Increased leucocyte adhesiveness/aggregation is a most useful indicator of disease activity in patients with inflammatory bowel disease.
The aim of the study was to determine the comparative usefulness of inflammatory markers, in evaluating disease activity in patients with inflammatory bowel disease. Disease activity was assessed by the Mayo Clinic score for ulcerative colitis, and Harvey-Bradshaw score for Crohn's disease. Five hundred normal blood donors who had no underlying inflammatory condition served as controls. The erythrocyte sedimentation rate, platelet and white blood cell count, C reactive protein, and the leucocyte adhesiveness/aggregation test (LAAT) were determined in each patient. One hundred and twenty four patients with inflammatory bowel disease were tested while in remission and 128 in relapse. Their mean (SD) per cent of aggregated white blood cells in the peripheral blood was 8 (5) and 17 (10) respectively compared with controls 6 (4) (p < 0.0001). Moreover, the LAAT could effectively discriminate between various grades of disease activity, the values in patients with active disease being 13 (6)% in mild, 17 (10)% in moderate, and 26 (10)% in severe disease (p < 0.0001). Other acute phase reactants including the erythrocyte sedimentation rate, the white blood cell count, the platelet count, neutrophil count, as well as, the C reactive protein concentration did not differentiate as well between the various groups. Using logistic regression analysis to differentiate between inflammatory bowel disease patients in remission or relapse, the LAAT was the single best indicator. The addition of any other test did not contribute to the discrimination. Among the different laboratory variables tested only the LAAT significantly discriminated between the five different subgroups of controls, remission and mild, moderate or severe disease activity.


Identification in Causal Models With Hidden Variables.
Targets of inference that establish causality are phrased in terms of counterfactual responses to interventions. These potential outcomes operationalize cause effect relationships by means of comparisons of cases and controls in hypothetical randomized controlled experiments. In many applied settings, data on such experiments is not directly available, necessitating assumptions linking the counterfactual target of inference with the factual observed data distribution. This link is provided by causal models. Originally defined on potential outcomes directly (Rubin, 1976), causal models have been extended to longitudinal settings (Robins, 1986), and reformulated as graphical models (Spirtes et al., 2001; Pearl, 2009). In settings where common causes of all observed variables are themselves observed, many causal inference targets are identified via variations of the expression referred to in the literature as the g-formula (Robins, 1986), the manipulated distribution (Spirtes et al., 2001), or the truncated factorization (Pearl, 2009). In settings where hidden variables are present, identification results become considerably more complicated. In this manuscript, we review identification theory in causal models with hidden variables for common targets that arise in causal inference applications, including causal effects, direct, indirect, and path-specific effects, and outcomes of dynamic treatment regimes. We will describe a simple formulation of this theory (Tian and Pearl, 2002; Shpitser and Pearl, 2006b,a; Tian, 2008; Shpitser, 2013) in terms of causal graphical models, and the fixing operator, a statistical analogue of the intervention operation (Richardson et al., 2017).


Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes.
The pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute-phase proteins produced by liver epithelial cells. PTX3 was recently cloned as an interleukin-1 (IL-1)-inducible gene in endothelial cells, with structural similarities to pentraxins in the C-terminal half of the molecule. The present study was designed to investigate the expression of PTX3 in the human leukocyte populations. Human peripheral blood mononuclear cells exposed to lipopolysaccharide (LPS) or IL-1 beta expressed significant levels of PTX3 mRNA. Tumor necrosis factor-alpha (TNF-alpha) was a less-effective inducer of PTX3, whereas IL-6, monocyte chemotactic protein-1, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interferon-gamma were inactive. Among leukocytes, only monocytes exposed to inflammatory cytokines or LPS expressed the PTX3 transcript, which was undetectable in resting or stimulated polymorphonuclear cells, T or B lymphocytes, and natural killer cells. PTX3 mRNA was also inducible in in vitro monocyte-derived macrophages, in tumor-associated macrophages, and in the myelomonocytic cell lines HL60, U937, and THP1, but not in GFD8, with the latter possibly representative of earlier stages of myelomonocytic differentiation. T- and B-cell lines had no detectable PTX3. Inhibition of transcription by actinomycin D blocked induction of PTX3 in monocytes and nuclear run-on analysis showed that LPS induces the expression of the PTX3 gene at the transcriptional level in isolated monocytes. Cycloheximide had no effect on PTX3 induction in U937 cells, but was inhibitory on monocytes exposed to LPS or IL-1 beta. Monoclonal antibody against TNF and the IL-1 receptor antagonists did not inhibit induction of PTX3 in monocytes by LPS, thus excluding these cytokines as secondary stimulators of PTX3. IL-4, but not dexamethasone or transforming growth factor-beta, inhibited PTX3 expression in monocytes. Using a PTX3-specific antiserum, release of PTX3 protein was demonstrated for the first time in stimulated monocytes as well as in endothelial and fibroblastic cells. Thus, PTX3, unlike the classical pentraxins CRP and SAP, is expressed and released by cells of the monocyte-macrophage lineage exposed to inflammatory signals.


Preventing Mitochondrial Disease: A Path Forward.
In a possible first, the heritable transmission of a fatal mitochondrial DNA disease (Leigh syndrome) may have been prevented by replacing the mutation-bearing mitochondria of oocytes with donated mutation-free counterparts. The procedure, carried out by a U.S.-led team, took place in Mexico in circumvention of a statutory U.S. moratorium on mitochondrial replacement. This development calls into question the regulatory utility of a national moratorium in a globalized world wherein cross-border care is increasingly prevalent. This development also calls to account the moral defensibility of a moratorium that acquiesces in the birth of gravely ill children whose afflictions could have been prevented. In this Current Commentary, we outline a potential path forward by analyzing the dual imprint of the moratorium, examining its legislative shortcomings, exploring its motivational roots, considering its national effect, and proposing its unlinking from the related yet distinct ban on editing the genome of the human embryo.


Adoption and diffusion of evidence-based addiction medications in substance abuse treatment.
To examine the roles of facility- and state-level factors in treatment facilities' adoption and diffusion of pharmaceutical agents used in addiction treatment. Secondary data from the National Survey of Substance Abuse Treatment Services (N-SSATS), Substance Abuse and Mental Health Services Administration (SAMHSA), Centers for Medicare and Medicaid Services, Alcohol Policy Information System, and Kaiser Family Foundation. We estimate ordered logit and multinomial logit models to examine the relationship of state and treatment facility characteristics to the adoption and diffusion of three pharmaceutical agents over 4 years when each was at a different stage of adoption or diffusion. N-SSATS data with facility codes, obtained directly from SAMHSA, were linked by state identifiers to the other publicly available, secondary data. The analysis confirms the importance of awareness and exposure to the adoption behavior of others, dissemination of information about the feasibility and effectiveness of innovations, geographical clustering, and licensing and accreditation in legitimizing facilities' adoption and continued use of pharmacotherapies in addiction treatment. Policy and administrative levers exist to increase the availability of pharmaceutical technologies and their continued use by substance abuse treatment facilities.


A Novel Peptide for Simultaneously Enhanced Treatment of Head and Neck Cancer and Mitigation of Oral Mucositis.
We have characterized a novel 21 amino acid-peptide derived from Antrum Mucosal Protein (AMP)-18 that mediates growth promotion of cultured normal epithelial cells and mitigates radiation-induced oral mucositis in animal models, while suppressing in vitro function of cancer cells. The objective of this study was to evaluate these dual potential therapeutic effects of AMP peptide in a clinically relevant animal model of head and neck cancer (HNC) by simultaneously assessing its effect on tumor growth and radiation-induced oral mucositis in an orthotopic model of HNC. Bioluminescent SCC-25 HNC cells were injected into the anterior tongue and tumors that formed were then subjected to focal radiation treatment. Tumor size was assessed using an in vivo imaging system, and the extent of oral mucositis was compared between animals treated with AMP peptide or vehicle (controls). Synergism between AMP peptide and radiation therapy was suggested by the finding that tumors in the AMP peptide/radiation therapy cohort demonstrated inhibited growth vs. radiation therapy-only treated tumors, while AMP peptide-treatment delayed the onset and reduced the severity of radiation therapy-induced oral mucositis. A differential effect on apoptosis appears to be one mechanism by which AMP-18 can stimulate growth and repair of injured mucosal epithelial cells while inhibiting proliferation of HNC cells. RNA microarray analysis identified pathways that are differentially targeted by AMP-18 in HNC vs. nontransformed cells. These observations confirm the notion that normal cells and tumor cells may respond differently to common biological stimuli, and that leveraging this finding in the case of AMP-18 may provide a clinically relevant opportunity.


T lymphocyte subsets in cancer immunity: Friends or foes.
Although immune-based therapy is proving to be a success in several cancer types, only a set of patients appear to respond to immune checkpoint blockade including PD-1 and CTLA-4. A better understanding of the crucial components of cancer immunity is therefore necessary. T lymphocytes, a key element, are found within the tumor microenvironment and seem to be critical in determining the efficacy of immune surveillance. In this review, we will depict the pro- and antitumor roles of major T cell subsets in distinct cancer tissues. The central role of the mainly antitumor subsets, cytotoxic T cells and Th1 cells, will be delineated. Subsequently, we will indicate how other subsets including Th2, Th17, and T regulatory cells exhibit ambivalent roles. We will also describe the emerging and favorable role of Th9 cells in cancer immunity. In parallel, we will go through main mechanisms by which these cells operate, and will pinpoint pathways, which could be used as potential therapeutic targets in order to positively impact the immune response and ameliorate patients' clinical outcome.


The relationship between anti-Mullerian hormone, androgen and insulin resistance on the number of antral follicles in women with polycystic ovary syndrome.
Anti-Müllerian hormone (AMH) is a biomarker that predicts the number of antral follicles and is involved in follicle arrest for women with polycystic ovary syndrome (PCOS). We investigated the association between the characteristic hyperandrogenemia, insulin resistance (IR), AMH, and the morphology and size of ovaries for women with PCOS. A total of 99 Taiwanese women with PCOS who were willing to undergo vaginal ultrasonography were enrolled in this cross-sectional study. The number of antral follicles and the ovarian volume showed a significant correlation with AMH, total testosterone and the free androgen index, but not with age, body mass index (BMI) or the homeostasis model assessment of insulin resistance (HOMA-IR). AMH had a significant negative association with both BMI and HOMA-IR. Multiple stepwise regression analysis demonstrated that AMH, BMI and total testosterone were independently related to the number of antral follicles. AMH and total testosterone were the main determinants for ovarian volume in a stepwise regression model. Our results suggest that not only the AMH level, but also obesity, IR and elevated androgen levels may relate to the development of the large size of antral follicle pool and ovarian volume in women with PCOS. Obesity and IR may enhance the follicular excess through the dysregulation of AMH or through the pathway of hyperandrogenemia. These findings might partly explain why adequate body weight management and improvement in IR can improve the ovulatory function for women with PCOS.


Gut Health in the era of the human gut microbiota: from metaphor to biovalue.
The human intestinal ecosystem, previously called the gut microflora is now known as the Human Gut Microbiota (HGM). Microbiome research has emphasized the potential role of this ecosystem in human homeostasis, offering unexpected opportunities in therapeutics, far beyond digestive diseases. It has also highlighted ethical, social and commercial concerns related to the gut microbiota. As diet factors are accepted to be the major regulator of the gut microbiota, the modulation of its composition, either by antibiotics or by food intake, should be regarded as a fascinating tool for improving the human health. Scientists, the food industry, consumers and policymakers alike are involved in this new field of nutrition. Defining how knowledge about the HGM is being translated into public perception has never been addressed before. This raises the question of metaphors associated with the HGM, and how they could be used to improve public understanding, and to influence individual decision-making on healthcare policy. This article suggests that a meeting of stakeholders from the social sciences, basic research and the food industry, taking an epistemological approach to the HGM, is needed to foster close, innovative partnerships that will help shape public perception and enable novel behavioural interventions that would benefit public health.


Genetic differentiation of the dengue vector, Aedes aegypti (Ho Chi Minh City, Vietnam) using microsatellite markers.
Dengue haemorrhagic fever emerged in the 1950s and has become a major public health concern in most Asian countries. In Vietnam, little is known about the intraspecific variation of the vector and its consequences on vectorial capacity. Here we report the use of microsatellite markers to differentiate Aedes aegypti populations in Ho Chi Minh City, a typical, overcrowded Asian city. Six microsatellite loci, with 5-14 alleles per locus, were scored in 20 mosquito samples collected in 1998 in Ho Chi Minh City. We found substantial differentiation among Ae. aegypti populations from the outskirts, whereas populations from the centre of the city showed less differentiation. These results are consistent with the hypothesis that populations of Ae. aegypti in central Ho Chi Minh City are panmictic because there are abundant larval breeding sites and an abundance of humans for adults to feed upon. In contrast, populations on the outskirts become differentiated largely through the processes of genetic drift because larval breeding sites are not as abundant. These findings implicate human activities associated with urbanization, as factors shaping the genetic structure of Ae. aegypti populations.


Carpenter-Coustan Compared With National Diabetes Data Group Criteria for Diagnosing Gestational Diabetes.
Use of Carpenter-Coustan compared with National Diabetes Data Group criteria increases the number of women diagnosed with gestational diabetes mellitus (GDM) by 30-50%, but whether treatment of this milder GDM reduces adverse outcomes is unknown. We explored the effects of the diagnostic criteria used on the benefits of GDM treatment. This was a secondary analysis of a randomized trial for treatment of mild GDM diagnosed using Carpenter-Coustan criteria. We evaluated the effect of treatment within two mutually exclusive diagnostic groups: 1) women who met the stricter National Diabetes Data Group as well as Carpenter-Coustan criteria (National Diabetes Data Group), and 2) those diagnosed by Carpenter-Coustan but not meeting National Diabetes Data Group criteria (Carpenter-Coustan only). Maternal outcomes examined were pregnancy-induced hypertension, shoulder dystocia, maternal weight gain, and cesarean delivery. Neonatal outcomes were large for gestational age, macrosomia (greater than 4,000 g), fat mass, small for gestational age, and a composite outcome of perinatal death, birth injury, hypoglycemia, hyperbilirubinemia, and hyperinsulinemia. Analysis of variance or the Breslow-Day test, as appropriate, was used to test for the interaction between diagnostic criteria and GDM treatment on the outcomes of interest. Of 958 patients, 560 (58.5%) met National Diabetes Data Group criteria and 398 (41.5%) met Carpenter-Coustan only. Compared with untreated women, the direction of treatment effect did not differ by diagnostic criteria used and was consistent with the original trial. The P value for interaction between diagnostic criteria and treatment status was not significant for any outcome. The overall beneficial treatment effect on pregnancy-induced hypertension, shoulder dystocia, cesarean delivery, and macrosomia was seen in patients diagnosed by the higher National Diabetes Data Group and by the lower thresholds of the Carpenter-Coustan criteria.


Restrictive versus liberal transfusion in patients with diabetes undergoing cardiac surgery: An open-label, randomized, blinded outcome evaluation trial.
To characterize the association between diabetes and transfusion and clinical outcomes in cardiac surgery, and to evaluate whether restrictive transfusion thresholds are harmful in these patients. The multinational, open-label, randomized controlled TRICS-III trial assessed a restrictive transfusion strategy (haemoglobin [Hb] transfusion threshold <75 g/L) compared with a liberal strategy (Hb <95 g/L for operating room or intensive care unit; or <85 g/L for ward) in patients undergoing cardiac surgery on cardiopulmonary bypass with a moderate-to-high risk of death (EuroSCORE ≥6). Diabetes status was collected preoperatively. The primary composite outcome was all-cause death, stroke, myocardial infarction, and new-onset renal failure requiring dialysis at 6 months. Secondary outcomes included components of the composite outcome at 6 months, and transfusion and clinical outcomes at 28 days. Of the 5092 patients analysed, 1396 (27.4%) had diabetes (restrictive, n = 679; liberal, n = 717). Patients with diabetes had more cardiovascular disease than patients without diabetes. Neither the presence of diabetes (OR [95% CI] 1.10 [0.93-1.31]) nor the restrictive strategy increased the risk for the primary composite outcome (diabetes OR [95% CI] 1.04 [0.68-1.59] vs. no diabetes OR 1.02 [0.85-1.22]; Pinteraction = .92). In patients with versus without diabetes, a restrictive transfusion strategy was more effective at reducing red blood cell transfusion (diabetes OR [95% CI] 0.28 [0.21-0.36]; no diabetes OR [95% CI] 0.40 [0.35-0.47]; Pinteraction = .04). The presence of diabetes did not modify the effect of a restrictive transfusion strategy on the primary composite outcome, but improved its efficacy on red cell transfusion. Restrictive transfusion triggers are safe and effective in patients with diabetes undergoing cardiac surgery.


High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis.
Female patients with multiple sclerosis (MS) are at risk for osteoporosis because of gender, immobility, and corticosteroid use. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in 80 female MS patients admitted to a tertiary care hospital. All patients completed a questionnaire that included measurements of dietary intake and sunlight exposure. Biochemical indices of bone metabolism and turnover were measured in a random sample of 52 patients. BMD of the lumbar spine and femoral neck was 1 to 2 SDs lower in MS women compared with a healthy reference population. BMD was lower in patients with more severe MS. The mean 25(OH)D level of the sample population (43 nmol/l) was in the insufficient range, and 12 patients (23%) had frank vitamin D deficiency (< 25 nmol/l). BMD and age-related BMD (z scores) at all skeletal sites measured were lowest when 25(OH)D levels were deficient. Parathyroid hormone (PTH) was frankly elevated in 13% of patients. PTH levels were negatively correlated with 25(OH)D levels and with BMD. Dietary intake of vitamin D was below the recommended level in 80% of patients, and 40% reported no weekly sunlight exposure. After controlling for age, cumulative steroid use was not a determinant of BMD. BMD was significantly reduced in female MS patients, which might increase fracture risk two- to threefold. Vitamin D deficiency with secondary hyperparathyroidism is prevalent and is probably a significant cause of low BMD in this population. Vitamin D deficiency in the female MS patient might be safely and inexpensively corrected by the routine use of vitamin D supplements.


The importance of host age and sex to patterns of reinfection with Ascaris lumbricoides following mass anthelmintic treatment in a South Indian fishing community.
Analysis of egg and worm counts of Ascaris recorded at various intervals following a mass anthelmintic treatment programme in a South Indian fishing community is presented. Three indices of infection in the community are compared, namely the prevalence and intensity of egg output (at 2, 6 and 11 months following treatment) and the number of worms expelled following an 11 month period of reinfection. Detailed examination of these measurements revealed significant associations with patient sex and age. The age-prevalence profile of Ascaris infection changed little over time (except immediately following treatment) with the peak prevalence found in the 5-9 year age group. Although 85% of both males and females harboured Ascaris initially, the prevalence following 11 months reinfection was decreased, due to a significantly lower proportion of males being reinfected. By the 11th month of reinfection, the age-intensity profiles of egg output were similar to those observed at initial treatment in the older age groups (10 years and above) and in male children (less than 10 years). However, a dramatic increase in the egg output of female children, greatly exceeding the initial mean, was observed within a 6 month period of reinfection. The intensity of egg output did not accurately reflect the abundance of Ascaris recovered via drug-induced expulsion following an 11 month period of reinfection. Although the egg output attained preintervention levels, the average worm intensity reached only half the initial value. The trends in the sex- and age-intensity profiles were consistent at the two sampling dates and showed similar patterns to the egg output curves. The relevance of the results to helminth control and the monitoring of reinfection is discussed.


Obsessive-compulsive disorder: identification, neurobiology, and treatment.
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder. It may go unrecognized, however, as many patients are embarrassed by their symptoms and are thus reluctant to report them. Recent research findings on OCD point to neurologic dysfunction in the circuitry of the orbitofrontal cortex and basal ganglia. The advent of the use of serotonin reuptake inhibitors (SRIs) as well as behavioral therapy has greatly improved treatment outcomes for patients with OCD. Given the likelihood that these patients are encountered in primary care consultations, physicians have the opportunity to play a crucial role in the early identification and proper treatment of OCD.


Pollen pool heterogeneity in shortleaf pine, Pinus echinata Mill.
Pollen is the dominant vector of gamete exchange for most temperate tree species. Because pollen movement influences the creation, maintenance and erosion of genetic structure in adult populations, it is important to understand what factors influence the process of pollen movement. Isolation by distance in pollen donor populations can create highly structured pollen polls by increased sampling of local fathers. Extrinsic factors, such as the intervening vegetative structure and local pollen donor densities, can also influence the genetic composition of local pollen pools. Using paternally inherited chloroplast microsatellite markers, we examined the structure and diversity of pollen pools in Pinus echinata Mill. in southern Missouri, USA. Our analysis is based on a multivariate AMOVA analysis of stands ( approximately 1 ha; six per region) nested within regions (approximately 800 ha; four each). Significant multilocus structure of the pollen pool within regions (phiSR = 0.095), but not among regions (phiRT = 0.010), indicates that pollen movement is relatively restricted. Furthermore, the significant correlation between pairwise genetic and physical distances (Mantel correlation; rho = 0.32) provided support for the isolation by distance hypothesis. Our results indicated that availability of pollen donors did not affect diversity of the pollen pool, measured by the number of unique multilocus genotypes at each stand. However, pollen pool diversity was negatively associated with vegetative structure, measured as total forest tree density. Our findings indicated that on-going pollen movement within continuous forest is relatively restricted as a result of both isolation by distance and vegetative structure.


A dual-factor model of mental health: toward a more comprehensive understanding of youth functioning.
Traditional mental health models focus on psychological problems and distress; accordingly, health is viewed as the absence of illness or disability. In contrast, a dual-factor model of mental health incorporates both indicators of positive subjective well-being (SWB) and measures of psychopathological symptoms to comprehensively determine an individual's psychological adjustment. This study used such a dual-factor model to measure the mental health status of young adolescents. A total of 764 middle school students were classified into one of four distinct groups based on having high or low psychopathology and high or low SWB. Furthermore, group differences in student engagement, academic achievement, and environmental support for learning were investigated. Results demonstrated the existence of a traditionally neglected group of adolescents (low SWB and low psychopathology) who are nonetheless at risk for academic and behavior problems in school and who performed no better than the most troubled group of adolescents. Overall, both the presence of positive well-being and the absence of symptoms were necessary for ensuring the most advantageous school performance. These results highlight the importance of incorporating positive indicators of well-being along with traditional negative factors in more fully understanding relationships between individuals' mental health and educational outcomes.


Drug Interactions of Psychiatric and COVID-19 Medications.
Coronavirus disease 2019 (COVID-19) has become a pandemic with 1771514 cases identified in the world and 70029 cases in Iran until April 12, 2020. The co-prescription of psychotropics with COVID-19 medication is not uncommon. Healthcare providers should be familiar with many Potential Drug-Drug Interactions (DDIs) between COVID-19 therapeutic agents and psychotropic drugs based on cytochrome P450 metabolism. This review comprehensively summarizes the current literature on DDIs between antiretroviral drugs and chloroquine/hydroxychloroquine, and psychotropics, including antidepressants, antipsychotics, mood stabilizers, and anxiolytics. Medical databases, including Google Scholar, PubMed, Web of Science, and Scopus were searched to identify studies in English with keywords related to psychiatric disorders, medications used in the treatment of psychiatric disorders and COVID-19 medications. There is a great potential for DDIs between psychiatric and COVID-19 medications ranging from interactions that are not clinically apparent (minor) to those that produce life-threatening adverse drug reactions, or loss of treatment efficacy. The majority of interactions are pharmacokinetic interactions via the cytochrome P450 enzyme system. DDIs are a major concern in the comorbidity of psychiatric disorders and COVID-19 infection resulting in the alteration of expected therapeutic outcomes. The risk of toxicity or lack of efficacy may occur due to a higher or lower plasma concentration of medications. However, psychiatric medication can be safely used in combination with COVID-19 pharmacotherapy with either a wise selection of medication with the least possibility of interaction or careful patient monitoring and management.


Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.
Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the nociceptin receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid receptors and antagonists at the nociceptin receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain.


Recurrence of ovarian cancer-living in limbo.
Few studies have shed light on women's life situation after being informed of having recurrent ovarian cancer. The present study aimed to elucidate women's experiences of living with this knowledge. Interviews were conducted with 12 women who were undergoing or had just completed chemotherapy, 5 to 10 months after learning of the recurrence. Data were collected and analyzed based on a life world perspective using a descriptive phenomenological method. The women's experiences are described via 3 key constituents: being denied one's future while simultaneously hoping to be able to delay the cancer's advancement, feeling alienated from both oneself and one's surroundings, and being responsible. The key constituents were integrated into the structure "living in limbo." The women lived on the threshold to the unknown. They were preparing themselves both for a continued life and for death. "Living in limbo" can be described as a phase of a health-illness transition characterized by loneliness. The vulnerable position and existential struggle of these women should be focused upon in nursing. The sensitive dialogue is essential in these cases.


Diagnostic strategies in venous thromboembolism.
Diagnosis of acute deep vein thrombosis (DVT) and of pulmonary embolism (PE) is often difficult: symptomatic patients are usually investigated employing several diagnostic tests, which should be appropriately selected and sequenced, taking into account their sensitivity, specificity, safety and cost. The objective of this paper is to evaluate the performance of the new diagnostic tests and their combination in rational diagnostic strategies. A literature review was made using a Medline(R) database search for the period 1988-1998 on the following key words in various combinations: diagnosis, diagnostic strategy, venous thrombosis, pulmonary embolism, venous thromboembolism. Results of a new study by our group on diagnosis of DVT in hospitalized patients are also discussed. In patients with symptoms or signs suggestive of DVT, compression ultrasound (CUS) appears to be the diagnostic test of first choice, since it is a noninvasive test with high specificity and sensitivity for proximal DVT (about 97%). When CUS gives a negative result it is usually recommended that the test is repeated after one week, since its sensitivity for calf DVT is poor. The positive and negative predictive values (PPV and NPV) of CUS in symptomatic outpatients can be improved if adequate consideration is given to clinical diagnosis, using a standardized model (ref. #9), which allows symptomatic outpatients to be categorized as having a high, moderate or low probability of DVT. In case of agreement between clinical diagnosis and CUS results, no further testing is needed: patients with high or intermediate clinical probability and positive CUS results are treated, while in patients with low clinical probability and negative CUS results the diagnosis of DVT is excluded. In the case of discrepancy between clinical diagnosis and CUS results, D-dimer test and/or venography are requested. However in patients who develop signs or symptoms of DVT in the hospital the clinical model does not work, and diagnosis should be based on an appropriate mix of CUS, D-dimer (DD) test and venography. In patients presenting with signs or symptoms of pulmonary embolism, the ventilation/perfusion (V/P) lung scan remains a pivotal diagnostic test, and pulmonary angiography the reference standard, but both methods have limitations and in recent years other diagnostic tests such as echocardiography, helical (or spiral) computerized tomography, and magnetic resonance imaging have been introduced into clinical practice. Moreover, all four diagnostic tools mentioned for DVT diagnosis can be considered. Several diagnostic strategies have been proposed and evaluated in comparative studies but there is still debate over the most efficient test combination or sequence. Diagnostic strategies which include adequate consideration of clinical diagnosis using standardized models have the potential of being more efficient for outpatients (but not for inpatients) with symptoms or signs suggesting DVT of lower limbs. For patients with suspected PE, several diagnostic strategies have been assessed: V/P lung scan remains a pivotal diagnostic test, but its limitations have been increasingly recognized and newer non-invasive techniques are gaining credit. A consensus is still to be reached over the most appropriate combination of diagnostic tests.


MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.
While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward.IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.


Magnetic NGF-releasing PLLA/iron oxide nanoparticles direct extending neurites and preferentially guide neurites along aligned electrospun microfibers.
Nerve growth factor releasing composite nanoparticles (NGF-cNPs) were developed to direct the extension of neurite outgrowth from dorsal root ganglia (DRG). Iron oxide magnetic nanoparticles were incorporated into poly-l-lactic acid (PLLA) nanoparticles in order to position the NGF-cNPs in a culture dish. Neurites growing from DRG extended toward the NGF released from the NGF-cNPs. DRG were then cultured on aligned PLLA microfibers in the presence of NGF-cNPs, and these biomaterials combined to align DRG neurite extension along one axis and preferentially toward the NGF-cNPs. This combinatorial biomaterial approach shows promise as a strategy to direct the extension of regenerating neurites.


Utilization and cost of behavioral health services: employee characteristics and workplace health promotion.
The study sought to (1) model demographic and employment-related influences on behavioral health care utilization and cost; (2) model behavioral health care utilization and cost influences on general health care cost, job performance, and earnings; and (3) assess workplace-based health promotion's impact on these factors. Behavioral health care utilization was more common in employees who were female, over age 30, with below-median earnings, or with above-median general (non-behavioral) health care costs. Among employees utilizing behavioral health care, related costs were higher for employees with below-median earnings. Employees utilizing behavioral health care had higher general health care costs and received lower performance ratings than other employees. Health promotion participants were compared with a nonparticipant random sample matched on gender, age, and pre-intervention behavioral health care utilization. Among employees without pre-intervention behavioral health care, participants and nonparticipants did not differ in post-intervention utilization. Among employees utilizing behavioral health care adjusting for pre-intervention costs, participants had higher short-term post-intervention behavioral health care costs than nonparticipants.


Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection.
Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1-2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16-1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.


The Health Profile of Street Children in Africa: A Literature Review.
The United Nations Children's Fund has labeled street children as children in difficult circumstances, which represent a minority population that has been under-represented for too long in health research. This is a concern because street children are at risk of carrying a greater disease burden. Their homeless lifestyle makes them more vulnerable to health risks and problems than children who live at home; as they roam the streets begging for food and money to obtain basic needs and are found sleeping in half-destroyed houses, abandoned basements, under bridges and in the open air. This paper presents health results from a systematic review of literature from 17 databases and including 16 countries in Africa. The review revealed that there are more boys than girls living on the street in their adolescence and who mainly have left home due to poverty and abuse. These children in these countries are vulnerable to poor health due to factors such as homelessness, risky sexual behavior, substance abuse and violence. Among the health problems identified are growth and nutritional disorders, physical injuries, violence, sexual abuse, communicable diseases including diarrheal diseases, malaria, respiratory diseases, neglected tropical diseases, mental health issues, substance abuse, reproductive health disorders, mortality, sexually transmitted diseases and HIV/AIDS. Primary interventions that could prevent poor health and improve the health status of street children include provision of safe shelter, proper nutrition, access to health care, health education, and sexual reproductive health, protection from any form of abuse, violence and substance abuse. Enforcing state policies and laws in all African countries is required to protect street children from neglect, abuse and to increase their access to education. More research on the health risks and health status of street children is still required, particularly in Sub-Saharan Africa, which carries the greatest disease burden and poverty.


Imaging the distribution of iron oxide nanoparticles in hypothermic perfused tissues.
Herein, we evaluate the use of MRI as a tool for assessing iron oxide nanoparticle (IONP) distribution within IONP perfused organs and vascularized composite allografts (VCAs) (i.e., hindlimbs) prepared for cryopreservation. Magnetic resonance imaging was performed on room-temperature organs and VCAs perfused with IONPs and were assessed at 9.4 T. Quantitative T1 mapping and T2∗ -weighted images were acquired using sweep imaging with Fourier transformation and gradient-echo sequences, respectively. Verification of IONP localization was performed through histological assessment and microcomputer tomography. Quantitative imaging was achieved for organs and VCAs perfused with up to 642 mMFe (36 mgFe /mL), which is above previous demonstrations of upper limit detection in agarose (35.7mMFe [2 mgFe /mL]). The stability of IONPs in the perfusate had an effect on the quality of distribution and imaging within organs or VCA. Finally, MRI provided more accurate IONP localization than Prussian blue histological staining in this system, wherein IONPs remain primarily in the vasculature. Using MRI, we were able to assess the distribution of IONPs throughout organs and VCAs varying in complexity. Additional studies are necessary to better understand this system and validate the calibration between T1 measurements and IONP concentration.


Infarct Core Expansion on Computed Tomography before and after Intravenous Thrombolysis.
Infarct core can expand rapidly in acute stroke patients receiving intravenous tissue plasminogen activator (IV t-PA). We investigated changes in the extent of infarct core during IV t-PA treatment, and explored the associative factors of this infarct core expansion in patients with proximal artery occlusion. We included patients who were considered for sequential intra-arterial therapy (IAT) due to occlusion of intracranial proximal artery after IV t-PA. Patients who had a baseline Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) ≥6 and who underwent two consecutive CT scans before and shortly after IV t-PA infusion were enrolled. Patients were classified into no, moderate, and marked expansion groups based on decreases in ASPECTS (0-1, 2-3, and ≥4, respectively) on follow-up CT. Collateral status was graded using CT angiography. Of the 104 patients, 16 (15.4%) patients showed moderate and 13 (12.5%) patients showed marked infarct core expansion on follow-up CT scans obtained at 71.1±19.1 min after baseline CT scan. Sixteen (15.4%) patients had an ASPECTS value <6 on the follow-up CT. None of the patients with marked expansion were independent at 3 months. Univariate analysis and ordinal logistic regression analysis demonstrated that the infarct core expansion was significantly associated with collateral status (p<0.001). Among patients who were considered for IAT after IV t-PA treatment, one out of every seven patients exhibited marked expansion of infarct core on follow-up CT before IAT. These patients tend to have poor collaterals and poor outcomes despite rescue IAT.


Blood Pressure-Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor.
Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg-1), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg-1 min-1) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascular relaxation to nitroprusside and acetylcholine, demonstrating an intact downstream NO-signaling pathway. We conclude that the acute blood pressure-lowering effect of nitrite requires an acidic gastric environment. Future studies will reveal if the cardiovascular complications associated with the use of proton pump inhibitors are linked to interference with the nitrate-nitrite-NO pathway.


Two-channel Kondo effect and renormalization flow with macroscopic quantum charge states.
Many-body correlations and macroscopic quantum behaviours are fascinating condensed matter problems. A powerful test-bed for the many-body concepts and methods is the Kondo effect, which entails the coupling of a quantum impurity to a continuum of states. It is central in highly correlated systems and can be explored with tunable nanostructures. Although Kondo physics is usually associated with the hybridization of itinerant electrons with microscopic magnetic moments, theory predicts that it can arise whenever degenerate quantum states are coupled to a continuum. Here we demonstrate the previously elusive 'charge' Kondo effect in a hybrid metal-semiconductor implementation of a single-electron transistor, with a quantum pseudospin of 1/2 constituted by two degenerate macroscopic charge states of a metallic island. In contrast to other Kondo nanostructures, each conduction channel connecting the island to an electrode constitutes a distinct and fully tunable Kondo channel, thereby providing unprecedented access to the two-channel Kondo effect and a clear path to multi-channel Kondo physics. Using a weakly coupled probe, we find the renormalization flow, as temperature is reduced, of two Kondo channels competing to screen the charge pseudospin. This provides a direct view of how the predicted quantum phase transition develops across the symmetric quantum critical point. Detuning the pseudospin away from degeneracy, we demonstrate, on a fully characterized device, quantitative agreement with the predictions for the finite-temperature crossover from quantum criticality.


Single-cell network profiling of peripheral blood mononuclear cells from healthy donors reveals age- and race-associated differences in immune signaling pathway activation.
A greater understanding of the function of the human immune system at the single-cell level in healthy individuals is critical for discerning aberrant cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-cell network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race-associated variations in signaling responses in discrete cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics.


MiRNAs of peripheral blood as the biomarker of schizophrenia.
The diagnosis of schizophrenia is currently based on the symptoms and bodily signs rather than on the pathological and physiological markers of the patient. In the search for new molecular targeted therapy medicines, and recurrence of early-warning indicators have become the major focus of contemporary research, because they improve diagnostic accuracy. Biomarkers reflect the physiological, physical and biochemical status of the body, and so have extensive applicability and practical significance. The ascertainment of schizophrenia biomarkers will help diagnose, stratify of disease, and treat of schizophrenia patients. The detection of biomarkers from blood has become a promising area of schizophrenia research. Recently, a series of studies revealed that, MiRNAs play an important role in the genesis of schizophrenia, and their abnormal expressions have the potential to be used as biomarkers of schizophrenia. This article presents and summarizes the value of peripheral blood miRNAs with abnormal expression as the biomarker of schizophrenia.


The influence of chronic high alcohol intake on blood pressure, plasma noradrenaline concentration and plasma renin concentration.
1. Sixteen 44-year-old males with chronic high alcohol intake were investigated. Seventeen 44-year-old males with low alcohol intake from the same population served as controls. 2. Plasma noradrenaline concentrations did not differ significantly between individuals with high and low alcohol intake, neither at rest nor after acute stimulation induced by ambulation for 15 min. However, 63% (10 out of 16) of the individuals with high intake showed resting values within the upper quartile range for individuals with low intake. 3. Plasma renin concentration was twice as high (P less than 0.01) in the group with high alcohol intake as in the group with low intake. 4. Systolic as well as diastolic blood pressure was significantly higher (P less than 0.01) in the group with high intake compared with the group with low intake. 5. Sympathetic nerve activity, as defined from measurements of plasma noradrenaline concentration, is not uniformly increased in individuals with chronic high alcohol intake. The mechanism behind the increased plasma renin level as well as the possible role of the renin--angiotensin system in alcohol-induced hypertension remain unsettled.


Palladin is a dynamic actin-associated protein in podocytes.
Palladin, a cytoskeletal protein with essential functions for stress fiber formation, is found in developing and mature tissues, including the kidney. To define its role in the kidney, we measured its expression in mouse kidney and found it co-localized with F-actin in smooth muscle cells of renal arterial vessels, mesangial cells, and podocytes but not in tubular epithelium. Using immunoelectron microscopy, we confirmed that palladin was present in podocytes. In cultured mouse podocytes, palladin co-localized with F-actin in dense regions of stress fibers, focal adhesions, cell-cell contacts and motile cell margins. Transfection with the N-terminal half of palladin targeted it to F-actin-containing structures in podocytes while the C-terminal half accumulated in the nucleus, a result also found for endogenous palladin in cultured cells after leptomycin B was used to block nuclear export. Green fluorescent protein (GFP)-tagged palladin was found in dynamic ring-like F-actin structures and ruffles in cultured podocytes after stimulation with epidermal growth factor. Inhibition of palladin expression by transfection of an antisense construct reduced the formation of ring-like structures. Photo-bleaching analysis showed that GFP-palladin turned over with a half-time of 10 s in focal adhesions and dense regions of stress fibers, suggesting that palladin is a dynamic scaffolding protein. Our study shows that palladin is expressed in podocytes and plays an important role in actin dynamics.


The impact of Helicobacter pylori infection on the gastric microbiota of the rhesus macaque.
Helicobacter pylori colonization is highly prevalent among humans and causes significant gastric disease in a subset of those infected. When present, this bacterium dominates the gastric microbiota of humans and induces antimicrobial responses in the host. Since the microbial context of H. pylori colonization influences the disease outcome in a mouse model, we sought to assess the impact of H. pylori challenge upon the pre-existing gastric microbial community members in the rhesus macaque model. Deep sequencing of the bacterial 16S rRNA gene identified a community profile of 221 phylotypes that was distinct from that of the rhesus macaque distal gut and mouth, although there were taxa in common. High proportions of both H. pylori and H. suis were observed in the post-challenge libraries, but at a given time, only one Helicobacter species was dominant. However, the relative abundance of non-Helicobacter taxa was not significantly different before and after challenge with H. pylori. These results suggest that while different gastric species may show competitive exclusion in the gastric niche, the rhesus gastric microbial community is largely stable despite immune and physiological changes due to H. pylori infection.


Field trial evaluation of the performances of point-of-care tests for screening G6PD deficiency in Cambodia.
User-friendly, accurate, point-of-care rapid tests to detect glucose-6-phosphate dehydrogenase deficiency (G6PDd) are urgently needed at peripheral level to safely recommend primaquine for malaria elimination. The CareStart G6PD RDT (AccessBio, New Jersey, USA), a novel rapid diagnostic test and the most commonly used test, the fluorescent spot test (FST) were assessed against the quantitatively measured G6PD enzyme activity for detecting G6PDd. Subjects were healthy males and non-pregnant females aged 18 years or older residing in six villages in Pailin Province, western Cambodia. Of the 938 subjects recruited, 74 (7.9%) were severe and moderately severe G6PD deficient (enzyme activity <30%), mostly in male population; population median G6PD activity was 12.0 UI/g Hb. The performances of the CareStart G6PD RDT and the FST, according to different cut-off values used to define G6PDd were very similar. For the detection of severe and moderately severe G6PDd (enzyme activity < 30%, < 3.6 UI/g Hb) in males and females, sensitivity and negative (normal status) predictive value were 100% for both point-of-care tools. When the G6PDd cut-off value increased (from < 40% to < 60%), the sensitivity for both PoCs decreased: 93.3% to 71.7% (CareStart G6PD RDT, p = 10(-6)) and 95.5% to 73.2% (FST, p = 10(-6)) while the specificity for both PoCs remained similar: 97.4% to 98.3% (CareStart G6PD RDT, p = 0.23) and 98.7% to 99.6% (FST, p = 0.06). The cut-off values for classifying individuals as normal were 4.0 UI/g Hb and 4.3 UI/g Hb for the CareStart G6PD RDT and the FST, respectively. The CareStart G6PD RDT reliably detected moderate and severe G6PD deficient individuals (enzyme activity <30%), suggesting that this novel point-of-care is a promising tool for tailoring appropriate primaquine treatment for malaria elimination by excluding individuals with severe G6PDd for primaquine treatment.


Why the Oregon CCO experiment could founder.
The most recent Oregon Medicaid experiment is the boldest attempt yet to limit health care spending. Oregon's approach using a Medicaid waiver from the Centers for Medicare and Medicaid Services utilizes global payments with two-sided risk at two levels - coordinated care organizations (CCOs) and the state. Equally important, the Oregon experiment mandates coverage of medical, behavioral, and dental health care using flexible coverage, with the locus of delivery innovation focused at the individual CCO level and with financial consequences for quality-of-care metrics. But insightful design alone is insufficient to overcome the vexing challenge of cost containment on a two- to five-year time horizon; well-tuned execution is also necessary. There are a number of reasons that the Oregon CCO model faces an uphill struggle in implementing the envisioned design.


Does consent bias research?
Researchers increasingly rely on large data sets of health information, often linked with biological specimens. In recent years, the argument has been made that obtaining informed consent for conducting records-based research is unduly burdensome and results in "consent bias." As a type of selection bias, consent bias is said to exist when the group giving researchers access to their data differs from the group denying access. Therefore, to promote socially beneficial research, it is argued that consent should be unnecessary. After analyzing the biostatistics evidence and bioethics arguments, the article concludes that (1) claims about the amount of consent bias are overstated; (2) commonly used statistical methods usually can account for consent bias; and (3) any residual effects of consent bias are below an acceptable level of imprecision and constitute a reasonable social cost for conducting ethically responsible research.


Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour.
Mirtazapine is a tetracyclic antidepressant drug available as a racemic mixture of S(+)- and R(-)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders-4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles *3, *4, *5 and *6 and gene duplication. Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/R(-) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)-N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/R(-) ratio and S(+)-N-desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(-)-N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(-) ratio (0.28 vs. 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.


Prediction of intrinsic disorder in proteins using MFDp2.
Intrinsically disordered proteins (IDPs) are either entirely disordered or contain disordered regions in their native state. IDPs were found to be abundant across all kingdoms of life, particularly in eukaryotes, and are implicated in numerous cellular processes. Experimental annotation of disorder lags behind the rapidly growing sizes of the protein databases and thus computational methods are used to close this gap and to investigate the disorder. MFDp2 is a novel webserver for accurate sequence-based prediction of protein disorder which also outputs well-described sequence-derived information that allows profiling the predicted disorder. We conveniently visualize sequence conservation, predicted secondary structure, relative solvent accessibility, and alignments to chains with annotated disorder. The webserver allows predictions for multiple proteins at the same time, includes help pages and tutorial, and the results can be downloaded as text-based (parsable) file. MFDp2 is freely available at http://biomine.ece.ualberta.ca/MFDp2/.


Characterization of the gene encoding the immunodominant 35 kDa protein of Mycobacterium leprae.
Analysis of the interaction between the host immune system and the intracellular parasite Mycobacterium leprae has identified a 35 kDa protein as a dominant antigen. The native 35 kDa protein was purified from the membrane fraction of M. leprae and termed MMPI (major membrane protein I). As the purified protein was not amenable to N-terminal sequencing, partial proteolysis was used to establish the sequences of 21 peptides. A fragment of the 35 kDa protein-encoding gene was amplified by the polymerase chain reaction from M. leprae chromosomal DNA with oligonucleotide primers derived from internal peptide sequences and the whole gene was subsequently isolated from a M. leprae cosmid library. The nucleotide sequence of the gene revealed an open reading frame of 307 amino acids containing most of the peptide sequences derived from the native 35 kDa protein. The calculated subunit mass was 33.7 kDa, but the native protein exists as a multimer of 950 kDa. Database searches revealed no identity between the 35 kDa antigen and known protein sequences. The gene was expressed in Mycobacterium smegmatis under the control of its own promoter or at a higher level using an 'up-regulated' promoter derived from Mycobacterium fortuitum. The gene product reacted with monoclonal antibodies raised to the native protein. Using the bacterial alkaline phosphatase reporter system, we observed that the 35 kDa protein was unable to be exported across the membrane of recombinant M. smegmatis. The 35 kDa protein-encoding gene is absent from members of the Mycobacterium tuberculosis complex, but homologous sequences were detected in Mycobacterium avium, Mycobacterium haemophilum and M. smegmatis. The availability of the recombinant 35 kDa protein will permit dissection of both antibody- and T-cell-mediated immune responses in leprosy patients.


Stillbirths: Where? When? Why? How to make the data count?
Despite increasing attention and investment for maternal, neonatal, and child health, stillbirths remain invisible-not counted in the Millennium Development Goals, nor tracked by the UN, nor in the Global Burden of Disease metrics. At least 2·65 million stillbirths (uncertainty range 2·08 million to 3·79 million) were estimated worldwide in 2008 (≥1000 g birthweight or ≥28 weeks of gestation). 98% of stillbirths occur in low-income and middle-income countries, and numbers vary from 2·0 per 1000 total births in Finland to more than 40 per 1000 total births in Nigeria and Pakistan. Worldwide, 67% of stillbirths occur in rural families, 55% in rural sub-Saharan Africa and south Asia, where skilled birth attendance and caesarean sections are much lower than that for urban births. In total, an estimated 1·19 million (range 0·82 million to 1·97 million) intrapartum stillbirths occur yearly. Most intrapartum stillbirths are associated with obstetric emergencies, whereas antepartum stillbirths are associated with maternal infections and fetal growth restriction. National estimates of causes of stillbirths are scarce, and multiple (>35) classification systems impede international comparison. Immediate data improvements are feasible through household surveys and facility audit, and improvements in vital registration, including specific perinatal certificates and revised International Classification of Disease codes, are needed. A simple, programme-relevant stillbirth classification that can be used with verbal autopsy would provide a basis for comparable national estimates. A new focus on all deaths around the time of birth is crucial to inform programmatic investment.


Melatonin's role in preventing toxin-related and sepsis-mediated hepatic damage: A review.
The liver is a central organ in detoxifying molecules and would otherwise cause molecular damage throughout the organism. Numerous toxic agents including aflatoxin, heavy metals, nicotine, carbon tetrachloride, thioacetamide, and toxins derived during septic processes, generate reactive oxygen species followed by molecular damage to lipids, proteins and DNA, which culminates in hepatic cell death. As a result, the identification of protective agents capable of ameliorating the damage at the cellular level is an urgent need. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other organs and many studies confirm its benefits against oxidative stress including lipid peroxidation, protein mutilation and molecular degeneration in various organs, including the liver. Recent studies confirm the benefits of melatonin in reducing the cellular damage generated as a result of the metabolism of toxic agents. These protective effects are apparent when melatonin is given as a sole therapy or in conjunction with other potentially protective agents. This review summarizes the published reports that document melatonin's ability to protect hepatocytes from molecular damage due to a wide variety of substances (aflatoxin, heavy metals, nicotine, carbon tetrachloride, chemotherapeutics, and endotoxins involved in the septic process), and explains the potential mechanisms by which melatonin provides these benefits. Melatonin is an endogenously-produced molecule which has a very high safety profile that should find utility as a protective molecule against a host of agents that are known to cause molecular mutilation at the level of the liver.


Impact of commonly used Ag-Cu ion doses on Desulfovibrio sp.: growth and microbiologically induced corrosion against stainless steel.
Ag-Cu ions in cooling water may inhibit the activity of sulfate-reducing bacteria and therefore provide solutions to microbiologically induced corrosion (MIC) problems, mainly caused by Desulfovibrio sp. To investigate this, the MIC behavior of Desulfovibrio sp. on 316L stainless steel in terms of growth and extracellular polymeric substances (EPS) production was investigated in the presence of Ag-Cu ions. Laboratory-scale systems were set up with final concentrations of 0.13 ppm Ag and 0.3 ppm Cu ions, as they are the frequently used doses for cooling waters, and operated over 720 hours. The corrosion rate was evaluated by gravimetric assay, scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) analyses. The growth of Desulfovibrio sp. was assessed by bacterial counting and EPS production. Ag-Cu ions in the biofilm were assessed by inductively coupled plasma - optical emission spectrometry (ICP-OES) and EDS-elemental mapping analyses. It was concluded that the ion concentrations used caused an increase in EPS production, especially of protein. The corrosion rate of the metal by Desulfovibrio sp. in the presence of ions was detected as being 29 times higher than that in the sterile medium with the ions after 720 hours. The results suggested that Desulfovibrio sp. exhibited more corrosive behavior in the presence of non-toxic concentrations of Ag-Cu ions.


Selective dysfunction of basal ganglia subterritories: From movement to behavioral disorders.
Historically, Parkinson's disease (PD) was defined as a pure movement disorder. Currently, it is widely accepted that this disease is also characterized by nonmotor signs, such as depression, apathy, and anxiety. On the other hand, the consideration of Gilles de la Tourette syndrome (GTS) as a neuropsychiatric disorder has also been debated. In this review, we will focus on these two disorders, which combine both motor and behavioral features and in which dysfunction of cortical and subcortical regions was suggested. Anatomical, experimental, and clinical data are reported to support the involvement of basal ganglia (BG) in cognitive and motivational functions in addition to motor control. In PD, the nonmotor signs could result from the heterogeneity of dopaminergic lesions and excessive activation of the dopamine receptors, particularly within the limbic neuronal networks. Experimental results obtained on nonhuman primates using local disinhibition within functional territories of BG allowed the precise mapping of their motor and nonmotor functions. Thus, impairment of inhibitory control inside specific striatal territories induced behavioral disorders and abnormal movements, which had striking similarities to clinical expressions of GTS. Establishing such a relationship between BG subterritories and motor and behavioral disorders could potentially be helpful for future target choices for DBS in many neuropsychiatric disorders. Furthermore, it is also of great interest for therapeutic research and for the efficient targeting of symptom relief to determine the precise pharmacological effects of the two main modulators of BG function, which are dopamine and serotonin.


How molecules stick together in organic crystals: weak intermolecular interactions.
This tutorial review introduces the fundamentals of intermolecular interactions in terms of the underlying physics and goes on to illustrate the most popular methods for the computer simulation of intermolecular interactions, from atom-atom potentials to ab initio methods, including intermediate, hybrid methods, with an appreciation of their relative merits and costs. Typical results are critically presented, culminating in the most difficult exercise of all, the computer prediction of crystal structures. Perspectives on our present and future ability to understand and exploit intermolecular interactions are given.


Biogeographical origin and speciation of the Anthocoris nemorum group.
The Anthocoris nemorum group belongs to the Anthocoridae (Hemiptera), and is an important group of predators of agricultural pests. A phylogeny was constructed in conjunction with dispersal-vicariance analysis of the Anthocoris nemorum group species in order to discern the relationships between the phylogeographical structuring of A. nemorum group species, and the effects of the Qinghai-Tibet plateau uplift. The divergence times were estimated using Bayesian inference as implemented in BEAST. A portion of the mitochondrial COI gene (1406 bp) and 16S rDNA (932 bp) were chosen as molecular markers to reconstruct evolutionary relationships among 10 species in this group. The combined approach, based on phylogeny, estimation of node dates, and dispersal-vicariance analyses, indicated that the phylogeographical structuring of A. nemorum has been primarily shaped by the two main periods of the Qinghai-Tibet plateau uplift. The DIVA optimal reconstructions suggest that A. nemorum diversified from the Miocene to the Pleistocene from a center of origin in the Hengduan Mountains. The rapid uplift of Mountain ranges associated with the uplift of the entire Qinghai-Tibet plateau may have promoted rapid divergence in the A. nemorum group. Vicariance and dispersal were both essential in shaping the present distribution patterns of A. nemorum.


Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.
Branching morphogenesis of the embryonic lung requires interactions between the epithelium and the mesenchyme. Previously, we reported that Sonic hedgehog (Shh) transcripts are present in the epithelium of the developing mouse lung, with highest levels in the terminal buds. Here, we report that transcripts of mouse patched (Ptc), the homologue of a Drosophila gene encoding a putative transmembrane protein required for hedgehog signaling, are expressed at high levels in the mesenchyme adjacent to the end buds. To investigate the function of SHH in lung development, Shh was overexpressed throughout the distal epithelium, using the surfactant protein-C (SP-C)-enhancer/promoter. Beginning around 16.5 dpc, when Shh and Ptc RNA levels are normally both declining, this treatment caused an increase in the ratio of interstitial mesenchyme to epithelial tubules in transgenic compared to normal lungs. Transgenic newborn mice die soon after birth. Histological analysis of the lungs at the light and electron microscope level shows an abundance of mesenchyme and the absence of typical alveoli. In vivo BrdU labeling indicates that Shh overexpression results in increased mesenchymal and epithelial cell proliferation at 16.5 and 17.5 dpc. However, analysis of CC-10 and SP-C expression reveals no significant inhibition in the differentiation of proximal and distal epithelial cells. The expression of genes potentially regulated by SHH was also examined. No difference could be observed between transgenic and control lungs in either the level or distribution of Bmp4, Wnt2 and Fgf7 RNA. By contrast, Ptc is clearly upregulated in the transgenic lung. These results thus establish a role for SHH in lung morphogenesis, and suggest that SHH normally regulates lung mesenchymal cell proliferation in vivo.


A population-based examination of racial and ethnic differences in receiving physicians' advice to quit smoking.
We examined the rate of physician-delivered smoking cessation advice in the United States over time for five different racial/ethnic groups. We analyzed three waves (1992--1993, 1995--1996, 1998--1999) of population-based survey data (Tobacco Use Supplement of the Current Population Survey) to examine the relationship between a smoker's race/ethnicity and past-year receipt of physician-delivered smoking cessation advice. Results of a multivariate logistic regression showed no difference in the receipt of advice as a function of a smoker's race/ethnicity in any of the surveys, with the exception of 1998--1999, after controlling for factors such as smoker's gender, years of education, household income, and cigarettes smoked per day. In the 1998--1999 survey, Asian smokers were more likely to report receiving smoking cessation advice from a physician relative to non-Hispanic White smokers. With the exception of American Indian/Alaska Native smokers, the receipt of advice by each racial/ethnic group increased significantly from the 1992--1993 survey to the 1998--1999 survey, after controlling for gender, age, education, and cigarettes smoked per day. Because rates of advice for American Indian/Alaska Native smokers did not increase over time, specific public health interventions should be developed and integrated into medical settings serving smokers from American Indian/Alaska Native communities.


Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.
Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations.


Guanidinium-based "molecular glues" for modulation of biomolecular functions.
Molecular adhesion based on multivalent interactions plays essential roles in various biological processes. Hence, "molecular glues" that can adhere to biomolecules may modulate biomolecular functions and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactions. We highlight a guanidinium ion-based salt-bridge as a key interaction for adhesion to biomolecules and discuss the application of molecular glues for manipulation of biomolecular assemblies, drug delivery systems, and modulation of biomolecular functions.


Monitoring biomarkers after pediatric heart surgery: a new paradigm on the horizon.
Until recently, risk scoring systems for adult patients consisted of only clinical criteria. Currently, we are experiencing an abundant surge of literature integrating a wide range of biomarker arrays to clinical criteria in assessing the risk in an adult. In fact, novel risk scoring systems such as Reynolds criteria have emerged by combining the validated biomarkers to the traditional risk factors. Novel biomarkers potentially improve clinical management of cardiovascular disease, but there are gaps in understanding their role during childhood. The reason might be related to relatively lower prevalence of cardiovascular disease in children compared to the adult population. One exceptional group is the children with congenital heart disease. Recent studies indicate that novel biomarkers can alert the clinician in a timely manner about neurological and myocardial injury and their inflammatory consequences. Current technologies enable us to measure several biomarkers using only a few microliters of plasma. The preliminary studies show that novel biomarkers in addition to the traditionally studied biomarkers can help the clinician to identify children at high risk following pediatric heart surgery. Future studies are needed to confirm the role of biomarkers in monitoring children after cardiopulmonary bypass.


Distribution of deep-water corals, sponges, and demersal fisheries landings in Southern California, USA: implications for conservation priorities.
Deep-sea corals in Southern California are diverse and abundant but subject to multiple stressors, including bottom-contact fisheries using mobile and fixed gear. There is a need for more information on the distribution of these taxa in relation to the distribution of demersal fishing effort, and the distribution of marine protected areas, in order to improve spatial planning. There are many marine managed areas in Southern California, including essential fish habitat (EFH) areas, conservation areas, and a national marine sanctuary, but specific areas of overlap between bottom fishing and benthic epifauna are poorly known. Groundfish surveys were conducted by the National Marine Fisheries Service using a remotely operated vehicle throughout Southern California between 2003 and 2011 to document abundance and distribution of deep-water rockfish and flatfish to a depth of 500 m. Corals and sponges were also common in these images, providing an opportunity to examine these communities. Analyses of 34,792 still images revealed abundance and diversity of coral and sponge taxa, as well as frequency of fishing debris. The occurrence data were overlaid in a geographic information system with landings data for deep-water (>50 m) demersal fisheries to identify areas of spatial overlap. Corals or sponges were observed in 23% of images. A total of 15 coral genera and six sponge morphotypes were identified. A total of 70 species codes were targeted by deep-water demersal fisheries operating below 50 m for years 2007-2011. A novel priority-setting algorithm was developed to identify areas of high richness, abundance, and fishing intensity (RAFi). Several highly-ranked areas were already protected as EFH (Footprint, Piggy Bank). Other highly-ranked sites (West Catalina Island, San Clemente Island, 9-Mile Bank, Santa Rosa Flats) were encompassed by transient gear restrictions, such as Rockfish conservation areas, but are now recommended for permanent protection by the Pacific Fishery Management Council.


[Surgical treatment of elbow dislocations accompanied by coronoid fractures].
We evaluated the results of surgical treatment for elbow dislocations accompanied by Regan-Morrey type 2-3 coronoid fractures. Eight patients (6 males, 2 females; mean age 44 years; range 23 to 76 years) underwent surgical treatment for elbow dislocations accompanied by a coronoid fracture. Three patients had Regan-Morrey type 2, five patients had type 3 coronoid fractures. Accompanying injuries were Mason-Johnston type 4 radial head fractures (n=6), olecranon fractures (n=4), lateral humeral condyle fracture (n=1), and lateral (n=5) or medial (n=2) collateral ligament ruptures. Coronoid fractures were fixed with a plate, screw, or a cerclage wire in all the patients except for one patient who underwent coronoid excision. For radial head fractures, plate or screw and K-wire fixation was performed in two patients and radial head prosthesis was used in four patients. Olecranon fractures were fixed with a plate or AO tension band. Functional results were assessed using the Mayo elbow performance score. The mean follow-up period was 22.6 months (range 1 to 65.5 months). Union was achieved in all the patients. At the latest assessments, the mean Mayo elbow performance score was 84.3 (range 50 to 100). All the patients expressed satisfaction with surgical treatment except for one patient who underwent coronoid excision. All the fixation materials used for olecranon fractures were removed after union due to implant-associated pain. Ulnar nerve transposition was required in two patients with fractures involving the anteromedial facet of the coronoid process. Two patients developed heterotopic ossification that did not affect the range of motion of the elbow. Surgical treatment of elbow dislocations associated with Regan-Morrey type 2-3 coronoid fractures enables a concentric reduction of the elbow, stability, and early motion.


Detecting Severe Incidents from Electronic Medical Records Using Machine Learning Methods.
The goal of this research was to design a solution to detect non-reported incidents, especially severe incidents. To achieve this goal, we proposed a method to process electronic medical records and automatically extract clinical notes describing severe incidents. To evaluate the proposed method, we implemented a system and used the system. The system successfully detected a non-reported incident to the safety management department.


A prospective study of Alzheimer disease in Down syndrome.
Ninety-six individuals with Down syndrome over age 35 years were evaluated and followed up for evidence of nontreatable dementia. Dementia was judged to be present when a functional decline occurred in areas such as orientation, memory, verbal and motor skills, and self-care abilities. Forty-nine patients with Down syndrome fit this criterion, with an average onset of dementia at 54.2 +/- 6.1 years. The prevalence of dementia in the institutionalized Down syndrome population of our study (n = 53) was 8% (2/25 patients) between 35 and 49 years, 55% (11/20 patients) between 50 and 59 years, and 75% (6/8 patients) of those over 60 years old. Of note, 41 (84%) demented individuals with Down syndrome developed seizures. Ten (20%) had parkinsonian features. Adequately treated hypothyroidism was present in 27 (59%) of 46 demented patients with Down syndrome tested. The average duration of dementia in the 23 patients who died was 4.6 +/- 3.2 years. Computed tomographic scans in 43 patients all showed brain tissue loss, most pronounced in the temporal lobes. Brains from 12 autopsied cases showed large numbers of plaques and tangles in the same locations as in persons with Alzheimer disease.


Differences in marital status and mortality by race/ethnicity and nativity among California cancer patients.
It has been observed that married cancer patients have lower mortality rates than unmarried patients, but data for different racial/ethnic groups are scarce. The authors examined the risk of overall mortality associated with marital status across racial/ethnic groups and sex in data from the California Cancer Registry. California Cancer Registry data for all first primary invasive cancers diagnosed from 2000 through 2009 for the 10 most common sites of cancer-related death for non-Hispanic whites (NHWs), blacks, Asians/Pacific Islanders (APIs), and Hispanics were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for marital status in relation to overall mortality by race/ethnicity and sex. The study cohort included 393,470 male and 389,697 female cancer patients and 204,007 and 182,600 deaths from all causes, respectively, through December 31, 2012. All-cause mortality was higher in unmarried patients than in married patients, but there was significant variation by race/ethnicity. Adjusted HRs (95% CIs) ranged from 1.24 (95% CI, 1.23-1.26) in NHWs to 1.11 (95% CI, 1.07-1.15) in APIs among males and from 1.17 (95% CI, 1.15-1.18) in NHWs to 1.07 (95% CI, 1.04-1.11) in APIs among females. All-cause mortality associated with unmarried status compared with married status was higher in US-born API and Hispanic men and women relative to their foreign-born counterparts. For patients who have the cancers that contribute most to mortality, being unmarried is associated with worse overall survival compared with being married, with up to 24% higher mortality among NHW males but only 6% higher mortality among foreign-born Hispanic and API females. Future research should pursue the identification of factors underlying these associations to inform targeted interventions for unmarried cancer patients. Cancer 2016;122:1570-8. © 2016 American Cancer Society.


Computational prediction of formulation strategies for beyond-rule-of-5 compounds.
The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets.


The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases.
Understanding of the personal risks for rheumatoid arthritis (RA) and other rheumatic diseases remains poor, despite advances in knowledge with regard to their pathogenesis, therapeutics, and clinical impact, in part because the personal lifetime risk of developing these diseases is unknown. This study was undertaken to estimate the lifetime risk of RA, as well as other inflammatory autoimmune rheumatic diseases, including systemic lupus erythematosus, psoriatic arthritis, polymyalgia rheumatica (PMR), giant cell arteritis, ankylosing spondylitis, and Sjögren's syndrome, and to provide an overall estimate of the risk of developing inflammatory autoimmune rheumatic disease over a lifetime. Using the incidence rates obtained from our population-based studies of rheumatic diseases among residents of Olmsted County, Minnesota, and mortality rates from life tables for the general population, we estimated the sex-specific lifetime risk of rheumatic disease. The lifetime risk of RA developing in US adults was 3.6% for women and 1.7% for men, and the lifetime risk of rheumatoid factor-positive RA was 2.4% for women and 1.1% for men. The second most common inflammatory autoimmune rheumatic disease was PMR, with a lifetime risk of 2.4% for women and 1.7% for men. The overall lifetime risk of inflammatory autoimmune rheumatic disease was 8.4% for women and 5.1% for men. One in 12 women and 1 in 20 men will develop an inflammatory autoimmune rheumatic disease during their lifetime. These results can serve as useful guides in counseling patients regarding their lifetime risk of these conditions and have important implications regarding disease awareness campaigns.


Practice Advisory on the Appropriate Use of NSAIDs in Primary Care.
Cyclo-oxygenase (COX)-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are important in managing acute and chronic pain secondary to inflammation. As a greater understanding of the risks of gastrointestinal (GI), cardiovascular (CV) and renal events with NSAIDs use has emerged, guidelines have evolved to reflect differences in risks among NSAIDs. Updated guidelines have yet to reflect new evidence from recent trials which showed similar CV event rates with celecoxib compared to naproxen and ibuprofen, and significantly better GI tolerability for celecoxib. This practice advisory paper aims to present consensus statements and associated guidance regarding appropriate NSAID use based on a review of current evidence by a multidisciplinary group of expert clinicians. This paper is especially intended to guide primary care practitioners within Asia in the appropriate use of NSAIDs in primary care. Following a literature review, group members used a modified Delphi consensus process to determine agreement with selected recommendations. Agreement with a statement by 75% of total voting members was defined a priori as consensus. For low GI risk patients, any nonselective NSAID plus proton pump inhibitor (PPI) or celecoxib alone is acceptable treatment when CV risk is low; for high CV risk patients, low-dose celecoxib or naproxen plus PPI is appropriate. For high GI risk patients, celecoxib plus PPI is acceptable for low CV risk patients; low-dose celecoxib plus PPI is appropriate for high CV risk patients, with the alternative to avoid NSAIDs and consider opioids instead. Appropriate NSAID prescription assumes that the patient has normal renal function at commencement, with ongoing monitoring recommended. In conclusion, appropriate NSAID use requires consideration of all risks.