Presentation and management of anxiety in individuals with acute symptomatic or asymptomatic COVID-19 infection, and in the post-COVID-19 recovery phase.
COVID-19 is associated with neuropsychiatric complications, the most frequent one being anxiety. Multiple biological and psychosocial factors contribute to anxiety in COVID-19. Among the biological factors, stress, genetics, gender, immune system, resilience, anosmia, hypogeusia, and central nervous system infection with SARS-CoV-2 are key. Anxiety is a complication of COVID-19 that may exacerbate the infection course, and the infection may exacerbate anxiety. We present the mechanisms of anxiety in symptomatic or asymptomatic COVID-19. We discuss the presentation of anxiety in patients without or with prior psychiatric illness, and with co-morbidities. Timely diagnosis and management of anxiety in COVID-19 patients is important. Given the frequent complication of COVID-19 with Acute Respiratory Distress Syndrome and Intensive Care Unit stay, anxiety may be a long-term complication. We review the diagnostic tools for anxiety in COVID-19, and summarise pharmacologic and non-pharmacologic treatments. We provide recommendations for diagnosis, treatment, prevention and follow up of anxiety in COVID-19.Key pointsPatients with COVID-19 (symptomatic or asymptomatic) exhibit a high frequency of neuropsychiatric complications with highest percentage attributed to anxiety.Multiple biological and psychosocial risk factors for anxiety exist in COVID-19-ill individuals. Biological risk factors include stress, resilience, genetics, gender, age, immune system, direct infection of the central nervous system (CNS) with SARS-CoV-2, comorbid psychiatric and general medical illnesses, ARDS and ICU stay. Anosmia and hypogeusia are COVID-19-specific anxiety risk factors. Knowledge of the anxiety risk factors is essential to focus on timely interventions, because anxiety may be a complication of and exacerbate the COVID-19 course.An inverse correlation exists between resilience and anxiety because of COVID-19, and therefore efforts should be made to increase resilience in COVID-19 patients.In COVID-19, important anxiety mechanism is neuroinflammation resulting from activation of the immune system and an ensuing cytokine storm.The general approach to management of anxiety in COVID-19 should be compassionate, similar to that during trauma or disaster, with efforts focussed on instilling a sense of hope and resilience.In selecting pharmacological treatment of anxiety, the stress response and immune system effects should be key. Medications with cardio-respiratory adverse effects should be avoided in patients with respiratory problems.Anxiety is a disorder that will require for long-term follow up at least one month after COVID-19.


Perspectives of applied collaborative sport science research within professional team sports.
The purpose of the study was to examine the perspectives of both academics and practitioners in relation to forming applied collaborative sport science research within team sports. Ninety-three participants who had previously engaged in collaborative research partnerships within team sports completed an online survey which focused on motivations and barriers for forming collaborations using blinded sliding scale (0-100) and rank order list. Research collaborations were mainly formed to improve the team performance (Academic: 73.6 ± 23.3; Practitioner: 84.3 ± 16.0; effect size (ES = 0.54), small). Academics ranked journal articles' importance significantly higher than practitioners did (Academic: Mrank = 53.9; Practitioner: 36.0; z = -3.18, p = .001, p < q). However, practitioners rated one-to-one communication as more preferential (Academic: Mrank = 41.3; Practitioner 56.1; z = -2.62, p = .009, p < q). Some potential barriers were found in terms of staff buy in (Academic: 70.0 ± 25.5; Practitioner: 56.8 ± 27.3; ES = 0.50, small) and funding (Academic: 68.0 ± 24.9; Practitioner: 67.5 ± 28.0; ES = 0.02, trivial). Both groups revealed low motivation for invasive mechanistic research (Academic: 36.3 ± 24.2; Practitioner: 36.4 ± 27.5; ES = 0.01, trivial), with practitioners have a preference towards 'fast' type research. There was a general agreement between academics and practitioners for forming research collaborations. Some potential barriers still exist (e.g. staff buy in and funding), with practitioners preferring 'fast' informal research dissemination compared to the 'slow' quality control approach of academics.


A randomized trial of computer kiosk-expedited management of cystitis in the emergency department.
The objective was to assess the efficiency and safety of an interactive computer kiosk module for the management of uncomplicated urinary tract infections (UTI) in emergency departments (EDs). This was a prospective unblinded randomized trial. Women age 18 to 64 years seeking care for suspected UTI in three urban EDs were referred to a computer kiosk after triage. The kiosk evaluated women for uncomplicated UTI (based on patient report of at least one irritable voiding symptom within 7 days and absence of complicating features), and eligible patients were randomized to expedited management or usual ED care. Expedited management consisted of a brief clinician encounter to confirm computer kiosk responses and selection of one of four standard antibiotic regimens. Study outcomes included urine culture results, duration of ED visit, time to illness resolution, return visits, and satisfaction with care. Seventeen percent (n = 103) of 624 participants with suspected UTI fulfilled uncomplicated criteria and were randomized. Sixty-nine percent of these women had a positive urine culture. Compared with the control group, the computer-expedited management group had lower median visit duration (89 minutes, interquartile range [IQR] = 65 to 150 minutes vs. 146 minutes, IQR = 105 to 216 minutes) for a decrease of 57 minutes (95% confidence interval [CI] = 27 to 87, p = 0.004). They had similar time to illness resolution, number of return visits, and satisfaction with care. An interactive computer kiosk accurately, efficiently, and safely expedited the management of women with uncomplicated UTI in a busy, urban ED. Expanding the use of this technology to other conditions could help to improve ED patient flow.


Experience in imaging medullary thyroid carcinoma using 99mTc (V) dimercaptosuccinic acid (DMSA).
99mTc (V) dimercaptosuccinic acid (DMSA) is a new tumor imaging agent that has been successfully used to image patients with medullary thyroid carcinoma (MTC). Since 1986, studies have been performed in 32 patients with histologically proven MTC at Guy's Hospital, London, England. Five patients with primary tumor were studied prior to surgery, four patients were studied after successful removal of the primary tumor, and 26 patients with biochemical evidence of recurrence were studied. Eight patients were studied serially to assess progression of disease, and four patients were studied before and after surgery. Twenty-one of the 26 patients with disease had positive scans with four false-negative scans and three true negative scans. One patient had a false-positive scan (sensitivity 80%, specificity 75%). Two of the false-negative scans were obtained in patients with moderate but stable elevations of calcitonin but no other evidence of recurrence. One false-negative scan was obtained in a patient who was discovered on screening to have an abnormal pentagastrin response, and a small 1 cm tumor was subsequently removed. Uptake in local neck recurrence was frequently intense, but uptake at sites of bone metastases was less marked. 99mTc (V) DMSA is an inexpensive radiopharmaceutical which produces good quality images and has been shown to have an acceptable sensitivity and specificity in the follow-up of patients with MTC and thereby contributes significantly to the management of these patients.


Selective linkage of beta-adrenergic receptors to functional responses in developing rat lung and liver: phosphatidic acid phosphatase, ornithine decarboxylase and lung liquid reabsorption.
Neurotransmitter receptors may exhibit transient linkage to specific developmental processes involved in physiological adaptation to extrauterine life and in cell maturation. We have examined the responsiveness of the developing rat lung to beta-adrenergic agonists, using fluid reabsorption, phosphatidic acid phosphatase (an enzyme involved in surfactant synthesis) and ornithine decarboxylase (an enzyme related to cellular development) as markers of these activities. The ability of beta-adrenergic agonists to stimulate phosphatidic acid phosphatase and to cause liquid reabsorption first appeared just before birth, a period in which few receptor binding sites are present; the reactivity of both these processes declined after birth, but the enzymatic stimulation reached a second peak of response during the second and third postnatal weeks. The ability of beta-adrenergic challenge to elicit stimulation of lung phosphatidic acid phosphatase then declined into adulthood, despite the fact that receptor binding sites are increasing during the same period. Lung ornithine decarboxylase activity was poorly linked to beta-receptors in the immediate perinatal period and reached a peak of reactivity during the late postnatal period in which the coupling to phosphatidic acid phosphatase was lost. The pattern for phosphatidic acid phosphatase and liquid content was selective for the lung, as no stimulatory effects were seen for these variables in the liver, despite the comparable beta-adrenergic effects on ornithine decarboxylase in the two tissues. These data suggest that, during development, the coupling of receptors to specific cellular events is more important than the number of receptor sites in determining the pattern of physiological and cellular responses mediated by neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)


rhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review.
Traditionally, withdrawal of thyroid hormone has been used to attain the increase in serum TSH concentrations that are believed to optimize the trapping and retention of radioiodine for diagnostic procedures, thyroid remnant ablation and treatment of patients with differentiated thyroid cancer (DTC). However, withdrawal frequently causes clinical hypothyroidism, with resultant cognitive impairment, emotional dysfunction, physical discomfort, health risks in patients who are elderly, frail or have concomitant illness, and impaired quality of life and ability to work. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and the associated morbidity. rhTSH has been approved as an adjunct for diagnostic procedures in patients with DTC, but is currently an experimental aid in thyroid remnant ablation and the treatment of thyroid tumours. In the period 1997-2004, nearly 30 medical centres worldwide have reported on almost 400 patients with DTC who were given rhTSH in preparation for radioiodine ablation of thyroid remnants or treatment of local tumours of metastatic disease. We have analysed and summarized the findings reported in this literature. Ablation aided by the standard course of rhTSH, two consecutive daily injections of 0.9 mg, had success rates better than 84% in 90 patients given radioiodine activities in excess of 4000 MBq. However, when 1110 MBq was administered, success rates were 81.2% in 16 patients given the standard course of rhTSH and 4-day withdrawal of thyroid hormone around the time of radioiodine administration in one study, but 54% in 70 patients in another study. rhTSH-aided treatment of persistent or recurrent local or metastatic cancer, or both, with from one to six courses of radioiodine 1000-19055 MBq, achieved 2% complete remission, 36% partial response and 27% disease stabilization rates, for a 65% clinical benefit rate, in 115 primarily elderly, late-stage patients for whom responses were reported. Twelve of these patients died as a result of progressive disease or were discharged from hospital into hospice care. Generally, rhTSH was very well tolerated. However, in a minority of patients with central nervous system, spinal or bone metastases, or bulky thyroid remnant or neck lesions with or without poor pulmonary reserve, administration of rhTSH, like thyroid hormone withdrawal, was found to stimulate expansion of the tumour, with ensuing compression of key anatomical structures and neurological, respiratory or other clinical complications. The rapid onset, response to glucocorticoids and radiological findings of peritumoural oedema or, less commonly, haemorrhage in the published cases, strongly suggest that the tumour expansion was the result of swelling rather than growth. As in the case of thyroid hormone withdrawal, special attention and glucocorticoid premedication are thus warranted when rhTSH is given to patients known or suspected to have the above characteristics. Dosimetric data suggest that whole-body and whole-blood radioiodine clearance may be faster in euthyroid patients after administration of rhTSH. In theory, the faster clearance could allow, or demand, increased radioiodine activities when rhTSH is used, but clinical data to date suggest that this may be unnecessary. The faster clearance also might result in safety or convenience benefits with the use of rhTSH, such as decreased exposure of extrathyroid areas to radiation, and shorter hospital stays. In conclusion, in preliminary results from open-label studies, both rhTSH-aided tumour ablation and treatment have been well tolerated and have shown efficacy in substantial proportions of patients. rhTSH-aided ablation merits further study. rhTSH-aided treatment may be preferred in patients who are at greater risk of hypothyroid complications from withdrawal of thyroid hormone or are unable to produce sufficient endogenous TSH, and warrants additional investigation in younger patients at earlier stages of thyroid cancer.


MVSE: An R-package that estimates a climate-driven mosquito-borne viral suitability index.
Viruses, such as dengue, Zika, yellow fever and chikungunya, depend on mosquitoes for transmission. Their epidemics typically present periodic patterns, linked to the underlying mosquito population dynamics, which are known to be driven by natural climate fluctuations. Understanding how climate dictates the timing and potential of viral transmission is essential for preparedness of public health systems and design of control strategies. While various alternative approaches have been proposed to estimate local transmission potential of such viruses, few open-source, ready to use and freely available software tools exist.We developed the Mosquito-borne Viral Suitability Estimator (MVSE) software package for the R programming environment. MVSE estimates the index P, a novel suitability index based on a climate-driven mathematical expression for the basic reproductive number of mosquito-borne viruses. By accounting for local humidity and temperature, as well as viral, vector and human priors, the index P can be estimated for specific host and viral species in different regions of the globe.We describe the background theory, empirical support and biological interpretation of the index P. Using real-world examples spanning multiple epidemiological contexts, we further demonstrate MVSE's basic functionality, research and educational potentials.


Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness.
Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood-retinal barrier and blood-cochlear barrier, which have a comparable structure to the blood-brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.


Two successive hepatitis C virus infections in an intravenous drug user.
We report the case of an occasional intravenous drug user who developed two successive hepatitis C virus (HCV) infections. The first infection led to seroconversion (anti-HCV antibodies detected) and the detection of HCV RNA in serum. After a spontaneous recovery (normalization of alanine aminotransferase levels and HCV RNA clearance), a second HCV infection was observed, with the recurrence of HCV viremia. Antibody directed against HCV serotype 1 was detected throughout the follow-up monitoring, but two different HCV strains were identified during the two infectious episodes: genotype 1a for the first and genotype 3a for the second. This observation shows that primary HCV infection does not confer protective immunity against subsequent infection with viruses of other genotypes. This may hamper the development of a vaccine. Conflicting results were obtained in genotyping and serotyping assays, suggesting that the serotyping method cannot be used to identify the HCV type in patients, such as intravenous drug users, who are exposed to successive HCV infections.


Genome analysis of Desulfotomaculum kuznetsovii strain 17(T) reveals a physiological similarity with Pelotomaculum thermopropionicum strain SI(T).
Desulfotomaculum kuznetsovii is a moderately thermophilic member of the polyphyletic spore-forming genus Desulfotomaculum in the family Peptococcaceae. This species is of interest because it originates from deep subsurface thermal mineral water at a depth of about 3,000 m. D. kuznetsovii is a rather versatile bacterium as it can grow with a large variety of organic substrates, including short-chain and long-chain fatty acids, which are degraded completely to carbon dioxide coupled to the reduction of sulfate. It can grow methylotrophically with methanol and sulfate and autotrophically with H2 + CO2 and sulfate. For growth it does not require any vitamins. Here, we describe the features of D. kuznetsovii together with the genome sequence and annotation. The chromosome has 3,601,386 bp organized in one contig. A total of 3,567 candidate protein-encoding genes and 58 RNA genes were identified. Genes of the acetyl-CoA pathway, possibly involved in heterotrophic growth with acetate and methanol, and in CO2 fixation during autotrophic growth are present. Genomic comparison revealed that D. kuznetsovii shows a high similarity with Pelotomaculum thermopropionicum. Genes involved in propionate metabolism of these two strains show a strong similarity. However, main differences are found in genes involved in the electron acceptor metabolism.


Surface apposition and multiple cell contacts promote myoblast fusion in Drosophila flight muscles.
Fusion of individual myoblasts to form multinucleated myofibers constitutes a widely conserved program for growth of the somatic musculature. We have used electron microscopy methods to study this key form of cell-cell fusion during development of the indirect flight muscles (IFMs) of Drosophila melanogaster. We find that IFM myoblast-myotube fusion proceeds in a stepwise fashion and is governed by apparent cross talk between transmembrane and cytoskeletal elements. Our analysis suggests that cell adhesion is necessary for bringing myoblasts to within a minimal distance from the myotubes. The branched actin polymerization machinery acts subsequently to promote tight apposition between the surfaces of the two cell types and formation of multiple sites of cell-cell contact, giving rise to nascent fusion pores whose expansion establishes full cytoplasmic continuity. Given the conserved features of IFM myogenesis, this sequence of cell interactions and membrane events and the mechanistic significance of cell adhesion elements and the actin-based cytoskeleton are likely to represent general principles of the myoblast fusion process.


Aplastic anemia and monosomy 7-associated dysmegakaryocytopoiesis.
Aplastic anemia (AA) is marrow failure due to an inadequate number of hematopoietic cells in the marrow. Prior reports have described a more aggressive clinical course in aplastic anemia with monosomy 7. We report 3 pediatric cases of AA with normal cytogenetics followed by acquisition of monosomy 7. Bone marrow biopsies were initially diagnostic of AA but later showed monosomy 7 and an increased number of megakaryocytes with small hypolobated nuclei. Immunohistochemical stains for CD61 highlighted the marked dysmegakaryocytopoiesis. The marrow blast percentage was increased in only 1 patient with 4.6% blasts. The 3 patients underwent bone marrow transplantation, and each has remained disease free for 7 to 18 months after transplantation. Pediatric patients with AA and normal cytogenetics may develop monosomy 7 with a myelodysplastic syndrome, unclassified. Patients with AA and monosomy 7 should be evaluated for dysmegakaryocytopoiesis.


Small molecule disruption of G protein βγ subunit signaling reprograms human macrophage phenotype and prevents autoimmune myocarditis in rats.
The purpose of this study was to determine whether blocking of G protein βγ (Gβγ) signaling halts heart failure (HF) progression by macrophage phenotype manipulation. Cardiac Gβγ signaling plays a crucial role in HF pathogenesis. Previous data suggested that inhibiting Gβγ signaling reprograms T helper cell 1 (Th1) and Th2 cytokines, suggesting that Gβγ might be a useful drug target for treating HF. We investigated the efficacy of a small molecule Gβγ inhibitor, gallein, in a clinically relevant, experimental autoimmune myocarditis (EAM) model of HF as well as in human macrophage phenotypes in vitro. In the myocardium of HF patients, we observed that G protein coupled receptor kinase (GRK)2 levels were down-regulated compared with healthy controls. In rat EAM, treatment with gallein effectively improved survival and cardiac function, suppressed cardiac remodeling, and further attenuated myocardial protein expression of GRK2 as well as high mobility group box (HMGB)1 and its cascade signaling proteins. Furthermore, gallein effectively inhibited M1 polarization and promoted M2 polarization in vivo in the EAM heart and in vitro in human monocyte-derived macrophages. Taken together, these data suggest that the small molecule Gβγ inhibitor, gallein, could be an important pharmacologic therapy for HF as it can switch the phenotypic reprogramming from M1 to M2 phenotype in a rat model of EAM heart and in human macrophages.


Thermally tolerant corals have limited capacity to acclimatize to future warming.
Thermal stress affects organism performance differently depending on the ambient temperature to which they are acclimatized, which varies along latitudinal gradients. This study investigated whether differences in physiological responses to temperature are consistent with regional differences in temperature regimes for the stony coral Oculina patagonica. To resolve this question, we experimentally assessed how colonies originating from four different locations characterized by >3 °C variation in mean maximum annual temperature responded to warming from 20 to 32 °C. We assessed plasticity in symbiont identity, density, and photosynthetic properties, together with changes in host tissue biomass. Results show that, without changes in the type of symbiont hosted by coral colonies, O. patagonica has limited capacity to acclimatize to future warming. We found little evidence of variation in overall thermal tolerance, or in thermal optima, in response to spatial variation in ambient temperature. Given that the invader O. patagonica is a relatively new member of the Mediterranean coral fauna, our results also suggest that coral populations may need to remain isolated for a long period of time for thermal adaptation to potentially take place. Our study indicates that for O. patagonica, mortality associated with thermal stress manifests primarily through tissue breakdown under moderate but prolonged warming (which does not impair symbiont photosynthesis and, therefore, does not lead to bleaching). Consequently, projected global warming is likely to cause repeat incidents of partial and whole colony mortality and might drive a gradual range contraction of Mediterranean corals.


Future of Automated Insulin Delivery Systems.
Advances in continuous glucose monitoring (CGM) have brought on a paradigm shift in the management of type 1 diabetes. These advances have enabled the automation of insulin delivery, where an algorithm determines the insulin delivery rate in response to the CGM values. There are multiple automated insulin delivery (AID) systems in development. A system that automates basal insulin delivery has already received Food and Drug Administration approval, and more systems are likely to follow. As the field of AID matures, future systems may incorporate additional hormones and/or multiple inputs, such as activity level. All AID systems are impacted by CGM accuracy and future CGM devices must be shown to be sufficiently accurate to be safely incorporated into AID. In this article, we summarize recent achievements in AID development, with a special emphasis on CGM sensor performance, and discuss the future of AID systems from the point of view of their input-output characteristics, form factor, and adaptability.


Differences in the determinants of overdrive suppression between sinus rhythm and slow atrioventricular junctional rhythm.
Sinus node recovery time was compared to the recovery time of a slow atrioventricular junctional rhythm in each of the same seven pentobarbital anesthetized dogs. Recovery time and the first five cardiac cycles were examined after pacing atria and ventricles for 20, 40, and 60 seconds at four or more pacing cycle lengths. Data relating recovery times and return to control conditions to prepacing cycle length, pacing cycle length, duration of pacing, site of pacing, and origin of rhythms were analyzed by covariance analysis. From the analyses, the relative contribution of the determinants are: the prepacing cycle length 73%, the site of pacing 3.5%, the pacing cycle length 2%, and the interaction of the site of pacing and pacing cycle length 1% for sinus node recovery time; and for slow atrioventricular junctional rhythm recovery time, the duration of pacing 40%, the interactions between the duration of pacing and the pacing cycle length 27%, and the prepacing cycle length 9%. A modified exponential decay model predicted 8 beats for return to prepacing conditions during sinus rhythm and 66-100 beats during atrioventricular junctional rhythm. We conclude that the single most important determinant of sinus node recovery time is the prepacing cycle length. Pacing cycle length and site of pacing have a significant but small influence on sinus node recovery time and duration of pacing, beyond 20 seconds, has no significant influence. In contrast, duration of pacing is the most important determinant of slow atrioventricular junctional recovery time. Another major determinant of slow atrioventricular junctional recovery time is the interactions between pacing cycle length and duration of pacing. Prepacing cycle length has a minor influence, and site of pacing has no influence, on slow atrioventricular junctional recovery time.


Asymmetric 1,8/13,2,x-M2C2B10 14-vertex metallacarboranes by direct electrophilic insertion reactions; the VCD and BHD methods in critical analysis of cage C atom positions.
The isolation of six isomeric, low-symmetry, dicobaltacarboranes with bicapped hexagonal antiprismatic cage structures, always in low yield, is described from reactions in which 13-vertex cobaltacarborane anions and sources of cobalt-containing cations were present. The vertex-to-centroid distance (VCD) and boron-H distance (BHD) methods are used to locate the correct C atom positions in the cages, thus allowing the compounds to be identified as 1,13-Cp2-1,13,2,10-closo-Co2C2B10H12 (1), 1,8-Cp2-3-OEt-1,8,2,10-closo-Co2C2B10H11 (2), 1,13-Cp2-1,13,2,9-closo-Co2C2B10H12 (3), 1,8-Cp2-1,8,2,4-closo-Co2C2B10H12 (4), 1,13-Cp2-1,13,2,4-closo-Co2C2B10H12 (5) and 1,8-Cp2-1,8,2,5-closo-Co2C2B10H12 (6). It is shown that a common alternative method of cage C atom identification, using refined (as B) U(eq) values, does not work well, at least in these cases. Having identified the correct isomeric forms of the six dicobaltacarboranes, their syntheses are tentatively rationalised in terms of the direct electrophilic insertion of a {CpCo(+)} fragment into [CpCoC2B10](-) anions and it is demonstrated that compounds 1, 4, 5 and 6 can be successfully prepared by deliberately performing such reactions.


Prevalence, correlates for early neurological disorders and association with functioning among children and adolescents with HIV/AIDS in Uganda.
The aim of this study was to determine the prevalence of neurological disorders and their associated correlates and relations with clinical and behavioural problems among children and adolescents with HIV/AIDS (CA-HIV). This study involved a sample of 1070 CA-HIV/caregiver dyads who were evaluated at their 6-month follow-up visit as part of their participation in the longitudinal study, 'Mental health among HIV infected CHildren and Adolescents in KAmpala and Masaka, Uganda (the CHAKA study)'. Participants completed an extensive battery of measures that included a standardized DSM-5- referenced rating scale, the parent version (5-18 years) of the Child and Adolescent Symptom Inventory-5 (CASI-5). Using logistic regression, we estimated the prevalence of neurological disorders and characterised their associations with negative clinical and behavioural factors. The overall prevalence of at least one neurological disorders was 18.5% (n = 198; 95% CI, 16.2-20.8). Enuresis / encopresis was the most common (10%), followed by motor/vocal tics (5.3%); probable epilepsy was the least prevalent (4%). Correlates associated with neurological disorders were in two domains: socio-demographic factors (age, ethnicity and staying in rural areas) and HIV-related factors (baseline viral load suppression). Enuresis/encopresis was associated with psychiatric comorbidity. Neurological disorders were associated with earlier onset of sexual intercourse (adjusted OR 4.06, 95% CI 1.26-13.1, P = 0.02). Neurological disorders impact lives of many children and adolescents with HIV/AIDS. There is an urgent need to integrate the delivery of mental and neurological health services into routine clinical care for children and adolescents with HIV/AIDS in sub-Saharan Africa.


Somatosensory discrimination deficits following pediatric cerebral malaria.
Pathologic studies of central nervous system damage in human falciparum malaria indicate primary localization in the cerebral white matter. We report a sensory-perceptual investigation of 20 Ghanaian children with a recent history of cerebral malaria who were age-, gender-, and education-matched with 20 healthy control subjects. Somatosensory examinations failed to show any evidence of hemianesthesia, pseudohemianesthesia, or extinction to double simultaneous tactile stimulation. While unilateral upper limb testing revealed intact unimanual tactile roughness discrimination, bimanual tactile discrimination, however, was significantly impaired in the cerebral malaria group. A strong negative correlation (r = -0.72) between coma duration and the bimanual tactile roughness discrimination test was also found. An inefficiency in the integrity of callosal fibers appear to account for our findings, although alternative subcortical mechanisms known to be involved in information transfer across the cerebral hemispheres may be compromised as well.


Analytical Pitfalls of Therapeutic Drug Monitoring of Thiopurines in Patients With Inflammatory Bowel Disease.
The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure.


Anthropogenic disturbance and the risk of flea-borne disease transmission.
Anthropogenic disturbance may lead to the spread of vector-borne diseases through effects on pathogens, vectors, and hosts. Identifying the type and extent of vector response to habitat change will enable better and more accurate management strategies for anthropogenic disease spread. We compiled and analyzed data from published empirical studies to test for patterns among flea and small mammal diversity, abundance, several measures of flea infestation, and host specificity in 70 small mammal communities of five biomes and three levels of human disturbance: remote/wild areas, agricultural areas, and urban areas. Ten of 12 mammal and flea characteristics showed a significant effect of disturbance category (six), biome (four), or both (two). Six variables had a significant interaction effect. For mammal-flea communities in forest habitats (39 of the 70 communities), disturbance affected all 12 characteristics. Overall, flea and mammal richness were higher in remote versus urban sites. Most measures of flea infestation, including percent of infested mammals and fleas/mammal and fleas/mammal species increased with increasing disturbance or peaked at intermediate levels of disturbance. In addition, host use increased, and the number of specialist fleas decreased, as human disturbance increased. Of the three most common biomes (forest, grassland/savanna, desert), deserts were most sensitive to disturbance. Finally, sites of intermediate disturbance were most diverse and exhibited characteristics associated with increased disease spread. Anthropogenic disturbance was associated with conditions conducive to increased transmission of flea-borne diseases.


Active subspace: toward scalable low-rank learning.
We address the scalability issues in low-rank matrix learning problems. Usually these problems resort to solving nuclear norm regularized optimization problems (NNROPs), which often suffer from high computational complexities if based on existing solvers, especially in large-scale settings. Based on the fact that the optimal solution matrix to an NNROP is often low rank, we revisit the classic mechanism of low-rank matrix factorization, based on which we present an active subspace algorithm for efficiently solving NNROPs by transforming large-scale NNROPs into small-scale problems. The transformation is achieved by factorizing the large solution matrix into the product of a small orthonormal matrix (active subspace) and another small matrix. Although such a transformation generally leads to nonconvex problems, we show that a suboptimal solution can be found by the augmented Lagrange alternating direction method. For the robust PCA (RPCA) (Candès, Li, Ma, & Wright, 2009 ) problem, a typical example of NNROPs, theoretical results verify the suboptimality of the solution produced by our algorithm. For the general NNROPs, we empirically show that our algorithm significantly reduces the computational complexity without loss of optimality.


Effects of melatonin treatment on follicular development and oocyte quality in Chios ewes - short communication.
Follicular development and oocyte quality were assessed by laparoscopic observation and in vitro fertilisation, respectively, in melatonin-treated (Group M) and control (Group C) anoestrous Chios ewes (n = 10 in each group). Fourteen days after melatonin insertion, all ewes had laparoscopic evaluation of the follicular population followed by oocyte pick-up (OPU); on day 22 intravaginal progestagen sponges were inserted for 14 days. Two days after sponge removal the follicular population was re-evaluated and a second follicular aspiration was performed. Collected oocytes from the second OPU underwent in vitro maturation, fertilisation and culture. The number of large follicles was higher in Group M than in the control ewes during the first OPU and tended to be so (P = 0.06) at the second. Morphologically, oocytes collected from controls were of better quality than those from Group M; however, more oocytes collected from melatonintreated animals fertilised and developed in vitro . These results indicate that melatonin is a potent regulator of follicular development and oocyte competence during the anoestrous period of the ewe.


Preliminary report of NAD+-dependent amino acid dehydrogenase producing bacteria isolated from soil.
Amino acid dehydrogenases (L-amino acid: oxidoreductase deaminating; EC 1.4.1.X) are members of the wider superfamily of oxidoreductases that catalyze the reversible oxidative deamination of an amino acid to its keto acid and ammonia with the concomitant reduction of either NAD+, NADP+ or FAD. These enzymes have been received much attention as biocatalysts for use in biosensors or diagnostic kits to screen amino acid metabolism disorders such as phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria (HCY) and hyperprolinemia. This study was aimed to isolation and screening of novel amino acid dehydrogenases from soil bacteriadehydrogenases from soil bacteria. The enzyme producing bacteria were selected among L-methionine and L-phenylalanine utilizers isolated from soil by thin layer chromatography, activity staining and confirmed by enzyme assay. Bacterial strains were identified by phenotypic and biochemical characteristics. The steady-state kinetic studies of enzymes were also performed. In total of 230 tested strains, four of them were recognized as amino acid dehydrogenase producers that belong to species of Pseudomonas, Citrobacter and Proteus. They exhibited the desired NAD+-dependent dehydrogenase activities toward L-isoleucine, L-methionine, L-cysteine, L-serine and L-glutamine in oxidative deamination reaction. The specific activity of L-isoleucine dehydrogenase, L-methionine dehydrogenase and L-glutamine dehydrogenase for oxidative deamination of L-isoleucine, L-methionine and L-glutamine were 1.59, 1.2 and 0.73 U/mg, respectively. The Kcat/Km (s(-1).mM(-1)) values in these strains were as follows: L-isoleucine, 113.6, L-methionine, 62.05 and L-glutamine, 95.83. This is the first report of occurrence a specific isoleucine dehydrogenase, glutamine dehydrogenase and methionine dehydrogenase in bacteria.


Spatial learning depends on both the addition and removal of new hippocampal neurons.
The role of adult hippocampal neurogenesis in spatial learning remains a matter of debate. Here, we show that spatial learning modifies neurogenesis by inducing a cascade of events that resembles the selective stabilization process characterizing development. Learning promotes survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors. These are three interrelated events mediating learning. Thus, blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation. In conclusion, during learning, similar to the selective stabilization process, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons.


Diagnostic and prognostic potential of the proteomic profiling of serum-derived extracellular vesicles in prostate cancer.
Extracellular vesicles (EVs) and their cargo represent an intriguing source of cancer biomarkers for developing robust and sensitive molecular tests by liquid biopsy. Prostate cancer (PCa) is still one of the most frequent and deadly tumor in men and analysis of EVs from biological fluids of PCa patients has proven the feasibility and the unprecedented potential of such an approach. Here, we exploited an antibody-based proteomic technology, i.e. the Reverse-Phase Protein microArrays (RPPA), to measure key antigens and activated signaling in EVs isolated from sera of PCa patients. Notably, we found tumor-specific protein profiles associated with clinical settings as well as candidate markers for EV-based tumor diagnosis. Among others, PD-L1, ERG, Integrin-β5, Survivin, TGF-β, phosphorylated-TSC2 as well as partners of the MAP-kinase and mTOR pathways emerged as differentially expressed endpoints in tumor-derived EVs. In addition, the retrospective analysis of EVs from a 15-year follow-up cohort generated a protein signature with prognostic significance. Our results confirm that serum-derived EV cargo may be exploited to improve the current diagnostic procedures while providing potential prognostic and predictive information. The approach proposed here has been already applied to tumor entities other than PCa, thus proving its value in translational medicine and paving the way to innovative, clinically meaningful tools.


Recovery of muscle strength following multi-level orthopaedic surgery in diplegic cerebral palsy.
Muscle strength changes following multi-level surgery in cerebral palsy and the impact of rehabilitation on functional recovery are largely unknown. The aim of this study was to quantify lower limb muscle strength changes in children with spastic diplegia after multi-level orthopaedic surgery and to compare the efficacy of progressive resistance strengthening (RS) versus active exercise (AE). Twenty children with spastic diplegia (mean age 12.5 years) participated in this prospective randomised controlled trial. Participants underwent multi-level orthopaedic surgery. Routine physiotherapy commenced immediately after surgery. At 6 months post-operatively, children were randomly assigned to the resistance strengthening RS (n=11) or active exercise AE (n=9) group and received intensive physiotherapy for 6 weeks. Gait, motor function and maximum isometric muscle strength in five lower limb muscle groups were measured pre-operatively and at 6 months (before and after intensive physiotherapy) and 12 months. As part of the study, we developed and validated a myometry protocol. Despite kinematic improvements, there was significant reduction of muscle strength (p<0.05) in all muscle groups at 6 months post-operatively. Following 6 weeks of intensive physiotherapy, both groups showed significant improvement in muscle strength, GMFM scores and gait parameters. Resistance training showed some advantages over active exercise. At 1 year after surgery, strength did not reach pre-operative values in some muscle groups but the benefit from physiotherapy was maintained. In conclusion, we quantified objectively the reduction in muscle strength 6 and 12 months following multi-level surgery. Furthermore, we demonstrated significant improvement in muscle strength, gait and function following post-operative strength training.


Strategies to improve HIV care outcomes for people with HIV who are out of care.
The aim of this study was to evaluate the effectiveness of five intervention strategies: patient navigation, appointment help/alerts, psychosocial support, transportation/appointment accompaniment, and data-to-care on HIV care outcomes among persons with HIV (PWH) who are out of care (OOC). A systematic review with meta-analysis. We searched CDC's Prevention Research Synthesis (PRS) Project's cumulative HIV database to identify intervention studies conducted in the U.S., published between 2000 and 2020 that included comparisons between groups or prepost, and reported at least one relevant outcome (i.e. re-engagement or retention in HIV care, and viral suppression). Effect sizes were meta-analyzed using random-effect models to assess intervention effectiveness. Thirty-nine studies reporting on 42 unique interventions met the inclusion criteria. Overall, intervention strategies are effective in improving re-engagement in care [odds ratio (OR) = 1.79;95% confidence interval (95% CI): 1.36-2.36, k = 14], retention in care (OR = 2.01; 95% CI: 1.64-2.64, k = 22), and viral suppression (OR = 2.50;95% CI: 1.87-3.34, k = 27). Patient navigation, appointment help/alerts, psychosocial support, and transportation/appointment accompaniment improved all three HIV care outcomes. Data-to-care improved re-engagement and retention but had insufficient evidence for viral suppression. Several strategies are effective for improving HIV care outcomes among PWH who are OOC. More work is still needed for consistent definitions of OOC and HIV care outcomes, better reporting of intervention and cost data, and identifying how best to implement and scale-up effective strategies to engage and retain OOC PWH in care and reach the ending the HIV epidemic goals.


Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regression.
Hypoxic tumor niches are chief causes of treatment resistance and tumor recurrence. Sickle erythrocytes' (SSRBCs') intrinsic oxygen-sensing functionality empowers them to access such hypoxic niches wherein they form microaggregates that induce focal vessel closure. In search of measures to augment the scale of SSRBC-mediated tumor vaso-occlusion, we turned to the vascular disrupting agent, combretastatin A-4 (CA-4). CA-4 induces selective tumor endothelial injury, blood stasis, and hypoxia but fails to eliminate peripheral tumor foci. In this article, we show that introducing deoxygenated SSRBCs into tumor microvessels treated with CA-4 and sublethal radiation (SR) produces a massive surge of tumor vaso-occlusion and broadly propagated tumor infarctions that engulfs treatment-resistant hypoxic niches and eradicates established lung tumors. Tumor regression was histologically corroborated by significant treatment effect. Treated tumors displayed disseminated microvessels occluded by tightly packed SSRBCs along with widely distributed pimidazole-positive hypoxic tumor cells. Humanized HbS-knockin mice (SSKI) but not HbA-knockin mice (AAKI) showed a similar treatment response underscoring SSRBCs as the paramount tumoricidal effectors. Thus, CA-4-SR-remodeled tumor vessels license SSRBCs to produce an unprecedented surge of tumor vaso-occlusion and infarction that envelops treatment-resistant tumor niches resulting in complete tumor regression. Strategically deployed, these innovative tools constitute a major conceptual advance with compelling translational potential.


The effect of standardised submaximal work load on intraocular pressure.
A relatively small decrease in intraocular pressure secondary to submaximal work can be demonstrated when factors other than the work load itself are eliminated--diurnal variation, body position, and the effect of repeated examinations. A feedback mechanism that causes a return of IOP towards its normal value after work-induced decreases is postulated.


The dress and individual differences in the perception of surface properties.
This study investigates systematic individual differences in the way observers perceive different kinds of surface properties and their relationship to the dress, which shows striking individual differences in colour perception. We tested whether these individual differences have a common source, namely differences in perceptual strategies according to which observers attribute features in two-dimensional images to surfaces or to their illumination. First, we reanalysed data from two previous experiments on the dress and colour constancy. The comparison of the two experiments revealed that the colour perception of the dress is strongly related to individual differences in colour constancy. Second, two online surveys measured individual differences in the perception of colour-ambiguous images including the dress, in colour constancy, in gloss perception, in the subjective grey-point, in colour naming, and in the perception of an image with ambiguous shading. The results of the surveys replicated and extended previous findings according to which individual differences in the colour perception of the dress are due to implicit assumptions about the illumination. However, results also showed that the individual differences for other phenomena were independent of the dress and of each other. Overall, these results suggest that the striking individual differences in dress colour perception are due to individual differences in the interpretation of illumination cues to achieve colour constancy. At the same time, they undermine the idea of an overall perceptual strategy that encompasses other phenomena more generally related to the interpretation of illumination and surface properties.


Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision).
Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.


The successful arthroscopic treatment of suprascapular intraneural ganglion cysts.
OBJECT High-resolution magnetic resonance imaging (MRI) can distinguish between intraneural ganglion cysts and paralabral (extraneural) cysts at the glenohumeral joint. Suprascapular intraneural ganglion cysts share the same pathomechanism as their paralabral counterparts, emanating from a tear in the glenoid labrum. The authors present 2 cases to demonstrate that the identification and arthroscopic repair of labral tears form the cornerstone of treatment for intraneural ganglion cysts of the suprascapular nerve. METHODS Two patients with suprascapular intraneural ganglion cysts were identified: 1 was recognized and treated prospectively, and the other, previously reported as a paralabral cyst, was identified retrospectively through the reinter-pretation of high-resolution MR images. RESULTS Both patients achieved full functional recovery and had complete radiological involution of the intraneural ganglion cysts at the 3-month and 12-month follow-ups, respectively. CONCLUSIONS Previous reports of suprascapular intraneural ganglion cysts described treatment by an open approach to decompress the cysts and resect the articular nerve branch to the glenohumeral joint. The 2 cases in this report demonstrate that intraneural ganglion cysts, similar to paralabral cysts, can be treated with arthroscopic repair of the glenoid labrum without resection of the articular branch. This approach minimizes surgical morbidity and directly addresses the primary etiology of intraneural and extraneural ganglion cysts.


Modulation of upper airway muscle activities by bronchopulmonary afferents.
Here we review the influence of bronchopulmonary receptors (slowly and rapidly adapting pulmonary stretch receptors, and pulmonary/bronchial C-fiber receptors) on respiratory-related motor output to upper airway muscles acting on the larynx, tongue, and hyoid arch. Review of the literature shows that all muscles in all three regions are profoundly inhibited by lung inflation, which excites slowly adapting pulmonary stretch receptors. This widespread coactivation includes the recruitment of muscles that have opposing mechanical actions, suggesting that the stiffness of upper airway muscles is highly regulated. A profound lack of information on the modulation of upper airway muscles by rapidly adapting receptors and bronchopulmonary C-fiber receptors prohibits formulation of a conclusive opinion as to their actions and underscores an urgent need for new studies in this area. The preponderance of the data support the view that discharge arising in slowly adapting pulmonary stretch receptors plays an important role in the initiation of the widespread and highly coordinated recruitment of laryngeal, tongue, and hyoid muscles during airway obstruction.


Mucosal expression of basic fibroblastic growth factor, Syndecan 1 and tumor necrosis factor-alpha in diverticular disease of the colon: a case-control study.
Inflammation may be detected in diverticular disease (DD), and fibrosis may also develop. We assessed the mucosal expression of bFGF, SD1, and TNF-α in DD according to the severity of the disease. Moreover, we assessed the response to therapy of these cytokines in acute uncomplicated diverticulitis (AUD). Fifteen patients affected by AUD and seven patients affected by symptomatic uncomplicated diverticular disease (SUDD) were enrolled. Patients with asymptomatic diverticulosis (AD), segmental colitis associated with diverticulosis (SCAD), ulcerative colitis (UC), and healthy subjects (HC) served as control groups. The expression of bFGF, SD1, and TNF-α was significantly higher in diverticulitis than in healthy controls, in diverticulosis, and in uncomplicated diverticular disease. Cytokines were significantly higher in uncomplicated diverticular disease than in healthy controls. Cytokine expression in diverticulitis did not differ significantly from that of ulcerative colitis. After treatment, TNF-α expression dropped significantly. Mucosal TNF-α is overexpressed only in symptomatic DD, while SD1 and bFGF are already overexpressed in AD. Finally, TNF-α but not SD1 or bFGF expression seems to be influenced by the treatment in AUD.


How clinicians analyze movement quality in patients with non-specific low back pain: a cross-sectional survey study with Dutch allied health care professionals.
Observation of movement quality (MQ) is an indelible element in the process of clinical reasoning for patients with non-specific low back pain (NS-LBP). However, the observation and evaluation of MQ in common daily activities are not standardized within allied health care. This study aims to describe how Dutch allied health care professionals (AHCPs) observe and assess MQ in patients with NS-LBP and whether AHCPs feel the need to have a specific outcome measure for assessing MQ in patients with NS-LBP. In this cross-sectional digital survey study, Dutch primary care AHCPs (n = 114) answered one open and three closed questions about MQ in NS-LBP management. Qualitative and quantitative analyses were applied. Qualitative analyses of the answers to the open questions revealed four main themes: 1) movement pattern features, 2) motor control features, 3) environmental influences and 4) non-verbal expressions of pain and exertion. Quantitative analyses clearly indicated that AHCPs observe MQ in the diagnostic (92%), therapeutic (91%) and evaluation phases (86%), that they do not apply any objective measurement of MQ and that 63% of the AHCPs consider it important to have a specific outcome measure to assess MQ. The AHCPs expressed added benefits and critical notes regarding clinical reasoning and quality of care. AHCPs recognize the importance of observing MQ in the assessment and management of LBP in a standardized way. However, there is no consensus amongst AHCPs how MQ should be standardized. Prior to standardization, it will be important to develop a theoretical framework to determine which observable and measurable dimensions of MQ are most valid and relevant for patients with NS-LBP to include in the assessment.


Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy.
Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.


Single-laser, one beam, tetrahedral magneto-optical trap.
We have realized a 4-beam pyramidal magneto-optical trap ideally suited for future microfabrication. Three mirrors split and steer a single incoming beam into a tripod of reflected beams, allowing trapping in the four-beam overlap volume. We discuss the influence of mirror angle on cooling and trapping, finding optimum efficiency in a tetrahedral configuration. We demonstrate the technique using an ex-vacuo mirror system to illustrate the previously inaccessible supra-plane pyramid MOT configuration. Unlike standard pyramidal MOTs both the pyramid apex and its mirror angle are non-critical and our MOT offers improved molasses free from atomic shadows in the laser beams. The MOT scheme naturally extends to a 2-beam refractive version with high optical access. For quantum gas experiments, the mirror system could also be used for a stable 3D tetrahedral optical lattice.


Technical feasibility and carbon footprint of biochar co-production with tomato plant residue.
World tomato production is in the increase, generating large amounts of organic agricultural waste, which are currently incinerated or composted, releasing CO2 into the atmosphere. Organic waste is not only produced from conventional but also urban agricultural practices due recently gained popularity. An alternative to current waste management practices and carbon sequestration opportunity is the production of biochar (thermally converted biomass) from tomato plant residues and use as a soil amendment. To address the real contribution of biochar for greenhouse gas mitigation, it is necessary to assess the whole life cycle from the production of the tomato biomass feedstock to the actual distribution and utilisation of the biochar produced in a regional context. This study is the first step to determine the technical and environmental potential of producing biochar from tomato plant (Solanum lycopersicum arawak variety) waste biomass and utilisation as a soil amendment. The study includes the characterisation of tomato plant residue as biochar feedstock (cellulose, hemicellulose, lignin and metal content); feedstock thermal stability; and the carbon footprint of biochar production under urban agriculture at pilot and small-scale plant, and conventional agriculture at large-scale plant. Tomato plant residue is a potentially suitable biochar feedstock under current European Certification based on its lignin content (19.7%) and low metal concentration. Biomass conversion yields of over 40%, 50% carbon stabilization and low pyrolysis temperature conditions (350-400°C) would be required for biochar production to sequester carbon under urban pilot scale conditions; while large-scale biochar production from conventional agricultural practices have not the potential to sequestrate carbon because its logistics, which could be improved. Therefore, the diversion of tomato biomass waste residue from incineration or composting to biochar production for use as a soil amendment would environmentally be beneficial, but only if high biochar yields could be produced.


Association of sub-microscopic malaria parasite carriage with transmission intensity in north-eastern Tanzania.
In malaria endemic areas, individuals are frequently asymptomatic and may be undetected by conventional microscopy or newer, rapid diagnostic tests. Molecular techniques allow a more accurate assessment of this asymptomatic parasite burden, the extent of which is important for malaria control. This study examines the relative prevalence of sub-microscopic level parasite carriage and clonal complexity of infections (multiplicity of infection) over a range of endemicities in a region of north-eastern Tanzania where altitude is an established proxy of malaria transmission. The PCR prevalence was then compared against other measures of transmission intensity collected in the same area. This study used 1,121 blood samples collected from a previously conducted cross-sectional malario-metric survey during the short rainy season in 2001 from 13 villages (three at < 600 m, four at 600-1,200 m and six at > 1,200 m in altitude above sea level). Samples were analysed by PCR for carriage of parasites and multiplicity of infection. These data were compared with other measures of transmission intensity collected from the same area. Parasite prevalence was 34.7% by PCR and 13.6% by microscopy; a 2.5-fold difference in line with other recent observations. This fold difference was relatively consistent at the different altitude bands despite a marked decrease in parasite prevalence with altitude: < 600 m 70.9 vs 28.6, 600-1,200 m 35.5 vs 9.9, > 1,200 m 15.8 vs 5.9. The difference between parasite prevalence by PCR was 3.2 in individuals aged between 15 and 45 years (34.5 vs 10.9) compared with 2.5 in those aged 1-5 (34.0 vs 13.5) though this was not statistically significant. Multiplicity of infection (MOI) ranged from 1.2 to 3.7 and was positively associated with parasite prevalence assessed by both PCR and microscopy. There was no association of MOI and age.Village level PCR parasite prevalence was strongly correlated with altitude, sero-conversion rate and predicted entomological inoculation rate. Asymptomatic, low density, multi-clone malaria infection was common in this study area. These infections are important as potential contributors to the infectious reservoir of parasites and need to be identified by control programmes especially in this era where malaria elimination is a focus. High throughput standardized PCR approaches are needed to identify individuals who are malaria carriers.


Predicting compliance with a regimen of digoxin therapy in family practice.
The ability of family physicians to predict patients' compliance with a regimen of digoxin therapy was studied by an analytic survey. Compliance was assessed by a pill count at a home visit and measurement of the serum digoxin level in a blood sample obtained at that visit. Of 74 patients 70% were found to be taking more than 80% of their pills and 86% had a therapeutic serum digoxin level. The 10 physicians were unable to predict compliance better than chance, even for the 58 patients they had known for 5 or more years. Physicians should be cautious in predicting compliance, and when they prescribe oral digoxin therapy they should monitor the patient's compliance by means of the serum digoxin levels.


Carbohydrate quality and human health: a series of systematic reviews and meta-analyses.
Previous systematic reviews and meta-analyses explaining the relationship between carbohydrate quality and health have usually examined a single marker and a limited number of clinical outcomes. We aimed to more precisely quantify the predictive potential of several markers, to determine which markers are most useful, and to establish an evidence base for quantitative recommendations for intakes of dietary fibre. We did a series of systematic reviews and meta-analyses of prospective studies published from database inception to April 30, 2017, and randomised controlled trials published from database inception to Feb 28, 2018, which reported on indicators of carbohydrate quality and non-communicable disease incidence, mortality, and risk factors. Studies were identified by searches in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and by hand searching of previous publications. We excluded prospective studies and trials reporting on participants with a chronic disease, and weight loss trials or trials involving supplements. Searches, data extraction, and bias assessment were duplicated independently. Robustness of pooled estimates from random-effects models was considered with sensitivity analyses, meta-regression, dose-response testing, and subgroup analyses. The GRADE approach was used to assess quality of evidence. Just under 135 million person-years of data from 185 prospective studies and 58 clinical trials with 4635 adult participants were included in the analyses. Observational data suggest a 15-30% decrease in all-cause and cardiovascular related mortality, and incidence of coronary heart disease, stroke incidence and mortality, type 2 diabetes, and colorectal cancer when comparing the highest dietary fibre consumers with the lowest consumers Clinical trials show significantly lower bodyweight, systolic blood pressure, and total cholesterol when comparing higher with lower intakes of dietary fibre. Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer. Similar findings for whole grain intake were observed. Smaller or no risk reductions were found with the observational data when comparing the effects of diets characterised by low rather than higher glycaemic index or load. The certainty of evidence for relationships between carbohydrate quality and critical outcomes was graded as moderate for dietary fibre, low to moderate for whole grains, and low to very low for dietary glycaemic index and glycaemic load. Data relating to other dietary exposures are scarce. Findings from prospective studies and clinical trials associated with relatively high intakes of dietary fibre and whole grains were complementary, and striking dose-response evidence indicates that the relationships to several non-communicable diseases could be causal. Implementation of recommendations to increase dietary fibre intake and to replace refined grains with whole grains is expected to benefit human health. A major strength of the study was the ability to examine key indicators of carbohydrate quality in relation to a range of non-communicable disease outcomes from cohort studies and randomised trials in a single study. Our findings are limited to risk reduction in the population at large rather than those with chronic disease. Health Research Council of New Zealand, WHO, Riddet Centre of Research Excellence, Healthier Lives National Science Challenge, University of Otago, and the Otago Southland Diabetes Research Trust.


Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Highly reactive oxygen free radicals are believed to be involved in the pathogenesis of the disease. In this study, RA patients were sub-grouped depending upon the presence or absence of rheumatoid factor, disease activity score and disease duration. RA Patients (120) and healthy controls (53) were evaluated for the oxidant-antioxidant status by monitoring ROS production, biomarkers of lipid peroxidation, protein oxidation and DNA damage. The level of various enzymatic and non-enzymatic antioxidants was also monitored. Correlation analysis was also performed for analysing the association between ROS and various other parameters. Intracellular ROS formation, lipid peroxidation (MDA level), protein oxidation (carbonyl level and thiol level) and DNA damage were detected in the blood of RA patients. Antioxidant status was evaluated by FRAP assay, DPPH reduction assay and enzymatic (SOD, catalase, GST, GR) and non-enzymatic (vitamin C and GSH) antioxidants. RA patients showed a higher ROS production, increased lipid peroxidation, protein oxidation and DNA damage. A significant decline in the ferric reducing ability, DPPH radical quenching ability and the levels of antioxidants has also been observed. Significant correlation has been found between ROS and various other parameters studied. RA patients showed a marked increase in ROS formation, lipid peroxidation, protein oxidation, DNA damage and decrease in the activity of antioxidant defence system leading to oxidative stress which may contribute to tissue damage and hence to the chronicity of the disease.


Steady-state mRNA levels of the sarcolemmal Na(+)-Ca2+ exchanger peak near birth in developing rabbit and rat hearts.
To functionally compensate for an underdeveloped sarcoplasmic reticulum in immature cardiomyocytes, it has been proposed that the sarcolemmal Na(+)-Ca2+ exchanger may assume a more predominant role for regulating cytosolic Ca2+. Previous studies using sarcolemma prepared from developing rabbit hearts demonstrated that Na(+)-dependent Ca2+ uptake and exchanger protein content were highest at birth and declined postnatally. To further investigate the significance of the Na(+)-Ca2+ exchanger during normal myocardial development, steady-state mRNA levels of the cardiac Na(+)-Ca2+ exchanger were quantitated by Northern blot and slot-blot analyses using poly(A+) RNA isolated from rabbit and rat ventricles at various fetal and postnatal ages. Northern analyses were performed with a 1.35-kb guinea pig cardiac Na(+)-Ca2+ exchanger cDNA probe. Exchanger mRNA levels were quantitated by densitometric scans of the slot blots, and results were normalized by reprobing the same blots with 32P 5'-end-labeled oligo(dT). In both species, exchanger mRNA levels peaked near birth and declined postnatally. Maximal levels were approximately sixfold greater in the late fetal rabbit (gestational day 29) and eightfold greater in the early newborn rat (postnatal day 1) compared with adults of the respective species. The parallel changes in exchanger mRNA and protein levels suggest that developmental regulation of cardiac Na(+)-Ca2+ exchanger expression involves pretranslational control mechanisms. These results support the concept that during normal cardiac development, Na(+)-Ca2+ exchanger expression is maximal near the time of birth and then declines postnatally as Ca2+ regulation by the sarcoplasmic reticulum reaches functional maturity.


GPCALMA: a Grid-based tool for mammographic screening.
The next generation of high energy physics (HEP) experiments requires a GRID approach to a distributed computing system: the key concept is the Virtual ORGANISATION (VO), a group of distributed users with a common goal and the will to share their resources. A similar approach, applied to a group of hospitals that joined the GPCALMA project (Grid Platform for Computer Assisted Library for MAmmography), will allow common screening programs for early diagnosis of breast and, in the future, lung cancer. The application code makes use of neural networks for the image analysis and is useful in improving the radiologists' diagnostic performance. GRID services allow remote image analysis and interactive online diagnosis, with a potential for a relevant reduction of the delays presently associated with screening programs. A prototype of the system, based on AliEn GRID Services [1], is already available, with a central server running common services [2] and several clients connecting to it. Mammograms can be acquired in any location; the related information required to select and access them at any time is stored in a common service called Data Catalogue, which can be queried by any client. Thanks to the PROOF facility [3], the result of a query can be used as input for analysis algorithms, which are executed on the nodes where the input images are stored,. The selected approach avoids data transfers for all the images with a negative diagnosis and allows an almost real time diagnosis for the set of images with high cancer probability.


A broad-host-range mobilizable shuttle vector for the construction of transcriptional fusions to beta-galactosidase in gram-positive bacteria.
A low-copy-number vector designated pTCV-lac has been constructed to provide a convenient system to analyze regulatory elements in Gram-positive bacteria. The main components of this vector are: (i) the origins of replication of pACYC184 and of the broad-host-range enterococcal plasmid pAM beta 1, (ii) erythromycin- and kanamycin-resistance-encoding genes for selection in Gram-negative and Gram-positive bacteria, (iii) the transfer origin of the IncP plasmid RK2, and (iv) a promoterless beta-galactosidase-encoding lacZ gene with a Gram-positive ribosome binding site. This 12 kb plasmid is present in Gram-positive hosts in three to five copies per chromosome equivalent and contains three unique cloning sites (EcoRI, SmaI, BamHI) for cloning of DNA inserts upstream of the lacZ gene. Plasmid pTCV-lac and derivatives carrying different promoter fragments have been transferred by conjugation from an Escherichia coli IncP mobilizing donor strain to Bacillus subtilis, Listeria monocytogenes, Enterococcus faecalis, and Streptococcus agalactiae. These plasmids were structurally stable in these hosts and the corresponding promoter activities, quantitated by the determination of the beta-galactosidase specific activities, were found to cover at least a 100-fold range in beta-galactosidase values. These results indicate that pTCV-lac should be useful for analysis of gene regulation in a wide range of Gram-positive bacteria.


Experimental metrics for detection of detailed balance violation.
We report on the measurement of detailed balance violation in a coupled, noise-driven linear electronic circuit consisting of two nominally identical RC elements that are coupled via a variable capacitance. The state variables are the time-dependent voltages across each of the two primary capacitors, and the system is driven by independent noise sources in series with each of the resistances. From the recorded time histories of these two voltages, we quantify violations of detailed balance by three methods: (1) explicit construction of the probability current density, (2) constructing the time-dependent stochastic area, and (3) constructing statistical fluctuation loops. In comparing the three methods, we find that the stochastic area is relatively simple to implement and computationally inexpensive and provides a highly sensitive means for detecting violations of detailed balance.


Modern contact investigation methods for enhancing tuberculosis control in aboriginal communities.
The Aboriginal communities in Canada are challenged by a disproportionate burden of TB infection and disease. Contact investigation (CI) guidelines exist but these strategies do not take into account the unique social structure of different populations. Because of the limitations of traditional CI, new approaches are under investigation and include the use of social network analysis, geographic information systems and genomics, in addition to the widespread use of genotyping to better understand TB transmission. Guidelines for the routine use of network methods and other novel methodologies for TB CI and outbreak investigation do not exist despite the gathering evidence that these approaches can positively impact TB control efforts, even in Aboriginal communities. The feasibility and efficacy of these novel approaches to CI in Aboriginal communities requires further investigation. The successful integration of these novel methodologies will require community involvement, capacity building and ongoing support at every level. The outcome will not only be the systematic collection, analysis, and interpretation of CI data in high-burden communities to assess transmission but the prioritization of contacts who are candidates for treatment of LTBI which will break the cycle of transmission. Ultimately, the measure of success will be a clear and sustained decline in TB incidence in Aboriginal communities.


Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid-resistant myeloid leukemic cells.
Complete remission is achieved in a high proportion of patients with acute promyelocytic leukemia (APL) after all-trans retinoic acid (RA) treatment, but most patients relapse and develop RA-resistant APL. We have previously reported that both RA-resistant HL-60 (HL-60R) and APL cells express P-glycoprotein and MDR1 transcripts; and these cells differentiate to mature granulocytes after culture with RA and P-glycoprotein antagonist. Ribozymes have been shown to be able to intercept a target RNA by catalytic activity. To address the role of MDR1 in overcoming RA-resistance in APL cells, we investigated the biologic effects of ribozymes against the MDR1 transcript in HL-60R cells. These ribozymes efficiently cleaved MDR1 mRNA at a specific site in vitro. The 196 MDR1 ribozyme was cloned into an expression vector, and stably transfected (HL-60R/196Rz) cells were obtained. Expression of MDR1 transcripts was decreased in HL-60R/196Rz cells compared with parental HL-60R and empty vector-transfected (HL-60R/neo) cells. Interestingly, RA inhibited cellular proliferation and induced differentiation of HL-60R/196Rz cells in a dose-dependent manner, suggesting reversal of drug resistance in HL-60R cells by the MDR1 ribozyme. These data are direct evidence that P-glycoprotein/MDR1 is responsible in part for acquired resistance to RA in myeloid leukemic cells. The MDR1 ribozyme may be a useful tool for investigating the biology of retinoid resistance and may have therapeutic potential for patients with RA-resistant APL.


The µ opioid receptor and ligands acting at the µ opioid receptor, as therapeutics and potential therapeutics.
Although the µ opioid receptor (MOR) was pharmacologically and biochemically identified in binding studies forty years ago, its structure, function, and true complexity only have emerged after its cloning in 1993. Continuous efforts from many laboratories have greatly advanced our understanding of MORs, ranging from their anatomic distribution to cellular and molecular mechanisms, and from cell lines to in vivo systems. The MOR is recognized as the main target for effective pain relief, but its involvement in many other physiological functions has also been recognized. This review provides a synopsis on the history of research on MORs and ligands acting at the MOR with the focus on their clinical and potential use as therapeutic drugs, or as valuable research tools. Since the elucidation of the chemical structure of morphine and the characterization of endogenous opioid peptides, research has stimulated the development of new generations of MOR ligands with distinct pharmacological profiles (agonist, antagonist, mixed agonist/antagonist and partial agonist) or site of action (central/peripheral). Discovery of therapeutically useful morphine-like drugs and innovative drugs with new scaffolds, with several outstanding representatives, is discussed. Extensive efforts on modifications of endogenous peptides to attain stable and MOR selective analogs are overviewed with stimulating results for the development of peptide-based pharmaceuticals. With pharmacophore modeling as an important tool in drug discovery, application of modern computational methodologies for the development of morphinans as new MOR ligands is described. Moreover, the crystal structure of the MOR available today will enable the application of structure-based approaches to design better drugs for the management of pain, addiction and other human diseases, where MORs play a key role.


Habitat formation prevails over predation in influencing fouling communities.
Coastal human-made structures, such as marinas and harbors, are expanding worldwide. Species assemblages described from these artificial habitats are novel relative to natural reefs, particularly in terms of the abundance of nonindigenous species (NIS). Although these fouling assemblages are clearly distinctive, the ecosystem functioning and species interactions taking place there are little understood. For instance, large predators may influence the fouling community development either directly (feeding on sessile fauna) or indirectly (feeding on small predators associated with these assemblages). In addition, by providing refuges, habitat complexity may modify the outcome of species interactions and the extent of biotic resistance (e.g., by increasing the abundance of niche-specific competitors and predators of NIS). Using experimental settlement panels deployed in the field for 2.5 months, we tested the influence of predation (i.e., caging experiment), artificial structural complexity (i.e., mimics of turf-forming species), and their interactions (i.e., refuge effects) on the development of sessile and mobile fauna in two marinas. In addition, we tested the role of biotic complexity-arising from the habitat-forming species that grew on the panels during the trial-on the richness and abundance of mobile fauna. The effect of predation and artificial habitat complexity was negligible, regardless of assemblage status (i.e., native, cryptogenic, and nonindigenous). Conversely, habitat-forming species and associated epibionts, responsible for biotic complexity, had a significant effect on mobile invertebrates (richness, abundance, and community structure). In particular, the richness and abundance of mobile NIS were positively affected by biotic complexity, with site-dependent relationships. Altogether, our results indicate that biotic complexity prevails over artificial habitat complexity in determining the distribution of mobile species under low predation pressure. Facilitation of native and non-native species thus seems to act upon diversity and community development: This process deserves further consideration in models of biotic resistance to invasion in urban marine habitats.


Clothes-on PUVA in psoriasis: single blind randomized comparative trial on 21 patients.
PUVASOL therapy has an inherent drawback of patient compliance in that Indian female patients with psoriasis lesions on covered parts of the body are reluctant to expose themselves. In this study we tried to evaluate a new method of administering PUVA therapy wearing a fabric. To compare the efficacy and safety of PUVA administration with and without wearing clothes in psoriasis. We first found the UV transmissibility of plain woven, lightweight cream colored cotton fabric with 30 x 30 threads per square cm. area and calculated its sun protection factor (SPF). A single blind, randomized, comparative, clinical trial was then conducted on 21 patients with psoriasis vulgaris who were treated with bath PUVA. The study group received ultraviolet light while wearing a gown made up of the above cotton fabric and the control group received ultraviolet light without wearing the gown. The study group was given an UV dose higher in proportion to the SPF of the worn fabric so that blockage caused by cloth could be neutralized. The cloth-uncovered areas were covered with a sunscreen. UVA from artificial light source was used for better patient monitoring. After 12 PUVA treatments both the treatments were found to be equally effective, and there were no differences in the side effects. Thus we conclude that PUVA can be given wearing a fabric provided the UV dosage is increased proportional to the SPF of the fabric. The same fabric may be used for PUVASOL therapy.


Loss of CAK phosphorylation of RAR{alpha} mediates transcriptional control of retinoid-induced cancer cell differentiation.
Although the role of the classic retinoic acid (RA)-induced genomic pathway in cancer cell differentiation is well recognized, the underlying mechanisms remain to be dissected. Retinoic acid receptor alpha (RARalpha) is a transcription factor activated by RA, and its serine 77 (RARalphaS77) is the main residue phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex. We report here that in both human myeloid leukemia and mouse embryonic teratocarcinoma stem cells, either RA-suppressed CAK phosphorylation of RARalpha or mutation of RARalphaS77 to alanine (RARalphaS77A) coordinates CAK-dependent G(1) arrest with cancer cell differentiation by transactivating RA-target genes. Both hypophosphorylated RARalpha and RARalphaS77A reduce binding to retinoic acid-responsive elements (RARE) in the promoters of RA-target genes while stimulating gene transcription. The enhanced transactivation and reduced RARalpha-chromatin interaction are accompanied by RARalpha dissociation from the transcriptional repressor N-CoR and are association with the coactivator NCoA-3. Such effects of decreased CAK phosphorylation of RARalphaS77 on mediating RA-dependent transcriptional control of cancer cell differentiation are examined correspondingly in both RA-resistant myeloid leukemia and embryonic teratocarcinoma stem RARalpha(-/-) cells. These studies demonstrate, for the first time, that RA couples G(1) arrest to transcriptional control of cancer cell differentiation by suppressing CAK phosphorylation of RARalpha to release transcriptional repression.-Wang, A., Alimova, I. N., Luo, P. Jong, A., Triche, T. J., Wu, L. Loss of CAK phosphorylation of RARalpha mediates transcriptional control of retinoid-induced cancer cell differentiation.


Eye development and photoreceptor differentiation in the cephalopod Doryteuthis pealeii.
Photoreception is a ubiquitous sensory ability found across the Metazoa, and photoreceptive organs are intricate and diverse in their structure. Although the morphology of the compound eye in Drosophila and the single-chambered eye in vertebrates have elaborated independently, the amount of conservation within the 'eye' gene regulatory network remains controversial, with few taxa studied. To better understand the evolution of photoreceptive organs, we established the cephalopod Doryteuthis pealeii as a lophotrochozoan model for eye development. Utilizing histological, transcriptomic and molecular assays, we characterize eye formation in Doryteuthis pealeii Through lineage tracing and gene expression analyses, we demonstrate that cells expressing Pax and Six genes incorporate into the lens, cornea and iris, and the eye placode is the sole source of retinal tissue. Functional assays demonstrate that Notch signaling is required for photoreceptor cell differentiation and retinal organization. This comparative approach places the canon of eye research in traditional models into perspective, highlighting complexity as a result of both conserved and convergent mechanisms.


The Maudsley Biomedical Research Centre (BRC) data linkage service user and carer advisory group: creating and sustaining a successful patient and public involvement group to guide research in a complex area.
Patient and Public Involvement (PPI) in health and social care research has been shown to improve the quality and relevance of research. PPI in data linkage research is important in ensuring the legitimacy of future health informatics initiatives, but remains sparse and under-developed. This article describes the setting up and evaluation of a service user and carer advisory group with the aim of providing feedback and advice to researchers developing or making use of database linkages in the field of mental health. The aim of this study is to describe the creation and formative evaluation of the service user and carer advisory group after a trial period of 12 months. Six individuals were recruited to the group all of whom had personal experience of mental illness. A formative evaluation was conducted after a trial period of 12 months. Evaluation revealed that the group succeeded in promoting dialogue between service users/carers and researchers. Factors that contributed to the success of the group's first year included the opportunity it provided for researchers to involve service users and carers in their projects, the training provided to group members, and the openness of researchers to receiving feedback from the group. The group encourages the incorporation of PPI in data linkage research which helps to ensure the legitimacy of data linkage practices and governance systems whilst also improving the quality and relevance of the research being conducted using linked data.


Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging.
HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brain-specific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies.


Increased average longevity among the "Tour de France" cyclists.
It is widely held among the general population and even among health professionals that moderate exercise is a healthy practice but long term high intensity exercise is not. The specific amount of physical activity necessary for good health remains unclear. To date, longevity studies of elite athletes have been relatively sparse and the results are somewhat conflicting. The Tour de France is among the most gruelling sport events in the world, during which highly trained professional cyclists undertake high intensity exercise for a full 3 weeks. Consequently we set out to determine the longevity of the participants in the Tour de France, compared with that of the general population. We studied the longevity of 834 cyclists from France (n=465), Italy (n=196) and Belgium (n=173) who rode the Tour de France between the years 1930 and 1964. Dates of birth and death of the cyclists were obtained on December 31 (st) 2007. We calculated the percentage of survivors for each age and compared them with the values for the pooled general population of France, Italy and Belgium for the appropriate age cohorts. We found a very significant increase in average longevity (17%) of the cyclists when compared with the general population. The age at which 50% of the general population died was 73.5 vs. 81.5 years in Tour de France participants. Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners. Our findings underpin the importance of exercising without the fear that becoming exhausted might be bad for one's health.


[Information disclosure and decision making preferences of patients with advanced cancer in a Pain and Palliative Care Unit in Chile].
Information disclosure and decision making process are important steps in advanced cancer patients management; however, there is no research done in this area in Chile. To know the preferences of patients with advanced cancer related to information disclosure and style of decision making process. Prospective observational study with patients in the Palliative Care Unit of Sótero del Río Hospital, in Santiago, Chile. The preferences were evaluated with a Disclosure Information and a Decision Making Preferences Questionnaire. 100 patients were recruited, 52% males, average age 63 years; 90% wanted to receive complete information about diagnosis and 89% complete information about prognosis. The preferences related to decision making process style were: 60% shared, 27% passive and 13% active. The expressed satisfaction with the information received was 89% and 87% with the way decisions were actually made. A majority of patients preferred to receive complete information about diagnosis and prognosis and to make shared decisions. The satisfaction with information disclosure and decision making process was very high. The data of this study supports the need of an adequate information disclosure and of exploring the individual preferences of our patients, with the goal of promoting an informed decision making process that respects the preferences of our patients.


Evolution of gene structure in the conifer Picea glauca: a comparative analysis of the impact of intron size.
A positive relationship between genome size and intron length is observed across eukaryotes including Angiosperms plants, indicating a co-evolution of genome size and gene structure. Conifers have very large genomes and longer introns on average than most plants, but impacts of their large genome and longer introns on gene structure has not be described. Gene structure was analyzed for 35 genes of Picea glauca obtained from BAC sequencing and genome assembly, including comparisons with A. thaliana, P. trichocarpa and Z. mays. We aimed to develop an understanding of impact of long introns on the structure of individual genes. The number and length of exons was well conserved among the species compared but on average, P. glauca introns were longer and genes had four times more intronic sequence than Arabidopsis, and 2 times more than poplar and maize. However, pairwise comparisons of individual genes gave variable results and not all contrasts were statistically significant. Genes generally accumulated one or a few longer introns in species with larger genomes but the position of long introns was variable between plant lineages. In P. glauca, highly expressed genes generally had more intronic sequence than tissue preferential genes. Comparisons with the Pinus taeda BACs and genome scaffolds showed a high conservation for position of long introns and for sequence of short introns. A survey of 1836 P. glauca genes obtained by sequence capture mostly containing introns <1 Kbp showed that repeated sequences were 10× more abundant in introns than in exons. Conifers have large amounts of intronic sequence per gene for seed plants due to the presence of few long introns and repetitive element sequences are ubiquitous in their introns. Results indicate a complex landscape of intron sizes and distribution across taxa and between genes with different expression profiles.