Where children drown, United States, 1995.
Drowning is the second leading cause of unintentional injury death among children ages 1 to 19 years. Details about the specific site of submersion are important for implementation of primary prevention efforts, but are not routinely available from national data. To provide national data about the specific sites of drowning among US children and to examine site-specific drowning rates by age, race, and gender. United States, 1995. Information was abstracted from death certificates for unintentional drownings among children <20 years of age. The site of drowning was coded from free text on death certificates. Proportional distributions of the site of drowning by age, region, gender, and race were examined. Site-specific drowning rates were calculated by age, race, and gender. Denominators were based on US Census Bureau, June 1995 estimates of the US population. For 1995, death certificates were obtained for 1420 unintentional drownings among children <20 years of age, 98% of the number of drowning deaths reported by the National Center for Health Statistics for the same year. Site of drowning was specified on 1308 (92%) death certificates. Fifty-five percent of infant drownings were in bathtubs. Among children between the ages of 1 to 4 years, 56% of drownings were in artificial pools and 26% were in other bodies of freshwater. Among older children, 63% of drownings were in natural bodies of freshwater. Site-specific drowning rates varied by race. Importantly, after the age of 5 years, the risk of drowning in a swimming pool was greater among black males compared with white males with rate ratios of 15.1 (95% confidence interval: 6.7-38.5) among 10- to 14-year-olds and 12.8 (95% confidence interval: 6.5-26.9) among 15- to 19-year-olds. The variety of sites in which children drown, even within specific age groups, emphasizes the need for a multifaceted approach to prevention. Reductions in the relatively high rates of drowning among black adolescent males will require targeted interventions to prevent swimming pool drownings among this group.


Factors associated with 1-year outcome of major depression in the community.
Evidence from outcome studies of major depression indicates a high rate of relapse and chronicity, and that prior chronicity, recurrent episodes, and the presence of psychosocial stressors are associated with a poor outcome. However, the generalizability of these findings is limited because most studies have focused on treated samples; thus, these studies may have been biased toward more chronic or severe illnesses. In prospectively surveying a large probability sample of the general population, the Epidemiologic Catchment Area program offers the opportunity to investigate prognosis without selection bias. In this study, the Epidemiologic Catchment Area subjects with a diagnosis of Major Depressive Disorder at first interview (n = 423) were categorized according to their diagnostic status 1 year later. The results confirmed a high rate of nonrecovery, with clinical features associated with a poor outcome that resembled those identified in previous clinical studies. Overall, clinical factors were more important prognostically than were sociodemographic characteristics. However, there was some evidence that a poorer outcome in older women may partially explain the greater female prevalence of depression in the community.


Biomechanical Behavior of Bioactive Material in Dental Implant: A Three-Dimensional Finite Element Analysis.
Dental implants are widely accepted for the rehabilitation of missing teeth due to their aesthetic compliance, functional ability, and great survival rate. The various components in implant design like thread design, thread angle, pitch, and material used for manufacturing play a critical role in its success. Understanding these influencing factors and implementing them properly in implant design can reduce cases of potential implant failure. Recently, finite element analysis (FEA) is being widely used in the field of health sciences to solve problems in designing medical devices. It provides valid and accurate assessment in the clinical and in vitro analysis. Hence, this study was conducted to evaluate the impact of thread design of the implant and 3 different bioactive materials, titanium alloy, graphene, and reduced graphene oxide (rGO) on stress, strain, and deformation in the implant system using FEA. In this study, the FEA model of the bones and the tissues are modeled as homogeneous, isotropic, and linearly elastic material with a titanium implant system with an assumption of it 100% osseointegrated into the bone. The titanium was functionalized with graphene and graphene oxide. A modeling software tool Catia® and Ansys Workbench® is used to perform the analysis and evaluate the von Mises stress distribution, strain, and deformation at the implant and implant-cortical bone interface. The results showed that the titanium implant with a surface coating of graphene oxide exhibited better mechanical behavior than graphene, with mean von Mises stress of 39.64 MPa in pitch 1, 23.65 MPa in pitch 2, and 37.23 MPa in pitch 3. It also revealed that functionalizing the titanium implant will help in reducing the stress at the implant system. Overall, the study emphasizes the use of FEA analysis methods in solving various biomechanical issues about medical and dental devices, which can further open up for invivo study and their practical uses.


An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population. In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic. All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic. Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively. Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020. Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both. The two groups differed in disease incidence (group 1 vs group 2, 0·3 vs ten per month), mean age (3·0 vs 7·5 years), cardiac involvement (two of 19 vs six of ten), KDSS (zero of 19 vs five of ten), MAS (zero of 19 vs five of ten), and need for adjunctive steroid treatment (three of 19 vs eight of ten; all p<0·01). In the past month we found a 30-fold increased incidence of Kawasaki-like disease. Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease. A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic. None.


Finding food: how marine invertebrates use chemical cues to track and select food.
Benthic marine invertebrates sense molecules from other organisms and use these molecules to find and evaluate the organisms as sources of food. These processes depend on the detection and discrimination of molecules carried in sea water around and in the mouths of these animals. To understand these processes, researchers have studied how molecules released from food distribute in the sea water as a plume, how animals respond to the plume, the molecular identity of the attractants in the plume, the effect of turbulence on food-searching success, and how animals evaluate the quality of food and make decisions to eat or not. This review covers recent progress on this topic involving interdisciplinary studies of natural products chemistry, fluid dynamics, neuroethology, and ecology.


Multi-scale analysis of bone chemistry, morphology and mechanics in the oim model of osteogenesis imperfecta.
Osteogenesis imperfecta is a congenital disease commonly characterized by brittle bones and caused by mutations in the genes encoding Type I collagen, the single most abundant protein produced by the body. The oim model has a natural collagen mutation, converting its heterotrimeric structure (two α1 and one α2 chains) into α1 homotrimers. This mutation in collagen may impact formation of the mineral, creating a brittle bone phenotype in animals. Femurs from male wild type (WT) and homozygous (oim/oim) mice, all at 12 weeks of age, were assessed using assays at multiple length scales with minimal sample processing to ensure a near-physiological state. Atomic force microscopy (AFM) demonstrated detectable differences in the organization of collagen at the nanoscale that may partially contribute to alterations in material and structural behavior obtained through mechanical testing and reference point indentation (RPI). Changes in geometric and chemical structure obtained from µ-Computed Tomography and Raman spectroscopy indicate a smaller bone with reduced trabecular architecture and altered chemical composition. Decreased tissue material properties in oim/oim mice are likely driven by changes in collagen fibril structure, decreasing space available for mineral nucleation and growth, as supported by a reduction in mineral crystallinity. Multi-scale analyses of this nature offer much in assessing how molecular changes compound to create a degraded, brittle bone phenotype.


Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice.
Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.


Record of Leptometopa latipes (Diptera: Milichiidae) from a human cadaver in the Mediterranean area.
In forensic entomology, insects are used mainly to obtain information about the time since death. This information is obtained studying the developmental rate of the first colonizers, principally species in the families Calliphoridae, Sarcophagidae, Muscidae, Stratiomyidae and Phoridae. However, species belonging to other families can provide information about body transfer or the season of the death. Among them Milichiidae are flies rarely reported from human cases despite the larvae of some species are known as saprophagous feeding on plant and animal decomposing matter. A potential cause of the lack of records of these species from forensic cases can be related with the paucity of descriptions and illustrations of the immature stages. In this article, the entomological samples collected from a human body found inside an apartment in a Maghreb country, in Northern Africa, is reported and Leptometopa latipes (Diptera: Milichiidae) is described in detail. Molecular analysis is also reported to confirm the morphological analysis.


Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress.
Neutrophils produce free radicals known as reactive oxygen species (ROS), which assist in the clearance of damaged host tissue. Tissue damage may occur during exercise due to muscle damage, thermal stress and ischaemia/reperfusion. When produced in excess, neutrophil-derived ROS may overwhelm the body's endogenous antioxidant defence mechanisms, and this can lead to oxidative stress. There is increasing evidence for links between oxidative stress and a variety of pathological disorders such as cardiovascular diseases, cancer, chronic inflammatory diseases and post-ischaemic organ injury. A small number of studies have investigated whether there is a link between neutrophil activation and oxidative stress during exercise. In this review, we have summarised the findings of these studies. Exercise promotes the release of neutrophils into the circulation, and some evidence suggests that neutrophils mobilised after exercise have an enhanced capacity to generate some forms of ROS when stimulated in vitro. Neutrophil activation during exercise may challenge endogenous antioxidant defence mechanisms, but does not appear to increase lipid markers of oxidative stress to any significant degree, at least in the circulation. Antioxidant supplements such as N-acetylcysteine are effective at attenuating increases in the capacity of neutrophils to generate ROS when stimulated in vitro, whereas vitamin E reduces tissue infiltration of neutrophils during exercise. Free radicals generated during intense exercise may lead to DNA damage in leukocytes, but it is unknown if this damage is the result of neutrophil activation. Exercise enhances the expression of inducible haem (heme)-oxygenase (HO-1) in neutrophils after exercise, however, it is uncertain whether oxidative stress is the stimulus for this response.


Economics of immunization information systems in the United States: assessing costs and efficiency.
One of the United States' national health objectives for 2010 is that 95% of children aged <6 years participate in fully operational population-based immunization information systems (IIS). Despite important progress, child participation in most IIS has increased slowly, in part due to limited economic knowledge about IIS operations. Should IIS need further improvement, characterizing costs and identifying factors that affect IIS efficiency become crucial. Data were collected from a national sampling frame of the 56 states/cities that received federal immunization grants under U.S. Public Health Service Act 317b and completed the federal 1999 Immunization Registry Annual Report. The sampling frame was stratified by IIS functional status, children's enrollment in the IIS, and whether the IIS had been developed as an independent system or was integrated into a larger system. These sites self-reported IIS developmental and operational program costs for calendar years 1998-2002 using a standardized data collection tool and underwent on-site interviews to verify reported data with information from the state/city financial management system and other financial records. A parametric cost-per-patient-record (CPR) model was estimated. The model assessed the impact of labor and non-labor resources used in development and operations tasks, as well as the impact of information technology, local providers' participation and compliance with federal IIS performance standards (e.g., ensuring the confidentiality and security of information, ensure timely vaccination data at the time of patient encounter, and produce official immunization records). Given the number of records minimizing CPR, the additional amount of resources needed to meet national health goals for the year 2010 was also calculated. Estimated CPR was as high as $10.30 and as low as $0.09 in operating IIS. About 20% of IIS had between 2.9 to 3.2 million records and showed CPR estimates of $0.09. Overall, CPR was highly sensitive to local providers' participation. To achieve the 2010 goals, additional aggregated costs were estimated to be $75.6 million nationwide. Efficiently increasing the number of records in IIS would require additional resources and careful consideration of various strategies to minimize CPR, such as boosting providers' participation.


Associations of Low- and High-Intensity Light Activity with Cardiometabolic Biomarkers.
Light-intensity physical activity (LIPA) accounts for much of adults' waking hours (≈40%) and substantially contributes to overall daily energy expenditure. Encompassing activity behaviors of low intensity (standing with little movement) to those of higher intensity (slow walking), LIPA is ubiquitous, yet little is known about how associations with health may vary depending on its intensity. We examined the associations of objectively assessed LIPA (categorized as either low LIPA [LLPA] or high LIPA [HLPA]) and moderate- to vigorous-intensity activity with cardiometabolic risk biomarkers. Cardiometabolic biomarkers were measured in 4614 US adults (47 ± 17 yr) who participated in the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey cycles. Multiple linear regression analyses examined the associations of three accelerometer-derived physical activity (SD increment per day) intensity categories (LLPA, 100-761 counts per minute; HLPA, 762-1951 counts per minute; moderate-intensity physical activity [MPA], 1952-5724 counts per minute; vigorous-intensity physical activity [VPA], ≥5725 counts per minute) with cardiometabolic biomarkers, adjusting for potential sociodemographic, behavioral, and medical confounders. All intensities of physical activity were beneficially associated with waist circumference, C-reactive protein, triglycerides, fasting insulin, β-cell function, and insulin sensitivity (P < 0.05); only some activity intensities showed significant associations with systolic blood pressure (LLPA), body mass index, HDL cholesterol, fasting glucose, and 2-h plasma glucose (HLPA, MPA, and VPA). Generally, effect size increased with intensity of physical activity. Overall, further adjustment for waist circumference attenuated associations with MPA and VPA to a greater extent than associations with LLPA and HLPA. The cross-sectional findings provide novel evidence for the potential benefits of increasing both LLPA and HLPA. They further reinforce the established importance of moderate- to vigorous-intensity activity, the mainstay of public health recommendations.


In Situ Analyses Directly in Diarrheal Stool Reveal Large Variations in Bacterial Load and Active Toxin Expression of Enterotoxigenic Escherichiacoli and Vibrio cholerae.
The bacterial pathogens enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae are major causes of diarrhea. ETEC causes diarrhea by production of the heat-labile toxin (LT) and heat-stable toxins (STh and STp), while V. cholerae produces cholera toxin (CT). In this study, we determined the occurrence and bacterial doses of the two pathogens and their respective toxin expression levels directly in liquid diarrheal stools of patients in Dhaka, Bangladesh. By quantitative culture and real-time quantitative PCR (qPCR) detection of the toxin genes, the two pathogens were found to coexist in several of the patients, at concentrations between 102 and 108 bacterial gene copies per ml. Even in culture-negative samples, gene copy numbers of 102 to 104 of either ETEC or V. cholerae toxin genes were detected by qPCR. RNA was extracted directly from stool, and gene expression levels, quantified by reverse transcriptase qPCR (RT-qPCR), of the genes encoding CT, LT, STh, and STp showed expression of toxin genes. Toxin enzyme-linked immunosorbent assay (ELISA) confirmed active toxin secretion directly in the liquid diarrhea. Analysis of ETEC isolates by multiplex PCR, dot blot analysis, and genome sequencing suggested that there are genetic ETEC profiles that are more commonly found as dominating single pathogens and others that are coinfectants with lower bacterial loads. The ETEC genomes, including assembled genomes of dominating ETEC isolates expressing LT/STh/CS5/CS6 and LT/CS7, are provided. In addition, this study highlights an emerging important ETEC strain expressing LT/STp and the novel colonization factor CS27b. These findings have implications for investigations of pathogenesis as well as for vaccine development. IMPORTANCE The cause of diarrheal disease is usually determined by screening for several microorganisms by various methods, and sole detection is used to assign the agent as the cause of disease. However, it has become increasingly clear that many infections are caused by coinfections with several pathogens and that the dose of the infecting pathogen is important. We quantified the absolute numbers of enterotoxigenic E. coli (ETEC) and Vibrio cholerae directly in diarrheal fluid. We noted several events where both pathogens were found but also a large dose dependency. In three samples, we found ETEC as the only pathogen sought for. These isolates belonged to globally distributed ETEC clones and were the dominating species in stool with active toxin expression. This suggests that certain superior virulent ETEC lineages are able to outcompete the gut microbiota and be the sole cause of disease and hence need to be specifically monitored.


Prevalence of stenoses and occlusions of brain-supplying arteries in young stroke patients.
Atherosclerosis is believed to be a minor cause of TIA and stroke in younger and middle-aged patients. However, data from large cohorts are limited. This study investigates the prevalence of extracranial and intracranial atherosclerosis in stroke and TIA patients aged 18-55 years in the multinational sifap1 study. From the sifap1 cohort (n = 5,023), we analyzed a subset of patients with complete data from carotid ultrasound studies. Patients with arterial dissections, vasculitis, and mobile thrombi were excluded. Among the remaining 2,187 patients (men: n = 1,319; 18-44 years: n = 744), intracranial arteries were additionally examined with ultrasonography in 1,612 patients (73.7%). Patients were stratified by sex and age groups (younger: 18-44 years; middle-aged: 45-55 years). In patients with ischemic stroke, the overall prevalence of carotid artery stenoses and occlusions was 8.9% (younger: 4.9%; middle-aged: 11.0%), of which 81% were symptomatic. Nonstenotic carotid plaques were more common in men than in women (15.8% vs. 7.7%; p < 0.001), and in middle-aged than in younger patients (17.0% vs. 4.9%; p < 0.001). Supratentorial intracranial artery stenoses and occlusions amounted to 11.8%. Supratentorial stenoses occurred more frequently in middle-aged patients (13.0% vs. 7.8%; p < 0.001), whereas occlusions were equally common (both 3.2%; not significant). We observed a substantial proportion of atherosclerotic carotid artery stenoses and occlusions in younger stroke patients. Intracranial stenoses and occlusions were even more prevalent than extracranial carotid artery disease. Together with nonstenotic plaques, one-fifth of patients (21.2%) had symptomatic or asymptomatic large-artery atherosclerosis, which should encourage future stroke prevention campaigns to target risk factor modification in young people.


Sexual behaviour and poor hygiene are related to recent hepatitis a virus community outbreaks.
there has been a global increase in the incidence of hepatitis A infection. The aim of this study was to examine the characteristics of the increase in our region and the degree of adherence to the recommended hygienic measures after discharge from hospital. demographic, clinical and biochemical variables were collected from patients with acute hepatitis A in our health area. The patients were grouped as follows: January 2010 to December 2016 (historical cohort) and January 2017 to October 2017 (recent cohort). A phylogenetic analysis was also performed in the recent cohort. One month after discharge, bacterial growth was evaluated by a culture of the dominant hand imprint and were compared with a control group. a total of 110 cases were registered with a median age of 36.3 years (range 3-89) and 77.3 % were male. The incidence was 0.82/100,000 inhabitants/year and 22.75/100,000 inhabitants/year in the historical and recent cohorts, respectively. Patients in the recent cohort were more frequently male (52.6 % vs. 82.4 %, p = 0.008) and younger (51.7 [3-89] vs. 33.4 [4-74] years, p < 0.001). In addition, 63.8 % of the recent cohort were men who had sex with other men and had unsafe sexual practices (37.5 %). Phylogenetic analysis showed a predominance of genotype A and a high frequency of the VRD 521-2016 sequence. A higher growth of enterobacteria was observed in patients with hepatitis A compared to the control group (7.3 % vs. 1.2 %, p = 0.005), despite specific hygienic measures given at discharge. a recent outbreak of hepatitis A in our area was related with gender, younger age and sexual practices. Hepatitis A infected subjects showed a poor adherence to hygienic measures. Our data suggests the need for policies that encourage preventive actions, particularly vaccination in this high-risk group.


Identification of key components in the energy metabolism of the hyperthermophilic sulfate-reducing archaeon Archaeoglobus fulgidus by transcriptome analyses.
Energy conservation via the pathway of dissimilatory sulfate reduction is present in a diverse group of prokaryotes, but is most comprehensively studied in Deltaproteobacteria. In this study, whole-genome microarray analyses were used to provide a model of the energy metabolism of the sulfate-reducing archaeon Archaeoglobus fulgidus, based on comparative analysis of litoautotrophic growth with H2/CO2 and thiosulfate, and heterotrophic growth on lactate with sulfate or thiosulfate. Only 72 genes were expressed differentially between the cultures utilizing sulfate or thiosulfate, whereas 269 genes were affected by a shift in energy source. We identified co-located gene cluster encoding putative lactate dehydrogenases (LDHs; lldD, dld, lldEFG), also present in sulfate-reducing bacteria. These enzymes may take part in energy conservation in A. fulgidus by specifically linking lactate oxidation with APS reduction via the Qmo complex. High transcriptional levels of Fqo confirm an important role of F420H2, as well as a menaquinone-mediated electron transport chain, during heterotrophic growth. A putative periplasmic thiosulfate reductase was identified by specific up-regulation. Also, putative genes for transport of sulfate and sulfite are discussed. We present a model for hydrogen metabolism, based on the probable bifurcation reaction of the Mvh:Hdl hydrogenase, which may inhibit the utilization of Fdred for energy conservation. Energy conservation is probably facilitated via menaquinone to multiple membrane-bound heterodisulfide reductase (Hdr) complexes and the DsrC protein-linking periplasmic hydrogenase (Vht) to the cytoplasmic reduction of sulfite. The ambiguous roles of genes corresponding to fatty acid metabolism induced during growth with H2 are discussed. Putative co-assimilation of organic acids is favored over a homologous secondary carbon fixation pathway, although both mechanisms may contribute to conserve the amount of Fdred needed during autotrophic growth with H2.


Postmenopausal hormone therapy: an Endocrine Society scientific statement.
Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.


Involvement of cyclic AMP in multiple, excitatory actions of biogenic amines on the cardiac ganglion of the horseshoe crab Limulus polyphemus.
Cyclic AMP appears to be involved in several excitatory actions of amines on neurones of the Limulus cardiac ganglion. Amines selectively increase levels of cardiac ganglion cyclic AMP with a magnitude and time course similar to that observed for amine-induced excitation of cardiac ganglion burst rate. With respect to either the physiological or biochemical effect, the apparent order of potency is octopamine greater than epinephrine approximately dopamine greater than norepinephrine. Elevation of cardiac ganglion cyclic AMP levels by octopamine or dopamine is dose-dependent and is potentiated by the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (IBMX). Several pharmacological agents which influence cyclic nucleotide metabolism, including forskolin, IBMX and 8-substituted cyclic AMP analogues, have amine-like effects on the Limulus cardiac ganglion. These effects include increased burst rate of the isolated cardiac ganglion and decreased burst duration, interburst interval and number of spikes per burst in follower neurones. Forskolin and IBMX increase levels of cardiac ganglion cyclic AMP, and IBMX also increases cyclic GMP levels in this tissue. Amines, forskolin and IBMX have direct effects on follower neurones pharmacologically isolated from pacemaker cell input. Octopamine, forskolin and IBMX depolarize follower neurones, while dopamine hyperpolarizes these cells. Amines, forskolin and IBMX elicit burst-like potentials in follower neurones, and increase the size of evoked, unitary junction potentials recorded in cardiac muscle fibres. These pharmacological and biochemical data suggest that multiple, excitatory effects of biogenic amines on the Limulus cardiac ganglion are mediated by simultaneous increases in cyclic AMP at several loci within this neural network.


Controlled whole body vibration to decrease fall risk and improve health-related quality of life of nursing home residents.
To investigate the effects of whole body vibration in the elderly. Randomized controlled trial. Nursing home. Forty-two elderly volunteers. Six-week vibration intervention plus physical therapy (PT) (n=22) or PT alone (n=20). We assessed gait and body balance using the Tinetti test (maximum scores of 12 for gait, 16 for body balance, 28 for global score), motor capacity using the Timed Up & Go (TUG) test, and health-related quality of life (HRQOL) using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). After 6 weeks, the vibration intervention group improved by a mean +/- standard deviation of 2.4+/-2.3 points on the gait score compared with no score change in the control group ( P <.001). The intervention group improved by 3.5+/-2.1 points on the body balance score compared with a decrease of 0.3+/-1.2 points in the control group ( P <.001). TUG test time decreased by 11.0+/-8.6 seconds in the treated group compared with an increase of 2.6+/-8.8 seconds in the control group ( P <.001). The intervention group had significantly greater improvements from baseline on 8 of 9 items on the SF-36 compared with the control group. Controlled whole body vibration can improve elements of fall risk and HRQOL in elderly patients.


mTOR inhibitor-associated dermatologic and mucosal problems.
Mammalian target of rapamycin inhibitor use is associated with numerous adverse events, including dermatologic and mucosal problems. Awareness of these complications, which clinically manifest across a severity spectrum from minor through severe and may occur at varied time points after initiation of sirolimus therapy, can be useful to clinicians in both managing these events and determining the appropriate intervention(s) for patients. This manuscript examines the dermatologic and mucosal problems associated with mammalian target of rapamycin inhibitor use, reviews the literature, and provides personal experiences regarding the management and treatment of these adverse events.


Thyroid autoimmunity may represent a predisposition for the development of fibromyalgia?
In our previous study, we observed that the presence of autoimmune thyroid disease worsens fibromyalgia (FM) symptoms. The aims of this study are to evaluate whether there is a predisposition for the development of FM in patients with Hashimoto's thyroiditis (HT) with or without subclinical hypothyroidism (SCH) and in patients with SCH alone and what is the weight of antithyroid antibody positivity and SCH on FM comorbidity. Fifty-two patients, 39 affected by HT with or without SCH and 13 by SCH, were matched with 37 patients affected by FM and 25 healthy subjects. Blood samples were collected from all study subjects for the determination of serum TSH, free triiodothyronine, free thyroxine, antithyroperoxidase antibody (TPOAb), antithyroglobulin antibody (TgAb) and non-organ-specific autoantibodies. Clinical assessment of patients and controls included the "Fibromyalgia Impact Questionnaire" (FIQ), while pain severity was evaluated using a visual analogue scale (VAS). Patients and controls were also characterized by the presence of diffuse pain, fatigue, paresthesiae, muscle spasms, non-restful sleep, tension headache and presence of mood disorders. FM comorbidity resulted in twelve HT subjects (31%) and none in SCH patient. In particular, FM comorbidity in HT patients without SCH was 33.3% and in HT patients with SCH was 28.5%. Based on our data, we speculate that maybe there is more than a hypothesis regarding the cause-effect relation between thyroid autoimmunity and the presence of FM, thus suggesting a hypothetical role of thyroid autoimmunity in FM pathogenesis.


Engineered skeletal muscle tissue for soft robotics: fabrication strategies, current applications, and future challenges.
Skeletal muscle is a scalable actuator system used throughout nature from the millimeter to meter length scales and over a wide range of frequencies and force regimes. This adaptability has spurred interest in using engineered skeletal muscle to power soft robotics devices and in biotechnology and medical applications. However, the challenges to doing this are similar to those facing the tissue engineering and regenerative medicine fields; specifically, how do we translate our understanding of myogenesis in vivo to the engineering of muscle constructs in vitro to achieve functional integration with devices. To do this researchers are developing a number of ways to engineer the cellular microenvironment to guide skeletal muscle tissue formation. This includes understanding the role of substrate stiffness and the mechanical environment, engineering the spatial organization of biochemical and physical cues to guide muscle alignment, and developing bioreactors for mechanical and electrical conditioning. Examples of engineered skeletal muscle that can potentially be used in soft robotics include 2D cantilever-based skeletal muscle actuators and 3D skeletal muscle tissues engineered using scaffolds or directed self-organization. Integration into devices has led to basic muscle-powered devices such as grippers and pumps as well as more sophisticated muscle-powered soft robots that walk and swim. Looking forward, current, and future challenges include identifying the best source of muscle precursor cells to expand and differentiate into myotubes, replacing cardiomyocytes with skeletal muscle tissue as the bio-actuator of choice for soft robots, and vascularization and innervation to enable control and nourishment of larger muscle tissue constructs.


Effect of age on the outcome of hospital treated depression.
Depression affects a significant proportion of the expanding elderly population in the UK. Reports of a poorer prognosis for older than for younger adult patients have been challenged by recent papers. The casenotes of 56 adults (mean age 47.8 years) and 54 elderly (mean age 72.9 years) patients with primary depression were assessed one year after receiving hospital treatment. Outcome measures were compared with earlier reported findings and factors possibly influencing outcome were explored. The pattern of outcome in both age groups was broadly similar, thus: adults v. elderly: recovered 44.6% v. 44.4%; relapsed and recovered 23.2% v. 24%; residual symptoms 19.6% v. 13% and chronic depression 7.1% v. 5.5%. In the adults there were two natural deaths and one suicide. In the elderly there were two cases of dementia and five natural deaths, which was double the expected death rate. Predictors of poor outcome were melancholic depression in adults and longer duration of illness at intake and an increasing number of previous episodes of affective disorder in the elderly. The outcome of treated depressive illnesses appears similar in elderly and adult patients. Associated physical ill health did not adversely affect outcome in the elderly group.


Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻₃ output.
Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. The nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled receptor, TGR5, regulate bile acid (BA) homeostasis and inflammation. Therefore, we hypothesized that activation of FXR and/or TGR5 could ameliorate liver injury in Mdr2(-/-) (Abcb4(-/-)) mice, a model of chronic cholangiopathy. Hepatic inflammation, fibrosis, as well as bile secretion and key genes of BA homeostasis were addressed in Mdr2(-/-) mice fed either a chow diet or a diet supplemented with the FXR agonist, INT-747, the TGR5 agonist, INT-777, or the dual FXR/TGR5 agonist, INT-767 (0.03% w/w). Only the dual FXR/TGR5 agonist, INT-767, significantly improved serum liver enzymes, hepatic inflammation, and biliary fibrosis in Mdr2(-/-) mice, whereas INT-747 and INT-777 had no hepatoprotective effects. In line with this, INT-767 significantly induced bile flow and biliary HCO 3- output, as well as gene expression of carbonic anhydrase 14, an important enzyme able to enhance HCO 3- transport, in an Fxr-dependent manner. In addition, INT-767 dramatically reduced bile acid synthesis via the induction of ileal Fgf15 and hepatic Shp gene expression, thus resulting in significantly reduced biliary bile acid output in Mdr2(-/-) mice. This study shows that FXR activation improves liver injury in a mouse model of chronic cholangiopathy by reduction of biliary BA output and promotion of HCO 3--rich bile secretion.


Hamsi scoring in the prediction of unfavorable outcomes from tuberculous meningitis: results of Haydarpasa-II study.
Predicting unfavorable outcome is of paramount importance in clinical decision making. Accordingly, we designed this multinational study, which provided the largest case series of tuberculous meningitis (TBM). 43 centers from 14 countries (Albania, Croatia, Denmark, Egypt, France, Hungary, Iraq, Italy, Macedonia, Romania, Serbia, Slovenia, Syria, Turkey) submitted data of microbiologically confirmed TBM patients hospitalized between 2000 and 2012. Unfavorable outcome was defined as survival with significant sequela or death. In developing our index, binary logistic regression models were constructed via 200 replicates of database by bootstrap resampling methodology. The final model was built according to the selection frequencies of variables. The severity scale included variables with arbitrary scores proportional to predictive powers of terms in the final model. The final model was internally validated by bootstrap resampling. A total of 507 patients' data were submitted among which 165 had unfavorable outcome. Eighty-six patients died while 119 had different neurological sequelae in 79 (16%) patients. The full model included 13 variables. Age, nausea, vomiting, altered consciousness, hydrocephalus, vasculitis, immunosuppression, diabetes mellitus and neurological deficit remained in the final model. Scores 1-3 were assigned to the variables in the severity scale, which included scores of 1-6. The distribution of mortality for the scores 1-6 was 3.4, 8.2, 20.6, 31, 30 and 40.1%, respectively. Altered consciousness, diabetes mellitus, immunosuppression, neurological deficits, hydrocephalus, and vasculitis predicted the unfavorable outcome in the scoring and the cumulative score provided a linear estimation of prognosis.


Impact of environmental temperature on optical power properties of intraocular lenses.
Optical power properties of lenses and materials in general can be influenced by thermal changes of the material and surrounding medium. In the case of an intraocular lens (IOL) implant, the spherical power (SP), cylinder power, (CP), astigmatism, and spherical aberration are the critical fundamental properties that can significantly impact its efficacy. Directly evaluating how changes in temperature can affect these optical properties may show the importance of considering temperature when evaluating IOL optical characteristics. In this paper, we present a quantitative study on evaluating the impact of environmental temperature changes on IOL fundamental optical properties by testing IOL samples with different materials (e.g., hydrophobic and hydrophilic) and designs (e.g., monofocal and toric) to better encompass types of IOLs in conventional use today. The results from this study demonstrate that significant changes are observed as temperatures are changed from room temperature (20°C) to slightly above body temperature (40°C). Findings indicate that evaluating optical properties at arbitrary temperatures could significantly affect the characterization of IOLs that are already near the tolerance thresholds.


A model for plate tectonic evolution of mantle layers.
In plate tectonic theory, lithosphere that descends into the mantle has a largely derivative composition, because it is produced as a refractory residue by partial melting, and cannot be resorbed readily by the parent mantle. We suggest that lithosphere sinks through the asthenosphere, or outer mantle, and accumulates progressively beneath to form an accretionary mesosphere, or inner mantle. According to this model, there is an irreversible physicochemical evolution of the mantle and its layers. We make the key assumption that the rate at which mass has been transferred from the lithosphere to the mesosphere is proportional to the rate of radiogenic heat production. Calculations of mass transfer with time demonstrate that the entire mass of the present mesosphere could have been produced in geologically reasonable times (3 x 10(9) to 4.5 x 10(9) years). The model is consistent with the generation of the continental crust during the last 3 x 1O(9) years and predicts an end to plate tectonic behavior within the next 10(9) years.


Fragile X mental retardation protein is a Zika virus restriction factor that is antagonized by subgenomic flaviviral RNA.
Subgenomic flaviviral RNA (sfRNA) accumulates during infection due to incomplete degradation of viral genomes and interacts with cellular proteins to promote infection. Here we identify host proteins that bind the Zika virus (ZIKV) sfRNA. We identified fragile X mental retardation protein (FMRP) as a ZIKV sfRNA-binding protein and confirmed this interaction in cultured cells and mouse testes. Depletion of FMRP elevated viral translation and enhanced ZIKV infection, indicating that FMRP is a ZIKV restriction factor. We further observed that an attenuated ZIKV strain compromised for sfRNA production was disproportionately stimulated by FMRP knockdown, suggesting that ZIKV sfRNA antagonizes FMRP activity. Importantly, ZIKV infection and expression of ZIKV sfRNA upregulated endogenous FMRP target genes in cell culture and ZIKV-infected mice. Together, our observations identify FMRP as a ZIKV restriction factor whose activity is antagonized by the sfRNA. Interaction between ZIKV and FMRP has significant implications for the pathogenesis of ZIKV infections.


Modeling crowd dynamics through coarse-grained data analysis.
Understanding and predicting the collective behaviour of crowds is essential to improve the efficiency of pedestrian flows in urban areas and minimize the risks of accidents at mass events. We advocate for the development of crowd traffic management systems, whereby observations of crowds can be coupled to fast and reliable models to produce rapid predictions of the crowd movement and eventually help crowd managers choose between tailored optimization strategies. Here, we propose a Bi-directional Macroscopic (BM) model as the core of such a system. Its key input is the fundamental diagram for bi-directional flows, i.e. the relation between the pedestrian fluxes and densities. We design and run a laboratory experiments involving a total of 119 participants walking in opposite directions in a circular corridor and show that the model is able to accurately capture the experimental data in a typical crowd forecasting situation. Finally, we propose a simple segregation strategy for enhancing the traffic efficiency, and use the BM model to determine the conditions under which this strategy would be beneficial. The BM model, therefore, could serve as a building block to develop on the fly prediction of crowd movements and help deploying real-time crowd optimization strategies.


Benchmarking Veterans Affairs Medical Centers in the delivery of preventive health services: comparison of methods.
To identify consistent provision of clinical preventive services, we sought to benchmark all acute care Veterans Affairs Medical Centers (VAMCs) against each other nationally on the basis of multiple evidence-based, performance measures to identify facilities performing consistently higher and lower than expected. The 1998 Veterans Health Survey assessed the self-reported delivery of evidence-based clinical preventive services in a stratified national sample of 450 ambulatory care patients seen at each VAMC. Proportions appropriately receiving each service within the recommended time interval were calculated for 138 VAMCs. Percentile ranks for each outcome were assigned. Two approaches were used for benchmarking performance. First, a scaled score for each facility was calculated across the set of 12 measures. Second, facilities were ranked based on the sum of the percentile ranks over a range of specific high cutoffs (eg, 70-80%) and above a range of lower cutoffs (eg, 40-50%). Ranking was validated by comparing with deciles of ranks on chart audit (External Peer Review Program, EPRP) data using Kendall's tau-b and chi2 quality-of-fit test. Differences between consistently high adherence (CHA) and low adherence (CLA) facilities were compared using the Wilcoxon rank sum test on 14 VHS and 11 EPRP outcomes. Data from 39,939 patients (67% response rate) were examined. In combination, cutoffs of greater than 50th percentile and greater than 75th percentile rank yielded 12 of 14 VHS and 6 of 11 EPRP measures different between CHA and CLA facilities. The scaled-score approach resulted in 20 CHA and 14 CLA facilities. The sum of outcomes ranked above 50th percentile and over 75th percentile for CHA facilities (n = 17) was 15 or more. The sum of outcomes ranked above the same cutoffs for CLA facilities (n = 16) was 3 or less. EPRP and 1998 VHS data demonstrated that the survey measures and benchmarking approaches were both reliable and valid. Both approaches resulted in multiple differences between CHA and CLA facilities; differences were greater using the percentile rank approach. The VA has successfully encouraged adoption of evidence-based clinical preventive services throughout its health care system. However, facilities show wide variation in their levels of delivery and can be distinguished on the basis of their consistently high or low levels of adherence. Examining service delivery across multiple performance indicators allows identification of opportunities to improve clinical practice guideline implementation and the delivery of preventive services. This approach identifies model institutions where focused investigation of factors associated with consistent performance may be particularly fruitful.


Narrow line width operation of a 980 nm gain guided tapered diode laser bar.
We demonstrate two different schemes for the spectral narrowing of a 12 emitter 980 nm gain guided tapered diode laser bar. In the first scheme, a reflective grating has been used in a Littman Metcalf configuration and the wavelength of the laser emission could be narrowed down from more than 5.5 nm in the free running mode to 0.04 nm (FWHM) at an operating current of 30 A with an output power of 8 W. The spectrum was found to be tunable within a range of 16 nm. In the second scheme, a volume Bragg grating has been used to narrow the wavelength of the laser bar from over 5 nm to less than 0.2 nm with an output of 5 W at 20 A. To our knowledge, this is the first time spectral narrowing has been performed on a gain guided tapered diode laser bar. In the Littman Metcalf configuration, the spectral brightness has been increased by 86 times and in the volume Bragg grating cavity the spectral brightness has been improved over 18 times when compared to the free running operation. These schemes could be also extended for other wavelengths of interest in the future.


Effect of chair design on feed-forward postural control in sitting.
The objective of this study was to determine if a forward-tilted seat and the resultant semi-kneeling body position associated with sitting on the Balans Multi Chair (BMC) affect postural control in sitting. Nine healthy subjects were seated on either the BMC or a regular (REG) chair with their arms extended. They were instructed to induce self-initiated body perturbations in four different directions by exerting brief pulses of force against a stationary frame positioned in front of them. Electromyographic (EMG) activities of trunk and leg muscles were recorded before and during the perturbations. The results show that sitting on both types of chairs was associated with anticipatory activation of trunk and upper leg muscles. In contrast, anticipatory activation of distal muscles was observed while sitting only on the REG chair and was absent while sitting on the BMC. The outcome of the study suggests that although the forward-tilting seat and semi-kneeling body position might help in preserving a normal lordosis, it is not associated with anticipatory activation of lower leg muscles, which might reduce the ability of an individual to counteract self-initiated body perturbations. These findings stress the important role of chair designs in the control of sitting posture.


Isothermal relaxation kinetics for the reduction and oxidation of SrFeO3 based perovskites.
The perovskite oxide SrFeO3 has favourable redox properties for oxygen exchange applications, including oxygen separation and oxygen production chemical looping cycles. For such applications, lower temperature operation can improve the energy demand and feasibility of the process, but can also lead to kinetic limitations. Here we investigate the oxidation and reduction reaction kinetics of SrFeO3 in the temperature range 450-750 K. Isothermal relaxation techniques are used to observe the reaction rates across this temperature range, using a thermogravimetric analysis system. Experimental data are analysed according to an isoconversional method and fit with a simple power law model to extract activation energies. The apparent activation energy of oxidation and reduction was found to be 92 ± 16 and 144 ± 17 kJ mol-1 respectively. Comparison of oxidation and reduction kinetics together with considerations of particle size indicate that the oxidation reaction rate may be limited by diffusion in the bulk, while the reduction reaction rate is limited by the surface reaction. Furthermore, we also investigated the mixed perovskite Sr0.93Ca0.07Fe0.9Co0.1O3, which exhibited a 4-fold increase in the oxidation rate.


The Role of Emotional Regulation and Affective Balance on Health Perception in Cardiovascular Disease Patients According to Sex Differences.
One of the challenges of aging is the increase of people with chronic diseases, such as cardiovascular disease (CVD). Men and women experience the disease differently. Therefore, it has an impact on how CVD is treated and its outcomes. This research analyzed the relationship between psychosocial variables and health promotion among cardiovascular patients, paying special attention to sex differences. A longitudinal study with cardiovascular patients (747 in phase 1 (122 women) and 586 in phase 2 (83 women)) was carried out. Participants were evaluated based on their sociodemographic characteristics, affective balance, regulatory negative affect self-efficacy, stress and anxiety regulation strategies, and perceived global health. Results showed that men presented significantly higher scores in positive affect, affective balance, and self-efficacy to regulate negative emotions, while women presented significantly higher scores in negative affect and the use of passive strategies to cope with stressful situations. Regression analyses showed that all psychological variables studied in phase 1 were significant predictors of health perception in phase 2. According to the results, it is necessary to include strategies to improve cardiovascular health through education and emotional regulation, with a gender focus.


Ultraflexible electrode arrays for months-long high-density electrophysiological mapping of thousands of neurons in rodents.
Penetrating flexible electrode arrays can simultaneously record thousands of individual neurons in the brains of live animals. However, it has been challenging to spatially map and longitudinally monitor the dynamics of large three-dimensional neural networks. Here we show that optimized ultraflexible electrode arrays distributed across multiple cortical regions in head-fixed mice and in freely moving rats allow for months-long stable electrophysiological recording of several thousand neurons at densities of about 1,000 neural units per cubic millimetre. The chronic recordings enhanced decoding accuracy during optogenetic stimulation and enabled the detection of strongly coupled neuron pairs at the million-pair and millisecond scales, and thus the inference of patterns of directional information flow. Longitudinal and volumetric measurements of neural couplings may facilitate the study of large-scale neural circuits.


Tape-stripping as a method for measuring dermal exposure to resin acids during wood pellet production.
The purpose of this study was to develop a sensitive and specific method for quantifying dermal exposure to the resin acids 7-oxodehydroabietic acid (7-OXO), dehydroabietic acid (DHAA), abietic acid (AA), and pimaric acid (PA). In addition the method was evaluated in occupational settings during production of wood pellets. Tape-strips were spiked with the substances to evaluate the recovery of the acids from the tape. The removal efficiency of the tape was assessed by tape-stripping a specified area on a glass plate spiked with resin acids. The recovery of the acids from human skin in vivo was evaluated by applying acids in methanol onto the skin of volunteers. Occupational dermal exposure to the resin acids was assessed by tape-stripping the skin of workers involved in the production of wood pellets. The resin acids were analyzed by liquid chromatography mass spectrometry (LC-MS). The limit of detection was 15 pg (7-OXO), 150 pg (DHAA), 285 pg (AA) and 471 pg (PA) per injection. The recovery from spiked tapes was in general 100%. The removal efficiency of the tape was 48-101%. Recovery tests from human skin in vivo showed a mean recovery of 27%. Quantifiable amounts of resin acids were observed on four different skin areas with an increase in exposure during a work shift. This study shows that occupational dermal exposure to resin acids can be assessed by tape-stripping and quantified by LC-MS.


TESTIN suppresses tumor growth and invasion via manipulating cell cycle progression in endometrial carcinoma.
The TESTIN gene was demonstrated to be a tumor suppressor in prostate and breast cancer through inhibiting tumor growth and invasion. Herein, we aimed to investigate the detailed functions of TESTIN in the highly sexual hormone (estrogen)-dependent malignancy, endometrial carcinoma. TESTIN mRNA and protein expression were measured by qRT-PCR, Western blot and immunohistochemistry. Upregulation of TESTIN was achieved by transfecting the pcDNA3.1-TESTIN plasmids into AN3CA cells. Knockdown of TESTIN was achieved by transfecting the shRNA-TESTIN into Ishikawa cells. MTT assay, colony formation assay, and Transwell assay were used to investigate the effects of TESTIN on cellular proliferation and invasion. The apoptotic status and cell cycle were analyzed using flow cytometry. MMP2 secretion was determined by ELISA assay. The xenograft assay was used to investigate the functions of TESTIN in nude mice. Compared to the non-malignant adjacent endometrium, 54% of tumor samples presented downregulation of TESTIN (P<0.001). Loss of TESTIN protein was correlated with advanced tumor stage (P=0.047), high grade (P=0.034), and lymphatic vascular space invasion (P=0.036). In vitro, overexpression of TESTIN suppressed cell proliferation, induced dramatic G1 arrest, and inhibited tumor invasion through blocking the secretion of MMP2. Loss of TESTIN accelerated cellular proliferation, promoted cell cycle progression, and enhanced tumor invasion by increasing the secretion of MMP2. Consistently, TESTIN could significantly delay the growth of xenografts in nude mice. TESTIN was commonly downregulated in human endometrial carcinoma and was associated with poor prognostic markers. Moreover, TESTIN significantly inhibited tumor growth and invasion via arresting cell cycle in in vitro and in vivo experiments. Therefore, we propose that TESTIN might be a prognostic marker and therapeutic target for endometrial carcinoma.


The representation of audiovisual regularities in the human brain.
Neural representation of auditory regularities can be probed using the MMN, a component of ERPs generated in the auditory cortex by any violation of that regularity. Although several studies have shown that visual information can influence or even trigger an MMN by altering an acoustic regularity, it is not known whether audiovisual regularities are encoded in the auditory representation supporting MMN generation. We compared the MMNs elicited by the auditory violation of (a) an auditory regularity (a succession of identical standard sounds), (b) an audiovisual regularity (a succession of identical audiovisual stimuli), and (c) an auditory regularity accompanied by variable visual stimuli. In all three conditions, the physical difference between the standard and the deviant sound was identical. We found that the MMN triggered by the same auditory deviance was larger for audiovisual regularities than for auditory-only regularities or for auditory regularities paired with variable visual stimuli, suggesting that the visual regularity influenced the representation of the auditory regularity. This result provides evidence for the encoding of audiovisual regularities in the human brain.


Impact of McKenzie Method Therapy Enriched by Muscular Energy Techniques on Subjective and Objective Parameters Related to Spine Function in Patients with Chronic Low Back Pain.
The high incidence and inconsistencies in diagnostic and therapeutic process of low back pain (LBP) stimulate the continuing search for more efficient treatment modalities. Integration of the information obtained with various therapeutic methods and a holistic approach to the patient seem to be associated with positive outcomes. The aim of this study was to analyze the efficacy of combined treatment with McKenzie method and Muscle Energy Technique (MET), and to compare it with the outcomes of treatment with McKenzie method or standard physiotherapy in specific chronic lumbar pain. The study included 60 men and women with LBP (mean age 44 years). The patients were randomly assigned to 1 of 3 therapeutic groups, which were further treated with: 1) McKenzie method and MET, 2) McKenzie method alone, or 3) standard physiotherapy for 10 days. The extent of spinal movements (electrogoniometry), level of experienced pain (Visual Analogue Scale and Revised Oswestry Pain Questionnaire), and structure of the spinal discs (MRI) were examined prior to the intervention, immediately thereafter, and 3 months after the intervention. McKenzie method enriched with MET had the best therapeutic outcomes. The mobility of cervical, thoracic, and lumbar spine normalized at levels corresponding to 87.1%, 66.7%, and 95% of respective average normative values. Implementation of McKenzie method, both alone and combined with MET, was associated with a significant decrease in Oswestry Disability Index, significant alleviation of pain (VAS), and significantly reduced size of spinal disc herniation. The combined method can be effectively used in the treatment of chronic LBP.


Sports injuries: An important cause of morbidity in urban youth. District of Columbia Child/Adolescent Injury Research Network.
Sports injuries account for substantial morbidity and medical cost. To direct intervention, a population-based study of the causes and types of sports injuries was undertaken. An injury surveillance system was established at all trauma center hospitals that treat residents 10 to 19 years old in the District of Columbia and the Chief Medical Examiner's Office. Medical record abstractions were completed for those seen in an emergency department, admitted to the hospital, or who died from injury June 1996 through June 1998. Seventeen percent (n = 2563) of all injuries occurred while participating in 1 of 6 sports (baseball/softball, basketball, biking, football, skating, and soccer) resulting in an event-based injury rate of 25.0 per 1000 adolescents or 25.0/1000 population year. Rates were higher in males for all sports. The most common mechanisms were falls (E880-888) and being struck by or against objects (E916-918). Hospitalization was required in 2% of visits and there were no deaths. Of those requiring hospitalization, 51% involved other persons, 12% were equipment-related, and 8% involved poor field/surface conditions. Of all baseball injuries, 55% involved ball or bat impact often of the head. Basketball injuries included several injuries from striking against the basketball pole or rim or being struck by a falling pole or backboard. Biking injuries requiring admission included 2 straddle injuries onto the bike center bar and collision with motor vehicles. Of all football injuries, 48 (7%) involved being struck by an opponent's helmet and 63 (9%) involved inappropriate field conditions including falls on or against concrete, glass, or fixed objects. In soccer there were 4 goal post injuries and a large proportion of intracranial injuries. There were 51 probable or clear assaults during sports and an additional 30 to 41 injuries from baseball bat assaults. Many sports including noncontact sports involved injuries of the head suggesting the need for improved head protection. Injuries involving collisions with others and assaults point to the need for supervision and enforcement of safety rules. The 16% of sports injury visits and 20% of hospitalizations related to equipment and environmental factors suggest that at least this proportion of injury may be amenable to preventive strategies. Design change may be warranted for prevention of equipment-related injuries. The many injuries involving inappropriate sports settings suggest the need for and use of available and safe locations for sports.


The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD): design of a multi-site, head-to-head study of three rapid tests to detect extensively drug-resistant tuberculosis.
Drug-resistant tuberculosis (DR-TB) remains a threat to global public health, owing to the complexity and delay of diagnosis and treatment. The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD) was formed to develop and evaluate assays designed to rapidly detect DR-TB, so that appropriate treatment might begin more quickly. This paper describes the methodology employed in a prospective cohort study for head-to-head assessment of three different rapid diagnostic tools. Subjects at risk of DR-TB were enrolled from three countries. Data were gathered from a combination of patient interviews, chart reviews, and laboratory testing from each site's reference laboratory. The primary outcome of interest was reduction in time from specimen arrival in the laboratory to results of rapid drug susceptibility tests, as compared with current standard mycobacterial growth indicator tube (MGIT) drug susceptibility tests. Successful implementation of the trial in diverse multinational populations is explained, in addition to challenges encountered and recommendations for future studies with similar aims or populations. The GCDD study was a head-to-head study of multiple rapid diagnostic assays aimed at improving accuracy and precision of diagnostics and reducing overall time to detection of DR-TB. By conducting a large prospective study, which captured epidemiological, clinical, and biological data, we have produced a high-quality unique dataset, which will be beneficial for analyzing study aims as well as answering future DR-TB research questions. Reduction in detection time for XDR-TB would be a major public health success as it would allow for improved treatment and more successful patient outcomes. Executing successful trials is critical in assessment of these reductions in highly variable populations. ClinicalTrials.gov NCT02170441.


Retail redlining in New York City: racialized access to day-to-day retail resources.
Racial residential segregation is associated with health inequalities in the USA, and one of the primary mechanisms is through influencing features of the neighborhood physical environment. To better understand how Black residential segregation might contribute to health risk, we examined retail redlining; the inequitable distribution of retail resources across racially distinct areas. A combination of visual and analytic methods was used to investigate whether predominantly Black census block groups in New York City had poor access to retail stores important for health. After controlling for retail demand, median household income, population density, and subway ridership, percent Black was associated with longer travel distances to various retail industries. Our findings suggest that Black neighborhoods in New York City face retail redlining. Future research is needed to determine how retail redlining may perpetuate health disparities and socioeconomic disadvantage.


Chemoenzymatic Synthesis of O-Mannose Glycans Containing Sulfated or Nonsulfated HNK-1 Epitope.
The human natural killer-1 (HNK-1) epitope is a unique sulfated trisaccharide sequence presented on O- and N-glycans of various glycoproteins and on glycolipids. It is overexpressed in the nervous system and plays crucial roles in nerve regeneration, synaptic plasticity, and neuronal diseases. However, the investigation of functional roles of HNK-1 in a more complex glycan context at the molecular level remains a big challenge due to lack of access to related structurally well-defined complex glycans. Herein, we describe a highly efficient chemoenzymatic approach for the first collective synthesis of HNK-1-bearing O-mannose glycans with different branching patterns, and for their nonsulfated counterparts. The successful strategy relies on both chemical glycosylation of a trisaccharide lactone donor for the introduction of sulfated HNK-1 branch and substrate promiscuities of bacterial glycosyltransferases that can tolerate sulfated substrates for enzymatic diversification. Glycan microarray analysis with the resulting complex synthetic glycans demonstrated their recognition by two HNK-1-specific antibodies including anti-HNK-1/N-CAM (CD57) and Cat-315, which provided further evidence for the recognition epitopes of these antibodies and the essential roles of the sulfate group for HNK-1 glycan-antibody recognition.


Adherence to Pre-Exposure Prophylaxis for HIV Prevention in a Clinical Setting.
The HIV epidemic in the United States (US) disproportionately affects gay, bisexual, and other men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) using co-formulated tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has demonstrated high efficacy in reducing HIV incidence among MSM. However, low adherence was reported in major efficacy trials and may present a substantial barrier to successful PrEP implementation. Rates of adherence to PrEP in "real-world" clinical settings in the US remain largely unknown. We reviewed demographic and clinical data for the first 50 patients to enroll in a clinical PrEP program in Providence, Rhode Island. We analyzed self-reported drug adherence as well as drug concentrations in dried blood spots (DBS) from patients who attended either a three- or six-month follow-up appointment. We further assessed drug concentrations and the resistance profile of a single patient who seroconverted while taking PrEP. Of the first 50 patients to be prescribed PrEP, 62% attended a follow-up appointment at three months and 38% at six months. Of those who attended an appointment at either time point (70%, n = 35), 92% and 95% reported taking ±4 doses/week at three and six months, respectively. Drug concentrations were performed on a random sample of 20 of the 35 patients who attended a follow-up appointment. TDF levels consistent with ±4 doses/week were found in 90% of these patients. There was a significant correlation between self-reported adherence and drug concentrations (r = 0.49, p = 0.02). One patient who had been prescribed PrEP seroconverted at his three-month follow-up visit. The patient's drug concentrations were consistent with daily dosing. Population sequencing and ultrasensitive allele-specific PCR detected the M184V mutation, but no other TDF- or FTC-associated mutations, including those present as minor variants. In this clinical PrEP program, adherence was high, and self-reported drug adherence accurately reflected drug concentrations as measured by DBS.


Habitat fragmentation and effects of herbivore (howler monkey) abundances on bird species richness.
Habitat fragmentation can alter herbivore abundances, potentially causing changes in the plant community that can propagate through the food web and eventually influence other important taxonomic groups such as birds. Here we test the relationship between the density of red howler monkeys (Alouatta seniculus) and bird species richness on a large set of recently isolated land-bridge islands in Lago Guri, Venezuela (n = 29 islands). Several of these islands host relict populations of howler monkeys at densities up to more than 30 times greater than those on the mainland. These "hyperabundant" herbivores previously have been shown to have a strong positive influence on aboveground plant productivity. We predicted that this should lead to a positive, indirect effect of howler monkey density on bird species richness. After accounting for passive sampling (the tendency for species richness to be positively associated with island area, regardless of differences in habitat quality) we found a significant positive correlation between howler monkey density and bird species richness. A path analysis incorporating data on tree growth rates from a subset of islands (n = 9) supported the hypothesis that the effect of howler monkeys on the resident bird communities is indirect and is mediated through changes in plant productivity and habitat quality. These results highlight the potential for disparate taxonomic groups to be related through indirect interactions and trophic cascades.


Lessons from the meiotic recombination landscape of the ZMM deficient budding yeast Lachancea waltii.
Meiotic recombination is a driving force for genome evolution, deeply characterized in a few model species, notably in the budding yeast Saccharomyces cerevisiae. Interestingly, Zip2, Zip3, Zip4, Spo16, Msh4, and Msh5, members of the so-called ZMM pathway that implements the interfering meiotic crossover pathway in S. cerevisiae, have been lost in Lachancea yeast species after the divergence of Lachancea kluyveri from the rest of the clade. In this context, after investigating meiosis in L. kluyveri, we determined the meiotic recombination landscape of Lachancea waltii. Attempts to generate diploid strains with fully hybrid genomes invariably resulted in strains with frequent whole-chromosome aneuploidy and multiple extended regions of loss of heterozygosity (LOH), which mechanistic origin is so far unclear. Despite the lack of multiple ZMM pro-crossover factors in L. waltii, numbers of crossovers and noncrossovers per meiosis were higher than in L. kluyveri but lower than in S. cerevisiae, for comparable genome sizes. Similar to L. kluyveri but opposite to S. cerevisiae, L. waltii exhibits an elevated frequency of zero-crossover bivalents. Lengths of gene conversion tracts for both crossovers and non-crossovers in L. waltii were comparable to those observed in S. cerevisiae and shorter than in L. kluyveri despite the lack of Mlh2, a factor limiting conversion tract size in S. cerevisiae. L. waltii recombination hotspots were not shared with either S. cerevisiae or L. kluyveri, showing that meiotic recombination hotspots can evolve at a rather limited evolutionary scale within budding yeasts. Finally, L. waltii crossover interference was reduced relative to S. cerevisiae, with interference being detected only in the 25 kb distance range. Detection of positive inference only at short distance scales in the absence of multiple ZMM factors required for interference-sensitive crossovers in other systems likely reflects interference between early recombination precursors such as DSBs.


Feeling hindered by health problems and functional capacity at 60 years and above.
It is common to use activities of daily living (ADL) rating scales to identify the impact of health problems such as diseases, impaired eyesight or hearing on daily life. However, for various reasons people with health problems might feel hindered in daily life before limitations in ability to perform ADL have occurred. In addition, there is sparse knowledge of what makes people feel hindered by health problems in relation to their ADL capacity. The aim was to investigate feeling hindered by health problems among 1297 people aged 60-89 living at home in relation to ADL capacity, health problems, life satisfaction, self-esteem, and social and financial resources, using a self-reported questionnaire, including questions from Older Americans' Resources and Services schedule (OARS), Rosenberg's self-esteem and Life Satisfaction Index Z (LSIZ). People feeling greatly hindered by health problems rarely had anyone who could help when they needed support, had lower life satisfaction and self-esteem than those not feeling hindered. Feeling hindered by health problems appeared to take on a different meaning depending on ADL capacity, knowledge that seems essential to include when accomplishing health promotion and rehabilitation interventions, especially at the early stages of reduced ADL capacity.


Role of income mobility for the measurement of inequality in life expectancy.
This work proposes a method to compute the income gradient in period life expectancy that accounts for income mobility. Using income and mortality records of the Danish population over the period 1980-2013, we validate the method and provide estimates of the income gradient. The period life expectancy of individuals at a certain age, and belonging to a certain income class, is normally computed by using the mortality of older cohorts in the same income class. This approach does not take into account that a substantial fraction of the population moves away from their original income class, which leads to an upward bias in the estimation of the income gradient in life expectancy. For 40-y-olds in the bottom 5% of the income distribution, the risk of dying before age 60 is overestimated by 25%. For the top 5% income class, the risk of dying is underestimated by 20%. By incorporating a classic approach from the social mobility literature, we provide a method that predicts income mobility and future mortality simultaneously. With this method, the association between income and life expectancy is lower throughout the income distribution. Without accounting for income mobility, the estimated difference in life expectancy between persons in percentiles 20 and 80 in the income distribution is 4.6 y for males and 4.1 y for females, while it is only half as big when accounting for mobility. The estimated rise in life-expectancy inequality over time is also halved when accounting for income mobility.


The bronchoscopic interventions for chronic obstructive pulmonary disease according to different phenotypes.
Bronchoscopic interventions are valuable adjuncts to the pharmacologic therapy for chronic obstructive pulmonary disease (COPD). But different phenotypes of COPD patients showed different clinical responses to the same or similar therapy. The optimal selection of bronchoscopic interventions for COPD patients also needs to be based on the phenotypes. According to the different phenotypes, novel interventional pulmonology techniques which were used for COPD treatments in daily clinical practice or clinical trials have been described extensively throughout our current review.


Expression of Vasohibin-1 in Human Carotid Atherosclerotic Plaque.
In patients with carotid plaque, intraplaque hemorrhage arising from ruptured neovascular vessels within the neointima is an important cause of stroke. The expression of Vasohibin-1 (VASH1), a negative feedback regulator of angiogenesis, occurs in the microvessel endothelial cells of various solid tumors and the arterial wall. However, the roles of VASH1 in the pathogenesis of atherosclerotic diseases remain unclear. The present study aimed to clarify the relevance of the VASH1 expression and plaque instability in human carotid plaques. We used quantitative real-time PCR and immunostaining to examine 12 atheromatous plaque specimens obtained via carotid endarterectomy. The distal areas of specimens lacking macroscopic atherosclerotic lesions served as controls. Compared with that observed in the controls, the VASH1 gene expression increased significantly in the atheromatous plaque (p=0.018). Moreover, the VASH1 mRNA levels correlated positively with those of VEGFA, CD31 and VCAM1 (r=0.788, p=0.004; r=0.99, p < 0.001; r=0.94, p < 0.001, respectively). Finally, the immunohistochemical analyses revealed the VASH1 expression in the neointimal microvessel endothelial cells of carotid plaque. The VASH1 expression levels in atheroma reflect both enhanced neovascularization and the inflammatory burden. Therefore, the VASH1 level may be a novel biomarker for evaluating plaque instability in patients with carotid arteriosclerosis and predicting ischemic stroke.


A novel polyamine acyltransferase responsible for the accumulation of spermidine conjugates in Arabidopsis seed.
Hydroxycinnamic acid amides are a class of secondary metabolites distributed widely in plants. We have identified two sinapoyl spermidine derivatives, N-((4'-O-glycosyl)-sinapoyl),N'-sinapoylspermidine and N,N'-disinapoylspermidine, which comprise the two major polyamine conjugates that accumulate in Arabidopsis thaliana seed. Using metabolic profiling of knockout mutants to elucidate the functions of members of the BAHD acyltransferase family in Arabidopsis, we have also identified two genes encoding spermidine disinapoyl transferase (SDT) and spermidine dicoumaroyl transferase (SCT) activities. At2g23510, which is expressed mainly in seeds, encodes a spermidine sinapoyl CoA acyltransferase (SDT) that is required for the production of disinapoyl spermidine and its glucoside in Arabidopsis seed. The structurally related BAHD enzyme encoded by At2g25150 is expressed specifically in roots and has spermidine coumaroyl CoA acyltransferase (SCT) activity both in vitro and in vivo.


KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer.
Aberrant activation of the Wnt/β-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations that activate the Wnt signaling pathway in many other cancers are rarely observed in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be identified. Here, it is demonstrated that KIF3a, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3a is upregulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, tumor-node-metastasis stage, and metastatic status of prostate cancer. Moreover, exogenous expression of KIF3a promoted cell growth in the benign prostate cells, whereas silencing KIF3a in cancer cells decreased cell proliferation, anchorage-independent cell growth, and cell migration/invasion. Mechanistically, KIF3a increases CK1-dependent DVL2 phosphorylation and β-catenin activation in prostate cancer cells, leading to transactivation of the Wnt-signaling target genes such as cyclin D1, HEF1, and MMP9. These findings support the notion that upregulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a-DVL2-β-catenin axis. Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated.


Mouse bronchiolar cell carcinogenesis. Histologic characterization and expression of Clara cell antigen in lesions induced by N-nitrosobis-(2-chloroethyl) ureas.
Female Swiss mice (Cr:NIH(S)) developed bronchiolar cell hyperplasia, dysplasia, metaplasia, and various morphologic types of bronchiolar cell tumors after topical (skin) application of N-nitroso-methyl-bis-chloroethylurea (NMBCU) or N-nitroso-tris-chloroethylurea (NTCU). These compounds are the first found to induce systemically bronchiolar cell tumors in mice in high incidence. Twice a week, with a 3-day interval, a 25-microliter drop of 0.04 mol/l (molar) NMBCU or NTCU in acetone was applied to the shaved interscapular integument for a maximum of 35 to 40 weeks. The earliest lung neoplasms were seen in mice that died after 23 weeks of treatment and affected 11 of 19 with NMBCU and 14 of 19 with NTCU treatment. Tumor growth pattern was nodular or the neoplastic tissue was frequently disseminated throughout the parenchyma, starting from multicentric peribronchiolar foci. The most common tumor types were squamous cell carcinomas and adenosquamous carcinomas, followed by adenocarcinomas with or without secretory cells, and a single ciliated-cell tumor. Histochemical and immunohistochemical studies were carried out on paraffin-embedded lungs using the avidin-biotin immunoperoxidase complex procedure and antisera against keratin, Clara cell antigen, surfactant apoprotein, neuron-specific enolase, bombesin, and chromogranin A. In several mice from both groups, hyperplasias and tumors were composed of cells expressing Clara cell antigen. No tumor cells were found expressing alveolar type II or neuroendocrine cell markers. It appeared that bronchiolar cells, in particular Clara cells, had migrated from terminal bronchioles or invaded bronchiolar walls to extend into the alveolar parenchyma. Squamous cell metaplasia with keratin expression was seen within airways or associated with glandular tumors, especially at the periphery. A unique cell type, with large eosinophilic globules and associated eosinophilic crystals, was seen lining airways or forming hyperplastic and neoplastic lesions. N-nitroso-methyl-bis-chloroethylurea- and NTCU-induced mouse bronchiolar cell alterations could be an interesting new model to study mechanisms of bronchiolar cell differentiation and tumor formation.


Physiological adaptations involved in alkane assimilation at a low temperature by Rhodococcus sp. strain Q15.
We examined physiological adaptations which allow the psychrotroph Rhodococcus sp. strain Q15 to assimilate alkanes at a low temperature (alkanes are contaminants which are generally insoluble and/or solid at low temperatures). During growth at 5 degrees C on hexadecane or diesel fuel, strain Q15 produced a cell surface-associated biosurfactant(s) and, compared to glucose-acetate-grown cells, exhibited increased cell surface hydrophobicity. A transmission electron microscopy examination of strain Q15 grown at 5 degrees C revealed the presence of intracellular electron-transparent inclusions and flocs of cells connected by an extracellular polymeric substance (EPS) when cells were grown on a hydrocarbon and morphological differences between the EPS of glucose-acetate-grown and diesel fuel-grown cells. A lectin binding analysis performed by using confocal scanning laser microscopy (CSLM) showed that the EPS contained a complex mixture of glycoconjugates, depending on both the growth temperature and the carbon source. Two glycoconjugates [beta-D-Gal-(1-3)-D-GlcNAc and alpha-L-fucose] were detected only on the surfaces of cells grown on diesel fuel at 5 degrees C. Using scanning electron microscopy, we observed strain Q15 cells on the surfaces of octacosane crystals, and using CSLM, we observed strain Q15 cells covering the surfaces of diesel fuel microdroplets; these findings indicate that this organism assimilates both solid and liquid alkane substrates at a low temperature by adhering to the alkane phase. Membrane fatty acid analysis demonstrated that strain Q15 adapted to growth at a low temperature by decreasing the degree of saturation of membrane lipid fatty acids, but it did so to a lesser extent when it was grown on hydrocarbons at 5 degrees C; these findings suggest that strain Q15 modulates membrane fluidity in response to the counteracting influences of low temperature and hydrocarbon toxicity.


An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I.
The human immunodeficiency virus type 1 (HIV-1) accessory protein Nef directs virus escape from immune surveillance by subverting host cell intracellular signaling and membrane traffic to down-regulate cell-surface major histocompatibility complex class I (MHC-I). The interaction of Nef with the sorting proteins PACS-1 and PACS-2 mediates key signaling and trafficking steps required for Nef-mediated MHC-I down-regulation. Little is known, however, about the molecular basis underlying the Nef-PACS interaction. Here we identify the sites on Nef and the PACS proteins required for their interaction and describe the consequences of disrupting this interaction for Nef action. A previously unidentified cargo subsite on PACS-1 and PACS-2 interacted with a bipartite site on Nef formed by the EEEE(65) acidic cluster on the N-terminal domain and W(113) in the core domain. Mutation of these sites prevented the interaction between Nef and the PACS proteins on Rab5 (PACS-2 and PACS-1)- or Rab7 (PACS-1)-positive endosomes as determined by bimolecular fluorescence complementation and caused a Nef mutant defective in PACS binding to localize to distorted endosomal compartments. Consequently, disruption of the Nef-PACS interaction repressed Nef-induced MHC-I down-regulation in peripheral blood mononuclear cells. Our results provide insight into the molecular basis of Nef action and suggest new strategies to combat HIV-1.


Diego Rivera, The History of Medicine in Mexico: Peopled Demand for Better Health, mural in 1953 still current.
Although public health and social medicine have a long history in Latin America going back to Co lonial times, their relevance has ebbed and flowed as a result of the development of a variety of social and political movements. The Mexican Revolution accelerated implementation of public health po licies in Mexico and resulted in the creation of the Mexican Institute of Social Security to serve the health and social security needs of the country's population. Construction of the Hospital La Raza and its embellishment by the mural paintings of Diego Rivera and David Alfaro Siqueiros correspon ded to the heyday of public health ideas in Mexico. This is clearly reflected in Rivera's mural painting from 1953, The History of Medicine in Mexico: People's Demand for Better Health. The left side of the painting, representing the history of modern medicine in Mexico, exemplifies the tensions between individuals and social groups demanding the fruits of modern medicine and public health, and en trenched bureaucracy and private interests resisting their demands. Rivera's artistry illustrates this tension by depicting urban social groups and a family with a pregnant mother and children reques ting medical attention on one side of the main panel, facing condescending physicians, bureaucrats and upper society gentlemen and ladies on the other side. The importance of social movements to the development of public health policies illustrated by Rivera in 1953 continues to be relevant in Latin America today where increasing millions still lack the benefits of health care and social security.


World's First Baby Born Through Natural Insemination by Father With Total Phalloplasty Reconstruction.
Techniques for neophallus reconstruction have become increasingly refined, fulfilling more criteria for what is considered to be the ideal penis reconstruction. For both trauma and transgender populations, the radial forearm free flap remains the gold standard, although the pedicled or free anterolateral thigh flap is becoming a favored alternative. Despite the remarkably high rates of sexual activity reported by patients having benefited from these techniques, sexual function remains a significant challenge due to frequent complications including autologous and prosthetic stiffener failure, fistula formation, and inadequate erogenous sensation. Perhaps the ultimate criterion for neophallus reconstruction is one which not only avoids these complications by meeting the immediate goals of a competent neourethra, sensitivity, bulk, and aesthetic form but also successfully combines them into their true overarching function: procreation. In this article, we report the case of a pedicled anterolateral thigh flap neophallus reconstruction which allowed a patient to naturally conceive a child through penetrative intercourse without use of a stiffener, and led to pregnancy and subsequent birth of a baby son. We review the surgical techniques and factors that led to this patient's successful progeny.


Meta-analytic Evidence for Neural Dysactivity Underlying Sexual Dysfunction.
About 30-40% of the population report sexual dysfunction. Although it is well known that the brain controls sexual behavior, little is known about the neural basis of sexual dysfunction. To assess convergence of altered brain activity associated with sexual dysfunction across available functional imaging studies. We used activation likelihood estimation meta-analysis to quantify interstudy concordance across 14 functional imaging studies reporting 179 foci from 40 individual analyses involving 191 subjects with sexual dysfunction and 123 controls. Activation likelihood estimation scores were used to assess convergence of findings. Consistently decreased brain activity associated with sexual dysfunction was identified in the dorsal anterior cingulate cortex, ventral striatum, dorsal midbrain, anterior midcingulate cortex, and lateral orbitofrontal cortex. These findings can serve as a basis for further studies on the pathophysiology of this highly common disorder with the view to development of more-specific treatment strategies. Findings are based on an observer-independent meta-analysis that provides robust evidence for and anatomic localization of altered brain activity related to sexual dysfunction. Our analysis cannot distinguish between the putative sources of sexual dysfunction, but it provides a more ubiquitous and general pattern of related altered neural activity. The identified regions have previously been shown to be critically involved in mediating sexual arousal and to be part of the sympathetic division of the autonomic nervous system. This suggests that the disturbance of brain activity associated with sexual dysfunction primarily affects sexual arousal already at early stages that are controlled by the sympathetic nervous system. Poeppl TB, Langguth B, Laird AR, et al. Meta-analytic Evidence for Neural Dysactivity Underlying Sexual Dysfunction. J Sex Med 2019;16:614-617.


Frequency analysis of cytotoxic T lymphocyte precursors in chimeric mice. Evidence for intrathymic maturation of clonally distinct self-major histocompatibility complex- and allo-major histocompatiblilty complex-restricted virus-specific T cells.
To study whether the thymic major histocompatibility complex (MHC) imposes a constraint on the receptor repertoire of maturating cytotoxic T lymphocyte (CTL) precursors, the restriction phenotypes of virus-specific CTL of MHC-compatible and of MHC-incompatible thymus- and bone marrow-grafted (A X B)F1 chimeric mice were compared. Dependent on the mode of in vitro sensitization, thymocytes or splenocytes of both types of chimeric mice generated Sendai virus-specific, self-MHC-or allo-MHC-restricted CTL. By applying the limiting-dilution technique, the CTL-precursor (CTL-P) frequencies of self-MHC-restricted and allo-MHC-restricted virus-specific T cells as well as of alloreactive T cells were determined. The data obtained revealed that independent of MHC differences between thymus and bone marrow, the frequencies of self-MHC-restricted and allo-MHC-restricted CTL-P were comparable, and in the same older of magnitude as those previously determined in conventionally reared mice. Self-MHC-restricted, virus-specific CTL-P were in a three- to fivefold excess over allo-MHC-restricted CTL-P. A segregation analysis revealed that clonally distinct CTL-P give rise to either self-restricted or allo-MHC-restricted, virus-specific CTL. Both sets were found not only in the spleen, but also in the thymus of chimeric mice, formally demonstrating the intrathymic differentiation pathway of self-MHC as well of allo-MHC-restricted CTL-P. These data reveal no major constraint of the thymic MHC on the capacity of T cells to recognize viral antigens either in the context of self-MHC or of allogeneic MHC products.