Adherence as therapeutic citizenship: impact of the history of access to antiretroviral drugs on adherence to treatment.
A dramatic increase in the use of antiretroviral drugs in Africa has increased focus on adherence to treatment, which has so far been equivalent if not superior to that in northern contexts. The reasons for this exceptional adherence are poorly understood. In this paper, we examine adherence in the historical and ethnographic context of access to treatment in Burkina Faso, Côte d'Ivoire and Mali. Living where there is no social security and minimal, if any, medical care, individuals diagnosed with HIV are faced with the threat of illness, death, ostracism and destitution, and were obliged to negotiate conflicting networks of obligation, reciprocity, and value. HIV and AIDS programmes value efforts to address social, and indeed biological, vulnerability. In contrast, kinship-based social relationships may value individuals in other ways. These conflicting moral economies often intersect in the worlds of people living with HIV. HIV status can be used to claim resources from the public or non-governmental organization programmes. This may interfere with social networks that are the most stable source of material and emotional support. Self-help and empowerment techniques provided effective tools for people living with HIV to fashion themselves into effective advocates. In the early years of the use of antiretroviral therapy (ART), access to treatment was thus mediated by confessional practices and forms of social triage. We introduce the term 'therapeutic citizenship' to describe the way in which people living with HIV appropriate ART as a set of rights and responsibilities to negotiate these at times conflicting moral economies. Exemplary adherence should be viewed through the lens of therapeutic citizenship.


Miller Fisher syndrome: a diagnosis not to be missed.
We report a case of Miller Fisher syndrome presenting in an ENT setting. The referral was made on the basis of worsening nasal regurgitation following Campylobacter jejuni enteritis. The aim of this report is not to add to the recorded instances of Miller Fisher syndrome, but to help raise the level of its awareness amongst otolaryngologists. Emphasis is placed on the mode of presentation and management issues, as early diagnosis is crucial and confers a favourable prognosis. In that respect, we consider this case noteworthy and instructive.


The roles of the C-terminal domain and type III domains of chitinase A1 from Bacillus circulans WL-12 in chitin degradation.
The mature form of chitinase A1 from Bacillus circulans WL-12 comprises a C-terminal domain, two type III modules (domains), and a large N-terminal domain which contains the catalytic site of the enzyme. In order to better define the roles of these chitinase domains in chitin degradation, modified chiA genes encoding various deletions of chitinase A1 were constructed. The modified chiA genes were expressed in Escherichia coli, and the gene products were analyzed after purification by high-performance liquid chromatography. Intact chitinase A1 specifically bound to chitin, while it did not show significant binding activity towards partially acetylated chitosan and other insoluble polysaccharides. Chitinases lacking the C-terminal domain lost much of this binding activity to chitin as well as colloidal chitin-hydrolyzing activity. Deletion of the type III domains, on the other hand, did not affect chitin-binding activity but did result in significantly decreased colloidal chitin-hydrolyzing activity. Hydrolysis of low-molecular-weight substrates, soluble high-molecular-weight substrates, and insoluble high-molecular-weight substrates to which chitinase A1 does not bind were not significantly affected by these deletions. Thus, it was concluded that the C-terminal domain is a chitin-binding domain required for the specific binding to chitin and that this chitin-binding activity is important for efficient hydrolysis of the sufficiently acetylated chitin. Type III modules are not directly involved in the chitin binding but play an important functional role in the hydrolysis of chitin by the enzyme bound to chitin.


A Dissolved Oxygen Threshold for Shifts in Bacterial Community Structure in a Seasonally Hypoxic Estuary.
Pelagic ecosystems can become depleted of dissolved oxygen as a result of both natural processes and anthropogenic effects. As dissolved oxygen concentration decreases, energy shifts from macrofauna to microorganisms, which persist in these hypoxic zones. Oxygen-limited regions are rapidly expanding globally; however, patterns of microbial communities associated with dissolved oxygen gradients are not yet well understood. To assess the effects of decreasing dissolved oxygen on bacteria, we examined shifts in bacterial community structure over space and time in Hood Canal, Washington, USA-a glacial fjord-like water body that experiences seasonal low dissolved oxygen levels known to be detrimental to fish and other marine organisms. We found a strong negative association between bacterial richness and dissolved oxygen. Bacterial community composition across all samples was also strongly associated with the dissolved oxygen gradient, and significant changes in bacterial community composition occurred at a dissolved oxygen concentration between 5.18 and 7.12 mg O2 L(-1). This threshold value of dissolved oxygen is higher than classic definitions of hypoxia (<2.0 mg O2 L(-1)), suggesting that changes in bacterial communities may precede the detrimental effects on ecologically and economically important macrofauna. Furthermore, bacterial taxa responsible for driving whole community changes across the oxygen gradient are commonly detected in other oxygen-stressed ecosystems, suggesting that the patterns we uncovered in Hood Canal may be relevant in other low oxygen ecosystems.


Patient Perspectives on Outcome Domains of Medication Adherence Trials in Inflammatory Arthritis: An International OMERACT Focus Group Study.
To describe the perspectives of patients with inflammatory arthritis (IA) on outcome domains of trials evaluating medication adherence interventions. Adult patients (≥ 18 yrs) with IA taking disease-modifying antirheumatic drugs from centers across Australia, Canada, and the Netherlands participated in 6 focus groups to discuss outcome domains that they consider important when participating in medication adherence trials. We analyzed the transcripts using inductive thematic analysis. Of the 38 participants, 23 (61%) had rheumatoid arthritis and 21 (55%) were female. The mean age was 57.3 ± (SD 15.0) years. Improved outcome domains that patients wanted from participating in an adherence trial were categorized into 5 types: medication adherence, adherence-related factors (supporting adherence; e.g., medication knowledge), pathophysiology (e.g., physical functioning), life impact (e.g., ability to work), and economic impact (e.g., productivity loss). Three overarching themes reflecting why these outcome domains matter to patients were identified: how taking medications could improve patients' emotional and physical fitness to maintain their social function; how improving knowledge and confidence in self-management increases patients' trust and motivation to take medications as agreed with minimal risk of harms; and how respect and reassurance, reflecting health care that values patients' opinions and is sensitive to patients' individual goals, could improve medication-taking behavior. Patients value various outcome domains related to their overall well-being, confidence in medication use, and patient-healthcare provider relationships to be evaluated in future adherence trials.


Segmentation of clustered nuclei based on concave curve expansion.
Segmentation of nuclei from images of tissue sections is important for many biological and biomedical studies. Many existing image segmentation algorithms may lead to oversegmentation or undersegmentation for clustered nuclei images. In this paper, we proposed a new image segmentation algorithm based on concave curve expansion to correctly and accurately extract markers from the original images. Marker-controlled watershed is then used to segment the clustered nuclei. The algorithm was tested on both synthetic and real images and better results are achieved compared with some other state-of-the-art methods.


Hospital Magnet Status, Unit Work Environment, and Pressure Ulcers.
To identify how organizational nursing factors at different structural levels (i.e., unit-level work environment and hospital Magnet status) are associated with hospital-acquired pressure ulcers (HAPUs) in U.S. acute care hospitals. A cross-sectional observational study used data from the National Database of Nursing Quality Indicators®. Responses from 33,845 registered nurses (RNs) were used to measure unit work environments. The unit of analysis was the nursing unit, and there were 1,381 units in 373 hospitals in the United States. Unit work environment was measured by the Practice Environment Scale of Nurse Working Index (PES-NWI). Multilevel logistic regressions were used to estimate the effects of unit work environment and hospital Magnet status on HAPUs. All models were controlled for hospital and unit characteristics when considering clustering of units within hospitals. Magnet hospital units had 21% lower odds of having an HAPU than non-Magnet hospital units (95% confidence interval [CI], 0.64-0.98). With one unit increase of the PES-NWI score, units had 29% lower odds of having an HAPU (95% CI, 0.55-0.91). When including both hospital Magnet status and unit work environment in the model, hospital Magnet status no longer had a significant effect on HAPUs (odds ratio [OR] = 0.82; 95% CI, 0.66-1.02), whereas the significant effect of unit work environment persisted (OR = 0.73; 95% CI, 0.56-0.93). Both hospital and unit environments were significantly associated with HAPUs, and the unit-level work environment can be more influential in reducing HAPUs. Investment in the nurse work environments at both the hospital level and unit level has the potential to reduce HAPUs; and additional to hospital-level initiatives (e.g., Magnet recognition program), efforts targeting on-unit work environments deserve more attention.


The international forum of ophthalmic simulation: developing a virtual reality training curriculum for ophthalmology.
To investigate the effect of a structured, supervised, cataract simulation programme on ophthalmic surgeons in their first year of training, and to evaluate the level of skill transfer. Trainees with minimal intraocular and simulator experience in their first year of ophthalmology undertook a structured, sequential, customised, virtual reality (VR) cataract training programme developed through the International Forum of Ophthalmic Simulation. A set of one-handed, bimanual, static and dynamic tasks were evaluated before and after the course and scores obtained. Statistical significance was evaluated with the Wilcoxon sign-rank test. The median precourse score of 101.50/400 (IQR 58.75-145.75) was significantly improved after completing the training programme ((postcourse score: 302/400, range: 266.25-343), p<0.001). While improvement was evident and found to be statistically significant in all parameters, greatest improvements were found for capsulorhexis and antitremor training ((Capsulorhexis: precourse score=0/100, range 0-4.5; postcourse score=81/100, range 13-87.75; p=0.002), (antitremor training: precourse score=0/100, range 0-0; postcourse score=80/100, range 60.25-91.50; p=0.001)). Structured and supervised VR training can offer a significant level of skills transfer to novice ophthalmic surgeons. VR training at the earliest stage of ophthalmic surgical training may, therefore, be of benefit.


A psychovisual quality metric in free-energy principle.
In this paper, we propose a new psychovisual quality metric of images based on recent developments in brain theory and neuroscience, particularly the free-energy principle. The perception and understanding of an image is modeled as an active inference process, in which the brain tries to explain the scene using an internal generative model. The psychovisual quality is thus closely related to how accurately visual sensory data can be explained by the generative model, and the upper bound of the discrepancy between the image signal and its best internal description is given by the free energy of the cognition process. Therefore, the perceptual quality of an image can be quantified using the free energy. Constructively, we develop a reduced-reference free-energy-based distortion metric (FEDM) and a no-reference free-energy-based quality metric (NFEQM). The FEDM and the NFEQM are nearly invariant to many global systematic deviations in geometry and illumination that hardly affect visual quality, for which existing image quality metrics wrongly predict severe quality degradation. Although with very limited or even without information on the reference image, the FEDM and the NFEQM are highly competitive compared with the full-reference SSIM image quality metric on images in the popular LIVE database. Moreover, FEDM and NFEQM can measure correctly the visual quality of some model-based image processing algorithms, for which the competing metrics often contradict with viewers' opinions.


Effects of temperature and gas-liquid mass transfer on the operation of small electrochemical cells for the quantitative evaluation of CO2 reduction electrocatalysts.
In the last few years, there has been increased interest in electrochemical CO2 reduction (CO2R). Many experimental studies employ a membrane separated, electrochemical cell with a mini H-cell geometry to characterize CO2R catalysts in aqueous solution. This type of electrochemical cell is a mini-chemical reactor and it is important to monitor the reaction conditions within the reactor to ensure that they are constant throughout the study. We show that operating cells with high catalyst surface area to electrolyte volume ratios (S/V) at high current densities can have subtle consequences due to the complexity of the physical phenomena taking place on electrode surfaces during CO2R, particularly as they relate to the cell temperature and bulk electrolyte CO2 concentration. Both effects were evaluated quantitatively in high S/V cells using Cu electrodes and a bicarbonate buffer electrolyte. Electrolyte temperature is a function of the current/total voltage passed through the cell and the cell geometry. Even at a very high current density, 20 mA cm-2, the temperature increase was less than 4 °C and a decrease of <10% in the dissolved CO2 concentration is predicted. In contrast, limits on the CO2 gas-liquid mass transfer into the cells produce much larger effects. By using the pH in the cell to measure the CO2 concentration, significant undersaturation of CO2 is observed in the bulk electrolyte, even at more modest current densities of 10 mA cm-2. Undersaturation of CO2 produces large changes in the faradaic efficiency observed on Cu electrodes, with H2 production becoming increasingly favored. We show that the size of the CO2 bubbles being introduced into the cell is critical for maintaining the equilibrium CO2 concentration in the electrolyte, and we have designed a high S/V cell that is able to maintain the near-equilibrium CO2 concentration at current densities up to 15 mA cm-2.


1-(4-Meth-oxy-phen-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone.
In the title compound, C(11)H(11)N(3)O(2), the dihedral angle between the central ethanone fragment and the 4-meth-oxy-phenyl group is 2.9 (2)°, while that between the ethanone fragment and the triazole ring is 83.4 (2)°. The dihedral angle between the planes of the triazole and benzene rings is 81.7 (1)°. The 4-meth-oxy-phenyl group is cis with respect to the ethanone fragment O atom across the exocyclic C-C bond. In the crystal, mol-ecules are linked by C-H⋯N inter-actions into C(9) chains along [001].


Infants with congenital nephrotic syndrome have comparable outcomes to infants with other renal diseases.
Children with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children. We conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS. Eighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6 months, 30 (68%) by 1 year, and 40 (91%) by 2 years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n = 5) or peritonitis (n = 4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6 months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months. Infants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data.


Whether to Waive Parental Permission in HIV Prevention Research Among Adolescents: Ethical and Legal Considerations.
Critical ethical questions arise concerning whether studies among adolescents of new behavioral and biomedical HIV preventive interventions such as Pre-Exposure Prophylaxis (PrEP) should obtain parental permission. This paper examines the relevant regulations and ethical guidance concerning waivers of parental permission, and arguments for and against such waivers. Opponents of such waivers may argue that adolescent decision-making is "too immature" and that parents always have rights to decide how to protect their children. Yet requiring parental permission may put adolescents at risk, and/or limit adolescent participation, jeopardizing study findings' validity. This paper presents recommendations on when researchers and Institutional Review Boards (IRB) should waive parental permission, and what special protections should be adopted for adolescents who consent for themselves, e.g., assuring adolescent privacy and confidentiality, screening for capacity to consent, and identifying adolescents who are at elevated risk from study participation. We also present a series of specific areas for future research to design tools to help make these assessments, and to inform researcher and IRB decisions. These recommendations can help ensure that research is conducted that can aid adolescents at risk for HIV, while minimizing risks and protecting these individuals' rights as much as possible.


Parents' experiences of universal screening for haemoglobin disorders: implications for practice in a new genetics era.
England is the only country in the world that currently has universal population screening for haemoglobin disorders through linked antenatal and newborn screening. Little is known about the acceptability of such screening. To explore parents' experiences of, and attitudes towards, new universal genetic screening for haemoglobin disorders. Narrative interview study. Primary and community care settings across England. Narrative interviews were undertaken with a maximum variation sample of 39 people who had experienced gene-carrier identification through antenatal and newborn screening for sickle cell, thalassaemia, and other haemoglobin variants within the previous 2 years. Most parents were unaware screening had occurred or had given it little consideration and so were surprised or shocked by results. However, they were glad to learn of their carrier status, reproductive genetic risk, or their newborn's carrier status. Participants emphasised that antenatal screening should happen as early as possible. Many would rather have known their carrier status before pregnancy or before entering a relationship. Although most were satisfied with the information they received, significant misunderstandings remained. There were culturally diverse attitudes towards prenatal diagnosis and termination. These procedures were acceptable to some parents with strong religious beliefs, including Christians and Muslims. Parents support screening for haemoglobin disorders but need to be better informed and better prepared for results and what they mean. Sensitivity to patient diversity in attitudes and choices is also required. Universal screening for genetic reproductive risk will increasingly involve generalists, particularly in primary care, presenting opportunities for screening before or earlier in pregnancy, which is likely to be welcomed by patients.


HIV-1 Mutation and Recombination Rates Are Different in Macrophages and T-cells.
High rates of mutation and recombination help human immunodeficiency virus (HIV) to evade the immune system and develop resistance to antiretroviral therapy. Macrophages and T-cells are the natural target cells of HIV-1 infection. A consensus has not been reached as to whether HIV replication results in differential recombination between primary T-cells and macrophages. Here, we used HIV with silent mutation markers along with next generation sequencing to compare the mutation and the recombination rates of HIV directly in T lymphocytes and macrophages. We observed a more than four-fold higher recombination rate of HIV in macrophages compared to T-cells (p < 0.001) and demonstrated that this difference is not due to different reliance on C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 5 (CCR5) co-receptors between T-cells and macrophages. We also found that the pattern of recombination across the HIV genome (hot and cold spots) remains constant between T-cells and macrophages despite a three-fold increase in the overall recombination rate. This indicates that the difference in rates is a general feature of HIV DNA synthesis during macrophage infection. In contrast to HIV recombination, we found that T-cells have a 30% higher mutation rate than macrophages (p < 0.001) and that the mutational profile is similar between these cell types. Unexpectedly, we found no association between mutation and recombination in macrophages, in contrast to T-cells. Our data highlights some of the fundamental difference of HIV recombination and mutation amongst these two major target cells of infection. Understanding these differences will provide invaluable insights toward HIV evolution and how the virus evades immune surveillance and anti-retroviral therapeutics.


Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.
Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.


A simple error classification system for understanding sources of error in automatic speech recognition and human transcription.
To (1) discover the types of errors most commonly found in clinical notes that are generated either using automatic speech recognition (ASR) or via human transcription and (2) to develop efficient rules for classifying these errors based on the categories found in (1). The purpose of classifying errors into categories is to understand the underlying processes that generate these errors, so that measures can be taken to improve these processes. We integrated the Dragon NaturallySpeaking v4.0 speech recognition engine into the Regenstrief Medical Record System. We captured the text output of the speech engine prior to error correction by the speaker. We also acquired a set of human transcribed but uncorrected notes for comparison. We then attempted to error correct these notes based on looking at the context alone. Initially, three domain experts independently examined 104 ASR notes (containing 29,144 words) generated by a single speaker and 44 human transcribed notes (containing 14,199 words) generated by multiple speakers for errors. Collaborative group sessions were subsequently held where error categorizes were determined and rules developed and incrementally refined for systematically examining the notes and classifying errors. We found that the errors could be classified into nine categories: (1) announciation errors occurring due to speaker mispronounciation, (2) dictionary errors resulting from missing terms, (3) suffix errors caused by misrecognition of appropriate tenses of a word, (4) added words, (5) deleted words, (6) homonym errors resulting from substitution of a phonetically identical word, (7) spelling errors, (8) nonsense errors, words/phrases whose meaning could not be appreciated by examining just the context, and (9) critical errors, words/phrases where a reader of a note could potentially misunderstand the concept that was related by the speaker. A simple method is presented for examining errors in transcribed documents and classifying these errors into meaningful and useful categories. Such a classification can potentially help pinpoint sources of such errors so that measures (such as better training of the speaker and improved dictionary and language modeling) can be taken to optimize the error rates.


Which Child with Asthma is a Candidate for Biological Therapies?
In asthmatic adults, monoclonals directed against Type 2 airway inflammation have led to major improvements in quality of life, reductions in asthma attacks and less need for oral corticosteroids. The paediatric evidence base has lagged behind. All monoclonals currently available for children are anti-eosinophilic, directed against the T helper (TH2) pathway. However, in children and in low and middle income settings, eosinophils may have important beneficial immunological actions. Furthermore, there is evidence that paediatric severe asthma may not be TH2 driven, phenotypes may be less stable than in adults, and adult biomarkers may be less useful. Children being evaluated for biologicals should undergo a protocolised assessment, because most paediatric asthma can be controlled with low dose inhaled corticosteroid if taken properly and regularly. For those with severe therapy resistant asthma, and refractory asthma which cannot be addressed, the two options if they have TH2 inflammation are omalizumab and mepolizumab. There is good evidence of efficacy for omalizumab, particularly in those with multiple asthma attacks, but only paediatric safety, not efficacy, data for mepolizumab. There is an urgent need for efficacy data in children, as well as data on biomarkers to guide therapy, if the right children are to be treated with these powerful new therapies.


Microsatellite instability and expression of MLH1 and MSH2 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members.
Mismatch repair deficiency is a characteristic molecular finding in hereditary nonpolyposis colorectal cancer (HNPCC), and has been demonstrated in both colorectal cancers and benign adenomas. Endometrial and ovarian cancers are common extracolonic tumors in this syndrome; however, few studies have investigated whether genetic changes occur in histologically normal endometrial and ovarian epithelia from HNPCC family members. If early genetic changes exist, they might be used as molecular markers to detect susceptibility to endometrial and ovarian cancers. In this study, we analyzed microsatellite instability (MSI) and MLH1 and MSH2 immunohistochemical expression in 20 histologically normal epithelia (12 endometrial and 8 ovarian) and 8 cancers (4 endometrial and 4 ovarian) obtained from 20 individuals representing 7 unrelated HNPCC families. While MSI was observed in endometrial (75%) and ovarian (100%) cancers, no case was determined to exhibit MSI in histologically normal epithelia of the endometrium or ovary. Similarly, in immunohistochemical expressions for MLH1 and MSH2, histologically normal epithelia had no genetic changes predisposing to malignancy. In cancer cases, a correlation existed between the expression of MLH1 and MSH2, the presence of germline mutations in the hMLH1 and hMSH2 genes, and the presence of tumor MSI. These data suggest that MSI and MLH1 and MSH2 expression are not useful biomarkers for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers. Further studies of other genetic changes in normal and premalignant precursor lesions are needed.


Does enhanced information at cancer genetic counseling improve counselees' knowledge, risk perception, satisfaction and negotiation of information to at-risk relatives?--a randomized study.
The aim of the present randomized intervention study was to investigate the effect of receiving extended cancer genetic information on counselees' knowledge, risk perception, information sharing and satisfaction with the service. In total, 147 counselees, affected by cancer and/or a family history of cancer, were randomized to extended or standard information. The levels of counselees' knowledge and personal risk estimations were measured at four time points. In addition, counselees' satisfaction with the counseling and sharing of the information to at-risk relatives was assessed. The intervention included meeting a specialist nurse, learning the breaking bad news method, receiving written material and video-taped counseling sessions. A significant increase in the level of knowledge in participants in the "breast cancer group" regardless of the randomization was observed over time. The correct estimation of personal risk increased significantly in both groups after two weeks, but declined at the eight month follow-up. Most of the participants had informed at-risk relatives about their visit at the cancer genetic clinic. The majority of respondents in both groups were highly satisfied with the counseling. The only observed effects of the intervention were that counselees in the intervention group were significantly more satisfied with the content of the given information and with the way of informing relatives. Apparently, the current genetic counseling is managed properly and extended information does not seem necessary in all cases. However, some counselees need additional sessions.


Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight.
The angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) is known as a regulator of peripheral lipid and glucose metabolism. In the present study, we investigated the physiological role of Angptl4 in central regulation of body weight homeostasis. Hypothalamic Angptl4 expression levels were measured using immunoblot assay during feeding manipulation or after administration of leptin, insulin, and nutrients. The effects of Angptl4 on food intake, body weight, and energy expenditure were determined following intracerebroventricular (ICV) administration of Angptl4 in C57BL/6 mice. Food intake, energy metabolism, and feeding responses to leptin, insulin, and nutrients were compared between Angptl4-null mice and their wild littermates. Finally, the relationship of hypothalamic AMP-activated protein kinase (AMPK) and Angptl4 was studied. Hypothalamic Angptl4 expression levels were increased upon food intake or administration of leptin, insulin, and nutrients. Furthermore, central administration of Angptl4 suppressed food intake and body weight gain but enhanced energy expenditure. These effects were mediated via suppression of hypothalamic AMPK activities. Consistently, Angptl4-null mice displayed increased body weight and hypothalamic AMPK activity but reduced energy expenditure. Food intake following a fast was significantly greater in Angptl4-null mice, which was normalized by centrally administered Angptl4. Moreover, anorectic responses to leptin, insulin, and glucose were diminished in Angptl4-null mice. In contrast, Angptl4-null mice were resistant to diet-induced obesity, indicating obesity-promoting effects of Angptl4 under the condition of fat-enriched diet. We have demonstrated that hypothalamic Angptl4 is regulated by physiological appetite regulators and mediates their anorexigenic effects via inhibition of hypothalamic AMPK activity. Therefore, Angptl4 appears to have an important role in central regulation of energy metabolism.


Response of renal lesions during systemic treatment with sunitinib in patients with metastatic renal cell carcinoma: a single center experience with 14 patients.
The tyrosine kinase inhibitor (TKI) sunitinib induces partial remissions (PR) in a substantial proportion of patients with metastatic renal cell carcinoma (mRCC). Only little is known about the activity of sunitinib in renal lesions in patients with metastatic disease, as most patients with synchronous metastases receive palliative nephrectomy. Fourteen patients with clear cell mRCC with renal lesions and sunitinib therapy (50 mg OD, 4/2 scheme) were retrieved retrospectively from clinic records. Tumor assessment consisted of CT scans at least every two cycles, analyzed according to RECIST. In 5 of 14 patients, renal tumors were considered as the primary tumor, while the remaining patients had kidney metastases. In total, 65 target lesions were evaluated. The median progression-free survival (PFS) of sunitinib was 8.7 months (range: 2.7-40.2). Median overall survival (OS) from initiation of TKI therapy was 26 months (range: 3-55). Best response according to RECIST consisted of partial remission (PR) in 4 patients, stable disease (SD) in 7 patients, a complete remission (CR) in 1 patient, and 2 patients with progressive disease (PD). Analyzing the response of renal lesions only, 1 patient had PD, 8 patients had SD, 4 patients had PR, and 1 had a CR. Palliative nephrectomy was performed after two courses of sunitinib in 2 patients. In our cohort, similar responses of renal tumors and peripheral metastases were achieved with sunitinib treatment. Our results support the use of sunitinib to control renal tumor lesions in metastatic patients.


The determination of morphine in urine and oral fluid following ingestion of poppy seeds.
In workplace drug-testing programs, the use of heroin, morphine, and codeine is currently determined by the analysis of urine specimens. It has been shown that ingestion of poppy seeds can cause a positive test result for morphine. In an attempt to differentiate positive results caused by poppy seed ingestion from those caused by heroin or morphine abuse, the screening cutoff concentration for urine opiates in the federal workplace drug-testing program was raised to 2000 ng/mL from 300 ng/mL. Currently, oral fluid is under consideration as a possible alternative to urine for drug testing. The suggested cutoff for oral fluid morphine is 40 ng/mL; however, the effect of poppy seed ingestion on morphine concentrations in this specimen type has not been widely investigated. Volunteers at two separate sites ingested commercially available poppy seeds and/or poppy seed bagels. Oral fluid and urine samples were collected at both sites. Oral fluid samples were collected for 24 h; urine was collected for 2 days. The samples were analyzed for the presence of codeine and morphine using gas chromatography-mass spectrometry. Morphine concentrations greater than the suggested cutoff concentrations were detected in oral fluid up to 1 h and in urine for up to 8 h. This study has demonstrated that a positive result for morphine in oral fluid may be due to the ingestion of poppy seeds.


FAP-1: a protein tyrosine phosphatase that associates with Fas.
Fas is a cell surface receptor that controls a poorly understood signal transduction pathway that leads to cell death by means of apoptosis. A protein tyrosine phosphatase, FAP-1, capable of interacting with the cytosolic domain of Fas, was identified. The carboxyl terminal 15 amino acids of Fas are necessary and sufficient for interaction with FAP-1. FAP-1 expression is highest in tissues and cell lines that are relatively resistant to Fas-mediated cytotoxicity. Gene transfer-mediated elevations in FAP-1 partially abolished Fas-induced apoptosis in a T cell line. These findings are consistent with an inhibitory effect of FAP-1 on Fas signal transduction.


Distinct roles of the repeat-containing regions and effector domains of the Vibrio vulnificus multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin.
Vibrio vulnificus is a seafood-borne pathogen that destroys the intestinal epithelium, leading to rapid bacterial dissemination and death. The most important virulence factor is the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin comprised of effector domains in the center region flanked by long repeat-containing regions which are well conserved among MARTX toxins and predicted to translocate effector domains. Here, we examined the role of the repeat-containing regions using a modified V. vulnificus MARTX (MARTX(Vv)) toxin generated by replacing all the internal effector domains with β-lactamase (Bla). Bla activity was detected in secretions from the bacterium and also in the cytosol of intoxicated epithelial cells. The modified MARTX(Vv) toxin without effector domains retained its necrotic activity but lost its cell-rounding activity. Further, deletion of the carboxyl-terminal repeat-containing region blocked toxin secretion from the bacterium. Deletion of the amino-terminal repeat-containing region had no effect on secretion but completely abolished translocation and necrosis. Neither secretion nor translocation was affected by enzymatically inactivating the cysteine protease domain of the toxin. These data demonstrate that the amino-terminal and carboxyl-terminal repeat-containing regions of the MARTXVv toxin are necessary and sufficient for the delivery of effector domains and epithelial cell lysis in vitro but that effector domains are required for other cytopathic functions. Furthermore, Ca(2+)-dependent secretion of the modified MARTX(Vv) toxin suggests that nonclassical RTX-like repeats found in the carboxyl-terminal repeat-containing region are functionally similar to classical RTX repeats found in other RTX proteins. Up to 95% of deaths from seafood-borne infections in the United States are due solely to one pathogen, V. vulnificus. Among its various virulence factors, the MARTX(Vv) toxin has been characterized as a critical exotoxin for successful pathogenesis of V. vulnificus in mouse infection models. Similarly to MARTX toxins of other pathogens, MARTX(Vv) toxin is comprised of repeat-containing regions, central effector domains, and an autoprocessing cysteine protease domain. Yet how each of these regions contributes to essential activities of the toxins has not been fully identified for any of MARTX toxins. Using modified MARTX(Vv) toxin fused with β-lactamase as a reporter enzyme, the portion(s) responsible for toxin secretion from bacteria, effector domain translocation into host cells, rapid host cell rounding, and necrotic host cell death was identified. The results are relevant for understanding how MARTX(Vv) toxin serves as both a necrotic pore-forming toxin and an effector delivery platform.


Online gaming in the context of social anxiety.
In 2014, over 23 million individuals were playing massive multiplayer online role-playing games (MMORPGs). In light of the framework provided by Davis's (2001) cognitive-behavioral model of pathological Internet use, social anxiety, expressions of true self, and perceived in-game and face-to-face social support were examined as predictors of Generalized Problematic Internet Use Scale (GPIUS) scores and hours spent playing MMORPGs per week. Data were collected from adult MMORPG players via an online survey (N = 626). Using structural equation modeling, the hypothesized model was tested on 1 half of the sample (N = 313) and then retested on the other half of the sample. The results indicated that the hypothesized model fit the data well in both samples. Specifically, expressing true self in game, higher levels of social anxiety, larger numbers of in-game social supports, and fewer supportive face-to-face relationships were significant predictors of higher GPIUS scores, and the number of in-game supports was significantly associated with time spent playing. The current study provides clinicians and researchers with a deeper understanding of MMORPG use by being the first to apply, test, and replicate a theory-driven model across 2 samples of MMORPG players. In addition, the present findings suggest that a psychometric measure of MMORPG usage is more indicative of players' psychological and social well-being than is time spent playing these games. (PsycINFO Database Record


Retinal changes in Alzheimer's disease- integrated prospects of imaging, functional and molecular advances.
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder of the brain, clinically characterised by cognitive deficits that gradually worsen over time. There is, at present, no established cure, or disease-modifying treatments for AD. As life expectancy increases globally, the number of individuals suffering from the disease is projected to increase substantially. Cumulative evidence indicates that AD neuropathological process is initiated several years, if not decades, before clinical signs are evident in patients, and diagnosis made. While several imaging, cognitive, CSF and blood-based biomarkers have been proposed for the early detection of AD; their sensitivity and specificity in the symptomatic stages is highly variable and it is difficult to justify their use in even earlier, pre-clinical stages of the disease. Research has identified potentially measurable functional, structural, metabolic and vascular changes in the retina during early stages of AD. Retina offers a distinctively accessible insight into brain pathology and current and developing ophthalmic technologies have provided us with the possibility of detecting and characterising subtle, disease-related changes. Recent human and animal model studies have further provided mechanistic insights into the biochemical pathways that are altered in the retina in disease, including amyloid and tau deposition. This information coupled with advances in molecular imaging has allowed attempts to monitor biochemical changes and protein aggregation pathology in the retina in AD. This review summarises the existing knowledge that informs our understanding of the impact of AD on the retina and highlights some of the gaps that need to be addressed. Future research will integrate molecular imaging innovation with functional and structural changes to enhance our knowledge of the AD pathophysiological mechanisms and establish the utility of monitoring retinal changes as a potential biomarker for AD.


Outcome after operative treatment of proximal humeral fractures in elderly patients.
The proximal humeral fracture (PHF) (5 %) of the elderly is the third most common fracture after proximal femoral and distal radius fractures. Proximal femoral fractures often lead to a loss of autonomy. The aim of this study is to show how PHF changes the patient's autonomy and the coping with everyday life as well as which factors influence the outcome 1 year (y) after surgery. Data of 62 patients with surgical treatment of a PHF ≥ 60 y was prospectively collected. With a telephone interview Short Form (SF) 12 (physical and mental health; PH, MH), Barthel Index (BI), range of motion, pain, and satisfaction was observed after 3 and 12 months. The dependence of outcome on different factors was investigated. The mean age was 73.3 y (median 73, 60-94). Mortality after 3 months was 3 % and after 1 y 11 %. The PH before the injury (47.9) was significantly better than after 3 months (37.1) and after 1 y (42.6). The MH showed no difference. The BI before the injury (92) was significantly better than after 3 months (86), but the same after 1 y (91). After 1 y > 50 % were able to abduct and flex the arm > 90°. More than two-thirds were able to perform everyday life activities for body care and nutrition after 1 y. Approximately, 73 % of the patients had little or no pain, and 84 % were satisfied with the result after 1 y. Good score values before the fracture resulted in better outcome. Higher severity in fracture led to a higher level of pain. A surgically treated PHF in the elderly does not lead to a relevant impairment in quality of life. Despite the lack of complete retrieval of range of motion patients achieve a good to very good result in coping with everyday life.


Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis.
The low-density lipoprotein receptor-related protein 5 gene (LRP5) was identified to be linked to the variation in BMD in high bone mass pedigrees. Subsequent population-based studies of the association between the LRP5 gene and BMD have yielded conflicting results. The present study was aimed at examining the association between LRP5 gene and BMD by using meta-analysis. A systematic electronic search of literature was conducted to identify all published studies in English on the association between LRP5 gene and osteoporosis-related phenotypes, including bone mineral density and fracture. BMD data were summarized from individual studies by LRP5 genotype, and a synthesis of data was performed with random-effects meta-analyses. After excluding studies on animal and review papers, there were 19 studies for the synthesis. Among these studies, 10 studies used the rs3736228 (A1330V) polymorphism and reported BMD values. The 10 eligible studies comprised 16,705 individuals, with the majority being women (n = 8444), aged between 18 - 81 years. The overall distribution of genotype frequencies was: AA, 68%, AV and VV, 32%. However, the genotype frequency varied significantly within as well as between ethnic populations. On random-effects meta-analysis, lumbar spine BMD among individuals with the AA genotype was on average 0.018 (95% confidence interval [CI]: 0.012 to 0.023) g/cm2 higher than those with either AV or VV genotype. Similarly, femoral neck BMD among carriers of the AA genotype was 0.011 (95%CI: 0.004 to 0.017) g/cm2 higher than those without the genotype. While there was no significant heterogeneity in the association between the A1330V polymorphism and lumbar spine BMD (p = 0.55), the association was heterogeneous for femoral neck BMD (p = 0.05). The probability that the difference is greater than one standard deviation was 0.34 for femoral neck BMD and 0.54 for lumbar spine BMD. These results suggest that there is a modest effect of the A1330V polymorphism on BMD in the general population, and that the modest association may limit its clinical use.


A treatable metabolic cause of encephalopathy: cobalamin C deficiency in an 8-year-old male.
Neurologic regression in a previously healthy child may be caused by metabolic or neurodegenerative disorders, many of which have no definitive treatment. We report a case of a previously healthy 8-year-old boy who presented with a month-long history of waxing and waning encephalopathy and acute regression, followed by seizures. Evaluation for a metabolic disorder revealed methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C type due to a single, presumed homozygous pathogenic c.394 C>T mutation in the MMACHC gene. With the appropriate diet restrictions and vitamin replacement, he improved significantly and returned to his premorbid level of behavior. This case illustrates an unusual presentation of a treatable metabolic disorder and highlights the need to consider cobalamin defects in the differential diagnosis of healthy children with neurologic regression.


'Relating' to voices: Exploring the relevance of this concept to people who hear voices.
Conceptualizing interactions between voice hearers and their voices as a 'relationship' has recently become an area of psychological inquiry. To date the literature exploring the details of a hearer-voice relationship has arguably privileged the researchers' account of voice hearing at the expense of the individual's explanatory framework and perspective. The present study aimed to establish the perspectives of voice hearers regarding any 'relationship' they may have developed with their voices. In-depth interviews were conducted with 10 service users who had heard voices for at least 12 months. The interviews were transcribed and analysed using interpretative phenomenological analysis (IPA). Analysis resulted in five major themes, three of which are discussed here: Defining the 'other' which detailed the personification process; 'Me vs. the Voice' which explored oppositional positioning between participants and their voice and strategies employed to retain power and 'the Voice and Me' which considered the union that was apparent, as well as participants' rejection of a relational concept. The concept of a 'relationship' was both accepted and rejected by participants. Acceptance of relating was relative to the poverty of social relationships. Rejections were considered in terms of preservation of self-hood, conflict with personal explanatory models and constructions of the term 'relationship'. This study has provided evidence that supports new developments in working relationally with voices. Working within this frame may help to emphasize hearers' strengths whilst ameliorating distress. However, this concept needs to be posed as a possible rather than an established conceptualization.


Fluorescent microspheres: a new tool for visualization of ischemic myocardium in rats.
Fluorescent microspheres (FM) were used in vivo to visualize and quantify an ischemic risk zone after experimental coronary artery occlusion (CAO). Anesthetized rats were subjected to CAO. After 5 min, FM were injected into the left ventricular cavity of seven rats. Six control rats received no FM. When examined with magnification under ultraviolet light, heart slices with FM showed a white-green particulate fluorescence in the nonischemic septum and a well-delineated transmural zone of nonfluorescence in the ischemic free wall. In hearts without FM, this fluorescence was not apparent nor was any perfusion defect observed. In other rats, relative regional myocardial blood flow in the nonfluorescent ischemic zone outlined by FM was measured using plastic radioactive microspheres and found to be approximately 12% of regional flow in normal areas where fluorescence was present. A close correlation (r = 0.92) existed between the amount of ischemic myocardium at risk as outlined by FM and that of necrotic myocardium as defined by tetrazolium staining after both 6 and 24 h of coronary occlusion. We conclude that FM is a promising technique in a small-animal model in which an ischemic risk zone can be established shortly after CAO and can be preserved for later quantification and analysis.


Measles immunization acceptance in Southeast Asia: past patterns and future challenges.
Despite substantial increases in immunization rates, measles remains a major health problem in developing countries of Southeast Asia. The authors of this paper undertook separate investigations which examined factors influencing measles immunization acceptance in the rural Philippines, Central Java, Indonesia, and an impoverished neighborhood in Bangkok, Thailand. We briefly summarize the findings of our three field investigations before presenting a synthesizing analysis of the psychosocial and demographic factors which affect measles immunization. We then review trends influencing measles acceptance in industrialized countries to anticipate possible future challenges to measles immunization acceptance in Southeast Asia in an era of increasing globalization and information transfer. We suggest that parental perceptions of the risks and benefits of immunization, philosophical and religious convictions and state and social regulatory policies will profoundly influence measles immunization in the new millennium.


The Limitations and Strengths of the Evidence-Based Practice Attitude Scale as a Measure of Correctional Employees' Attitudes: A Psychometric Evaluation.
Evidence-based practices (EBPs) hold tremendous potential for improving the outcomes of corrections interventions. The implementation of EBPs requires support from staff at all levels of an organization; however, the study of correctional staff attitudes toward organizational change and EBPs is in its infancy. The current study examines the psychometric properties of the Evidence-Based Practice Attitude Scale (EBPAS), an instrument originally designed for mental health professionals, to measure correctional employees' readiness to implement EBPs. The results indicate mixed conclusions regarding the use of the EBPAS with correctional staff. We found that the total scale and subscales are reliable and exhibit high internal consistency. However, the results of an exploratory and confirmatory factor analysis failed to replicate the factor structure from previous research with mental health providers. The findings indicate potential drawbacks regarding the construct validity of the EBPAS for use with correctional personnel.


Hepatitis B and/or C co-infection in HIV infected patients: a study in a tertiary care centre from South India.
Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in human immunodeficiency virus (HIV) infected individuals results in increased hepatic complications. We undertook this study to evaluate the presence of HBV and HCV in HIV infected individuals attending a tertiary care centre in southern India. A total of 120 cases with HIV infection and 120 healthy adult control subjects were included in the study. Samples were tested for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies by enzyme linked immunosorbent assay (ELISA) method. HBsAg and anti-HCV positive serum samples were further tested for the presence of hepatitis B e antigen (HBeAg), anti-HBe antibodies, HBV-DNA and HCV-RNA. The most common mode of transmission was sexual promiscuity (79%), followed by spouse positivity (15%) and history of blood transfusion (6%). HBsAg and anti-HCV were positive in 18 (15%) and 10 (8.3%) HIV infected patients; the corresponding figures in healthy controls being 2 (1.6%) 0 (0%) (P<0.0001). Among HIV infected patients, presence of HBeAg and anti-HBe antibodies was seen in 33.3 and 55.5 per cent, respectively; both HBeAg and anti-HBe antibodies were negative in 11.1 per cent. HBV DNA and HCV RNA were positive in 10 of 18 and in all anti-HCV positive samples. Triple infection with HBV, HCV and HIV was seen in three patients. CD4+ T-lymphocyte count less than 200/μl was seen in 22 of 28 co-infected cases. The findings of our study showed presence of HBV (15%) and HCV (8.3%) co-infections in HIV positive patients which was higher than that seen in HIV negative controls. Co-infection with HBV and HCV is a common problem in HIV infected patients in India. Hence, all HIV patients need to be routinely tested for markers of HBV and HCV infection.


Trends in the health care use and expenditures associated with no-lost-time claims in Ontario: 1991 to 2006.
To examine trends in health care usage and expenditures associated with no-lost-time claims in Ontario over a 15-year period. A secondary analysis of administrative workers' compensation claims occurring between 1991 and 2006 (N = 2,290,101). We used regression analysis to model health care expenditures using a zero-inflated linear model, adjusting for age, gender, industry group and size of payroll. The probability of using health care increased over the time period. Health care expenditures per claim declined between 1991 and 1997, but then increased between 1998 and 2006, coinciding with the introduction of occupational health and safety legislation promoting early return to work in Ontario. Our results provide support to the hypothesis that the increasing use of workplace accommodation since 1998 is a driver of the relatively stable rate of no-lost-time claims in Ontario.


'Suicide' of crickets harbouring hairworms: a proteomics investigation.
Despite increasing evidence of host phenotypic manipulation by parasites, the underlying mechanisms causing infected hosts to act in ways that benefit the parasite remain enigmatic in most cases. Here, we used proteomics tools to identify the biochemical alterations that occur in the head of the cricket Nemobius sylvestris when it is driven to water by the hairworm Paragordius tricuspidatus. We characterized host and parasite proteomes during the expression of the water-seeking behaviour. We found that the parasite produces molecules from the Wnt family that may act directly on the development of the central nervous system (CNS). In the head of manipulated cricket, we found differential expression of proteins specifically linked to neurogenesis, circadian rhythm and neurotransmitter activities. We also detected proteins for which the function(s) are still unknown. This proteomics study on the biochemical pathways altered by hairworms has also allowed us to tackle questions of physiological and molecular convergence in the mechanism(s) causing the alteration of orthoptera behaviour. The two hairworm species produce effective molecules acting directly on the CNS of their orthoptera hosts.


Unbiased Genetic Screen to Identify Factors Involved in X-Chromosome Inactivation Using a Pooled Bar-Coded shRNA Library.
In mammals, a dosage compensation mechanism exists to equalize gene expression levels between male and female. This process is initiated by Xist RNA, a long noncoding RNA that mediates the transcriptional silencing of a complete chromosome. The kinetics of events occurring on the future inactive X-chromosome has been described in detail over the last 20 years. More recently, parallel studies using advanced biochemical assays and genetic screens identified key factors critical for the silencing cascade. Here, we describe the procedure adopted in one of these studies, an shRNA-based loss-of-function screen in mouse embryonic stem cells (mESCs).The screen made use of a reporter cell line in which Xist-mediated silencing could be monitored by changes in GFP fluorescence. Loss of function was achieved using a custom made bar-coded pooled shRNA library. The screen aimed to identify shRNAs that lessen Xist mediated repression of the GFP reporter. The methods that were applied are of potential relevance for the development of related screens, for example to better understand how specific repressors silence one or several genes.


Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs.
Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugsNeedle syringe programmes (NSP) and opioid substitution therapy (OST) are the primary interventions to reduce hepatitis C (HCV) transmission in people who inject drugs. There is good evidence for the effectiveness of NSP and OST in reducing injecting risk behaviour and increasing evidence for the effectiveness of OST and NSP in reducing HIV acquisition risk, but the evidence on the effectiveness of NSP and OST for preventing HCV acquisition is weak. To assess the effects of needle syringe programmes and opioid substitution therapy, alone or in combination, for preventing acquisition of HCV in people who inject drugs. We searched the Cochrane Drug and Alcohol Register, CENTRAL, the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA), the NHS Economic Evaluation Database (NHSEED), MEDLINE, Embase, PsycINFO, Global Health, CINAHL, and the Web of Science up to 16 November 2015. We updated this search in March 2017, but we have not incorporated these results into the review yet. Where observational studies did not report any outcome measure, we asked authors to provide unpublished data. We searched publications of key international agencies and conference abstracts. We reviewed reference lists of all included articles and topic-related systematic reviews for eligible papers. We included prospective and retrospective cohort studies, cross-sectional surveys, case-control studies and randomised controlled trials that measured exposure to NSP and/or OST against no intervention or a reduced exposure and reported HCV incidence as an outcome in people who inject drugs. We defined interventions as current OST (within previous 6 months), lifetime use of OST and high NSP coverage (regular attendance at an NSP or all injections covered by a new needle/syringe) or low NSP coverage (irregular attendance at an NSP or less than 100% of injections covered by a new needle/syringe) compared with no intervention or reduced exposure. We followed the standard Cochrane methodological procedures incorporating new methods for classifying risk of bias for observational studies. We described study methods against the following 'Risk of bias' domains: confounding, selection bias, measurement of interventions, departures from intervention, missing data, measurement of outcomes, selection of reported results; and we assigned a judgment (low, moderate, serious, critical, unclear) for each criterion. We identified 28 studies (21 published, 7 unpublished): 13 from North America, 5 from the UK, 4 from continental Europe, 5 from Australia and 1 from China, comprising 1817 incident HCV infections and 8806.95 person-years of follow-up. HCV incidence ranged from 0.09 cases to 42 cases per 100 person-years across the studies. We judged only two studies to be at moderate overall risk of bias, while 17 were at serious risk and 7 were at critical risk; for two unpublished datasets there was insufficient information to assess bias. As none of the intervention effects were generated from RCT evidence, we typically categorised quality as low. We found evidence that current OST reduces the risk of HCV acquisition by 50% (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63, I2 = 0%, 12 studies across all regions, N = 6361), but the quality of the evidence was low. The intervention effect remained significant in sensitivity analyses that excluded unpublished datasets and papers judged to be at critical risk of bias. We found evidence of differential impact by proportion of female participants in the sample, but not geographical region of study, the main drug used, or history of homelessness or imprisonment among study samples.Overall, we found very low-quality evidence that high NSP coverage did not reduce risk of HCV acquisition (RR 0.79, 95% CI 0.39 to 1.61) with high heterogeneity (I2 = 77%) based on five studies from North America and Europe involving 3530 participants. After stratification by region, high NSP coverage in Europe was associated with a 76% reduction in HCV acquisition risk (RR 0.24, 95% CI 0.09 to 0.62) with less heterogeneity (I2 =0%). We found low-quality evidence of the impact of combined high coverage of NSP and OST, from three studies involving 3241 participants, resulting in a 74% reduction in the risk of HCV acquisition (RR 0.26 95% CI 0.07 to 0.89). OST is associated with a reduction in the risk of HCV acquisition, which is strengthened in studies that assess the combination of OST and NSP. There was greater heterogeneity between studies and weaker evidence for the impact of NSP on HCV acquisition. High NSP coverage was associated with a reduction in the risk of HCV acquisition in studies in Europe.


The healing process of intracorporeally and in situ devitalized distal femur by microwave in a dog model and its mechanical properties in vitro.
Limb-salvage surgery has been well recognized as a standard treatment and alternative to amputation for patients with malignant bone tumors. Various limb-sparing techniques have been developed including tumor prosthesis, allograft, autograft and graft-prosthesis composite. However, each of these methods has short- and long-term disadvantages such as nonunion, mechanical failures and poor limb function. The technique of intracorporeal devitalization of tumor-bearing bone segment in situ by microwave-induced hyperthermia after separating it from surrounding normal tissues with a safe margin is a promising limb-salvage method, which may avoid some shortcomings encountered by the above-mentioned conventional techniques. The purpose of this study is to assess the healing process and revitalization potential of the devitalized bone segment by this method in a dog model. In addition, the immediate effect of microwave on the biomechanical properties of bone tissue was also explored in an in vitro experiment. We applied the microwave-induced hyperthermia to devitalize the distal femurs of dogs in situ. Using a monopole microwave antenna, we could produce a necrotic bone of nearly 20 mm in length in distal femur. Radiography, bone scintigraphy, microangiography, histology and functional evaluation were performed at 2 weeks and 1, 2, 3, 6, 9 and 12 months postoperatively to assess the healing process. In a biomechanical study, two kinds of bone specimens, 3 and 6 cm in length, were used for compression and three-point bending test respectively immediately after extracorporeally devitalized by microwave. An in vivo study showed that intracorporeally and in situ devitalized bone segment by microwave had great revitalization potential. An in vitro study revealed that the initial mechanical strength of the extracorporeally devitalized bone specimen may not be affected by microwave. Our results suggest that the intracorporeal microwave devitalization of tumor-bearing bone segment in situ may be a promising limb-salvage method.


The child survival impact of the Ghana Essential Health Interventions Program: A health systems strengthening plausibility trial in Northern Ghana.
The Ghana Health Service in collaboration with partner institutions implemented a five-year primary health systems strengthening program known as the Ghana Essential Health Intervention Program (GEHIP). GEHIP was a plausibility trial implemented in an impoverished region of northern Ghana around the World Health Organizations (WHO) six pillars combined with community engagement, leadership development and grassroots political support, the program organized a program of training and action focused on strategies for saving newborn lives and community-engaged emergency referral services. This paper analyzes the effect of the GEHIP program on child survival. Birth history data assembled from baseline and endline surveys are used to assess the hazard of child mortality in GEHIP treatment and comparison areas prior to and after the start of treatment. Difference-in-differences (DiD) methods are used to compare mortality change over time among children exposed to GEHIP relative to children in the comparison area over the same time period. Models test the hypothesis that a package of systems strengthening activities improved childhood survival. Models adjusted for the potentially confounding effects of baseline differentials, secular mortality trends, household characteristics such as relative wealth and parental educational attainment, and geographic accessibility of clinical care. The GEHIP combination of health systems strengthening activities reduced neonatal mortality by approximately one half (HR = 0.52, 95% CI = 0.28,0.98, p = 0.045). There was a null incremental effect of GEHIP on mortality of post-neonate infants (from 1 to 12 months old) (HR = 0.72; 95% CI = 0.30,1.79; p = 0.480) and post-infants (from 1 year to 5 years old) -(HR = 1.02; 95% CI = 0.55-1.90; p = 0.940). Age-specific analyses show that impact was concentrated among neonates. However, effect ratios for post-infancy were inefficiently assessed owing to extensive survival history censoring for the later months of childhood. Children were observed only rarely for periods over 40 months of age. GEHIP results show that a comprehensive approach to newborn care is feasible, if care is augmented by community-based nurses. It supports the assertion that if appropriate mechanisms are put in place to enable the various pillars of the health system as espoused by WHO in rural impoverished settings where childhood mortality is high, it could lead to accelerated reductions in mortality thereby increasing survival of children. Policy implications of the pronounced neonatal effect of GEHIP merit national review for possible scale-up.


Fish oil and indomethacin in combination potently reduce dyslipidemia and hepatic steatosis in LDLR(-/-) mice.
Fish oil (FO) is a potent anti-inflammatory and lipid-lowering agent. Because inflammation can modulate lipid metabolism and vice versa, we hypothesized that combining FO with cyclooxygenase inhibitors (COXIBs), well-known anti-inflammatory drugs, can enhance the anti-inflammatory and lipid-lowering effect of FO. LDLR(-/-) mice were fed a high-fat diet supplemented with 6% olive oil or FO for 12 wk in the presence or absence of indomethacin (Indo, 6 mg/l drinking water). FO reduced plasma total cholesterol by 30% but, in combination with Indo, exerted a greater decrease (44%). The reduction of liver cholesterol ester (CE) and triglycerides (TG) by FO (63% and 41%, respectively) was enhanced by Indo (80% in CE and 64% in TG). FO + Indo greatly increased the expression of genes modulating lipid metabolism and reduced the expression of inflammatory genes compared with control. The mRNA and/or protein expression of pregnane X receptor (PXR) and cytochrome P450 isoforms that alter inflammation and/or lipid metabolism are increased to a greater extent in mice that received FO + Indo. Moroever, the nuclear level of PXR is significantly increased in FO + Indo group. Combining FO with COXIBs may exert their beneficial effects on inflammation and lipid metabolism via PXR and cytochrome P450.


Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial.
As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.


Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress.
Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil-derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse.


Synthesis of hydrophilic conjugated porphyrin dimers for one-photon and two-photon photodynamic therapy at NIR wavelengths.
We report the synthesis of a series of hydrophilic butadiyne-linked conjugated zinc porphyrin dimers, designed as photodynamic therapy (PDT) agents. These porphyrin dimers exhibit exceptionally high two-photon absorption cross sections (delta(max) approximately 8,000-17,000 GM) and red-shifted linear absorption spectra (lambda(max) approximately 700-800 nm) making them ideal candidates for one-photon and two-photon excited photodynamic therapy. Four polar triethyleneglycol substituents are positioned along the sides of each dimer, but, on their own, these TEG chains do not confer sufficient solubility in aqueous physiological media for reproducible delivery into live cells. Charged cationic (methylpyridinium and trimethylammonium) and anionic (sulfonate and carboxylate) substituents have been appended to the meso-positions of porphyrin dimers using three synthetic strategies: 1) Suzuki coupling, 2) Sonogashira coupling, and 3) nucleophilic Senge arylation. Approaches 1 and 3 both allow attachment of aromatic substituents directly to the meso-positions of porphyrins. Approach 2 provides a route to hydrophilic porphyrin dimers with an ethyne link between the porphyrin and the polar aromatic substituent. The palladium-catalysed approaches 1 and 2 allow the synthesis of a broader range of meso-capped porphyrins, as many aryl halides are available. However the synthesis of the intermediate required for these routes necessitates a statistical reaction step, which decreases the overall yield. On the other hand, Senge-arylation provides highly regioselective nucleophilic aromatic substitution, and offers higher overall yield than the other routes. All these charged dimers exhibit good solubility in polar solvents (e.g. methanol) and aqueous solvent mixtures (aqueous DMSO or DMF).


Broadening Humor: Comic Styles Differentially Tap into Temperament, Character, and Ability.
The present study introduces eight comic styles (i.e., fun, humor, nonsense, wit, irony, satire, sarcasm, and cynicism) and examines the validity of a set of 48 marker items for their assessment, the Comic Style Markers (CSM). These styles were originally developed to describe literary work and are used here to describe individual differences. Study 1 examines whether the eight styles can be distinguished empirically, in self- and other-reports, and in two languages. In different samples of altogether more than 1500 adult participants, the CSM was developed and evaluated with respect to internal consistency, homogeneity, test-retest reliability, factorial validity, and construct and criterion validity. Internal consistency was sufficiently high, and the median test-retest reliability over a period of 1-2 weeks was 0.86 (N = 148). Exploratory and confirmatory factor analyses showed that the eight styles could be distinguished in both English- (N = 303) and German-speaking samples (N = 1018 and 368). Comparing self- and other-reports (N = 210) supported both convergent and discriminant validity. The intercorrelations among the eight scales ranged from close to zero (between humor and sarcasm/cynicism) to large and positive (between sarcasm and cynicism). Consequently, second-order factor analyses revealed either two bipolar factors (based on ipsative data) or three unipolar factors (based on normative data). Study 2 related the CSM to instruments measuring personality (N = 999), intelligence (N = 214), and character strengths (N = 252), showing that (a) wit was the only style correlated with (verbal) intelligence, (b) fun was related to indicators of vitality and extraversion, (c) humor was related to character strengths of the heart, and (d) comic styles related to mock/ridicule (i.e., sarcasm, cynicism, but also irony) correlated negatively with character strengths of the virtues temperance, transcendence, and humanity. By contrast, satire had a moral goodness that was lacking in sarcasm and cynicism. Most importantly, the two studies revealed that humor might be related to a variety of character strengths depending on the comic style utilized, and that more styles may be distinguished than has been done in the past. The CSM is recommended for future explorations and refinements of comic styles.


Vision-Language Navigation Policy Learning and Adaptation.
Vision-language navigation (VLN) is the task of navigating an embodied agent to carry out natural language instructions inside real 3D environments. In this paper, we study how to address three critical challenges for this task: the cross-modal grounding, the ill-posed feedback, and the generalization problems. First, we propose a novel Reinforced Cross-Modal Matching (RCM) approach that enforces cross-modal grounding both locally and globally via reinforcement learning (RL). Particularly, a matching critic is used to provide an intrinsic reward to encourage global matching between instructions and trajectories, and a reasoning navigator is employed to perform cross-modal grounding in the local visual scene. Evaluation on a VLN benchmark dataset shows that our RCM model significantly outperforms baseline methods by 10 percent on Success Rate weighted by Path Length (SPL) and achieves the state-of-the-art performance. To improve the generalizability of the learned policy, we further introduce a Self-Supervised Imitation Learning (SIL) method to explore and adapt to unseen environments by imitating its own past, good decisions. We demonstrate that SIL can approximate a better and more efficient policy, which tremendously minimizes the success rate performance gap between seen and unseen environments (from 30.7 to 11.7 percent).


Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins.
There are several reports of ultrastructural and protein changes affecting synapses in the anterior cingulate cortex in schizophrenia. Altered cytoarchitecture has also been described in this region in schizophrenia as well as in mood disorders. In this paper we review the literature and present a new study investigating synaptic abnormalities in the anterior cingulate cortex (area 24) in the Stanley Foundation brain series. We used Western blotting to assess four synaptic proteins: synaptophysin, growth-associated protein-43 (GAP-43), complexin I and complexin II, which inform about somewhat different aspects of the synaptic circuitry. Synaptophysin, complexin II and GAP-43 were reduced in bipolar disorder. The decreases correlated with the duration of illness and tended to be greater in subjects without a family history. Complexin II was also reduced in major depression. Complexin I and the housekeeping protein beta-actin did not differ between groups. None of the proteins changed significantly in schizophrenia. The results indicate the presence of a synaptic pathology in the anterior cingulate cortex in mood disorders, especially bipolar disorder. The abnormalities may contribute to the dysfunction of cingulate neural circuits. The loss of synaptophysin is suggestive of decreased synaptic density whilst the decrease in GAP-43 may denote impaired synaptic plasticity and the reduction of complexin II but not complexin I implies that the alterations particularly affect excitatory connections. The reductions may be progressive.


The Source of Glycolytic Intermediates in Mammalian Tissues.
Glycolysis plays a central role in organismal metabolism, but its quantitative inputs across mammalian tissues remain unclear. Here we use 13C-tracing in mice to quantify glycolytic intermediate sources: circulating glucose, intra-tissue glycogen, and circulating gluconeogenic precursors. Circulating glucose is the main source of circulating lactate, the primary end product of tissue glycolysis. Yet circulating glucose highly labels glycolytic intermediates in only a few tissues: blood, spleen, diaphragm, and soleus muscle. Most glycolytic intermediates in the bulk of body tissue, including liver and quadriceps muscle, come instead from glycogen. Gluconeogenesis contributes less but also broadly to glycolytic intermediates, and its flux persists with physiologic feeding (but not hyperinsulinemic clamp). Instead of suppressing gluconeogenesis, feeding activates oxidation of circulating glucose and lactate to maintain glucose homeostasis. Thus, the bulk of the body slowly breaks down internally stored glycogen while select tissues rapidly catabolize circulating glucose to lactate for oxidation throughout the body.


Deformation of the lamina cribrosa and anterior scleral canal wall in early experimental glaucoma.
To test the hypothesis that pathophysiologic deformation of the lamina cribrosa and anterior scleral canal wall underlies the onset of confocal scanning laser tomography (CSLT)-detected optic nerve head (ONH) surface change in early experimental glaucoma. Both eyes of four normal (two normal eyes) monkeys and four with early glaucoma (one eye with laser-induced IOP elevation, observed until the onset of CSLT-detected ONH surface change) were enucleated immediately after death and immersion fixed at IOP 0 mm Hg. In an additional four normal monkeys and five with early glaucoma, both eyes were cannulated, and IOP set to 10 mm Hg in one normal eye and either 30 or 45 mm Hg in the other (normal or early-glaucoma) eye. After 15 to 80 minutes of acute IOP elevation, these nine monkeys were perfusion-fixed. Within images of serial sagittal sections of the ONH tissues in all 17 monkeys, anterior lamina cribrosa position, laminar thickness, and scleral canal diameter were measured. For each parameter, differences between the two eyes of each monkey and between treatment groups were assessed by ANOVA. Within the eyes of the eight monkeys with IOP 0 mm Hg, the lamina cribrosa was posteriorly displaced and thicker and the scleral canal was enlarged at Bruch's membrane and at the anterior laminar insertion in the early-glaucoma eyes compared with the contralateral normal eyes (plastic deformation). Within the high-IOP normal eyes, the lamina cribrosa was posteriorly displaced compared with that in the low-IOP normal eyes, but there were no significant differences in laminar thickness or scleral canal diameter (normal compliance). Within the high-IOP early-glaucoma eyes, the lamina cribrosa was posteriorly displaced and thicker and the scleral canal enlarged, compared with both low-IOP normal eyes and high-IOP normal eyes (hypercompliant deformation). Differences in laminar position between the high-IOP early-glaucoma eyes and the contralateral low-IOP normal eyes (hypercompliant plus plastic deformation) were more than eight times greater than the differences between the high-IOP normal eyes and the contralateral low-IOP normal eyes (normal compliance). Both plastic (permanent) and hypercompliant deformation of the lamina cribrosa and anterior scleral canal wall are present in young adult monkey eyes with early experimental glaucoma. These findings suggest that damage to the ONH connective tissues occurs early in the monkey model of experimental glaucoma.


Collinear generation of ultrashort UV and XUV pulses.
We demonstrate the collinear generation of few-femtosecond ultraviolet and attosecond extreme ultraviolet pulses via a combination of third-harmonic and high harmonic generation in noble gases. The ultrashort coherent light bursts are produced by focusing a sub-1.5-cycle near-infrared/visible laser pulse in two subsequent quasi-static noble gas targets. This approach provides an inherently synchronized pair of UV and XUV pulses, where the UV radiation has a photon energy of approximately 5 eV and a pulse energy of up to 1 microJ and the XUV radiation contains up to 3.5 10(6) XUV photons per shot with a photon energy exceeding 100 eV. This source represents a novel tool for future UV pump/XUV probe experiments with unprecedented time-resolution.


What contribution do detergent fatty alcohols make to sewage discharges and the marine environment?
To investigate the potential sources of fatty alcohols arriving at a WWTP and entering the receiving waters, a study was conducted at Treborth North Wales using compound specific stable isotope mass spectrometry (¹³C and ²H). Samples were collected from soils, marine sediments, detergents used in the catchment and in the WWTP. Total fatty alcohol concentrations decreased in the liquid phases through the treatment works with the majority of the compounds accumulating in the sludge (biosolids). Natural plant based detergents have δ¹³C values between -26 and -32‰ while petroleum-based detergents occupy a range between -25 and -30‰. The corresponding δ²H values are -250‰ for natural sourced materials and -50‰ for oil-based detergents which enable these two sources to be separated. The influent to the WWTP contained fatty alcohols which originated mainly from faecal sources and natural surfactants (∼75%) with a smaller amount potentially derived from petroleum-based surfactants (∼25%). The effluents from the WWTP contained mainly short chain compounds with a chain length less than C¹⁶. Their δ²H stable isotope signature was different to the other potential sources examined and suggests bacterial synthesis during the treatment processes. The sludge had relatively high concentrations of fatty alcohols as would be expected from their low water solubility. The stable isotopic signatures were consistent with a mixture of faecal and detergent sources. The sludge in this area is routinely spread on agricultural land as a fertiliser and may find its way back into the sea via land runoff. On the basis of the mean discharge rates and the mean C₁₂ concentration in the effluent, this WWTP would contribute ∼300 g day⁻¹ to the receiving waters. The marine sediment samples had short chain fatty alcohols that are typical of marine production and with stable isotope values that indicate exclusive marine production for the C₁₄ potentially mixed with terrestrial sources for the C₁₆ and C₁₈ compounds. Therefore, the fatty alcohols in the marine sediments are not the same as those that were discharged in the liquid effluent and these fatty alcohols were not the ones that entered the works through the influent but were synthesised or recycled within the works.


Impact of sampled data on an optical joint transform correlator.
Coherent optical systems are well known for performing certain operations such as Fourier and Fresnel transformation and pattern recognition. The basis for pattern recognition in many coherent optical systems is the correlator. This paper discusses the effect of undersampling in an optical joint transform correlator which has a sampled-data input, detectors of size 1 x i resolution elements in the Fourier plane, and detectors of size 1 x 1 resolution elements in the correlation plane, where i is an integer. After the undersampling, it is shown that the correlation plane still contains the needed data, the shape of the correlation surfaces are unchanged, and the different correlation terms just move closer together. It is shown that the penalty for undersampling is that the amount of input data must be reduced by a factor of i. It is also shown that a digital simulation using a discrete Fourier transform gives an accurate prediction of the optical correlator performance. Results from the simulation are given to verify the theory.


Does cell-saver blood administration and free hemoglobin load cause renal dysfunction?
Our aim was to evaluate the impact of cell-saver volume and free hemoglobin load on renal dysfunction. Intraoperative blood salvage was conducted in standard fashion, and in each case a sample of the blood was removed for testing. Outcome data on individual patients were collected during a 6-year period (1992-1998). The total amount of free hemoglobin each patient received was calculated. Renal dysfunction was defined as a rise in creatinine level of 1.0 mg/dL above baseline. There were a total of 125 patients who received salvaged blood. The free hemoglobin concentration ranged from 19 to 304 mg/dL (mean, 87.5 mg/dL). Patients were stratified into groups on the basis of the total free hemoglobin received, and the Kruskal-Wallis test demonstrated a difference between groups in the prevalence of renal dysfunction (P < 0.001). A total of 15 patients (12%) had significant postoperative renal dysfunction. There was an association between the amount of free hemoglobin load and subsequent renal dysfunction. This may warrant further study toward establishing policies and limits regarding maximal free hemoglobin blood.


Serum neurofilament light in atrial fibrillation: clinical, neuroimaging and cognitive correlates.
Emerging evidence suggests that atrial fibrillation is associated with cognitive dysfunction independently of stroke, but the underlying mechanisms remain unclear. In this cross-sectional analysis from the Swiss-atrial fibrillation Study (NCT02105844), we investigated the association of serum neurofilament light protein, a neuronal injury biomarker, with (i) the CHA2DS2-VASc score (congestive heart failure, hypertension, age 65-74 or >75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, sex), clinical and neuroimaging parameters and (ii) cognitive measures in atrial fibrillation patients. We measured neurofilament light in serum using an ultrasensitive single-molecule array assay in a sample of 1379 atrial fibrillation patients (mean age, 72 years; female, 27%). Ischaemic infarcts, small vessel disease markers and normalized brain volume were assessed on brain MRI. Cognitive testing included the Montreal cognitive assessment, trail-making test, semantic verbal fluency and digit symbol substitution test, which were summarized using principal component analysis. Results were analysed using univariable and multivariable linear regression. Neurofilament light was associated with the CHA2DS2-VASc score, with an average 19.2% [95% confidence interval (17.2%, 21.3%)] higher neurofilament per unit CHA2DS2-VASc increase. This association persisted after adjustment for age and MRI characteristics. In multivariable analyses, clinical parameters associated with neurofilament light were higher age [32.5% (27.2%, 38%) neurofilament increase per 10 years], diabetes mellitus, heart failure and peripheral artery disease [26.8% (16.8%, 37.6%), 15.7% (8.1%, 23.9%) and 19.5% (6.8%, 33.7%) higher neurofilament, respectively]. Mean arterial pressure showed a curvilinear association with neurofilament, with evidence for both an inverse linear and a U-shaped association. MRI characteristics associated with neurofilament were white matter lesion volume and volume of large non-cortical or cortical infarcts [4.3% (1.8%, 6.8%) and 5.5% (2.5%, 8.7%) neurofilament increase per unit increase in log-volume of the respective lesion], as well as normalized brain volume [4.9% (1.7%, 8.1%) higher neurofilament per 100 cm3 smaller brain volume]. Neurofilament light was inversely associated with all cognitive measures in univariable analyses. The effect sizes diminished after adjusting for clinical and MRI variables, but the association with the first principal component was still evident. Our results suggest that in atrial fibrillation patients, neuronal loss measured by serum neurofilament light is associated with age, diabetes mellitus, heart failure, blood pressure and vascular brain lesions, and inversely correlates with normalized brain volume and cognitive function.


Global survey-based assessment of lifestyle changes during the COVID-19 pandemic.
Along with the major impact on public health, the COVID-19 outbreak has caused unprecedented concerns ranging from sudden loss of employment to mental stress and anxiety. We implemented a survey-based data collection platform to characterize how the COVID-19 pandemic has affected the socio-economic, physical and mental health conditions of individuals. We focused on three broad areas, namely, changes in social interaction during home confinement, economic impact and their health status. We identified a substantial increase in virtual interaction among individuals, which might be a way to alleviate the sudden unprecedented mental health burden, exacerbated by general awareness about viral infections or other manifestations associated with them. The majority of participants (85%) lived with one or more companions and unemployment issues did not affect 91% of the total survey takers, which was one of the crucial consequences of the pandemic. Nevertheless, measures such as an increased frequency of technology-aided distant social interaction, focus on physical fitness and leisure activities were adopted as coping mechanisms during this period of home isolation. Collectively, these metrics provide a succinct and informative summary of the socio-economic and health impact of the COVID-19 pandemic on the individuals. Findings from our study reflect that continuous surveillance of the psychological consequences for outbreaks should become routine as part of preparedness efforts worldwide. Given the limitations of analyzing the large number of variables, we have made the raw data publicly available on the OMF ME/CFS Data Center server to facilitate further analyses (https://igenomed.stanford.edu/dataset/survey-study-on-lifestyle-changes-during-covid-19-pandemic).


A proposal for dichroic experiments in the electron microscope.
Building upon the similarities between inelastic electron scattering and X-ray absorption we show that dichroism can be observed in electron energy loss spectrometry (EELS) in the transmission electron microscope (TEM). Natural or magnetic linear dichroism can be studied in electron scattering experiment with definite wave vector transfer in the interaction.The detection of circular dichroism in the TEM relies on interferometric EELS in a particular scattering geometry that allows extraction of the mixed dynamic form factor from energy loss spectra. Similarities between dichroic signals in energy loss near edge structures and X-ray absorption near edge structures are discussed, and a new experimental setup for dichroic measurements in the TEM is proposed.


Senescence of foveal and parafoveal cone sensitivities and their relations to macular pigment density.
Foveal and parafoveal increment thresholds were measured for 50 observers (12-88 years of age) under conditions that isolated retinal mechanisms dominated by short- (S-), middle- (M-), or long- (L-) wave-sensitive cones. Thresholds were obtained on the plateau of the threshold-versus-intensity function of each isolated mechanism and were referred to the retina by using individual measurements of ocular media and macular pigment density. Age-related increases in foveal thresholds, specified at the retina, were found for all three cone mechanisms. Parallel sensitivity losses for each cone mechanism were also observed at 4 degrees and 8 degrees in the temporal retina. A significant positive correlation was found between foveal macular pigment density and the S-cone, but not the M- and L-cone, log sensitivity difference (0 degrees-8 degrees) specified at the retina. This relation is expected from the hypothesis that the macular pigment protects the photoreceptors from senescent losses in sensitivity. However, because this result is independent of age, it is interpreted as being due to local gain changes resulting from differential filtering of incident light by the macular pigment between the fovea and the parafovea.