Why the war on drugs in sport will never be won.
Recent exposes of drug use in sports suggest that doping might be more problematic than doping-control test results reveal. A zero-tolerance (ZT) model, which aims to eliminate the use, has dominated the thinking of sport's policy makers over the last 15 years. In light of the limitations associated with ZT-based policy, we propose an alternative policy, one based on controlled use and harm reduction principles. We argue that substance control policies underpinned by harm reduction (HR) principles of social utility and public value will deliver superior social outcomes. First, a harm reduction approach better accommodates the competitive realities of sports and the impact of elite sports' emphasis on performance at all costs. Second, HR prioritises athlete welfare over sport and brand reputation. Finally, while appreciating the regulatory and risk management responsibilities of sports' governing bodies, the HR model offers greater space to the athlete's right to privacy, and right to personal autonomy.


The association between different patterns of hand symptoms and objective evidence of median nerve compression: a community-based survey.
To examine the association between different patterns of hand symptoms and the presence of delayed nerve conduction in the general population. We performed a 2-stage screening survey involving a questionnaire on current hand symptoms, and nerve conduction testing in samples of subjects with and without symptoms. Of 648 respondents to the symptom questionnaire, 212 reported hand symptoms. In all, 155 were tested for nerve conduction of sensory and motor median nerve latencies, including 40 who had reported no symptoms. Patterns of hand symptoms were compared with nerve conduction results and associations weighted back to the general population. The presence of any hand symptoms had only a 40% sensitivity for delayed nerve conduction on latency testing. The presence of typical symptoms of carpal tunnel syndrome had a much lower sensitivity. In a community setting, the distribution of hand symptoms does not usefully correlate with the presence of delayed nerve conduction in the median nerve.


The effect of AM281, a cannabinoid antagonist, on memory performance during spontaneous morphine withdrawal in mice.
Abrupt cessation of morphine leads to withdrawal signs and cognitive deficits. Endocannabinoid system is activated during withdrawal; therefore, the aim of the present study was to assess the effects of AM281, cannabinoid antagonist/inverse agonist, on memory deficit following spontaneous morphine withdrawal. Cognition was evaluated by using the object recognition task. The novel object recognition task was tested in a square wooden open-field box using objects. The test was consisting of three sections: 15 min exploration, first trial for 12 min and second one for 5 min. In the second trial the difference in exploration between a previously seen object and a novel one, was considered as an index of memory performance (recognition index - RI). Male mice were made dependent by increasing doses of morphine (30-90 mg/kg) subcutaneously twice daily for 3 days. AM281 (0.62, 1.25 and 2.5 mg/kg) were used in chronic form concurrent with morphine i.p. or acutely (2.5, 5 and 10 mg/kg) on the last day. RI was evaluated on the third day 4 h after the last dose of morphine. Chronic administration of AM281 at 2.5 mg/kg improved RI to the 22.1 ± 4.8 and single dose of AM281 at 5 mg/kg improved the memory impairment to the 8.5 ± 4, as compared with vehicle-treated which was 4.8 ± 2.5. The results suggested that administration of AM281 at a dose of 2.5 mg/kg in chronic form and 5 mg/kg in acute dose improved memory.


The effects of microcarrier culture on recombinant CHO cells under biphasic hypothermic culture conditions.
A Chinese hamster ovary (CHO) cell line, producing recombinant secreted human placental alkaline phosphatase (SEAP) was investigated under three different culture conditions (suspension cells, cells attached to Cytodex 3 and Cytopore 1 microcarriers) in a biphasic culture mode using a temperature shift to mild hypothermic conditions (33 degrees C) in a fed-batch bioreactor. The cell viability in both the suspension and the Cytodex 3 cultures was maintained for significantly longer periods under hypothermic conditions than in the single-temperature cultures, leading to higher integrated viable cell densities. For all culture conditions, the specific productivity of SEAP increased after the temperature reduction; the specific productivities of the microcarrier cultures increased approximately threefold while the specific productivity of the suspension culture increased nearly eightfold. The glucose and glutamine consumption rates and lactate and ammonia production rates were significantly lowered after the temperature reduction, as were the yields of lactate from glucose. However, the yield of ammonia from glutamine increased in response to the temperature shift.


The hippocampus is necessary for the consolidation of a task that does not require the hippocampus for initial learning.
During sleep, the hippocampus plays an active role in consolidating memories that depend on it for initial encoding. There are hints in the literature that the hippocampus may have a broader influence, contributing to the consolidation of memories that may not initially require the area. We tested this possibility by evaluating learning and consolidation of the motor sequence task (MST) in hippocampal amnesics and demographically matched control participants. While the groups showed similar initial learning, only controls exhibited evidence of overnight consolidation. These results demonstrate that the hippocampus can be required for normal consolidation of a task without being required for its acquisition, suggesting that the area plays a broader role in coordinating memory consolidation than has previously been assumed.


Clinical assessment of motor imagery after stroke.
The aim of this study was to investigate: (1) the effects of a stroke on motor imagery vividness as measured by the Kinesthetic and Visual Imagery Questionnaire (KVIQ-20); (2) the influence of the lesion side; and (3) the symmetry of motor imagery. Thirty-two persons who had sustained a stroke, in the right (n = 19) or left (n = 13) cerebral hemisphere, and 32 age-matched healthy persons participated. The KVIQ-20 assesses on a 5-point ordinal scale the clarity of the image (visual scale) and the intensity of the sensations (kinesthetic scale) that the subjects are able to imagine from the first-person perspective. In both groups, the visual scores were higher (P = .0001) than the kinesthetic scores and there was no group difference. Likewise, visual scores remained higher than kinesthetic scores irrespective of the lesion side. The visual scores poststroke were higher (P = .001) when imagining upper limb movements on the unaffected side than those on the affected side. When focusing on the lower limb only, however, the kinesthetic scores were higher (P = .001) when imagining movements of the unaffected compared to those on the affected side. The vividness of motor imagery poststroke remains similar to that of age-matched healthy persons and is not affected by the side of the lesion. However, after stroke motor imagery is not symmetrical and motor imagery vividness is better when imagining movements on the unaffected than on the affected side, indicating an overestimation possibly related to a hemispheric imbalance or a recalibration of motor imagery perception.


Primary thermosensory events in cells.
Temperature sensing is essential for the survival of living organisms. Since thermal gradients are almost everywhere, thermoreception could represent one of the oldest sensory transduction processes that evolved in organisms. There are many examples of temperature changes affecting the physiology of living cells. Almost all classes of biological macromolecules in a cell (nucleic acids, lipids, proteins) can serve as a target of the temperature-related stimuli. This review is devoted to some common features of different classes of temperature-sensing molecules as well as molecular and biological processes involved in thermosensation. Biochemical, structural and thermodynamic approaches are discussed in order to overview the existing knowledge on molecular mechanisms of thermosensation.


International clinical trials setting for rare cancers: organisational and regulatory constraints-the EORTC perspective.
Rare diseases are a serious public health problem that presents unique challenges to many countries. There is no internationally accepted definition for rare diseases. Patients suffering from rare cancers often face challenges, including late or incorrect diagnoses, difficulties finding clinical expertise and accessing appropriate treatments, and uncertainty in clinical decision making, with difficult and rare access for these patients to clinical trials. Treatment choice is difficult as little information is available in the literature. In such situations, clinicians will base treatment decisions on retrospective data or case report series with a lower scientific level of evidence than that obtained from randomised controlled clinical trials. The only way forward is clinical trials organisation, but to perform it within rare indications we are always faced with many methodological, regulatory, and organisational challenges, besides stakeholders' different views, which are not usually concurrent. The aims of the European Organisation for Research and Treatment of Cancer (EORTC) are to develop, conduct, coordinate, and stimulate translational and clinical research in Europe to improve the management of cancer and related problems by increasing survival but also patient quality of life. In particular, extensive and comprehensive research in the field of rare cancers is beyond the means of individual European hospitals and can be best accomplished through the multidisciplinary multinational efforts of basic scientists and clinicians. In this paper, we will present an overview of the clinical research scene for rare cancers and will try to propose possible steps to improve the current situation.


ALSUntangled No. 7: Investigating hyperimmune goat serum (Aimspro) for ALS.
The mechanism of Aimspro remains unproven; if it is an immunomodulator and/or a modulator of sodium channels, it theoretically could be useful in ALS. A single, detailed but significantly flawed case report documents slowing in decline of certain respiratory functions in a patient claiming to have ALS, who started Aimspro shortly after bipap. Based upon this limited information, ALSUntangled supports further study of Aimspro, either in ALS animal models or in a small phase 2 trial with clear and objective endpoints carried out by skilled trialists familiar with the problems inherent with ALS clinical studies. Until a trial is undertaken, however, we do not support further use of this product by PALS.


The costs of guideline-concordant care and of care according to patients' needs in anxiety and depression.
To describe the direct and indirect costs for people with anxiety and depressive disorders where guidelines are adhered to and patients' perceived needs are fully met. Data were derived from the Netherlands Study of Depression and Anxiety. At baseline, adult patients were interviewed and they completed questionnaires to measure DSM-IV diagnoses, socio-demographic characteristics and perceived need for care. Actual care data were also derived from electronic medical records. Criteria for guideline adherence were based on general practice guidelines, issued by the Dutch College of General Practitioners. Direct and indirect costs were inferred from the Perceived Need for Care Questionnaire administered at baseline, and the Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness administered at 1-year follow-up. For 568 patients with a current anxiety or depressive disorder a complete dataset on health care use and absenteeism was available. Guideline adherence was significantly associated with increased care use and corresponding costs, while fully met perceived need was unrelated to costs. Socio-demographic characteristics, severity of symptoms and guideline adherence all affected the societal costs of patients with fully met perceived needs compared with patients with perceived unmet needs. It appears that guideline-concordant care for anxiety and depression costs more than non-concordant care, while care that has fulfilled all of a patient's needs seems not to be more expensive than care that has not met all perceived needs. However, randomized controlled trials should first confirm this conclusion.


Detection and quantification of methylation in DNA using solid-state nanopores.
Epigenetic modifications in eukaryotic genomes occur primarily in the form of 5-methylcytosine (5 mC). These modifications are heavily involved in transcriptional repression, gene regulation, development and the progression of diseases including cancer. We report a new single-molecule assay for the detection of DNA methylation using solid-state nanopores. Methylation is detected by selectively labeling methylation sites with MBD1 (MBD-1x) proteins, the complex inducing a 3 fold increase in ionic blockage current relative to unmethylated DNA. Furthermore, the discrimination of methylated and unmethylated DNA is demonstrated in the presence of only a single bound protein, thereby giving a resolution of a single methylated CpG dinucleotide. The extent of methylation of a target molecule could also be coarsely quantified using this novel approach. This nanopore-based methylation sensitive assay circumvents the need for bisulfite conversion, fluorescent labeling, and PCR and could therefore prove very useful in studying the role of epigenetics in human disease.


Quality of life improvement with rehabilitation according to constitution of the World Health Organization for coronary artery bypass graft surgery patients: A descriptive review.
This is a descriptive review focusing on trends of treatments required for postoperative coronary artery bypass graft surgery (CABG) patients to improve the quality of life (QOL). The sources of literary research to understand the concepts of coronary artery disease according to Indian scriptures are Ayurveda texts, Bhagavad Gita, Patanjali Yoga Sutra. The data was typed in Sanskrit using Devanagari script and explanation in English was given. As per new research techniques, surgery, physiotherapy rehabilitation and Yoga are serving CABG patient's medical and psychological health better. The World Health Organization (WHO) defines health as physical, mental and social well-being later redefined with additional terms like environmental and spiritual health. This definition is similar to the Panchakosha concept in Yoga and Pancha Mahabhutas in Ayurveda. In cases of emergency or passive treatment, medication serves as a better option for physical health. In circumstances where the person is able to move in daily activities (just after discharge), rehabilitation serves as a better option for physical, mental and social health. Travel and reactions to climatic change serve environmental health. Last strategy, belief, cultural and traditional methods with scientific background serves as the spiritual health. These step-wise treatments are required for CABG patients to get the overall health or QOL. However, surgery and physiotherapy rehabilitation are advanced as per modern era which serves physical, mental, and social health also, but environmental health and spiritual health have yet to be addressed. As an ancient system of medicine, Yoga combines physical, mental, social, environmental and spiritual practices and it should be added as treatment along with surgery and physiotherapy rehabilitation. If all of these therapies were in the treatment protocol for CABG surgery patients, we would observe the changes of QOL and fulfill the requirements of constitution of the WHO. Integrating concepts of Yoga, Ayurveda, modern rehabilitation, surgery and patient cooperation with lifestyle change are the key to QOL improvements after CABG.


The antioxidant effects of aqueous and organic extracts of Panax quinquefolium, Panax notoginseng, Codonopsis pilosula, Pseudostellaria heterophylla and Glehnia littoralis.
The roots of Panax quinquefolium, Panax notoginseng, Glehnia littoralis, Codonopsis pilosula and Pseudostellaria heterophylla were extracted with an aqueous extraction method and also with an organic extraction method. The aqueous extracts of Glehnia littoralis and Codonopsis pilosula were the most potent in inhibiting erythrocyte hemolysis. The aqueous extracts of Panax quinquefolium and Panax notoginseng had lower potencies while the aqueous extract of Pseudostellaria heterophylla and the organic extract of Panax quinquefolium were only weakly active. The organic extracts of Glehnia littoralis, Panax heterophylla and Panax quinquefolium were potent in inhibiting lipid peroxidation while the organic extracts of Codonopsis pilosula and Panax notoginseng had weaker potencies. The aqueous extracts possessed much lower potencies the corresponding organic extracts. However, the Glehnia littoralis extract was the most potent aqueous extract. The results suggest that Glehnia littoralis, Codonopsis pilosula, Panax notoginseng and Panax heterophylla are cheaper substitutes of Panax quinquefolium with regard to antioxidant activity.


Nursing Work Environment, Turnover Intention, Job Burnout, and Quality of Care: The Moderating Role of Job Satisfaction.
The purpose of this study was twofold: (a) to assess predictors of the turnover intention, burnout, and perceived quality of care among nurses working in Oman, and (b) to examine the potential moderating role of job satisfaction on the relationship between work environment and nurse turnover intention. A cross-sectional design was used to collect data from a sample of 207 nurses working in a public hospital in Muscat, Oman. An electronic survey was used to assess nurses' perceptions of work environment, burnout, job satisfaction, turnover intention, and quality of care. Participation in hospital affairs, a foundation for quality of care, and staffing adequacy were predictors of burnout among nurses and perceived quality of care. Logistic regression analysis revealed that working in a favorable environment was associated with less turnover intention, but only when job satisfaction was high. Improving nurse job satisfaction is a mechanism through which future interventions could enhance working conditions and promote better nurse retention. Organizational strategies are needed to increase nurse job satisfaction by empowering nurses to take more active roles in hospital affairs as a strategy to reduce turnover intention and enhance the quality of patient care.


Capillary saturation and desaturation.
Capillary desaturation experiments produce disconnected (trapped) ganglia of mesoscopic sizes intermediate between pore size and system size. Experimental evidence for interactions between these mesoscale clusters during desaturation is analyzed and discussed within the established microscopic and macroscopic laws of Newton, Young-Laplace, and Darcy. A theoretical expression for capillary number correlations is introduced that seems to have remained unnoticed. It expresses capillary desaturation curves in terms of stationary capillary pressures and relative permeabilities. The theoretical expression shows that the plateau saturation in capillary desaturation curves may in general differ from the residual nonwetting saturation defined through the saturation limit of the main hysteresis loop. Hysteresis effects as well as the difference between wetting and nonwetting fluids are introduced into the analysis of capillary desaturation experiments. The article examines experiments with different desaturation protocols and discusses the existence of a mesoscopic length scale intermediate between pore scale and sample scale. The theoretical expression is derived entirely within the existing traditional theory of two-phase flow in porous media and compared to a recent experiment.


States' Merger Review Authority Is Associated With States Challenging Hospital Mergers, But Prices Continue To Increase.
States can challenge proposed hospital mergers by using antitrust laws to prevent anticompetitive harms. This observational study examined additional state laws-principally charitable trust, nonprofit corporation, health and safety, and certificate-of-need laws-that can serve as complements and substitutes for antitrust laws by empowering states to be notified of, review, and challenge proposed hospital mergers through administrative processes. During the period 2010-19, 862 hospital mergers were proposed, but only forty-two (4.9 percent) were challenged by states, including thirty-five by states without federal involvement, of which twenty-five (71.4 percent) originated in the eight states with the most robust merger review authority. The twenty-five challenges resulted in two mergers being blocked; three being abandoned; and twenty being approved with conditions, including seven with competitive-impact conditions. Hospital market concentration and prices increased at similar rates in these eight states versus other states, potentially because most challenges allowed mergers to proceed with conditions that did not adequately address competitive concerns. Although these findings do not reveal an optimal state framework, elements of advanced state merger review authority may have the potential to improve poorly functioning hospital markets.


Three-dimensional multi-photon direct laser writing with variable repetition rate.
We perform multi-photon direct laser writing as a function of laser repetition rate over many orders of magnitude and otherwise unchanged experimental conditions. These new data serve as basis for investigating the influence of different proposed mechanisms involved in the photopolymerization: two-photon absorption, photoionization, avalanche ionization and heat accumulation. We find different non-linearities for high and low repetition rates consistent with different initiation processes being involved. The scaling of the resulting linewidths, however, is neither expected nor found to depend on repetition rate or non-linearity.


Ocular disorders among schoolchildren in Khartoum State, Sudan.
From December 2005 to June 2007, a total screening of all 1418 government primary schools in Khartoum State, Sudan, was performed to estimate ocular problems among children aged 6-15 years. We screened 671,119 children (56.7% males) for significant refractive error and other eye ailments. Ocular problems were found in 20,321 (3.03%) children. The 3 localities with highest ocular pathology were Karary (26.2%), Ummbada (21.0%) and Jabal Awlia (15.7%). The overall prevalence of refractive error was 2.19%. Myopia was found in 10,064 (1.50%) children while 4661 (0.70%) were hyperopic. Other ocular problems included vernal keratoconjunctivitis, vitamin A deficiency, microbial conjunctivitis, strabismus and corneal opacity. Only 288 (0.04%) children were diagnosed with active trachoma: 86.5% of these were from Ummbada locality, on the periphery ofthe State, where transportation facilities are poor and poverty is widespread. Overall, 99% of the eye ailments identified are either treatable or preventable. To reduce these and to achieve the goals of Vision 2020, an effective and efficient school health programme is needed.


Transcriptomic analysis of endangered Chinese salamander: identification of immune, sex and reproduction-related genes and genetic markers.
The Chinese salamander (Hynobius chinensis), an endangered amphibian species of salamander endemic to China, has attracted much attention because of its value of studying paleontology evolutionary history and decreasing population size. Despite increasing interest in the Hynobius chinensis genome, genomic resources for the species are still very limited. A comprehensive transcriptome of Hynobius chinensis, which will provide a resource for genome annotation, candidate genes identification and molecular marker development should be generated to supplement it. We performed a de novo assembly of Hynobius chinensis transcriptome by Illumina sequencing. A total of 148,510 nonredundant unigenes with an average length of approximately 580 bp were obtained. In all, 60,388 (40.66%) unigenes showed homologous matches in at least one database and 33,537 (22.58%) unigenes were annotated by all four databases. In total, 41,553 unigenes were categorized into 62 sub-categories by BLAST2GO search, and 19,468 transcripts were assigned to 140 KEGG pathways. A large number of unigenes involved in immune system, local adaptation, reproduction and sex determination were identified, as well as 31,982 simple sequence repeats (SSRs) and 460,923 putative single nucleotide polymorphisms (SNPs). This dataset represents the first transcriptome analysis of the Chinese salamander (Hynobius chinensis), an endangered species, to be also the first time of hynobiidae. The transcriptome will provide valuable resource for further research in discovery of new genes, protection of population, adaptive evolution and survey of various pathways, as well as development of molecule markers in Chinese salamander; and reference information for closely related species.


Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review.
Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed.


Predicting clinical outcome in feline oral squamous cell carcinoma: tumour initiating cells, telomeres and telomerase.
Feline oral squamous cell carcinoma (SCC) has very poor prognosis. Here, a retrospective pilot study was conducted on 20 feline oral SCC patients who underwent stereotactic radiation therapy (SRT), to evaluate: (1) the value of putative tumour initiating cell (TIC) markers of human head and neck SCC (CD44, Bmi-1); (2) telomere length (TL) specifically in putative TICs; and (3) tumour relative telomerase activity (TA). Significant inverse correlations were found between treatment outcomes and Bmi-1 expression, supporting the predictive value of Bmi-1 as a negative prognostic indicator. While TL exhibited a wide range of variability, particularly in very short fractions, many tumours possessed high levels of TA, which correlated with high levels of Bmi-1, Ki67 and EGFR. Taken together, our results imply that Bmi-1 and telomerase may represent novel therapeutic targets in feline oral SCC, as their inhibition - in combination with SRT - would be expected to have beneficial treatment outcome.


Prevalence, Clinical Management, and Natural Course of Incidental Findings on Brain MR Images: The Population-based Rotterdam Scan Study.
Purpose To present an updated prevalence estimate for incidental findings on brain magnetic resonance (MR) images and provide information on clinical relevance, including natural course, over a period of up to 9 years. Materials and Methods This study was approved by the institutional review board and all participants gave informed consent. In a prospective population-based setting, structural brain MR imaging was performed in 5800 participants (mean age, 64.9 years; 3194 women [55.1%]). Trained reviewers recorded abnormalities, which were subsequently evaluated by neuroradiologists. The prevalence with 95% confidence interval (CI) of incidental findings was determined, and clinical management of findings that required the attention of a medical specialist was followed. Follow-up imaging in the study context provided information on the natural course of findings that were not referred. Results In 549 of 5800 participants (9.5% [95% CI: 8.7%, 10.3%]), incidental findings were found, of which meningiomas (143 of 5800; 2.5% [95% CI: 2.1%, 2.9%]) and cerebral aneurysms (134 of 5800; 2.3% [95% CI: 2.0%, 2.7%]) were most common. A total of 188 participants were referred to medical specialists for incidental findings (3.2% [95% CI: 2.8%, 3.7%]). Of these, 144 (76.6% [95% CI: 70.1%, 82.1%]) either underwent a wait-and-see policy or were discharged after the initial clinical visit. The majority of meningiomas and virtually all aneurysms not referred or referred but untreated remained stable in size during follow-up. Conclusion Incidental findings at brain MR imaging that necessitate further diagnostic evaluation occur in over 3% of the general middle-aged and elderly population, but are mostly without direct clinical consequences. © RSNA, 2016.


The prevalence of symptoms attributed to electromagnetic field exposure: a cross-sectional representative survey in Switzerland.
To investigate health risk perception as well as to assess the prevalence of self-reported symptoms attributed to electromagnetic fields (EMF) and other environmental exposures in the general population of Switzerland. Between May and June 2004, telephone interviews of a representative sample of the Swiss population (n=2048, >14 years old) about: (1) health symptoms attributed to five environmental factors (one of which was EMF), (2) health risk perception related to 12 environmental risk factors (five of which were different EMF sources). We found a prevalence of 5% (95% CI 4-6%) for electromagnetic hypersensitivity (EHS) in our study sample. The most common health complaints among EHS individuals were sleep disorders (43%) and headaches (34%), which were mostly attributed to power lines and mobile phone handsets. In addition, 53 percent (95% CI 51-55%) were worried about adverse health effects from EMF, without attributing their own health symptoms to them. The large proportion of the population who is concerned or attributes own symptoms to EMF may cause societal conflicts given the ubiquity of EMF in our everyday life.


Shaping legal abortion provision in Ghana: using policy theory to understand provider-related obstacles to policy implementation.
Unsafe abortion is a major public health problem in Ghana; despite its liberal abortion law, access to safe, legal abortion in public health facilities is limited. Theory is often neglected as a tool for providing evidence to inform better practice; in this study we investigated the reasons for poor implementation of the policy in Ghana using Lipsky's theory of street-level bureaucracy to better understand how providers shape and implement policy and how provider-level barriers might be overcome. In-depth interviews were conducted with 43 health professionals of different levels (managers, obstetricians, midwives) at three hospitals in Accra, as well as staff from smaller and private sector facilities. Relevant policy and related documents were also analysed. Findings confirm that health providers' views shape provision of safe-abortion services. Most prominently, providers experience conflicts between their religious and moral beliefs about the sanctity of (foetal) life and their duty to provide safe-abortion care. Obstetricians were more exposed to international debates, treaties, and safe-abortion practices and had better awareness of national research on the public health implications of unsafe abortions; these factors tempered their religious views. Midwives were more driven by fundamental religious values condemning abortion as sinful. In addition to personal views and dilemmas, 'social pressures' (perceived views of others concerning abortion) and the actions of facility managers affected providers' decision to (openly) provide abortion services. In order to achieve a workable balance between these pressures and duties, providers use their 'discretion' in deciding if and when to provide abortion services, and develop 'coping mechanisms' which impede implementation of abortion policy. The application of theory confirmed its utility in a lower-middle income setting and expanded its scope by showing that provider values and attitudes (not just resource constraints) modify providers' implementation of policy; moreover their power of modification is constrained by organisational hierarchies and mid-level managers. We also revealed differing responses of 'front line workers' regarding the pressures they face; whilst midwives are seen globally as providers of safe-abortion services, in Ghana the midwife cadre displays more negative attitudes towards them than doctors. These findings allow the identification of recommendations for evidence-based practice.


Ecological design of augmentation improves helicopter ship landing maneuvers: An approach in augmented virtuality.
Helicopter landing on a ship is a visually regulated "rendezvous" task during which pilots must use fine control to land a powerful rotorcraft on the deck of a moving ship tossed by the sea while minimizing the energy at impact. Although augmented reality assistance can be hypothesized to improve pilots' performance and the safety of landing maneuvers by guiding action toward optimal behavior in complex and stressful situations, the question of the optimal information to be displayed to feed the pilots' natural information-movement coupling remains to be investigated. Novice participants were instructed to land a simplified helicopter on a ship in a virtual reality simulator while minimizing energy at impact and landing duration. The wave amplitude and related ship heave were manipulated. We compared the benefits of two types of visual augmentation whose design was based on either solving cockpit-induced visual occlusion problems or strengthening the online regulation of the deceleration by keeping the current [Formula: see text] variable around an ideal value of -0.5 to conduct smooth and efficient landing. Our results showed that the second augmentation, ecologically grounded, offers benefits at several levels of analysis. It decreases the landing duration, improves the control of the helicopter displacement, and sharpens the sensitivity to changes in [Formula: see text]. This underlines the importance for designers of augmented reality systems to collaborate with psychologists to identify the relevant perceptual-motor strategy that must be encouraged before designing an augmentation that will enhance it.


Acute respiratory distress syndrome: shifting the emphasis from treatment to prevention.
Although results from clinical trials have advanced the treatment of acute respiratory distress syndrome (ARDS), mortality remains high. More recently, focus has shifted from treatment of ARDS to early identification and prevention in at-risk populations. There have been 30 published and registered clinical trials with either the primary or secondary goal of reducing ARDS. With this change in paradigm, come additional challenges and consideration in study design that depends not only on the intervention but also whether the intervention aims for a primary, secondary, or tertiary prevention of ARDS that targets a patient population for universal, selective, or indicated prevention. These epidemiologic concepts of prevention in public health also apply to ARDS and are relevant to the study population to target, the timing of the intervention relative to critical illness, the study design and outcomes to measure in an ARDS prevention study. This shift in focus is reflected by the new National Heart Lung Blood Institute Prevention and Early Treatment of Acute Lung Injury network, and signifies an overall movement away from reacting to and supporting acute organ failure after it is established to early detection and prevention in acute critical illness wherever and whenever it may occur.


Advanced Hepatocellular Carcinoma Tumor Stage at Diagnosis in the 1945-1965 Birth Cohort Reflects Poor Use of Hepatocellular Carcinoma Screening.
Individuals from the 1945-1965 birth cohort account for the majority of hepatocellular carcinoma (HCC) cases in the United States. Understanding trends in HCC among this birth cohort is vital given the increasing burden of chronic liver disease among this group. We retrospectively evaluated trends and disparities in HCC tumor stage at the time of diagnosis among the 1945-1965 birth cohort in the United States using the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Tumor stage at the time of HCC diagnosis was assessed using Milan criteria and SEER HCC staging systems. Among 38,045 patients with HCC within the 1945-1965 birth cohort (81.6% male, 50.1% non-Hispanic white, 16.2% African American, 12.6% Asian, 19.8% Hispanic), 66.2% had Medicare or commercial insurance, 27.2% had Medicaid, and 6.6% were uninsured. During the period 2004-2006 to 2013-2014, the number of patients with HCC from the 1945-1965 birth cohort increased by 58.7% (5.9% increase per year). While the proportion of patients with HCC within the Milan criteria increased with time (36.4% in 2003-2006 to 46.3% in 2013-2014; P < 0.01), less than half were within the Milan criteria. On multivariate analysis within the Milan criteria, men were 12% less likely to have HCC compared to women, and African Americans were 27% less likely to have HCC compared to non-Hispanic whites (odds ratio, 0.73; 95% confidence interval, 0.68-0.78; P < 0.01). Conclusion: From 2004 to 2014, the burden of newly diagnosed HCC among the 1945-1965 birth cohort increased by 5.9% per year. While improvements in earlier staged HCC at diagnosis were observed, the majority of patients with HCC among the 1945-1965 birth cohort were beyond the Milan criteria at diagnosis; this may reflect poor utilization or suboptimal performance of HCC screening tests.


Inspiratory muscle training for intensive care patients: A multidisciplinary practical guide for clinicians.
To describe a multidisciplinary approach to inspiratory muscle training (IMT) for patients in the intensive care unit (ICU). Inspiratory muscle weakness is a known consequence of prolonged mechanical ventilation, and there is emerging evidence that specific IMT can ameliorate this weakness. However, IMT is not yet standard practice in many ICUs, possibly because of the wide variety of methods reported and a lack of published practical guidelines. While the optimal parameters for IMT are yet to be established, we share our detailed methodology which has been shown to be safe in selected ventilator-dependent patients and is the only approach which has been shown to increase quality of life in ICU patients. Patients who have experienced invasive mechanical ventilation for at least 7 days can commence IMT in either the ventilator-dependent phase or when weaned from mechanical ventilation. Intensity should be prescribed based on maximum inspiratory pressure, which is measurable through the tracheostomy or endotracheal tube via the ventilator or a respiratory pressure meter. Using a removable threshold device, we recommend high-intensity training (5 sets of 6 breaths at a minimum of 50% of maximum inspiratory pressure) performed once per day, supervised by the physiotherapist, with intensity increased daily such that patients can only just complete the 6th breath in each set. Using this high-intensity approach, IMT is likely to improve not only inspiratory muscle strength but also quality of life in patients recently weaned from mechanical ventilation of 7 days' duration or longer. Effective IMT requires a multidisciplinary approach to maximise feasibility, with doctors, nurses, and therapists working closely to optimise conditions for successful IMT. This multidisciplinary approach to implement IMT in ICU patients should assist clinicians in translating best-available evidence into practice, with the potential to enhance patient recovery.


Thyroid Swelling: A Common Phenomenon in Art?
Representations of thyroid swelling, intended as an enlarged anterior neck region, in the artworks of various periods are sporadically reported in the scientific literature, and different intents may be hypothesized. A comprehensive review of the international literature was performed on PubMed, Embase, and ResearchGate with the aim to analyze the modalities of representation of thyroid swelling through the ages by different artistic movements. Thyroid swelling is frequently represented in the artworks of many stylistic periods and seems to be a known condition even by the earliest cultures. Thyroid swelling may be considered a common finding among forms of art distant in time and style. It is not always possible to define whether thyroid swelling is a realistic representation or a detail added by the author. Although the function of the gland was discovered only at the end of the 19th century, thanks to the artworks of authors in many cultures, it is nowadays possible to formulate hypotheses about the distribution of thyroid diseases over the centuries.


Repurposing Drugs in Oncology (ReDO)-nitroglycerin as an anti-cancer agent.
Nitroglycerin (NTG), a drug that has been in clinical use for more than a century, has a range of actions which make it of particular interest in an oncological setting. It is generally accepted that the main mechanism of action of NTG is via the production of nitric oxide (NO), which improves cardiac oxygenation via multiple mechanisms including improved blood flow (vasodilation), decreased platelet aggregation, increased erythrocyte O2 release and decreased mitochondrial utilization of oxygen. Its vasoactive properties mean that it has the potential to exploit more fully the enhanced permeability and retention effect in delivering anti-cancer drugs to tumour tissues. Moreover NTG can reduce HIF-1α levels in hypoxic tumour tissues and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. Additionally NTG may enhance anti-tumour immunity. Pre-clinical and clinical data on these anti-cancer properties of NTG are summarised and discussed. While there is evidence of a positive action as a monotherapy in prostate cancer, there are mixed results in NSCLC where initially positive results have yet to be fully replicated. Based on the evidence presented, a case is made that further exploration of the clinical benefits that may accrue to cancer patients is warranted. Additionally, it is proposed that NTG may synergise with a number of other drugs, including other repurposed drugs, and these are discussed in the supplementary material appended to this paper.


Species similarities and differences in pharmacokinetics.
One of the fundamental challenges drug metabolism scientists face in drug discovery and development is the extrapolation of metabolic data and risk assessment from animals to humans. Although it is generally believed that data from animal studies can be reasonably extrapolated to humans with the application of appropriate pharmacokinetic principles, there are certainly some limitations. The purpose of this review is to show some species similarities and differences in absorption, distribution, metabolism, and excretion, with an attempt to address the questions of whether animal data can be extrapolated and what the limitations are. The underlying mechanisms responsible for these similarities and differences are discussed and examples given for illustration. In addition, the concepts of allometric and physiological models for extrapolation of kinetic data are briefly highlighted. In conclusion, although pharmacokinetics has been advanced greatly in recent years, it is not yet possible to predict all of the pharmacokinetic parameters of a drug in humans from animal studies. Nevertheless, under certain well-defined conditions, it may be possible to make reasonably good predictions. For example, the intrinsic absorption of a given drug across the wall of the gastrointestinal tract is probably similar among species, because the nature of the biomembrane of epithelial cells is similar in mammals and because the absorption process is basically an interaction between the drug and the biomembrane. However, other factors, such as pH-dependent solubility and first-pass metabolism that affect the absorption, may differ from species to species resulting in species differences in absorption. Predicting the renal excretion of drugs in humans has been relatively successful using the glomerular filtration rate ratio between humans and animals. Similarity, if the elimination of a drug is mainly by the liver and the rate of elimination is limited by hepatic blood flow, one could predict the clearance of the drug in humans by the hepatic blood flow. However, biochemical parameters, such as protein binding and drug metabolism, are less predictable. These parameters vary considerably among species.


Altered myocardial shear strains are associated with chronic ischemic mitral regurgitation.
Ischemic mitral regurgitation (IMR) limits life expectancy and can lead to postinfarction global left ventricular (LV) dilatation and remodeling, the pathogenesis of which is not completely known. We tested the hypothesis that IMR perturbs adjacent myocardial LV systolic strains. Thirteen sheep had three columns of miniature beads inserted across the lateral LV wall, with additional epicardial markers silhouetting the ventricle. One week later posterolateral infarction was created. Seven weeks thereafter, the animals were divided into two groups according to severity of IMR (< or = 1+, n = 7, IMR[-] vs > or = 2+, n = 6, IMR[+]). Four dimensional marker coordinates and quantitative histology were used to calculate ventricular volumes, transmural myocardial systolic strains, and systolic fiber shortening. Seven weeks after infarction, end-diastolic (ED) volume increased similarly in both groups, end-systolic (ES) E13 (circumferential-radial) shear increased in both groups, but more so in IMR(+) than IMR(-) (+0.12 vs 0.04, p < 0.005), and E12 (circumferential-longitudinal) shear increased in IMR(-) but not IMR(+) (+0.04 vs -0.01, p < 0.005). There were no significant differences in ED or ES remodeling strains or systolic fiber shortening between IMR(-) and IMR(+). An equivalent increase in LV end-diastolic (ED) volume in both groups, coupled with unchanged ED and end-systolic remodeling strains as well as systolic circumferential, longitudinal, and radial strains, argue against a global LV or regional myocardial geometric basis for the cardiomyopathy associated with IMR. Further, similar systolic fiber shortening in both groups militates against an intracellular (cardiomyocyte) mechanism. The differences in subepicardial E12 and E13 shears, however, suggest a causal role of altered interfiber (cytoskeleton and extracellular-matrix) interactions.


Ocular changes due to the treatment of juvenile systemic lupus erythematosus.
To assess retrospectively the ocular changes in children and adolescents with juvenile systemic lupus erythematosus (JSLE) in a tertiary pediatric rheumatology service. This study assessed 117 JSLE patients (85.5% female, 60.7% non-Caucasian), who met at least four criteria of the 1997 SLE classification of the American College of Rheumatology. Their mean age was 10.4 years, and their mean time of disease progression was 5.4 years. A protocol containing clinical and demographic data, ophthalmologic complaints and changes, age of onset, duration of medication use, and cumulative medication dose was applied. Of the 117 patients, 24 (20.5%) had ocular changes. Sixteen of them had abnormal fundoscopy associated with systemic hypertension and/or use of chloroquine; four had cataract; two had glaucoma; and two had cataract and glaucoma. The mean age of ocular change onset was 14.1 years. Patients with ocular changes received statistically higher and longer doses of glucocorticoid pulse therapy as compared with patients without ocular changes [1.5 (0.4 to 1.6) versus 1 (0.2 to 1.6) mg/kg, P = 0.003; 25.7 (2-99) versus 17.8 (1-114) months, P = 0.0001, respectively]. A high prevalence of ocular changes relating mainly to the treatment of JSLE was observed. This demonstrates the need for regular ophthalmologic examinations even in asymptomatic patients, aiming at the early diagnosis and intervention, and at decreasing the ocular morbidity related to that disease.


Usability of Academic Electronic Medical Record Application for Nursing Students' Clinical Practicum.
Nursing curricula for undergraduate nursing students need to reflect the information technology used in current nursing practice. A smart-device Academic Electronic Medical Record (AEMR) application can help nursing students access and document records for the clinical practicum. We conducted a pilot study to evaluate the usability of an AEMR application before applying it to the clinical nursing practicum. A previously developed EMR application was modified as an AEMR to access patient information at bedside and to practice documentation. We added several features to the current EMR application to create an AEMR environment. We created a series of document forms and several useful scales on an external application, which included nursing admission notes, vital signs, and intake/output. The case scenarios and tasks were created by a research team to evaluate aspects of AEMRs, including their usability and functionality. Five nursing students completed 15 tasks using a think-aloud method with a tablet device. Minor usability issues were identified and rectified. All participants indicated that they became familiar with the application with little effort. They said that the application icons were intuitive, which helped them find patient information more quickly and accurately. The application will improve timely access to patient data and documentation for nursing students. We are confident that this AEMR application will enhance nursing students' experience with their clinical practicum, and help them to better understand patient conditions and document them with ideal accessibility.


Everybody else is doing it: exploring social transmission of lying behavior.
Lying is a common occurrence in social interactions, but what predicts whether an individual will tell a lie? While previous studies have focused on personality factors, here we asked whether lying tendencies might be transmitted through social networks. Using an international sample of 1,687 socially connected pairs, we investigated whether lying tendencies were related in socially connected individuals, and tested two moderators of observed relationships. Participants recruited through a massive open online course reported how likely they would be to engage in specific lies; a friend or relative responded to the same scenarios independently. We classified lies according to their beneficiary (antisocial vs. prosocial lies), and their directness (lies of commission vs. omission), resulting in four unique lying categories. Regression analyses showed that antisocial commission, antisocial omission, and prosocial commission lying tendencies were all uniquely related in connected pairs, even when the analyses were limited to pairs that were not biologically related. For antisocial lies of commission, these relationships were strongest, and were moderated by amount of time spent together. Randomly paired individuals from the same countries were also related in their antisocial commission lying tendencies, signifying country-level norms. Our results indicate that a person's lying tendencies can be predicted by the lying tendencies of his or her friends and family members.


Molecular pathology of hepatic neoplasms: classification and clinical significance.
Recent technological advances have enabled investigators to characterize the molecular genetics and genomics of hepatic neoplasia in remarkable detail. From these studies, an increasing number of molecular markers are being identified that correlate with clinically important tumor phenotypes. This paper discusses current knowledge relevant to the molecular classification of epithelial primary hepatic tumors that arise in adults, including focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA), hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and combined HCC-CC. Genetic analysis has defined molecular subtypes of HCA that are clinicopathologically distinct and can be distinguished through immunohistochemistry. Gene expression studies have identified molecular signatures of progression from dysplastic nodules (DNs) to early HCC in cirrhosis. Analyses of the mutational spectra, chromosomal aberrations and instability, transcriptomics, and microRNA profiles of HCC have revealed the existence of biologically distinct subtypes of this common malignancy, with prognostic implications. Molecular characterization of biliary and hepatic progenitor cell phenotypes in liver cancer has shed new light on the histogenesis of these tumors and has focused attention on novel therapeutic targets. In coming years, the molecular classification of hepatic neoplasms will be increasingly valuable for guiding patient care, as targeted therapies for liver cancer are developed and brought into clinical practice.


Trust, conversations and the 'middle space': A qualitative exploration of the experiences of physiotherapists with clients with suicidal thoughts and behaviours.
In Australia, physiotherapists are registered healthcare practitioners who possess the knowledge and skills to care for clients with poor physical health as a result of musculoskeletal, neurological, and respiratory conditions. Although physiotherapists are not considered a primary profession in the Australian mental health workforce, the association between suicide and poor physical health suggests that they may encounter clients with suicidal thoughts and behaviours. We used a qualitative approach inspired by phenomenology to explore the experiences of nine physiotherapists who encountered clients with suicidal thoughts and behaviours. We used a combination of focus groups and in-depth interviews to collect this data. The data were analysed inductively using framework analysis. The main themes identified in the data were: i) the importance of trust, ii) the mechanism of conversation, and iii) the 'middle space'. The middle space refers to the experience of working with clients at risk of low or medium risk of suicide. A trusting practitioner-client relationship was reported to be essential in facilitating the disclosure of suicidal thoughts and behaviours. Physiotherapists also reported that less structured subjective assessments encourage clients to talk more openly, which in turn facilitates the disclosure of suicidal thoughts and behaviours. Once the disclosure of suicidal thoughts and behaviours occurred, physiotherapists reported a lack of confidence regarding role clarity and issues associated with this. Difficulties were most evident during encounters with clients with low to medium suicide risk due to a lack of confidence in the accuracy of assessment of these clients. The findings suggest that physiotherapists are well placed to detect and/or receive disclosure of suicidal thoughts and behaviours, as well as the need for physiotherapists to be trained in how to support clients who disclose suicidal thoughts and behaviours.


The effect of rational emotive behavior therapy (REBT) on antiretroviral therapeutic adherence and mental health in women infected with HIV/AIDS.
To identify the effectiveness of rational-emotive-behavior-based therapy (REBT-based therapy) on improved mental health and antiretroviral (ART) therapeutic adherence in women infected with HIV/AIDS (female subjects with HIV/AIDS). A randomized and single-blinded clinical trial in women infected with HIV/AIDS who had their treatment at the outpatient clinic of Pokdiksus AIDS RSCM and at the AIDS Comprehensive Diagnostic Unit of Dharmais Hospital was conducted between October 2011 and March 2012. A block randomization of 160 female subjects with AIDS was performed that resulted in a REBT-based treatment group (n=80) and a control group (n=80). The treatment group received REBT-based intervention of 8 sessions weekly including 6 individual-therapeutic sessions/week and 2 group-therapeutic sessions/week. Instruments used in the study were questionnaires on demography, ART adherence (measured by self report and pill count), and mental health (SRQ-20). Data were analyzed using Chi-Square test, Generalized Linear Model, and Generalized Estimating Equations. There were 148 respondents analyzed including in the REBT-based group (n=72) and in the control group (n=76) with mean age of 33-34 years. After 8 weeks of REBT-based intervention, there was improved (increased) mean value of the self-reported adherence score (self-report) compared to control group (100%; CI 95%,83.3-96.7 vs. 84%; CI 95%,77.5-87.8) and improved (decreased) SRQ-20 mean score in REBT-based treatment group compared to control group (2.9; CI 95%, 2.7-13.0 vs. 5.4; CI 95%: 5.0-13.6). ART adherence based on viral load titer was not analyzed in both group since most of VL titer were undetected (<400 copies/mL). GLM analysis showed decreased SRQ-20 mean score and increased mean value of self-reported ART adherence (self-report) in the REBT-based treatment group, which were more significant (p<0.000) than control group on the 8th week. GEE analysis showed that 1 point decrement of SRQ-20 would increase self-reported ART adherence as much as 0.722 point and the correlation was statistically significant (p<0.00). After 8 weeks of REBT-based intervention to female subjects with HIV/AIDS, there is a decrease of SRQ-20 mean score which may result in increased ART adherence mean score in the treatment group compared to the control.


Surface normal overlap: a computer-aided detection algorithm with application to colonic polyps and lung nodules in helical CT.
We developed a novel computer-aided detection (CAD) algorithm called the surface normal overlap method that we applied to colonic polyp detection and lung nodule detection in helical computed tomography (CT) images. We demonstrate some of the theoretical aspects of this algorithm using a statistical shape model. The algorithm was then optimized on simulated CT data and evaluated using a per-lesion cross-validation on 8 CT colonography datasets and on 8 chest CT datasets. It is able to achieve 100% sensitivity for colonic polyps 10 mm and larger at 7.0 false positives (FPs)/dataset and 90% sensitivity for solid lung nodules 6 mm and larger at 5.6 FP/dataset.


Shotgun metagenomic sequencing of the first case of monkeypox virus in Brazil, 2022.
Monkeypox virus (MPXV), a zoonotic virus endemic to the African continent, has been reported in 33 non-endemic countries since May 2022. We report an almost complete genome of the first confirmed case of MPXV in Brazil. Shotgun metagenomic sequencing was completed in 18 hours, from DNA extraction to consensus sequence generation.


Validation of 4D Components for Measuring Quality of the Public Health Data Collection Process: Elicitation Study.
Identification of the essential components of the quality of the data collection process is the starting point for designing effective data quality management strategies for public health information systems. An inductive analysis of the global literature on the quality of the public health data collection process has led to the formation of a preliminary 4D component framework, that is, data collection management, data collection personnel, data collection system, and data collection environment. It is necessary to empirically validate the framework for its use in future research and practice. This study aims to obtain empirical evidence to confirm the components of the framework and, if needed, to further develop this framework. Expert elicitation was used to evaluate the preliminary framework in the context of the Chinese National HIV/AIDS Comprehensive Response Information Management System. The research processes included the development of an interview guide and data collection form, data collection, and analysis. A total of 3 public health administrators, 15 public health workers, and 10 health care practitioners participated in the elicitation session. A framework qualitative data analysis approach and a quantitative comparative analysis were followed to elicit themes from the interview transcripts and to map them to the elements of the preliminary 4D framework. A total of 302 codes were extracted from interview transcripts. After iterative and recursive comparison, classification, and mapping, 46 new indicators emerged; 24.8% (37/149) of the original indicators were deleted because of a lack of evidence support and another 28.2% (42/149) were merged. The validated 4D component framework consists of 116 indicators (82 facilitators and 34 barriers). The first component, data collection management, includes data collection protocols and quality assurance. It was measured by 41 indicators, decreased from the original 49% (73/149) to 35.3% (41/116). The second component, data collection environment, was measured by 37 indicators, increased from the original 13.4% (20/149) to 31.9% (37/116). It comprised leadership, training, funding, organizational policy, high-level management support, and collaboration among parallel organizations. The third component, data collection personnel, includes the perception of data collection, skills and competence, communication, and staffing patterns. There was no change in the proportion for data collection personnel (19.5% vs 19.0%), although the number of its indicators was reduced from 29 to 22. The fourth component, the data collection system, was measured using 16 indicators, with a slight decrease in percentage points from 18.1% (27/149) to 13.8% (16/116). It comprised functions, system integration, technical support, and data collection devices. This expert elicitation study validated and improved the 4D framework. The framework can be useful in developing a questionnaire survey instrument for measuring the quality of the public health data collection process after validation of psychometric properties and item reduction.


Exploring customers' responses to online service failure and recovery strategies during Covid-19 pandemic: An actor-network theory perspective.
While the debate on online service failure and recovery strategies has been given considerable attention in the marketing and information systems literature, the evolving Covid-19 pandemic has brought about new challenges both theoretically and empirically in the consumption landscape. To fully understand customers' responses to service failure during a crisis we asked 70 millennials from three European Countries-Italy, France, and the UK-to describe their responses to service failure during the Covid-19 pandemic (30 completed a 4-week diary and 40 completed a 4-week qualitative survey). Drawing on phenomenological, constructivist, and hermeneutical approaches, and utilizing an actor-network theory perspective, the current study proposes a new framework for understanding customers' responses to online service failure and recovery strategies during the Covid-19 pandemic. Conclusions highlight implications for theory, policy, and management practice through extending comprehensions of service failure recovery processes by examining how marketing policies generate different social impacts during a crisis situation which facilitate the achievement of customer satisfaction and positive outcomes.


Maternal sepsis: new concepts, new practices.
Sepsis is a leading cause of severe maternal morbidity and maternal death. As pregnancy-related sepsis can be difficult to recognize, clinicians should maintain a low threshold for early evaluation and treatment. Definitions and treatment guidelines for maternal sepsis were recently revised in 2016 and 2017 by the Surviving Sepsis Campaign and WHO. Multiple clinical decision tools have been created to aid clinicians in early recognition and risk prediction for sepsis in obstetric populations, but currently, an optimal screening tool does not exist. Early recognition and urgent treatment is paramount for patient survival. Antibiotics should be started within 1 h and fluid resuscitation should be initiated if sepsis-induced hypoperfusion is present. Care should be escalated to appropriate settings and source control provided. Obstetricians have a heightened understanding of the physiologic changes in pregnancy and play a vital role in coordinating patient care and improving outcomes. The recent 2016 and 2017 revisions of definitions for maternal sepsis and treatment should be incorporated into clinical practice.


An open data ecosystem for cell migration research.
Cell migration research has recently become both a high content and a high throughput field thanks to technological, computational, and methodological advances. Simultaneously, however, urgent bioinformatics needs regarding data management, standardization, and dissemination have emerged. To address these concerns, we propose to establish an open data ecosystem for cell migration research.


Structural studies of Rubisco from tobacco.
An electron density map of ribulose 1,5-bisphosphate carboxylase-oxygenase (Rubisco) from tobacco (Nicotiana tabacum) has been obtained by X-ray crystallography at a nominal resolution of 0.34 nm. Phases were determined by multiple isomorphous replacement with three heavy atom derivatives and then refined by solvent flattening. Rubisco is barrel-shaped, and has (422) symmetry. The fourfold axis runs down an open central channel, concentric with the barrel. The molecule measures 10.5 nm along the fourfold axis, and has a diameter of 13 nm perpendicular to the fourfold axis at the widest point. The diameter of the central channel is 2.8 nm at the centre of the molecule, and 0.6 nm at its narrowest constriction. Portions of the polypeptide backbone of the promoter have been traced and some 127 residues have been assigned to 14 alpha-helices. The amino acid sequences of Rubisco from Rhodospirillum rubrum and from the large subunit of tobacco are sufficiently similar to suggest that the two chains are folded in the same general way.


Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility.
Mutations in the androgen receptor (AR) gene can cause the androgen insensitivity syndrome (AIS). For complete and severe partial AIS, well-characterized in vitro functional assays can be used for genotype-phenotype correlation; however, for mild forms of AIS, as associated with male infertility, experimental evidence is scarce or lacking. In particular, optimal in vitro functional tests informative about the genotype-phenotype relation have not been described. The objective of this study was to investigate the association among genotype and phenotype for AR mutations found in infertile males by conventional functional assays and additional in-depth studies performed with several gene reporters. To this aim, we selected four AR missense mutations associated with isolated male infertility (L547F and two novel mutations A474V and S650G) or partial AIS (Y571H). After introduction of the specific mutations in AR expression plasmid, we performed classical in vitro studies (Western immunoblotting, electrophoretic mobility shift assay, hormone-response curves) and transactivation assays with different reporter constructs (MMTV, Sc-ARU-TK, TAT-GRE- 2X, Slp-ARU-TK and PEM). Our results showed that standard functional tests provide sufficient information only for severe AR mutations, whereas for AR mutations found in mild AIS patients with male infertility, only an extensive analysis with different in vitro systems, and in particular with PEM promoter, can give information on the functionality of the AR and therefore on the pathogenicity of the mutations and on genotype-phenotype correlation.


Cell docking inside microwells within reversibly sealed microfluidic channels for fabricating multiphenotype cell arrays.
We present a soft lithographic method to fabricate multiphenotype cell arrays by capturing cells within an array of reversibly sealed microfluidic channels. The technique uses reversible sealing of elastomeric polydimethylsiloxane (PDMS) molds on surfaces to sequentially deliver various fluids or cells onto specific locations on a substrate. Microwells on the substrate were used to capture and immobilize cells within low shear stress regions inside channels. By using an array of channels it was possible to deposit multiple cell types, such as hepatocytes, fibroblasts, and embryonic stem cells, on the substrates. Upon formation of the cell arrays on the substrate, the PDMS mold could be removed, generating a multiphenotype array of cells. In addition, the orthogonal alignment and subsequent attachment of a secondary array of channels on the patterned substrates could be used to deliver fluids to the patterned cells. The ability to position many cell types on particular regions within a two dimensional substrate could potentially lead to improved high-throughput methods applicable to drug screening and tissue engineering.


THE CUTTING EDGE OF RETINOPATHY OF PREMATURITY CARE: Expanding the Boundaries of Diagnosis and Treatment.
To discuss the latest advances and controversies in the diagnosis and care of infants with retinopathy of prematurity (ROP). Literature review. Retinopathy of prematurity remains a major global issue. Industrialized nations now treat profoundly premature infants with posterior and aggressive disease, and middle-income nations are experiencing ROP epidemics. Remote digital imaging may address the decreasing ratio of ROP providers to premature infants, in addition to improving patient care. Widefield angiography, optical coherence tomography, and the Wnt signaling pathway have provided new insights into ROP pathogenesis. Anti-vascular endothelial growth factor treatment is increasing in popularity, but the dearth of information to guide dosing, unpredictable reactivation, persistent vascular abnormalities, the "crunch" phenomenon, and the presently unknown effects of systemic vascular endothelial growth factor suppression remain issues to continue investigating. Neurodevelopmental delay has been raised as a potential consequence, but the evidence currently is weak. Vitrectomy is the treatment of choice for Stages 4 and 5. Illumination techniques, ab interno incisions, plasmin-assisted vitrectomy, staged surgery in the interest of corneal clearing for advanced Stage 5, and immediate sequential bilateral vitreoretinal surgery, are useful techniques. We are making progress in ROP management. Our goal as clinicians is to continue expanding the boundaries of our abilities to keep this blinding disease in check globally.


Uphill energy transfer in photosystem I from Chlamydomonas reinhardtii. Time-resolved fluorescence measurements at 77 K.
Energetic properties of chlorophylls in photosynthetic complexes are strongly modulated by their interaction with the protein matrix and by inter-pigment coupling. This spectral tuning is especially striking in photosystem I (PSI) complexes that contain low-energy chlorophylls emitting above 700 nm. Such low-energy chlorophylls have been observed in cyanobacterial PSI, algal and plant PSI-LHCI complexes, and individual light-harvesting complex I (LHCI) proteins. However, there has been no direct evidence of their presence in algal PSI core complexes lacking LHCI. In order to determine the lowest-energy states of chlorophylls and their dynamics in algal PSI antenna systems, we performed time-resolved fluorescence measurements at 77 K for PSI core and PSI-LHCI complexes isolated from the green alga Chlamydomonas reinhardtii. The pool of low-energy chlorophylls observed in PSI cores is generally smaller and less red-shifted than that observed in PSI-LHCI complexes. Excitation energy equilibration between bulk and low-energy chlorophylls in the PSI-LHCI complexes at 77 K leads to population of excited states that are less red-shifted (by ~ 12 nm) than at room temperature. On the other hand, analysis of the detection wavelength dependence of the effective trapping time of bulk excitations in the PSI core at 77 K provided evidence for an energy threshold at ~ 675 nm, above which trapping slows down. Based on these observations, we postulate that excitation energy transfer from bulk to low-energy chlorophylls and from bulk to reaction center chlorophylls are thermally activated uphill processes that likely occur via higher excitonic states of energy accepting chlorophylls.


Evaluating conservation biology texts for bias in biodiversity representation.
A critical component of textbooks is fair representation of the material they cover. Within conservation biology, fair coverage is particularly important given Earth's breadth of species and diversity of ecosystems. However, research on species tends to be biased towards certain taxonomic groups and geographic areas and their associated ecosystems, so it is possible that textbooks may exhibit similar biases. Considering the possibility of bias, our goal was to evaluate contemporary conservation biology textbooks to determine if they are representative of Earth's biodiversity. We found that textbooks did not accurately reflect Earth's biodiversity. Species, ecosystems, and continents were unevenly represented, few examples mentioned genetic diversity, and examples of negative human influence on the environment outweighed positive examples. However, in terms of aquatic versus terrestrial representation, textbooks presented a representative sample. Our findings suggest that modern conservation biology textbooks are biased in their coverage, which could have important consequences for educating our next generation of scientists and practitioners.


Estimated Perinatal HIV Infection Among Infants Born in the United States, 2002-2013.
Perinatal transmission of human immunodeficiency virus (HIV) can be reduced through services including antiretroviral treatment and prophylaxis. Data on the national incidence of perinatal HIV transmission and missed prevention opportunities are needed to monitor progress toward elimination of mother-to-child HIV transmission. To estimate the number of perinatal HIV cases among infants born in the United States. Data were obtained from the National HIV Surveillance System on infants with HIV born in the United States (including the District of Columbia) and their mothers between 2002 and 2013 (reported through December 31, 2015). Estimates were adjusted for delay in diagnosis and reporting by weighting each reported case based on a model incorporating time from birth to diagnosis and report. Analysis was performed from April 1 to August 15, 2016. Maternal HIV infection and antiretroviral medication, including maternal receipt prenatally or during labor/delivery and infant receipt postnatally. Diagnosis of perinatally acquired HIV infection in infants born in the United States. Infant and maternal characteristics, including receipt of perinatal HIV testing, treatment, and prophylaxis. The estimated annual number of perinatally infected infants born in the United States decreased from 216 (95% CI, 206-230) in 2002 to 69 (95% CI, 60-83) in 2013. Among perinatally HIV-infected children born in 2002-2013, 836 (63.0%) of the mothers identified as black or African American and 243 (18.3%) as Hispanic or Latino. A total of 236 (37.5%) of the mothers had HIV infection diagnosed before pregnancy in 2002-2005 compared with 120 (51.5%) in 2010-2013; the proportion of mother-infant pairs receiving all 3 recommended arms of antiretroviral prophylaxis or treatment (prenatal, intrapartum, and postnatal) was 22.4% in 2002-2005 and 31.8% in 2010-2013, with approximately 179 (28.4%) (2002-2005) and 94 (40.3%) (2010-2013) receiving antiretroviral prophylaxis or treatment during pregnancy. Five Southern states (Florida, Texas, Georgia, Louisiana, and Maryland) accounted for 687 (38.0%) of infants born with HIV infection in the United States during the overall period. According to national data for live births, the incidence of perinatal HIV infection among infants born in the United States in 2013 was 1.75 per 100 000 live births. Despite reduced perinatal HIV infection in the United States, missed opportunities for prevention were common among infected infants and their mothers in recent years. As of 2013, the incidence of perinatal HIV infection remained 1.75 times the proposed Centers for Disease Control and Prevention elimination of mother-to-child HIV transmission goal of 1 per 100 000 live births.


EBOVAC-Salone: Lessons learned from implementing an Ebola vaccine trial in an Ebola-affected country.
Background/aims During the 2014-2016 West African Ebola epidemic, clinical trials were fast-tracked in order to identify prophylactic vaccines and experimental treatments that might be useful in preventing or treating Ebola. These trials included the ongoing EBOVAC-Salone study, which was established and implemented in Sierra Leone to assess the safety and immunogenicity of the Ad26.ZEBOV/MVA-BN-Filo prime-boost Ebola vaccine regimen. Methods This article describes the experiences of the EBOVAC-Salone research team in setting up and implementing the trial, and provides recommendations for research teams aiming to conduct clinical trials in future outbreak situations. Results Establishing a clinical trial during an outbreak brought some unique challenges, including those related to trial design and the regulatory environment, operational issues, and community engagement. The situation was further complicated by the weak infrastructure and limited experience of clinical trials in Sierra Leone. However, operating in an outbreak context also brought some benefits to the research team, including strong stakeholder support. The EBOVAC-Salone study recruited participants both during and after the outbreak, leading to additional challenges to trial implementation during the post-outbreak transition. Conclusion Many lessons have been learned about setting up and implementing a clinical trial during a devastating Ebola epidemic, and some of the experiences of the EBOVAC-Salone team were mirrored by those of other researchers operating in the region. Common to several of these research groups is a recommendation that research should be more closely incorporated into outbreak response planning, which could expedite the establishment of timely and appropriate research projects. We recommend that the lessons learned by researchers during the West African Ebola epidemic are built into programmes and strategies to improve the responses to future epidemics, wherever they occur.


Successful treatment of pure red cell aplasia with cyclosporin A and erythropoietin after thymectomy in a 88-year old woman.
An 88-year old Japanese female with pure red cell aplasia was treated safely and effectively by a combination of thymectomy, cyclosporin A, and erythropoietin. The thymoma was histologically classified as lymphocytic type or cortical type, which are uncommon in cases of a thymoma accompanied by pure red cell aplasia. Immunohistochemical analysis of the thymoma and bone marrow revealed a predominance of CD8(+) cells. Thymectomy alone was ineffective, but cyclosporin A treatment subsequent to thymectomy was safe and effective and resulted in the disappearance of a Vbeta12 bearing T-cell clone in the bone marrow. Additional treatment with erythropoietin enhanced the effects of cyclosporin A and restored the patient's hemoglobin to normal levels. The beneficial effect of cyclosporin A may be attributed not to a broad immunomodulatory effect, but to a local effect on a limited T-cell subset.


Calmodulin kinase II inhibition shortens action potential duration by upregulation of K+ currents.
The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by elevated intracellular Ca(2+) (Ca(2+)(i)), and mice with chronic myocardial CaMKII inhibition (Inh) resulting from transgenic expression of a CaMKII inhibitory peptide (AC3-I) unexpectedly showed action potential duration (APD) shortening. Inh mice exhibit increased L-type Ca(2+) current (I(Ca)), because of upregulation of protein kinase A (PKA) activity, and decreased CaMKII-dependent phosphorylation of phospholamban (PLN). We hypothesized that CaMKII is a molecular signal linking Ca(2+)(i) to repolarization. Whole cell voltage-clamp recordings revealed that the fast transient outward current (I(to,f)) and the inward rectifier current (I(K1)) were selectively upregulated in Inh, compared with wild-type (WT) and transgenic control, mice. Breeding Inh mice with mice lacking PLN returned I(to,f) and I(K1) to control levels and equalized the APD and QT intervals in Inh mice to control and WT levels. Dialysis of AC3-I into WT cells did not result in increased I(to,f) or I(K1), suggesting that enhanced cardiac repolarization in Inh mice is an adaptive response to chronic CaMKII inhibition rather than an acute effect of reduced CaMKII activity. Increasing PKA activity, by cell dialysis with cAMP, or inhibition of PKA did not affect I(K1) in WT cells. Dialysis of WT cells with cAMP also reduced I(to,f), suggesting that PKA upregulation does not increase repolarizing K(+) currents in Inh mice. These findings provide novel in vivo and cellular evidence that CaMKII links Ca(2+)(i) to cardiac repolarization and suggest that PLN may be a critical CaMKII target for feedback regulation of APD in ventricular myocytes.


Profile of genetic alterations and tumorigenicity of human breast cancer cells.
The profile of genetic alterations in four breast carcinoma cell lines, SK-BR-3, BT-474, MDA-MB361 and ZR-75-1 was examined by comparative genomic hybridization, G-band karyotyping, reverse chromosome painting and fluorescence in situ hybridization of single-copy genes. These lines are aneuploid with complex structural rearrangements and have DNA copy-number imbalances involving multiple sites that include amplification of ERBB-2 and MYC proto-oncogenes which are implicated in breast cancer pathogenesis. A novel site of high level amplification was mapped on chromosome 15. All lines were tumorigenic in nude mice, however, the latency and the incidence of tumor formation varied; SK-BR-3 and MDA-MB361 produced tumors in a shorter time and had a higher total number of genomic imbalances compared to BT-474 and ZR-75-1 cells. Tumor cell behavior in vivo was not reflected by the rate of in vitro cell proliferation. Underrepresentation on the long arm of chromosome 18 was the sole alteration that correlated with an increased tumorigenicity. Chromosome 18q is rich in tumor suppressor genes and its loss is prevalent in primary node-positive breast tumors. Cell lines with monoclonal populations preserve the genetic characteristics of the primary tumor and their use may facilitate the detection of specific alterations associated with breast cancer progression.


Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: a comprehensive review.
Coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV (RAAS-SCoV) axis. There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV axis (informed by prior studies of SARS-CoV), how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner. This review discusses the role of the RAAS-SCoV axis in acute lung injury and the effects, risks and benefits of pharmacological modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favour a protective effect of RAAS-SCoV axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remain limited. Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiological effects caused by the virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV axis on acute lung injury in COVID-19.


The geological evolution of the Tibetan Plateau.
The geological evolution of the Tibetan plateau is best viewed in a context broader than the India-Eurasia collision zone. After collision about 50 million years ago, crust was shortened in western and central Tibet, while large fragments of lithosphere moved from the collision zone toward areas of trench rollback in the western Pacific and Indonesia. Cessation of rapid Pacific trench migration ( approximately 15 to 20 million years ago) coincided with a slowing of fragment extrusion beyond the plateau and probably contributed to the onset of rapid surface uplift and crustal thickening in eastern Tibet. The latter appear to result from rapid eastward flow of the deep crust, probably within crustal channels imaged seismically beneath eastern Tibet. These events mark a transition to the modern structural system that currently accommodates deformation within Tibet.


Endemic goitre and hypothyroidism in an adult female patient dependent on total parenteral nutrition.
We present the case of a thirty-year-old female patient who was referred to the endocrinology team with an enlarging goitre and biochemical hypothyroidism. She had been dependent on total parenteral nutrition for the previous six years as a result of intestinal failure thought to be caused by possible underlying mitochondrial disease. The patient also suffers from a Desmin myopathy, and at present, the exact aetiology behind her intestinal failure is not certain. The goitre was smooth and had been enlarging slowly over the previous few months. Thyroid peroxidase antibodies were found to be within normal range. Further analysis of the case showed that twelve months earlier the patients total parenteral nutrition (TPN) feed had been altered as a result of manganese toxicity. The current feeding regimen did not contain a trace element additive which had previously supplied iodine supplementation. A little detective work established that iodine content to the TPN had been reduced, the trace element additive (Additrace) was recommenced providing 1 µmol of iodine per day, equating to 130 µg of iodine. Following this change, thyroid-stimulating hormone levels returned to normal and the goitre quickly reduced in size. We present a rare case of endemic goitre and hypothyroidism in a patient receiving inadequate iodine supplementation through total parenteral nutrition. Endemic goitre and hypothyroidism secondary to iodine deficiency are rare in the developed world. However, the diagnosis should be considered in the setting of a diffuse goitre and negative thyroid antibodies.Although rare, endemic goitre should be considered in patients who present with hypothyroidism and who are dependent on total parenteral nutrition.Treatment with levothyroxine is not required in endemic goitre as thyroid function tests generally normalise with the addition of iodine to the diet/total parenteral nutrition regimen.Iodine supplementation at a level recommended by the European Society for Clinical Nutrition and Metabolism (ESPEN) was observed to quickly normalise this patient's thyroid function tests.


Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial.
To evaluate whether tocilizumab (TCZ) monotherapy is noninferior to treatment with TCZ plus methotrexate (MTX) for maintaining clinical responses in patients with rheumatoid arthritis (RA) in whom low disease activity is achieved with TCZ plus MTX. Patients with RA who experienced an inadequate response to MTX received MTX plus TCZ 162 mg subcutaneously. At 24 weeks, patients who achieved a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) of ≤3.2 were randomized to receive TCZ monotherapy or to continue treatment with TCZ plus MTX until week 52. The primary outcome measure was the comparison of the mean change in the DAS28-ESR from week 24 to week 40 between the TCZ monotherapy and TCZ plus MTX arms (noninferiority margin of 0.6). Secondary outcome measures included worsening of the DAS28-ESR by ≥1.2, achievement of a DAS28-ESR of <2.6 and ≤3.2, and safety and immunogenicity. Among the 718 patients enrolled, 296 were randomized at week 24 to receive TCZ monotherapy (n = 147) or TCZ plus MTX (n = 147). The mean changes in the DAS28-ESR from week 24 to week 40 were 0.46 and 0.14 in the TCZ monotherapy arm and the TCZ plus MTX arm, respectively (weighted difference between the groups, 0.318 [95% confidence interval 0.045, 0.592]); discontinuing MTX in TCZ responders was noninferior to continuing MTX. Safety events were broadly similar between the randomized treatment groups; the most common serious adverse event was infection, which occurred in 2.1% of patients in the TCZ monotherapy group and 2.2% of patients receiving TCZ plus MTX. Patients with RA receiving TCZ plus MTX who achieve low disease activity can discontinue MTX without significant worsening of disease activity during the 16 weeks following MTX discontinuation.


Stable nanoconjugates of transferrin with alloyed quaternary nanocrystals Ag-In-Zn-S as a biological entity for tumor recognition.
One way to limit the negative effects of anti-tumor drugs on healthy cells is targeted therapy employing functionalized drug carriers. Here we present a biocompatible and stable nanoconjugate of transferrin anchored to Ag-In-Zn-S quantum dots modified with 11-mercaptoundecanoic acid (Tf-QD) as a drug carrier versus typical anticancer drug, doxorubicin. Detailed investigations of Tf-QD nanoconjugates without and with doxorubicin by fluorescence studies and cytotoxic measurements showed that the biological activity of both the transferrin and doxorubicin was fully retained in the nanoconjugate. In particular, the intercalation capabilities of free doxorubicin versus ctDNA remained essentially intact upon its binding to the nanoconjugate. In order to evaluate these capabilities, we studied the binding constant of doxorubicin attached to Tf-QDs with ctDNA as well as the binding site size on the ctDNA molecule. The binding constant slightly decreased compared to that of free doxorubicin while the binding site size, describing the number of consecutive DNA lattice residues involved in the binding, increased. It was also demonstrated that the QDs alone and in the form of a nanoconjugate with Tf were not cytotoxic towards human non-small cell lung carcinoma (H460 cell line) and the tumor cell sensitivity of the DOX-Tf-QD nanoconjugate was comparable to that of doxorubicin alone.


Exciting journey of 10 years from genomes to fields and markets: Some success stories of genomics-assisted breeding in chickpea, pigeonpea and groundnut.
Legume crops such as chickpea, pigeonpea and groundnut, mostly grown in marginal environments, are the major source of nutrition and protein to the human population in Asia and Sub-Saharan Africa. These crops, however, have a low productivity, mainly due to their exposure to several biotic and abiotic stresses in the marginal environments. Until 2005, these crops had limited genomics resources and molecular breeding was very challenging. During the last decade (2005-2015), ICRISAT led demand-driven innovations in genome science and translated the massive genome information in breeding. For instance, large-scale genomic resources including draft genome assemblies, comprehensive genetic and physical maps, thousands of SSR markers, millions of SNPs, several high-throughput as well as low cost marker genotyping platforms have been developed in these crops. After mapping several breeding related traits, several success stories of translational genomics have become available in these legumes. These include development of superior lines with enhanced drought tolerance in chickpea, enhanced and pyramided resistance to Fusarium wilt and Ascochyta blight in chickpea, enhanced resistance to leaf rust in groundnut, improved oil quality in groundnut and utilization of markers for assessing purity of hybrids/parental lines in pigeonpea. Some of these stories together with future prospects have been discussed.


Does this patient have acute cholecystitis?
Although few patients with acute abdominal pain will prove to have cholecystitis, ruling in or ruling out acute cholecystitis consumes substantial diagnostic resources. To determine if aspects of the history and physical examination or basic laboratory testing clearly identify patients who require diagnostic imaging tests to rule in or rule out the diagnosis of acute cholecystitis. Electronic search of the Science Citation Index, Cochrane Library, and English-language articles from January 1966 through November 2000 indexed in MEDLINE. We also hand-searched Index Medicus for 1950-1965, and scanned references in identified articles and bibliographies of prominent textbooks of physical examination, surgery, and gastroenterology. To identify relevant articles appearing since the comprehensive search, we repeated the MEDLINE search in July 2002. Included studies evaluated the role of the history, physical examination, and/or laboratory tests in adults with abdominal pain or suspected acute cholecystitis. Studies had to report data from a control group found not to have acute cholecystitis. Acceptable definitions of cholecystitis included surgery, pathologic examination, hepatic iminodiacetic acid scan or right upper quadrant ultrasound, or clinical course consistent with acute cholecystitis and no evidence for an alternate diagnosis. Studies of acalculous cholecystitis were included. Seventeen of 195 identified studies met the inclusion criteria. Two authors independently abstracted data from the 17 included studies. Disagreements were resolved by discussion and consensus with a third author. No clinical or laboratory finding had a sufficiently high positive likelihood ratio (LR) or low negative LR to rule in or rule out the diagnosis of acute cholecystitis. Possible exceptions were the Murphy sign (positive LR, 2.8; 95% CI, 0.8-8.6) and right upper quadrant tenderness (negative LR, 0.4; 95% CI, 0.2-1.1), though the 95% CIs for both included 1.0. Available data on diagnostic confirmation rates at laparotomy and test characteristics of relevant radiological investigations suggest that the diagnostic impression of acute cholecystitis has a positive LR of 25 to 30. Unfortunately, the available literature does not identify the specific combinations of clinical and laboratory findings that presumably account for this diagnostic success. No single clinical finding or laboratory test carries sufficient weight to establish or exclude cholecystitis without further testing (eg, right upper quadrant ultrasound). Combinations of certain symptoms, signs, and laboratory results likely have more useful LRs, and presumably inform the diagnostic impressions of experienced clinicians. Pending further research characterizing the pretest probabilities associated with different clinical presentations, the evaluation of patients with abdominal pain suggestive of cholecystitis will continue to rely heavily on the clinical gestalt and diagnostic imaging.