Antiviral activities of extracts and selected pure constituents of Ocimum basilicum.
1. Ocimum basilicum (OB), also known as sweet basil, is a well known medicinal herb in traditional Chinese medicine preparations. In the present study, extracts and purified components of OB were used to identify possible antiviral activities against DNA viruses (herpes viruses (HSV), adenoviruses (ADV) and hepatitis B virus) and RNA viruses (coxsackievirus B1 (CVB1) and enterovirus 71 (EV71)). 2. The results show that crude aqueous and ethanolic extracts of OB and selected purified components, namely apigenin, linalool and ursolic acid, exhibit a broad spectrum of antiviral activity. Of these compounds, ursolic acid showed the strongest activity against HSV-1 (EC50 = 6.6 mg/L; selectivity index (SI) = 15.2), ADV-8 (EC50 = 4.2 mg/L; SI = 23.8), CVB1 (EC50 = 0.4 mg/L; SI = 251.3) and EV71 (EC50 = 0.5 mg/L; SI = 201), whereas apigenin showed the highest activity against HSV-2 (EC50 = 9.7 mg/L; SI = 6.2), ADV-3 (EC50 = 11.1 mg/L; SI = 5.4), hepatitis B surface antigen (EC50 = 7.1 mg/L; SI = 2.3) and hepatitis B e antigen (EC50 = 12.8 mg/L; SI = 1.3) and linalool showed strongest activity against AVD-II (EC50 = 16.9 mg/L; SI = 10.5). 3. No activity was noted for carvone, cineole, beta-caryophyllene, farnesol, fenchone, geraniol, beta-myrcene and alpha-thujone. 4. The action of ursolic acid against CVB1 and EV71 was found to occur during the infection process and the replication phase. 5. With SI values greater than 200, the potential use of ursolic acid for treating infection with CVB1 and EV71 merits further investigation.


Production of PGE2 by bovine cultured airway smooth muscle cells: regulation by cAMP.
Prostaglandin E2 (PGE2) is thought to be an important inhibitory modulator of inflammatory processes in the airway. Previous studies have shown that it is produced by bovine cultured airway smooth muscle (ASM) cells in large quantities, but its regulation by second messengers has not been studied in this tissue. To determine whether PGE2 production by ASM might be an important action of beta-adrenoceptor agonists in asthma, the regulation of PGE2 production by adenosine 3',5'-cyclic monophosphate (cAMP) was assessed using dibutyryl cAMP (DBcAMP), forskolin, and albuterol. DBcAMP increased PGE2 production over a 24-h time course. Forskolin and albuterol both increased PGE2 production over control cells to similar levels after 24 h. Incubation of albuterol-treated cells with propranolol significantly (70%) reduced the stimulatory effect of albuterol on PGE2 production. Incubation of forskolin-treated cells with Rp-cAMP, a cAMP antagonist, inhibited the PGE2 response evoked by forskolin by 80%. Ro-20-1724, a selective inhibitor of type IV phosphodiesterase, stimulated PGE2 production (P = 0.02). Cycloheximide, a protein-synthesis inhibitor, did not inhibit the response to DBcAMP. The effects of DBcAMP were additive with the effects of bradykinin, a proinflammatory mediator known to increase PGE2 production (P < 0.05). These studies suggest that cAMP may play an important regulatory role in stimulating PGE2 production by ASM. This may be a novel beneficial action of beta-adrenoceptor agonists in asthma.


Epidermal neural crest stem cells (EPI-NCSC) and pluripotency.
This article serves three purposes. We summarize current knowledge of the origin and characteristics of EPI-NCSC, review their application in a mouse model of spinal cord injury, and we present new data that highlight aspects of pluripotency of EPI-NCSC. EPI-NCSC are multipotent stem cells, which are derived from the embryonic neural crest and are located in the bulge of hair follicles. EPI-NCSC can undergo self-renewal and they are able to generate all major neural crest derivatives, including neurons, nerve supporting cells, smooth muscle cells, bone/cartilage cells and melanocytes. Despite their ectodermal origin, neural crest cells can also generate cell types that typically are derived from mesoderm. We were therefore interested in exploring aspects of EPI-NCSC pluripotency. We here show that EPI-NCSC can fuse with adult skeletal muscle fibers and that incorporated EPI-NCSC nuclei are functional. Furthermore, we show that adult skeletal muscle represents an environment conducive to long-term survival of neurogenic EPI-NCSC. Genes used to create induced pluripotent stem (iPS) cells are present in our EPI-NCSC longSAGE gene expression library. Here we have corroborated this notion by real-time PCR. Our results show similarities in the expression of Myc, Klf4, Sox2 and Lin28 genes between EPI-NCSC and embryonic stem cells (ESC). In contrast there were major differences in Nanog and Pou5f1 (Oct-4) expression levels between EPI-NCSC and ESC, possibly explaining why EPI-NCSC are not tumorigenic. Overall, as embryonic remnants in an adult location EPI-NCSC show several attractive characteristics for future cell replacement therapy and/or biomedical engineering: Due to their ability to migrate, EPI-NCSC can be isolated as a highly pure population of multipotent stem cells by minimally-invasive procedures. The cells can be expanded in vitro into millions of stem cells/progenitors and they share some characteristics with pluripotent stem cells without being tumorigenic. Since the patients' own EPI-NCSC could be used for autologous transplantation, this would avoid graft rejection.


Constructing Spin-Adiabatic States for the Modeling of Spin-Crossing Reactions. I. A Shared-Orbital Implementation.
In the modeling of spin-crossing reactions, it has become popular to directly explore the spin-adiabatic surfaces. Specifically, through constructing spin-adiabatic states from a two-state Hamiltonian (with spin-orbit coupling matrix elements) at each geometry, one can readily employ advanced geometry optimization algorithms to acquire a "transition state" structure, where the spin crossing occurs. In this work, we report the implementation of a fully-variational spin-adiabatic approach based on Kohn-Sham density functional theory spin states (sharing the same set of molecular orbitals) and the Breit-Pauli one-electron spin-orbit operator. For three model spin-crossing reactions [predissociation of N2O, singlet-triplet conversion in CH2, and CO addition to Fe(CO)4], the spin-crossing points were obtained. Our results also indicated the Breit-Pauli one-electron spin-orbit coupling can vary significantly along the reaction pathway on the spin-adiabatic energy surface. On the other hand, due to the restriction that low-spin and high-spin states share the same set of molecular orbitals, the acquired spin-adiabatic energy surface shows a cusp (i.e. a first-order discontinuity) at the crossing point, which prevents the use of standard geometry optimization algorithms to pinpoint the crossing point. An extension with this restriction removed is being developed to achieve the smoothness of spin-adiabatic surfaces.


Micropatternable Double-Faced ZnO Nanoflowers for Flexible Gas Sensor.
Micropatternable double-faced (DF) zinc oxide (ZnO) nanoflowers (NFs) for flexible gas sensors have been successfully fabricated on a polyimide (PI) substrate with single-walled carbon nanotubes (SWCNTs) as electrode. The fabricated sensor comprises ZnO nanoshells laid out on a PI substrate at regular intervals, on which ZnO nanorods (NRs) were grown in- and outside the shells to maximize the surface area and form a connected network. This three-dimensional network structure possesses multiple gas diffusion channels and the micropatterned island structure allows the stability of the flexible devices to be enhanced by dispersing the strain into the empty spaces of the substrate. Moreover, the micropatterning technique on a flexible substrate enables highly integrated nanodevices to be fabricated. The SWCNTs were chosen as the electrode for their flexibility and the Schottky barrier they form with ZnO, improving the sensing performance. The devices exhibited high selectivity toward NO2 as well as outstanding sensing characteristics with a stable response of 218.1, fast rising and decay times of 25.0 and 14.1 s, respectively, and percent recovery greater than 98% upon NO2 exposure. The superior sensing properties arose from a combination of high surface area, numerous active junction points, donor point defects in the ZnO NRs, and the use of the SWCNT electrode. Furthermore, the DF-ZnO NF gas sensor showed sustainable mechanical stability. Despite the physical degradation observed, the devices still demonstrated outstanding sensing characteristics after 10 000 bending cycles at a curvature radius of 5 mm.


Gender differences measured by the MATRICS consensus cognitive battery in chronic schizophrenia patients.
Using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), previous study showed significant gender differences for cognitive deficits in immediate and delayed memory in schizophrenia patients. However, RBANS does not include reasoning and problem solving, and social cognition. These cognitive functions can significantly affect the outcomes and daily life in patients. This study examined the gender differences of cognition using the measurement and treatment research to improve cognition in schizophrenia (MATRICS) consensus cognitive battery (MCCB), especially focusing on reasoning and problem solving, and social cognition in schizophrenia patients. The results showed that healthy controls exemplified better cognition than patients in both genders in all examined MCCB scores. Male healthy controls had better reasoning and problem solving and working memory than females, but these gender differences were not presented in schizophrenia patients. Also, male schizophrenia patients showed worse cognition than females on social cognition, processing speed, verbal learning and visual learning. Our results support that male schizophrenia patients had more cognitive impairment than females on reasoning and problem solving, social cognition, processing speed, working memory, verbal learning and visual learning.


Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.
Acute and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and drives therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe acute hypoxia (16 hours with 0.02% O(2)) followed by reoxygenation or moderate chronic hypoxia (72 hours with 0.2% O(2)) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 overexpression. PARP1(-/-) murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypoxic gassing when compared with PARP1(+/+) MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor-treated xenografts displayed increased γH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated "contextual synthetic lethality." As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations.


Incidence and cumulative frequency of endemic Lyme disease in a community.
We conducted an epidemiological study of the cumulative frequency and incidence of Lyme disease in a summer community on Fire Island, New York, an area endemic for the disease. Fifteen (7.5%) of 200 persons studied in the community in 1982 reported a history of Lyme disease. An indirect immunofluorescent antibody assay showed that seventeen (9.7%) of 176 persons had serological evidence of exposure to the Lyme spirochete, including six of the 15 persons with a history of Lyme disease. Seven (0.7%-1.2%) of 600-1,000 persons in the community developed clinical symptoms and serological evidence of Lyme disease during the summer season, including two (1%) of the 200 persons in the study group. Four (3.1%) of 129 persons who had sera collected before and after the summer season demonstrated fourfold or greater rises in IgG antibody titers to the Lyme spirochete, including 2 (1.6%) persons without symptoms of Lyme disease. We conclude that the incidence of Lyme disease can be appreciably higher in endemic areas than previously recognized and that subclinical or inapparent seroconversion may occur after infection.


Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome.
The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non-human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. We conducted a large-scale genetic analysis on a case-control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels (r=0.760; P<0.00001).We localized, with immunofluorescence staining, BTNL2 in CD68-positive macrophages of the coronary artery plaques. In homozygous cases, BTNL2 blocking, in T-cell stimulation assays, enhanced CD4(+)FOXP3(+) regulatory T cell proliferation significantly (blocking versus nonblocking; P<0.05). In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3(+) T cell proliferation, especially in patients homozygous for the risk alleles. https://www.clinicaltrials.gov; Unique Identifier: NCT00417534.


Oesophageal atresia.
Oesophageal atresia (OA) encompasses a group of congenital anomalies comprising of an interruption of the continuity of the oesophagus with or without a persistent communication with the trachea. In 86% of cases there is a distal tracheooesophageal fistula, in 7% there is no fistulous connection, while in 4% there is a tracheooesophageal fistula without atresia. OA occurs in 1 in 2500 live births. Infants with OA are unable to swallow saliva and are noted to have excessive salivation requiring repeated suctioning. Associated anomalies occur in 50% of cases, the majority involving one or more of the VACTERL association (vertebral, anorectal, cardiac, tracheooesophageal, renal and limb defects). The aetiology is largely unknown and is likely to be multifactorial, however, various clues have been uncovered in animal experiments particularly defects in the expression of the gene Sonic hedgehog (Shh). The vast majority of cases are sporadic and the recurrence risk for siblings is 1%. The diagnosis may be suspected prenatally by a small or absent stomach bubble on antenatal ultrasound scan at around 18 weeks gestation. The likelihood of an atresia is increased by the presence of polyhydramnios. A nasogastric tube should be passed at birth in all infants born to a mother with polyhydramnios as well as to infants who are excessively mucusy soon after delivery to establish or refute the diagnosis. In OA the tube will not progress beyond 10 cm from the mouth (confirmation is by plain X-ray of the chest and abdomen). Definitive management comprises disconnection of the tracheooesophageal fistula, closure of the tracheal defect and primary anastomosis of the oesophagus. Where there is a "long gap" between the ends of the oesophagus, delayed primary repair should be attempted. Only very rarely will an oesophageal replacement be required. Survival is directly related to birth weight and to the presence of a major cardiac defect. Infants weighing over 1500 g and having no major cardiac problem should have a near 100% survival, while the presence of one of the risk factors reduces survival to 80% and further to 30-50% in the presence of both risk factors.


Performance measures have a major effect on cardiovascular outcomes: a review.
Improved application of existing therapies, directed by evidence-based guidelines, may offer immediate savings of life and function to patients with cardiovascular disease. We sought to evaluate the evidence that use of performance measures derived from clinical practice guidelines is associated with better clinical outcomes in this context. We conducted a search of the MEDLINE database for published studies evaluating the relationship of evidence-based therapies and outcomes in patients with coronary artery disease or heart failure. Studies examined included single-center, regional, national, and international experiences, and varied considerably in design. Most studies linking guidelines-based care to outcomes focused on patients with coronary artery disease; relatively few addressed patients with heart failure. Few studies, all nonrandomized, examined the use of specific interventions to improve quality of care in the context of standardized care tools. Almost all studies showed a strong and "dose-response" association between adherence to guidelines and performance measures and outcomes. Higher quality of care, as documented by better performance based on measures derived from practice guidelines, is associated with improved outcomes in patients with cardiovascular disease.


Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.
The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education.


Effects of centralizing acute stroke services: A prospective cohort study.
To investigate the effects of centralizing the acute stroke services in the Central Denmark Region (CDR). The CDR (1.3 million inhabitants) centralized acute stroke care from 6 to 2 designated acute stroke units with 7-day outpatient clinics. We performed a prospective "before-and-after" cohort study comparing all strokes from the CDR with strokes in the rest of Denmark to discover underlying general trends, adopting a difference-in-differences approach. The population comprised 22,141 stroke cases hospitalized from May 2011 to April 2012 and May 2013 to April 2014. Centralization was associated with a significant reduction in length of acute hospital stay from a median of 5 to 2 days with a length-of-stay ratio of 0.53 (95% confidence interval 0.38-0.75, data adjusted) with no corresponding change seen in the rest of Denmark. Similarly, centralization led to a significant increase in strokes with same-day admission (mainly outpatients), whereas this remained unchanged in the rest of Denmark. We observed a significant improvement in quality of care captured in 11 process performance measures in both the CDR and the rest of Denmark. Centralization was associated with a nonsignificant increase in thrombolysis rate. We observed a slight increase in readmissions at day 30, but this was not significantly different from the general trend. Mortality at days 30 and 365 remained unchanged, as in the rest of Denmark. Centralizing acute stroke care in the CDR significantly reduced the length of acute hospital stay without compromising quality. Readmissions and mortality stayed comparable to the rest of Denmark.


Evaluating the medical malpractice system and options for reform.
The U.S. medical malpractice liability system has two principal objectives: to compensate patients who are injured through the negligence of healthcare providers and to deter providers from practicing negligently. In practice, however, the system is slow and costly to administer. It both fails to compensate patients who have suffered from bad medical care and compensates those who haven't. According to opinion surveys of physicians, the system creates incentives to undertake cost-ineffective treatments based on fear of legal liability--to practice "defensive medicine." The failures of the liability system and the high cost of health care in the United States have led to an important debate over tort policy. How well does malpractice law achieve its intended goals? How large of a problem is defensive medicine and can reforms to malpractice law reduce its impact on healthcare spending? The flaws of the existing system have led a number of states to change their laws in a way that would reduce malpractice liability--to adopt "tort reforms." Evidence from several studies suggests that wisely chosen reforms have the potential to reduce healthcare spending significantly with no adverse impact on patient health outcomes.


Use of distal perfusion in peripheral extracorporeal membrane oxygenation.
Extra corporeal membrane oxygenation (ECMO) is a life-saving technique to manage refractory cardiopulmonary failure. Its usage and indication continue to increase. Femoral venoarterial ECMO (VA ECMO) is relatively less invasive and the cardiac support may be more rapidly instituted in in these extremely tenuous patients. Vascular injuries and limb ischemia unfortunately occur in these emergent access settings. Here we will discuss the optimal techniques of preventing this complication which might affect patient survival and impact the patient quality of life.


Removal of trihalomethanes from drinking water by nanofiltration membranes.
Chlorine reacts with the natural organic matter (NOM) in waters and forms disinfection by-products (DBP). Major of these by-products are trihalomethanes (THM) and haloacetic acids (HAA). They have been known to cause cancer and other toxic effects to human beings. This study determined the removal efficiencies of THM by nanofiltration (NF) techniques with NF200 and DS5 membrane. The rejection of this chlorination by-products was studied at various feed concentration by changing transmembrane pressure. Experimental results indicated that in general increasing operating pressure produces a higher flux but does not have a significant effect on THM rejection. On the other hand, increasing the feed concentration produces a little change in the overall flux and rejection capacity. NF200 membrane removed more THM than DS5 membrane. The higher removal efficiency of dibromochloromethane (DBCM) was attributed to brominating characteristics (higher molecular weight (MW) and molecular size). As a consequence, the results of this study suggest that the NF membrane process is one of the best available technologies for removing THM compounds.


Values associated with public involvement in health and social care research: a narrative review.
Much has been written about public involvement (PI) in health and social care research, but underpinning values are rarely made explicit despite the potential for these to have significant influence on the practice and assessment of PI. The narrative review reported here is part of a larger MRC-funded study which is producing a framework and related guidance on assessing the impact of PI in health and social care research. The review aimed to identify and characterize the range of values associated with PI that are central elements of the framework. We undertook a review and narrative synthesis of diverse literatures of PI in health and social care research, including twenty existing reviews and twenty-four chapters in sixteen textbooks. Three overarching value systems were identified, each containing five value clusters. (i) A system concerned with ethical and/or political issues including value clusters associated with empowerment; change/action; accountability/transparency; rights; and ethics (normative values). (ii). A system concerned with the consequences of public involvement in research including value clusters associated with effectiveness; quality/relevance; validity/reliability; representativeness/objectivity/generalizability; and evidence (substantive values). (iii) A system concerned with the conduct of public involvement in including value clusters associated with Partnership/equality; respect/trust; openness and honesty; independence; and clarity (process values). Our review identified three systems associated with PI in health and social care research focused on normative, substantive and process values. The findings suggest that research teams should consider and make explicit the values they attach to PI in research and discuss ways in which potential tensions may be managed in order to maximize the benefits of PI for researchers, lay experts and the research.


Emphasizing the health benefits of vitamin D for those with neurodevelopmental disorders and intellectual disabilities.
People with neurodevelopmental disorders and intellectual disabilities have much greater health care needs. Mainly staying indoors, such people generally have low 25-hydroxyvitamin D (25(OH)D) concentrations. The Vitamin D Task Force of the American Academy of Developmental Medicine and Dentistry (AADMD) reviewed the evidence of 25(OH)D concentrations that benefit the health of persons with developmental disabilities. Maintaining recommended optimal serum 25(OH)D concentrations year long will benefit skeletal development in infants, children, and adolescents, and benefit musculoskeletal health and neuromuscular coordination in adult patients, and decrease risk of falls. Maintaining optimal concentrations decreases risks and severities of autoimmune diseases, cardiovascular disease, many types of cancer, dementia, types 1 and 2 diabetes mellitus, and respiratory tract infections. Other benefits include improved dental and oral health and improved physical performance. The Task Force recommends that 25(OH)D concentrations for optimal health to be in the range of 75 to 125 nmol/L, which can be achieved using between 800 and 4000 IU/day vitamin D3 and sensible exposure to solar UVB radiation. The paper also discusses the potential risks of higher 25(OH)D concentrations, the evidence from and limitations of randomized controlled trials, and the recommendations by various groups and agencies.


Metagenomic pyrosequencing and microbial identification.
The Human Microbiome Project has ushered in a new era for human metagenomics and high-throughput next-generation sequencing strategies. This review describes evolving strategies in metagenomics, with a special emphasis on the core technology of DNA pyrosequencing. The challenges of microbial identification in the context of microbial populations are discussed. The development of next-generation pyrosequencing strategies and the technical hurdles confronting these methodologies are addressed. Bioinformatics-related topics include taxonomic systems, sequence databases, sequence-alignment tools, and classifiers. DNA sequencing based on 16S rRNA genes or entire genomes is summarized with respect to potential pyrosequencing applications. Both the approach of 16S rDNA amplicon sequencing and the whole-genome sequencing approach may be useful for human metagenomics, and numerous bioinformatics tools are being deployed to tackle such vast amounts of microbiological sequence diversity. Metagenomics, or genetic studies of microbial communities, may ultimately contribute to a more comprehensive understanding of human health, disease susceptibilities, and the pathophysiology of infectious and immune-mediated diseases.


Production of recombinant human transthyretin with biological activities toward the understanding of the molecular basis of familial amyloidotic polyneuropathy (FAP).
Transthyretin (TTR) is a plasma protein interacting with thyroxine T4 and retinol binding protein (RBP). Several variants of TTR with single amino acid substitutions have been identified as the major components of the amyloid fibrils of familial amyloidotic polyneuropathy (FAP), a fetal, autosomal dominant genetic disease. The elucidation of the molecular nature of the variants distinct from that of the wild-type TTR is crucial for understanding the amyloidogenesis in FAP, but our understanding is very poor mainly because of the unavailability of pure variant TTRs. In the present study, we used an Escherichia coli OmpA secretion vector (Ghrayeb et al., 1984) and achieved an effective production of the variant TTRs related to FAP including Met-30, Ile-33, Ala-60, Tyr-77, Met-111, and Ile-122 types. The variant TTRs produced in this system were efficiently secreted to the culture media. The chemical analysis showed that the secreted TTR (Met-30 type) has the same N-terminus as the native one. IEF analyses also indicated that the secreted product is properly processed as assessed by its pI. Furthermore, the secreted TTR was shown to have biological activities, namely, the thyroxin binding activity and the ability to associate with retinol binding protein, indicating that the secreted TTR polypeptide is properly folded. The present work also demonstrated that the processing/secretion of the recombinant TTR molecules in E. coli was strongly affected by single amino acid substitutions.


Genetic diversity of male and female Chinese bayberry (Myrica rubra) populations and identification of sex-associated markers.
Chinese bayberry (Myrica rubra Sieb. & Zucc.) is an important subtropical evergreen fruit tree in southern China. Generally dioecious, the female plants are cultivated for fruit and have been studied extensively, but male plants have received very little attention. Knowledge of males may have a major impact on conservation and genetic improvement as well as on breeding. Using 84 polymorphic SSRs, we genotyped 213 M. rubra individuals (99 male individuals, 113 female varieties and 1 monoecious) and compared the difference in genetic diversity between the female and the male populations. Neighbour-joining cluster analysis separated M. rubra from three related species, and the male from female populations within M. rubra. By structure analysis, 178 M. rubra accessions were assigned to two subpopulations: Male dominated (98) and Female dominated (80). The well-known cultivars 'Biqi' and 'Dongkui', and the landraces 'Fenhong' are derived from three different gene pools. Female population had a slightly higher values of genetic diversity parameters (such as number of alleles and heterozygosity) than the male population, but not significantly different. The SSR loci ZJU062 and ZJU130 showed an empirical Fst value of 0.455 and 0.333, respectively, which are significantly above the 95 % confidence level, indicating that they are outlier loci related to sex separation. The male and female populations of Chinese bayberry have similar genetic diversity in terms of average number of alleles and level of heterozygosity, but were clearly separated by genetic structure analysis due to two markers associated with sex type, ZJU062 and ZJU130. Zhejiang Province China could be the centre of diversity of M. rubra in China, with wide genetic diversity coverage; and the two representative cultivars 'Biqi' and 'Dongkui', and one landrace 'Fenhong' in three female subpopulations. This research provides genetic information on male and female Chinese bayberry and will act as a reference for breeding programs.


Effects of meditation on frontal alpha-asymmetry in previously suicidal individuals.
This study investigated the effects of a meditation-based treatment for preventing relapse to depression, mindfulness-based cognitive therapy (MBCT), on prefrontal alpha-asymmetry in resting electroencephalogram (EEG), a biological indicator of affective style. Twenty-two individuals with a previous history of suicidal depression were randomly assigned to either MBCT (N=10) or treatment-as-usual (TAU, N=12). Resting electroencephalogram was measured before and after an 8-week course of treatment. The TAU group showed a significant deterioration toward decreased relative left-frontal activation, indexing decreases in positive affective style, while there was no significant change in the MBCT group. The findings suggest that MBCT can help individuals at high risk for suicidal depression to retain a balanced pattern of baseline emotion-related brain activation.


Effects of search difficulty on the selection, maintenance, and learning of attentional templates.
Prominent theories of attention claim that visual search is guided through attentional templates stored in working memory. Recently, the contralateral delay activity (CDA), an electrophysiological index of working memory storage, has been found to rapidly decrease when participants repeatedly search for the same target, suggesting that, with learning, the template moves out of working memory. However, this has only been investigated with pop-out search for distinct targets, for which a strong attentional template may not be necessary. More effortful search tasks might rely more on an active attentional template in working memory, leading to a slower handoff to long-term memory and thus a slower decline of the CDA. Using ERPs, we compared the rate of learning of attentional templates in pop-out and effortful search tasks. In two experiments, the rate of decrease in the CDA was the same for both search tasks. Similar results were found for a second component indexing working memory effort, the late positive complex. However, the late positive complex was also sensitive to anticipated search difficulty, as was expressed in a greater amplitude before the harder search task. We conclude that the amount of working memory effort invested in maintaining an attentional template, but not the rate of learning, depends on search difficulty.


Assessing the reliability of measurements from the Krusen limb load monitor to analyze temporal and loading characteristics of normal gait.
This study assessed the reliability of measurements made by four physical therapists on healthy subject gait data recorded from the Krusen limb load monitor. The five components of step (stance time, time up, time to second peak, and force at the first and second peaks) were analyzed. Six components contributing to gait (ambulation time; velocity; cadence; average swing phase duration, left lower extremity; average swing phase duration, right lower extremity; and ratio of unilateral weight bearing, right lower extremity to left lower extremity) were also analyzed. Intraclass correlation coefficients for the five step components and the gait measures of ambulation time, velocity, and cadence showed high measurement reliability. The other measures of gait showed low intraclass correlation coefficients. The limb load monitor can, therefore, be used by clinicians to measure the five step components and three gait measures (ambulation time, velocity, and cadence) with high measurement reliability.


Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome.
Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance. Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the FIO2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome. Five academic centers in the United States. Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome. Aerosolized budesonide/formoterol versus placebo bid for up to 5 days. Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%). Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.


Critical role of the transcriptional repressor neuron-restrictive silencer factor in the specific control of connexin36 in insulin-producing cell lines.
Connexin36 (Cx36) is specifically expressed in neurons and in pancreatic beta-cells. Cx36 functions as a critical regulator of insulin secretion and content in beta-cells. In order to identify the molecular mechanisms that control the beta-cell expression of Cx36, we initiated the characterization of the human 5' regulatory region of the CX36 gene. A 2043-bp fragment of the human CX36 promoter was identified from a human BAC library and fused to a luciferase reporter gene. This promoter region was sufficient to confer specific expression to the reporter gene in insulin-secreting cell lines. Within this 5' regulatory region, a putative neuron-restrictive silencer element conserved between rodent and human species was recognized and binds the neuron-restrictive silencing factor (NRSF/REST). This factor is not expressed in insulin-secreting cells and neurons; it functions as a potent repressor through the recruitment of histone deacetylase to the promoter of neuronal genes. The NRSF-mediated repression of Cx36 in HeLa cells was abolished by trichostatin A, confirming the functional importance of histone deacetylase activity. Ectopic expression, by viral gene transfer, of NRSF/REST in different insulin-secreting beta-cell lines induced a marked reduction in Cx36 mRNA and protein content. Moreover, mutations in the Cx36 neuron-restrictive silencer element relieved the low transcriptional activity of the human CX36 promoter observed in HeLa cells and in INS-1 cells expressing NRSF/REST. The data showed that cx36 gene expression in insulin-producing beta-cell lines is strictly controlled by the transcriptional repressor NRSF/REST indicating that Cx36 participates to the neuronal phenotype of the pancreatic beta-cells.


A sensitive real-time PCR based assay to estimate the impact of amino acid substitutions on the competitive replication fitness of human immunodeficiency virus type 1 in cell culture.
Fixation of mutations in human immunodeficiency virus type 1 (HIV-1), such as those conferring drug resistance and immune escape, can result in a change in replication fitness. To assess these changes, a real-time TaqMan PCR detection assay and statistical methods for data analysis were developed to estimate sensitively relative viral fitness in competitive viral replication experiments in cell culture. Chimeric viruses with the gene of interest in an HIV-1NL4-3 backbone were constructed in two forms, vifA (native vif gene in NL4-3) and vifB (vif gene with six synonymous nucleotide differences from vifA). Subsequently, mutations of interest were introduced into the chimeric viruses in NL4-3VifA backbones, and the mutants were competed against the chimera with the isogenic viral sequence in the NL4-3VifB backbone in cell culture. In order to assess subtle fitness differences, culture supernatants were sampled longitudinally, and the viruses differentially quantified using vifA- and vifB-specific primers in real-time PCR assays. Based on an exponential net growth model, the growth rate of each virus was determined and the fitness cost of the mutation(s) distinguishing the two viruses represented as the net growth rate difference between the mutant and the native variants. Using this assay, the fitness impact of eight amino acid substitutions was quantitated at highly conserved sites in HIV-1 Gag and Env.


Hierarchy of evidence: where observational studies fit in and why we need them.
Although randomized controlled designs are considered the so-called gold standard in medical trials and sit atop the hierarchy of evidence in evidence-based medicine, there are situations in which they are impractical or unethical to undertake, especially in surgical trials. Then, observational studies often provide the best source of information. In this paper, we use examples from the literature to explain the importance of observational studies in furthering the boundaries of orthopaedic surgery and knowledge of musculoskeletal disorders.


A critical review of endoscopic indices in ulcerative colitis: inter-observer variation of the endoscopic index.
Various endoscopic indices (EIs) are available for evaluating the endoscopic features of ulcerative colitis (UC), but those currently used in clinical trials are not uniform and have been reported to vary considerably. The currently available EIs for UC include qualitative indices (Baron, Matts and Blackstone scores), the Rachmilewitz endoscopic index (REI; total sum of scores of four types of severity of mucosal lesions), among others. As each of these indices has its own unique characteristics, the selection of the proper EI has to be taken into account in the design of the clinical trial. Endoscopy is an observer-dependent diagnostic method, and inter-observer and intra-observer variations are often problematic. Among other factors, the reliability of clinical trials might be reduced considerably if inter-observer agreement is too low. To date, however, few analyses have focused on inter-observer variation in EIs for UC. The study reported here was undertaken to analyze inter-observer variations in the Baron score and REI. The κ statistics, an indicator of inter-observer agreement, was fair and not particularly high for either the Baron score (κ = 0.31) or REI (κ = 0.27). Modifications made to the REI (modified into a 4-point scale by the authors of this study), making it similar to the Baron score, resulted in κ statistics of 0.44 (moderate). The REI, designed to evaluate many mucosal abnormalities, seemed to enhance the validity of endoscopic grading of UC. It is desirable that inter-observer variations in various EIs are analyzed properly and reviewed comparatively. We emphasize the necessity of establishing the optimal EI for designing clinical trials of UC.


Unfolding simulations of holomyoglobin from four mammals: identification of intermediates and β-sheet formation from partially unfolded states.
Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulations of holoMb and the first comparative study of unfolding of protein orthologs from different species (sperm whale, pig, horse, and harbor seal). We also provide new interpretations of experimental mean molecular ellipticities of myoglobin intermediates, notably correcting for random coil and number of helices in intermediates. The simulated holoproteins at 310 K displayed structures and dynamics in agreement with crystal structures (R g ~1.48-1.51 nm, helicity ~75%). At 400 K, heme was not lost, but some helix loss was observed in pig and horse, suggesting that these helices are less stable in terrestrial species. At 500 K, heme was lost within 1.0-3.7 ns. All four proteins displayed exponentially decaying helix structure within 20 ns. The C- and F-helices were lost quickly in all cases. Heme delayed helix loss, and sperm whale myoglobin exhibited highest retention of heme and D/E helices. Persistence of conformation (RMSD), secondary structure, and ellipticity between 2-11 ns was interpreted as intermediates of holoMb unfolding in all four species. The intermediates resemble those of apoMb notably in A and H helices, but differ substantially in the D-, E- and F-helices, which interact with heme. The identified mechanisms cast light on the role of metal/cofactor in poorly understood holoMb unfolding. We also observed β-sheet formation of several myoglobins at 500 K as seen experimentally, occurring after disruption of helices to a partially unfolded, globally disordered state; heme reduced this tendency and sperm-whale did not display any sheet propensity during the simulations.


Integrative review of lycopene and breast cancer.
To perform an integrative research analysis of the literature regarding lycopene, its antioxidant capacity, and its nutritive and physiologic effects on breast cancer. Articles published from 1990-2004 using PubMed as the primary retrieval base. Forty articles were retrieved and a dimensional analysis was performed based on Fawcett's integrative review process that focused on the following categories: antioxidant, bioavailability, breast cancer risk, and dietary factors. Noted gaps in the literature included lack of a theoretical model and multiple nutritional variables studied that affected statistical interpretation and application. Findings suggest that additional research is needed to effectively study the specific phytochemical attributes of lycopene with regard to breast cancer. The emerging area of health-derived benefits from food sources such as lycopene requires additional inquiry into the examination of physiological and nutritional parameters. Nurses should include antioxidant therapy in their base of knowledge when caring for patients with breast cancer.


Mongoliicoccus alkaliphilus sp. nov. and Litoribacter alkaliphilus sp. nov., isolated from salt pans.
Four bacterial strains (JC165(T), JC166(T), JC169 and JC170) were isolated from salt pan soils from a coastal region of Tamilnadu, India. They were obligately aerobic, pink- to red-pigmented, mesophilic, haloalkaliphiles having chemoorganoheterotrophic growth on various carbon sources and were catalase- and oxidase-positive. Phototrophic growth and bacteriochlorophyll a were absent in all four strains. Major carotenoids present were β-carotene and rhodoxanthin. The main fatty acid in all strains was iso-C(15:0). The main polar lipids were phosphatidylethanolamine (PE) and phosphatidylcholine (PC) as well as a few unidentified lipids. Bacterial hopane derivatives and diplopterol (DPL) were detected in all four strains. Based on the 16S rRNA gene sequences, all four strains belong to the family Cyclobacteriaceae in the phylum Bacteroidetes. Strains JC165(T) and JC169 had a sequence similarity of 97.2% with Mongoliicoccus roseus MIM28(T), while strains JC166(T) and JC170 had a sequence similarity of 99.5% with Litoribacter ruber YIM CH208(T). Strains JC165(T)/JC169 and JC166(T)/JC170 had genomic DNA reassociation values (based on DNA-DNA hybridization) of 21 ± 2% and 23 ± 1% with M. roseus KCTC 19808(T) ( = MIM28(T)) and L. ruber KCTC 22899(T) ( = YIM CH208(T)), respectively, suggesting that they represented novel species. The reassociation values of >85% between strains JC165(T) and JC169, and JC166(T) and JC170 suggested they were strains of the same species. The genomic information was supported by phenotypic observations leading to the proposal of two novel species, Mongoliicoccus alkaliphilus sp. nov. (type strain, JC165(T) = KCTC 32210(T) =LMG 27255(T)) and Litoribacter alkaliphilus sp. nov. (type strain, JC166(T) = KCTC 32217(T) =LMG 27256(T)).


Hydration at the work site.
When performing physical work, sweat output often exceeds water intake, producing a body water deficit or dehydration. Specific to the work place, dehydration can adversely affect worker productivity, safety, and morale. Legislative bodies in North America such as the Occupational Safety and Health Administration (OSHA) and the American Conference of Governmental Industrial Hygienists (ACGIH) recommend replacing fluids frequently when exposed to heat stress, such as one cup (250 ml) every 20 minutes when working in warm environments. However, the majority of legislative guidelines provide vague guidance and none take into account the effects of work intensity, specific environments, or protective clothing. Improved occupational guidelines for fluid and electrolyte replacement during hot weather occupational activities should be developed to include recommendations for fluid consumption before, during, and after work.


[Evaluation of efficacy of ripe and unripe fruit oil extracts of Melia azedarach against Rhipicephalus (Boophilus) microplus (Acari: ixodidae)].
Hexanic extracts gotten of the fruits of cinamomo (Melia azedarach) were tested on engorged females and larvae of Rhipicephalus (Boophilus) microplus. Four extracts were produced: one of unripe fruits and three of ripe fruits, being one with the fruits immediately processed, another one with fruits stored for five months and one tested after storage of the extract for 2 (two) years at 4 degrees C. The tests were made in triplicate, in 0.25% - 0.0156% dilutions. The effectiveness of extracts was evaluated through the comparison of the Reproduction Estimate of the groups "controlled and treated" for females, of mortality for the larvae, and of the calculation of the DL50 and the relative power for larvae and females. The extract of unripe fruits presented the effectiveness varying the 3.6% - 100% for females, and of ripe fruits it varied of 5.2% - 99.7%. The two extracts caused a mortality of 100% of the larvae in the highest concentrations. The extract of stored fruits presented effectiveness of 14% - 83% on females, while the extract stored in refrigerator presented effectiveness of 8.4% 100% and both did not present larvicidal effect. The results demonstrate a superiority of the unripe extract, with a minor DL50 and superior power 1.497 times to the extract of ripe fruits.


Effect of Seedborne Potato virus Y on Performance of Russet Burbank, Russet Norkotah, and Shepody Potato.
Potato virus Y (PVY) is one of the most important of the potato viruses, but little is known about the impact on yield of seedborne infection levels below 100%. Blending infected and healthy seed from different seed lots introduces the variable of performance differences between the seed lots, which may obscure the effect of virus alone. Seed lots containing various levels of seedborne PVY (0, 2, 10, 20, and 50% incidence of infected tubers) were created by combining in different proportions seed pieces from healthy and infected tubers from the same seed source. These seed lots were planted in replicated field plots at the University of Idaho Parma R & E Center in Parma, ID from 1995 to 1997. Regression analyses on data from the three consecutive seasons indicate that seedborne PVY has virtually the same negative impact on yield for all three cultivars.


To chew or not to chew: fecal particle size in herbivorous reptiles and mammals.
A major difference between reptile and mammalian herbivores is that the former do not masticate their food. Actually, food particle size reduction by chewing is usually considered one of the adaptations facilitating the higher metabolic rates of mammals. However, quantitative comparisons of ingesta particle size between the clades have, to our knowledge, not been performed so far. We measured mean fecal particle size (MPS) in 79 captive individuals of 14 reptile herbivore species (tortoises, lizards, and Corucia zebrata) by wet sieving and compared the results with a mammalian dataset. MPS increased with body mass in both clades, but at a significantly higher level in reptiles. Limited evidence in free-ranging and captive individuals of Testudo hermanni indicates that in reptiles, the ability to crop food and food particle size significantly influence fecal particle size. The opportunistic observation of a drastic particle size difference between stomach and intestinal contents corroborates findings that in reptiles, in contrast to terrestrial mammals, significant ingesta particle size reduction does occur in the gastrointestinal tract, most likely owing to microbial action during very long ingesta retention. Whether behavioral adaptations to controlling ingesta particle size, such as deliberate small bite sizes, are adaptive strategies in reptiles remains to be investigated.


Manikin-based clinical simulation in chiropractic education.
The purpose of this pilot investigation was to describe the development and implementation of simulation exercises and investigate the feasibility, satisfaction, and relative effectiveness of a manikin-based simulation program in chiropractic undergraduate education. This investigation consisted of (1) a qualitative review of other simulation environments and evaluation of related simulation literature to develop the educational processes to be used, (2) implementation of simulation scenarios for 95 student interns and their 11 supervising clinicians, and (3) implementation of simulation scenarios in a random sample of 35 1st-year and 24 2nd-year chiropractic students. Assessment of success was based on results from satisfaction and usability questionnaires and perceived achievement of learning outcomes. Anxiety scores were measured for all participants via a visual analog scale. The level of successful integration of 2nd-year basic science material was assessed using a t test comparing test results between students who participated in the pilot and those who did not. Implementation methods were developed on the basis of qualitative investigation. Simulation program feedback from all participants indicated high levels of satisfaction, usability, and perceived achievement of learning outcomes. Anxiety levels among interns differed according to role chosen (F = 8.07, p =.00). Mean difference in course examination scores of students who participated in simulations versus those who did not was 3.25% favoring students who participated (t = 1.28, p =.10). High levels of student satisfaction and perceived achievement of learning outcomes were consistently achieved. A trend to successful integration of basic science knowledge provides reason for cautious optimism. More research is recommended.


Candidate genes for the progression of malignant gliomas identified by microarray analysis.
Malignant astrocytomas of World Health Organization (WHO) grade III or IV have a reduced median survival time, and possible pathways have been described for the progression of anaplastic astrocytomas and glioblastomas, but the molecular basis of malignant astrocytoma progression is still poorly understood. Microarray analysis provides the chance to accelerate studies by comparison of the expression of thousands of genes in these tumours and consequently identify targeting genes. We compared the transcriptional profile of 4,608 genes in tumours of 15 patients including 6 anaplastic astrocytomas (WHO grade III) and 9 glioblastomas (WHO grade IV) using microarray analysis. The microarray data were corroborated by real-time reverse transcription-polymerase chain reaction analysis of two selected genes. We identified 166 gene alterations with a fold change of 2 and higher whose mRNA levels differed (absolute value of the t statistic of 1.96) between the two malignant glioma groups. Further analyses confirmed same transcription directions for Olig2 and IL-13Ralpha2 in anaplastic astrocytomas as compared to glioblastomas. Microarray analyses with a close binary question reveal numerous interesting candidate genes, which need further histochemical testing after selection for confirmation. IL-13Ralpha2 and Olig2 have been identified and confirmed to be interesting candidate genes whose differential expression likely plays a role in malignant progression of astrocytomas.


Arousal, valence, and the uncanny valley: psychophysiological and self-report findings.
The main prediction of the Uncanny Valley Hypothesis (UVH) is that observation of humanlike characters that are difficult to distinguish from the human counterpart will evoke a state of negative affect. Well-established electrophysiological [late positive potential (LPP) and facial electromyography (EMG)] and self-report [Self-Assessment Manikin (SAM)] indices of valence and arousal, i.e., the primary orthogonal dimensions of affective experience, were used to test this prediction by examining affective experience in response to categorically ambiguous compared with unambiguous avatar and human faces (N = 30). LPP and EMG provided direct psychophysiological indices of affective state during passive observation and the SAM provided self-reported indices of affective state during explicit cognitive evaluation of static facial stimuli. The faces were drawn from well-controlled morph continua representing the UVH' dimension of human likeness (DHL). The results provide no support for the notion that category ambiguity along the DHL is specifically associated with enhanced experience of negative affect. On the contrary, the LPP and SAM-based measures of arousal and valence indicated a general increase in negative affective state (i.e., enhanced arousal and negative valence) with greater morph distance from the human end of the DHL. A second sample (N = 30) produced the same finding, using an ad hoc self-rating scale of feelings of familiarity, i.e., an oft-used measure of affective experience along the UVH' familiarity dimension. In conclusion, this multi-method approach using well-validated psychophysiological and self-rating indices of arousal and valence rejects - for passive observation and for explicit affective evaluation of static faces - the main prediction of the UVH.


Custodianship as an ethical framework for biospecimen-based research.
Human biological specimens (biospecimens) are increasingly important for research that aims to advance human health. Yet, despite significant proliferation in specimen-based research and discoveries during the past decade, research remains challenged by the inequitable access to high-quality biospecimens that are collected under rigorous ethical standards. This is primarily caused by the complex level of control and ownership exerted by the myriad of stakeholders involved in the biospecimen research process. This article discusses the ethical model of custodianship as a framework for biospecimen-based research to promote fair research access and resolve issues of control and potential conflicts between biobanks, investigators, human research participants (human subjects), and sponsors. Custodianship is the caretaking obligation for biospecimens from initial collection to final dissemination of research findings. It endorses key practices and operating principles for responsible oversight of biospecimens collected for research. Embracing the custodial model would ensure transparency in research, fairness to human research participants, and shared accountability among all stakeholders involved in biospecimen-based research.


Early intervention and child physical health: Evidence from a Dublin-based randomized controlled trial.
This article investigates the impact of an early intervention program, which experimentally modifies the parenting and home environment of disadvantaged families, on child physical health in the first 3 years of life. We recruited and randomized 233 (115 intervention, 118 control) pregnant women from a socioeconomically disadvantaged community in Dublin, Ireland into an intervention or control group. The treatment includes regular home visits commencing antenatally and an additional parenting course commencing at 2 years. Maternal reports of child health are assessed at 6, 12, 18, 24, and 36 months. Treatment effects are estimated using permutation testing to account for small sample size, inverse probability weighting to account for differential attrition, and both the stepdown procedure and an indices approach to account for multiple hypothesis testing. Following adjustment for multiple testing and attrition, we observe a positive and statistically significant main treatment effect for wheezing/asthma. The intervention group are 15.5 percentage points (pp) less likely to require medical attention for wheezing/asthma compared to the control group. Subgroup analysis reveals more statistically significant adjusted treatment effects for boys than girls regarding fewer health problems (d=0.63), accidents (23.9pp), and chest infections (22.8-37.9pp). Our results suggest that a community-based home visiting program may have favorable impacts on early health conditions.


Evaluation of algorithms for Multi-Modality Whole Heart Segmentation: An open-access grand challenge.
Knowledge of whole heart anatomy is a prerequisite for many clinical applications. Whole heart segmentation (WHS), which delineates substructures of the heart, can be very valuable for modeling and analysis of the anatomy and functions of the heart. However, automating this segmentation can be challenging due to the large variation of the heart shape, and different image qualities of the clinical data. To achieve this goal, an initial set of training data is generally needed for constructing priors or for training. Furthermore, it is difficult to perform comparisons between different methods, largely due to differences in the datasets and evaluation metrics used. This manuscript presents the methodologies and evaluation results for the WHS algorithms selected from the submissions to the Multi-Modality Whole Heart Segmentation (MM-WHS) challenge, in conjunction with MICCAI 2017. The challenge provided 120 three-dimensional cardiac images covering the whole heart, including 60 CT and 60 MRI volumes, all acquired in clinical environments with manual delineation. Ten algorithms for CT data and eleven algorithms for MRI data, submitted from twelve groups, have been evaluated. The results showed that the performance of CT WHS was generally better than that of MRI WHS. The segmentation of the substructures for different categories of patients could present different levels of challenge due to the difference in imaging and variations of heart shapes. The deep learning (DL)-based methods demonstrated great potential, though several of them reported poor results in the blinded evaluation. Their performance could vary greatly across different network structures and training strategies. The conventional algorithms, mainly based on multi-atlas segmentation, demonstrated good performance, though the accuracy and computational efficiency could be limited. The challenge, including provision of the annotated training data and the blinded evaluation for submitted algorithms on the test data, continues as an ongoing benchmarking resource via its homepage (www.sdspeople.fudan.edu.cn/zhuangxiahai/0/mmwhs/).


Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir.
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1 A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir. Efavirenz, an UGT1A1 inducer, was used to assess the impact of altered UGT activity on a 1200 mg QD dose of raltegravir. An open label, randomized, 2-period fixed-sequence Phase 1 study was performed in adult healthy male and female subjects (non-childbearing potential) ≥ 19 and ≤55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤32.0 kg/m2 . Subjects (n = 21) received a single oral dose of 1200 mg raltegravir at bedtime on an empty stomach on Day 1 in Period 1. After a washout period of at least 7 days, subjects received oral doses of 600 mg efavirenz QD at bedtime for 14 consecutive days in Period 2. Subjects received a single oral dose of 1200 mg raltegravir co-administered with 600 mg efavirenz on Day 12 of Period 2. Pharmacokinetic (PK) samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. PK parameters were estimated using non-compartmental analysis. Administration of single 1200 mg oral doses of raltegravir alone and co-administered with multiple oral doses of efavirenz were generally well tolerated in healthy subjects. Co-administration with efavirenz yielded geometric mean ratios (GMRs) and their associated 90% confidence intervals (90% CIs) for raltegravir AUC0-∞, Cmax , and C24 of 0.86 (0.73, 1.01), 0.91 (0.70, 1.17), and 0.94 (0.76, 1.17), respectively. The results show that efavirenz modestly reduced the exposure of raltegravir. The reduction in raltegravir exposure is not considered clinically meaningful. Copyright © 2016 John Wiley & Sons, Ltd.


Kinematic features of whole-body reaching movements underwater: Neutral buoyancy effects.
Astronauts' training is conventionally performed in a pool to reproduce weightlessness by exploiting buoyancy which is supposed to reduce the impact of gravity on the body. However, this training method has not been scientifically validated yet, and requires first to study the effects of underwater exposure on motor behavior. We examined the influence of neutral buoyancy on kinematic features of whole-body reaching underwater and compared them with those produced on land. Eight professional divers were asked to perform arm reaching movements toward visual targets while standing. Targets were presented either close or far from the subjects (requiring in the latter case an additional whole-body displacement). Reaching movements were performed on land or underwater in two different contexts of buoyancy. The divers either wore a diving suit only with neutral buoyancy applied to their center of mass or were additionally equipped with a submersible simulated space suit with neutral buoyancy applied to their body limbs. Results showed that underwater exposure impacted basic movement features, especially movement speed which was reduced. However, movement kinematics also differed according to the way buoyancy was exerted on the whole-body. When neutral buoyancy was applied to the center of mass only, some focal and postural components of whole-body reaching remained close to land observations, notably when considering the relative deceleration duration of arm elevation and concomitant forward trunk bending when reaching the far target. On the contrary, when neutral buoyancy was exerted on body segments, movement kinematics were close to those reported in weightlessness, as reflected by the arm deceleration phase and the whole-body forward displacement when reaching the far target. These results suggest that astronauts could benefit from the application of neutral buoyancy across the whole-body segments to optimize underwater training and acquire specific motor skills which will be used in space.


Identification of Developmental Delay in Infants Using Wearable Sensors: Full-Day Leg Movement Statistical Feature Analysis.
This paper examines how features extracted from full-day data recorded by wearable sensors are able to differentiate between infants with typical development and those with or at risk for developmental delays. Wearable sensors were used to collect full-day (8-13 h) leg movement data from infants with typical development ([Formula: see text]) and infants at risk for developmental delay ([Formula: see text]). At 24 months, at-risk infants were assessed as having good ([Formula: see text]) or poor ([Formula: see text]) developmental outcomes. With this limited size dataset, our statistical analysis indicated that accelerometer features collected earlier in infancy differentiated between at-risk infants with poor and good outcomes at 24 months, as well as infants with typical development. This paper also tested how these features performed on a subset of the data for which the infant movement was known, i.e., 5-min intervals more representative of clinical observations. Our results on this limited dataset indicated that features for full-day data showed more group differences than similar features for the 5-min intervals, supporting the usefulness of full-day movement monitoring.


Rapid restoration of normoglycaemia using intravenous insulin boluses.
The reduction of elevated fasting plasma glucose levels to near normal by repeated intravenous bolus insulin doses, given according to a simple algorithm, has been studied in 17 Type I and 23 Type II, healthy diabetic patients. Using a formula based on the patient's plasma glucose, height and bodyweight with insulin boluses given every 30 min if the plasma glucose remained above 6 mmol/1, plasma glucose levels were reduced to less than 7.5 mmol/1 in 28 (70%) patients by 60 min at which time the mean (+/- 1 SD) plasma glucose level in the Type I diabetic patients had reduced from 18.2 +/- 4.9 to 8.9 +/- 3.5 mmol/1 and in the Type II diabetic patients from 12.3 +/- 3.1 to 5.9 +/- 1.4 mmol/1. None of the patients had symptomatic hypoglycaemia although in one Type I patient the plasma glucose level fell to 2.2 mmol/1. The rate of fall of glucose in the less insulin sensitive patients was not increased by giving more insulin. The regimen allows a reproducible and prompt glycaemic reduction in fasting diabetic patients.


Determinants of zinc potentiation on the alpha4 subunit of neuronal nicotinic receptors.
We have shown previously that the function of neuronal nicotinic acetylcholine receptors can be modulated by zinc. This modulation varies from potentiation to inhibition, depending on receptor subunit composition and zinc concentration, with the alpha4beta2 and alpha4beta4 receptors displaying the most dramatic potentiation. In this study, we used site-directed mutagenesis to identify glutamate 59 and histidine 162 on the rat alpha4 subunit as potential mediators of zinc potentiation. By modeling the extracellular domain of the receptor pentamer, we locate these residues to two subunit-subunit interfaces that alternate with the two acetylcholine-binding interfaces. Substitution of a cysteine at either position allows additional reduction of zinc potentiation upon treatment with the methanethiosulfonate reagents N-biotinoylaminoethyl methanethiosulfonate (MTSEA-biotin) and [2-(trimethylammonium)ethyl] methanethiosulfonate. Mutagenesis and methanethiosulfonate treatment are most effective at position 162, and the presence of zinc hinders the reaction of MTSEA-biotin with the substituted cysteine at this position, suggesting that alpha4His162 participates in forming a coordination site for zinc. Mutagenesis and methanethiosulfonate treatment are less effective at position 59, suggesting that whereas alpha4Glu59 may be near the zinc coordination site, it may not be participating in coordination of the zinc ion. It is noteworthy that the position of alpha4Glu59 within the neuronal nAChR is identical to that of a residue that lines the benzodiazepine-binding site on GABA(A) receptors. We suggest that the zinc potentiation sites on neuronal nAChRs are structurally and functionally similar to the benzodiazepine-binding sites on GABA(A) receptors.


Whole-genome diversity, population structure and linkage disequilibrium analysis of globally diverse wheat genotypes using genotyping-by-sequencing DArTseq platform.
In this study, 129 wheat genotypes from globally diverse origins were genotyped using DArTseq (SilicoDArT and SNP) markers. After filtering markers for quality-filtering, 14,270 SilicoDArTs and 6484 SNPs were retained and used for genetic diversity, population structure and linkage disequilibrium analyses. The highest number of SilicoDArT and SNP markers mapped on genome A and B compared to genome D. In both marker types, polymorphism information content (PIC) values ranged from 0.1 to 0.5, while > 0.80% of SilicoDArTs and > 0.44% SNPs showed PIC value more than median (0.25%). Un-weighted Neighbor Joining cluster analysis and Bayesian-based model population structure grouped wheat genotypes into three and four clusters, respectively. Principal component analysis and discriminant analysis of principal component results showed highly match with cluster and population structure analysis. Linkage disequilibrium (LD) was more extensive in both marker types, while graphical display of LD decay for both marker types showed that LD declined in the region close to 15 kbp, where r 2-values corresponded to r 2 = 0.16. Overall, our genetic diversity analysis showed high level of variation in studied wheat genotypes, even though there was no relationship between wheat grouping and origins. This might be attributed to admixture level that occurred during long-term natural selection of wheat genotypes in different parts of the world. Highly diverse wheat genotypes used in this study may possess unique genes and are useful sources in breeding programs to improve grain yield and quality.


Translation information processing is regulated by protein kinase C-dependent mechanism in Purkinje cells in murine posterior vermis.
The cerebellar posterior vermis generates an estimation of our motion (translation) and orientation (tilt) in space using cues originating from semicircular canals and otolith organs. Theoretical work has laid out the basic computations necessary for this signal transformation, but details on the cellular loci and mechanisms responsible are lacking. Using a multicomponent modeling approach, we show that canal and otolith information are spatially and temporally matched in mouse posterior vermis Purkinje cells and that Purkinje cell responses combine translation and tilt information. Purkinje cell-specific inhibition of protein kinase C decreased and phase-shifted the translation component of Purkinje cell responses, but did not affect the tilt component. Our findings suggest that translation and tilt signals reach Purkinje cells via separate information pathways and that protein kinase C-dependent mechanisms regulate translation information processing in cerebellar cortex output neurons.


Surface charged species and electrochemistry of ferroelectric thin films.
The combination of scanning probe microscopy and ambient pressure X-ray photoelectron spectroscopy opens up new perspectives for the study of combined surface chemical, electrochemical and electromechanical properties at the nanoscale, providing both nanoscale resolution of physical information and the chemical sensitivity required to identify surface species and bulk ionic composition. In this work, we determine the nature and evolution over time of surface chemical species obtained after water-mediated redox reactions on Pb(Zr0.2,Ti0.8)O3 thin films with opposite as-grown polarization states. Starting with intrinsically different surface chemical composition on the oppositely polarized films (as a result of their ferroelectric-dominated interaction with environmental water), we identify the reversible and irreversible electrochemical reactions under an external electric field, distinguishing switching and charging events. We find that while reversible ionic displacements upon polarization switching dominate screening in the bulk of the sample, polarization dependent irreversible redox reactions determine surface chemical composition, which reveals itself as a characteristic fingerprint of the ferroelectric polarization switching history.


Time-dependent density functional methods for Raman spectra in open-shell systems.
We present an implementation of a time-dependent density functional theory (TD-DFT) linear response module in NWChem for unrestricted DFT calculations and apply it to the calculation of resonant Raman spectra in open-shell molecular systems using the short-time approximation. The new source code was validated and applied to simulate Raman spectra on several doublet organic radicals (e.g., benzyl, benzosemiquinone, TMPD, trans-stilbene anion and cation, and methyl viologen) and the metal complex copper phthalocyanine. We also introduce a divide-and-conquer approach for the evaluation of polarizabilities in relatively large systems (e.g., copper phthalocyanine). The implemented tool gives comparisons with experiment that are similar to what is commonly found for closed-shell systems, with good agreement for most features except for small frequency shifts, and occasionally large deviations for some modes that depend on the molecular system studied, experimental conditions not being accounted in the modeling such as solvation effects and extra solvent-based peaks, and approximations in the underlying theory. The approximations used in the quantum chemical modeling include (i) choice of exchange-correlation functional and basis set; (ii) harmonic approximation used in the frequency analysis to determine vibrational normal modes; and (iii) short-time approximation (omission of nuclear motion effects) used in calculating resonant Raman spectra.


Do clinical prediction models improve concordance of treatment decisions in reproductive medicine?
To assess whether the use of clinical prediction models improves concordance between gynaecologists with respect to treatment decisions in reproductive medicine. We constructed 16 vignettes of subfertile couples by varying fertility history, postcoital test, sperm motility, follicle-stimulating hormone level and Chlamydia antibody titre. Thirty-five gynaecologists estimated three probabilities, i.e. the 1-year probability of spontaneous pregnancy, the pregnancy chance after intrauterine insemination (IUI) and the pregnancy chance after in vitro fertilisation (IVF). Subsequently they proposed therapeutic regimens for these 16 fictional couples, i.e. expectant management, IUI or IVF. Three months later, the participant gynaecologists again had to propose therapeutic regimes for the same 16 fictional cases but this time accompanied by pregnancy chances obtained from prediction models: predictions on spontaneous pregnancy, IUI and IVF. Thirty-five gynaecologists working in academic and nonacademic hospitals in the Netherlands. Setting section. Main outcome measures The concordance between gynaecologists of probability estimates, expressed as interclass correlation coefficient (ICC) and the concordance between gynaecologists of treatment decisions, analysed by calculating Cohen's kappa (kappa). The gynaecologists differed widely in estimating pregnancy chances (ICC: 0.34). Furthermore, there was a huge variation in the proposed therapeutic regimens (kappa: 0.21). The treatment decisions made by gynaecologists were consistent with the ranking of their probability estimates. When prediction models were used, the concordance (kappa) for treatment decisions increased from 0.21 to 0.38. The number of gynaecologists counselling for expectant management increased from 39 to 51%, whereas counselling for IVF dropped from 23 to 14%. Gynaecologists differed widely in their estimation of prognosis in 16 fictional cases of subfertile couples. Their therapeutic regimens showed likewise huge variation. After confrontation with prediction models in the same 16 fictional cases, the proposed therapeutic regimens showed only slightly better concordance. Therefore a simple introduction of validated prediction models is insufficient to introduce concordant management between doctors.


Fast and accurate inference of local ancestry in Latino populations.
It is becoming increasingly evident that the analysis of genotype data from recently admixed populations is providing important insights into medical genetics and population history. Such analyses have been used to identify novel disease loci, to understand recombination rate variation and to detect recent selection events. The utility of such studies crucially depends on accurate and unbiased estimation of the ancestry at every genomic locus in recently admixed populations. Although various methods have been proposed and shown to be extremely accurate in two-way admixtures (e.g. African Americans), only a few approaches have been proposed and thoroughly benchmarked on multi-way admixtures (e.g. Latino populations of the Americas). To address these challenges we introduce here methods for local ancestry inference which leverage the structure of linkage disequilibrium in the ancestral population (LAMP-LD), and incorporate the constraint of Mendelian segregation when inferring local ancestry in nuclear family trios (LAMP-HAP). Our algorithms uniquely combine hidden Markov models (HMMs) of haplotype diversity within a novel window-based framework to achieve superior accuracy as compared with published methods. Further, unlike previous methods, the structure of our HMM does not depend on the number of reference haplotypes but on a fixed constant, and it is thereby capable of utilizing large datasets while remaining highly efficient and robust to over-fitting. Through simulations and analysis of real data from 489 nuclear trio families from the mainland US, Puerto Rico and Mexico, we demonstrate that our methods achieve superior accuracy compared with published methods for local ancestry inference in Latinos.


Limits to trophic levels and omnivory in complex food webs: theory and data.
While trophic levels have found broad application throughout ecology, they are also in much contention on analytical and empirical grounds. Here, we use a new generation of data and theory to examine long-standing questions about trophic-level limits and degrees of omnivory. The data include food webs of the Chesapeake Bay, U.S.A., the island of Saint Martin, a U.K. grassland, and a Florida seagrass community, which appear to be the most trophically complete food webs available in the primary literature due to their inclusion of autotrophs and empirically derived estimates of the relative energetic contributions of each trophic link. We show that most (54%) of the 212 species in the four food webs can be unambiguously assigned to a discrete trophic level. Omnivory among the remaining species appears to be quite limited, as judged by the standard deviation of omnivores' energy-weighted food-chain lengths. This allows simple algorithms based on binary food webs without energetic details to yield surprisingly accurate estimates of species' trophic and omnivory levels. While maximum trophic levels may plausibly exceed historically asserted limits, our analyses contradict both recent empirical claims that these limits are exceeded and recent theoretical claims that rampant omnivory eliminates the scientific utility of the trophic-level concept.


Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow.
Vascular endothelial cells (ECs) are exposed to different flow patterns (i.e., disturbed vs. laminar), and the associated oscillatory shear stress (OSS) or pulsatile shear stress (PSS) lead to differential responses. We investigated the roles of class I and II histone deacetylases (HDAC-1/2/3 and HDAC-5/7, respectively) in regulating NF-E2-related factor-2 (Nrf2) and Krüppel-like factor-2 (KLF2), two transcription factors governing many shear-responsive genes, and the cell cycle in ECs in response to OSS. Application of OSS (0.5 ± 4 dynes/cm(2)) to cultured ECs sustainably up-regulated class I and II HDACs and their nuclear accumulation, whereas PSS (12 ± 4 dynes/cm(2)) induced phosphorylation-dependent nuclear export of class II HDACs. En face immunohistochemical examination of rat aortic arch and experimentally stenosed abdominal aorta revealed high HDAC-2/3/5 levels in ECs in areas exposed to disturbed flow. OSS induced the association of HDAC-1/2/3 with Nrf2 and HDAC-3/5/7 with myocyte enhancer factor-2; deacetylation of these factors led to down-regulation of antioxidant gene NAD(P)H quinone oxidoreductase-1 (NQO1) and KLF2. HDAC-1/2/3- and HDAC-3/5/7-specific small interfering RNAs eliminated the OSS-induced down-regulation of NQO1 and KLF2, respectively. OSS up-regulated cyclin A and down-regulated p21(CIP1) in ECs and induced their proliferation; these effects were mediated by HDAC-1/2/3. Intraperitoneal administration of the class I-specific HDAC inhibitor valproic acid into bromodeoxyuridine (BrdU)-infused rats inhibited the increased EC uptake of BrdU at poststenotic sites. The OSS-induced HDAC signaling and EC responses are mediated by phosphatidylinositol 3-kinase/Akt. Our findings demonstrate the important roles of different groups of HDACs in regulating the oxidative, inflammatory, and proliferative responses of ECs to disturbed flow with OSS.


Crystal structures of brain group-VIII phospholipase A2 in nonaged complexes with the organophosphorus nerve agents soman and sarin.
Insecticide and nerve agent organophosphorus (OP) compounds are potent inhibitors of the serine hydrolase superfamily of enzymes. Nerve agents, such as sarin, soman, tabun, and VX exert their toxicity by inhibiting human acetycholinesterase at nerve synapses. Following the initial phosphonylation of the active site serine, the enzyme may reactivate spontaneously or through reaction with an appropriate nucleophilic oxime. Alternatively, the enzyme-nerve agent complex can undergo a secondary process, called "aging", which dealkylates the nerve agent adduct and results in a product that is highly resistant to reactivation by any known means. Here we report the structures of paraoxon, soman, and sarin complexes of group-VIII phospholipase A2 from bovine brain. In each case, the crystal structures indicate a nonaged adduct; a stereoselective preference for binding of the P(S)C(S) isomer of soman and the P(S) isomer of sarin was also noted. The stability of the nonaged complexes was corroborated by trypsin digest and electrospray ionization mass spectrometry, which indicates nonaged complexes are formed with diisopropylfluorophosphate, soman, and sarin. The P(S) stereoselectivity for reaction with sarin was confirmed by reaction of racemic sarin, followed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate each stereoisomer. The P(S) stereoisomers of soman and sarin are known to be the more toxic stereoisomers, as they react preferentially to inhibit human acetylcholinesterase. The results obtained for nonaged complexes of group-VIII phospholipase A2 are compared to those obtained for other serine hydrolases and discussed to partly explain determinants of OP aging. Furthermore, structural insights can now be exploited to engineer variant versions of this enzyme with enhanced nerve agent binding and hydrolysis functions.


Doctors' views about training and future careers expressed one year after graduation by UK-trained doctors: questionnaire surveys undertaken in 2009 and 2010.
The UK medical graduates of 2008 and 2009 were among the first to experience a fully implemented, new, UK training programme, called the Foundation Training Programme, for junior doctors. We report doctors' views of the first Foundation year, based on comments made as part of a questionnaire survey covering career choices, plans, and experiences. Postal and email based questionnaires about career intentions, destinations and views were sent in 2009 and 2010 to all UK medical graduates of 2008 and 2009. This paper is a qualitative study of 'free-text' comments made by first-year doctors when invited to comment, if they wished, on any aspect of their work, education, training, and future. The response rate to the surveys was 48% (6220/12952); and 1616 doctors volunteered comments. Of these, 61% wrote about their first year of training, 35% about the working conditions they had experienced, 33% about how well their medical school had prepared them for work, 29% about their future career, 25% about support from peers and colleagues, 22% about working in medicine, and 15% about lifestyle issues. When concerns were expressed, they were commonly about the balance between service provision, administrative work, and training and education, with the latter often suffering when it conflicted with the needs of medical service provision. They also wrote that the quality of a training post often depended on the commitment of an individual senior doctor. Service support from seniors was variable and some respondents complained of a lack of team work and team ethic. Excessive hours and the lack of time for reflection and career planning before choices about the future had to be made were also mentioned. Some doctors wrote that their views were not sought by their hospital and that NHS management structures did not lend themselves to efficiency. UK graduates from non-UK homes felt insecure about their future career prospects in the UK. There were positive comments about opportunities to train flexibly. Although reported problems should be considered in the wider context, in which the majority held favourable overall views, many who commented had been disappointed by aspects of their first year of work. We hope that the concerns raised by our respondents will prompt trainers, locally, to determine, by interaction with junior staff, whether or not these are concerns in their own training programme.


Opportunities and Challenges for ChatGPT and Large Language Models in Biomedicine and Health.
ChatGPT has drawn considerable attention from both the general public and domain experts with its remarkable text generation capabilities. This has subsequently led to the emergence of diverse applications in the field of biomedicine and health. In this work, we examine the diverse applications of large language models (LLMs), such as ChatGPT, in biomedicine and health. Specifically we explore the areas of biomedical information retrieval, question answering, medical text summarization, information extraction, and medical education, and investigate whether LLMs possess the transformative power to revolutionize these tasks or whether the distinct complexities of biomedical domain presents unique challenges. Following an extensive literature survey, we find that significant advances have been made in the field of text generation tasks, surpassing the previous state-of-the-art methods. For other applications, the advances have been modest. Overall, LLMs have not yet revolutionized biomedicine, but recent rapid progress indicates that such methods hold great potential to provide valuable means for accelerating discovery and improving health. We also find that the use of LLMs, like ChatGPT, in the fields of biomedicine and health entails various risks and challenges, including fabricated information in its generated responses, as well as legal and privacy concerns associated with sensitive patient data. We believe this survey can provide a comprehensive and timely overview to biomedical researchers and healthcare practitioners on the opportunities and challenges associated with using ChatGPT and other LLMs for transforming biomedicine and health.


Amblyopia screening in children in Bandar Abbas (Iran) during 2011-2012.
Amblyopia is an acquired defect of vision caused by abnormal visual experience that occurs during childhood. Since early diagnosis is important in preventing further irreparable effects, the aim of this study was to investigate the outcome of amblyopia screening in children. Data from the amblyopia screening program in the Welfare Department of Bandar Abbas during 2011-2012 were used. Suspected cases were referred to specialists in the Optometry clinic for screening purposes. Subsequently, patients who suffered from strabismus, amblyopia, or refractive errors were referred to ophthalmologists. SPSS version16 was used to analyze the data. The significance level was set at P < 0.05. Of the 16,599 children examined in 2012, 2486 suspected cases of amblyopia were diagnosed and 168 being diagnosed with amblyopia after visit with ophthalmologist. The prevalence rate of amblyopia was 1.01%. In 2011, of 17,733 cases, 2013 children were diagnosed as suspected cases and 171 patients were diagnosed to be amblyopic finally. The prevalence of amblyopia in this study was 0.96% and 1.01% in years 2011 and 2012 respectively, which was consistent with the results of studies in other countries. By considering the importance of diagnosing the prevalence of amblyopia on time in preschool and in order to prevent children`s low vision or blindness in future, it is essential to increase the quality of the examinations that are conducted by the trainers.


Viral vectors, animal models and new therapies for Parkinson's disease.
The involvement of alpha-synuclein in familial forms of Parkinson's disease suggests a potential causative role in the pathogenesis. We have explored the possibility of generating animal models of Parkinson's disease by overexpressing alpha-synuclein in the nigrostriatal pathway using viral vectors. Both lentiviral and adeno-associated vectors efficiently transduce dopaminergic neurons in the substantia nigra, and transgenic expression of alpha-synuclein leads to the progressive loss of neurons positive for dopaminergic markers, with the formation of intraneuronal alpha-synuclein aggregates. With a high tropism for nigral dopaminergic neurons, adeno-associated vectors allow for the monitoring of dopaminergic function using spontaneous and drug-induced behaviour. We propose that virus-based rodent alpha-synuclein models provide a valuable approach for the preclinical testing of therapeutics.


Resting network plasticity following brain injury.
The purpose of this study was to examine neural network properties at separate time-points during recovery from traumatic brain injury (TBI) using graph theory. Whole-brain analyses of the topological properties of the fMRI signal were conducted in 6 participants at 3 months and 6 months following severe TBI. Results revealed alterations of network properties including a change in the degree distribution, reduced overall strength in connectivity, and increased "small-worldness" from 3 months to 6 months post injury. The findings here indicate that, during recovery from injury, the strength but not the number of network connections diminishes, so that over the course of recovery, the network begins to approximate what is observed in healthy adults. These are the first data examining functional connectivity in a disrupted neural system during recovery.


The dishevelled protein is modified by wingless signaling in Drosophila.
Wingless (Wg) is an important signaling molecule in the development of Drosophila, but little is known about its signal transduction pathway. Genetic evidence indicates that another segment polarity gene, dishevelled (dsh) is required for Wg signaling. We have recently developed a cell culture system for Wg protein activity, and using this in vitro system as well as intact Drosophila embryos, we have analyzed biochemical changes in the Dsh protein as a consequence of Wg signaling. We find that Dsh is a phosphoprotein, normally present in the cytoplasm. Wg signaling generates a hyperphosphorylated form of Dsh, which is associated with a membrane fraction. Overexpressed Dsh becomes hyperphosphorylated in the absence of extracellular Wg and increases levels of the Armadillo protein, thereby mimicking the Wg signal. A deletional analysis of Dsh identifies several conserved domains essential for activity, among which is a so-called GLGF/DHR motif. We conclude that dsh, a highly conserved gene, is not merely a permissive factor in Wg signaling but encodes a novel signal transduction molecule, which may function between the Wg receptor and more downstream signaling molecules.