were walking, biking, weightlifting, swimming, running, and golf. Compared to preoperatively, patients rated 27.4% of activities as less difficult, 51.2% as the same, and 21.4% as more difficult. Patients returned to 44.6% of preoperative physical activities in less than 6 months and reached their maximal level of participation in 88.6% of physical activities. Ninety-six percent of patients (48/50) were satisfied with the procedure regarding return to sports and physical activities. Improvements in the FAOS Symptoms subscore were associated with increased postoperative running and walking duration, and improvements in FAOS Pain subscores were associated with greater patient satisfaction. Patients were able to participate in a wide variety of sports and physical activities postoperatively. Some patients reported increased difficulty, but were nonetheless satisfied with the procedure regarding physical activity participation. These findings suggest that first MTP joint arthrodesis is a reasonable option in young, active patients, and may be used to guide postoperative expectations. Level IV, retrospective case series.


Functional Movement Screen (FMS™) Scores and Demographics of US Army Pre-Ranger Candidates.
The United States Army Rangers are a unique population whose training requirements are intensive, and physically and mentally demanding. The Functional Movement Screen (FMS) is a movement screening tool designed to assess movement quality and asymmetries in movement with the potential to identify injury risk. This study was a descriptive, cross-sectional investigation examining associations between FMS scores and the various measures of health and performance of active duty soldiers in light infantry units who were involved in the U.S. Army Pre-Ranger Course (PRC). Before the PRC, 491 male soldiers (mean age = 24.0 ± 3.8 years; mean height = 176.6 ± 7.2 cm; mean body mass = 80.2 ± 9.8 kg) completed a questionnaire which included items on self-assessed physical fitness, last Army physical fitness test (APFT) score, tobacco use, and injury history. The soldiers then completed the FMS, which consisted of seven movements and three clearing tests. From the FMS results, a determination of asymmetries (i.e., differences in FMS scores between the right and left side of the body) was made. Differences between groups were analyzed via an independent sample t-test, a one-way analysis of variance, or a chi-square as appropriate. Significance was set at 0.05 a priori. The average composite FMS score was 16.4 (±1.9) points. Soldiers reporting ≥290 APFT points achieved a higher FMS score than those reporting lower APFT scores (16.5 ± 2.0 vs 16.1 ± 2.0 points, P = 0.03). Soldiers reporting either tobacco use or a previous musculoskeletal injury had lower FMS scores than those not reporting these (tobacco: 16.1 ± 2.1 vs 16.5 ± 1.8 points, P = 0.02; injury: 16.0 ± 2.2 vs 16.6 ± 1.8 points, P < 0.01). FMS asymmetries were not related to APFT scores, tobacco use, or self-rated fitness. As self-rated fitness increased so did APFT scores. Active duty soldiers of a light infantry division achieved FMS scores similar to other military populations tested, and the composite FMS score was related to higher APFT scores, absence of tobacco use, and absence of previous musculoskeletal injuries. Improving PRC candidate healthy habits through highlighting the negative associations between poorer fitness, cigarette tobacco use and movement quality, may reduce injury risk and increase PRC completion potential.


Selection-driven evolution of sex-biased genes is consistent with sexual selection in Arabidopsis thaliana.
Sex-biased genes are genes with a preferential or specific expression in one sex and tend to show an accelerated rate of evolution in animals. Various hypotheses--which are not mutually exclusive--have been put forth to explain observed patterns of rapid evolution. One possible explanation is positive selection, but this has been shown only in few animal species and mostly for male-specific genes. Here, we present a large-scale study that investigates evolutionary patterns of sex-biased genes in the predominantly self-fertilizing plant Arabidopsis thaliana. Unlike most animal species, A. thaliana does not possess sex chromosomes, its flowers develop both male and female sexual organs, and it is characterized by low outcrossing rates. Using cell-specific gene expression data, we identified genes whose expression is enriched in comparison with all other tissues in the male and female gametes (sperm, egg, and central cell), as well as in synergids, pollen, and pollen tubes, which also play an important role in reproduction. Genes specifically expressed in gametes and synergids show higher rates of protein evolution compared with the genome-wide average and no evidence for positive selection. In contrast, pollen- and pollen tube-specific genes not only have lower rates of protein evolution but also exhibit a higher proportion of adaptive amino acid substitutions. We show that this is the result of increased levels of purifying and positive selection among genes with pollen- and pollen tube-specific expression. The increased proportion of adaptive substitutions cannot be explained by the fact that pollen- and pollen tube-expressed genes are enriched in segmental duplications, are on average older, or have a larger effective population size. Our observations are consistent with prezygotic sexual selection as a result of interactions during pollination and pollen tube growth such as pollen tube competition.


Priorities for content for a short-course on postoperative care relevant for low- and middle-income countries: an e-Delphi process with training facilitators.
Most surgical and anaesthetic mortality and morbidity occurs postoperatively, disproportionately affecting low- and middle-income countries. Various short courses have been developed to improve patient outcomes in low- and middle-income countries, but none specifically to address postoperative care and complications. We aimed to identify key features of a proposed short-course addressing this topic using a Delphi process with low- and middle-income country anaesthesia providers trained as short-course facilitators. An initial questionnaire was co-developed from literature review and exploratory workshops to include 108 potential course features. Features included content; teaching method; appropriate participants; and appropriate faculty. Over three Delphi rounds (panellists numbered 86, 64 and 35 in successive cycles), panellists indicated which features they considered most important. Responses were analysed by geographical regions: Africa, the Americas, south-east Asia and Western Pacific. Ultimately, panellists identified 60, 40 and 54 core features for the proposed course in each region, respectively. There were high levels of consensus within regions on what constituted core course content, but not between regions. All panellists preferred the small group workshop teaching method irrespective of region. All regions considered anaesthetists to be key facilitators, while all agreed that both anaesthetists and operating theatre nurses were key participants. The African and Americas regional panels recommended more multidisciplinary healthcare professionals for participant roles. Faculty from high-income countries were not considered high priority. Our study highlights variability between geographical regions as to which course features were perceived as most locally relevant, supporting regional adaptation of short-course design rather than a one-size-fits-all model.


Sinus node function and conduction system after complete repair of tetralogy of Fallot.
Twenty-three children underwent electrophysiological studies during routine postoperative catheterization two months to five years after complete correction of tetralogy of Fallot. The aim of the study was to investigate the whole conduction system, including sinus node function, suing His bundle recordings and atrial pacing. H-V intervals were normal at rest and with pacing in twenty-two patients, including four patients with evidence of bifascicular block on the surface ECG. One patient with cardiomegaly and evidence of diffuse myocardial damage had a prolonged H-V interval but did not develop a block at this level during pacing A-H interval was slightly prolonged in four patients and normal in all others. The threshold of pacing-induced atrioventricular block ranged from 75 to 240/min and was somewhat age dependent (r = -0.55). Two patients fell below the 95% confidence limit of this regression and are considered abnormal. One returned to normal after intravenous injectionof atropine. Corrected sinus node recovery time ranged from 60 to 2000 msec. Three patients had values above 500 msec which are considered abnormal. These patients had other minor signs of sinus node dysfunction, i.e., episodes of sino-atrial block at rest or intermittent sinus bradycardia. Thus, while the His Purkinje system performed satisfactorily in all patients, sinus node dysfunctional and A-V node dysfunction were demonstrated in a few patients after correction of tetralogy of Fallot.


Extended photoresponse and multi-band luminescence of ZnO/ZnSe core/shell nanorods.
Aligned ZnO/ZnSe core/shell nanorods (NRs) with type-II energy band alignment were fabricated by pulsed laser deposition of ZnSe on the surfaces of hydrothermally grown ZnO NRs. The obtained ZnO/ZnSe core/shell NRs are composed of wurtzite ZnO cores and zinc blende ZnSe shells. The bare ZnO NRs are capable of emitting strong ultraviolet (UV) near band edge (NBE) emission at 325-nm light excitation, while the ZnSe shells greatly suppress the emission from the ZnO cores. High-temperature processing results in an improvement in the structures of the ZnO cores and the ZnSe shells and significant changes in the optical properties of ZnO/ZnSe core/shell NRs. The fabricated ZnO/ZnSe core/shell NRs show optical properties corresponding to the two excitonic band gaps of wurtzite ZnO and zinc blende ZnSe and the effective band gap between the conduction band minimum of ZnO and the valence band maximum ZnSe. An extended photoresponse much wider than those of the constituting ZnO and ZnSe and a multi-band photoluminescence including the UV NBE emission of ZnO and the blue NBE emission of ZnSe are observed.


Antitumor constituents from Alternanthera philoxeroides.
Two new compounds, alternanthin B (1) and N-trans-feruloyl-3,5-dimethoxytyramine (2), along with four known compounds (3-6) were isolated from the aerial parts of Alternanthera philoxeroides. Their structures were elucidated on the basis of spectroscopic methods. The antitumor activity of the isolated compounds was also evaluated.


Fractal analyses of osseous healing using tuned aperture computed tomography images.
The aim of this study was to evaluate osseous healing in mandibular defects using fractal analyses on conventional radiographs and tuned aperture computed tomography (TACT; OrthoTACT, Instrumentarium Imaging, Helsinki, Finland) images. Eighty test sites on the inferior margins of rabbit mandibles were subject to lesion induction and treated with one of the following: no treatment (controls); osteoblasts only; polymer matrix only; or osteoblast-polymer matrix (OPM) combination. Images were acquired using conventional radiography and TACT, including unprocessed TACT (TACT-U) and iteratively restored TACT (TACT-IR). Healing was followed up over time and images acquired at 3, 6, 9, and 12 weeks post-surgery. Fractal dimension (FD) was computed within regions of interest in the defects using the TACT workbench. Results were analyzed for effects produced by imaging modality, treatment modality, time after surgery and lesion location. Histomorphometric data were available to assess ground truth. Significant differences (p < 0.0001) were noted based on imaging modality with TACT-IR recording the highest mean fractal dimension (MFD), followed by TACT-U and conventional images, in that order. Sites treated with OPM recorded the highest MFDs among all treatment modalities (p < 0.0001). The highest MFD based on time was recorded at 3 weeks and differed significantly with 12 weeks (p < 0.035). Correlation of FD with results of histomorphometric data was high (r = 0.79; p < 0.001). The FD computed on TACT-IR showed the highest correlation with histomorphometric data, thus establishing the fact TACT is a more efficient and accurate imaging modality for quantification of osseous changes within healing bony defects.


Innovative Partnership Between Intensive Care Unit Nurses and Therapists to Care for Patients With COVID-19.
When patients with COVID-19 began presenting to hospitals in early 2020, medical professionals were unprepared to handle the severity of disease and the number of severely ill patients. In response to critical needs of patients with COVID-19 and the threat of nurse burnout, a special operations team comprising physical and occupational therapists was convened to (1) provide help to intensive care unit nurses, (2) help therapists be productive, and (3) use therapists' specialties for critical patients. Two therapists teamed up each shift to work with every critical patient with COVID-19, performing numerous nursing and therapy activities. Activity frequency was documented by the therapists daily, and duration was estimated and data were summarized by nursing leadership. During the 9-week program, 35 critical patients with COVID-19 were included in the special operations program. During the program, the teams performed 10 activities, including prone positioning, turning, and mobilization, 1937 times with the patients with COVID-19. The partnership saved between 5 and 40 minutes of intensive care nurse time per activity, which resulted in a total of 677.2 hours of nursing time saved. Implementation of the special operations program had a positive impact on patients, nurses, and therapists. Patients benefited both clinically and socially from additional time with special operations teams. Nurses benefited from having help caring for critical patients, and therapists benefited from increased productivity during redeployment. Deployment of nonnursing clinical staff could be an effective strategy to leverage available resources while maintaining clinical standards of care and reducing nursing burden during a pandemic or crisis surge.


[Surgical therapy of hepatic fibrolamellar carcinoma].
Hepatic fibrolamellar carcinoma (FLC) is an uncommon tumour that differs from hepatocellular carcinoma (HCC) in demographics, condition of the affected liver, tumour markers, and prognosis. FLC characteristically manifests as a large hepatic mass in adolescents or young adults with female predominance (mean age 23 years). Cirrhosis, elevated alpha-fetoprotein levels, and risk factors for HCC such as viral hepatitis are typically absent. FLC is usually associated with serum tumour markers such as vitamin B12 binding protein, and neurotensin. FLC is characterized pathologically by cords of tumour cells surrounded by abundant collagenous fibrous tissue arranged in a parallel or lamellar distribution. FLC usually appears on radiologic images as a lobulated heterogeneous mass with a central scar in an otherwise normal liver. The clinical presentation of patients with FLC is variable. These patients commonly have pain, and palpable right upper quadrant abdominal mass. An uncommon presenting sign is gynaecomastia in men. Use of percutaneous biopsy (FNAB) is beneficial if there is diagnostic uncertainty about the radiologic diagnosis (US, CT MRI). Although FLC is frequently recurrent, patients have a better prognosis than those with HCC, and aggressive surgical liver resection with extended lymphadenectomy or liver transplantation may be indicated. The presence of advanced-stage disease, direct invasion of adjacent organs, lymphadenopathy, or limited metastasis does not preclude attempts at curative resection. In inoperable cases, the patient may benefit from chemotherapy, permitting in up to 50% of these cases a curative resection. The case is reported of a 18-year-old man with bilateral gynecomastia secondary to an unknown hepatic fibrolamellar carcinoma producing oestrogens. Serum alpha-fetoprotein was negative; des-gamma-carboxy prothrombin (DCP) level was elevated. CT scan and MRI showed a solid hepatic tumour (theta 10 cm) without evidence of extrahepatic spreading. By a needle biopsy a fibrolamellar carcinoma was diagnosed. On March 1995 a right hemihepatectomy was performed. The postoperative course was uneventful and the patient recovered. Specimen's histologic examination confirmed the preoperative diagnosis. Intracellular (hepatocytes) oestrogens were found, but oestrogen and androgen receptors were negative. After surgery DCP and oestradiol levels rapidly decreased and gynaecomastia disappeared. A follow-up program was established. On April 2000 a probable recurrence within the caudate lobe was discovered by a liver CT scan without evidence of extrahepatic spreading. Tumour markers, FNAB, and bone scintigraphy were negative. On July 2000 the patient underwent second look laparotomy. Only a coeliac lymphadenopathy was found and a lymphadenectomy performed. Specimen's histologic examination showed a metastatic lymph nodal disease (FLC). The postoperative course was uneventful and the patient recovered. He is currently alive without evidence of recurrence 5 years after the second operation.


Wrist actigraphy predicts outcome in patients with pulmonary hypertension.
Pulmonary hypertension (PH) impairs quality of life, exercise performance and survival. Simple measures to monitor the disease are needed. We tested whether actigraphy by a wrist-worn device in the patient's home reflects disease severity in PH patients. Twenty-three outpatients with pulmonary arterial and chronic thromboembolic PH (15 females), functional classes II-IV, underwent clinical examination and actigraphy over 2 weeks while pursuing their usual life at home. Actigraphies were correlated with clinical data and mean pulmonary artery pressure (mPAP). Deaths, lung transplantations and pulmonary endarterectomy were recorded over 4 years. Actigraphies revealed a mean ± SD daytime activity duration of 14:57 ± 1:14 h with 146 ± 125 activity counts/min. Very severely impaired patients (mPAP 50 ± 7 mm Hg) were inactive for longer periods at night (8:25 ± 1:18 h) and less active during the day (54 ± 44 counts/min) when compared to modestly impaired patients (mPAP 33 ± 7 mm Hg; inactive at night for 6:58 ± 0:39 h; daytime activity 229 ± 148 counts/min, p < 0.05 in all instances). Out of 19 patients followed for 4 years, 5 died and 1 received a lung transplantation. Kaplan-Meier analysis revealed a shorter survival without lung transplantation in patients with a duration of daytime activity of <15 h/day than those with >15 h/day duration (log rank, p = 0.026). A long nocturnal rest and reduced daytime activity recorded by actigraphy are associated with severe hemodynamic impairment and reduced survival in patients with PH. Therefore, wrist actigraphy performed during everyday life in the patient's home holds promise as a simple tool for the assessment of disease severity and prognosis in patients with PH.


Strontium ranelate: a new treatment for postmenopausal osteoporosis with a dual mode of action.
In vitro, strontium ranelate increases collagen and noncollagen protein synthesis by mature osteoblast-enriched cells. Its effects on bone formation were confirmed as the drug enhanced preosteoblastic cell replication. In the isolated osteoclast, preincubation of bone slices with strontium ranelate-induced dose-dependent inhibition of the bone-resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. Its effect in postmenopausal women with established osteoporosis was assessed during an international, prospective, double-blind, randomized, placebo-controlled phase 3 program comparing strontium ranelate 2 g daily with placebo. The 3-year analysis of the phase 3 study, Spinal Osteoporosis Therapeutic Intervention, evaluating the effect of strontium ranelate 2 g/day on vertebral fracture rates, revealed a significant 41% reduction in the relative risk of patients experiencing new vertebral fracture with strontium ranelate over 3 years. A second phase 3 study showed a significant reduction in the relative risk of experiencing a nonvertebral fracture in the group treated with strontium ranelate over 3 years. These results show that strontium ranelate is a new, effective, and safe treatment for vertebral and hip osteoporosis, with a unique mode of action, increasing bone formation and decreasing bone resorption leading to a rebalance of bone turnover in favor of bone formation.