We revisit known constructions of efficient learning algorithms from various notions of constructive circuit lower bounds such as distinguishers breaking pseudorandom generators or efficient witnessing algorithms which find errors of small circuits attempting to compute hard functions. As our main result we prove that if it is possible to find efficiently, in a particular interactive way, errors of many p-size circuits attempting to solve hard problems, then p-size circuits can be PAC learned over the uniform distribution with membership queries by circuits of subexponential size. The opposite implication holds as well. This provides a new characterisation of learning algorithms and extends the natural proofs barrier of Razborov and Rudich. The proof is based on a method of exploiting Nisan-Wigderson generators introduced by Kraj\'{i}\v{c}ek (2010) and used to analyze complexity of circuit lower bounds in bounded arithmetic. An interesting consequence of known constructions of learning algorithms from circuit lower bounds is a learning speedup of Oliveira and Santhanam (2016). We present an alternative proof of this phenomenon and discuss its potential to advance the program of hardness magnification.


Background: Keloid and hypertrophic scars (HTS) caused by an imbalance between the production and destruction of collagen during wound healing with an unknown underlying pathophysiological mechanism. This study was designed to evaluate the histamine level in the Keloid and HTS and comparison of results with normal skin.
Materials and Methods: This pilot study included 36 participants, aged from 18 to 70 years with keloid (n=11), HTS (n=13) and normal (n=12) skin. The level of histamine in the skin samples was measured using enzyme-linked immunosorbent assay (ELISA).
Results: Histamine level in keloid samples was significantly higher than in the normal (p=0.0012) or HTS (p=0.0028) groups. However, there was no significant difference between the normal and HTS samples (p=0.92).
Conclusion: The increased histamine level in the keloid tissue may contribute to its pathogenesis and the application of anti-histamines could be of benefit for the prevention and treatment of keloids.


We present numerical results relative to a bistable optical device comprised of an asymmetric Fabry-Perot cavity embedding a nonlinear optical medium. Both the real and imaginary part of the third order nonlinear susceptibility are considered in our calculations. Optimized device operation, expressed in terms of the contrast ratio between the two stable states, is then discussed as a function of the different cavity parameters. The presented method can be a useful tool for designing practical devices with application in the field of all-optical switching, optical regeneration and optical signal processing.


Compared to human‐ and wildlife‐transmitted pathogens, less emphasis has been placed on developing models of plant pathogen transmission by insects. Here, we describe the transmission ecology of the bacterium Xylella fastidiosa Wells et al., the causal agent of Pierce's disease in grapevines, by its leafhopper vectors. First, we performed a meta‐analysis of transmission studies of X. fastidiosa by its two most important vectors in the Western USA, the invasive glassy‐winged sharpshooter, Homalodisca vitripennis Germar, and the native blue‐green sharpshooter, Graphocephala atropunctata Signoret (both Hemiptera: Cicadellidae). The importance of vector number, pathogen acquisition period, and inoculation access period (IAP) for transmission differed between the two species. We fit these transmission datasets to two biologically derived transmission models, i.e., a binomial and a Poisson probability model. The Poisson model provided substantially better fit and produced estimates of H. vitripennis transmission efficiency that were dramatically lower than for G. atropunctata. We also conducted a separate pair of experiments that decoupled vector number from IAP. These experiments supported the results of the meta‐analysis. Interestingly, high vector loads not only increased transmission rate, but also shortened X. fastidiosa incubation period in grapevines. This work provides quantitative estimates of transmission of an economically important pathogen that is analogous to risk models for arthropod‐vectored human and wildlife diseases. In addition, this work suggests that heterogeneous vector loads may accelerate the disease cycle, increasing the potential for secondary spread in vineyards.


In this experimental investigation, a pulse flow control system on a high-lift device of a wing with a NASA SC(2)-0714 airfoil within the Reynolds number range of the take-off and landing phases, is proposed. In this study, an innovative method of signal modulation has been used in order to simultaneously exploit the benefits of both low and high excitation frequencies in one actuator driving signal that are known to be effective in separation control. It is observed that the lift and drag coefficients are improved due to the use of modulated pulse jets compared to the simple pulse jet. Keywords: Flow Control, High-lift configuration, Pulsed jet, Burst modulation, aerodynamic efficiency


Since the 1978 model year, Ford Motor Company (FORD) has been collecting and analyzing on-road fuel economy data for ford vehicles leased by company employees. Based on these data, on-road mpg for 1983-84 model passenger cars is approximately 40% better than for 1978 models. Also, the percent by which average on-road results are below EPA-approved CAFE values (i.e., mean ''% offset'') is 15% for recent models versus 20% for 1978 models. Since 1981, on-road results have been compared to label (i.e., ''city'') values approved by EPA to determine the percentage of drivers who meet or exceed the label mpg. For 1983 and 1984 models, on-road comparisons also are made to mpg values adjusted downward consistent with EPA's fuel economy labeling rules for 1985 models. Comparisons to EPA-approved CAFE and label values, plus to adjusted label values, also are made based on specific driving patterns and for summer vs. winter surveys.


The multi-source and single-sink (MSSS) topology is defined as the network topology in wireless sensor networks (WSNs), where all of nodes can gather, receive and transmit data to the sink. We consider the problem of finding the joint optimal scheme with consideration of physical, medium access control (MAC), and network layers to maximize the network lifetime (NL) for the MSSS topology in the energy-constrained WSNs. We note that the multiple-hop (MH) routing is globally optimal scheme to maximize the NL for the single-source and single-sink (SSSS) topology in WSNs. However, since the scheme will cause the source nearest to the sink to run out of its energy earliest in the MSSS case, the results for network lifetime maximization (NLM) in the SSSS topology cannot be directly applied to the MSSS case. The optimization problem, when the link access is an interference-free time division multiple access (TDMA) scheme, can be formulated as a mixed integer-convex programming. When the integer constraints are relaxed to be real values, it becomes a convex problem. First of all, we employ the Karush-Kuhn-Tucker(KKT) optimality conditions to derive analytical expressions of the globally optimal NL for a linear SSSS topology. Then a decomposition and combination (D&C) approach is proposed to obtain suboptimal solutions. As a result, an analytical expression of the suboptimal NL is derived for WSNs with a linear MSSS topology. We also derive the globally optimal NL in the planar SSSS network. The analytical results can be applied to obtain the results in the Planar MSSS case based on the D&C idea. To validate the analysis, numerical results show that the upper-bounds of the NL obtained by our proposed optimization models are tight.


This paper describes the rate of naturally occurring abortion and fetal death that were diagnosed by the use of an ultrasonographical device in 683 pregnant cynomolgus monkeys (Macaca fascicularis) of which 542 were wild-imported monkeys and 141 were colony-bred monkeys. All of these animals had become pregnant by the 3-day timed mating system. The combined rate of abortion and fetal death was 7.0% in the wild-imported animals and 7.8% in the colony-bred animals. There were no significant differences in the rate with respect to different ages and to different period of feeding at Tsukuba Primate Center. Seventy-eight per cent (38 monkeys) of the total cases occurred during the first 5 to 9 pregnancy-weeks.


Objective This study assessed the relation of stressful life events with survival after breast cancer. Methods This study was based on women with histologically confirmed, newly diagnosed, localized or regional stage breast cancer first treated in 1 of 11 Quebec City (Canada) hospitals from 1982 through 1984. Among 765 eligible patients, 673 (88%) were interviewed 3 to 6 months after diagnosis about the number and perceived impact of stressful events in the 5 years before diagnosis. Three scores were calculated: number of events; number weighted by reported impact; and for almost 80% of events, number weighted by community-derived values reflecting adjustment required by the event. Scores were divided into quartiles to assess possible dose-response relationships. Survival was assessed in 1993. Hazard ratios and 95% confidence intervals (CIs) comparing all-cause and breast cancer–specific mortality were calculated with adjustment for age, presence of invaded axillary nodes, adjuvant radiotherapy, and systemic therapy (ie, chemotherapy and hormone therapy). Results When quartiles 2, 3, and 4 were compared with the appropriate lowest quartile, adjusted hazard ratios for all-cause mortality were 0.99 (CI = 0.70–1.38), 0.97 (CI = 0.73–1.31), and 1.04 (CI = 0.78–1.40) for number, number weighted by impact, and number weighted by community-derived values, respectively. Results were essentially similar for the relation between stressful life events limited to those occurring within the 12 months before diagnosis and overall mortality and between stressful life events in the 5 years before diagnosis and breast cancer–specific mortality. Conclusions Stress was conceptualized as life events presumed to be negative, undesirable, or to require adjustment by the person confronting them. We found no evidence indicating that this kind of stress during the 5 years before diagnosis negatively affected survival among women with nonmetastatic breast cancer. Evidence from this study and others on the lack of effect of this type of stress on survival may be reassuring for women living with breast cancer.


Thyroid glands from 260 consecutive autopsies of patients over the age of 20 were examined. Seventeen (6.5%) latent carcinomas of the thyroid were found-11 papillary and 6 follicular. In 15 cases no metastases were found, but in two cases of latent papillary carcinoma diffuse metastases were present in the lungs at death. The frequency of carcinoma increased with age with a peak in the seventh decade. There was no female predominance. The tumors were more frequent in Jews born in Europe. The rates of adenoma, goiter and primary malignancies of other sites were increased in patients with latent thyroid carcinoma.


Background Treatment with TNF-α inhibitors (TNFi) is associated with an increased incidence rate (IR) of tuberculosis (TB).1 Proper screening can reduce TB IR.2,3 Recent reports suggest comparable TB IR for certolizumab (CZP) and monoclonal TNF-α inhibiting antibodies adalimumab ADA, golimumab (GOL) and infliximab (IFX) (0.47–0.69 vs 0.29–0.50 per 100 person years (PY), respectively).4 Etanercept (ETA) was associated with a TB IR of 0.009–0.08 per 100 PY.5–7 In February 2012 we showed that in our setting with a background annual TB IR of 8.4 per 105 persons and stringent screening for latent tuberculosis infection prior to the initiation of the first TNFi since 2002 a TB IR of 0.16 (95% CI 0.02–0.58) per 100 PY in RA patients treated with TNFi.8 Objectives To compare the TB IR in patients treated for RA with different TNFi. Methods In February 2015 we cross-linked the data from the mandatory BioRx.si and the national TB registries to identify cases of TB in patients who were ever treated with TNFi to avoid underreporting. TB IR for RA patients were calculated and compared for different TNFi. Results At the time of data extraction the BioRx.si contained data for 1693 RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients treated with at least one TNFi for 4574 PY. There were no TB cases among the patients with AS and PsA. In 945 RA patients treated with TNFi for 2453 PY (41% ADA, 9% CZP, 36% ETA, 4% GOL, 10% IFX) 5 cases of TB were identified (Table 1) which translates into an overall IR of 0.20 (95%CI 0.07–0.47) in RA patients. There were no TB cases in RA patients on GOL or IFX, but 3 on CZP, 1 on ADA, and 1 on ETA. The TB IR for CZP was 1.39 (95% CI 0.29–4.02) per 100 PY which is significantly higher than TB IR for ADA at 0.10 (95% CI 0.002–0.55; p=0.002) per 100 PY or ETA at 0.11 (95% CI 0.003–0.63; p=0.005) per 100 PY or all TNFi other than CZP combined at 0.09 (95% CI 0.01–0.32; p=0.006) per 100 PY.Table 1 Age (years) Sex TST (mm) CXR QF CP TNFi MP ever MP (mg qd) 54 F 18 – – yes ETA yes 8 57 F 20 – + yes CZP yes 4 62 M 0 – ND no ADA yes 4 70 F 10 – – no CZP no 0 80 F 0 – ND no CZP yes 4 F, female; M, male; MP, methylprednisolone; ND, not done; WNL, within normal limits; pts, patients; TNFi, tumor necrosis factor inhibitor; ADA, adalimumab; CZP, certolizumab; ETA, etanercept; RA, rheumatoid arthriti;, CP, tuberculosis chemoprophylaxis; TST, tuberculin skin test; QF, Quantiferon TB Gold test; CXR, chest X-ray suggestive of tuberculosis. Conclusions In our TNFi treated observational RA cohort, admitting all the shortcomings of the registry data, we observed a very strong signal suggesting a significantly higher TB IR in patients treated with CZP than those treated with any other TNFi. References Gόmez-Reino JJ et al. Arthritis Rheum 2003;48:2085–91. Carmona L et al. Arthritis Rheum 2005;52:1766–72. Gόmez-Reino JJ et al. Arthritis Rheum 2007;57:756–61. Ramiro S et al. Ann Rheum Dis 2010;69:522–8. Askling J et al. Arthritis Rheum 2005;52:1986–92. Tubach F et al. Arthritis Rheum 2009;60:1884–94. Dixon WG et al. Ann Rheum Dis 2010;69:522–8. Tomsic M et al. Ann Rheum Dis 2012;71:1909–11. Disclosure of Interest None declared


Passion fruit is a type of wild exotic plant in Malaysia. Common passion fruits planted in Malaysia are Passiflora edulis Sims (purple) and Passiflora edulis var flavicarpa (yellow). These fruits contain a high amount of antioxidants, polyphenols and vitamin C and are widely used as fruit juice, jam, and syrup product. However, there is a lack of information about the nutritional composition of the juice and seed of P. edulis (purple) cultivated in Malaysia. This study aims to determine the total phenolic contents, antioxidant activity and Vitamin C (ascorbic acid) content of P. edulis (purple) using two different solvent extraction, 70% of ethanol and 70% of methanol. The total phenolic content (TPC) was carried out by using Folin-Ciocalteu (FC) method, while the antioxidant activity was analysed using 1, 1-diphenyl-2-picrylhydrazyl (DPPH) assay to determine the IC 50 value of extracted samples. Ascorbic acid content from fresh juice and seeds samples were analysed by using Indophenol (DCPIP) method. The result showed that the extraction using ethanol produced the highest TPC with 9.249±0.04 mg GAE/g in seeds and 0.0139±0.02 mg GAE/g in juice, respectively. The lowest IC 50 value was obtained by a sample extracted with ethanol, which was 83.85±4.66 mg/L in seed and 305.47±5.28 mg/L in juice. The seed sample (53.68±4.95 mg/100mg) exhibited a high ascorbic acid content compared to the juice sample (46.66±3.28 mg/100mg). In conclusion, seeds of P. edulis possessed the strongest antioxidant activity and vitamin C content. This study could contribute to information regarding the phytochemical constituents and suitable solvents for extraction of phenolic compounds that can act as antioxidants and thus promote health effects on the human body.


This study aims to detect the food safety of blood coockle satay sold by street vendors in Surabaya Indonesia, in terms of bacterial contamination and Cadmium heavy metal content. This research is descriptive research with survey method. The sampling technique was carried out randomly from 15 street vendors, for further testing of bacterial contamination which included total bacteria, Coliform bacteria, and detection of heavy metal Cadmium (Cd) in blood coockle satay. The results showed that of all (15) satay samples studied have the average total microbes was 7.22 Log CFU/gr, Coliform bacterial contamination exceeded the maximum limit determined by the food regulatory agency Food and Drug Supervisory Agency of Republic Indonesia in 2009 ((> 3 MPN/gram). As many as 5 (33.33%) of the 15 samples of scallop satay containing heavy metal Cd exceeded the maximum limit determined by Food and Drug Supervisory Agency of Republic Indonesia in 2017 (> 0.1 mg/kg).


The negative KdV hierarchy is reobtained from the conformal invariance of its Schwartz form. By means of the Schrödinger operator, the negative KdV hierarchy can be rewritten to an equivalent differential equation system. The new method used for the KdV equation can be extended to get more symmetries from known ones for arbitrary partial differential equations without using a recursion operator. The general theory can also be used as a new criterion to verify whether a model is integrable or not. Using the new method on the KP equation, a set of infinitely many nonlocal symmetries and then a negative KP hierarchy is obtained. The negative KP hierarchy can also be written as an equivalent differential equation system by using two "time (y)" dependent Schrödinger operators. The only difference between the negative KdV hierarchy and the negative KP hierarchy is that one time independent Schrödinger operator in the KdV case is replaced by two time dependent Schrödinger operators in the KP case. A (2+1)-dimensional sinh-Gordon hierarchy is obtained from the negative KP hierarchy by using the (2+1)-dimensional Miura transformation.


This research is a case study of stakeholders' perceptions of learning and provision during a specific English language program. The pedagogical context of the program was clearly defined. English teachers from Hong Kong who had either Cantonese or Mandarin as their first language (L1) came to Australia for intensive language proficiency training and assessment. The Hong Kong government determined the program's syllabus, including assessment instruments and criteria in the Syllabus Specifications for the Language Proficiency Assessment for Teachers (English Language) (LPATE) (Government of the Hong Kong Special Administrative Region (HKSAR), 2000). The Australian provider had created the program from the specifications and had developed appropriate teaching and assessment materials for its implementation in all syllabus components. Additionally, the provider was responsible for administering and marketing the program. Delivery was in immersion mode with the Hong Kong teachers travelling to Australia and residing with Australian 'homestay' families for the 6-week program. The 'guiding issue/question' for the case study was: How did the multiple stakeholders perceive learning and provision? The study drew on a corpus of data collected from the perspectives of various stakeholders within provision of a 6-week in-service and education training program (INSET) (Bolam, 1986) for Chinese first language (L1) primary and secondary school teachers. Stakeholders represented in the study were teachers who participated as learners; the researcher who was a part-time language instructor; a course designer who was a full-time language instructor in the program; and an administrator who also held a wider role in the general marketing of INSET. Multiple forms of data were collected and analysed within a case study design (Stake, 1995, 2000). These included: a document analysis; pretest and posttest questionnaires; semi-structured interviews from individuals and focus groups; stimulated recall interviews from individuals; learner journals; and a researcher journal. Existing knowledge was reviewed through a search of literature, policies and accounts that examined four contextual layers that framed the study and situated it in terms of global, local and intercultural issues. Specifically, the layers were: (a) imperatives for Australian higher education to internationalise; (b) provision of INSET for teachers of English as a Second or Foreign Language (ESL/EFL); (c) language education and proficiency in Hong Kong; and (d) intercultural communication and culture learning as they pertained to an immersion program. While higher education institutions in Australia have recognised the imperative to internationalise, some recent initiatives are poorly researched. Bodycott and Crew (2001a, p. 23) noted a "dearth" (p. 2) of literature surrounding short-term, immersion versions of INSET such as that used in the current research. A review of literature where INSET had been used for the education of language teachers provided important insights into issues that might affect learning and provision. These involved the extent to which teachers' home country contexts were included in the design and content of programs, whether 'one-off' programs could be effective in the long-term, and what models underpinned the current design of INSET. The major gaps in the literature were (a) reported research on INSET where it is delivered as a short-term, immersion program to South East Asian teachers; and (b) published work on the LPATE as a learning-teaching experience. The current study attempted to address these gaps. While there was an absence of literature on the specific context of the INSET under study, the literature did reveal ways for the teacher/researcher to objectify and reflect on INSET provision. Literature on interactionism and social constructivism provided insights into the role and effect of the teacher/researcher in a data-gathering process. The case study approach was reviewed and Stake's (1995, 2000) design used in the study within a theoretical framework of social constructivism. In its reporting, the case accounts for forces of change surrounding the participants' INSET. These included the internationalisation of Australian higher education and curriculum reform in Hong Kong. At more personal levels, participants provided reflective data throughout the immersion experience. These data from the Hong Kong teachers indicated perceptions of strong positive growth in their English proficiency. This is an outcome consistent with the purpose of the INSET, which was to improve and benchmark proficiency standards. The data also revealed that the teachers had learned much about pedagogy and culture, which formed insights into intercultural negotiation and learning. The providers an administrator and an instructor supported accounts their learners had given of learning and provision. Yet, each had particular views regarding what constituted success in delivery of an INSET. While the case study provided detailed explication of the "nature" of this particular INSET, this researcher supports Crew and Bodycott's (2001) call for further, longitudinal research into the phenomenon. Drawing on findings from this study, specific research questions are suggested to investigate the effects of immersion INSET. Within the constraints of case study method, implications are drawn for the design and delivery of future short-term, immersion INSET. A detailed mapping of what stakeholders reported as culture learning and cross-cultural experiences provided an account of this aspect of the phenomenon. There was strong evidence that a component based on intercultural communication should be included in any future trial to inform INSET design. A new model, entitled 'Intercultural INSET', is proposed for future implementation and research. It incorporates domains of learning established from the case study data and is informed by a theoretical construct designed in the current study and termed, 'Positive Effect Chain'. The proposed model embeds the design within contexts significant to the teacher/participants and to their ongoing critical reflection. This ongoing reflection informs thinking about the proposed INSET course evaluation. Finally, the proposed model extends INSET into a post-immersion phase. This subsequent phase extends participants' INSET interaction, once they have returned to their own countries and to their work in home classrooms. The model seeks enduring and effective learning and requires trial and further study. The case study approach provided a successful vehicle for organising the data of the research and for framing the discussion. It also yielded indications as to the means by which INSET providers might structure ongoing feedback and assessment of their intended curriculum design. These indications are reflected in the proposed 'Intercultural INSET' design.


Data quality is a primary barrier to using electronic medical records (EMR) data for clinical and research purposes. Although EMR has been in use for a long time in LMICs, its data has been seldomly used. This study aimed to assess the completeness of demographic and clinical data in a tertiary hospital in Rwanda. We conducted a cross-sectional study and assessed 92,153 patient data recorded in EMR from October 1st to December 31st, 2022. The findings indicated that over 92% of social demographic data elements were complete, and the completeness of clinical data elements ranged from 27% to 89%. The completeness of data varied markedly by departments. We recommend an exploratory study to understand further reasons associated with the completeness of data in clinical departments.


Keywords: English day program, English speaking improvement
Speaking is a linguistic activity to share information because speaking is the productive oral skill in daily life. English day program is a program of language to improve proficiency in speaking. English day program implemented after school because it is including extracurricular activities that organized by an intra student organization. English day program based on habit in female student Wali Songo Islamic boarding school. This research aimed to know the implementation of English Day Program in English Speaking Improvement.
The method of this research was qualitative method. The data was taken from the field research in Wali Songo Islamic Boarding School Ngabar Siman Ponorogo, particularly in the 4th grade of female student Wali Songo Islamic Boarding School. The subjects of this research were 10 students and 1 organizer of language that purposively chosen by the researcher. The data collection used observation and interview techniques.
Based on the research result, English day program consists of idof (mastering vocabulary), conversation, tasji'ullughoh (mastering lesson), public speaking, and language area. The programs are implemented every day and every week. Students always apply what they have already gotten although in the school and extracurricular because all of that connected each other. Students feel that the practices in daily activities are forced but slowly they realize that the activities become their habit. The activities become a good program for language habit skill especially for student's speaking. Students learn language from the basic until they apply it every day and the environment supports the activities as well. So, the implementation of English day program has been improved well for students' speaking.
Finally, the researcher gives suggestion that language section should make this program more variety to motivate student fun and love in learning foreign language. Furthermore, LIS should also add facility for student in learning language. Last, the researcher hopes that the result of this study will be useful for the next researcher.


This study sought to determine if coccoid forms of Helicobacter pylori are virulent for gnotobiotic piglets. Coccoid forms were generated by maintaining broth cultures of H. pylori under microaerobic conditions for 16 days. The resulting cultures contained bacteria with a coccoid morphology that could not be cultured in vitro. Coccoid H. pylori did not colonize any of 6 gnotobiotic piglets that were inoculated, whereas bacillary H. pylori colonized 6 of 6 inoculated piglets. Piglets colonized by bacillary H. pylori developed lymphocytic gastritis, but no gastritis developed in piglets inoculated with coccoid H. pylori, and coccoid-inoculated piglets were sero-negative for H. pylori-specific antibody. Thus, coccoid H. pylori appears to be a degenerate nonviable morphologic phase.


Targeting of antigen to dendritic cells (DCs) increase the efficiency of immunization procedures and may facilitate the development of more effective vaccines. Several surface molecules on DCs have shown to be useful for antigen targeting, but many more deserves investigation for their efficacy in this respect. With this end in mind, a simple in vitro assay for screening of optimal targets for antigen‐delivery to murine DCs was established. Splenocytes from mice immunized with rat IgG were targeted in vitro with a panel of different rat monoclonal antibodies (mAbs) directed against surface markers on murine DCs. The resulting T‐cell activation was analysed by determining the number of IFN‐γ and IL‐4 secreting cells by ELISPOT. A positive effect of targeting was evident with several of the mAbs. Thus, mAbs against CD11c, CD36, CD205 and Clec7A all induced IFN‐γ responses that were significantly higher than those induced by non‐targeting control mAbs. Anti‐CD36 also induced IL‐4 responses that were significantly higher than the control. The assay described here allows simultaneous analysis of a large number of potential target structures and facilitates direct comparison between the different targets regarding the strength of the T‐cell responses induced by the targeted DCs. The assay could be useful as a first‐line screening of potential target structures on murine DCs.


The lay media have long come under attack for not adequately scrutinising the information emerging from Big Pharma about new prescription drugs, but now they stand accused of helping to publicise and promote drug company products. In a hardhitting article in the current issue of the prestigious US periodical the Columbia Journalism Review, the press is criticised, in its coverage of drug industry matters, for failing as a public watchdog. "Americans have always been obsessed with all things health-related," says the article, "but today a drug can move almost instantaneously from medical research to miracle cure through news media that too often seem more interested in hype and hope than in critically appraising new drugs on behalf of the public" (www.cjr.org/issues/2005/4/lieberman.asp).

The article's author, Trudy Lieberman, who is health policy editor of US watchdog organisation Consumers Union, blames various factors. In short, she says, journalists all too often fail to:

find information sources and case studies other than those offered by drug companies and their public relations people

disclose the financial or other interests of those they quote

seek out and evaluate research data.

Other factors exacerbate the situation, she says: there is the increasingly sophisticated way that drug companies hide aggressive marketing activities; there is the growth in direct to consumer advertising leading to conflict between advertising and editorial in media organisations; and there is the hard to break culture of newsrooms in which simplistic black and white stories are seen as so much sexier than reports painted in more realistic shades of grey. Ms Lieberman also points a finger at the US Food and Drug Administration and its "somewhat cozy relationship with the companies it regulates," which sees those reporters asking tough questions being "frozen out."

Overall, she says, such a mix finds the press caught up in a drug industry marketing web that leaves the public without a reliable watchdog.

Ms Lieberman—whose article analyses coverage of various drugs that have since been withdrawn, such as rofecoxib (Vioxx)—is writing about the United States, but the scenario she outlines is recognised all too clearly by Dr Ike Iheanacho, editor of the UK based Drug and Therapeutics Bulletin. "These themes of how the drug industry interacts with the public involving the media are universal and perennial," he says.

Dr Iheanacho points to the standard health reporting formula: "There's a `break-through,' an interview or quotes from somebody who has benefited, and maybe a quote from the manufacturer. You don't get a sense of balance, that there might be side effects, or that the drug might not even be available for a few years." He adds: "It takes time to be truly critical. Either you have to look at the studies yourself or talk to someone or several people in detail. Having done all that you may end up with a very confused picture and that doesn't make easy journalism."

Indeed, for journalists not content to settle for "easy journalism," reporting can be more than just time consuming. Jo Revill, health editor of the UK Sunday broadsheet the Observer, believes that UK journalists do at least display a greater scepticism toward the drug industry than their US counterparts—but you need more than scepticism to cover the health beat critically and effectively. The big drug companies, she says, are reluctant to talk to journalists outside of the trade press, and while invitations to press conferences about drug launches are forthcoming, "when you want to ask more detailed questions about a drug it can be really difficult getting information. The PRs won't deal with these questions and people in-house don't want to deal with you either."

On the other hand, when drug companies are keen to speak to journalists, they can be incredibly forthcoming—from offering trips abroad to attend launches to paying "honorariums" to attend evening "think tanks."

According to Dr Iheanacho, however, there are glimmers of hope for a better informed public. There are growing demands for clinical trial information to be made public and patients are exhibiting a new enthusiasm for asking questions about their health care. In addition, uncritical reporting often has a fixed lifespan: as in the case of Vioxx, today's miracle cure can turn out to be tomorrow's disaster. "The public will become more sceptical," he says.


Summary: Breasts reconstructed with implants, following mastectomy, lack the soft-tissue envelope of natural breasts. Further implant-related complications such as implant visibility, rippling/wrinkling, and/or hollowing/depression of the skin that often appear in the vicinity of the upper pole may be attributed to soft-tissue deficits. To address these shortcomings, the authors have developed the "bioengineered breast" concept that uses a combination of biological matrix and/or autologous fat grafting at the upper pole to augment the soft-tissue volume of breasts at the second stage of a two-stage breast reconstruction procedure. Enhancing the soft-tissue cover not only supplements volume and shape but further alters how the recipient's host tissue responds to the foreign body implant. The authors have used the bioengineered breast concept in over 500 reconstructions, with good outcomes and low complication rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.


In this paper we present the results  of a case study in a Swedish university regarding students' acceptance of digital exams. Technology Acceptance Model (TAM), which has been widely used in research concerning technology acceptance, was used to measure the level of students' acceptance of digital exams. The aim of the study is to investigate students' acceptance of digital exams and if there are any factors that are responsible for this behavior. A survey based on the two main factors of TAM, perceived ease of use and perceived usefulness, was conducted. The survey was targeting the degree of acceptance along with students' demographic characteristics. The results showed that the students demonstrated a high degree of acceptance of digital exams, with students in their second and third year having a more positive perception rather than students in their first year. However, other factors, such as gender, subject, and age did not appear to have a strong impact on the overall acceptance of digital exams but did show a moderate impact on external factors such as perceived accessibility and computer self-efficacy, which work as predictors for perceived ease of use for a system. Overall, the knowledge about the level of acceptance of the students is valuable since we can highlight strengths and weaknesses associated with digital exams. This can be a useful tool in deciding upon a suitable digital solution for digital exams, as well as in learning how to increase the level of acceptance among the students in the future.


Real-time and accurate detection of the sailing or water area will help realize unmanned surface vehicle (USV) systems. Although there are some methods for using optical images in USV-oriented environmental modeling, both the robustness and precision of these published waterline detection methods are comparatively low for a real USV system moving in a complicated environment. This paper proposes an efficient waterline detection method based on structure extraction and texture analysis with respect to optical images and presents a practical application to a USV system for validation. First, the basic principles of local binary patterns (LBPs) and gray level co-occurrence matrix (GLCM) were analyzed, and their advantages were integrated to calculate the texture information of river images. Then, structure extraction was introduced to preprocess the original river images so that the textures resulting from USV motion, wind, and illumination are removed. In the practical application, the waterlines of many images captured by the USV system moving along an inland river were detected with the proposed method, and the results were compared with those of edge detection and super pixel segmentation. The experimental results showed that the proposed algorithm is effective and robust. The average error of the proposed method was 1.84 pixels, and the mean square deviation was 4.57 pixels.


This paper presents a model for designing a distribution network considering the demand under uncertainty, in a multi-products and multiperiods environment. The proposal model integrates a Facility Location Problem and a Distribution Problem with fuzzy constraints in demands satisfying which is solved using the soft constraints method proposed by Zimmermman, which considers fuzzy parameters in the right hand side of a Mixed Integer Linear Programming problem and linear membership functions. The obtained results show how the localization of the plants and distribution centers can be conserved for different membership degrees, while there is a balance between the inventory and the cost.


The diversity of animal genetic resources has a qua si-public good nature that makes market prices inadequate indicator of its economic worth. Applying the characteristics theory of value, this research estimated the relati ve economic worth of the attributes of cattle genetic resources in Central Ethiopia. Trans action level data were collected over four seasons in a year and choice experiment survey was done in five markets to generate data on both revealed and stated preferences of cat tle buyers. Heteroscedasticity efficient estimation and random parameters logit were employe d to analyze the data. The results essentially show that attributes related to the sub si tence functions of cattle are more valued than attributes that directly influence mark etable products of the animals. The findings imply the strong need to invest on improve ment of attributes of cattle in the study area that enhance the subsistence functions o f cattle that their owners accord higher priority to support their livelihoods than they do to tradable products.


We propose a novel deep learning framework for sports field registration. The typical algorithmic flow for sports field registration involves extracting field-specific features (e.g., corners, lines, etc.) from field image and estimating the homography matrix between a 2D field template and the field image using the extracted features. Unlike previous methods that strive to extract sparse field features from field images with uniform appearance, we tackle the problem differently. First, we use a grid of uniformly distributed keypoints as our field-specific features to increase the likelihood of having sufficient field features under various camera poses. Then we formulate the keypoints detection problem as an instance segmentation with dynamic filter learning. In our model, the convolution filters are generated dynamically, conditioned on the field image and associated keypoint identity, thus improving the robustness of prediction results. To extensively evaluate our method, we introduce a new soccer dataset, called TS-WorldCup, with detailed field markings on 3812 time-sequence images from 43 videos of Soccer World Cup 2014 and 2018. The experimental results demonstrate that our method outperforms state-of-the-arts on the TS-WorldCup dataset in both quantitative and qualitative evaluations. Both the code and dataset are available online1.


In this paper, the speed regulation problem for permanent magnet synchronous motor (PMSM) systems under vector control framework is studied. A modified composite control strategy combining model reference adaptive control (MRAC) method and extended state observer (ESO) technology, called MRAC+ESO method, is proposed. Controller is designed for the speed loop of the permanent magnet synchronous motor (PMSM) to improve the performance of the system. The stability analysis, simulation and experimental results are presented to show the effectiveness of the proposed control method.


ABSTRACT Head and neck surgery is a well-defined discipline studied by general surgeons, otolaryngologists, plastic surgeons, and surgical oncologists, but there are few books designed to teach the basic principles of this discipline. One of these books appeared 13 years ago, Freund's Principles of Head and Neck Surgery. The author has now completely revised and updated the text in this second edition to incorporate new ideas and approaches to head and neck operations.The book's 12 chapters include the topics of diagnosis and methods of examination, behavior of head and neck tumors, technique of radical neck dissection, postoperative care, and reconstruction and rehabilitation. In addition, individual chapters are devoted to the oral cavity, larynx, salivary glands, thyroid, and maxilla.The highlight of the book is chapter four, a description of the technique of performing a radical neck dissection. It is one of the most detailed and well illustrated approaches in this


By means of a biographic analysis from historic sources an attempt is made to illustrate the psychopathologically relevant substratum of the life-history of Joan the Mad, Charles V., Philipp II. and Don Carlos. According to the author, it seems that, apart from the psychoanalytical concept, the phenomenological, descriptive-analytical procedure ist particularly suitable for the presentation of the mental aspect in the historiography.


Training GPs with real-life cases is evidence-based teaching. It is a powerful tool not only to manage uncertainty in general practice and to increase decision-making capacity but also to enhance quality of care, timely diagnosis, improved prognosis and survival of the patient and avoiding preventable deaths. In teaching with cases, co-operation between the general practitioner and other medical professionals acquires new dimensions, especially when targeting higher expertize. Using real-life cases is important both for presenting interesting difficult to interpret and ambiguous cases, as well as for the subsequent discussion and analysis, which usually goes beyond one or more differentiated medical specialties. We present three vascular cases as well as key points for discussing them: case 1 with aortic atherosclerosis of the aorta and left-artery artery and occlusion of the right artery; case 2 with deep venous thrombosis of the lower leg; case 3 of rupture of abdominal aneurysm. In conclusion teaching with vascular cases is not only an important part of the training of students and postgraduates to acquire a specialty in General practice/Family medicine, for continuing medical education of working physicians, but saves life and contributes to better quality of life


Machine learning technology helps multi-robot systems to carry out desired tasks in an unknown dynamic environment. In this paper, we extend the single-agent Q-learning algorithm to a multi-robot box-pushing system in an unknown dynamic environment with random obstacle distribution. There are two kinds of extensions available: directly extending MDP (Markov decision process) based Q-learning to the multi-robot domain, and SG-based (stochastic game based) Q-learning. Here, we select the first kind of extension because of its simplicity. The learning space, the box dynamics, and the reward function etc. are presented in this paper. Furthermore, a simulation system is developed and its results show effectiveness, robustness and adaptivity of this learning-based multi-robot system. Our statistical analysis of the results also shows that the robots learned correct cooperative strategy even in a dynamic environment.


Lysine monooxygenase catalyzes the oxygenative decarboxylation of L-lysine and produces a corresponding acid amide. L-Alanine was inactive as substrate. However, when propylamine was present, oxidation, but not oxygenation, of alanine was demonstrated with the oxygenase. Alanine was converted to pyruvate, with the liberation of ammonia and hydrogen peroxide, but propylamine remained unchanged. Other alpha-monoamino acids were also oxidized in the presence of alkylamines with various carbon chain lengths. The highest oxidase activity was observed when the total chain length of both amino acid and amine was nearly identical with that of lysine. Available evidence indicates that the amine-dependent amino-acid oxidase activity is associated with the lysine oxygenase activity.


Gene expression data (GED) can be indicative of the status of a cell, i.e., healthy or not, type 1 or type 2 of a disease, etc. However, GED differences between cells may be so subtle that most pattern recognition tools can not accurately discriminate them. Toure and Basu (2001) explored the ability of monolithic neural networks and modular neural networks to classify two type of acute leukemia: acute myeloid leukemia (AML) and acute lymphoblastic leukemia(ALL). In this work, we show that modular neural networks are better suited for GED based classification due the high dimensionality and multistructural properties of the input data. A modular network has the ability to examine the data simultaneously in more than one input space. This approach provides more information to the classifier and overcomes various limitations present in the training data.


This paper deals with an original method to estimate the noise introduced by optical imaging systems, such as CCD cameras, multispectral scanners and imaging spectrometers. The power of the signal-dependent photonic noise is decoupled from the power of the signal-independent noise generated by the electronic circuitry. The method relies on the multivariate regression of local sample statistics such as mean and variance, in which statistically homogeneous pixels produce scatter-points that are clustered along a straight line, whose slope and intercept measure the signal-dependent and signal-independent components of the noise power, respectively. Experimental results carried out on a simulated noisy image and on true data from a modern generation airborne imaging spectrometer highlight the accuracy of the proposed method and its robustness to image textures that may lead to a gross overestimation of the noise, especially for high SNR.


Catechin and their derivatives have been studied to have antiviral potential against COVID-19 through in silico method "pharmacokinetics screening and molecular docking". Pharmacokinetics and toxicity profiles were obtained through the ADMETSAR server and SwissADME server. Then proceed with the prediction of affinity through the method molecular docking using the software application MOE 2007.09. The test material is in the form of a 3D catechin structure and its derivatives as well as several control ligands downloaded via Pubmed. While template the Receptor M pro protein and the Spike glycoprotein are downloaded from pdb.org (PDB ID: 6LU7 and 6LXT). The pharmacokinetic profile of catechins is relatively better than all control ligands with the lowest toxicity. Molecular docking results also show that catechins and their derivatives have a stronger affinity than control ligands. This research proves that catechin has antiviral potential through inhibition of M pro protein and Spike glycoprotein COVID-19 virus.


Interest in measuring data citation and developing metrics for data is increasing. Despite this interest, basic bibliometric research investigating data sharing, data reuse and data citation practices remains relatively nascent. In this research in progress article, we use the DataCite GraphQL API to gather data for an initial investigation into dataset sharing and reuse as well as consider the current challenges. With over 8 million datasets in DataCite, we look at how datasets are dispersed by publication year, discipline, number of citations, license, institutional affiliation, and language. We find some patterns emerging, such as a recent increase in dataset publishing. However, there are still many limitations to doing this research that are discussed. As well, the future use of DataCite as a resource for doing this research and additional methods of analysis are considered.


It was performed a descriptive, transversal study in the medical office at Zamuro community, Saint Rafael parish, Tucupita, in Delta Amacuro state, the universe was made by the children between the etharian groups of 5 to 9 years old, the sample consisted on 112 children that came to the consult with clinical manifestations of intestinal parasitism produced by helminths, there were excluded  28 of them that did not fulfill the inclusion criteria, the patients were selected at random with the objective to show the behavior of the treatment with the pumpkin seeds for this parasitic illness, during the period between January to July, 2012. The male sex prevailed, obtaining the healing in children after the application of the treatment with the seed of pumpkin and it was evidenced the inocuity and effectiveness of the treatment, for that purpose it was performed a clinical comparison using the variable of time, before and after the treatment.


Tissue diagnosis with vitreous and/or retinal biopsy usually confirms the diagnosis of primary vitreoretinal lymphoma. Multiple imaging modalities like fundus fluorescein angiography, fundus autofluorescence, and optical coherence tomography have been used to support the diagnosis of vitreoretinal lymphoma. We report a case of a 74-year-old lady diagnosed with primary vitreoretinal lymphoma showing a novel fluorescein angiographic finding of capillary dropout. We hypothesize that this clinical finding on the fluorescein angiogram may be due to the occlusion of the retinal vasculature by the malignant tumor cells. This finding also suggests the possible intraocular invasion of the malignant lymphomatous cells into the inner retinal layers.


Aotearoa-New Zealand's urban streams are complex and diverse but have been degraded and neglected for years. For the most part, hegemonic management regimes are technocratic, separating streams into discrete parts, and thus have failed to improve or maintain the state of urban streams. The hydrosocial cycle is a way of exploring streams that takes account of whole systems, flows of water, more than humans, infrastructure and technology, and the social structures and institutions that make up water. The framework has been used to study the impacts of urbanisation on water around the world, including issues around stormwater, wastewater, water supply, and rivers, but it has rarely been used to study buried urban streams. This research uses a case study of the Waimapihi Stream in Te Whanganui-a-Tara-Wellington, Aotearoa-New Zealand to explore how the hydrosocial cycle could be used to understand urban streams. A hydrosocial approach, alongside a more-than-human methodology, demonstrated the varying meanings of the stream, including those of the different phases along its length. Connections to the buried section of the Waimapihi arose through the presence of fish, physical markers, and stories, but there was dissatisfaction with the extent of these. As a result, alternative methods of connection such as windows to the stream and areas of it to be daylighted were explored. A hydrosocial approach enabled an examination of meanings and values of the Waimapihi Stream; to encourage critical analysis of how streams are defined and how they are managed. This demonstrated that the hydrosocial cycle provides a valuable framework for understanding urban streams, as it encompasses the various components that make up urban streams and is flexible enough to explore the diversity between and within them.    Key words: Hydrosocial cycle, more-than-human, stormwater, wastewater, urban streams, Te Whanganui-a-Tara-Wellington, Aotearoa-New Zealand.


A model has been developed for calculating the rates of general corrosion of carbon steel and 13%Cr steel in aqueous systems containing carbon dioxide, hydrogen sulfide and other components. The model combines a comprehensive thermodynamic speciation module with electrochemical computations based on the mixed-potential theory. The electrochemical calculations recognize the effects of various partial cathodic and anodic processes and incorporate a model for the active-passive transition and the effect of solution species on passivity. The model has been verified by comparing calculated corrosion rates with experimental data over substantial ranges of temperature, pressure and solution composition. In particular, the effects of salinity, hydrogen sulfide and acetic acid on CO2 corrosion can be simulated. Very good agreement with experimental data has been obtained. The model has been implemented in a program that makes it possible to analyze the effects of various environmental variables on the rates of general corrosion.


This paper explores the challenges of evaluating social policies directed by states and highlights several lessons learned in this area through the Assessing the New Federalism project: broad-based analyses are hard, limits on research breadth are essential, data needs cannot be compromised, and clear, timely presentation of results is more important than ever. The paper also focuses on a particularly daunting analytic challenge: determining which state reforms are helping low-income citizens and advancing broader social objectives and which are not. The author examines four basic analytic techniques to determine their potential for measuring the contribution of policy reforms to outcomes.


Older drivers, who are the fastest growing segment of the U.S. population, experience high crash rates. An analysis was performed to evaluate potential problem maneuvers that may lead to higher crash involvement. Left turns against oncoming traffic, gap acceptance for crossing non-limited-access highways, and high-speed lane changes on limited-access highways are identified as such maneuvers. Older and younger driver accident propensities are measured, using Kentucky crash data. The findings of the analysis show that older drivers are more likely to be involved in crashes related with these maneuvers compared with younger drivers; older male drivers are safer than older female drivers in left-turn crashes and gap acceptance–related crashes, and having a passenger beside the older drivers makes for a safer driving environment. Potential countermeasures aiming to reduce the accident rates of older drivers are discussed.


Trust and reputation are central to effective interactions in open multi-agent systems in which agents, that are owned by a variety of stakeholders, can enter and leave the system at any time. This openness means existing trust and reputation models cannot readily be used. To this end, we present FIRE, a trust and reputation model that integrates a number of information sources to produce a comprehensive assessment of an agent's likely performance. Specifically, FIRE incorporates interaction trust, role-based trust, witness reputation, and certified reputation to provide a trust metric in virtually all circumstances. FIRE is empirically benchmarked and is shown to help agents effectively select appropriate interaction partners.


[reaction: see text] A novel organocatalytic, enantioselective domino double Michael addition reaction of alpha,beta-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate has been developed. The process is promoted by chiral diphenylprolinol TMS ether to give chiral tetrahydrothiophenes in high to excellent levels of enantioselectivities.


Background: Oxidative stress may be a key risk factor for cataract and glaucoma, and many previous reports have suggested that antioxidants could be a promising treatment. Here, we investigated the effects of a novel supplement containing three food-derived antioxidants (hesperidin, crocetin, and tamarindus indica) on markers of oxidative stress in patients with these conditions. Methods: This study had a prospective, single arm design. Fifty Japanese subjects with cataract and glaucoma were recruited and asked to refrain from the use of vitamin or carotenoid supplements for 2 weeks before the study. The subjects took 4 tablets together with ample water twice a day for 8 weeks, stopped the treatment, and were then followed for an additional 8 weeks. The subjects were examined at four-week intervals, for a total of 5 examinations. We measured biological antioxidant potential (BAP) with a free radical analyzer. Clinical laboratory data, including malondialdehyde (MDA) and superoxide dismutase (SOD), were measured in venous blood samples. Clinical parameters were also recorded. The Mann-Whitney U test and Fisher's exact test were used to determine the significance of differences between groups. Other comparisons used a one-way analysis of variance (ANOVA) followed by the Student's t-test or Dunnett's test.Results: BAP was significantly elevated at weeks 8, 12, and 16 (P = 0.007, P = 0.035, P = 0.015). The MDA level was significantly reduced at week 8 (P = 0.019). BAP changes were recorded by subtracting the value at week 8 from week 0. Multiple regression analysis revealed that SOD, total bilirubin and diabetes were independent contributing factors to the change in BAP (P = 0.039, P = 0.019, P = 0.013). There were no supplement-related adverse events or abnormal results in blood testing in any of the patients.Conclusion: Our study found that an 8-week oral course of antioxidant supplementation was effective in patients with a low antioxidative stress level. Dietary supplementation holds promise in the treatment of systemic oxidative stress-related diseases.Trial registration: UMIN-CTR UMIN 000032050


Background:
Surgical site infection (SSI) is one of the most common healthcare-associated infections. The use of negative pressure wound therapy (NPWT) has shown to decrease the overall rate of SSI, wound dehiscence, and length of hospital stay in surgical conditions. This study aims to determine the impact of NPWT applied on closed surgical incisions on patients with coexisting ostomy undergoing exploratory laparotomy.

Methods:
A retrospective study on patients who underwent exploratory laparotomies from 2017 to 2019 was conducted. NPWT was compared to standard post-operative surgical wound dressing. A sub-analysis of patients with ostomies was performed.

Results:
A total of 286 patients who underwent exploratory laparotomy were identified; 51 patients received NPWT and 235 received standard dressing. The NPWT group had a higher percentage of patients with an ostomy (37.3% vs 20.4%, P=.016), of which 25.5% were colostomies (vs 12.3%) and 11.8% were ileostomies (vs 8.1%) with P=.002. No significant difference in the overall rate of SSI (7.8% vs 5.5%, P= .517), wound dehiscence (7.8% vs 2.1 %, P=.057), and seroma formation (3.9% vs 2.1%, P=.612) were observed. The mean length of ICU stay (3.5 vs 7.0, P=.051) and unplanned reoperation (5.9% vs 16.6%, P=.051) were lower in the NPWT group compared to the control group. Sub analysis of patients with stoma found no significant difference in SSI.

Conclusions:
In our study, the use of NPWT on closed surgical incision wound was not associated with the reduction of SSI in patients with ostomies. Large studies are needed to ascertain significant benefits in patients with ostomies.

Keywords: negative pressure wound therapy, surgical site infection, ostomy, exploratory laparotomy


The changes in grain size and concentration with time were studied in relatively dilute settling suspensions of varying initial concentration and constituent grain size and composition. During single grain settling in distilled water and dispersant solution, i.e., in the absence of flocculation, a narrow range of sizes at a time were lost from suspension at a rate dependent on the initial size distribution. In salt water the importance of single grain settling relative to floe settling decreased with increase in concentration. The decrease in total concentration with time due to floe settling was proportional to the minus four-thirds power of the time. The overall sorting of the sediment had some effect on the flocculation rate but the effect of grain mineralogy appeared to be minor. Comparison between the size distributions of the settled sediment and textures of recent clastic sediments and experimental turbidites indicates that the relative effectiveness of single grain and floe settling largely determ...


The presence of adsorbate species on diamond surfaces, even in small concentrations, strongly influences electrical, chemical, and structural properties. Despite the technological significance, coverage of diamond by transition metals has received relatively little attention. In this paper, we present the results of density functional calculations examining up to a monolayer of selected metals (Cu, Ni, Ti, and V) on the (001) diamond surface. We find that addition of carbide forming species (Ti and V) results in significantly higher adsorption energies at all surface coverages relative to those of the non-carbide-forming species. For monolayer coverage by Cu or Ni, and submonolayer coverage by Ti and V, we find large, negative electron affinities. We propose that based upon the electron affinities and binding energies, metal-terminated (001) diamond surfaces are promising candidates for electron emission device applications. © 2012 American Physical Society.


Starting with the equations of motion for a perfect, incompressible fluid referred to a coordinate system which rotates about a vertical axis with uniform angular velocity R, the physical condition of 'small motion' is determined which permits the equations to be linearized. The small motions resulting from forced oscillations of a rotating liquid are investigated. It is shown that there are three types of flow depending on the relative magnitudes of the impressed frequency β and the angular velocity R of the fluid. Two of the regimes are studied in detail. A similarity law is developed which gives the solution of a class of problems of oscillations for β > 2R in terms of the solutions to similar irrotational problems. An attempt is made to explain how slow, two-dimensional motion can be produced by introducing a boundary condition which is three-dimensional (as observed in experiments performed by G. I. Taylor), by considering problems from the moment at which the disturbance is created from rest relative to the rotating system, with the only initial assumption that the fluid is rotating uniformly like a solid body. For the particular cases studied the results are in agreement with Taylor's experiments, in that the flow is found to become steady and two-dimensional if the disturbance which causes it approaches a steady state. If the disturbance is due to a body which moves along the axis of rotation of the fluid, the steady two-dimensional behaviour may be expected everywhere except in the neighbourhood of the surface of an infinite cylinder which encloses the body and whose generators are parallel to the axis of rotation. To resolve an apparent disagreement between certain theoretical results by Grace on the one hand, and experimental evidence by Taylor and the author's conclusions, on the other, arguments are advanced that the various results may be in agreement, provided Grace's are given a new interpretation.


Developing optimal strategies for constructing and testing decoding algorithms is an important question in computational neuroscience, In this field, decoding algorithms are mathematical methods that model ensemble neural spiking activity as they dynamically represent a biological signal. We present a recursive decoding algorithm based on a Bayesian point process model of individual neuron spiking activity and a linear stochastic state-space model of the biological signal. We assess the accuracy of the algorithm by computing, along with the decoding error, the true coverage probability of the approximate 0.95 confidence regions for the individual signal estimates. We illustrate the new algorithm by analyzing the position and ensemble neural spiking activity of CA1 hippocampal neurons from a rat foraging in an open circular environment The median decoding error during 10 minutes of open foraging was 5.5 cm, and the true coverage probability for 0.95 confidence regions was 0.75 using 32 neurons. These findings improve significantly on our previous results and suggest an approach to reading dynamically information represented in ensemble neural spiking activity.


Six Sigma is a methodology for process improvement as well as a statistical concept that looks for to determine the variation intrinsic in any process. Six Sigma represents process, that is having 3.4 defects per million opportunities. i.e. 99.99966 % of the products from a Six Sigma process are perfect. Firms can impact their sigma level by combining main principles from the Six Sigma methodology into leadership styles, process management, and improvement activities. Main principle of the technique is a focus on the customer. There are many challenges in the implementation of Six Sigma. A well-run manufacturing team can make the entire firm more successful through cost-saving measures, increased quality and a larger inventory of products that the company can market. The Six Sigma objective is to make sure the process has minimum defects(3.4 defects per million chances). Every aspect of the process must be carefully planned and documented in detail in order for manufacturing to go efficiently. The main aspect of Six Sigma for enhancement in the manufacturing industry is to maximize the financial returns.


A new model incorporating muscle fatigue has been developed to predict the effect of muscle fatigue on the force-time relationship of skeletal muscle by using the PAK-program. Differential equations in the incremental form have been implemented into Hill's muscle model. In order to describe the effect of muscle fatigue and recovery on skeletal muscle behaviors, a set of equations in terms of three phenomenological parameters which are a fatigue curve under sustained maximal activation, a recovery curve and an endurance function were developed. With reference to existing models and experimental results, the input parameters for fatigue curve under sustained maximal activation and endurance function were determined. The model has been investigated under an isometric condition. The effects of different shapes of the recovery curves have also been considered in this model. Validation of the model has been performed by comparing the predicted results with the experimental data from an existing literature.


The title compounds, bis(dimethylformamide)-1 kappa O,3 kappa O-bis[mu-2,2'-[2,2'-dimethylpropane-1,3-diylbis(nitrilomethylidyne)]diphenolato]-1 kappa(4)N,N',O,O':2 kappa(2)O,O';2 kappa(2)O,:3 kappa(4)N,N'prime prime or minute,O,O'-di-mu-nitrito-1:2 kappa(2)N:O;2:3 kappa(2)O:N-dinickel(II)cobalt(II), [CoNi(2)(NO(2))(2)(C(19)H(22)N(2)O(2))(2)(C(3)H(7)NO)(2)], (I), -copper(II), [CuNi(2)(NO(2))(2)(C(19)H(22)N(2)O(2))(2)(C(3)H(7)NO)(2)], (II), and -manganese(II), [MnNi(2)(NO(2))(2)(C(19)H(22)N(2)O(2))(2)(C(3)H(7)NO)(2)], (III), consist of centrosymmetric linear heterotrinuclear metal complexes. The three complexes are isostructural. There are three bridges across the Ni-M atom pairs (M is Co(2+), Cu(2+) or Mn(2+)) in each complex, involving two O atoms of a mu-N,N'-bis(salicylidene)-2,2'-1,3-propanediaminate ligand and an N-O moiety of a mu-nitrito group. The coordination sphere around each metal atom, whether Co(2+), Cu(2+), Mn(2+) or Ni(2+), can be described as distorted octahedral. The Ni...M distances are 2.9988 (5) A in (I), 2.9872 (5) A in (II) and 3.0624 (8) A in (III).


Familial polyposis coli has been considered a disease in which polyps are confined to the colon and rectum. The authors recently saw 3 cases in which either adenomatous or hyperplastic polyps were also present in the stomach and duodenum. The polyps were detected only by endoscopy or air-contrast radiographic examination. These cases and other recent studies indicate that gastric and duodenal polyps are more common in familial polyposis coli than previously recognized and should be considered an integral part of the syndrome.


Abstract Classifying gender compared to others and is used in this work. Biometry is the use of physical characteristics like face, fingerprints, iris, etc. of an individual for personal identification. Some of the difficult issues of face biometrics are face detection, face recognition, and face identification. These problems are being researched by the computer vision community for the last few decades. Considering the big population, the authentication process of an individual usually consumes a significant amount of time. One of the attainable solutions is to divide the population into two halves supported gender. This will facilitate to scale back the search area of authentication to nearly half the present information and save substantial quantity of your time. Gender identification through face demands use of sturdy discriminative options and strong classifiers to separate the feminine and male faces with no ambiguity. In this thesis, an investigation has been created on gender classification through facial pictures mistreatment principal part analysis ((2D) 2 PCA), and support vector machine (SVM). Principle Component Analysis (PCA) could be a spatial property reduction technique, which is used to represent each image as a feature vector in a low dimensional subspace. SVM could be a binary classifier that PCA is the input within the style of options and predicts which of the two attainable categories forms the output. Initially face region is extracted employing a planned complexion segmentation approach. The face region is then subjected to PCA for feature extraction that encodes second order statistics of information. These principal elements area unit fed as input to SVM for classification. Keywords: Biometrics, face detection, gender classification, (2D) 2 PCA, SVM


Dynorphin-A and its related peptides are derived from prodynorphin, one of the three known endogenous opioid precursors. The prodynorphin gene is expressed in the vasopressinergic magnocellular neurons of the hypothalamus, while its peptide products are present in the vasopressin (AVP) neurosecretory vesicles of the neurohypophysis. The concentration of immunoreactive (IR) dynorphin is orders of magnitude higher in the neurohypophysis than in any other tissue, suggesting that perhaps the prodynorphin-derived peptides are secreted from the hypothalamic-neurohypophyseal unit into the general circulation. Experiments in rats have shown that osmotic stimuli increase both AVP and prodynorphin in the hypothalamus. To determine whether human hypothalamic prodynorphin is also under osmotic regulation, we measured plasma IR-dynorphin, plasma IR-AVP, and serum sodium immediately before and during the infusion of normal or hypertonic saline in normal human volunteers. Because of the unusual susceptibility of the prodynorphin-derived peptides to cleavage by endopeptidases, we also developed an appropriate plasma dynorphin extraction technique. We found that the IR-dynorphin present in human plasma was composed of 6K- and 4K-sized peptides and that no larger than 6K or smaller than 4K dynorphins were present. The infusion of normal saline did not have any significant effect on plasma IR-dynorphin, while 3% hypertonic saline increased its plasma levels. Thus, the mean IR-dynorphin level in the plasma of the volunteers infused with normal saline was 40.3 +/- 6.4 fmol/mL (mean +/- SE; n = 6) at zero time; after 30 min of infusion, plasma IR-dynorphin was 36.0 +/- 6.3, after 60 min it was 29.9 +/- 5, after 90 min it was 36.0 +/- 4.7, after 120 min it was 36.8 +/- 3.2, and after 150 min it was 36.0 +/- 6.1. The plasma IR-dynorphin level in the volunteers infused with hypertonic saline was 31.7 +/- 3.5 fmol/mL (mean +/- SE; n = 10) at zero time. After 30 min of infusion it increased to 37.4 +/- 3.8, after 60 min to 46.4 +/- 7.7, after 90 min to 56.2 +/- 9.1, after 120 min to 53.6 +/- 8.7, and after 150 min to 99.0 +/- 14.2. The increase in plasma IR-dynorphin with time was significant (P less than 0.0001) and correlated positively with serum sodium and plasma AVP. The physiological role of the prodynorphin-derived peptides of the hypothalamic-neurohypophyseal unit is not yet known.(ABSTRACT TRUNCATED AT 400 WORDS)


This paper represent review on analysis of dome for different bracing system. In this work the proposed dome is modelled, analysis and design to be done by using SAP2000. The designed reinforced concrete domes have been made for normal braces i.e. polygonal faces, triangular faces, and zipper bracing system. The vertical member added in triangular faces i.e. strut is called as zipper frame. Analysis and design is done for three bracing system. These bracing systems are works as column and beam in dome structure. The diameter of dome is kept common for all three cases i.e. 80m dia. and rise of dome is 27m. Various loads are considered such as Dead load, Live load, Static and dynamic earthquake loads on dome structure and Response spectrum analysis method has been used.


MERLIN polarization measurements of 1665-,1667- and 1720-MHz OH masers in the bipolar outflow source W75N are presented. The OH masers are distributed over a region 5 arcsec across (10 000 au at 2 kpc), which is elongated in a north-west‐ south-east (NW ‐SE) direction. The distribution is interpreted in terms of a rotating disc orthogonal to the bipolar outflow that is seen in CO and H2. A compact cluster of OH masers with a large velocity spread appears to mark the source of the outflow. Most of the OH masers detected have strong circular polarization up to 100 per cent. Seven Zeeman groups are identified, including the first example of a complete Zeeman triplet (two s-components and one p-component). The field strength measured from Zeeman pairs of opposite circular polarization ranges from 2 8 toa 8 mG, with a field reversal on opposite sides of the disc. This is interpreted in terms of a toroidal component of the magnetic field in the disc. Linear polarization is also detected in many of the OH masers with some 1665-MHz masers showing up to 100 per cent linear polarization. The polarization position angles are preferentially along the direction of the bipolar outflow or perpendicular to it. The polarization data lend support to the twisted magnetic field model originally proposed by Uchida & Shibata.


We present Flame Hydrolysis Deposition (FHD) silica micromilled with nanoscale surface roughness, sub-micron form control and micron scale depths of cut for photonic applications. Using our in-house developed high-precision micromill and industrially standard micromill tools, we have machined slots 1.5 mm long and 17 µm deep, enabling access and interaction with the evanescent field of nearby UV-written waveguides. Potential applications vary from: biological sensing, plasmonic devices, refractometers and chemical sensing. The micromilling approach offers advantages over conventional cleanroom and laser-based machining of optical materials in both form control and achievable surface roughness. To assess optimum cutting conditions a wide parameter test was conducted, where the rotational and translational speeds were varied and feed speeds optimized to allow cutting in the high-quality low-chipping ductile regime. Whilst milling in the ductile regime our smoothest form slots had a surface roughness of 3.0 nm (Sa) at a 17.0µm depth of cut. This represents a forty times increase in cut depth and an eight times improvement in surface roughness over previously reported silica slot micromilling. We will present our latest machining results with studies into sequential slot milling and report on the subsequent slot form, surface roughness, and mill wear from prolonged sequential machining. We will also show results of integrating milled slots with optical waveguides and Bragg gratings to create refractometer devices.


Given the importance of agriculture in developing economies, food processing industries often dominate the industrial sector when considering employment and value addition in these settings. For example, it is estimated that the food processing industry in Ethiopia employs 1 million people, around 2 percent of the economically active population. However, the way this food processing industry is changing and how it functions is little understood. Based on a unique survey, we study the case of markets in urban Ethiopia for commercial ready-to-eat enjera, the traditional staple pancake of the country. We find that commercial enjera markets are quickly growing, employing more than 100,000 people in urban Ethiopia. Moreover, enjera is now being prepared by mixing flour from locally produced teff with that of imported rice, thus absorbing an important part of the rapidly growing rice imports (almost 200 million USD in 2015) in the country, and leading to higher profits for those enterprises engaged in this type of mixing. Increasing numbers of enjera-making enterprises (EMEs) – which mostly employ women – are emerging. Further, we note upscaling by those enjera-making enterprises that supply the growing urban food service sector. Larger enjera-making companies have better quality, different procurement mechanisms and technologies, and higher value-added. These findings are important for the policy debates in Ethiopia on food systems transformation, employment and job creation, and international trade.


Introduction: In a serious brain disorder like Alzheimer's disease, the levels of acetylcholine (Ach) drop significantly. The gradual death of cholinergic brain cells leads to a profound loss of memory and learning ability. Acetylcholine is the chemical messenger that sends messages from one neuron to another in the area of the brain used for memory. Many of the current medications act to enhance the low levels of ACh in the patient's brain. For example; those that inhibit cholinesterase and prevent the normal breakdown of ACh. The presynaptic phospholipase A2 (PLA2) neurotoxins from snake venom including: Bungarotoxin, taipoxin, crotoxin, and ammodytoxin are primarily characterized by their ability to affect ACh release from motor nerve terminals on the indirectly stimulated twitch in vitro and respiratory failure in vivo. Materials and Methods: Lyophilized PLA2 neurotoxins, twitch tension recording and whole cell patch clamp recording. Results: All these PLA2 neurotoxins exhibit a triphasic modulation of ACh release at the neuromuscular junction on isolated mammalian nerve-muscle preparations. The first phase is a transient initial reduction in the amount of ACh release in response to an action potential, is followed by the second phase or facilitatory phase which is a period of time when ACh release is facilitated and quantal content is increased. Finally, the third phase is a progressive decline, leading to complete block of transmitter release. Although the mechanism of this facilitatory effect is unknown, but several hypotheses such as blockade of some types of K+ channels etc, have been suggested. With patch clamp experiments we found evidence that facilitation is not due to direct block of nerve terminal K+ channels. Conclusion: Despite elusive mechanism, understanding the mechanism by which PLA2 neurotoxins increase the release of ACh in phase II, may facilitate the development of novel therapeutic agents to improve Alzheimer's disease symptoms.


Communication is very important role for human life in socializing even in the teaching and learning process. This study describes prophetic communication in Islamic boarding school which aims to understand the process of prophetic communication in inviting non-resident Islamic Boarding School students to memorize the Qur'an. This study presents two substance problems, namely: 1) How does the implementation of prophetic communication in inviting non-resident students to memorize Al-Qur'an at Al-Ittifaqiah Islamic Boarding School ?. 2) What are the obstacles encountered when inviting non-resident students to memorize the Qur'an? To obtain answers to the problems above, this study uses descriptive qualitative research methods of analysis that is grouping data according to their categories and outlining all concepts related to the research discussion. The data sources of this study are non-resident students and tahfizh teachers of Al-Ittifaqiah Islamic Boarding School. Furthermore, data collection methods used are through observation, interviews, and documentation. The data obtained will be analyzed using data reduction, data presentation, and drawing conclusions. This research uses the theory of message reinforcement (reinforcement theory). The results of this study indicate that prophetic communication conducted by Al-Ittifaqiah Islamic Boarding School, namely the teachers communicate well (ma'ruf) to their students, so that it has a good effect on the students. Then provide motivation that can increase the spirit of memorizing the students. Socialization was also held by Islamic boarding schools by giving awards to high-achieving students. While the inhibiting factor in inviting non-resident students to memorize the Qur'an is, it is difficult to communicate directly with students because of the influence of distance. Then the residential environment that does not support where non-resident students do not live in boarding school resulting negligence in memorizing and inhibiting the process of memorizing students.


In this paper, a pixel structure called the optimal pseudoactive pixel sensor (OPAPS) is proposed and analyzed for the applications of CMOS imagers. The shared zero-biased-buffer in the pixel is used to suppress both dark current of photodiode and leakage current of pixel switches by keeping both biases of photodiode and parasitic pn junctions in the pixel bus at zero voltage or near zero voltage. The factor of photocurrent-to-dark-current ratio per pixel area (PDRPA) is defined to characterize the performance of the OPAPS structure. It is found that a zero-biased-buffer shared by four pixels can achieve the highest PDRPA. In addition, the column sampling circuits and output correlated double sampling circuits are also used to suppress fixed-pattern noise, clock feedthrough noise, and channel charge injection. An experimental chip of the proposed OPAPS CMOS imager with the format of 352/spl times/288 (CIF) has been designed and fabricated by using 0.25-/spl mu/m single-poly-five-level-metal (1P5M) N-well CMOS process. In the fabricated CMOS imager, one shared zero-biased-buffer is used for four pixels where the PDRPA is equal to 47.29 /spl mu/m/sup -2/. The fabricated OPAPS CMOS imager has a pixel size of 8.2/spl times/.2 /spl mu/m, fill factor of 42%, and chip size of 3630/spl times/3390 /spl mu/m. Moreover, the measured maximum frame rate is 30 frames/s and the dark current is 82 pA/cm/sup 2/. Additionally, the measured optical dynamic range is 65 dB. It is found that the proposed OPAPS structure has lower dark current and higher optical dynamic range as compared with the active pixel sensor (APS) and the conventional passive pixel sensor (PPS). Thus, the proposed OPAPS structure has high potential for the applications of high-quality and large-array-size CMOS imagers.


The addition of coal tar pitch mainly composed of polycyclic aromatic hydrocarbons (PAHs), increases the dilatation of coal. We investigated the effect of PAHs on the maximum dilatation (MD) of hard coking coals and semi-soft coking coals. Twenty-six kinds of PAHs and aliphatic hydrocarbon were used as additive agents. The use of a PAH with a molecular weight in the range 152.19–178.23 as an additive agent almost unchanged the MD. When a PAH with a molecular weight in the range 178.23–378.47 was added to the coal, the MD of the coal increased. The increase in MD achieved with the addition of 9,10-dihydrophen-anthrene was larger than that obtained with the addition of phenanthrene. This is likely because the hydrogen atoms in the ninth and tenth positions in 9,10-dihydrophenanthrene inhibit the polymerization of the coal structure. The MD was hardly affected by the addition of a linear aliphatic hydrocarbon (C 28 H 58 ) but MD decreased due to the addition of anthraquinone with carbonyl carbon. When a PAH with non-planar structure was added to the coal, the increase in MD was smaller than when a PAH with planar structure was added.


A temperature-dependent Raman scattering study of the E g(1) mode was carried out at 83 to 723K for nanocrystalline anatase TiO 2 with different sizes of 194,86 and 56nm. By means of a combined model of anharmonic coupling and phonon confinement,the E g(1) Raman spectra were fitted and calculated. The results show that,the temperature-dependent lattice vibration fundamentals are essentially the same for the three samples. The blue shift of Raman frequencies mainly comes from the contribution of three-phonon processes. In order to get good fittings,both the three- and four-phonon processes need to be considered. With increasing temperature,the four-phonon process becomes more important and counteracts the effect of the three-phonon process. The anharmonic-decay-related phonon lifetime increases as nanocrystalline size decreases,and the smaller nanoparticles have slower anharmonic decay. At low temperatures,the phonon confinement is responsible for a much shorter phonon lifetime for the 56-nm nanocrystals. The phonon confinement induces a blue shift of the E g(1) mode and an asymmetrical broadening at high frequencies. It has a relatively larger effect on the linewidth broadening than on the peak shift.


There is increasing evidence that infection with the Epstein-Barr virus (EBV) plays a role in the development of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS. This article provides a four-tier hypothesis proposing (1) EBV infection is essential for the development of MS; (2) EBV causes MS in genetically susceptible individuals by infecting autoreactive B cells, which seed the CNS where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells that would otherwise die in the CNS by apoptosis; (3) the susceptibility to develop MS after EBV infection is dependent on a genetically determined quantitative deficiency of the cytotoxic CD8+ T cells that normally keep EBV infection under tight control; and (4) sunlight and vitamin D protect against MS by increasing the number of CD8+ T cells available to control EBV infection. The hypothesis makes predictions that can be tested, including the prevention and successful treatment of MS by controlling EBV infection.


The aim of this paper is to examine the impact of liquidity on profitability in Nepalese commercial banks. Market price, earning per share, net profit margin and return on assets are taken as the indicators of profitability. Deposit-credit ratio, cash reserve ratio and capital adequacy ratio are taken as the indicators of liquidity. This study has tried to determine the association between liquidity and profitability indicators of 27 commercial banks out of 28 commercial banks in Nepal. The cross-sectional secondary data of these banks were used. Descriptive and causal comparative research strategies were applied to analyse the data. Correlation analysis and multiple general linear regression analysis were applied to establish the association. This study has found that there is no statistically significant association between liquidity and profitability indicators in Nepalese commercial banking industry. The data were analysed using statistical software mini tab.


Objective: We report a rare case of revision total knee arthroplasty for monoarthritis of the knee due to rheumatoid arthritis (RA). Case: The patient was a 72-year-old woman, who underwent revision surgery at 8 years and 7 months after left unicompartmental knee arthroplasty. Bacteriological examination of the synovial fluid was negative, and no crystals were found by microscopic examination. When the Knee Society score was determined, the knee score was 43 points and the function score was 45 points. No periprosthetic radiolucent lines were observed and there was no loosening. Erosion of the lateral femoral and tibial condyles was observed. CRP 3.6 mg/dL, erythrocyte sedimentation rate 129 mm/h, RF 101 U/mL, MMP3 732.2 ng/mL, anti-CCP antibody 190.3 U/mL. Revision TKA was done with a NexGen CR Flex (Zimmer Corp.) RA was diagnosed by histopathological examination of the synovium. Detailed investigation with bone scintigraphy and gallium scintigraphy did not identify inflammation of any other joints. However, pain and swelling of the right knee joint appeared 5 months after revision surgery, and right TKA was performed. Histopathological examination of the synovium resected from the right knee also revealed findings typical of RA. Discussion: Revision TKA is likely to increase in the future because of more patients undergoing UKA and an increase in the age of onset of RA. If knee pain occurs in patients after unicompartmental knee arthroplasty, monoarthritis due to RA should be considered as a possibility. Accordingly, we should follow patients after UKA while keeping the possibility of RA in mind.


Forty-nine different samples (crude oil, surface soil, produced water and sludge) from onshore oil fields in the Western Desert of Egypt were assessed for naturally occurring radioactive material (NORM) levels using HPGe gamma-ray spectrometer. The average activity concentrations of 226Ra, 232Th and 40K were 25 ± 1.3, 26 ± 1.0 and 21 ± 1.5; 9.8 ± 0.50, 11 ± 0.40 and 94 ± 6.9; 130 ± 6.6, 91 ± 3.4 and 41 ± 3.0; and 180 ± 16, 70 ± 6.9 and 1300 ± 110 Bq kg-1 for crude oil, surface soil, produced water and sludge, respectively. The obtained NORM levels are much below the International Atomic Energy Agency NORM clearance levels. Radiological parameters (radium equivalent activity, absorbed dose rate and annual effective dose) were calculated and compared with the international acceptable limits. The annual effective doses are below 1 and 20 mSv, the ICRP safety limits for the public and workers, respectively. Consequently, insignificant radiological hazards could present for the workers and surrounding environment from petroleum extraction activities in the studied area.


β-hemoglobinopathies are caused by mutations affecting the adult hemoglobin production. In sickle cell disease (SCD), the β6 Glu→Val substitution leads to sickle hemoglobin (HbS) polymerization and red blood cell (RBC) sickling. In β-thalassemia, reduced β-globin production leads to precipitation of uncoupled α-chains causing ineffective erythropoiesis and the production of poorly hemoglobinized RBCs. Transplantation of autologous, genetically modified hematopoietic stem/progenitor cells (HSPCs) is an attractive therapeutic option.
 The clinical severity of β-hemoglobinopathies is alleviated by the co-inheritance of mutations causing hereditary persistence of fetal Hb (HPFH). HPFH mutations clustering 200 nucleotides upstream of the TSS of the fetal γ-globin (HBG) genes either disrupt the binding site (BS) of the fetal Hb (HbF) repressor LRF or generate a de novo BS for the KLF1 activator. To reactivate γ-globin expression, nuclease-based approaches have been explored. However, nucleases generate double-strand breaks (DSBs), raising safety concerns for clinical applications. Base editing (BE) allows the introduction of point mutations without generating DSBs.
 In this study, we designed BE systems to introduce a variety of HPFH or HPFH-like mutations in the -200 region of the HBG promoters. First, we screened in erythroid cell lines known and novel BEs, and we selected combinations of BEs and guide RNAs that edit alternative bases of the -200 region. We then developed a clinically-relevant protocol based on RNA-transfection to deliver the BE system to HSPCs. The expression profile of genes activated by RNA stimuli revealed no immune response in HSPCs. A progenitor assay indicated no alteration in the growth and multilineage differentiation of edited HSPCs. We applied this protocol to SCD and β-thalassemia HSPCs, achieving editing efficiencies up to ~70% of the HBG promoters.
 In RBCs differentiated from edited SCD HSPCs, RT-qPCR, HPLC and flow cytometry showed a potent γ-globin reactivation with a high frequency of HbF + cells and a concomitant decrease in the HbS content/cell. Importantly, the pathological RBC sickling phenotype was corrected in the samples derived from edited HSPCs.
 Similarly, in β-thalassemia samples, RT-qPCR and HPLC analyses showed strong γ-globin induction and decrease of the α-globin precipitates. HbF expression rescued the delay in erythroid differentiation and ineffective erythropoiesis characterizing β-thalassemia, as demonstrated by the increased RBC enucleation rate and the reduced apoptosis and oxidative stress.
 We then compared BE strategies that either disrupt the LRF BS or create a de novo KLF1 BS in single colonies derived from erythroid progenitors. Generation of the KLF1 BS was associated with higher levels of HbF compared to the LRF BS disruption. These results suggest that eviction of the LRF repressor is sufficient to reactivate HBG genes, but recruitment of an activator is more effective to achieve high levels of gene expression. HbF expression induced by both LRF BS disruption and KLF1 BS generation was sufficient to rescue the SCD cell phenotype, but higher HbF levels - achieved only through KLF1 BS generation - were necessary to fully correct the β-thalassemia phenotype.
 In the majority of cases, we detected no DSB-induced insertions, deletions, or large genomic rearrangements in base-edited samples. Accordingly, DSB-induced DNA damage response (DDR) was absent in base-edited HSPCs, as measured by evaluating the expression of p21, a readout of p53-induced DDR. DNA off-target activity was assessed by GUIDE-seq and targeted sequencing of the potential off-target sites in edited HSPCs, while RNA off-target activity was evaluated by RNA-seq in HSPCs. Finally, BE-treated HSPCs were transplanted in immunodeficient mice to evaluate the engraftment and differentiation capability of edited HSCs. We detected good frequencies of human cells with up to ~60% of edited promoters in the peripheral blood of transplanted mice.
 In conclusion, we developed a clinically-relevant strategy to perform efficient BE in the HBG promoters that led to therapeutically-relevant HbF levels and rescued both the SCD and β-thalassemia phenotypes, thus providing sufficient proof of efficacy and safety to enable the clinical development of base-edited HSPCs for the therapy of β-hemoglobinopathies.

 El Nemer: Hemanext: Consultancy.


The regional geology of Colombia consists of a composite Palaeozoic to Cenozoic sedimentary basin overlying Precambrian shield rocks, which are exposed in the Eastern Cordillera, Magdalena Valley and at least part of the extensive Llanos Plains. A Palaeozoic metamorphic schist belt with abundant post-metamorphic igneous rocks comprises the Central Cordillera. A Mesozoic volcanic suite extends from the western flank of the Central Cordillera and accounts for the bulk of the Western Cordillera. A Cenozoic sedimentary sequence, probably overlying a Late Cretaceous oceanic crust and fore-arc complex, forms the Pacific Coastal Plain. The continental edge of central and southern Colombia is interpreted as a composite margin made up of successively-accreted oceanic island arc related sequences of Palaeozoic, Early Mesozoic and Late Cretaceous ages. The present-day cycle, which began in the Miocene, is not associated with island arc volcanism.


We report on the ninth evaluation campaign organized by the IWSLT workshop. This year, the evaluation offered multiple tracks on lecture translation based on the TED corpus, and one track on dialog translation from Chinese to English based on the Olympic trilingual corpus. In particular, the TED tracks included a speech transcription track in English, a speech translation track from English to French, and text translation tracks from English to French and from Arabic to English. In addition to the official tracks, ten unofficial MT tracks were offered that required translating TED talks into English from either Chinese, Dutch, German, Polish, Portuguese (Brazilian), Romanian, Russian, Slovak, Slovene, or Turkish. 16 teams participated in the evaluation and submitted a total of 48 primary runs. All runs were evaluated with objective metrics, while runs of the official translation tracks were also ranked by crowd-sourced judges. In particular, subjective ranking for the TED task was performed on a progress test which permitted direct comparison of the results from this year against the best results from the 2011 round of the evaluation campaign.