Compressing liquid nanofoam systems: liquid infiltration or nanopore deformation?
Understanding the invasion of a liquid into porous structures is the foundation of the characterization of the porosity-related properties of materials and is also of fundamental importance in the design of porous solid-liquid enabled energy protection systems, yet whether solid pores deform has been unclear so far. Here, we present a competition mechanism between liquid infiltration and cell wall buckling deformation by investigating a liquid nanofoam (LN) system subjected to quasi-static compression. The critical buckling stress of the cell wall and the infiltration pressure of liquid invasion into nanopores are studied and correlated through numerical simulation and experimental validation to reveal the quantitative relationship between nanopore deformation and liquid invasion. The analysis shows that liquid infiltration occurs, independent of the axial buckling stress of the cell wall; in contrast, the nanopore collapses radially when the radial collapse pressure is lower than the pressure of liquid infiltration, preventing the liquid invasion. Comprehensive molecular dynamics (MD) simulations are performed and demonstrate the deformation behavior of nanopores and cell wall-liquid interactions in a broad range. Pressure-induced compression experiments on a silica-based LN system are carried out and validate these theoretical and MD results.


Hamming Distance as a Concept in DNA Molecular Recognition.
DNA microarrays constitute an in vitro example system of a highly crowded molecular recognition environment. Although they are widely applied in many biological applications, some of the basic mechanisms of the hybridization processes of DNA remain poorly understood. On a microarray, cross-hybridization arises from similarities of sequences that may introduce errors during the transmission of information. Experimentally, we determine an appropriate distance, called minimum Hamming distance, in which the sequences of a set differ. By applying an algorithm based on a graph-theoretical method, we find large orthogonal sets of sequences that are sufficiently different not to exhibit any cross-hybridization. To create such a set, we first derive an analytical solution for the number of sequences that include at least four guanines in a row for a given sequence length and eliminate them from the list of candidate sequences. We experimentally confirm the orthogonality of the largest possible set with a size of 23 for the length of 7. We anticipate our work to be a starting point toward the study of signal propagation in highly competitive environments, besides its obvious application in DNA high throughput experiments.


Transport of germ plasm on astral microtubules directs germ cell development in Drosophila.
In many organisms, germ cells are segregated from the soma through the inheritance of the specialized germ plasm, which contains mRNAs and proteins that specify germ cell fate and promote germline development. Whereas germ plasm assembly has been well characterized, mechanisms mediating germ plasm inheritance are poorly understood. In the Drosophila embryo, germ plasm is anchored to the posterior cortex, and nuclei that migrate into this region give rise to the germ cell progenitors, or pole cells. How the germ plasm interacts with these nuclei for pole cell induction and is selectively incorporated into the forming pole cells is not known. Live imaging of two conserved germ plasm components, nanos mRNA and Vasa protein, revealed that germ plasm segregation is a dynamic process involving active transport of germ plasm RNA-protein complexes coordinated with nuclear migration. We show that centrosomes accompanying posterior nuclei induce release of germ plasm from the cortex and recruit these components by dynein-dependent transport on centrosome-nucleated microtubules. As nuclei divide, continued transport on astral microtubules partitions germ plasm to daughter nuclei, leading to its segregation into pole cells. Disruption of these transport events prevents incorporation of germ plasm into pole cells and impairs germ cell development. Our results indicate that active transport of germ plasm is essential for its inheritance and ensures the production of a discrete population of germ cell progenitors endowed with requisite factors for germline development. Transport on astral microtubules may provide a general mechanism for the segregation of cell fate determinants.


A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics.
This literature review was performed to elucidate the relationship between bisphosphonate use and development of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates for the treatment of osteoporosis. MEDLINE, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and EMBASE were searched for English-language articles published from 1966 to September 2006 whose titles included the term osteonecrosis of the jaw in conjunction with bisphosphonates, alendronate, risedronate, ibandronate, etidronate, clodronate, zoledronic acid, or pamidronate. Articles were included in the review if the population consisted of adults with ONJ; patients received bisphosphonates for the treatment of osteoporosis only; the reported data included baseline characteristics of the study population (age; sex; comorbidities; concomitant medications; history of dental surgery, trauma, or infection), characteristics of bisphosphonate treatment (specific bisphosphonate, dose, duration of treatment, mode of administration), clinical features of ONJ (signs, symptoms, site), the treatment protocol used to manage ONJ, or the prevalence of ONJ in patients with osteoporosis treated with bisphosphonates; and the publication involved a case report, case series, or observational study. After application of the search strategy and the inclusion/exclusion criteria, 11 publications reporting 26 cases of ONJ in patients receiving bisphosphonates for the treatment of osteoporosis were included in the review. The most commonly affected site was the mandible (16 patients), followed by the maxilla (6 patients). Among the 23 patients whose age was reported, 18 (78%) were aged >or=60 years. Among the 23 patients whose sex was reported, only 3 (13%) were men. Of 15 patients with a history of invasive dental treatment, 12 (80%) had undergone dental surgery or experienced dental trauma at the site of ONJ. Among the 10 patients for whom the duration of bisphosphonate treatment was reported, no clear relationship between the duration of bisphosphonate treatment and the development of ONJ was observed. Considering that millions of patients have been prescribed bisphosphonates for the treatment of osteoporosis, the relative prevalence of ONJ in these patients was low. Age >or=60 years, female sex, and previous invasive dental treatment were the most common characteristics of those who developed ONJ. However, it is not possible to draw further conclusions about the potential association between oral bisphosphonate use and ONJ in the identified studies because of incomplete reporting and the presence of confounding factors.


Comprehensive identification of novel proteins and N-glycosylation sites in royal jelly.
Royal jelly (RJ) is a proteinaceous secretion produced from the hypopharyngeal and mandibular glands of nurse bees. It plays vital roles in honeybee biology and in the improvement of human health. However, some proteins remain unknown in RJ, and mapping N-glycosylation modification sites on RJ proteins demands further investigation. We used two different liquid chromatography-tandem mass spectrometry techniques, complementary N-glycopeptide enrichment strategies, and bioinformatic approaches to gain a better understanding of novel and glycosylated proteins in RJ. A total of 25 N-glycosylated proteins, carrying 53 N-glycosylation sites, were identified in RJ proteins, of which 42 N-linked glycosylation sites were mapped as novel on RJ proteins. Most of the glycosylated proteins were related to metabolic activities and health improvement. The 13 newly identified proteins were also mainly associated with metabolic processes and health improvement activities. Our in-depth, large-scale mapping of novel glycosylation sites represents a crucial step toward systematically revealing the functionality of N-glycosylated RJ proteins, and is potentially useful for producing a protein with desirable pharmacokinetic and biological activity using a genetic engineering approach. The newly-identified proteins significantly extend the proteome coverage of RJ. These findings contribute vital and new knowledge to our understanding of the innate biochemical nature of RJ at both the proteome and glycoproteome levels.


Whole genome analyses of African G2, G8, G9, and G12 rotavirus strains using sequence-independent amplification and 454® pyrosequencing.
High mortality rates caused by rotaviruses are associated with several strains such as G2, G8, G9, and G12 rotaviruses. Rotaviruses with G9 and G12 genotypes emerged worldwide in the past two decades. G2 and G8 rotaviruses are however also characterized frequently across Africa. To understand the genetic constellation of African G2, G8, G9, and G12 rotavirus strains and their possible origin, sequence-independent cDNA synthesis, amplification, and 454(®) pyrosequencing of the whole genomes of five human African rotavirus strains were performed. RotaC and phylogenetic analysis were used to assign and confirm the genotypes of the strains. Strains RVA/Human-wt/MWI/1473/2001/G8P[4], RVA/Human-wt/ZAF/3203WC/2009/G2P[4], RVA/Human-wt/ZAF/3133WC/2009/G12P[4], RVA/Human-wt/ZAF/3176WC/2009/G12P[6], and RVA/Human-wt/ZAF/GR10924/1999/G9P[6] were assigned G8-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2, G2-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2, G12-P[4]-I1-R1-C1-M1-A1-N1-T1-E1-H1, G12-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1, and G9-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genotypes, respectively. The detection of both Wa- and DS-1-like genotypes in strain RVA/Human-wt/ZAF/3133WC/2009/G12P[4] and Wa-like, DS-1-like and P[6] genotypes in strain RVA/Human-wt/ZAF/GR10924/1999/G9P[6] implies that these two strains were generated through intergenogroup genome reassortment. The close similarity of the genome segments of strain RVA/Human-wt/MWI/1473/2001/G8P[4] to artiodactyl-like, human-bovine reassortant strains and human rotavirus strains suggests that it originated from or shares a common origin with bovine strains. It is therefore possible that this strain might have emerged through interspecies genome reassortment between human and artiodactyl rotaviruses. This study illustrates the swift characterization of all the 11 rotavirus genome segments by using a single set of universal primers for cDNA synthesis followed by 454(®) pyrosequencing and RotaC analysis.


Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial.
Improving the quality of mental health care requires moving clinical interventions from controlled research settings into real-world practice settings. Although such advances have been made for depression, little work has been performed for anxiety disorders. To determine whether a flexible treatment-delivery model for multiple primary care anxiety disorders (panic, generalized anxiety, social anxiety, and posttraumatic stress disorders) would be better than usual care (UC). A randomized controlled effectiveness trial of Coordinated Anxiety Learning and Management (CALM) compared with UC in 17 primary care clinics in 4 US cities. Between June 2006 and April 2008, 1004 patients with anxiety disorders (with or without major depression), aged 18 to 75 years, English- or Spanish-speaking, were enrolled and subsequently received treatment for 3 to 12 months. Blinded follow-up assessments at 6, 12, and 18 months after baseline were completed in October 2009. CALM allowed choice of cognitive behavioral therapy (CBT), medication, or both; included real-time Web-based outcomes monitoring to optimize treatment decisions; and a computer-assisted program to optimize delivery of CBT by nonexpert care managers who also assisted primary care clinicians in promoting adherence and optimizing medications. Twelve-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptoms score. Secondary outcomes included proportion of responders (> or = 50% reduction from pretreatment BSI-12 score) and remitters (total BSI-12 score < 6). A significantly greater improvement for CALM vs UC in global anxiety symptoms was found (BSI-12 group mean differences of -2.49 [95% confidence interval {CI}, -3.59 to -1.40], -2.63 [95% CI, -3.73 to -1.54], and -1.63 [95% CI, -2.73 to -0.53] at 6, 12, and 18 months, respectively). At 12 months, response and remission rates (CALM vs UC) were 63.66% (95% CI, 58.95%-68.37%) vs 44.68% (95% CI, 39.76%-49.59%), and 51.49% (95% CI, 46.60%-56.38%) vs 33.28% (95% CI, 28.62%-37.93%), with a number needed to treat of 5.27 (95% CI, 4.18-7.13) for response and 5.50 (95% CI, 4.32-7.55) for remission. For patients with anxiety disorders treated in primary care clinics, CALM compared with UC resulted in greater improvement in anxiety symptoms, depression symptoms, functional disability, and quality of care during 18 months of follow-up. clinicaltrials.gov Identifier: NCT00347269.


Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression.
We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy.


Thinning of the corpus callosum in older alcoholic men: a magnetic resonance imaging study.
A brain image averaging technique was applied to three-dimensional magnetic resonance images to identify visually detectable brain volume abnormalities in chronically alcoholic men, compared with healthy control men. This technique, which was based on pixel-by-pixel statistical probability mapping, revealed a dramatic reduction in the area of the corpus callosum in older alcoholics (age 45 years or older), relative to age-matched controls. Subsequent analysis used anatomical landmarks to outline the borders of midsagittal sections of the corpus callosum in a larger group of alcoholics and controls, who spanned the adult age range from 23 to 71 years. This analysis revealed significant reduction, most prominent in the genu and body, of total callosal area in the alcoholic group relative to the control group; the results were the same whether raw area measures or head size plus age adjusted measure were analyzed. Significant thinning of the callosal body in alcoholics is usually attributed to the relatively rare, nutritional-deficient condition, Marchiafava-Bignami disease. However, callosal thinning was present in vivo in chronic alcoholics without clinical symptoms of severe liver disease, amnesia, or alcoholic dementia. These data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic-related subsyndromes, such as Marchiafava-Bignami disease.


Evaluation of international case studies within 'Live.Learn.Laugh.': a unique global public-private partnership to promote oral health.
The partnership between the Féderation Dentaire International (FDI), and Unilever Oral Care, aims to raise awareness of oral health globally; to enable FDI member associations to promote oral health; and to increase the visibility of the FDI and authority of Unilever oral care brands worldwide. Country Projects between National Dental Associations (NDAs), the member associations of FDI, and Unilever Oral Care local companies have been established as a key strand of the partnership. This paper reports on the evaluation of an in-depth sample of Country Projects (n=5) to determine their potential to impact on oral health. Five country sites were selected as being indicative of different programme delivery types. Each site received a two-day visit during Spring-Summer 2009, which enabled the evaluators to audit what was delivered in practice compared with the original written project briefs and to undertake interviews of study site staff. 39 projects in 36 countries have been initiated. In those examined by site visits, clear evidence was found of capacity building to deliver oral health. In some countries, widespread population reach had been prioritised. Effectiveness of partnership working varied depending on the strength of the relationship between the NDA and local Unilever Oral Care representatives and alignment with national marketing strategy. The quality of internal evaluation varied considerably. Over a million people had been reached directly by Country Projects and this public-private partnership has made a successful start. To move towards improving oral health rather than only awareness raising; future Country Projects would benefit from being limited to certain evidence-based intervention designs, and using an agreed core indicator set in order to allow cross-country comparison of intervention outcomes.


Food Insecurity amid the COVID-19 Pandemic: Food Charity, Government Assistance, and Employment.
To mitigate the effects of the coronavirus disease 2019 (COVID-19) pandemic, the federal government has implemented several financial assistance programs, including unprecedented funding to food charities. Using the Canadian Perspectives Survey Series 2, we examine the demographic, employment, and behavioural characteristics associated with food insecurity in April-May 2020. We find that one-quarter of job-insecure individuals experienced food insecurity that was strongly associated with pandemic-related disruptions to employment income, major financial hardship, and use of food charity, yet the vast majority of food-insecure households did not report receiving any charitable food assistance. Increased financial support for low-income households would reduce food insecurity and mitigate negative repercussions of the pandemic.


Linking Medicaid Expansion and Cuts to Disproportionate-Share Hospitals: Will Safety Nets Survive?
The predominant mechanism by which the health care reforms of the Patient Protection and Affordable Care Act of 2010 are to be financed is through the government's simultaneous defunding of major portions of Medicare and Medicaid, including the reduction of up to 75% of federal payments to disproportionate-share hospitals. The justification for curtailment of other public programs is that after Medicaid expansion under the Affordable Care Act, the decrease in the proportion of uninsured among the U.S. population will render disproportionate-share hospital payments extraneous and unnecessary. Such justification was reiterated in the recent American College of Obstetricians and Gynecologists Committee Opinion No. 627, entitled Health Care for Unauthorized Immigrants. Herein, the soundness of the Committee Opinion's proposed policy is evaluated by reviewing available literature on the potential effect of Medicaid disproportionate-share hospital cuts with and without concomitant Medicaid expansion. Limitations of Medicaid expansion efforts before and under the Affordable Care Act, the disproportionate-share hospital payment program, and other legislation providing safety net hospitals with (some) relief of financial burdens related to uncompensated care are explicated. Findings raise concern that acceptance of cuts of up to 75% of federal disproportionate-share hospital funds on the premise that nationwide state expansion of Medicaid will offset the difference may be overly optimistic. Indeed, foregoing disproportionate-share hospital payments undercuts the otherwise laudable intent of Committee Opinion No. 627, namely to advocate for universal health care for all women, including undocumented immigrants.


New synthetic approaches towards analogues of bedaquiline.
Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.


Outcome of strict patient selection for surgical treatment of hepatic and pulmonary metastases from colorectal cancer.
Surgery is currently the only potentially curative treatment for hepatic or pulmonary metastases from colorectal cancer. However, the benefit of surgery and the criteria for the inclusion of patients developing hepatic and pulmonary metastases are not well defined. The aim of this study was to describe the outcome for patients who undergo surgery for both hepatic and pulmonary metastases from colorectal cancer, to present a set of preoperative criteria for use in patient selection, and to analyze potential prognostic factors related to survival. This was an observational study with retrospective analysis of data collected with a prospective protocol. This investigation was conducted at a tertiary centre. Between January 1996 and January 2010, of 319 patients who underwent surgery for hepatic metastases from colorectal cancer, 44 also had resection of pulmonary metastases. A set of strict selection criteria established by a panel of liver surgeons, chest surgeons, oncologists, and radiologists was used. Survival was estimated with the Kaplan-Meier method, and univariate analyses were performed to evaluate potential prognostic factors for survival, including variables related to patient, primary tumour, hepatic, and pulmonary metastases and chemotherapy. The 44 patients received a total of 53 pulmonary resections: 36 patients had 1, 7 patients had 2, and 1 patient had 3 resections. There was no postoperative mortality and the morbidity rate after pulmonary resection was 1.8%. No patient was lost to follow-up. Overall survival was 93% at 1 year, 81% at 3 years, and 64% at 5 years. Factors related to poor prognosis in the univariate analysis were presence of more than 1 pulmonary metastasis (p = 0.04), invasion of the surgical margin (p = 0.006), and administration of neoadjuvant chemotherapy (p = 0.01 for hepatic metastases and p = 0.02 for pulmonary metastases). The study was limited by its observational nature and the relatively small number of patients. In patients with hepatic and pulmonary metastases from colorectal cancer selected according to strict inclusion criteria, surgical treatment performed in a specialized center is a safe option that offers prolonged survival.


Sleep duration and psychotic experiences in patients at risk of psychosis: A secondary analysis of the EDIE-2 trial.
Sleep disturbance is common among individuals at risk of psychosis, yet few studies have investigated the relationship between sleep disturbance and clinical trajectory. The Early Detection and Intervention Evaluation (EDIE-2) trial provides longitudinal data on sleep duration and individual psychotic experiences from a cohort of individuals at risk of psychosis, which this study utilises in an opportunistic secondary analysis. Shorter and more variable sleep was hypothesised to be associated with more severe psychotic experiences and lower psychological wellbeing. Mixed effect models were used to test sleep duration and range as predictors of individual psychotic experiences and psychological wellbeing over the 12-24 months (with assessments every 3 months) in 160 participants. Shorter sleep duration was associated with more severe delusional ideas and hallucinations cross-sectionally and longitudinally. The longitudinal relationships did not remain significant after conservative controls were added for the previous severity of psychotic experiences. No significant relationships were found between the sleep variables and other psychotic experiences (e.g. cognitive disorganisation), or psychological wellbeing. The results support a relationship between shorter sleep duration and delusional ideas and hallucinations. Future studies should focus on improving sleep disturbance measurement, and test whether treating sleep improves clinical trajectory in the at-risk group.


A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma.
A pair of isogenic colon carcinoma cells, SW480 and 620, was used to investigate the mechanisms of acquired tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance during tumour progression. Whereas primary tumour SW480 cells are sensitive to TRAIL-induced apoptosis, metastatic SW620 cells are resistant. The apoptotic signalling activated by TRAIL in SW480 cells is a type II pathway. We show that in SW620 cells, although caspase-8 is recruited and activated at the death-inducing-signalling complex and Bid is cleaved, this does not lead to caspase-9 activation. Comparison of Bcl-2, Bcl-xL and Mcl-1 levels in both cell lines showed no difference. In SW620 cells transfected with a tBid-GFP construct, tBid-GFP was correctly localized to the mitochondria. Thus, the resistance of SW620 cells is at the level of the mitochondria that can withstand large amounts of tBid. Although caspase-3 was directly cleaved by caspase-8 in SW620 cells to yield the p20 fragment, no further autocatalytic maturation into the p17 fragment was observed. We show that, in contrast to SW480 cells, the SW620 cell line expresses high amounts of X-linked inhibitor of apoptosis (XIAP). Downregulation of XIAP with bortezomib or small-interfering RNA was sufficient to restore the sensitivity of SW620 cells to TRAIL-induced apoptosis in the absence of SMAC/Diablo or cytochrome c release from the mitochondria. Thus, SW620 cells have developed a dual resistance to TRAIL-induced apoptosis: a block at the level of the mitochondria and, after a conversion to a type I pathway, an increased expression of XIAP which inhibits this pathway.


Nanomaterials for renewable energy production and storage.
Over the past decades, there have been many projections on the future depletion of the fossil fuel reserves on earth as well as the rapid increase in green-house gas emissions. There is clearly an urgent need for the development of renewable energy technologies. On a different frontier, growth and manipulation of materials on the nanometer scale have progressed at a fast pace. Selected recent and significant advances in the development of nanomaterials for renewable energy applications are reviewed here, and special emphases are given to the studies of solar-driven photocatalytic hydrogen production, electricity generation with dye-sensitized solar cells, solid-state hydrogen storage, and electric energy storage with lithium ion rechargeable batteries.


[Relation of binding by metabolism of gamma-aminobutyric acid and various reactions of the Krebs cycle in the rat brain].
The comparison has been made for the following items: intensity of pyruvate alpha-ketoglutarate, succinate oxidation, the gamma-aminobutyric acid (GABA) formation rate, utilization, total content of GABA, glutamate and alanine, the bound/free form ratio of GABA and glutamate, intensity of binding and desorption of exogenic [I-14C]GABA in homogenates of the cortex, cerebellum and brainstem of the Wistar rats. It is revealed that the intensity of ketoacids oxidation is significantly lower in the cerebellum than in the cortex, but the maximal activity of the enzymes of GABA formation and utilization is higher, due to which considerable oxidation of alpha-ketoglutarate transforming into succinate is possible proceeding the GABA shunt pathway. The cortex homogenates contrary to the cerebellum ones are characterized by the reliably higher intensity of ketoacid oxidation and by insignificant contribution of the GABA-shunt to the succinate production. These differences are in line with the reliably higher content of endogenic bound GABA in the cortex as compared to the cerebellum, with a higher level of binding of exogenic labelled GABA and with less pronounced desorption of the label from neurostructures. An assumption is advanced that the observed differences are related to the known high sensitivity of the cortex and to relative resistance of cerebellum to hypoxia and hypoglycemia.


Diffusion-weighted MRI of bone marrow oedema, soft tissue oedema and synovitis in paediatric patients: feasibility and initial experience.
MRI has become the mainstay of diagnostic imaging in paediatric rheumatology for lesion detection, differential diagnosis and therapy surveillance. MR imaging of synovitis, in particular, is indispensable for early diagnosis and follow-up in arthritis patients. We used diffusion-weighted MRI (DWI) as a new imaging modality in comparison to standard MRI sequences to study bone marrow oedema, soft-tissue oedema and synovitis in paediatric patients. A total of 52 patients (mean age 11 ± 5 years) with bone marrow oedema (n = 31), soft-tissue oedema (n = 20) and synovitis (n = 15) were examined with transversal diffusion-weighted single-shot echoplanar imaging in addition to standard MR sequences (T2W TIRM, T1W pre- and post-contrast). Diffusion-weighted images were used for lesion detection and apparent diffusion coefficient (ADC, unit × 10-3 mm2/s) values were measured with ROI technique on ADC maps. In 50 of 52 patients, DWI delineated the lesion of interest corresponding to pathological signal increase on standard sequences. Mean ADC was 1.60 ± 0.14 (range 1.38 - 1.99) in osseous lesions, 1.72 ± 0.31 (range 1.43 - 2.56) in soft tissue oedema and 2.82 ± 0.24 (range 2.47 - 3.18) for joint effusion (ANOVA p < 0.001). No significant difference in mean ADC was seen for inflammatory vs. non-inflammatory lesions. Relative signal intensity of oedema was similar for DWI and T2W TIRM. DWI visualised synovial restricted diffusion with a mean ADC of 2.12 ± 0.45 in 12 of 15 patients with synovitis. Diffusion-weighted MRI reliably visualises osseous and soft tissue oedema, as compared to standard sequences. DWI of synovitis is feasible in large joints and presents a novel approach to contrast-free imaging of synovitis. Whole-body DWI for chronic non-bacterial osteomyelitis should be evaluated in future studies.


Quest for the artificial pancreas: combining technology with treatment.
The various components of the artificial pancreas puzzle are being put into place. Features such as communication, control, modeling, and learning are being realized presently. Steps have been set in motion to carry the conceptual design through simulation to clinical implementation. The challenging pieces still to be addressed include stress and exercise; as integral parts of the ultimate goal, effort has begun to shift toward overcoming the remaining hurdles to the full artificial pancreas. The artificial pancreas is close to becoming a reality, driven by technology, and the expectation that lives will be improved.


Exploring barriers to participation and adoption of telehealth and telecare within the Whole System Demonstrator trial: a qualitative study.
Telehealth (TH) and telecare (TC) interventions are increasingly valued for supporting self-care in ageing populations; however, evaluation studies often report high rates of non-participation that are not well understood. This paper reports from a qualitative study nested within a large randomised controlled trial in the UK: the Whole System Demonstrator (WSD) project. It explores barriers to participation and adoption of TH and TC from the perspective of people who declined to participate or withdrew from the trial. Qualitative semi-structured interviews were conducted with 22 people who declined to participate in the trial following explanations of the intervention (n = 19), or who withdrew from the intervention arm (n = 3). Participants were recruited from the four trial groups (with diabetes, chronic obstructive pulmonary disease, heart failure, or social care needs); and all came from the three trial areas (Cornwall, Kent, east London). Observations of home visits where the trial and interventions were first explained were also conducted by shadowing 8 members of health and social care staff visiting 23 people at home. Field notes were made of observational visits and explored alongside interview transcripts to elicit key themes. Barriers to adoption of TH and TC associated with non-participation and withdrawal from the trial were identified within the following themes: requirements for technical competence and operation of equipment; threats to identity, independence and self-care; expectations and experiences of disruption to services. Respondents held concerns that special skills were needed to operate equipment but these were often based on misunderstandings. Respondents' views were often explained in terms of potential threats to identity associated with positive ageing and self-reliance, and views that interventions could undermine self-care and coping. Finally, participants were reluctant to risk potentially disruptive changes to existing services that were often highly valued. These findings regarding perceptions of potential disruption of interventions to identity and services go beyond more common expectations that concerns about privacy and dislike of technology deter uptake. These insights have implications for health and social care staff indicating that more detailed information and time for discussion could be valuable especially on introduction. It seems especially important for potential recipients to have the opportunity to discuss their expectations and such views might usefully feed back into design and implementation.


Network- and attribute-based classifiers can prioritize genes and pathways for autism spectrum disorders and intellectual disability.
Autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders with significant combined prevalence (∼1%) and high heritability. Dozens of individually rare genes and loci associated with high-risk for ASD have been identified, which overlap extensively with genes for intellectual disability (ID). However, studies indicate that there may be hundreds of genes that remain to be identified. The advent of inexpensive massively parallel nucleotide sequencing can reveal the genetic underpinnings of heritable complex diseases, including ASD and ID. However, whole exome sequencing (WES) and whole genome sequencing (WGS) provides an embarrassment of riches, where many candidate variants emerge. It has been argued that genetic variation for ASD and ID will cluster in genes involved in distinct pathways and protein complexes. For this reason, computational methods that prioritize candidate genes based on additional functional information such as protein-protein interactions or association with specific canonical or empirical pathways, or other attributes, can be useful. In this study we applied several supervised learning approaches to prioritize ASD or ID disease gene candidates based on curated lists of known ASD and ID disease genes. We implemented two network-based classifiers and one attribute-based classifier to show that we can rank and classify known, and predict new, genes for these neurodevelopmental disorders. We also show that ID and ASD share common pathways that perturb an overlapping synaptic regulatory subnetwork. We also show that features relating to neuronal phenotypes in mouse knockouts can help in classifying neurodevelopmental genes. Our methods can be applied broadly to other diseases helping in prioritizing newly identified genetic variation that emerge from disease gene discovery based on WES and WGS.


Sural nerve biopsy: current role and comparison with serum neurofilament light chain levels.
The diagnosis of peripheral neuropathies can be challenging with consequent difficulties in patients' management. The aim of this study was to explore the current diagnostic role of sural nerve biopsy and to compare pathological findings with serum neurofilament light chain levels (NfL) as biomarkers of axonal damage. We collected demographic, clinical, and paraclinical data of patients referred over 1 year to the Neurology Unit, University of Verona, Italy, to perform nerve biopsy for diagnostic purposes, and we analyzed NfL levels in available paired sera using a high sensitive technique (Quanterix, Simoa). Eighty-two patients were identified (37.8% females, median age 65.5 years). Neuropathy onset was frequently insidious (68.3%) with a slowly progressive course (76.8%). Lower limbs were usually involved (81.7%), with a predominance of sensory over motor symptoms (74.4% vs 42.7%). The most common neuropathological findings were a demyelinating pattern (76.8%), clusters of regenerations (58.5%), and unmyelinated fibers involvement on ultrastructural evaluation (52.4%). A definite pathological diagnosis was achieved in 29 cases, and in 20.7% of patients, the referral clinical diagnosis was modified. Coexistent hematological conditions and hepatitis were diagnostic confounding factors (p = 0.012 and 0.034, respectively). In the analyzed paired sera (n = 37), an inverse despite not significant relationship between NfL values and fiber density was observed (Spearman's rho - 0.312, p = 0.056). In addition, we noted increased serum NfL values of patients with active axonal degeneration. Nerve biopsy remains a useful diagnostic investigation to achieve a correct diagnosis and guide patients' management in selected cases of peripheral neuropathy. Serum NfL is an accessible and potential valuable marker of axonal damage in these conditions.


Genetic variation in DROSHA 3'UTR regulated by hsa-miR-27b is associated with bladder cancer risk.
miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk. We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs. We found that rs10719T>C polymorphism located in 3' untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein. Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3'UTR.


Phosphorylation of RCC1 in mitosis is essential for producing a high RanGTP concentration on chromosomes and for spindle assembly in mammalian cells.
Spindle assembly is subject to the regulatory controls of both the cell-cycle machinery and the Ran-signaling pathway. An important question is how the two regulatory pathways communicate with each other to achieve coordinated regulation in mitosis. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. Moreover, phosphorylation of the NLS of RCC1 is required to prevent the binding of importin alpha and beta to RCC1, thereby allowing RCC1 to couple RanGTP production to chromosome binding. These findings reveal that the cell-cycle machinery directly regulates the Ran-signaling pathway by placing a high RanGTP concentration on the mitotic chromosome in mammalian cells.


Therapeutic assessment of mesenchymal stem cells delivered within a PEGylated fibrin gel following an ischemic injury.
The intent of the current study was to investigate the therapeutic contribution of MSCs to vascular regeneration and functional recovery of ischemic tissue. We used a rodent hind limb ischemia model and intramuscularly delivered MSCs within a PEGylated fibrin gel matrix. Within this model, we demonstrated that MSC therapy, when delivered in PEGylated fibrin, results in significantly higher mature blood vessel formation, which allows for greater functional recovery of skeletal muscle tissue as assessed using force production measurements. We observed initial signs of vascular repair at early time points when MSCs were delivered without PEGylated fibrin, but this did not persist or lead to recovery of the tissue in the long-term. Furthermore, animals which were treated with PEGylated fibrin alone exhibited a greater number of mature blood vessels, but they did not arterialize and did not show improvements in force production. These results demonstrate that revascularization of ischemic tissue may be a necessary but not sufficient step to complete functional repair of the injured tissue. This work has implications on stem cell therapies for ischemic diseases and also potentially on how such therapies are evaluated.


Speciation, physical and electrolytic properties of eutectic mixtures based on CrCl₃·6H₂O and urea.
The electrodeposition of chromium is a technologically vital process, which is principally carried out using aqueous chromic acid. In the current study, it is shown that eutectic mixtures of urea and hydrated chromium(III) chloride provide a liquid which reduces the toxicological issues associated with the current aqueous Cr(VI) electroplating solution. Using EXAFS, mass spectrometry and UV-Vis spectroscopy, it is shown that chromium is present predominantly as a cationic species. Conductivities are higher than for most comparable ionic liquids. It is shown that the electrodeposition of chromium is electrochemically reversible, with a current efficiency much higher than in aqueous electrolytes. Surface tension and density measurements indicate that hole theory is a valid model to describe transport properties in these liquids. Bulk Cr deposits are not macrocrystalline but they are generally crack-free. The deposits have a hardness of 600 ± 10 Vickers and, as such, are comparable to deposits from aqueous systems.


Patients Refusing Transcatheter Aortic Valve Replacement Even Once Have Poorer Clinical Outcomes.
Background Although transcatheter aortic valve replacement ( TAVR ) is the least invasive treatment for patients with symptomatic aortic stenosis, some patients hesitate to undergo the procedure. We investigated the clinical impact of treatment delay after patient refusal of TAVR . Methods and Results We used the Japanese OCEAN (Optimized Catheter valvular intervention) regsitry data of 1542 patients who underwent TAVR . Refusal was defined as at least 1 refusal of TAVR at the time of informed consent. Patients were separated into 2 groups: refusal (28/1542, 1.8%) and non-refusal (1514/1542, 98.2%). We compared the baseline characteristics, procedural outcomes, and mortality rates between the groups. Additionally, data on reasons for refusal and those leading to eventually undergoing TAVR were collected. Age, surgical risk scores, and frailty were higher in the refusal group than in the non-refusal group ( P<0.05 for all). Periprocedural complications did not differ between groups, whereas 30-day and cumulative 1-year mortality were significantly higher in the refusal group than in the non-refusal group (7.1% versus 1.3%, P=0.008 and 28.8% versus 10.3%, P=0.010, respectively). Multivariate Cox regression analysis revealed that TAVR refusal was an independent predictor of increased midterm mortality (hazard ratio: 3.37; 95% confidence interval: 1.52-7.48; P=0.003). The most common reason for refusal was fear (13/28, 46.4%), and the most common reason for changing their mind was worsening heart failure (21/28, 75.0%). All patients in the refusal group decided to undergo TAVR within 20 months (median: 5.5 months). Conclusions Refusing TAVR even once led to poorer prognosis; therefore, this fact should be clearly discussed when obtaining informed consent.


Approaching microjoule-level pulse energy with mode-locked femtosecond fiber lasers.
We report on the generation of high-energy ultrashort pulses from a mode-locked Yb-doped large-mode-area fiber laser operating in the all-normal dispersion regime. The self-starting fiber laser emits 9 W of average output power at a pulse repetition rate of 9.7 MHz, corresponding to a pulse energy of 927 nJ. The laser produces positively chirped 8 ps output pulses, which are then compressed down to 711 fs. These compressed pulses exhibit megawatt-level peak powers. To our knowledge, this is the first time that a mode-locked fiber oscillator has generated femtosecond pulses with pulse energies approaching the microjoule level in combination with high average output power. Numerical simulations show excellent agreement with experimental results and reveal further scaling potential, which is discussed.


Cross regulation of sirtuin 1, AMPK, and PPARγ in conjugated linoleic acid treated adipocytes.
Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) reduces triglyceride (TG) levels in adipocytes through multiple pathways, with AMP-activated protein kinase (AMPK) generally facilitating, and peroxisome proliferator-activated receptor γ (PPARγ) generally opposing these reductions. Sirtuin 1 (SIRT1), a histone/protein deacetylase that affects energy homeostasis, often functions coordinately with AMPK, and is capable of binding to PPARγ, thereby inhibiting its activity. This study investigated the role of SIRT1 in the response of 3T3-L1 adipocytes to t10c12 CLA by testing the following hypotheses: 1) SIRT1 is functionally required for robust TG reduction; and 2) SIRT1, AMPK, and PPARγ cross regulate each other. These experiments were performed by using activators, inhibitors, or siRNA knockdowns that affected these pathways in t10c12 CLA-treated 3T3-L1 adipocytes. Inhibition of SIRT1 amounts or activity using siRNA, sirtinol, nicotinamide, or etomoxir attenuated the amount of TG loss, while SIRT1 activator SRT1720 increased the TG loss. SRT1720 increased AMPK activity while sirtuin-specific inhibitors decreased AMPK activity. Reciprocally, an AMPK inhibitor reduced SIRT1 activity. Treatment with t10c12 CLA increased PPARγ phosphorylation in an AMPK-dependent manner and increased the amount of PPARγ bound to SIRT1. Reciprocally, a PPARγ agonist attenuated AMPK and SIRT1 activity levels. These results indicated SIRT1 increased TG loss and that cross regulation between SIRT1, AMPK, and PPARγ occurred in 3T3-L1 adipocytes treated with t10c12 CLA.


Results From India's 2016 Report Card on Physical Activity for Children and Youth.
Physical inactivity in children and youth in India is a major public health problem. The 2016 Indian Report Card on Physical Activity for Children and Youth has been conceptualized to highlight this epidemic by appraising behaviors, contexts, strategies, and investments related to physical activity of Indian children and youth. An international research collaboration resulted in the formation of a Research Working Group (RWG). RWG determined key indicators; identified, synthesized, and analyzed existing evidence; developed criteria for assigning grades; and, finally, assigned grades to indicators based on consensus. Overall Physical Activity Levels were assigned a grade of C-. Active Transportation and Sedentary Behaviors were both assigned a grade of C. Government Strategies and Investments was assigned a grade of D. Six other indicators, including the country-specific indicator Physical Fitness, were graded as INC (incomplete) due to the lack of nationally representative evidence. Based on existing evidence, it appears that most Indian children do not achieve recommended levels of physical activity and spend most of their day in sedentary pursuits. The report card identifies gaps in both investments and research that need to be addressed before understanding the complete picture of active living in children and youth in India.


CMV infection of the renal allograft is much more common than the pathology indicates: a retrospective analysis of qualitative and quantitative buffy coat CMV-PCR, renal biopsy pathology and tissue CMV-PCR.
Quantitative blood polymerase chain reaction (PCR) for cytomegalovirus (CMV) is used to direct therapy in kidney transplant patients, but cytomegalic inclusions are rarely found in allograft renal biopsies even with an elevated serum creatinine and apparent CMV disease. The relationship between quantitative blood CMV and renal allograft pathology is unknown. Thirteen biopsy samples were available for analysis from patients suspected of CMV disease, who had a buffy coat CMV-PCR drawn within 2-5 days of a renal allograft biopsy for an elevated creatinine. All were evaluated for CMV pathologically, by light microscopy, immunohistochemistry, in situ hybridization and tissue PCR. Qualitative and quantitative buffy coat CMV-PCR were positive in 10/13 (77%) patients. Tissue CMV-PCR was positive in five (50%) biopsies, including two with CMV inclusions and three with no inclusions. Quantitative buffy coat CMV-PCR levels did not correlate with detection of CMV inclusions in renal tissue. Paradoxically, quantitative buffy coat CMV-PCR was low (239 and 538 copies/microg of DNA) when CMV inclusions were detected. All five biopsies with acute rejection were associated with CMV viraemia and two of the five with allograft CMV inclusions. A quantitative buffy coat CMV-PCR of <100 copies/microg of DNA ruled out disease with CMV inclusions. CMV nephropathy is much more common than previously reported when sensitive techniques are used for detection in tissue. Acute rejection and CMV viraemia occur commonly together in patients at risk for CMV. Quantitative buffy coat CMV-PCR does not correlate with the presence of CMV inclusions. These findings have implications for management of patients who have elevated serum creatinine and are at risk for CMV disease.


Hysteresis in the force-calcium relation in muscle.
Calcium ions activate muscle contraction. The mechanism depends on the calcium sensitivity of the proteins that regulate contraction. Evidence is presented for the reverse phenomenon, where contraction modulates calcium sensitivity. Increasing the force level increased calcium sensitivity in intact fibers showing that the relation between force and calcium is not unique. A particular calcium concentration can maintain a higher force level than it can create. The results were confirmed in skinned fiber experiments. Transient reduction of the force led to a transient reduction in calcium binding, suggesting a simple mechanism for the hysteresis.


A time-series study of sick building syndrome: chronic, biotoxin-associated illness from exposure to water-damaged buildings.
The human health risk for chronic illnesses involving multiple body systems following inhalation exposure to the indoor environments of water-damaged buildings (WDBs) has remained poorly characterized and the subject of intense controversy. The current study assessed the hypothesis that exposure to the indoor environments of WDBs with visible microbial colonization was associated with illness. The study used a cross-sectional design with assessments at five time points, and the interventions of cholestyramine (CSM) therapy, exposure avoidance following therapy, and reexposure to the buildings after illness resolution. The methodological approach included oral administration of questionnaires, medical examinations, laboratory analyses, pulmonary function testing, and measurements of visual function. Of the 21 study volunteers, 19 completed assessment at each of the five time points. Data at Time Point 1 indicated multiple symptoms involving at least four organ systems in all study participants, a restrictive respiratory condition in four participants, and abnormally low visual contrast sensitivity (VCS) in 18 participants. Serum leptin levels were abnormally high and alpha melanocyte stimulating hormone (MSH) levels were abnormally low. Assessments at Time Point 2, following 2 weeks of CSM therapy, indicated a highly significant improvement in health status. Improvement was maintained at Time Point 3, which followed exposure avoidance without therapy. Reexposure to the WDBs resulted in illness reacquisition in all participants within 1 to 7 days. Following another round of CSM therapy, assessments at Time Point 5 indicated a highly significant improvement in health status. The group-mean number of symptoms decreased from 14.9+/-0.8 S.E.M. at Time Point 1 to 1.2+/-0.3 S.E.M., and the VCS deficit of approximately 50% at Time Point 1 was fully resolved. Leptin and MSH levels showed statistically significant improvement. The results indicated that CSM was an effective therapeutic agent, that VCS was a sensitive and specific indicator of neurologic function, and that illness involved systemic and hypothalamic processes. Although the results supported the general hypothesis that illness was associated with exposure to the WDBs, this conclusion was tempered by several study limitations. Exposure to specific agents was not demonstrated, study participants were not randomly selected, and double-blinding procedures were not used. Additional human and animal studies are needed to confirm this conclusion, investigate the role of complex mixtures of bacteria, fungi, mycotoxins, endotoxins, and antigens in illness causation, and characterize modes of action. Such data will improve the assessment of human health risk from chronic exposure to WDBs.


Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs.
An analog of pyrazinamide (PZA), 5-chloropyrazinamide (5-Cl-PZA), has previously been shown to inhibit mycobacterial fatty acid synthase I (FASI). FASI has been purified from a recombinant strain of M. smegmatis (M. smegmatis Deltafas1 attB::M. tuberculosis fas1). Following purification, FASI activity and inhibition were assessed spectrophotometrically by monitoring NADPH oxidation. The observed inhibition was both concentration and structure dependent, being affected by both substitution at the 5 position of the pyrazine nucleus and the nature of the ester or N-alkyl group. Under the conditions studied, both 5-Cl-PZA and PZA exhibited concentration and substrate dependence consistent with competitive inhibition of FASI with K(i)s of 55 to 59 microM and 2,567 to 2,627 microM, respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. This assay showed that FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs.


Alanine-scanning mutations in the "primer grip" of p66 HIV-1 reverse transcriptase result in selective loss of RNA priming activity.
Alanine-scanning mutants of the primer grip region of human immunodeficiency virus type 1 reverse transcriptase were tested for their ability to extend RNA and DNA versions of the polypurine tract primer, and an oligonucleotide representing the 18-nucleotide sequence at the 3' end of tRNALys3. A majority of the mutant enzymes were either completely or severely deficient in RNA priming activity, but, with only one exception, were able to efficiently extend DNA versions of the same primers. The mutant enzymes were able to bind to RNA primers, indicating that the defect in RNA priming was not simply a loss of binding activity. Mutations at positions 229, 233, and 235 dramatically reduced the amount of specific RNase H cleavage at the 3' terminus of the polypurine tract, which is required for primer removal. An alanine substitution at position 232 led to loss of cleavage specificity, although total activity was close to the wild-type level. Taken together, these results demonstrate for the first time that there are residues in human immunodeficiency virus type 1 reverse transcriptase which are specifically involved in protein-nucleic acid interactions with RNA primers.


A new method to quantify prey acquisition in diving seabirds using wing stroke frequency.
To understand the foraging strategies of free-ranging diving animals, time series information on both foraging effort and foraging success is essential. Theory suggests that wing stroke frequency for aerial flight should be higher in heavier birds. Based on this premise, we developed a new methodology using animal-borne accelerometers to estimate fine-scale temporal changes in body mass of a pursuit-diving, piscivorous seabird, the European shag, Phalacrocorax aristotelis. We hypothesized that variations in body mass determined from changes in wing stroke frequency before and after a series of dives would be related to the amount of prey captured. The estimated net gain in body mass during a foraging trip was highly variable, ranging from -30 to 260 g, values that were extremely similar to food loads obtained from shags on the Isle of May in previous years using water-offloading and nest balances. Load sizes estimated using the wing stroke method were strongly and positively related to both cumulative flight time and return flight time. At the trip level, load size was unrelated to cumulative dive bout duration and the total amount of time spent underwater. However, highly significant relationships were apparent at the individual bout level, with birds showing bigger mass gains following longer dive bouts. Results from this study are therefore extremely encouraging and suggest that changes in body mass determined from changes in wing stroke frequency may provide a reliable method of obtaining short- to medium-term information on foraging effort and success of diving seabirds.


Effects of potential partners' physical attractiveness and socioeconomic status on sexuality and partner selection.
Male (n = 170) and female (n = 212) college students viewed photographs, which had been prerated for physical attractiveness, of three opposite-sex individuals. These photographs were paired with three levels of occupational status and income. Subjects indicated their willingness to engage in relationships of varying levels of sexual intimacy and marital potential with the portrayed individuals. Analyses of variance, correlations, and trend analyses supported the hypotheses. Compared to men, women are more likely to prefer or insist that sexual intercourse occur in relationships that involve affection and marital potential, and women place more emphasis than men do on partners' SES in such relationships. Consequently, men's SES and their willingness and ability to invest affection and resources in relationships may often outweigh the effects of their physical attractiveness in women's actual selection of partners. These results and the literature reviewed are more consistent with parental investment theory than with the view that these sex differences are solely the result of differential access to resources and differential socialization.


Balanced genetic diversity improves population fitness.
Although genetic diversity within a population is suggested to improve population-level fitness and productivity, the existence of these effects is controversial because empirical evidence for an ecological effect of genetic diversity and the underlying mechanisms is scarce and incomplete. Here, we show that the natural single-gene behavioural polymorphism (Rover and sitter) in Drosophila melanogaster has a positive effect on population fitness. Our simple numerical model predicted that the fitness of a polymorphic population would be higher than that expected with two monomorphic populations, but only under balancing selection. Moreover, this positive diversity effect of genetic polymorphism was attributable to a complementarity effect, rather than to a selection effect. Our empirical tests using the behavioural polymorphism in D. melanogaster clearly supported the model predictions. These results provide direct evidence for an ecological effect of genetic diversity on population fitness and its condition dependence.


Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.
Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Merck KGaA (Darmstadt, Germany).


Paying more for faster care? Individuals' attitude toward price-based priority access in health care.
Increased competition in the health care sector has led hospitals and other health care institutions to experiment with new access allocation policies that move away from traditional expert based allocation of care to price-based priority access (i.e., the option to pay more for faster care). To date, little is known about individuals' attitude toward price-based priority access and the evaluation process underlying this attitude. This paper addresses the role of individuals' evaluations of collective health outcomes as an important driver of their attitude toward (price-based) allocation policies in health care. The authors investigate how individuals evaluate price-based priority access by means of scenario-based survey data collected in a representative sample from the Dutch population (N = 1464). They find that (a) offering individuals the opportunity to pay for faster care negatively affects their evaluations of both the total and distributional collective health outcome achieved, (b) however, when health care supply is not restricted (i.e., when treatment can be offered outside versus within the regular working hours of the hospital) offering price-based priority access affects total collective health outcome evaluations positively instead of negatively, but it does not change distributional collective health outcome evaluations. Furthermore, (c) the type of health care treatment (i.e., life saving liver transplantation treatment vs. life improving cosmetic ear correction treatment - priced at the same level to the individual) moderates the effect of collective health outcome evaluations on individuals' attitude toward allocation policies. For policy makers and hospital managers the results presented in this article are helpful because they provide a better understanding of what drives individuals' preferences for health care allocation policies. In particular, the results show that policies based on the "paying more for faster care" principle are more attractive to the general public when treatment takes place outside the regular working hours of a hospital.


Use of the Internet for Sexual Health Among Sexually Experienced Persons Aged 16 to 44 Years: Evidence from a Nationally Representative Survey of the British Population.
Those who go online regarding their sexual health are potential users of new Internet-based sexual health interventions. Understanding the size and characteristics of this population is important in informing intervention design and delivery. We aimed to estimate the prevalence in Britain of recent use of the Internet for key sexual health reasons (for chlamydia testing, human immunodeficiency virus [HIV] testing, sexually transmitted infection [STI] treatment, condoms/contraceptives, and help/advice with one's sex life) and to identify associated sociodemographic and behavioral factors. Complex survey analysis of data from 8926 sexually experienced persons aged 16-44 years in a 2010-2012 probability survey of Britain's resident population. Prevalence of recent (past year) use of Internet sources for key sexual health reasons was estimated. Factors associated with use of information/support websites were identified using logistic regression to calculate age-adjusted odds ratios (AORs). Recent Internet use for chlamydia/HIV testing or STI treatment (combined) was very low (men: 0.31%; women: 0.16%), whereas 2.35% of men and 0.51% of women reported obtaining condoms/contraceptives online. Additionally, 4.49% of men and 4.57% of women reported recent use of information/support websites for advice/help with their sex lives. Prevalence declined with age (men 16-24 years: 7.7%; 35-44 years: 1.84%, P<.001; women 16-24 years: 7.8%; 35-44 years: 1.84%, P<.001). Use of information/support websites was strongly associated with men's higher socioeconomic status (managerial/professional vs semiroutine/routine: AOR 1.93, 95% CI 1.27-2.93, P<.001). Despite no overall association with area-level deprivation, those in densely populated urban areas were more likely to report use of information/support websites than those living in rural areas (men: AOR 3.38, 95% CI 1.68-6.77, P<.001; women: AOR 2.51, 95% CI 1.34-4.70, P<.001). No statistically significant association was observed with number of sex partners reported after age adjustment, but use was more common among men reporting same-sex partners (last 5 years: AOR 2.44, 95% CI 1.27-4.70), women reporting sex with multiple partners without condoms (last year: AOR 1.90, 95% CI 1.11-3.26), and, among both sexes, reporting seeking sex online (last year, men: AOR 1.80, 95% CI 1.16-2.79; women: AOR 3.00, 95% CI 1.76-5.13). No association was observed with reporting STI diagnosis/es (last 5 years) or (after age adjustment) recent use of any STI service or non-Internet sexual health seeking. A minority in Britain used the Internet for the sexual health reasons examined. Use of information/support websites was reported by those at greater STI risk, including younger people, indicating that demand for online STI services, and Internet-based sexual health interventions in general, may increase over time in this and subsequent cohorts. However, the impact on health inequalities needs addressing during design and evaluation of online sexual health interventions so that they maximize public health benefit.


The Impact of Preexposure Prophylaxis Among Men Who Have Sex With Men: An Individual-Based Model.
Preexposure prophylaxis (PrEP) is recommended for preventing HIV infection among individuals at high risk, including men who have sex with men (MSM). Although its individual-level efficacy is proven, questions remain regarding population-level impact of PrEP implementation. We developed an agent-based simulation of HIV transmission among MSM, accounting for demographics, sexual contact network, HIV disease stage, and use of antiretroviral therapy. We use this framework to compare PrEP delivery strategies in terms of impact on HIV incidence and prevalence. The projected reduction in HIV incidence achievable with PrEP reflects both population-level coverage and individual-level adherence (as a proportion of days protected against HIV transmission). For example, provision of PrEP to 40% of HIV-negative MSM reporting more than one sexual partner in the last 12 months, taken with sufficient adherence to provide protection on 40% of days, can reduce HIV incidence by 9.5% (95% uncertainty range: 8%-11%) within 5 years. However, if this could be increased to 80% coverage on 80% of days (eg, through mass campaigns with a long-acting injectable formulation), a 43% (42%-44%) reduction in HIV incidence could be achieved. Delivering PrEP to MSM at high risk for HIV acquisition can augment population-level impact up to 1.8-fold. If highly ambitious targets for coverage and adherence can be achieved, PrEP can substantially reduce HIV incidence in the short-term. Although the reduction in HIV incidence largely reflects the proportion of person-years protected, the efficiency of PrEP delivery can be enhanced by targeting high-risk populations.


A selfish genetic element influencing longevity correlates with reactive behavioural traits in female house mice (Mus domesticus).
According to theory in life-history and animal personality, individuals with high fitness expectations should be risk-averse, while individuals with low fitness expectations should be more bold. In female house mice, a selfish genetic element, the t haplotype, is associated with increased longevity under natural conditions, representing an appropriate case study to investigate this recent theory empirically. Following theory, females heterozygous for the t haplotype (+/t) are hypothesised to express more reactive personality traits and be more shy, less explorative and less active compared to the shorter-lived homozygous wildtype females (+/+). As males of different haplotype do not differ in survival, no similar pattern is expected. We tested these predictions by quantifying boldness, exploration, activity, and energetic intake in both +/t and +/+ mice. +/t females, unlike +/+ ones, expressed some reactive-like personality traits: +/t females were less active, less prone to form an exploratory routine and tended to ingest less food. Taken together these results suggest that differences in animal personality may contribute to the survival advantage observed in +/t females but fail to provide full empirical support for recent theory.


Short report: use of the polymerase chain reaction to detect Paracoccidioides brasiliensis in murine paracoccidioidomycosis.
The polymerase chain reaction (PCR) was used to detect the presence of Paracoccidioides brasiliensis in a murine model of disseminated paracoccidioidomycosis. Using a previously identified P. brasiliensis-specific DNA sequence, P. brasiliensis DNA was detected in serum of five experimentally infected mice. The PCR method was able to detect as little as 10 pg of P. brasiliensis DNA in serum, and it was more sensitive than blood culture isolation (five of five were PCR positive versus two of five blood culture positive). There were no amplified fragments in serum from three noninfected control mice. Lung colony counts were similar in all infected mice and reflected a similar degree of P. brasiliensis infection at the time the samples were drawn. The relatively short processing time for the PCR, when compared with culture, its sensitivity, and the possibility of using serum samples for analysis, are important factors favoring this method for the diagnosis of paracoccidioidomycosis. Future studies should include the detection of P. brasiliensis in patients with different clinical forms of paracoccidioidomycosis.


Parasitic infections in asymptomatic homosexual men: cost-effective screening.
The purpose of this study was to develop a cost-effective strategy for screening for enteric protozoan infections in homosexual men without gastrointestinal symptoms suggesting infection. One hundred and one homosexual men in Portland, Oregon, each submitted at least one unpurged stool sample; 91% submitted three samples each. Of these, 27% had Entamoeba histolytica, 61% had nonpathogenic protozoa with or without E. histolytica, 36% had a nonpathogen alone, and 3% had Giardia lamblia. Protozoan infection was highly associated with the practice of anilingus (p less than 0.005). Infection with E. histolytica correlated significantly with the presence of nonpathogenic protozoa (p less than 0.005). The following screening strategy was judged to be the most cost-effective: examine one sample first; if E. histolytica is found or if the sample is negative, no further investigation is required; if a nonpathogen is found, one additional sample should be obtained. This strategy had a sensitivity for E. histolytica of 85% and a cost of $136 per case detected.


Impact of COVID-19 lockdown on emergency asthma admissions and deaths: national interrupted time series analyses for Scotland and Wales.
The COVID-19 pandemic's impact on people with asthma is poorly understood. We hypothesised that lockdown restrictions were associated with reductions in severe asthma exacerbations requiring emergency asthma admissions and/or leading to death. Using data from Public Health Scotland and the Secure Anonymised Information Linkage Databank in Wales, we compared weekly counts of emergency admissions and deaths due to asthma over the first 18 weeks in 2020 with the national averages over 2015-2019. We modelled the impact of instigating lockdown on these outcomes using interrupted time-series analysis. Using fixed-effect meta-analysis, we derived pooled estimates of the overall changes in trends across the two nations. We also investigated trends in asthma-related primary care prescribing and emergency department (ED) attendances in Wales. Lockdown was associated with a 36% pooled reduction in emergency admissions for asthma (incidence rate ratio, IRR: 0.64, 95% CI: 0.49 to 0.83, p value 0.001) across both countries. There was no significant change in asthma deaths (pooled IRR: 0.57, 95% CI: 0.17 to 1.94, p value 0.37). ED asthma attendances in Wales declined during lockdown (IRR: 0.85, 95% CI: 0.73 to 0.99, p value 0.03). A large spike of 121% more inhaled corticosteroids and 133% more oral corticosteroid prescriptions was seen in Wales in the week before lockdown. National lockdowns were associated with substantial reductions in severe asthma exacerbations leading to hospital admission across both Scotland and Wales, with no corresponding increase in asthma deaths.


Determinants of Physical Activity Maintenance in Breast Cancer Survivors After a Community-Based Intervention.
To determine whether empirically selected and social cognitive theory-based factors, including baseline characteristics and modifiable behavioral and psychosocial factors, were determinants of physical activity (PA) maintenance in breast cancer survivors (BCSs) six months after a PA intervention. . Single-group longitudinal study. . The Breast Health Centre in Winnipeg, Manitoba, Canada. . 42 survivors with stage 0-III breast cancer who completed chemotherapy and/or radiation therapy. . The community-based PA intervention included six weekly education and practice sessions on home-based aerobic, resistance, balance, and flexibility exercises. . The dependent variable, PA maintenance, was determined based on PA level measurement at six months postintervention. The independent variables of baseline characteristics (age, stage of cancer, and chronic musculoskeletal symptoms) and modifiable behavioral and psychosocial factors (PA level, fatigue, PA self-efficacy in overcoming barriers and performing tasks) were assessed at baseline and postintervention. . Multivariate regression analyses revealed that baseline fatigue and chronic musculoskeletal symptoms were the only factors significantly associated with PA maintenance. . Baseline fatigue level and chronic musculoskeletal symptoms were significant determinants of PA maintenance in breast cancer survivors who had completed a community-based PA intervention. However, other key factors were considered. . Prior to participation in community-based PA interventions, clinicians should take into account the effects of high baseline fatigue levels and chronic musculoskeletal symptoms on potential PA maintenance, and consider additional assessments and support for BCSs to sustain their PA behavioral change. .


Role of Fas and Treg cells in fracture healing as characterized in the fas-deficient (lpr) mouse model of lupus.
Previous studies showed that loss of tumor necrosis factor α (TNFα) signaling delayed fracture healing by delaying chondrocyte apoptosis and cartilage resorption. Mechanistic studies showed that TNFα induced Fas expression within chondrocytes; however, the degree to which chondrocyte apoptosis is mediated by TNFα alone or dependent on the induction of Fas is unclear. This question was addressed by assessing fracture healing in Fas-deficient B6.MRL/Fas(lpr) /J mice. Loss of Fas delayed cartilage resorption but also lowered bone fraction in the calluses. The reduced bone fraction was related to elevated rates of coupled bone turnover in the B6.MRL/Fas(lpr) /J calluses, as evidenced by higher osteoclast numbers and increased osteogenesis. Analysis of the apoptotic marker caspase 3 showed fewer positive chondrocytes and osteoclasts in calluses of B6.MRL/Fas(lpr) /J mice. To determine if an active autoimmune state contributed to increased bone turnover, the levels of activated T cells and Treg cells were assessed. B6.MRL/Fas(lpr) /J mice had elevated Treg cells in both spleens and bones of B6.MRL/Fas(lpr) /J but decreased percentage of activated T cells in bone tissues. Fracture led to ∼30% to 60% systemic increase in Treg cells in both wild-type and B6.MRL/Fas(lpr) /J bone tissues during the period of cartilage formation and resorption but either decreased (wild type) or left unchanged (B6.MRL/Fas(lpr) /J) the numbers of activated T cells in bone. These results show that an active autoimmune state is inhibited during the period of cartilage resorption and suggest that iTreg cells play a functional role in this process. These data show that loss of Fas activity specifically in chondrocytes prolonged the life span of chondrocytes and that Fas synergized with TNFα signaling to mediate chondrocyte apoptosis. Conversely, loss of Fas systemically led to increased osteoclast numbers during later periods of fracture healing and increased osteogenesis. These findings suggest that retention of viable chondrocytes locally inhibits osteoclast activity or matrix proteolysis during cartilage resorption.


Psychophysical differences in processing of global motion and form detection and position discrimination.
In models of complex motion processing of expanding, contracting or rotating patterns, localization of the center of motion is regarded as an implicit function of the system, used for heading determination and achieved by coarse population encoding. The situation modeled contains an optic flow pattern that is modified by including translational motion, as occurs when the observer is not looking directly at their heading, and relies on global processing of the entire optic flow field. Our psychophysics experiments show that accurately localizing the center of a symmetrical complex motion pattern, or an analogous complex radial or concentric form pattern, relies on local processing near the center of the pattern. This contrasts with detection of the same patterns, which involves considerable spatial summation, relies on global processing, and is very tolerant of noisy stimuli. Coarse localization uses both central and peripheral information, involving some spatial summation. Some differences are seen between different pattern types. The low level of spatial summation seen in position discrimination is surprising if position discrimination is seen as an implicit function of the global processing system, and suggests modifications may be needed to models of heading determination.


Ageing as a mindset: a study protocol to rejuvenate older adults with a counterclockwise psychological intervention.
Although ageing is generally perceived as a biologically determined process, the literature increasingly points to the importance of psychological factors in the ageing process, specifically age-related stereotypes or cognitive mindsets. Such stereotypes reflect self-perceptions and others' perceptions about the ageing process and can have a strong influence on health and life satisfaction, specifically through self-fulfilling prophecy mechanisms. This study aimed to investigate whether changes in mindsets can change the ageing process. This study replicates in large part the original 1979 'Counterclockwise' experiment by Ellen Langer and will involve a group of older adults (aged 75+) taking part of a 1-week retreat outside of Milan, Italy. Participants will be instructed and helped to relive their younger selves, acting as if they are living in the year 1989. The week-long residential programme is designed to prime this perception by incorporating a completely retrofitted physical environment, as well as providing opportunities to engage in social activities that would have been common in the late 1980s. This 'counterclockwise' intervention will be tested as a randomised control trial comprised of the experimental ('counterclockwise') group, an active control group (same activities, no time manipulation) and a no-treatment group. Ninety participants will be randomly allocated to one of these three conditions. Every participant will be assessed for medical, cognitive, psychological and age appearance at four time points: at the time of recruitment, after the intervention (ie, after a week for the no-treatment group) and again after 6 and 12 months. The study has been approved by the Ethics Committees of the Department of Psychology of Università Cattolica del Sacro Cuore and Don Gnocchi Foundation. Results will be disseminated through peer-reviewed journals, scientific meetings and direct presentation to the general population. NCT03552042; Pre-results.


Single-cell analyses of regulatory network perturbations using enhancer-targeting TALEs suggest novel roles for PU.1 during haematopoietic specification.
Transcription factors (TFs) act within wider regulatory networks to control cell identity and fate. Numerous TFs, including Scl (Tal1) and PU.1 (Spi1), are known regulators of developmental and adult haematopoiesis, but how they act within wider TF networks is still poorly understood. Transcription activator-like effectors (TALEs) are a novel class of genetic tool based on the modular DNA-binding domains of Xanthomonas TAL proteins, which enable DNA sequence-specific targeting and the manipulation of endogenous gene expression. Here, we report TALEs engineered to target the PU.1-14kb and Scl+40kb transcriptional enhancers as efficient new tools to perturb the expression of these key haematopoietic TFs. We confirmed the efficiency of these TALEs at the single-cell level using high-throughput RT-qPCR, which also allowed us to assess the consequences of both PU.1 activation and repression on wider TF networks during developmental haematopoiesis. Combined with comprehensive cellular assays, these experiments uncovered novel roles for PU.1 during early haematopoietic specification. Finally, transgenic mouse studies confirmed that the PU.1-14kb element is active at sites of definitive haematopoiesis in vivo and PU.1 is detectable in haemogenic endothelium and early committing blood cells. We therefore establish TALEs as powerful new tools to study the functionality of transcriptional networks that control developmental processes such as early haematopoiesis.


Anti-tumour activity of flavone acetic acid (NSC 347512) in mice--influence of immune status.
Flavone acetic acid (FAA) is a synthetic flavonoid with dramatic pre-clinical anti-tumour activity involving a vascular component in its mechanism but no clinical effects have been seen to date. As FAA also has immunomodulatory activity, immunological factors might explain differences in activity between mouse and man. This study examines the influence of host immune status on the anti-tumour activity of FAA. Two human colon tumour xenografts (COBA, HT-29) fail to respond to FAA in nude mice. The lack of activity of FAA against HT-29 xenografts cannot be explained on the basis of limited drug bioavailability as achievable plasma, and tumour levels of FAA are similar to those seen in sensitive murine colon tumours. The immune status of the host also influences the activity of FAA against two transplantable tumours of the mouse colon. Both these tumours are highly responsive to FAA in their normal NMRI hosts, but neither tumours exhibited significant growth delay in thymectomised NMRI or nude hosts. Histological examination of treated tumours revealed significant areas of haemorrhagic necrosis in all three hosts. These data suggest a clear immunological component in the mechanism of action of FAA which is separate from the previously described haemorrhagic necrosis.


The validity of the diagnostic code for hidradenitis suppurativa in an electronic database.
Electronic claims and medical record databases are important sources of information for medical research. However, potential sources of error and bias, including inaccurate diagnoses, incomplete data, incorrect data entry and misclassification bias, necessitate studies that assess the validity of these databases. To assess the validity of the diagnostic code for hidradenitis suppurativa (HS), which is an increasingly studied disease. In this retrospective study, the medical records of 1168 patients in the Massachusetts General Hospital database who had received at least two International Classification of Diseases, Ninth Revision 705·83 codes were manually screened. Of the screened patients, 1046 (89·6%) were confirmed as having HS. The mean age ± SD was 44·0 ± 15·7 years, the median age was 43·0 years and 748 (71·5%) were female. The majority were white (66·7%), while a significant minority were black (13·9%) or Hispanic (13·4%). An increasing number of codes and specific terms used to describe HS in the medical record, including 'hydradenitis', 'boil', 'draining', 'abscess', 'fistula', 'cyst' and 'nodule', could be used to improve the positive predictive value of the search. Our results highlight the importance of establishing the validity of diagnostic codes in electronic databases, and allow for refinements of appropriate ways to design future searches. Given the potential for misclassification of patients with HS, establishing the validity of diagnostic codes and search strategies in electronic databases represents a crucial step for subsequent studies utilizing these databases.


A Computational Approach for the Assessment of Executive Functions in Patients with Obsessive-Compulsive Disorder.
Previous studies on obsessive-compulsive disorder (OCD) showed impairments in executive domains, particularly in cognitive inhibition. In this perspective, the use of virtual reality showed huge potential in the assessment of executive functions; however, unfortunately, to date, no study on the assessment of these patients took advantage of the use of virtual environments. One of the main problems faced within assessment protocols is the use of a limited number of variables and tools when tailoring a personalized program. The main aim of this study was to provide a heuristic decision tree for the future development of tailored assessment protocols. To this purpose, we conducted a study that involved 58 participants (29 OCD patients and 29 controls) to collect both classic neuropsychological data and precise data based on a validated protocol in virtual reality for the assessment of executive functions, namely, the VMET (virtual multiple errands test). In order to provide clear indications for working on executive functions with these patients, we carried out a cross-validation based on three learning algorithms and computationally defined two decision trees. We found that, by using three neuropsychological tests and two VMET scores, it was possible to discriminate OCD patients from controls, opening a novel scenario for future assessment protocols based on virtual reality and computational techniques.


Critical care monitoring for cerebrovascular disease.
Frequent or continuous monitoring of crucial variables in patients with cerebrovascular disease allows the intensive care team to identify progression of the pathophysiologic mechanisms involved, intervene to halt or reverse this progression, and identify the response to treatment in order to modify the intervention if necessary. Central nervous system physiologic monitoring modalities include: a) the clinically-apparent function, b) physical and mechanical variables, c) circulation or perfusion, d) bioelectrical measures, and e) biochemical measures. The neurologic examination of the critically ill patient is an indispensable monitoring tool in the ICU. Patterns of neurologic signs and the trend of the examination, whether worsening or improving, are the most important factors to follow because there is no single sign or symptom which forecasts impending disaster. Intracranial pressure monitoring is applicable to all subsets of cerebrovascular disease, providing information about cerebral perfusion pressure and risk of secondary cerebral injury. Cerebral blood flow is not easily quantified in the ICU, but transcranial Doppler sonography is a reliable bedside technique that can be used for intermittent or continuous monitoring. Neurophysiologic monitoring with electroencephalography (EEG) and evoked potential (EP) testing can be used as a supplement to the neurologic exam and other diagnostic studies. EEG and EP can provide an early indication of clinically relevant change due to evolving disease or in response to therapy, which is especially helpful when the neurologic examination is limited due to severe coma, therapeutic barbiturate coma, or neuromuscular blockade. Neurometabolic monitoring in cerebrovascular disease with microdialysis is a promising technique that may be able to identify markers of cellular energy state or excitotoxicity in carefully selected areas of the brain.


Patient-Reported Outcomes in Athletes Following Hip Arthroscopy for Femoroacetabular Impingement With Subanalysis on Return to Sport and Performance Level: A Systematic Review.
To identify present trends in demographics, surgical indications, preoperative findings, and surgical treatment of athletes undergoing hip arthroscopy for femoroacetabular impingement and (2) to investigate the outcomes in this patient population, including patient-reported outcome scores (PROS), return-to-sport, complications, and reoperation data at minimum 2-year follow-up in the athletic population. Cochrane, Embase, and PubMed databases were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to distinguish articles that reported PROS after hip arthroscopy in athletes. Athletes were defined as anyone who played a sport for minimum 2 years at any level. The standardized mean difference was calculated to compare the effect size of hip arthroscopy on various PROS. Eighteen studies, with 904 athlete hips and a collective study period of January 1993 to April 2017, were included in this systematic review. Across all studies, the mean age and body mass index ranged from 15.7-36.7 years and 20.3-26.3, respectively. The follow-up range was 24-240 months. Mean preoperative alpha angle ranged from 57.7° to 80.0°. Athletes most commonly underwent femoroplasty and labral management. At latest follow-up, the modified Harris Hip Score were excellent in 6 studies (range, 92.1-98), good in 10 studies (range, 84.2-88.5), and fair in 1 study (77.1). Each studies' individual athletic cohort showed significant improvement on the modified Harris Hip Score, Nonarthritic Hip Score, the Hip Outcome Score-Activities of Daily Living, the Hip Outcome Score-Sport-Specific Subscale, visual analog scale for pain, and International Hip Outcome Tool at latest follow-up (P < .05). The return-to-sport rate ranged from 72.7% to 100%, with 74.2-100% of these athletes returning to preinjury or greater level. Athletes undergoing arthroscopic hip surgery in the setting of femoroacetabular impingement, not only exhibit significant functional improvement, but also have a high rate of return to sport at the same or greater competition level compared with preinjury level. IV, systematic review of Level III and IV studies.


Selected C8 two-chain linkers enhance the adenosine A1/A2A receptor affinity and selectivity of caffeine.
Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker (1e A1Ki = 1.52 μM) displayed the highest affinity for the A1 adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A2AKi = 1.33 μM) linker the best A2A adenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A1 adenosine receptor selectivity over the benzyloxy linker and, by introducing a para-chloro substituent, A2A adenosine receptor selectivity was obtained. Selected compounds (1c, 1e) behaved as A1 adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A1 and A2A adenosine receptor antagonists that may have potential for treating neurological disorders.


Proteomic analysis of tendon extracellular matrix reveals disease stage-specific fragmentation and differential cleavage of COMP (cartilage oligomeric matrix protein).
During inflammatory processes the extracellular matrix (ECM) is extensively remodeled, and many of the constituent components are released as proteolytically cleaved fragments. These degradative processes are better documented for inflammatory joint diseases than tendinopathy even though the pathogenesis has many similarities. The aims of this study were to investigate the proteomic composition of injured tendons during early and late disease stages to identify disease-specific cleavage patterns of the ECM protein cartilage oligomeric matrix protein (COMP). In addition to characterizing fragments released in naturally occurring disease, we hypothesized that stimulation of tendon explants with proinflammatory mediators in vitro would induce fragments of COMP analogous to natural disease. Therefore, normal tendon explants were stimulated with IL-1β and prostaglandin E2, and their effects on the release of COMP and its cleavage patterns were characterized. Analyses of injured tendons identified an altered proteomic composition of the ECM at all stages post injury, showing protein fragments that were specific to disease stage. IL-1β enhanced the proteolytic cleavage and release of COMP from tendon explants, whereas PGE2 had no catabolic effect. Of the cleavage fragments identified in early stage tendon disease, two fragments were generated by an IL-1-mediated mechanism. These fragments provide a platform for the development of neo-epitope assays specific to injury stage for tendon disease.