Interactive telemedicine: effects on professional practice and health care outcomes.
Telemedicine (TM) is the use of telecommunication systems to deliver health care at a distance. It has the potential to improve patient health outcomes, access to health care and reduce healthcare costs. As TM applications continue to evolve it is important to understand the impact TM might have on patients, healthcare professionals and the organisation of care. To assess the effectiveness, acceptability and costs of interactive TM as an alternative to, or in addition to, usual care (i.e. face-to-face care, or telephone consultation). We searched the Effective Practice and Organisation of Care (EPOC) Group's specialised register, CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers to June 2013, together with reference checking, citation searching, handsearching and contact with study authors to identify additional studies. We considered randomised controlled trials of interactive TM that involved direct patient-provider interaction and was delivered in addition to, or substituting for, usual care compared with usual care alone, to participants with any clinical condition. We excluded telephone only interventions and wholly automatic self-management TM interventions. For each condition, we pooled outcome data that were sufficiently homogenous using fixed effect meta-analysis. We reported risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) for continuous outcomes. We included 93 eligible trials (N = 22,047 participants), which evaluated the effectiveness of interactive TM delivered in addition to (32% of studies), as an alternative to (57% of studies), or partly substituted for usual care (11%) as compared to usual care alone.The included studies recruited patients with the following clinical conditions: cardiovascular disease (36), diabetes (21), respiratory conditions (9), mental health or substance abuse conditions (7), conditions requiring a specialist consultation (6), co morbidities (3), urogenital conditions (3), neurological injuries and conditions (2), gastrointestinal conditions (2), neonatal conditions requiring specialist care (2), solid organ transplantation (1), and cancer (1).Telemedicine provided remote monitoring (55 studies), or real-time video-conferencing (38 studies), which was used either alone or in combination. The main TM function varied depending on clinical condition, but fell typically into one of the following six categories, with some overlap: i) monitoring of a chronic condition to detect early signs of deterioration and prompt treatment and advice, (41); ii) provision of treatment or rehabilitation (12), for example the delivery of cognitive behavioural therapy, or incontinence training; iii) education and advice for self-management (23), for example nurses delivering education to patients with diabetes or providing support to parents of very low birth weight infants or to patients with home parenteral nutrition; iv) specialist consultations for diagnosis and treatment decisions (8), v) real-time assessment of clinical status, for example post-operative assessment after minor operation or follow-up after solid organ transplantation (8) vi), screening, for angina (1).The type of data transmitted by the patient, the frequency of data transfer, (e.g. telephone, e-mail, SMS) and frequency of interactions between patient and healthcare provider varied across studies, as did the type of healthcare provider/s and healthcare system involved in delivering the intervention.We found no difference between groups for all-cause mortality for patients with heart failure (16 studies; N = 5239; RR:0.89, 95% CI 0.76 to 1.03, P = 0.12; I(2) = 44%) (moderate to high certainty of evidence) at a median of six months follow-up. Admissions to hospital (11 studies; N = 4529) ranged from a decrease of 64% to an increase of 60% at median eight months follow-up (moderate certainty of evidence). We found some evidence of improved quality of life (five studies; N = 482; MD:-4.39, 95% CI -7.94 to -0.83; P < 0.02; I(2) = 0%) (moderate certainty of evidence) for those allocated to TM as compared with usual care at a median three months follow-up. In studies recruiting participants with diabetes (16 studies; N = 2768) we found lower glycated haemoglobin (HbA1c %) levels in those allocated to TM than in controls (MD -0.31, 95% CI -0.37 to -0.24; P < 0.00001; I(2)= 42%, P = 0.04) (high certainty of evidence) at a median of nine months follow-up. We found some evidence for a decrease in LDL (four studies, N = 1692; MD -12.45, 95% CI -14.23 to -10.68; P < 0.00001; I(2 =) 0%) (moderate certainty of evidence), and blood pressure (four studies, N = 1770: MD: SBP:-4.33, 95% CI -5.30 to -3.35, P < 0.00001; I(2) = 17%; DBP: -2.75 95% CI -3.28 to -2.22, P < 0.00001; I(2) = 45% (moderate certainty evidence), in TM as compared with usual care.Seven studies that recruited participants with different mental health and substance abuse problems, reported no differences in the effect of therapy delivered over video-conferencing, as compared to face-to-face delivery. Findings from the other studies were inconsistent; there was some evidence that monitoring via TM improved blood pressure control in participants with hypertension, and a few studies reported improved symptom scores for those with a respiratory condition. Studies recruiting participants requiring mental health services and those requiring specialist consultation for a dermatological condition reported no differences between groups. The findings in our review indicate that the use of TM in the management of heart failure appears to lead to similar health outcomes as face-to-face or telephone delivery of care; there is evidence that TM can improve the control of blood glucose in those with diabetes. The cost to a health service, and acceptability by patients and healthcare professionals, is not clear due to limited data reported for these outcomes. The effectiveness of TM may depend on a number of different factors, including those related to the study population e.g. the severity of the condition and the disease trajectory of the participants, the function of the intervention e.g., if it is used for monitoring a chronic condition, or to provide access to diagnostic services, as well as the healthcare provider and healthcare system involved in delivering the intervention.


Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.


Clinical challenges of a co-secreting TSH/GH pituitary adenoma.
Co-secreting thyrotropin/growth hormone (GH) pituitary adenomas are rare; their clinical presentation and long-term management are challenging. There is also a paucity of long-term data. Due to the cell of origin, these can behave as aggressive tumours. We report a case of a pituitary plurihormonal pit-1-derived macroadenoma, with overt clinical hyperthyroidism and minimal GH excess symptoms. The diagnosis was confirmed by pathology showing elevated thyroid and GH axes with failure of physiological GH suppression, elevated pituitary glycoprotein hormone alpha subunit (αGSU) and macroadenoma on imaging. Pre-operatively the patient was rendered euthyroid with carbimazole and underwent successful transphenoidal adenomectomy (TSA) with surgical cure. Histopathology displayed an elevated Ki-67 of 5.2%, necessitating long-term follow-up. Thyrotropinomas are rare and likely under-diagnosed due to under-recognition of secondary hyperthyroidism. Thyrotropinomas and other plurihormonal pit-1-derived adenomas are more aggressive adenomas according to WHO guidelines. Co-secretion occurs in 30% of thyrotropinomas, requiring diligent investigation and long-term follow-up of complications.


Persistent high frequencies of varicella-zoster virus ORF4 protein-specific CD4+ T cells after primary infection.
Open reading frame 4 (ORF4) of varicella-zoster virus (VZV) encodes an immediate-early protein that is believed to be important for viral infectivity and establishing latency. Evidence suggests that VZV-specific T cells are crucial in the control of viral replication, but there are no data addressing the existence of potential ORF4 protein-specific CD4+ T cells. We tested the hypothesis that VZV ORF4 protein-specific CD4+ T cells could be identified and characterized within the peripheral blood of healthy immune donors following primary infection. Gamma interferon (IFN-gamma) immunosorbent assays were used to screen peripheral blood mononuclear cells obtained from healthy seropositive donors for responses to overlapping ORF4 peptides, viral lysate, and live vaccine. High frequencies of ORF4 protein-specific T cells were detected ex vivo in individuals up to 52 years after primary infection. Several immunogenic regions of the ORF4 protein were identified, including a commonly recognized epitope which was restricted through HLA-DRB1*07. Total ORF4 protein-specific responses comprised 19.7% and 20.7% of the total lysate and vaccine responses, respectively, and were dominated by CD4+ T cells. Indeed, CD4+ T cells were found to dominate the overall virus-specific IFN-gamma cellular immune response both ex vivo and after expansion in vitro. In summary, we have identified an ORF4 protein as a novel target antigen for persistent VZV-specific CD4+ T cells, with implications for disease pathogenesis and future vaccine development.


First-morning urinary melatonin and breast cancer risk in the Guernsey Study.
It has been hypothesized that suppressed nocturnal melatonin production is associated with an increased risk of breast cancer, but results from several small prospective studies of the association have been inconclusive. We examined the association between nocturnal melatonin and breast cancer risk in a case-control study nested within the Guernsey III Study, a British prospective cohort study (1977-2009). Concentrations of 6-sulfatoxymelatonin were measured in prediagnostic first-morning urine samples from 251 breast cancer cases and 727 matched controls. Conditional logistic regression models were used to calculate odds ratios for breast cancer in relation to 6-sulfatoxymelatonin level. No significant association was found between 6-sulfatoxymelatonin level and breast cancer risk, either overall (for highest third vs. lowest, multivariable-adjusted odds ratio = 0.90, 95% confidence interval: 0.61, 1.33) or by menopausal status. However, in a meta-analysis of all published prospective data, including 1,113 cases from 5 studies, higher 6-sulfatoxymelatonin levels were associated with lower breast cancer risk (for highest fourth vs. lowest, odds ratio = 0.81, 95% confidence interval: 0.66, 0.99). In summary, we found no evidence that 6-sulfatoxymelatonin level in a first-morning urine sample was associated with breast cancer risk among British women. However, overall the published data suggest a modest inverse association between melatonin levels and breast cancer risk. Further data are needed to confirm this association.


CCR2 modulates inflammatory and metabolic effects of high-fat feeding.
The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.


Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms.
Friedreich's ataxia (FRDA) is the most common form of hereditary ataxia caused by recessive mutations in the FXN gene. Recent results have indicated the presence of different frataxin isoforms due to alternative gene expression mechanisms. Our previous studies demonstrated the advantages of using high-capacity herpes simplex virus type 1 (HSV-1) amplicon vectors containing the entire FXN genomic locus (iBAC-FXN) as a gene-delivery vehicle capable of ensuring physiologically-regulated and long-term persistence. Here we describe how expression from the 135 kb human FXN genomic locus produces the three frataxin isoforms both in cultured neuronal cells and also in vivo. Moreover, we also observed the correct expression of these frataxin isoforms in patient-derived cells after delivery of the iBAC-FXN. These results lend further support to the potential use of HSV-1 vectors containing entire genomic loci whose expression is mediated by complex transcriptional and posttranscriptional mechanisms for gene therapy applications.


Physical activity of subjects aged 50-64 years involved in the European Prospective Investigation into Cancer and Nutrition (EPIC).
To describe physical activity of participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). A cross-sectional analysis of baseline data of a European prospective cohort study. This analysis was restricted to participants in the age group 50-64 years, which was represented in all EPIC centres. It involved 236 386 participants from 25 centres in nine countries. In each EPIC centre, physical activity was assessed by standardised and validated questions. Frequency distribution of type of professional activity and participation in non-professional activities, and age-adjusted means, medians and percentiles of time dedicated to non-professional activities are presented for men and women from each centre. Professional activity was most frequently classified as sedentary or standing in all centres. There was a wide variation regarding participation in different types of non-professional activities and time dedicated to these activities across EPIC centres. Over 80% of all EPIC participants engaged in walking, while less than 50% of the subjects participated in sport. Total time dedicated to recreational activities was highest among the Dutch participants and lowest among men from Malmö (Sweden) and women from Naples (Italy). In all centres, total time dedicated to recreational activity in the summer was higher than in the winter. Women from southern Europe spent the most time on housekeeping. There is a considerable variation of physical activity across EPIC centres. This variation was especially evident for recreational activities in both men and women.


Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome.
Paraneoplastic pemphigus is the term used for an exclusive subset of pemphigus. The clinical lesions may resemble pemphigus, pemphigoid, erythema multiforme, graft-vs.-host disease, or lichen planus. A common denominator in all patients is the concomitant occurrence of either occult or confirmed systemic neoplasm. It is imperative to confirm the diagnosis through microscopy, where intraepidermal suprabasal cleavage, epidermal acantholysis, dyskeratotic keratinocytes and vacuolar changes in the basal epidermis, interfacial dermatitis, and epidermal exocytosis can be seen. Furthermore, the deposition of immunoglobulin G (IgG) and complement in the epidermal intercellular spaces, detected by direct and/or indirect immunofluorescence, is equally crucial for confirming the diagnosis.


Immunometabolism of pro-repair cells.
Immune cell populations determine the balance between ongoing damage and repair following tissue injury. Cells responding to a tissue-damaged environment have significant bioenergetic and biosynthetic needs. In addition to supporting these needs, metabolic pathways govern the function of pro-repair immune cells, including regulatory T cells and tissue macrophages. In this Review, we explore how specific features of the tissue-damaged environment such as hypoxia, oxidative stress, and nutrient depletion serve as metabolic cues to promote or impair the reparative functions of immune cell populations. Hypoxia, mitochondrial DNA stress, and altered redox balance each contribute to mechanisms regulating the response to tissue damage. For example, hypoxia induces changes in regulatory T cell and macrophage metabolic profiles, including generation of 2-hydroxyglutarate, which inhibits demethylase reactions to modulate cell fate and function. Reactive oxygen species abundant in oxidative environments cause damage to mitochondrial DNA, initiating signaling pathways that likewise control pro-repair cell function. Nutrient depletion following tissue damage also affects pro-repair cell function through metabolic signaling pathways, specifically those sensitive to the redox state of the cell. The study of immunometabolism as an immediate sensor and regulator of the tissue-damaged environment provides opportunities to consider mechanisms that facilitate healthy repair of tissue injury.


Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval 2·9-3·0) for men and 3·5 years (3·4-3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78-0·92) and 1·2 years (1·1-1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Bill & Melinda Gates Foundation.


CRAC channels drive digital activation and provide analog control and synergy to Ca(2+)-dependent gene regulation.
Ca(2+)-dependent gene expression is critical for cell growth, proliferation, plasticity, and adaptation [1-3]. Because a common mechanism in vertebrates linking cytoplasmic Ca(2+) signals with activation of protein synthesis involves the nuclear factor of activated T cells (NFAT) family of transcription factors [4, 5], we have quantified protein expression in single cells following physiological Ca(2+) signals by using NFAT-driven expression of a genetically encoded fluorescent protein. We find that gene expression following CRAC channel activation is an all-or-nothing event over a range of stimulus intensities. Increasing agonist concentration recruits more cells but each responding cell does so in an essentially digital manner. Furthermore, Ca(2+)-dependent gene expression shows both short-term memory and strong synergy, where two pulses of agonist, which are ineffectual individually, robustly activate gene expression provided that the time interval between them is short. Such temporal filtering imparts coincidence detection to Ca(2+)-dependent gene activation. The underlying molecular basis mapped to time-dependent, nonlinear accumulation of nuclear NFAT. Local Ca(2+) near CRAC channels has to rise above a threshold level to drive gene expression, providing analog control to the digital activation process and a means to filter out fluctuations in background noise from activating transcription while ensuring robustness and high fidelity in the excitation-transcription coupling mechanism.


Unexplained gastrointestinal symptoms: think mitochondrial disease.
Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic. We describe the clinical, histopathological and genetic findings of six patients from three families with gastrointestinal manifestations of mitochondrial disease. In two of the patients, anorexia nervosa was considered as an initial diagnosis. These cases illustrate the challenges of both diagnosing and managing mitochondrial disease and highlight two important but poorly understood aspects, the clinical and the genetic. The pathophysiology of gastrointestinal involvement in mitochondrial disease is discussed and emerging treatments are described. Finally, we provide a checklist of investigations for the gastroenterologist when mitochondrial disease is suspected.


Exploring variability in basal ganglia connectivity with functional MRI in healthy aging.
Changes in functional connectivity (FC) measured using resting state fMRI within the basal ganglia network (BGN) have been observed in pathologies with altered neurotransmitter systems and conditions involving motor control and dopaminergic processes. However, less is known about non-disease factors affecting FC in the BGN. The aim of this study was to examine associations of FC within the BGN with dopaminergic processes in healthy older adults. We explored the relationship between FC in the BGN and variables related to demographics, impulsive behavior, self-paced tasks, mood, and motor correlates in 486 participants in the Whitehall-II imaging sub-study using both region-of-interest- and voxel-based approaches. Age was the only correlate of FC in the BGN that was consistently significant with both analyses. The observed adverse effect of aging on FC may relate to alterations of the dopaminergic system, but no unique dopamine-related function seemed to have a link with FC beyond those detectable in and linearly correlated with healthy aging.


Challenges to using evidence from systematic reviews to stop ineffective practice: an interview study.
To examine the challenges to using systematic review evidence to develop guidance for decommissioning ineffective health services, and the problems experienced by clinicians and commissioners when they attempt to implement the evidence from this guidance. Interviews with 23 clinicians and 15 commissioners from nine commissioning organizations (Primary Care Trusts) in the south of England. Participants identified generic and intervention-specific barriers to using systematic review evidence to develop and implement decommissioning. Generic barriers included: contradictions within the health care system arising from policy; managing a high volume of evidence; difficulty in applying the evidence to the local context; and patient or parent expectations. Intervention-specific factors included: the influence of industry; an absence of systems for monitoring local implementation of guidance; and the availability of different codes for the same procedure which made monitoring some practices unreliable. The micro practices of commissioners are shaped by the wider system of health policy, the knowledge producing and delivery agencies associated with health care, and power dynamics within the health care system. If decommissioning is to be guided by evidence, then adequate resources to support the process are necessary. This includes long-term engagement of clinicians, providing alternatives to the decommissioned activity and tackling perverse incentives. An important precursor to decommissioning is obtaining data on the nature and extent of current clinical practice and using these data to monitor variation in the implementation of guidance.


A proposal to classify happiness as a psychiatric disorder.
It is proposed that happiness be classified as a psychiatric disorder and be included in future editions of the major diagnostic manuals under the new name: major affective disorder, pleasant type. In a review of the relevant literature it is shown that happiness is statistically abnormal, consists of a discrete cluster of symptoms, is associated with a range of cognitive abnormalities, and probably reflects the abnormal functioning of the central nervous system. One possible objection to this proposal remains--that happiness is not negatively valued. However, this objection is dismissed as scientifically irrelevant.


[Investigation of gestagenic effect of raw drone milk in rats].
Numerous honeybee products are used in traditional medicine. The best-known honeybee products are the honey, the propolis and the royal jelly. Drone milk is a relatively little-known honeybee product. Although, drone milk is traditionally used to treat infertility and to promote vitality in both men and women in certain countries, the literature furnishes no information concerning effects of the drone milk. The oestrogenic and androgenic effects of drone milk have recently been reported in rats and the effective compounds have also been identified. The aim of this study was to determine the putative gestagenic effect of raw drone milk in rats. Maintenance of pregnancy assays revealed that drone milk was able to increase the number of surviving fetuses. This results suggested some gestagenic effects. This effect was confirmed by RT-PCR and Western blot methods in which the mRNA and protein expressions of gestagen-dependent CRLR (Calcitonin Receptor-Like Receptor) peptide were determined. To determine the efficacy of gestagenic effect of drone milk, spironolactone (weak gestagen compound) was used. The combination of drone milk and spironolactone showed more potent gestagenic effect. These results lead us to suppose that raw drone milk shows weak gestagenic effect and this effect can be increased by another weak gestagen. Further studies are required to clarify the gestagenic mechanisms of action of drone milk.


Transgenerational Bisphenol A Causes Deficits in Social Recognition and Alters Postsynaptic Density Genes in Mice.
Bisphenol A (BPA) is a ubiquitous endocrine-disrupting chemical. Developmental exposure produces changes in behavior and gene expression in the brain. Here, we examined social recognition behaviors in mice from the third familial generation (F3) after exposure to gestational BPA. Second-generation mice were bred in one of four mating combinations to reveal whether characteristics in F3 were acquired via maternal or paternal exposures. After repeated habituation to the same mouse, offspring of dams from the BPA lineage failed to display increased investigation of a novel mouse. Genes involved in excitatory postsynaptic densities (PSDs) were examined in F3 brains using quantitative PCR. Differential expression of genes important for function and stability of PSDs were assessed at three developmental ages. Several related PSD genes-SH3 and multiple ankyrin repeat domains 1 (Shank1), Homer scaffolding protein 1c (Homer1c), DLG associated protein 1 (Gkap), and discs large MAGUK scaffold protein 4 (PSD95)-were differentially expressed in control- vs BPA-lineage brains. Using a second strain of F3 inbred mice exposed to BPA, we noted the same differences in Shank1 and PSD95 expression in C57BL/6J mice. In sum, transgenerational BPA exposure disrupted social interactions in mice and dysregulated normal expression of PSD genes during neural development. The fact that the same genetic effects were found in two different mouse strains and in several brain regions increased potential for translation. The genetic and functional relationship between PSD and abnormal neurobehavioral disorders is well established, and our data suggest that BPA may contribute in a transgenerational manner to neurodevelopmental diseases.


Feasibility, safety and cost of outpatient management of acute minor ischaemic stroke: a population-based study.
Outpatient management safely and effectively prevents early recurrent stroke after transient ischaemic attack (TIA), but this approach may not be safe in patients with acute minor stroke. To study outcomes of clinic and hospital-referred patients with TIA or minor stroke (National Institute of Health Stroke Scale score ≤3) in a prospective, population-based study (Oxford Vascular Study). Of 845 patients with TIA/stroke, 587 (69%) were referred directly to outpatient clinics and 258 (31%) directly to inpatient services. Of the 250 clinic-referred minor strokes (mean age 72.7 years), 237 (95%) were investigated, treated and discharged on the same day, of whom 16 (6.8%) were subsequently admitted to hospital within 30 days for recurrent stroke (n=6), sepsis (n=3), falls (n=3), bleeding (n=2), angina (n=1) and nursing care (n=1). The 150 patients (mean age 74.8 years) with minor stroke referred directly to hospital (median length-of-stay 9 days) had a similar 30-day readmission rate (9/150; 6.3%; p=0.83) after initial discharge and a similar 30-day risk of recurrent stroke (9/237 in clinic patients vs 8/150, OR=0.70, 0.27-1.80, p=0.61). Rates of prescription of secondary prevention medication after initial clinic/hospital discharge were higher in clinic-referred than in hospital-referred patients for antiplatelets/anticoagulants (p<0.05) and lipid-lowering agents (p<0.001) and were maintained at 1-year follow-up. The mean (SD) secondary care cost was £8323 (13 133) for hospital-referred minor stroke versus £743 (1794) for clinic-referred cases. Outpatient management of clinic-referred minor stroke is feasible and may be as safe as inpatient care. Rates of early hospital admission and recurrent stroke were low and uptake and maintenance of secondary prevention was high.


Knockdown of SMN by RNA interference induces apoptosis in differentiated P19 neural stem cells.
Spinal muscular atrophy (SMA) is a common neurodegenerative disease that is caused by mutations in the survival of motor neuron gene (SMN), leading to reduced levels of the SMN protein in affected individuals. In SMA, motor neurons selectively degenerate, however, the mechanism of cell death and the precise role of SMN in this process are not completely understood. In this study, we apply RNA interference (RNAi) to knockdown Smn gene expression in the murine embryonal carcinoma stem cell line P19, which can be differentiated into neuronal cells. A direct effect of Smn loss on apoptotic cell death in differentiated P19 neuronal cells, and to a lesser extent in undifferentiated cells was observed. Apoptosis could be partly reversed by expression of an SMN rescue construct, was reversible by the addition of the caspase-inhibitor ZVAD-fmk and involved the cytochrome c pathway. This study shows for the first time that knockdown of SMN results in apoptosis in mammalian neuronal cells and has implications for understanding the cause of motor neuron-specific cell loss in SMA, and for identifying novel therapeutic targets for this disease.


Impact of aging: sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease.
The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.


[Factors related to patient satisfaction with hospital emergency services].
To determine the perceived quality variables related to satisfaction and to identify the influence of sociodemographic factors on user satisfaction with hospital emergencies. A telephone survey was conducted with a specifically designed questionnaire for use in a sample of 3,600 users of hospital emergency services in nine public hospitals in 2008 and 2009. The adjusted model including all perceived quality and sociodemographic variables explained 47.1% of the variance (adjusted R(2)). Of all the independent variables included, only eight were significant in predicting the level of patient satisfaction. These variables were related to the patient's opinion of the relationship with medical staff (p = 0.041), nurses' and porters' professionalism (p = 0.010 and 0.022), infrastructure (cleanliness and comfort) (p = 0.033 and 0.008), information received at discharge (p = 0.000), waiting time in the emergency department (p = 0.000) and the perception of treatment-diagnosis without failure (p = 0.028). The variables influencing emergency patients' satisfaction were determined, allowing areas where corrective action could be introduced to be identified. In addition, possible confounding factors that should be controlled for when comparing results among distinct hospitals were identified. The emergency satisfaction questionnaire is a useful instrument to evaluate and improve quality of care.


Successful use of cinacalcet to treat parathyroid-related hypercalcemia in two pediatric patients.
Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity.Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed.Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients.Treatment has been well tolerated and no side effects have been detected.


Brazilian green propolis modulates inflammation, angiogenesis and fibrogenesis in intraperitoneal implant in mice.
Chronic inflammatory processes in the peritoneal cavity develop as a result of ischemia, foreign body reaction, and trauma. Brazilian green propolis, a beeswax product, has been shown to exhibit multiple actions on inflammation and tissue repair. Our aim was to investigate the effects of this natural product on the inflammatory, angiogenic, and fibrogenic components of the peritoneal fibroproliferative tissue induced by a synthetic matrix. Chronic inflammation was induced by placing polyether-polyurethane sponge discs in the abdominal cavity of anesthetized Swiss mice. Oral administration of propolis (500/mg/kg/day) by gavage started 24 hours after injury for four days. The effect of propolis on peritoneal permeability was evaluated through fluorescein diffusion rate 4 days post implantation. The effects of propolis on the inflammatory (myeloperoxidase and n-acetyl-β-D-glucosaminidase activities and TNF-α levels), angiogenic (hemoglobin content-Hb), and fibrogenic (TGF-β1 and collagen deposition) components of the fibrovascular tissue in the implants were determined 5 days after the injury. Propolis was able to decrease intraperitoneal permeability. The time taken for fluorescence to peak in the systemic circulation was 20±1 min in the treated group in contrast with 15±1 min in the control group. In addition, the treatment was shown to down-regulate angiogenesis (Hb content) and fibrosis by decreasing TGF-β1 levels and collagen deposition in fibroproliferative tissue induced by the synthetic implants. Conversely, the treatment up-regulated inflammatory enzyme activities, TNF-α levels and gene expression of NOS2 and IFN-γ (23 and 7 fold, respectively), and of FIZZ1 and YM1 (8 and 2 fold) when compared with the untreated group. These observations show for the first time the effects of propolis modulating intraperitoneal inflammatory angiogenesis in mice and disclose important action mechanisms of the compound (downregulation of angiogenic components and activation of murine macrophage pathways).


Impact of miR-21, miR-126 and miR-221 as prognostic factors of clear cell renal cell carcinoma with tumor thrombus of the inferior vena cava.
Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.


Optogenetics in neural systems.
Both observational and perturbational technologies are essential for advancing the understanding of brain function and dysfunction. But while observational techniques have greatly advanced in the last century, techniques for perturbation that are matched to the speed and heterogeneity of neural systems have lagged behind. The technology of optogenetics represents a step toward addressing this disparity. Reliable and targetable single-component tools (which encompass both light sensation and effector function within a single protein) have enabled versatile new classes of investigation in the study of neural systems. Here we provide a primer on the application of optogenetics in neuroscience, focusing on the single-component tools and highlighting important problems, challenges, and technical considerations.


Phenotypic analysis of antigen-specific T lymphocytes.
Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.


ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases.
The importance of the Notch signaling in the development of glomerular diseases has been recently described. Therefore we analyzed in podocytes the expression and activity of ADAM10, one important component of the Notch signaling complex. By Western blot, immunofluorescence and immunohistochemistry analysis we characterized the expression of ADAM10 in human podocytes, human urine and human renal tissue. We present evidence, that differentiated human podocytes possessed increased amounts of mature ADAM10 and released elevated levels of L1 adhesion molecule, one well known substrate of ADAM10. By using specific siRNA and metalloproteinase inhibitors we demonstrate that ADAM10 is involved in the cleavage of L1 in human podocytes. Injury of podocytes enhanced the ADAM10 mediated cleavage of L1. In addition, we detected ADAM10 in urinary podocytes from patients with kidney diseases and in tissue sections of normal human kidney. Finally, we found elevated levels of ADAM10 in urinary vesicles of patients with glomerular kidney diseases. The activity of ADAM10 in human podocytes may play an important role in the development of glomerular kidney diseases.


Imperfection and radiation damage in protein crystals studied with coherent radiation.
Fringes and speckles occur within diffraction spots when a crystal is illuminated with coherent radiation during X-ray diffraction. The additional information in these features provides insight into the imperfections in the crystal at the sub-micrometre scale. In addition, these features can provide more accurate intensity measurements (e.g. by model-based profile fitting), detwinning (by distinguishing the various components), phasing (by exploiting sampling of the molecular transform) and refinement (by distinguishing regions with different unit-cell parameters). In order to exploit these potential benefits, the features due to coherent diffraction have to be recorded and any change due to radiation damage properly modelled. Initial results from recording coherent diffraction at cryotemperatures from polyhedrin crystals of approximately 2 µm in size are described. These measurements allowed information about the type of crystal imperfections to be obtained at the sub-micrometre level, together with the changes due to radiation damage.


Reduced subjective response to acute ethanol administration among young men with a broad bipolar phenotype.
Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects ('feel high': F=14.2, p=0.001; 'feel effects': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD.


Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing.
Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBDs). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified what we believe is a new, ROS-independent mechanism whereby activated tissue-infiltrating PMNs release microparticles armed with proinflammatory microRNAs (miR-23a and miR-155). Using IBD clinical samples, and in vitro and in vivo injury models, we show that PMN-derived miR-23a and miR-155 promote accumulation of double-strand breaks (DSBs) by inducing lamin B1-dependent replication fork collapse and inhibition of homologous recombination (HR) by targeting HR-regulator RAD51. DSB accumulation in injured epithelium led to impaired colonic healing and genomic instability. Targeted inhibition of miR-23a and miR-155 in cultured intestinal epithelial cells and in acutely injured mucosa decreased the detrimental effects of PMNs and enhanced tissue healing responses, suggesting that this approach can be used in therapies aimed at resolution of inflammation, in wound healing, and potentially to prevent neoplasia.


Adding vibrotactile feedback to a myoelectric-controlled hand improves performance when online visual feedback is disturbed.
We investigated whether adding vibrotactile feedback to a myoelectric-controlled hand, when visual feedback is disturbed, can improve performance during a functional test. For this purpose, able-bodied subjects, activating a myoelectric-controlled hand attached to their right hand performed the modified Box & Blocks test, grasping and manipulating wooden blocks over a partition. This was performed in 3 conditions, using a repeated-measures design: in full light, in a dark room where visual feedback was disturbed and no auditory feedback - one time with the addition of tactile feedback provided during object grasping and manipulation, and one time without any tactile feedback. The average time needed to transfer one block was measured, and an infrared camera was used to give information on the number of grasping errors during performance of the test. Our results show that when vibrotactile feedback was provided, performance time was reduced significantly, compared with when no vibrotactile feedback was available. Furthermore, the accuracy of grasping and manipulation was improved, reflected by significantly fewer errors during test performance. In conclusion, adding vibrotactile feedback to a myoelectric-controlled hand has positive effects on functional performance when visual feedback is disturbed. This may have applications to current myoelectric-controlled hands, as adding tactile feedback may help prosthesis users to improve their functional ability during daily life activities in different environments, particularly when limited visual feedback is available or desirable.


Current knowledge and future perspectives on acute hepatitis C infection.
Acute hepatitis C virus (HCV) infections are frequently seen worldwide in certain risk groups, with an annual incidence rate varying between 0.08% and 66%. Although this incidence is substantial, a delayed diagnosis during chronic infection is most often made in the absence of clinical symptoms in the acute phase of the infection. Currently used methods to diagnose acute HCV infection are IgG antibody seroconversion and repeated HCV RNA measurements, although no definitive diagnostic test is currently available. Progress in the field of adaptive and innate immune responses has aided both advances in the field of HCV vaccine development and a more basic understanding of viral persistence. The rapid changes in the treatment of chronic HCV infection will affect therapeutic regimens for acute HCV infection in the coming years, leading to shorter treatment courses and pegylated interferon-free modalities. This review gives an overview of the current knowledge and uncertainties, together with some future perspectives on acute hepatitis C epidemiology, virology, immunology, and treatment.


A genome-wide linkage study of individuals with high scores on NEO personality traits.
The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (>90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD)=5.86) and suggestive evidence of linkage (LOD >2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values = 0.009, 0.007), in 17q24 for agreeableness (marginal P-value = 0.018) and in 20p13 for conscientiousness (marginal P-values = 0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques.


Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma.
Admission of infants to hospital with bronchiolitis consumes considerable healthcare resources each winter. We report an analysis of hospital admissions in England over five decades. Data were analysed from the Hospital In-Patient Enquiry (HIPE, 1968-1985), Hospital Episode Statistics (HES, 1989-2011), Oxford Record Linkage Study (ORLS, 1963-2011) and Paediatric Intensive Care Audit Network (PICANet, 2003-2012). Cases were identified using International Classification of Diseases (ICD) codes in discharge records. Bronchiolitis was given a separate code in ICD9 (used in England from 1979). Geographical variation was analysed using Local Authority area boundaries. Maternal and perinatal risk factors associated with bronchiolitis and subsequent admissions for asthma were analysed using record-linkage. All-England HIPE and HES data recorded 468 138 episodes of admission for bronchiolitis in infants aged <1 year between 1979 and 2011. In 2011 the estimated annual hospital admission rate was 46.1 (95% CI 45.6 to 46.6) per 1000 infants aged <1 year. Between 2004 and 2011 the rates rose by an average of 1.8% per year in the all-England HES data, whereas admission rates to paediatric intensive care changed little (1.3 to 1.6 per 1000 infants aged <1 year). A fivefold geographical variation in hospital admission rates was observed. Young maternal age, low social class, low birth weight and maternal smoking were among factors associated with an increased risk of hospital admission with bronchiolitis. Hospital admissions for infants with bronchiolitis have increased substantially in recent years. However, cases requiring intensive care have changed little since 2004.


Impact of a web-based tool (WebCONSORT) to improve the reporting of randomised trials: results of a randomised controlled trial.
The CONSORT Statement is an evidence-informed guideline for reporting randomised controlled trials. A number of extensions have been developed that specify additional information to report for more complex trials. The aim of this study was to evaluate the impact of using a simple web-based tool (WebCONSORT, which incorporates a number of different CONSORT extensions) on the completeness of reporting of randomised trials published in biomedical publications. We conducted a parallel group randomised trial. Journals which endorsed the CONSORT Statement (i.e. referred to it in the Instruction to Authors) but do not actively implement it (i.e. require authors to submit a completed CONSORT checklist) were invited to participate. Authors of randomised trials were requested by the editor to use the web-based tool at the manuscript revision stage. Authors registering to use the tool were randomised (centralised computer generated) to WebCONSORT or control. In the WebCONSORT group, they had access to a tool allowing them to combine the different CONSORT extensions relevant to their trial and generate a customised checklist and flow diagram that they must submit to the editor. In the control group, authors had only access to a CONSORT flow diagram generator. Authors, journal editors, and outcome assessors were blinded to the allocation. The primary outcome was the proportion of CONSORT items (main and extensions) reported in each article post revision. A total of 46 journals actively recruited authors into the trial (25 March 2013 to 22 September 2015); 324 author manuscripts were randomised (WebCONSORT n = 166; control n = 158), of which 197 were reports of randomised trials (n = 94; n = 103). Over a third (39%; n = 127) of registered manuscripts were excluded from the analysis, mainly because the reported study was not a randomised trial. Of those included in the analysis, the most common CONSORT extensions selected were non-pharmacologic (n = 43; n = 50), pragmatic (n = 20; n = 16) and cluster (n = 10; n = 9). In a quarter of manuscripts, authors either wrongly selected an extension or failed to select the right extension when registering their manuscript on the WebCONSORT study site. Overall, there was no important difference in the overall mean score between WebCONSORT (mean score 0.51) and control (0.47) in the proportion of CONSORT and CONSORT extension items reported pertaining to a given study (mean difference, 0.04; 95% CI -0.02 to 0.10). This study failed to show a beneficial effect of a customised web-based CONSORT checklist to help authors prepare more complete trial reports. However, the exclusion of a large number of inappropriately registered manuscripts meant we had less precision than anticipated to detect a difference. Better education is needed, earlier in the publication process, for both authors and journal editorial staff on when and how to implement CONSORT and, in particular, CONSORT-related extensions. ClinicalTrials.gov: NCT01891448 [registered 24 May 2013].


Resting discharge of human muscle spindles is not modulated by increases in sympathetic drive.
There is evidence in experimental animals that, in addition to receiving fusimotor drive, muscle spindles are subject to modulation by the sympathetic nervous system. We examined the validity of this idea in human subjects by recording from muscle spindles in the relaxed ankle and toe extensor muscles during a strong and sustained physiological activation of muscle sympathetic outflow. Unitary recordings were made from 20 primary and 17 secondary muscle spindle afferents via a tungsten microelectrode inserted percutaneously into the peroneal nerve in 10 awake, healthy subjects seated with the legs supported in the extended position. ECG, blood pressure, respiration and calf circumference were also recorded. The majority of the muscle spindles were spontaneously active at rest; a background discharge was induced in four silent spindles by vibrating the tendon. A sustained increase in muscle vasoconstrictor activity, an increase in calf volume and a fall in pulse pressure were produced by subjects performing a 30-40 s maximal inspiratory breath-hold. Despite this strong increase in muscle sympathetic outflow no significant changes occurred in the discharge of either primary or secondary muscle spindle afferents, measured as a change in mean frequency and variability over sequential 5 s epochs and compared with the preceding period of rest. Strong chemoreceptor-driven sympathetic bursts during sustained expiratory breath-holds also failed to modulate the firing of 14 spindle endings. We conclude that a sustained, physiological increase in muscle sympathetic activity causes no detectable change in muscle spindle firing, lending no support to the concept that the sympathetic nervous system can influence the sensitivity of human muscle spindles directly.


Combinatorial HLA-peptide bead libraries for high throughput identification of CD8⁺ T cell specificity.
Comprehensive antigenic characterization of a T cell population of unknown specificity is challenging. Existing MHC class I expression systems are limited by the practical difficulty of probing cell populations with an MHC class I peptide library and the cross-reactivity of T cells that are able to recognise many variants of an index peptide. Using emulsion PCR and emulsion in vitro transcription/translation of a random library of peptides conjugated to CD8-null HLA-A*0201 on beads, we probed HLA-A*0201-restricted T cells with specificity for influenza, CMV and EBV. We observed significant enrichment for sequences containing HLA-A2 anchors and correct viral fragments for all T cell populations. HLA bead display provides a novel approach to identify the specificity of T cells.


Mapping hydroxyl variability throughout the global remote troposphere via synthesis of airborne and satellite formaldehyde observations.
The hydroxyl radical (OH) fuels tropospheric ozone production and governs the lifetime of methane and many other gases. Existing methods to quantify global OH are limited to annual and global-to-hemispheric averages. Finer resolution is essential for isolating model deficiencies and building process-level understanding. In situ observations from the Atmospheric Tomography (ATom) mission demonstrate that remote tropospheric OH is tightly coupled to the production and loss of formaldehyde (HCHO), a major hydrocarbon oxidation product. Synthesis of this relationship with satellite-based HCHO retrievals and model-derived HCHO loss frequencies yields a map of total-column OH abundance throughout the remote troposphere (up to 70% of tropospheric mass) over the first two ATom missions (August 2016 and February 2017). This dataset offers unique insights on near-global oxidizing capacity. OH exhibits significant seasonality within individual hemispheres, but the domain mean concentration is nearly identical for both seasons (1.03 ± 0.25 × 106 cm-3), and the biseasonal average North/South Hemisphere ratio is 0.89 ± 0.06, consistent with a balance of OH sources and sinks across the remote troposphere. Regional phenomena are also highlighted, such as a 10-fold OH depression in the Tropical West Pacific and enhancements in the East Pacific and South Atlantic. This method is complementary to budget-based global OH constraints and can help elucidate the spatial and temporal variability of OH production and methane loss.


Management of lymphadenitis due to non-tuberculous mycobacterial infection in children.
Non-tuberculous mycobacterial (NTM) infection is an important cause of cervico-facial lymph node enlargement in young children. The optimal treatment is thought to be early complete excision without chemotherapy. We compared management of patients referred to our centre to this "gold standard" and determined clinical outcomes by type of primary surgical intervention (complete excision vs. incomplete excision). Retrospective study of management and clinical outcomes of all children (<12 years) with NTM lymphadenitis referred to a single UK centre between May 1998 and May 2008. We identified 43 children. Median time from onset of swelling to operation was 6 weeks. Management was: no operation (n = 1, 2 %), complete excision (n = 20, 47 %), incision and drainage (n = 17, 40 %) and fine needle aspirate (n = 5, 12 %). Children not treated by primary complete excision were more likely to have: re-operation (91 vs. 30 %; χ(2) = 16.48; p < 0.0001); persistent lymphadenitis (77 vs. 30 %; χ(2) = 9.45; p = 0.002); sinus formation (26 vs. 5 %; χ2 = 3.74; p = 0.05). Failure to undertake primary complete excision leads to further morbidity. A high index of suspicion is required for timely appropriate management to avoid unnecessary morbidity and further intervention.


Findings of a feasibility study of pre-operative pulmonary rehabilitation to reduce post-operative pulmonary complications in people with chronic obstructive pulmonary disease scheduled for major abdominal surgery.
Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of complications and death following surgery. Pulmonary complications are particularly prominent. Pulmonary rehabilitation is a course of physical exercise and education that helps people with COPD manage their condition. Although proven to improve health outcomes in patients with stable COPD, it has never been formally tested as a pre-surgical intervention in patients scheduled for non-cardiothoracic surgery. If a beneficial effect were to be demonstrated, pulmonary rehabilitation for pre-surgical patients with COPD might be rapidly implemented across the National Health Service, as pulmonary rehabilitation courses are already well established across much of the United Kingdom (UK). Methods: We performed a feasibility study to test study procedures and barriers to identification and recruitment to a randomised controlled trial testing whether pulmonary rehabilitation, delivered before major abdominal surgery in a population of people with COPD, would reduce the incidence of post-operative pulmonary complications. This study was run in two UK centres (Oxford and Newcastle upon Tyne). Results: We determined that a full randomised controlled trial would not be feasible, due to failure to identify and recruit participants. We identified an unmet need to identify more effectively patients with COPD earlier in the surgical pathway. Service evaluations suggested that barriers to identification and recruitment would likely be the same across other UK hospitals. Conclusions: Although pulmonary rehabilitation is a potentially beneficial intervention to prevent post-operative pulmonary complications, a randomised controlled trial is unlikely to recruit sufficient participants to answer our study question conclusively at the present time, when spirometry is not automatically conducted in all patients planned for surgery. As pulmonary rehabilitation is a recommended treatment for all people with COPD, alternative study methods combined with earlier identification of candidate patients in the surgical pathway should be considered. Trial registration: ISRCTN29696295, 31/08/2017.


Roads to Health in Developing Countries: Understanding the Intersection of Culture and Healing.
The most important attribute to which all human beings aspire is good health because it enables us to undertake different forms of activities of daily living. The emergence of scientific knowledge in Western societies has enabled scientists to explore and define several parameters of health by drawing boundaries around factors that are known to influence the attainment of good health. For example, the World Health Organization defined health by taking physical and psychological factors into consideration. Their definition of health also included a caveat that says, "not merely the absence of sickness." This definition has guided scientists and health care providers in the Western world in the development of health care programs in non-Western societies. However, ethnomedical beliefs about the cause(s) of illness have given rise to alternative theories of health, sickness, and treatment approaches in the developing world. Thus, there is another side to the story. Much of the population in developing countries lives in rural settings where the knowledge of health, sickness, and care has evolved over centuries of practice and experience. The definition of health in these settings tends to orient toward cultural beliefs, traditional practices, and social relationships. Invariably, whereas biomedicine is the dominant medical system in Western societies, traditional medicine-or ethnomedicine-is often the first port of call for patients in developing countries. The 2 medical systems represent, and are influenced by, the cultural environment in which they exist. On one hand, biomedicine is very effective in the treatment of objective, measurable disease conditions. On the other hand, ethnomedicine is effective in the management of illness conditions or the experience of disease states. Nevertheless, an attempt to supplant 1 system of care with another from a different cultural environment could pose enormous challenges in non-Western societies. In general, we, as human beings, are guided in our health care decisions by past experiences, family and friends, social networks, cultural beliefs, customs, tradition, professional knowledge, and intuition. No medical system has been shown to address all of these elements; hence, the need for collaboration, acceptance, and partnership between all systems of care in cultural communities. In developing countries, the roads to health are incomplete without an examination of the intersection of culture and healing. Perhaps mutual exclusiveness rather inclusiveness of these 2 dominant health systems is the greatest obstacle to health in developing countries.


A comparative study of the lateral geniculate body of rat (Rattus norvegicus), bat (Eidolon helvum) and pangolin (Manis tricuspis).
In this study, the lateral geniculate bodies (LGB) of rats, bats and pangolins were compared using histological and quantitative histochemical parameters to observe possible modifications that enable these mammals to cope with their habitation particularly with respect to their diet. The study was conducted using ten adult Wistar rats, ten fruit bats and eight pangolins comprising of both sexes. After being sacrificed by cervical dislocation, their skulls were opened using bone forceps to expose the brains. The lateral geniculate bodies were excised from each brain tissue, homogenized and homogenate studied spectrophotometrically for the activities of lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-PDH), acid phosphatase (ACP), alkaline phosphatase (ALP) and acetylcholinesterase (AChE). The LGB tissue samples meant for histological studies were fixed in 10% formol calcium and processed for paraffin wax embedding. Serial sections of 3?m thickness were stained with Hematoxylin and Eosin (H & E) and Cresyl fast violet (CFV) stains. The stained tissues were studied under the light microscope. Application of one-way ANOVA statistical method showed that there were significant differences (p<0.05) in the activities of LDH, G-6-PDH, ACP, ALP and AChE of the LGB of the three mammals as revealed in the quantitative histochemistry of these enzymes and markers. Histological observations revealed no observable differences in the relative distribution of neurons and their supporting glial cells within the LGB of the three mammalian species. The comparison of the differences observed in the histological and the quantitative histochemical activities in these mammalian species revealed a variation in the visual perception and their individual peculiarities in relation to their mode and pattern of living.


Cross-population analysis of the growth of long bones and the os coxae of three Early Medieval Austrian populations.
Inter-population variability in long-bone and pelvic-bone growth during the Early Medieval period is examined. The materials comprise four archaeological populations: two Slavonic (Gars-Thunau, Zwentendorf, Austria, 10th-century AD), one Avar (Zwölfaxing, Austria, 8th-century AD), and one Anglo-Saxon (Raunds, England, 10th-century AD). Bone measurements are analyzed against dental age estimates in order to assess inter-population differences in growth rates for long-bone and os coxae bone dimensions. Growth curves of the upper and lower extremities of additional archaeological populations and a modern North-American population are also assessed. The expectation was that the greatest differences in growth patterns would be found between the Anglo-Saxon and the Austrian samples, due to their distinct genetic and biocultural background. Minimal differences were expected between the two Slavonic populations, as these were approximately contemporaneous, recovered from geographically close locations, and shared relatively similar archaeological contexts. Growth curves were estimated for each bone dimension by fitting least-squares fourth-order polynomials (which allowed testing of population differences by analysis of covariance), and iteratively estimating Gompertz growth curves. The results showed differences between bones in the extent of inter-population variability, with diaphyseal long-bone growth showing equivalent patterns across the four populations, but significant differences between populations in the growth patterns of distal diaphyseal dimensions of the femur and humerus and the dimensions of the ilium. Varying growth patterns are therefore associated with inter-population differences in absolute dimensions in relation to age as well as variations in growth velocities. Inter-population variability in growth curves in the case of femoral and humeral dimensions were most pronounced during infancy (0-2 years). The most consistent differences in bone growth and related dimensions are between Zwölfaxing and the other samples. No significant differences in growth were detected between the Anglo-Saxon and the Austrian populations.


Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations.
Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited mutations demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe the somatic acquisition of promoter mutations in telomerase reverse transcriptase (TERT) in blood leukocytes of approximately 5% of individuals with inherited loss-of-function coding mutations in TERT or poly(A)-specific ribonuclease (PARN), another gene linked to telomerase function. While these promoter mutations were initially identified as oncogenic drivers of cancer, individuals expressing the mutations have no history of cancer. Neither promoter mutation was found in population-based cohorts of similar or advanced age. The TERT promoter mutations were found more frequently in cis with the WT allele than the TERT coding sequence mutation. EBV-transformed lymphoblastoid B cell lines (LCLs) derived from subjects with TERT promoter mutations showed increased telomerase expression and activity compared with cell lines from family members with identical coding mutations. TERT promoter mutations resulted in an increased proliferation of LCLs and demonstrated positive selection over time. The persistence and recurrence of noncoding gain-of-function mutations in these cases suggests that telomerase activation is not only safely tolerated but also advantageous for clonal expansion.


Clinical evaluation of a mobile sensor-based gait analysis method for outcome measurement after knee arthroplasty.
Clinical scores and motion-capturing gait analysis are today's gold standard for outcome measurement after knee arthroplasty, although they are criticized for bias and their ability to reflect patients' actual quality of life has been questioned. In this context, mobile gait analysis systems have been introduced to overcome some of these limitations. This study used a previously developed mobile gait analysis system comprising three inertial sensor units to evaluate daily activities and sports. The sensors were taped to the lumbosacral junction and the thigh and shank of the affected limb. The annotated raw data was evaluated using our validated proprietary software. Six patients undergoing knee arthroplasty were examined the day before and 12 months after surgery. All patients reported a satisfactory outcome, although four patients still had limitations in their desired activities. In this context, feasible running speed demonstrated a good correlation with reported impairments in sports-related activities. Notably, knee flexion angle while descending stairs and the ability to stop abruptly when running exhibited good correlation with the clinical stability and proprioception of the knee. Moreover, fatigue effects were displayed in some patients. The introduced system appears to be suitable for outcome measurement after knee arthroplasty and has the potential to overcome some of the limitations of stationary gait labs while gathering additional meaningful parameters regarding the force limits of the knee.


Structural studies of orbivirus particles.
We are using crystallographic methods to investigate the structure of AHSV and BTV. Our initial approach was to investigate the structure of the major protein component of the viral core, VP7(T13). This trimeric protein has been studied in several crystal forms from both orbiviruses and reveals a structure made up of conserved domains, capable of conformational changes and possessing a cleavage site. Further crystallographic analyses of native particles have provided a picture of the VP7(T13) and VP3(T2) layers of the BTV core. The VP7(T13) layer consists of 260 trimers arranged rather symmetrically and possessing very similar structures, thereby following the rules of quasi equivalence. The VP3(T2) layer is thin and contains 120 copies of 100 kDa protein arranged as 60 approximate dimers. This type of icosahedral construction has not been observed before and appears to contain a genome which is highly ordered. We anticipate that all of these features will be common to AHSV.


Electron Bio-Imaging Centre (eBIC): the UK national research facility for biological electron microscopy.
The recent resolution revolution in cryo-EM has led to a massive increase in demand for both time on high-end cryo-electron microscopes and access to cryo-electron microscopy expertise. In anticipation of this demand, eBIC was set up at Diamond Light Source in collaboration with Birkbeck College London and the University of Oxford, and funded by the Wellcome Trust, the UK Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) to provide access to high-end equipment through peer review. eBIC is currently in its start-up phase and began by offering time on a single FEI Titan Krios microscope equipped with the latest generation of direct electron detectors from two manufacturers. Here, the current status and modes of access for potential users of eBIC are outlined. In the first year of operation, 222 d of microscope time were delivered to external research groups, with 95 visits in total, of which 53 were from unique groups. The data collected have generated multiple high- to intermediate-resolution structures (2.8-8 Å), ten of which have been published. A second Krios microscope is now in operation, with two more due to come online in 2017. In the next phase of growth of eBIC, in addition to more microscope time, new data-collection strategies and sample-preparation techniques will be made available to external user groups. Finally, all raw data are archived, and a metadata catalogue and automated pipelines for data analysis are being developed.


NOVOcan: a molecular link among selected glial cells.
The nervous system is generated from cells lining the ventricular system. Our understanding of the fate potentials and lineage relationships of these cells is being re-evaluated, both because of recent demonstrations that radial glia can generate neurons and because of the identification of fate-determining genes. A variety of intrinsic and extrinsic molecules, including proteoglycans, regulate embryonic and postnatal brain development. Using probes modeled after species conserved domains of heparan sulfate proteoglycans, we cloned a novel gene called novocan, raised monoclonal antibodies against a segment of the predicted amino acid sequence of the expressed protein (NOVOcan) and used the antibodies to establish the cell and tissue localization of NOVOcan in postnatal rat brains by immunohistochemistry. NOVOcan was expressed in cells lining the ventricles, including a variety of radial glia during early postnatal development. Later, as radial glia disappeared and ependymal cells appeared, NOVOcan was detected in ependymal cells and in tanycytes, a specialized form of ependymal cell resembling radial glia. NOVOcan was absent in two known progeny of radial glia, mature astrocytes and neurons. Whereas NOVOcan was also absent in mature oligodendrocytes (OLGs), it was present in OLG precursors in developing white matter. These studies set the stage for determining the roles of NOVOcan in brain cell lineage patterns as well as in other aspects of development.


Paracellular epithelial sodium transport maximizes energy efficiency in the kidney.
Efficient oxygen utilization in the kidney may be supported by paracellular epithelial transport, a form of passive diffusion that is driven by preexisting transepithelial electrochemical gradients. Claudins are tight-junction transmembrane proteins that act as paracellular ion channels in epithelial cells. In the proximal tubule (PT) of the kidney, claudin-2 mediates paracellular sodium reabsorption. Here, we used murine models to investigate the role of claudin-2 in maintaining energy efficiency in the kidney. We found that claudin-2-null mice conserve sodium to the same extent as WT mice, even during profound dietary sodium depletion, as a result of the upregulation of transcellular Na-K-2Cl transport activity in the thick ascending limb of Henle. We hypothesized that shifting sodium transport to transcellular pathways would lead to increased whole-kidney oxygen consumption. Indeed, compared with control animals, oxygen consumption in the kidneys of claudin-2-null mice was markedly increased, resulting in medullary hypoxia. Furthermore, tubular injury in kidneys subjected to bilateral renal ischemia-reperfusion injury was more severe in the absence of claudin-2. Our results indicate that paracellular transport in the PT is required for efficient utilization of oxygen in the service of sodium transport. We speculate that paracellular permeability may have evolved as a general strategy in epithelial tissues to maximize energy efficiency.


DOGS: reaction-driven de novo design of bioactive compounds.
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated 'in silico' assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H₄ receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.


Acute disseminated encephalomyelitis associated with positive voltage gated potassium channel complex antibody.
Voltage gated potassium channel (VGKC) complex antibodies are associated with encephalopathies both in adult and children. The incidence of antibodies in the central nervous system demyelinating disorders is increasingly reported although their direct pathogenic role remains to be evaluated, with the exception of Aquaporin 4 antibodies. Here we describe a case of a 28 month old boy presenting with acute disseminated encephalomyelitis, with positive VGKC-complex antibodies and low sodium levels. He was treated with steroids and made a clinical and radiological recovery with normalisation of antibody levels.


Network medicine strikes a blow against breast cancer.
Drug development for complex diseases is shifting from targeting individual proteins or genes to systems-based attacks targeting dynamic network states. Lee et al. now reveal how the progressive rewiring of a signaling network over time following EGF receptor inhibition leaves triple-negative breast tumors vulnerable to a second, later hit with DNA-damaging drugs, demonstrating that time- and order-dependent drug combinations can be more efficacious in killing cancer cells.


Improved HPLC method for determination of four PPIs, omeprazole, pantoprazole, lansoprazole and rabeprazole in human plasma.
To develop a simple and rapid HPLC method for measuring of four proton-pump inhibitors (PPIs), omeprazole (OPZ), pantoprazole (PPZ), lansoprazole (LPZ) and rabeprazole (RPZ) concentrations in human plasma. Following a single step liquid-liquid extraction analytes along with an internal standard (IS) were separated using an isocratic mobile phase of phosphate buffer (10 mM)/acetonitrile (53/47, v/v adjusted pH to 7.3 with triethylamine) at flow rate of 1 mL/min on reverse phase TRACER EXCEL 120 ODS-A column at room temperature. Total analytical run time for selected PPIs was 10 min. The assays exhibited good linearity (r(2)>0.99) over the studied range of 20 to 2500 ng/mL for OPZ, 20 to 4000 ng/mL for PPZ, 20 to 3000 ng/mL for LPZ and 20 to 1500 ng/mL for RPZ. The recovery of method was equal or greater than 80% and lower limit of quantification (LLOQ) was 20 ng/mL for four PPIs. Coefficient of variation and error at all of the intra-day and inter-day assessment were less than 9.2% for all compounds. The results indicated that this method is a simple, rapid, precise and accurate assay for determination of four PPIs concentrations in human plasma. This validated method is sensitive and reproducible enough to be used in pharmacokinetic studies and also is time- and cost-benefit when selected PPIs are desired to be analyzed.


Evaluating tidal marsh sustainability in the face of sea-level rise: a hybrid modeling approach applied to San Francisco Bay.
Tidal marshes will be threatened by increasing rates of sea-level rise (SLR) over the next century. Managers seek guidance on whether existing and restored marshes will be resilient under a range of potential future conditions, and on prioritizing marsh restoration and conservation activities. Building upon established models, we developed a hybrid approach that involves a mechanistic treatment of marsh accretion dynamics and incorporates spatial variation at a scale relevant for conservation and restoration decision-making. We applied this model to San Francisco Bay, using best-available elevation data and estimates of sediment supply and organic matter accumulation developed for 15 Bay subregions. Accretion models were run over 100 years for 70 combinations of starting elevation, mineral sediment, organic matter, and SLR assumptions. Results were applied spatially to evaluate eight Bay-wide climate change scenarios. Model results indicated that under a high rate of SLR (1.65 m/century), short-term restoration of diked subtidal baylands to mid marsh elevations (-0.2 m MHHW) could be achieved over the next century with sediment concentrations greater than 200 mg/L. However, suspended sediment concentrations greater than 300 mg/L would be required for 100-year mid marsh sustainability (i.e., no elevation loss). Organic matter accumulation had minimal impacts on this threshold. Bay-wide projections of marsh habitat area varied substantially, depending primarily on SLR and sediment assumptions. Across all scenarios, however, the model projected a shift in the mix of intertidal habitats, with a loss of high marsh and gains in low marsh and mudflats. Results suggest a bleak prognosis for long-term natural tidal marsh sustainability under a high-SLR scenario. To minimize marsh loss, we recommend conserving adjacent uplands for marsh migration, redistributing dredged sediment to raise elevations, and concentrating restoration efforts in sediment-rich areas. To assist land managers, we developed a web-based decision support tool (www.prbo.org/sfbayslr).


The treatment pathways followed by cases of human African trypanosomiasis in western Kenya and eastern Uganda.
Although early diagnosis and treatment are key factors in the effective control of human African trypanosomiasis (HAT), many cases of the disease delay taking appropriate action, leading to untold suffering. As a better understanding of treatment-seeking behaviour should help in identifying the obstacles to early diagnosis and effective treatment, the treatment pathways followed by 203 former HAT cases in western Kenya and eastern Uganda have recently been explored. About 86% of the HAT cases had utilized more than two different healthcare options before being correctly diagnosed for HAT, with about 70% each using more than three different health facilities. Only about 8% of the cases reported that they had been correctly diagnosed the first time they sought treatment. Just over half (51%) of the HAT cases had been symptomatic for >2 months before being correctly diagnosed for HAT, and such time lags in diagnosis contributed to 72% of the cases receiving their first appropriate treatment only in the late stage of the disease. The likelihood of a correct diagnosis increased with the time the case had been symptomatic. These observations indicate an urgent need to build the diagnostic capacity of the primary healthcare facilities in the study area, so that all HAT cases can be identified and treated in the early stage of the disease.


Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials.
To assess the effects of the neuraminidase inhibitors oseltamivir and zanamivir in treatment of children with seasonal influenza and prevention of transmission to children in households. Systematic review and meta-analysis of data from published and unpublished randomised controlled trials. Medline and Embase to June 2009, trial registries, and manufacturers and authors of relevant studies. Review methods Eligible studies were randomised controlled trials of neuraminidase inhibitors in children aged </=12 in the community (that is, not admitted to hospital) with confirmed or clinically suspected influenza. Primary outcome measures were time to resolution of illness and incidence of influenza in children living in households with index cases of influenza. We identified four randomised trials of treatment of influenza (two with oseltamivir, two with zanamivir) involving 1766 children (1243 with confirmed influenza, of whom 55-69% had influenza A), and three randomised trials for postexposure prophylaxis (one with oseltamivir, two with zanamivir) involving 863 children; none of these trials tested efficacy with the current pandemic strain. Treatment trials showed reductions in median time to resolution of symptoms or return to normal activities, or both, of 0.5-1.5 days, which were significant in only two trials. A 10 day course of postexposure prophylaxis with zanamivir or oseltamivir resulted in an 8% (95% confidence interval 5% to 12%) decrease in the incidence of symptomatic influenza. Based on only one trial, oseltamivir did not reduce asthma exacerbations or improve peak flow in children with asthma. Treatment was not associated with reduction in overall use of antibiotics (risk difference -0.30, -0.13 to 0.01). Zanamivir was well tolerated, but oseltamivir was associated with an increased risk of vomiting (0.05, 0.02 to 0.09, number needed to harm=20). Neuraminidase inhibitors provide a small benefit by shortening the duration of illness in children with seasonal influenza and reducing household transmission. They have little effect on asthma exacerbations or the use of antibiotics. Their effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.


Profibrotic mediators in tendon disease: a systematic review.
Tendon disease is characterized by the development of fibrosis. Transforming growth factor beta (TGF-β), bone morphogenic proteins (BMPs) and connective tissue growth factor (CTGF) are key mediators in the pathogenesis of fibrotic disorders. The aim of this systematic review was to investigate the evidence for the expression of TGF-β, BMPs and CTGF along tendon disease progression and the response of tendon cells to these growth factors accordingly. We conducted a systematic screen of the scientific literature using the Medline database. The search terms used were "tendon AND TGF-β," "tendon AND BMP" or "tendon AND CTGF." Studies of human samples, animal tendon injury and overuse models were included. Thirty-three studies were included. In eight studies the expression of TGF-β, BMPs or CTGF was dysregulated in chronic tendinopathy and tendon tear patient tissues in comparison with healthy control tissues. The expression of TGF-β, BMPs and CTGF was increased and showed temporal changes in expression in tendon tissues from animal injury or overuse models compared with the healthy control (23 studies), but the pattern of upregulation was inconsistent between growth factors and also the type of animal model. No study investigated the differences in the effect of TGF-β, BMPs or CTGF treatment between patient-derived cells from healthy and diseased tendon tissues. Tendon cells derived from animal models of tendon injury showed increased expression of extracellular matrix protein genes and increased cell signaling response to TGF-β and BMP treatments compared with the control cells (two studies). The expression of TGF-β, BMPs and CTGF in tendon tissues is altered temporally during healing in animal models of tendon injury or overuse, but the transition during the development of human tendon disease is currently unknown. Findings from this systematic review suggest a potential and compelling role for TGF-β, BMPs and CTGF in tendon disease; however, there is a paucity of studies analyzing their expression and stimulated cellular response in well-phenotyped human samples. Future work should investigate the dynamic expression of these fibrotic growth factors and their interaction with tendon cells using patient samples at different stages of human tendon disease.