Pilot study of the association of the DDAH2 -449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis

Background

Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock.

Methodology/Principal Findings

In a prospective study, blood and buccal swabs were obtained from 82 patients ≤18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the −871 6g/7g insertion/deletion and −449G/C single nucleotide polymorphisms. Shock type (“warm” versus “cold”) was characterized by clinical assessment. The −871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between −871 6g/7g genotypes. While genotype frequencies also did not vary between groups for the −449G/C SNP (p = 0.75), septic patients with at least one −449G allele had lower ADMA (median, IQR 0.36, 0.30–0.41 µmol/L) than patients with the −449CC genotype (0.55, 0.49–0.64 µmol/L, p = 0.008) and exhibited a higher incidence of “cold” shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration.

Conclusions/Significance

The −449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with “cold” shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology.     

Thyroid Nodules and Thyroid Cancer

A review of clinical and laboratory features of thyroid cancer, designed to help in a more precise selection of patients for operation, showed that factors contributing to a high index of suspicion of cancer include previous exposure to low doses of radiation, the presence of a firm, solitary thyroid nodule clearly different from the rest of the gland, a young patient, nodules that are “cold” on scan with radioiodine, and nodules that fail to regress after an adequate trial of thyroxine therapy. Factors contributing to a low index of suspicion of thyroid cancer include soft or cystic lesions, multinodular goiters, nodules that are “hot” on ¹³¹ I scan, and those that regress during thyroxine treatment.When these factors are used to select patients for surgical operation, about 30 percent are found to have thyroid cancer.Until more precise methods for preoperative diagnosis are established, it is suggested that this type of clinical selection may be very helpful in the management of patients with thyroid nodules or nontoxic goiter.     

A cost-effectiveness analysis of "test" versus "treat" patients hospitalized with suspected influenza in Hong Kong

Background

Seasonal and 2009 H1N1 influenza viruses may cause severe diseases and result in excess hospitalization and mortality in the older and younger adults, respectively. Early antiviral treatment may improve clinical outcomes. We examined potential outcomes and costs of test-guided versus empirical treatment in patients hospitalized for suspected influenza in Hong Kong.

Methods

We designed a decision tree to simulate potential outcomes of four management strategies in adults hospitalized for severe respiratory infection suspected of influenza: “immunofluorescence-assay” (IFA) or “polymerase-chain-reaction” (PCR)-guided oseltamivir treatment, “empirical treatment plus PCR” and “empirical treatment alone”. Model inputs were derived from literature. The average prevalence (11%) of influenza in 2010–2011 (58% being 2009 H1N1) among cases of respiratory infections was used in the base-case analysis. Primary outcome simulated was cost per quality-adjusted life-year (QALY) expected (ICER) from the Hong Kong healthcare providers'' perspective.

Results

In base-case analysis, “empirical treatment alone” was shown to be the most cost-effective strategy and dominated the other three options. Sensitivity analyses showed that “PCR-guided treatment” would dominate “empirical treatment alone” when the daily cost of oseltamivir exceeded USD18, or when influenza prevalence was <2.5% and the predominant circulating viruses were not 2009 H1N1. Using USD50,000 as the threshold of willingness-to-pay, “empirical treatment alone” and “PCR-guided treatment” were cost-effective 97% and 3% of time, respectively, in 10,000 Monte-Carlo simulations.

Conclusions

During influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza, from the perspective of healthcare providers in Hong Kong.     

Molecular Diagnostics of Fine Needle Aspiration for the Presurgical Screening of Thyroid Nodules

“The incidence of thyroid cancer, the most common endocrine malignancy, is rising. The two most common types of thyroid cancer are papillary and follicular” thyroid carcinomas. “Fine-needle aspiration (FNA) of thyroid nodules” can permit to detect many genetic mutations and other molecular alterations, including RAS and BRAF point mutations, PAX8/peroxisome proliferator-activated receptor (PPAR)γ and “RET/PTC rearrangements, occurring in thyroid papillary and follicular carcinomas” (more than 70% of cases), which can be used successfully to improve the diagnosis “and the management of patients with thyroid nodules”. The most extensive experience has been accumulated with “the diagnostic use of BRAF mutation”, which is highly specific for malignancy. “Testing FNA samples for a panel of mutations” that typically includes RAS, BRAF, PAX8/PPARγ and RET/PTC could permit to achieve the biggest diagnostic impact. “The accuracy of cancer diagnosis in thyroid nodules could be improved significantly using these and other emerging molecular markers”.     

Growth and asymmetry of soil microfungal colonies from "Evolution Canyon," Lower Nahal Oren, Mount Carmel, Israel

Background

Fluctuating asymmetry is a contentious indicator of stress in populations of animals and plants. Nevertheless, it is a measure of developmental noise, typically obtained by measuring asymmetry across an individual organism''s left-right axis of symmetry. These individual, signed asymmetries are symmetrically distributed around a mean of zero. Fluctuating asymmetry, however, has rarely been studied in microorganisms, and never in fungi.

Objective and Methods

We examined colony growth and random phenotypic variation of five soil microfungal species isolated from the opposing slopes of “Evolution Canyon,” Mount Carmel, Israel. This canyon provides an opportunity to study diverse taxa inhabiting a single microsite, under different kinds and intensities of abiotic and biotic stress. The south-facing “African” slope of “Evolution Canyon” is xeric, warm, and tropical. It is only 200 m, on average, from the north-facing “European” slope, which is mesic, cool, and temperate. Five fungal species inhabiting both the south-facing “African” slope, and the north-facing “European” slope of the canyon were grown under controlled laboratory conditions, where we measured the fluctuating radial asymmetry and sizes of their colonies.

Results

Different species displayed different amounts of radial asymmetry (and colony size). Moreover, there were highly significant slope by species interactions for size, and marginally significant ones for fluctuating asymmetry. There were no universal differences (i.e., across all species) in radial asymmetry and colony size between strains from “African” and “European” slopes, but colonies of Clonostachys rosea from the “African” slope were more asymmetric than those from the “European” slope.

Conclusions and Significance

Our study suggests that fluctuating radial asymmetry has potential as an indicator of random phenotypic variation and stress in soil microfungi. Interaction of slope and species for both growth rate and asymmetry of microfungi in a common environment is evidence of genetic differences between the “African” and “European” slopes of “Evolution Canyon.”     

Early enteral feeding versus "nil by mouth" after gastrointestinal surgery: systematic review and meta-analysis of controlled trials

ObjectiveTo determine whether a period of starvation (nil by mouth) after gastrointestinal surgery is beneficial in terms of specific outcomes.DesignSystematic review and meta-analysis of randomised controlled trials comparing any type of enteral feeding started within 24 hours after surgery with nil by mouth management in elective gastrointestinal surgery. Three electronic databases (PubMed, Embase, and the Cochrane controlled trials register) were searched, reference lists checked, and letters requesting details of unpublished trials and data sent to pharmaceutical companies and authors of previous trials.ResultsEleven studies with 837 patients met the inclusion criteria. In six studies patients in the intervention group were fed directly into the small bowel and in five studies patients were fed orally. Early feeding reduced the risk of any type of infection (relative risk 0.72, 95% confidence interval 0.54 to 0.98, P=0.036) and the mean length of stay in hospital (number of days reduced by 0.84, 0.36 to 1.33, P=0.001). Risk reductions were also seen for anastomotic dehiscence (0.53, 0.26 to 1.08, P=0.080), wound infection, pneumonia, intra-abdominal abscess, and mortality, but these failed to reach significance (P>0.10). The risk of vomiting was increased among patients fed early (1.27, 1.01 to 1.61, P=0.046).ConclusionsThere seems to be no clear advantage to keeping patients nil by mouth after elective gastrointestinal resection. Early feeding may be of benefit. An adequately powered trial is required to confirm or refute the benefits seen in small trials.

What is already known on this topic

Enteral feeding within 24 hours after gastrointestinal surgery is toleratedTheoretically, early enteral feeding improves tissue healing and reduces septic complications after gastrointestinal surgery

What this study adds

There is no benefit in keeping patients “nil by mouth” after gastrointestinal surgerySeptic complications and length of hospital stay were reduced in those patients who received early enteral feedingIn patients who received early enteral feeding there were no significant reductions in incidence of anastomotic dehiscence, wound infection, pneumonia, intra-abdominal abscess, and mortality     

围小丛壳Glomerella cingulata子囊孢子交配繁殖、生物学特性及致病性

炭疽叶枯病（Glomerella leaf spot）是我国苹果上新发现的一种病害。为了解围小丛壳Glomerella cingulata子囊孢子的交配方式、生物学特性和致病性,从安徽砀山、山东牟平等地采集病害样品,经分离培养和纯化获得单孢菌株。在适宜条件下单孢菌株可产生子囊和子囊孢子,经过毛细管破子囊壁后单孢分离,获得12个子囊,每个子囊有8个子囊孢子。其中10个子囊中有4个“正”孢子（+）和4个“负”孢子（-）,2个子囊中只有“负”孢子。子囊孢子单孢菌株培养72h,“正”菌株菌落白色,以营养生长为主;“负”菌株菌落灰白色,直径略小于正菌株,菌丝稀疏,边缘菌丝白色,中部有大量橙色的分生孢子堆。“正”、“负”菌株异宗配合后,可产生大量可育子囊壳;单独的“正”菌株有性生殖产生稀疏丛簇状的可育子囊壳;单个的“负”菌株只能产生分散且不育的子囊壳。“正”、“负”菌株菌落的生长速度没有差异,对温度、营养、光照和pH值的敏感性也没有差异,但“正”、“负”菌株的致病性存在差异。正菌株的有性生殖没有导致rDNA-ITS、β-tubulin基因碱基序列变异。     

SCINTIGRAMS OF THE THYROID GLAND—The Diagnosis of Morphologic Abnormalities with I131

Functioning thyroid tissue containing sufficient radioiodine can be visualized by scanning the gland with a directional scintillation counter.⁴ This visual representation of the gland is called a “scintigram.” Scintigrams have been invaluable in the detection and study of both “toxic” and non-functioning nodules, diffuse enlargement in hyperthyroidism and the subsequent reduction in gland size after treatment, carcinoma, and aberrant thyroid tissue.     

Retention in care and connection to care among HIV-infected patients on antiretroviral therapy in Africa: estimation via a sampling-based approach

Introduction

Current estimates of retention among HIV-infected patients on antiretroviral therapy (ART) in Africa consider patients who are lost to follow-up (LTF) as well as those who die shortly after their last clinic visit to be no longer in care and to represent limitations in access to care. Yet many lost patients may have “silently” transferred and deaths shortly after the last clinic visit more likely represent limitations in clinical care rather than access to care after initial linkage.

Methods

We evaluated HIV-infected adults initiating ART from 1/1/2004 to 9/30/2007 at a clinic in rural Uganda. A representative sample of lost patients was tracked in the community to obtain updated information about care at other ART sites. Updated outcomes were incorporated with probability weights to obtain “corrected” estimates of retention for the entire clinic population. We used the competing risks approach to estimate “connection to care”—the percentage of patients accessing care over time (including those who died while in care).

Results

Among 3,628 patients, 829 became lost, 128 were tracked and in 111, updated information was obtained. Of 111, 79 (71%) were alive and 35/48 (73%) of patients interviewed in person were in care and on ART. Patient retention for the clinic population assuming lost patients were not in care was 82.3%, 68.9%, and 60.1% at 1, 2 and 3 years. Incorporating updated care information from the sample of lost patients increased estimates of patient retention to 85.8% to 90.9%, 78.9% to 86.2% and 75.8% to 84.7% at the same time points.

Conclusions

Accounting for “silent transfers” and early deaths increased estimates of patient retention and connection to care substantially. Deaths soon after the last clinic visit (potentially reflecting limitations in clinical effectiveness) and disconnection from care among patient who were alive each accounted for approximately half of failures of retention.     

Q-Elastography in the Presurgical Diagnosis of Thyroid Nodules with Indeterminate Cytology

Quantitative ultrasound (US) elastography (Q-USE), able to evaluate tissue stiffness has been indicated as a new diagnostic tool to differentiate benign from malignant thyroid lesions. Aim of this prospective study, conducted at the Department of Surgical Sciences, of the “Sapienza” University of Rome, was to evaluate the diagnostic accuracy of Q-USE, compared with US parameters, in thyroid nodules with indeterminate cytology (Thy3).The case study included 140 nodules from 140 consecutive patients. Patient’s thyroid nodules were evaluated by Q-USE, measuring the strain ratio (SR) of stiffness between nodular and surrounding normal thyroid tissue, and conventional US parameters prior fine-needle aspiration cytology. Those with Thy3 diagnosis were included in the study. Forty of the nodules analyzed harbored a malignant lesion. Q-USE demonstrated that malignant nodules have a significant higher stiffness with respect to benign one and an optimun SR cut-off value of 2.05 was individuated following ROC analysis. Univariate analysis showed that hypoechogenicity, irregular margins and SR >2.05 associated with malignancy, with an accuracy of 67.2%, 81,0% and 89.8%, respectively. Data were unaffected by nodule size or thyroiditis. These findings were confirmed in multivariate analysis demonstrating a significant association of the SR and the irregular margins with thyroid nodule’s malignancy. In conclusion, we demonstrated the diagnostic utility of Q-USE in the differential diagnosis of thyroid nodules with indeterminate cytology that, if confirmed, could be of major clinical utility in patients’ presurgical selection.     

Qualitative analysis of stroke patients' motivation for rehabilitation

ObjectiveTo explore the attitudes and beliefs of stroke patients identified by professionals as having either “high” or “low” motivation for rehabilitation.DesignQualitative study with semistructured interviews.SettingThe stroke unit of an inner city teaching hospital.Participants22 patients with stroke who were undergoing rehabilitation; 14 with high motivation for rehabilitation and eight with low motivation.ResultsAll patients thought rehabilitation was important for recovery. High motivation patients were more likely to view rehabilitation as the most important means of recovery and to accord themselves an active role in rehabilitation. These patients were also more likely to understand rehabilitation and in particular to understand the specialist role of the nursing staff. Many patients reported independence at home as a personal goal, though few low motivation patients related this goal to success in rehabilitation. Information from professionals about rehabilitation, favourable comparisons with other stroke patients, and the desire to leave hospital had a positive effect on motivation. Conversely, overprotection from family members and professionals, lack of information or the receipt of “mixed messages” from professionals, and unfavourable comparisons with other patients had a negative effect.ConclusionsThere are some differences in beliefs between stroke patients identified as having low or high motivation for rehabilitation. These beliefs seem to be influenced by the environment in which the patient is rehabilitated. Professionals and carers should be made aware of the ways in which their behaviour can positively and negatively affect motivation.     

Health insurance coverage of mothers and children (1974).

One aspect of establishing effective communication between physicians and patients has not received adequate attention: the special needs and challenges presented by patients with impaired hearing. In this article the term “hearing impaired” is generic and is applied to both those persons who are commonly labeled “deaf” and those labeled “hard of hearing” as a result of a bilateral hearing loss. The general skills, both verbal and nonverbal, that a physician must have in order to communicate successfully with a hearing-impaired patient are in essence the same as those required for a hearing patient. Where the divergence occurs is not in the basic skills (empathy, probing and the like) but rather in the means of applying them. Communicating with a hearing-impaired patient makes the use of some combination of the following necessary: speech, hearing, speechreading (lipreading), writing, visual aids, visual language systems and the assistance of an interpreter.     

Twin Town in South Brazil: A Nazi's Experiment or a Genetic Founder Effect?

Cândido Godói (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the “Twins'' Town” due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the “Nazi''s experiment” and of the “founder effect” hypotheses. We surveyed a total of 6,262 baptism records from 1959–2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the “Nazi''s experiment hypothesis”, there is no spurt in twinning between the years (1964–1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927–1958 and 1959–2008 (P = 0.638). On the other hand, the “founder effect hypothesis” is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the “Nazi''s experiment hypothesis” and strongly suggest that the “founder effect hypothesis” is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified.     

Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma

Background

A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC.

Methodology/Principal Findings

Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a “microglia-like” appearance on these cells which we termed “Ramified TAMs” (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells.

Conclusion

ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined.     

Crop shortages

A lack of breeders to apply the knowledge from plant science is jeopardizing public breeding programmes and the training of future plant scientistsIn the midst of an economic downturn, many college and university students in the USA face an uncertain future. There is one crop of graduates, though, who need not worry about unemployment: plant breeders. “Our students start with six-digit salaries once they leave and they have three or four offers. We have people coming to molecular biology and they can''t find jobs. People coming to plant breeding, they have as many jobs as they want,” said Edward Buckler, a geneticist with the US Department of Agriculture''s Agricultural Research Service Institute for Genomic Diversity at Cornell University (Ithaca, NY, USA).The lure of Big Ag depletes universities and research institutes of plant breeders […] and jeopardizes the training of future generations of plant scientists and breedersThe secret behind the success of qualified breeders on the job market is that they can join ‘Big Ag''—big agriculture—that is, major seed companies. Roger Boerma, coordinator of academic research for the Center for Applied Genetic Technologies at the University of Georgia (Athens, GA, USA), said that most of his graduate and postdoctoral students find jobs at companies such as Pioneer, Monsanto and Syngenta, rather than working in the orchards and fields of academic research. According to Todd Wehner, a professor and cucurbit breeder at the Department of Horticultural Science, North Carolina State University (Raleigh, NC, USA), the best-paying jobs—US$100,000 plus good benefits and research conditions—are at seed companies that deal with the main crops (Guner & Wehner, 2003). By contrast, university positions typically start at US$75,000 and tenure track.As a result, Wehner said, public crop breeding in the USA has begun to disappear. “To be clear, there is no shortage of plant breeders,” he said. “There is a shortage of plant breeders in the public sector.” The lure of Big Ag depletes universities and research institutes of plant breeders—who, after all, are the ones who create new plant varieties for agriculture—and jeopardizes the training of future generations of plant scientists and breeders. Moreover, there is an increasing demand for breeders to address the challenge of creating environmentally sustainable ways to grow more food for an increasing human population on Earth.At the same time, basic plant research is making rapid progress. The genomes of most of the main crop plants and many vegetables have been sequenced, which has enabled researchers to better understand the molecular details of how plants fend off pests and pathogens, or withstand drought and flooding. This research has also generated molecular markers—short regions of DNA that are linked to, for example, better resistance to fungi or other pathogens. So-called marker-assisted breeding based on this information is now able to create new plant varieties more effectively than would be possible with the classical strategy of crossing, selection and backcrossing.However, applying the genomic knowledge requires both breeders and plant scientists with a better understanding of each other''s expertise. As David Baulcombe, professor of botany at the University of Cambridge, UK, commented, “I think the important gap is actually in making sure that the fundamental scientists working on genomics understand breeding, and equally that those people doing breeding understand the potential of genomics. This is part of the translational gap. There''s incomplete understanding on both sides.”…applying the genomic knowledge requires both breeders and plant scientists with a better understanding of each other''s expertiseIn the genomic age, plant breeding has an image problem: like other hands-on agricultural work, it is dirty and unglamorous. “A research project in agriculture in the twenty-first century resembles agriculture for farmers in the eighteenth century,” Wehner said. “Harvesting in the fields in the summer might be considered one of the worst jobs, but not to me. I''m harvesting cucumbers just like everybody else. I don''t mind working at 105 degrees, with 95% humidity and insects biting my ankles. I actually like that. I like that better than office work.”For most students, however, genomics is the more appealing option as a cutting-edge and glamorous research field. “The exciting photographs that you always see are people holding up glass test tubes and working in front of big computer screens,” Wehner explained.In addition, Wehner said that federal and state governments have given greater priority and funding to molecular genetics than to plant breeding. “The reason we''ve gone away from plant breeding of course is that faculty can get competitive grants for large amounts of money to do things that are more in the area of molecular genetics,” he explained. “Plant breeders have switched over to molecular genetics because they can get money there and they can''t get money in plant breeding.”“The frontiers of science shifted from agriculture to genetics, especially the genetics of corn, wheat and rice,” agreed Richard Flavell, former Director of the John Innes Centre (Norwich, UK) and now Chief Scientific Officer of Ceres (Thousand Oaks, CA, USA). “As university departments have chased their money, chased the bright students, they have [focused on] programmes that pull in research dollars on the frontiers, and plant breeding has been left behind as something of a Cinderella subject.”In the genomic age, plant breeding has an image problem: like other hands-on agricultural work, it is dirty and unglamorousIn a sense, public plant breeding has become a victim of its own success. Wehner explained that over the past century, the protection of intellectual property has created a profitable market for private corporations to the detriment of public programmes. “It started out where they could protect seed-propagated crops,” he said. “The companies began to hire plant breeders and develop their own varieties. And that started the whole agricultural business, which is now huge.”As a result, Wehner said, the private sector can now outmanoeuvre public breeders at will. “[Seed companies] have huge teams that can go much faster than I can go. They have winter nurseries and big greenhouses and lots of pathologists and molecular geneticists and they have large databases and seed technologists and sales reps and catalogue artists and all those things. They can do much faster cucumber breeding than I can. They can beat me in any area that they choose to focus on.”He said that seed corporations turn only to public breeders when they are looking for rare seeds obtained on expeditions around the world or special knowledge. These crops and the breeders and other scientists who work on them receive far less financial support from government than do the more profitable crops, such as corn and soybean. In effect, these crops are in an analogous position to orphan drugs that receive little attention because the patients who need them represent a small economic market.The dwindling support for public breeding programmes is also a result of larger political developments. Since the 1980s, when British Prime Minister Margaret Thatcher and US President Ronald Regan championed the private sector in all things, government has consistently withdrawn support for public research programmes wherever the private sector can profit. “Plant breeding programmes are expensive. My programme costs about US$500,000 a year to run for my crops, watermelon and cucumber. Universities don''t want to spend that money if they don''t have to, especially if it''s already being done by the private sector,” Wehner said.“Over the last 30 years or so, food supplies and food security have fallen off the agenda of policymakers”…“Over the last 30 years or so, food supplies and food security have fallen off the agenda of policymakers,” Baulcombe explained. “Applied research in academic institutions is disappearing, and so the opportunities for linking the achievements of basic research with applications, at least in the public sector, are disappearing. You''ve got these two areas of the work going in opposite directions.”There''s another problem for plant breeding in the publish-or-perish world of academia. According to Ian Graham, Director of the Centre for Novel Agricultural Products at York University in the UK, potential academics in the plant sciences are turned off by plant breeding as a discipline because it is difficult to publish the research in high-impact journals.Graham, who is funded by the Bill & Melinda Gates Foundation to breed new varieties of Artemisia—the plant that produces the anti-malarial compound artemisinin—said this could change. “Now with the new [genomic] technologies, the whole subject of plant breeding has come back into the limelight. We can start thinking seriously about not just the conventional crops […] but all the marginal crops as well that we can really start employing these technologies on and doing exciting science and linking phenotypes to genes and phenotypes to the underlying biology,” he said. “It takes us back again closer to the science. That will bring more people into plant breeding.”…potential academics in the plant sciences are turned off by plant breeding as a discipline because it is difficult to publish the research in high-impact journalsBuckler, who specializes in functional genomic approaches to dissect complex traits in maize, wheat and Arabidopsis, said that public breeding still moves at a slower pace. “The seed companies are trying to figure out how to move genomics from gene discovery all the way to the breeding side. And it''s moving forward,” he said. “There have been some real intellectual questions that people are trying to overcome as to how fast to integrate genomics. I think it''s starting to occur also with a lot of the public breeders. A lot of it has been that the cost of genotyping, especially for specialty crops, was too high to develop marker systems that would really accelerate breeding.”Things might be about to change on the cost side as well. Buckler said that decreasing costs for sequencing and genotyping will give public breeding a boost. Using today''s genomic tools, researchers and plant breeders could match the achievements of the last century in maize breeding within three years. He said that comparable gains could be made in specialty crops, the forte of public breeding. “Right now, most of the simulations suggest that we can accelerate it about threefold,” Buckler said. “Maybe as our knowledge increases, maybe we can approach a 15-fold rate increase.”Indeed, the increasing knowledge from basic research could well contribute to significant advances in the coming years. “We''ve messed around with genes in a rather blind, sort of non-predictive process,” said Scott Jackson, a plant genomics expert at Purdue University (West Lafayette, IN, USA), who headed the team that decoded the soybean genome (Schmutz et al, 2010). “Having a full genome sequence, having all the genes underlying all the traits in whatever plant organism you''re looking at, makes it less blind. You can determine which genes affect the trait and it has the potential to make it a more predictive process where you can take specific genes in combinations and you can predict what the outcome might be. I think that''s where the real revolution in plant breeding is going to come.”Nevertheless, the main problem that could hold back this revolution is a lack of trained people in academia and the private sector. Ted Crosbie, Head of Plant Breeding at Monsanto (St Louis, MO, USA), commented at the national Plant Breeding Coordinating Committee meeting in 2008 that “[w]e, in the plant breeding industry, face a number of challenges. More plant breeders are reaching retirement age at a time when the need for plant breeders has never been greater […] We need to renew our nation''s capacity for plant breeding.”“…with the new [genomic] technologies, the whole subject of plant breeding has come back into the limelight”Dry bean breeder James Kelly, a professor of crop and soil sciences at Michigan State University (East Lansing, MI, USA), said while there has been a disconnect between public breeders and genomics researchers, new federal grants are designed to increase collaboration.In the meantime, developing countries such as India and China have been filling the gap. “China is putting a huge amount of effort into agriculture. They actually know the importance of food. They have plant breeders all over the place,” Wehner said. “The US is starting to fall behind. And now, agricultural companies are looking around wondering—where are we going to get our plant breeders?”To address the problem, major agriculture companies have begun to fund fellowships to train new plant breeders. Thus far, Buckler said, these efforts have had only a small impact. He noted that 500 new PhDs a year are needed just in maize breeding. “It''s not uncommon for the big companies like Monsanto, Pioneer and Syngenta to spend money on training, on endowing chairs at universities,” Flavell said. “It''s good PR, but they''re serious about the need for breeders.”The US government has also taken some measures to alleviate the problem. Congress decided to establish the US National Institute of Food and Agriculture (Washington, DC, USA) under the auspices of the US Department of Agriculture to make more efficient use of research money, advance the application of plant science and attract new students to plant breeding (see the interview with Roger Beachy in this issue, pp 504–507). Another approach is to use distance education to train breeders, such as technicians who want to advance their careers, in certificate programmes rather than master''s or doctorate programmes.“If [breeding] is not done in universities in the public sector, where is it done?”…“If [breeding] is not done in universities in the public sector, where is it done?” Flavell asked about the future of public breeding. “I can wax lyrical and perhaps be perceived as being over the top, but if we''re going to manage this planet on getting more food out of less land, this has to be almost one of the highest things that has got to be taken care of by government.” Wehner added, “The public in the developed world thinks food magically appears in grocery stores. There is no civilization without agriculture. Without plant breeders to work on improving our crops, civilization is at risk.”     

The Hot (Invisible?) Hand: Can Time Sequence Patterns of Success/Failure in Sports Be Modeled as Repeated Random Independent Trials?

The long lasting debate initiated by Gilovich, Vallone and Tversky in is revisited: does a “hot hand” phenomenon exist in sports? Hereby we come back to one of the cases analyzed by the original study, but with a much larger data set: all free throws taken during five regular seasons () of the National Basketball Association (NBA). Evidence supporting the existence of the “hot hand” phenomenon is provided. However, while statistical traces of this phenomenon are observed in the data, an open question still remains: are these non random patterns a result of “success breeds success” and “failure breeds failure” mechanisms or simply “better” and “worse” periods? Although free throws data is not adequate to answer this question in a definite way, we speculate based on it, that the latter is the dominant cause behind the appearance of the “hot hand” phenomenon in the data.     

Health Risk or Resource? Gradual and Independent Association between Self-Rated Health and Mortality Persists Over 30 Years

Background

Poor self-rated health (SRH) is associated with increased mortality. However, most studies only adjust for few health risk factors and/or do not analyse whether this association is consistent also for intermediate categories of SRH and for follow-up periods exceeding 5–10 years. This study examined whether the SRH-mortality association remained significant 30 years after assessment when adjusting for a wide range of known clinical, behavioural and socio-demographic risk factors.

Methods

We followed-up 8,251 men and women aged ≥16 years who participated 1977–79 in a community based health study and were anonymously linked with the Swiss National Cohort (SNC) until the end of 2008. Covariates were measured at baseline and included education, marital status, smoking, medical history, medication, blood glucose and pressure.

Results

92.8% of the original study participants could be linked to a census, mortality or emigration record of the SNC. Loss to follow-up 1980–2000 was 5.8%. Even after 30 years of follow-up and after adjustment for all covariates, the association between SRH and all-cause mortality remained strong and estimates almost linearly increased from “excellent” (reference: hazard ratio, HR 1) to “good” (men: HR 1.07 95% confidence interval 0.92–1.24, women: 1.22, 1.01–1.46) to “fair” (1.41, 1.18–1.68; 1.39, 1.14–1.70) to “poor”(1.61, 1.15–2.25; 1.49, 1.07–2.06) to “very poor” (2.85, 1.25–6.51; 1.30, 0.18–9.35). Persons answering the SRH question with “don''t know” (1.87, 1.21–2.88; 1.26, 0.87–1.83) had also an increased mortality risk; this was pronounced in men and in the first years of follow-up.

Conclusions

SRH is a strong and “dose-dependent” predictor of mortality. The association was largely independent from covariates and remained significant after decades. This suggests that SRH provides relevant and sustained health information beyond classical risk factors or medical history and reflects salutogenetic rather than pathogenetic pathways.     

Repeat Diagnoses of Bethesda Category III Thyroid Nodules: What To Do Next?

Objectives

To assess the malignancy rates of thyroid nodules repeatedly classified as Bethesda category III on fine needle aspiration (FNA), and to suggest management guidelines for these lesions.

Methods

This is a retrospective study that included 395 thyroid nodules categorized as Bethesda III undergone either surgery or ultrasound (US) follow-up. There were 67 nodules classified a second time as Bethesda category III on repeat FNA. We compared malignancy rates, clinicopathologic and ultrasonographic characteristics between direct surgery and repeat FNA groups and between the initial and repeat Bethesda category III groups, each. And in the repeat Bethesda III group, clinicopathologic and US variables were compared between benign and malignant nodules.

Results

Incidence of concurrent cancer, underlying thyroiditis and positive BRAF mutation were significantly higher in 142 nodules with direct surgery than 243 nodules with repeat FNA (p < 0.05). Of the 395 nodules with Bethesda category III cytology on initial FNA, the malignancy rate was 59.5%. In 67 nodules with repeat Bethesda III classification, however, the malignancy rate was 73.1% (p < 0.05). However, none of the variables were significantly different between the initial Bethesda category III group and the repeat Bethesda category III group (p > 0.05). In the repeat Bethesda category III group, solid consistency, irregular/microlobulated margins, nonparallel shape, and number of suspicious findings or “suspicious malignant” US assessments were associated with a high malignancy rate (p < 0.05). On multivariate logistic regression analysis, the factor associated with malignancy in the repeat Bethesda category III group was irregular/microlobulated margin (odds ratio = 15.576; 95% CI, 2.097–115.6804, p = 0.007) with a sensitivity, specificity, positive and negative predictive values, and accuracy of 81.6%, 83.3%, 93.0%, 62.5% and 82.1%, respectively.

Conclusion

Thyroid nodules with repeated Bethesda category III classification and irregular/microlobulated margins on US are at increased risk of malignancy, and operative management should be considered as opposed to repeat FNA.