Hospital pharmacists' perceptions of medication counseling: A focus group study.
Medication counseling sessions are key times for a pharmacist to speak to patients about their medications and the changes made to their therapies during their hospital stay. To explore hospital pharmacists' perceptions of their roles and goals in patient medication counseling, and perceived barriers and facilitators to achieving their goals. Hospital pharmacist focus groups were held in two tertiary referral hospitals. Eligible pharmacists had provided medication counseling within the previous six months in inpatient and/or outpatient settings. Interested pharmacists attended a focus group designed to elicit their opinions and perceptions of patient medication counseling. Focus groups were audio recorded and transcribed verbatim. Inductive thematic analysis was applied to the data to identify initial patterns (codes) which were then organized into common overarching themes using NVivo(®) software. The codes were reviewed for reliability by pharmacists independent of the focus groups. Six, 1-h focus groups were conducted with a total of 24 pharmacists participating. Saturation of information was determined after four focus groups. Greater than 80% consensus was achieved for reliability of the identified codes. A number of themes emerged from these codes around the goals, roles, and the barriers and facilitators to meeting these goals. Pharmacists' patient-centered goals in medication counseling were to build rapport, to empower patients and to improve patients' experience, health and safety. These goals would be accomplished through specific roles such as being an assessor, educator and problem-solver. Pharmacists frequently cited time pressures caused by systemic (hospital), and pharmacy specific processes as key challenges to achieving their goals. Factors that enabled pharmacists to meet their goals were those related to effective interprofessional collaboration and the quality of professional practice (such as training, expanded roles and advanced planning for discharge). Hospital pharmacists emphasized patient-centered goals in medication counseling and outlined the challenges to meet those goals. The findings from this study will be used to develop strategies for effective communication and inform pharmacy practice changes to improve patient care.


The future of immune checkpoint therapy.
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.


The Complications of Bariatric Surgery Patients with Type 2 Diabetes in the World: A Systematic Review and Meta-Analysis.
In this Meta-analysis, we aimed to quantify the incidence of complications of different methods of bariatric surgery on diabetic patients. Type 2 Diabetes Mellitus (T2DM) is increasing worldwide specifically in obese cases. Additionally, obesity worsens T2DM. Complications of each bariatric surgery method were assessed separately; but, a meta-analysis of these complications and comparison between procedures in T2DM patients have not been investigated previously. The result of this study will help surgeons to choose the most appropriate surgical technique, considering individual conditions for a diabetic patient. We searched PubMed, Scopus, and ISI for original papers including bariatric surgical procedures for diabetic population and the reported consequences. Data analyses were done using Stata software. Mortality percentage between diabetic and non-diabetic patients was statistically nonsignificant (P = 0.987). Early and late complications were higher in diabetic group in comparison with non-diabetic (6.0% vs. 1.8%, P = 0.024 and 0.6% vs. 0.3%, P = 0.04, respectively). Most prevalent findings in malabsorptive (7.8%, P < 0.001) and restrictive procedures (80%, P < 0.001) were major complications and hypoglycemic episodes, respectively. As our study showed, most of the complications are not necessarily higher in diabetic population but dependent on the method of surgery.


Chiral symmetry breaking in a microscopic model with asymmetric autocatalysis and inhibition.
Asymmetric autocatalysis and inhibition have been proposed as key processes in the spontaneous emergence of chiral symmetry breaking in a prebiotic world. An elementary lattice model is formulated to simulate the kinetics of chiral symmetry breaking via autocatalysis and inhibition in a mixture of prochiral reactants, chiral products, and inert solvent. Starting from a chirally unbiased initial state, spontaneous symmetry breaking occurs in spite of equal a priori probability for creating either product enantiomer, and the coupled reaction-diffusion processes subsequently amplify the random early-stage symmetry breaking. The processes of reaction and diffusion are kinetically intertwined in a way leading to competition in the appearance of enantiomeric excess. An effective transition temperature can be identified below which spontaneous symmetry breaking appears. In the absence of inhibition, reactions are predominantly autocatalytic under both reaction control (fast diffusion, slow reaction) or diffusion control (fast reaction, slow diffusion) conditions. In the presence of inhibition, simulations with different system sizes converge to the same transition temperature under reaction control conditions, and in this limit the reactions are predominantly nonautocatalytic.


Clinical pharmacology of furosemide in neonates: a review.
Furosemide is the diuretic most used in newborn infants. It blocks the Na+-K+-2Cl- symporter in the thick ascending limb of the loop of Henle increasing urinary excretion of Na+ and Cl-. This article aimed to review the published data on the clinical pharmacology of furosemide in neonates to provide a critical, comprehensive, authoritative and, updated survey on the metabolism, pharmacokinetics, pharmacodynamics and side-effects of furosemide in neonates. The bibliographic search was performed using PubMed and EMBASE databases as search engines; January 2013 was the cutoff point. Furosemide half-life (t1/2) is 6 to 20-fold longer, clearance (Cl) is 1.2 to 14-fold smaller and volume of distribution (Vd) is 1.3 to 6-fold larger than the adult values. t1/2 shortens and Cl increases as the neonatal maturation proceeds. Continuous intravenous infusion of furosemide yields more controlled diuresis than the intermittent intravenous infusion. Furosemide may be administered by inhalation to infants with chronic lung disease to improve pulmonary mechanics. Furosemide stimulates prostaglandin E2 synthesis, a potent dilator of the patent ductus arteriosus, and the administration of furosemide to any preterm infants should be carefully weighed against the risk of precipitation of a symptomatic patent ductus arteriosus. Infants with low birthweight treated with chronic furosemide are at risk for the development of intra-renal calcifications.


Degeneration and plasticity of the optic pathway in Alström syndrome.
Alström syndrome is a rare inherited ciliopathy in which early progressive cone-rod dystrophy leads to childhood blindness. We investigated functional and structural changes of the optic pathway in Alström syndrome by using MR imaging to provide insight into the underlying pathogenic mechanisms. Eleven patients with genetically proved Alström syndrome (mean age, 23 years; range, 6-45 years; 5 females) and 19 age- and sex-matched controls underwent brain MR imaging. The study protocol included conventional sequences, resting-state functional MR imaging, and diffusion tensor imaging. In patients with Alström syndrome, the evaluation of the occipital regions showed the following: 1) diffuse white matter volume decrease while gray matter volume decrease spared the occipital poles (voxel-based morphometry), 2) diffuse fractional anisotropy decrease and radial diffusivity increase while mean and axial diffusivities were normal (tract-based spatial statistics), and 3) reduced connectivity in the medial visual network strikingly sparing the occipital poles (independent component analysis). After we placed seeds in both occipital poles, the seed-based analysis revealed significantly increased connectivity in patients with Alström syndrome toward the left frontal operculum, inferior and middle frontal gyri, and the medial portion of both thalami (left seed) and toward the anterior portion of the left insula (right and left seeds). The protean occipital brain changes in patients with Alström syndrome likely reflect the coexistence of diffuse primary myelin derangement, anterograde trans-synaptic degeneration, and complex cortical reorganization affecting the anterior and posterior visual cortex to different degrees.


Sex determination in Drosophila: the X-chromosomal gene liz is required for Sxl activity.
In Drosophila, females require products of the gene Sxl for sex determination, dosage compensation and fertility. I show here that the X-chromosomal gene liz, located in 4F1 to 4F11 and previously called fs(1)1621, provides maternal and zygotic functions necessary for Sxl activity in germ line and soma. In XX animals, the mutation SxlM1 which was reported to express the female-specific functions of Sxl constitutively can rescue all phenotypes resulting from lack of liz product. XY animals carrying SxlM1 and lacking maternal or zygotic liz activity survive as males with some female traits. A stock was constructed in which the females are liz SxlM1/liz SxlM1 and males liz SxlM1/Y. This shows that SxlM1 is not truly expressed constitutively in animals with an X:A ratio of 0.5, but requires activity of liz for initiation or maintenance.


Bee pollen and honey for the alleviation of hot flushes and other menopausal symptoms in breast cancer patients.
Hot flushes, night sweats, pain during sexual intercourse, hair loss, forgetfulness, depression and sleeping disturbances are common problems among breast cancer patients undergoing antihormonal treatment. The aim of this study was to investigate whether bee pollen can alleviate menopausal symptoms in patients receiving tamoxifen and aromatase inhibitors/inactivators. We compared a pollen-honey mixture with pure honey (placebo) in a prospective, randomized crossover trial in breast cancer patients receiving antihormonal treatment. The menopausal complaints were assessed using the Menopause Rating Scale (MRS). A total of 46 patients were recruited; 68.3% (28/41) of the patients reported an improvement in their symptoms while taking honey, compared with 70.9% (22/31) who reported an improvement with pollen (the difference was non-significant). The results were confirmed by significant improvements in the postmenopausal complaints in the two groups in a pre-post analysis in the MRS and its 3 subscales. This study provided evidence that honey and bee pollen may improve the menopausal symptoms of breast cancer patients on antihormonal treatment. Of note, honey, which was intended to be used as a placebo, produced similar effects as pollen and they both exceeded the extent of a placebo effect in this setting (~25%).


The clinicopathological characteristics with long-term outcomes in malignant mesothelioma.
Malignant mesothelioma (MM) is a neoplasm which originates from serous membranes. It is relatively more common in Turkey. Ninety-nine patients between 2002-2009 were evaluated for survival and patient characteristics with chest pain, dyspnea, weight loss, loss of appetite, anemia, leukocytosis, thrombocytosis and lactate dehydrogenase (LDH) elevation, retrospectively. Male/female ratio was 1.41(58/41). Median age was 53(27-88). Asbestosis exposure rate was 78.5%. Most of the patients had better ECOG-PS (88.7% for 1-2). Chest pain (47.7%), dyspnea (44.8%), weight loss (49%), loss of appetite (50%), anemia (38%), leukocytosis (37.2%), thrombocytosis (26.6%) and LDH elevation (10.1%) were found with median values such as 11.8 g/dL (5-17.1) for hemoglobin, 8,800/mm3 for WBC (2,600-38,300), 382,000/mm(3) for platelets (28,000-1,504,000) and 253 IU/L for LDH (85-1,877), respectively. The most common site was pleura (62.3%). Half of the patients were unclassified, while epitheloid histopathology (39.4%) was most common in classified ones. RT rate was 42.1% in operated patients and all had pleural MM. Median OS was 22.9 months. Eighty percent of the patients had first-line CT with a clinical benefit rate of 63.3%. Second-line CT rate was 29% with a clinical benefit rate of 44%. Most preferred CT regimen was cisplatinum and pemetrexed. Most of the patients were male in their 50 s with pleural MM. They had chest pain, dyspnea, weight loss and loss of appetite as the most common symptoms at diagnosis. Only half of the patients could be subtyped with a predominance of epitheloid histology.


3D Bioprinting: from Benches to Translational Applications.
Over the last decades, the fabrication of 3D tissues has become commonplace in tissue engineering and regenerative medicine. However, conventional 3D biofabrication techniques such as scaffolding, microengineering, and fiber and cell sheet engineering are limited in their capacity to fabricate complex tissue constructs with the required precision and controllability that is needed to replicate biologically relevant tissues. To this end, 3D bioprinting offers great versatility to fabricate biomimetic, volumetric tissues that are structurally and functionally relevant. It enables precise control of the composition, spatial distribution, and architecture of resulting constructs facilitating the recapitulation of the delicate shapes and structures of targeted organs and tissues. This Review systematically covers the history of bioprinting and the most recent advances in instrumentation and methods. It then focuses on the requirements for bioinks and cells to achieve optimal fabrication of biomimetic constructs. Next, emerging evolutions and future directions of bioprinting are discussed, such as freeform, high-resolution, multimaterial, and 4D bioprinting. Finally, the translational potential of bioprinting and bioprinted tissues of various categories are presented and the Review is concluded by exemplifying commercially available bioprinting platforms.


Are the national preventive health initiatives likely to reduce health inequities?
This paper examines commitments to address health inequities within current (2008-11) Australian government initiatives on health promotion and chronic disease prevention. Specifically, the paper considers: the Council of Australian Governments' 'National partnership agreement on preventive health'; the National Preventative Health Taskforce report, 'Australia: the healthiest country by 2020'; and the Australian Government's response to the taskforce report, 'Taking preventative action'. Arising from these is the recent establishment of the Australian National Preventive Health Agency. Together, these measures represent a substantial public investment in health promotion and disease prevention. The present paper finds that these initiatives clearly acknowledge significantly worse health outcomes for those subject to social or economic disadvantage, and contain measures aimed to improve health outcomes among Indigenous people and those in low socioeconomic status communities. However, we argue that, as a whole, these initiatives have (thus far) largely missed an opportunity to develop a whole of government approach to health promotion able to address upstream social determinants of health and health inequities in Australia. In particular, they are limited by a primary focus on individual health behaviours as risk factors for chronic disease, with too little attention on the wider socioeconomic and cultural factors that drive behaviours, and so disease outcomes, in populations.


Improving Post-Release Care Engagement for People Living with HIV Involved in the Criminal Justice System: A Systematic Review.
Given sub-optimal HIV care outcomes for people living with HIV (PLWH) post-release from incarceration, we systematically searched peer-reviewed literature (2010-2021) describing controlled trial interventions aimed at improving Antiretroviral Therapy (ART) adherence and care linkage following release from correctional facilities for PLWH. Of 392 studies, 16 (4%) met the inclusion criteria. All studies were conducted in the United States and involved some form of intensive case management. Trials that scored highest in terms of study quality provided cell phones for engagement, reported sustained viral load suppression as a measurable outcome to infer ART adherence, and measured longitudinal data collected for at least 3-to-6 months following release. The two trials that demonstrated improved HIV viral load suppression involved Peer Navigators, and incentivized undetectable viral load, respectively. Facilitating support for addictions and addressing other social and structural barriers to achieving optimal health is also of vital importance in bridging care gaps for PLWH.


Dominance rank-associated gene expression is widespread, sex-specific, and a precursor to high social status in wild male baboons.
In humans and other hierarchical species, social status is tightly linked to variation in health and fitness-related traits. Experimental manipulations of social status in female rhesus macaques suggest that this relationship is partially explained by status effects on immune gene regulation. However, social hierarchies are established and maintained in different ways across species: While some are based on kin-directed nepotism, others emerge from direct physical competition. We investigated how this variation influences the relationship between social status and immune gene regulation in wild baboons, where hierarchies in males are based on fighting ability but female hierarchies are nepotistic. We measured rank-related variation in gene expression levels in adult baboons of both sexes at baseline and in response to ex vivo stimulation with the bacterial endotoxin lipopolysaccharide (LPS). We identified >2,000 rank-associated genes in males, an order of magnitude more than in females. In males, high status predicted increased expression of genes involved in innate immunity and preferential activation of the NF-κB-mediated proinflammatory pathway, a pattern previously associated with low status in female rhesus macaques. Using Mendelian randomization, we reconcile these observations by demonstrating that high status-associated gene expression patterns are precursors, not consequences, of high social status in males, in support of the idea that physiological condition determines who attains high rank. Together, our work provides a test of the relationship between social status and immune gene regulation in wild primates. It also emphasizes the importance of social context in shaping the relationship between social status and immune function.


Contributing influences of work environment on sleep quantity and quality of nursing assistants in long-term care facilities: A cross-sectional study.
The effect of shift work on nurses' sleep is well-studied, but there are other challenging aspects of health care work that might also affect the sleep of direct caregivers. This study examined the influence of the long-term care work environment on sleep quantity and quality of nursing assistants. A cross-sectional survey collected data from 650 nursing assistants in 15 long-term care facilities; 46% reported short sleep duration and 23% reported poor sleep quality. A simple additive index of the number of beneficial work features (up to 7) was constructed for analysis with Poisson regression. With each unit increase of beneficial work features, nursing assistants were 7% less likely to report short sleep duration and 17% less likely to report poor sleep quality. These results suggest that effective workplace interventions should address a variety of work stressors, not only work schedule arrangements, in order to improve nursing assistants' sleep health.


Dynamics of social contagions with memory of nonredundant information.
A key ingredient in social contagion dynamics is reinforcement, as adopting a certain social behavior requires verification of its credibility and legitimacy. Memory of nonredundant information plays an important role in reinforcement, which so far has eluded theoretical analysis. We first propose a general social contagion model with reinforcement derived from nonredundant information memory. Then, we develop a unified edge-based compartmental theory to analyze this model, and a remarkable agreement with numerics is obtained on some specific models. We use a spreading threshold model as a specific example to understand the memory effect, in which each individual adopts a social behavior only when the cumulative pieces of information that the individual received from his or her neighbors exceeds an adoption threshold. Through analysis and numerical simulations, we find that the memory characteristic markedly affects the dynamics as quantified by the final adoption size. Strikingly, we uncover a transition phenomenon in which the dependence of the final adoption size on some key parameters, such as the transmission probability, can change from being discontinuous to being continuous. The transition can be triggered by proper parameters and structural perturbations to the system, such as decreasing individuals' adoption threshold, increasing initial seed size, or enhancing the network heterogeneity.


Multisensory Bayesian Inference Depends on Synapse Maturation during Training: Theoretical Analysis and Neural Modeling Implementation.
Recent theoretical and experimental studies suggest that in multisensory conditions, the brain performs a near-optimal Bayesian estimate of external events, giving more weight to the more reliable stimuli. However, the neural mechanisms responsible for this behavior, and its progressive maturation in a multisensory environment, are still insufficiently understood. The aim of this letter is to analyze this problem with a neural network model of audiovisual integration, based on probabilistic population coding-the idea that a population of neurons can encode probability functions to perform Bayesian inference. The model consists of two chains of unisensory neurons (auditory and visual) topologically organized. They receive the corresponding input through a plastic receptive field and reciprocally exchange plastic cross-modal synapses, which encode the spatial co-occurrence of visual-auditory inputs. A third chain of multisensory neurons performs a simple sum of auditory and visual excitations. The work includes a theoretical part and a computer simulation study. We show how a simple rule for synapse learning (consisting of Hebbian reinforcement and a decay term) can be used during training to shrink the receptive fields and encode the unisensory likelihood functions. Hence, after training, each unisensory area realizes a maximum likelihood estimate of stimulus position (auditory or visual). In cross-modal conditions, the same learning rule can encode information on prior probability into the cross-modal synapses. Computer simulations confirm the theoretical results and show that the proposed network can realize a maximum likelihood estimate of auditory (or visual) positions in unimodal conditions and a Bayesian estimate, with moderate deviations from optimality, in cross-modal conditions. Furthermore, the model explains the ventriloquism illusion and, looking at the activity in the multimodal neurons, explains the automatic reweighting of auditory and visual inputs on a trial-by-trial basis, according to the reliability of the individual cues.


Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage.
A zone of hypoperfusion surrounding acute intracerebral hemorrhage (ICH) has been interpreted as regional ischemia. To determine if ischemia is present in the periclot area, the authors measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) with positron emission tomography (PET) in 19 patients 5 to 22 hours after hemorrhage onset. Periclot CBF, CMRO2, and OEF were determined in a 1-cm-wide area around the clot. In the 16 patients without midline shift, periclot data were compared with mirror contralateral regions. All PET images were masked to exclude noncerebral structures, and all PET measurements were corrected for partial volume effect due to clot and ventricles. Both periclot CBF and CMRO2 were significantly reduced compared with contralateral values (CBF: 20.9 +/- 7.6 vs. 37.0 +/- 13.9 mL 100 g(-1) min(-1), P = 0.0004; CMRO2: 1.4 +/- 0.5 vs. 2.9 +/- 0.9 mL 100 g(-1) min(-1), P = 0.00001). Periclot OEF was less than both hemispheric OEF (0.42 +/- 0.15 vs. 0.47 +/- 0.13, P = 0.05; n = 19) and contralateral regional OEF (0.44 +/- 0.16 vs. 0.51 +/- 0.13, P = 0.05; n = 16). In conclusion, CMRO2 was reduced to a greater degree than CBF in the periclot region in acute ICH, resulting in reduced OEF rather than the increased OEF that occurs in ischemia. Thus, the authors found no evidence for ischemia in the periclot zone of hypoperfusion in acute ICH patients studied 5 to 22 hours after hemorrhage onset.


The social consequences of conspiracism: Exposure to conspiracy theories decreases intentions to engage in politics and to reduce one's carbon footprint.
The current studies explored the social consequences of exposure to conspiracy theories. In Study 1, participants were exposed to a range of conspiracy theories concerning government involvement in significant events such as the death of Diana, Princess of Wales. Results revealed that exposure to information supporting conspiracy theories reduced participants' intentions to engage in politics, relative to participants who were given information refuting conspiracy theories. This effect was mediated by feelings of political powerlessness. In Study 2, participants were exposed to conspiracy theories concerning the issue of climate change. Results revealed that exposure to information supporting the conspiracy theories reduced participants' intentions to reduce their carbon footprint, relative to participants who were given refuting information, or those in a control condition. This effect was mediated by powerlessness with respect to climate change, uncertainty, and disillusionment. Exposure to climate change conspiracy theories also influenced political intentions, an effect mediated by political powerlessness. The current findings suggest that conspiracy theories may have potentially significant social consequences, and highlight the need for further research on the social psychology of conspiracism.


Muscle disuse atrophy is not accompanied by changes in skeletal muscle satellite cell content.
Muscle disuse leads to a considerable loss in skeletal muscle mass and strength. However, the cellular mechanisms underlying disuse-induced muscle fibre atrophy remain to be elucidated. Therefore we assessed the effect of muscle disuse on the CSA (cross-sectional area), muscle fibre size, satellite cell content and associated myocellular signalling pathways of the quadriceps muscle. A total of 12 healthy young (24±1 years of age) men were subjected to 2 weeks of one-legged knee immobilization via a full-leg cast. Before and immediately after the immobilization period and after 6 weeks of natural rehabilitation, muscle strength [1RM (one-repetition maximum)], muscle CSA [single slice CT (computed tomography) scan] and muscle fibre type characteristics (muscle biopsies) were assessed. Protein and/or mRNA expression of key genes [i.e. MYOD (myogenic differentiation), MYOG (myogenin) and MSTN (myostatin)] in the satellite cell regulatory pathways were determined using Western blotting and RT-PCR (real-time PCR) analyses respectively. The present study found that quadriceps CSA declined following immobilization by 8±2% (P<0.05). In agreement, both type I and type II muscle fibre size decreased 7±3% and 13±4% respectively (P<0.05). No changes were observed in satellite cell content following immobilization in either type I or type II muscle fibres. Muscle MYOG mRNA expression doubled (P<0.05), whereas MSTN protein expression decreased 30±9% (P<0.05) following immobilization. Muscle mass and strength returned to the baseline values within 6 weeks of recovery without any specific rehabilitative programme. In conclusion, 2 weeks of muscle disuse leads to considerable loss in skeletal muscle mass and strength. The loss in muscle mass was attributed to both type I and type II muscle fibre atrophy, and was not accompanied by a decline in satellite cell content.


Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin.
Mycobacterium ulcerans (Mu), the aetiological agent of Buruli ulcer, is an extracellular pathogen producing the macrolide toxin mycolactone. Using a mouse model of intradermal infection, we found that Mu was initially captured by phagocytes and transported to draining lymph nodes (DLN) within host cells. Similar to Buruli ulcers in humans, the infection site eventually became ulcerated with tissue necrosis and extracellular bacteria, at later stages. In contrast to Mycobacterium bovis BCG (BCG), Mu did not disseminate to the spleen. However, mice infected with Mu or BCG developed comparable primary cellular responses to mycobacterial antigens in DLN and spleen. The role of mycolactone in this sequence of events was examined with a mycolactone-deficient (mup045) mutant of Mu. Mup045 bacilli were better internalized than wild-type (wt) bacteria by mouse phagocytes in vitro. Moreover, infection with wt but not mup045 Mu led to inhibition of TNF-alpha expression, upregulation of MIP-2 chemokine, and host cell death within 1 day. Our results suggest that mycolactone expression during the intracellular life of Mu may contribute to immune evasion by inhibiting phagocytosis, provoking apoptosis of antigen presenting cells and altering the establishment of an appropriate inflammatory reaction.


Mobilization of endothelial progenitors by recurrent bacteremias with a periodontal pathogen.
Periodontal infections are independent risk factors for atherosclerosis. However, the exact mechanisms underlying this link are yet unclear. Here, we evaluate the in vivo effects of bacteremia with a periodontal pathogen on endothelial progenitors, bone marrow-derived cells capable of endothelial regeneration, and delineate the critical pathways for these effects. 12-week old C57bl6 wildtype or toll-like receptor (TLR)-2 deficient mice were repeatedly intravenously challenged with 10⁹ live P. gingivalis 381 or vehicle. Numbers of Sca1+/flk1+ progenitors, circulating angiogenic cells, CFU-Hill, and late-outgrowth EPC were measured by FACS/culture. Endothelial function was assessed using isolated organ baths, reendothelization was measured in a carotid injury model. RANKL/osteoprotegerin levels were assessed by ELISA/qPCR. In wildtype mice challenged with intravenous P.gingivalis, numbers of Sca1+/flk1+ progenitors, CAC, CFU-Hill, and late-outgrowth EPC were strongly increased in peripheral circulation and spleen, whereas Sca1+/flk1+ progenitor numbers in bone marrow decreased. Circulating EPCs were functional, as indicated by improved endothelial function and improved reendothelization in infected mice. The osteoprotegerin/RANKL ratio was increased after P. gingivalis challenge in the bone marrow niche of wildtype mice and late-outgrowth EPC in vitro. Conversely, in mice deficient in TLR2, no increase in progenitor mobilization or osteoprotegerin/RANKL ratio was detected. Recurrent transient bacteremias, a feature of periodontitis, increase peripheral EPC counts and decrease EPC pools in the bone marrow, thereby possibly reducing overall endothelial regeneration capacity, conceivably explaining pro-atherogenic properties of periodontal infections. These effects are seemingly mediated by toll-like receptor (TLR)-2.


Tetraspanins CD81 and CD82 facilitate α4β1-mediated adhesion of human erythroblasts to vascular cell adhesion molecule-1.
The proliferation and terminal differentiation of erythroid progenitors occurs in human bone marrow within erythroblastic islands, specialised structures consisting of a central macrophage surrounded by developing erythroid cells. Many cell-cell and cell-matrix adhesive interactions maintain and regulate the co-ordinated daily production of reticulocytes. Erythroid cells express only one integrin, α4β1, throughout differentiation, and its interactions with both macrophage Vascular Cell Adhesion Molecule-1 and with extracellular matrix fibronectin are critical for erythropoiesis. We observed that proerythroblasts expressed a broad tetraspanin phenotype, and investigated whether any tetraspanin could modulate integrin function. A specific association between α4β1 and CD81, CD82 and CD151 was demonstrated by confocal microscopy and co-immune precipitation. We observed that antibodies to CD81 and CD82 augmented adhesion of proerythroblasts to Vascular Cell Adhesion Molecule-1 but not to the fibronectin spliceoforms FnIII12-IIICS-15 and FnIII12-15. In contrast, different anti-CD151 antibodies augmented or inhibited adhesion of proerythroblasts to Vascular Cell Adhesion Molecule-1 and the fibronectin spliceoform FnIII12-IIICS-15 but not to FnIII12-15. These results strongly suggest that tetraspanins have a functional role in terminal erythropoiesis by modulating interactions of erythroblast α4β1 with both macrophages and extracellular matrix.


Effects of exercise on insulin resistance and body composition in overweight and obese women with and without polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is an insulin-resistant (IR) state. Visceral fat (VF) is independently associated with IR. The objectives of the study were to explore mechanisms underpinning IR by assessing the effect of exercise training on IR and body composition in overweight PCOS and non-PCOS women. This was a prospective exercise intervention study. The study was conducted at an academic medical center. Participants included 20 overweight PCOS and 14 overweight non-PCOS women. The intervention included 12 wk of intensified aerobic exercise (3 h/wk). IR on euglycemic hyperinsulinemic clamp, body composition including abdominal visceral and sc fat distribution by computer tomography and lipids was measured. PCOS subjects were more IR (P = 0.02) and had more VF (P = 0.04 age adjusted) than non-PCOS women. In PCOS women, IR correlated with VF (r = -0.78, P < 0.01). With exercise training, both groups maintained weight but within PCOS, VF (-12.0 cm(2), P = 0.03) and within non-PCOS abdominal sc fat (-40.2 cm(2), P = 0.02) decreased. Despite exercise-induced improvement in IR within PCOS (+27.9 mg · m(-2) · min(-1), P = 0.03), no relationship with decreased VF (r = -0.08, P = 0.84) and no differential changes in IR and VF between groups were noted. Triglycerides decreased within PCOS (-0.27 mmol/liter, P = 0.02) and decreased differentially between groups (P < 0.01). Higher IR was related to increased VF in PCOS, suggesting an etiological role for VF in intrinsic IR in PCOS; however, changes with exercise intervention did not support a causal relationship. Triglycerides were modulated more by exercise training in PCOS than non-PCOS women. Within-group exercise-induced reductions in cardiometabolic risk factors including IR, triglycerides, and VF in PCOS were observed without significant weight loss and if confirmed in future controlled trials, suggest weight loss should not be the sole focus of exercise programs.


Effects of Short-term Exercise Training on Cardiorespiratory Fitness of Male Adults with Myocardial Infarction.
[Purpose] The purpose of this study was to determine the effects of short-term exercise training on the cardiorespiratory fitness (CRF) of individuals suffering from myocardial infarction. [Subjects] A total of 60 participants were divided into experimental (EXP; n=30, mean age 56.7 ± 2.8 years, body mass 80.7 ± 10.7 kg, body height 171.9 ± 7.2 cm) and control (CON; n=30, mean age 56.5 ± 3.1 years, body mass 84.4 ± 12.4 kg, body height 171.5 ± 12.4 cm) groups. [Methods] The members of the EXP group took part in an organized daily physical exercise program (Monday through Sunday), for a period of 3 weeks. The exercise program consisted of 60 min daily specialized fitness exercises with an intensity ranging from 55-70% of the maximum heart rate, which was determined by test on a bicycle ergometer. The effects of the exercise were monitored by means of the following parameters: maximum oxygen uptake (VO2peak), resting heart rate, systolic blood pressure and diastolic blood pressure. [Results] The results indicate statistically significant post-exercise improvements in heart rate, relative oxygen uptake and systolic blood pressure, among the members of the EXP group. The results indicate that at the initial measurement of cardiorespiratory fitness no statistically significant differences were found between the groups at the multivariate level (Wilk's λ=0.83), while statistically significant differences in the cardiorespiratory fitness were found at the final measurement (Wil's λ=0.430). [Conclusion] The obtained results indicate that the exercise program, which lasted for a period of 21 days, though shorter in duration than other programs still led to statistically significant changes in the CRF of individuals suffering from MI.


Water ecosystem services in northern Australia--how much are they worth and who should pay for their provision?
There is ongoing pressure to develop the largely unaltered Daly River catchment in northern Australia for agriculture. However, a choice experiment among people in the region and in Australia's largest city, Sydney, shows that people are prepared to pay substantial amounts to maintain the quality of its ecosystem services. The total stated willingness-to-pay (WTP) for a Daly River conservation programme was about $300, of which people would be willing to pay over half ($161) if the programme retained waterholes for Aboriginal people in good condition. The WTP for high quality recreational fishing and biodiversity values was $120 and $91 respectively. Using the average cost of a recreational fishing license in Australia ($35) as a basis for grounding the stated preferences in empirical values, as well as the cost of park entry fees and the amount of support society provides to agriculture in Australia, the total amount that the 110,000 people in the region are likely to be willing to pay for the retention of the values in the Daly River catchment is about $6 million, while the 4.5 million people in Sydney would be willing to pay about $81 million. A significant finding in this research is that, while fishing, biodiversity and agricultural values all have equivalents in the market economy, the value for which people were willing to pay most, the cultural value, has no equivalent at all and is thus receives almost no investment.


Comparison of the Position-Matching and Position-Reproducing Tasks to Detect Deficits in Knee Position Sense After Reconstruction of the Anterior Cruciate Ligament.
Deficits in knee position sense following reconstruction of the anterior cruciate ligament (ACL) can delay an athlete's return to sport participation and increase the risk of reinjury. Deficits in position sense postreconstruction have been evaluated using either a position-reproducing or position-matching task. The aim of our study was to combine both to determine which assessment would be more effective to identify deficits in knee position sense. Longitudinal laboratory-based study. Eleven athletes (6 men and 5 women; mean age, 20.5 [1.2] y), who had undergone ACL reconstruction with an ipsilateral hamstring autograft, and 12 age-matched controls. Position sense was evaluated at 6 and 12 months postreconstruction and once for the control group. In addition, peak isokinetic knee extension and flexion strength, at 60°/s and 180°/s, was assessed for the ACL reconstruction group to evaluate possible influences of muscle strength on knee joint position sense. The variables include the angular differences between the reference limb and indicator limb, and peak torque values of isokinetic knee extension and flexion. Significant matching differences were identified at 6 months postsurgery on the position-matching task, but not at 12 months postsurgery. No significant between-group and within-subject differences were identified on the position-reproducing task. No significant matching errors were identified for the control group. There was no correlation between errors in position sense and maximum isokinetic strength. The position-matching task is more sensitive than the position-reproducing task to identify deficits in knee position sense over the first year following ACL reconstruction surgery.


Characterisation of bacteria in ascites--reporting the potential of culture-independent, molecular analysis.
Spontaneous bacterial peritonitis (SBP) is a severe complication of liver disease. A significant proportion of patients have culture-negative ascites, despite having similar signs, symptoms and mortality to those with SBP. Therefore, empirical antibiotic treatment for infection is often started without knowledge of the causative organisms. Here, we investigated the potential of molecular techniques to provide rapid and accurate characterisation of the bacteria present in ascitic fluid. Ascites samples were obtained from 29 cirrhotic patients undergoing clinically indicated therapeutic paracentesis. Bacterial content was determined by terminal restriction fragment length polymorphism (T-RFLP) analysis, quantitative polymerase chain reaction (PCR) and 16S ribosomal clone sequence analysis. Bacterial signal was detected in all samples, compared to three out of ten using standard methods. Bacterial loads ranged from 5.5 x 10(2) to 5.4 x 10(7) cfu/ml, with a mean value of 1.9 x 10(6) cfu/ml (standard deviation +/- 9.6 x 10(6) cfu/ml). In all but one instance, bacterial species identified by culture were also confirmed by molecular analyses. Preliminary data presented here suggests that culture-independent, molecular analyses could provide rapid characterisation of the bacterial content of ascites fluid, providing a basis for the investigation of SBP development and allowing early and targeted antibiotic intervention.


By-product of Tropical Vermicelli Waste as a Novel Alternative Feedstuff in Broiler Diets.
Two experiments were conducted to determine physical and chemical properties of vermicelli waste (VW) and effect of VW inclusion levels on growth performance of broilers. In experiment 1, VW samples were randomly collected from vermicelli industry in Thailand to analyze nutritional composition. Vermicelli waste contained 9.96% moisture, 12.06% CP, 32.30% crude fiber (CF), and 0.57% ether extract (EE), as DM basis. The ratio of insoluble:soluble non-starch polysaccharide (NSP) was 43.4:8.9. A total of 120 chicks (6 pens per treatment and 10 chicks per pen) were fed a corn-soybean meal-based diet or 20% VW substituted diet to determine the apparent metabolizable energy corrected for nitrogen retention (AMEn) of VW. The AMEn of VW was 1,844.7±130.71 kcal/kg. In experiment 2, a total of 1,200 chicks were randomly allotted to 1 of 4 dietary treatments for 42-d growth assay. There were 300 chicks with 6 pens per treatment and 50 chicks per pen. The dietary treatments contained 0%, 5%, 10%, or 15% VW, respectively. All diets were formulated to be isocaloric and isonitrogenous. From 0 to 18 d of age chicks fed VW diets had higher (p<0.001) feed conversion ratio (FCR) compared with those fed the control diet. No difference was observed during grower and finisher phase (19 to 42 d). Chicks fed VW diets had lower relative weight of abdominal fat (p<0.001) but higher relative weight of gizzard (p<0.05) than those of chicks fed the control diet. Increasing VW inclusion levels increased ileal digesta viscosity (p<0.05) and intestinal villus height of chicks (p< 0.001). For apparent total tract digestibility assay, there were 4 metabolic cages of 6 chicks that were fed experimental treatment diets (the same as in the growth assay) in a 10-d total excreta collection. Increasing VW inclusion levels linearly decreased (p<0.05) apparent total tract digestibility of DM and CF.


p38α Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis.
The stress-activated protein kinase (SAPK) p38 can induce apoptosis, and its inhibition facilitates mammary tumorigenesis. We found that during mammary acinar morphogenesis in MCF-10A cells grown in three-dimensional culture, detachment of luminal cells from the basement membrane stimulated mitogen-activated protein kinase (MAPK) kinases 3 and 6 (MKK3/6) and p38α signaling to promote anoikis. p38α signaling increased transcription of the death-promoting protein BimEL by phosphorylating the activating transcription factor 2 (ATF-2) and increasing c-Jun protein abundance, leading to cell death by anoikis and acinar lumen formation. Inhibition of p38α or ATF-2 caused luminal filling reminiscent of that observed in ductal carcinoma in situ (DCIS). The mammary glands of MKK3/6 knockout mice (MKK3(-/-)/MKK6(+/- )) showed accelerated branching morphogenesis relative to those of wild-type mice, as well as ductal lumen occlusion due to reduced anoikis. This phenotype was recapitulated by systemic pharmacological inhibition of p38α and β (p38α/β) in wild-type mice. Moreover, the development of DCIS-like lesions showing marked ductal occlusion was accelerated in MMTV-Neu transgenic mice treated with inhibitors of p38α and p38β. We conclude that p38α is crucial for the development of hollow ducts during mammary gland development, a function that may be crucial to its ability to suppress breast cancer.


Efficient implementation of constant pH molecular dynamics on modern graphics processors.
The treatment of pH sensitive ionization states for titratable residues in proteins is often omitted from molecular dynamics (MD) simulations. While static charge models can answer many questions regarding protein conformational equilibrium and protein-ligand interactions, pH-sensitive phenomena such as acid-activated chaperones and amyloidogenic protein aggregation are inaccessible to such models. Constant pH molecular dynamics (CPHMD) coupled with the Generalized Born with a Simple sWitching function (GBSW) implicit solvent model provide an accurate framework for simulating pH sensitive processes in biological systems. Although this combination has demonstrated success in predicting pKa values of protein structures, and in exploring dynamics of ionizable side-chains, its speed has been an impediment to routine application. The recent availability of low-cost graphics processing unit (GPU) chipsets with thousands of processing cores, together with the implementation of the accurate GBSW implicit solvent model on those chipsets (Arthur and Brooks, J. Comput. Chem. 2016, 37, 927), provide an opportunity to improve the speed of CPHMD and ionization modeling greatly. Here, we present a first implementation of GPU-enabled CPHMD within the CHARMM-OpenMM simulation package interface. Depending on the system size and nonbonded force cutoff parameters, we find speed increases of between one and three orders of magnitude. Additionally, the algorithm scales better with system size than the CPU-based algorithm, thus allowing for larger systems to be modeled in a cost effective manner. We anticipate that the improved performance of this methodology will open the door for broad-spread application of CPHMD in its modeling pH-mediated biological processes. © 2016 Wiley Periodicals, Inc.


Preclinical Assessment of Efficacy of Radiation Dose Painting Based on Intratumoral FDG-PET Uptake.
We tested therapeutic efficacy of two dose painting strategies of applying higher radiation dose to tumor subvolumes with high FDG uptake (biologic target volume, BTV): dose escalation and dose redistribution. We also investigated whether tumor response was determined by the highest dose in BTV or the lowest dose in gross tumor volume (GTV). FDG uptake was evaluated in rat rhabdomyosarcomas prior to irradiation. BTV was defined as 30% of GTV with the highest (BTVhot) or lowest (BTVcold) uptake. To test efficacy of dose escalation, tumor response (time to reach two times starting tumor volume, TGTV2) to Hot Boost irradiation (40% higher dose to BTVhot) was compared with Cold Boost (40% higher dose to BTVcold), while mean dose to GTV remained 12 Gy. To test efficacy of dose redistribution, TGTV2 after Hot Boost was compared with uniform irradiation with the same mean dose (8 or 12 Gy). TGTV2 after 12 Gy delivered heterogeneously (Hot and Cold Boost) or uniformly were not significantly different: 20.2, 19.5, and 20.6 days, respectively. Dose redistribution (Hot Boost) with 8 Gy resulted in faster tumor regrowth as compared with uniform irradiation (13.3 vs. 17.1 days; P = 0.026). Further increase in dose gradient to 60% led to a more pronounced decrease in TGTV2 (10.9 days; P < 0.0001). Dose escalation effect was independent of FDG uptake in target tumor volume, while dose redistribution was detrimental in this tumor model for dose levels applied here. Our data are consistent with the hypothesis that tumor response depends on the minimum intratumoral dose.


Sex differences in subjective and objective measures of pain, functional impairment, and health-related quality of life in patients with lumbar degenerative disc disease.
Sex differences in pain perception are known to exist; however, the exact pathomechanism remains unclear. This work aims to elucidate sex differences in subjective and objective measures of pain, functional impairment, and health-related quality of life (HRQoL) in patients with lumbar degenerative disc disease. In a prospective 2-center study, back and leg pain (visual analogue scale [VAS]), functional disability (Oswestry Disability Index and Roland-Morris Disability Index), and HRQoL (EuroQol-5D and Short Form [SF12]) were collected for consecutive patients undergoing lumbar spine surgery. Objective functional impairment (OFI) was estimated using age-adjusted and sex-adjusted cutoff values for the timed-up-and-go (TUG) test. A healthy cohort of n = 110 subjects served as the control group. Univariate and multivariate analyses were performed to test the association between sex and pain, subjective and OFIs, and HRQoL. The study comprised n = 305 patients (41.6% females). Female patients had more VAS back pain (P = 0.002) and leg pain (P = 0.014). They were more likely to report higher functional impairment in terms of Oswestry Disability Index (P = 0.005). Similarly, HRQoL measured with the EuroQol-5D index (P = 0.012) and SF12 physical composite score (P = 0.005) was lower in female patients. Female patients reported higher VAS back and leg pain, functional impairment, and reduced HRQoL than male patients. However, there were no sex differences with respect to the presence and degree of OFI measured by the TUG test using age-adjusted and sex-adjusted cutoff values. As such, the TUG may be a good test to overcome sex bias for the clinical assessment of patients with degenerative disc disease.


Fluorescence based strategies for genetic analysis.
Synthetic chemistry has been central to the design of modern methods of genetic analysis. In this article, we discuss the underlying chemistry and biophysical principles that have been used in the development of robust methods for the analysis of DNA in the diagnostic laboratory.


Dietary intake of trans fatty acids and breast cancer risk in 9 European countries.
Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted. In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors. After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes. These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations.


Characterization and use of tricyclic fluorescent nucleic acid base analogues.
The two recently developed nucleic acid probe molecules tC and tC(O) both have unique properties compared to other molecules in the family of fluorescent base analogues.(1-5) These tricyclic base analogues both form very stable base pairs with guanine and give minimal perturbations to the native structure of DNA.(2) We have found that tC(O) is the brightest fluorescent base analogue reported(4) and that tC also is very bright and has a fluorescence quantum yield that is virtually insensitive to its surrounding microenvironment within the nucleic acid(3). These base analogues have so far been used in FRET-studies of a DNA-polymerase system(6) and in initial anisotropy-studies of DNA-containing systems(4).


Health System Preparedness for COVID-19 and Its Impacts on Frontline Health-Care Workers in Nepal: A Qualitative Study Among Frontline Health-Care Workers and Policy-Makers.
Rapidly growing coronavirus disease 2019 (COVID-19) pandemic has brought unprecedented challenges to the health system in Nepal. The main objective of this study was to explore the health system preparedness for COVID-19 and its impacts on frontline health-care workers in Nepal. Semi-structured interviews were conducted among 32 health-care workers who were involved in clinical care of COVID-19 patients and four policy-makers who were responsible for COVID-19 control and management at central and provincial level. Interviews were conducted through telephone or Internet-based tools such as Zoom and Skype. All interviews were audio-recorded, transcribed into English, and coded using inductive and deductive approaches. Both health-care workers and policy-makers reported failure to initiate pre-emptive control measures at the early stages of the outbreak as the pivot in pandemic control. Although several measures were rolled out when cases started to appear, the overall health system preparedness was low. The poor governance, and coordination between three tiers of government was compounded by the inadequate personal protective equipment for health-care workers, insufficient isolation beds for patients, and poor engagement of the private sector. Frontline health-care workers experienced various degrees of stigma because of their profession and yet were able to maintain their motivation to continue serving patients. Preparedness for COVID-19 was affected by the poor coordination between three tiers of governance. Specifically, the lack of human resources, inadequate logistic chain management and laboratory facilities for testing COVID-19 appeared to have jeopardized the health system preparedness and escalated the pandemic in Nepal. Despite the poor preparedness, and health and safety concerns, health-care workers maintained their motivation. There is an urgent need for an effective coordination mechanism between various tiers of health structure (including private sector) in addition to incentivizing the health-care workers for the current and future pandemics.


When you hear /baksɛt/ do you think /baskɛt/? Evidence for transposed-phoneme effect with multisyllabic words.
In this study we asked whether nonwords created by transposing two phonemes (/biksɔt/) are perceived as being more similar to their base words (/biskɔt/) than nonwords created by substituting two phonemes (/bipfɔt/). Using the short-term phonological priming and a lexical-decision task, Experiment 1 showed that transposed-phoneme nonword primes lead to shorter RTs on the target base words than substituted-phoneme nonword primes. Using a single-presentation lexical-decision task, Experiment 2 showed that transposed-phoneme nonwords lead to longer "no" decision responses than substituted-phoneme nonwords. In both Experiments 1 and 2, the transposed-phoneme effect was observed when the transposed phonemes were adjacent (/biksɔt/-/biskɔt/) but not when they were distant (/ʃoloka/-/ʃokola/). Our findings suggest that nonwords created by transposing adjacent phonemes in real words generate more activation of the lexical representations associated with the base words than do matched control nonwords. More generally, our findings present a challenge for models of spoken word recognition that code for the precise order of speech segments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Bacillus thuringiensis pulmonary infection: critical role for bacterial membrane-damaging toxins and host neutrophils.
The occurrence of Bacillus thuringiensis bacteremia in a neutropenic patient suffering from severe pulmonary disease addressed the question of whether the aggressive behavior of B. thuringiensis depended on the host status and/or on the membrane-damaging toxins the isolate produced. After intratracheal injection, BALB/c mice developed pneumonia followed by fatal dissemination into deep organs, with mice rendered neutropenic by cyclophosphamide injection being extremely more susceptible to infection than normal animals. In animals infected with isogenic strains of B. thuringiensis progressively more defective in membrane-damaging toxins (407 Cry->IP2>MP02), an increase in the 50% lethal dose was registered (3.9x10(5), 1.1x10(6), 1.2x10(7)CFU). Consistently, after non-lethal dose application, only 407 Cry- replicated intrapulmonary, reaching a bacterial burden 4.7-fold and 40.9-fold higher than IP2 (P=0.018) and MP02 (P=0.008) at 48h post-inoculation. Notably, the time-course of infection was similar in animals infected with viable bacilli or spores, with neutropenic mice always being more susceptible to infection. The overall results indicate that B. thuringiensis may be responsible for opportunistic infections and strongly suggest that membrane-damaging toxins contribute to intrapulmonary bacterial persistence favoring dissemination.


c-erbB-2 gene product directly associates with beta-catenin and plakoglobin.
Association of the c-erbB-2 oncogene product with the cadherin-catenin complex has been demonstrated in human cancer cell lines. Although beta-catenin and plakoglobin have been proven to be crucial for the association, no previous study has shown whether the interactions are direct or indirect. In the present study, the c-erbB-2 gene product was shown by far-Western blotting analysis to associate directly with both beta-catenin and plakoglobin through its cytoplasmic domain core region, which showed extensive homology with epidermal growth factor receptor. These data suggest that c-erbB-2-induced signaling is also directly liked to the cadherin-mediated cell adhesion and "invasion-suppressor" system through beta-catenin and plakoglobin in cancers.


Patient readmission and mortality after colorectal surgery for colon cancer: impact of length of stay relative to other clinical factors.
Data on readmission as well as the potential impact of length of stay (LOS) after colectomy for colon cancer remain poorly defined. The objective of the current study was to evaluate risk factors associated with readmission among a nationwide cohort of patients after colorectal surgery. We identified 149,622 unique individuals from the Surveillance, Epidemiology, and End Results-Medicare dataset with a diagnosis of primary colorectal cancer who underwent colectomy between 1986 and 2005. In-hospital morbidity, mortality, LOS, and 30-day readmission were examined using univariate and multivariate logistic regression models. Primary surgical treatment consisted of right (37.4%), transverse (4.9%), left (10.5%), sigmoid (22.8%), abdominoperineal resection (7.3%), low anterior resection (5.6%), total colectomy (1.2%), or other/unspecified (10.3%). Mean patient age was 76.5 years and more patients were female (52.9%). The number of patients with multiple preoperative comorbidities increased over time (Charlson comorbidity score ≥3: 1986 to 1990, 52.5% vs 2001 to 2005, 63.1%; p < 0.001). Mean LOS was 11.7 days and morbidity and mortality were 36.5% and 4.2%, respectively. LOS decreased over time (1986 to 1990, 14.0 days; 1991 to 1995, 12.0 days; 1996 to 2000, 10.4 days; 2001 to 2005, 10.6 days; p < 0.001). In contrast, 30-day readmission rates increased (1986 to 1990, 10.2%; 1991 to 1995, 10.9%; 1996 to 2000, 12.4%; 2001 to 2005, 13.7%; p < 0.001). Factors associated with increased risk of readmission included LOS (odds ratio = 1.02), Charlson comorbidities ≥3 (odds ratio = 1.27), and postoperative complications (odds ratio = 1.17) (all p < 0.01). Readmission rates after colectomies have increased during the past 2 decades and mean LOS after this operation has declined. More research is needed to understand the balance and possible trade off between these hospital performance measures for all surgical procedures.


Perioperative Antihypertensive Treatment in Patients With Spontaneous Intracerebral Hemorrhage.
Studies on antihypertensive treatment for surgical patients with spontaneous intracerebral hemorrhage are insufficient. This pilot study was conducted to investigate the safety of the perioperative intensive blood pressure lowering in surgical patients with spontaneous intracerebral hemorrhage. This study was a prospective, parallel, randomized, assessor-blinded trial. Patients allocated to the intensive group received perioperative intensive antihypertensive treatment aiming to achieve a target systolic blood pressure between 120 and 140 mm Hg, whereas the patients in the conservative group received conservative treatment aiming to achieve a target systolic blood pressure between 140 and 180 mm Hg for 7 days. The primary outcome was the rate of rehemorrhage at 7 days after surgery. Rehemorrhage was noted in 11 patients (11%) in the intensive group and 14 (14%) in the conservative group (P=0.689). There was no significant difference in mortality at 7 days (4.0% versus 10.0%; P=0.164), 30 days (10.4% versus 17.2%; P=0.247), and 90 days (13.5% versus 18.2%; P=0.490) between the 2 groups. Perioperative intensive blood pressure lowering was not associated with a reduced incidence of rehemorrhage, death, or other serious adverse events. URL: http://www.chictr.org.cn/. Unique identifier: ChiCTR-TRC-13004304.


Novel TiO₂-Pt@SiO₂ nanocomposites with high photocatalytic activity.
This article reports a facile and controllable two-step method to construct TiO(2)-Pt@SiO(2) nanocomposites. TiO(2) nanoparticles (NPs), with small size and high surface energy, were synthesized by a solvothermal reaction process. The TiO(2)-Pt@SiO(2) nanocomposites were fabricated by a reverse micro-emulsion method. SiO(2) shell coated NPs were adopted for further photocatalytic reaction. Because of their small size and high surface energy, TiO(2)@SiO(2) and TiO(2)-Pt@SiO(2) nanocomposites show higher photocatalytic activity than commercial Degussa P25. Compared with TiO(2)@SiO(2), TiO(2)-Pt@SiO(2)nanocomposites have improved photocatalytic activity due to the Pt induced spatial separation of electrons and holes. The silica shells not only maintain the structure of the nanocomposites but also prevent their aggregation during the photocatalytic reactions, which is highly important for the good durability of the photocatalyst. This strategy is simple, albeit efficient, and can be extended to the synthesis of other composites of noble metals. It has opened a new window for the construction of hetero-nanocomposites with high activity and durability, which would serve as excellent models in catalytic systems of both theoretical and practical interest.


Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders.
Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD-BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD.


Loop-Mediated Isothermal Amplification In Microchambers On A Cell Microarray Chip For Identification of Plasmodium Species.
Malaria is caused by Plasmodium spp., a parasitic protist that infects erythrocytes. A method that can detect the parasite with high sensitivity and that can identify the parasite species is urgently required for the control of malaria. The cell microarray chip was made using polystyrene with 200 cone-shaped frustum microchambers (800-μm top diameter, 636-μm bottom diameter, and 225 μm deep). Approximately 3,000 erythrocytes could be accommodated in each microchamber with monolayer formation, there being 60,000 erythrocytes in total microchambers on a cell microarray. Plasmodium could be quantitatively detected with high sensitivity with the use of cell microarray chips. Plasmodium parasitizing in erythrocytes was labeled with a cell-permeant fluorescent nucleic acid stain (SYTO 21), which could be detected in erythrocytes in the microchambers. Next, we used loop-mediated isothermal amplification (LAMP) in the microchambers (on-chip LAMP) to identify the parasite species detected in the microchambers. LAMP was performed in the microchambers (in a reaction volume of 0.09 μl) using Plasmodium falciparum-infected erythrocytes as the template and specific primers targeting 18S rRNA. To avoid evaporation of the reaction buffer during heat treatment, mineral oil was overlaid on each microchamber and the cell microarray chips were heated at 63 C for 1 hr. The results of on-chip LAMP were assessed using a portable ultraviolet transilluminator. We showed that this method has the potential for detection of parasites in 600,000 erythrocytes and for identification of the parasite species on a cell microarray chip. In conclusion, the parasites can be detected quantitatively with high sensitivity, and the species can be identified with the use of cell microarray chips.


Orthopyroxene exsolution in augite: a two-step, diffusion-transformation process.
Orthopyroxene lamellae exsolved from augite on (100) are shown to grow by a two-step process involving (i) the diffusion of calcium and (magnesium, iron) to form clinohypersthene and (ii) the inversion of clinohypersthene to orthopyroxene, probably by glide twinning. If complete inversion is prevented by cooling or steep concentration gradients, the two-step process produces orthopyroxene with narrow margins of clinohypersthene. Measured elemental concentration gradients at (100) lamellar interfaces support this mechanism.


Adenosine prevents K+-induced Ca2+ loading: insight into cardioprotection during cardioplegia.
In clinical practice, hyperkalemic cardioplegia induces sarcolemmic depolarization, and therefore is used to arrest the heart during open heart operations. However, the elevated concentration of K+ that is present in cardioplegic solutions promotes intracellular Ca2+ loading, which could aggravate ventricular dysfunction after cardiac operations. This review highlights recent findings that have established, at the single cell level, the protective action of adenosine against hyperkalemia-induced Ca2+ loading. When it was added to hyperkalemic cardioplegic solutions, adenosine, at millimolar concentrations and through a direct action on ventricular cardiomyocytes, prevented K+-induced Ca2+ loading. This action of adenosine required the activation of protein kinase C, and it was effective only in cardiomyocytes with low diastolic Ca2+ levels. Of importance, adenosine did not diminish the magnitude of K+-induced membrane depolarization, allowing unimpeded cardiac arrest. Taken together, these findings provide direct support for the idea that adenosine is valuable when used as an adjunct to hyperkalemic cardioplegia. This idea has emerged from previous clinical studies that have shown improvement of the clinical outcome after cardiac operations when adenosine or related substances were used to supplement cardioplegic solutions. Further studies are required to define more precisely the mechanism of action of adenosine, and the conditions that may determine the efficacy of adenosine as a cytoprotective supplement to cardioplegia.


Metals in tissues of seabass and seabream reared in sites with oxic and anoxic substrata and risk assessment for consumers.
Twenty-eight metals and elements were measured in the muscle, liver, gills, bone and intestine of farmed seabass and gilthead seabream from four Mediterranean fish farms. The influence of fish species and the effect of environmental conditions on the metal accumulation in fish tissues was investigated. Most concentrations were lower in muscle and higher in liver and bone than in other body tissues. Seabass accumulates more elements in its tissues than seabream. Fish reared in coarse, oxic sites accumulate more elements with higher concentrations in muscle, bone and intestine and with lower concentrations in liver and gills than fish reared in silty, anoxic sites. This may be attributed to feed type and sediment properties. According to the metal pollution index, hazard quotient, selenium health benefit values, carcinogenic risk of arsenic, maximum safe consumption and the permitted limits, the consumption of both farmed species should be considered as safe for human health.


Automatic layout of structured hierarchical reports.
Domain-specific database applications tend to contain a sizable number of table-, form-, and report-style views that must each be designed and maintained by a software developer. A significant part of this job is the necessary tweaking of low-level presentation details such as label placements, text field dimensions, list or table styles, and so on. In this paper, we present a horizontally constrained layout management algorithm that automates the display of structured hierarchical data using the traditional visual idioms of hand-designed database UIs: tables, multi-column forms, and outline-style indented lists. We compare our system with pure outline and nested table layouts with respect to space efficiency and readability, the latter with an online user study on 27 subjects. Our layouts are 3.9 and 1.6 times more compact on average than outline layouts and horizontally unconstrained table layouts, respectively, and are as readable as table layouts even for large datasets.


Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers.
Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.


Elevated parathyroid hormone after parathyroidectomy delays symptom improvement.
Curative parathyroidectomy for primary hyperparathyroidism (PHPT) resolves various nonspecific symptoms related to the disease. Between 8% and 40% of patients with normocalcemia after parathyroidectomy have persistently elevated parathyroid hormone (ePTH) levels at follow-up. We investigated whether ePTH in the early postoperative period was associated with the timing of symptom improvement. This prospective study included adult patients with PHPT who underwent curative parathyroidectomy from November 2011 to September 2012. Biochemical testing at 2 wk postoperatively identified ePTH (defined as PTH>72 pg/mL) versus normal PTH (nPTH). A questionnaire administered pre- and post-operatively at 6 wk and 6 mo asked patients to rate the frequency of 18 symptoms of PHPT on a five-point Likert scale. Student t-tests were used to compare pre- with postoperative changes in scores for individual symptoms. Of 194 patients who underwent parathyroidectomy, 129 (66%) participated in the study. Preoperatively, all patients were symptomatic, with a mean of 13±4 symptoms. Two weeks postoperatively, 20 patients (16%) had ePTH. The percentage of patients with postoperative improvement for individual symptoms was compared between groups. At the early time point (6 wk), the ePTH group showed less improvement in 14 of 18 symptoms. This difference reached statistical significance for four symptoms: anxiety, constipation, thirst, and polyuria. By the 6-mo time point, these differences had resolved, and symptom improvement was similar between groups. ePTH after curative parathyroidectomy may result in a delay in symptom improvement 6 wk postoperatively; however, this difference resolves in 6 mo.


A Reconciliation for the Future of Psychiatry: Both Folk Psychology and Cognitive Science.
Philosophy of psychiatry faces a tough choice between two competing ways of understanding mental disorders. The folk psychology (FP) view puts our everyday normative conceptual scheme in the driver's seat - on the assumption that it, and it only, tells us what mental disorders are (1). Opposing this, the scientific image (SI) view (2, 3) holds that our understanding of mental disorders must come, wholly and solely, from the sciences of the mind, unfettered by FP. This paper argues that the FP view is problematic because it is too limited: there is more to the mind than FP allows; hence, we must look beyond FP for properly deep and illuminating explanations of mental disorders. SI promises just this. But when cast in its standard cognitivist formulations, SI is unnecessarily and unjustifiably neurocentric. After rejecting both the FP view, in its pure form, and SI view, in its popular cognitivist renderings, this paper concludes that a more liberal version of SI can accommodate what is best in both views - once SI is so formulated and the FP view properly edited and significantly revised, the two views can be reconciled and combined to provide a sound philosophical basis for a future psychiatry.


Flow cytometry: a diagnostic aid.
Flow cytometry can provide the clinician with a wealth of information on a given disease entity. It uses fluorescence and laser technology, thereby allowing characterization of a host of cell parameters and functions. Flow cytometry can be used to diagnose and prognose immunologic, infectious, and malignant disease, with minimal invasiveness. Any material within the reach of an aspiration needle is amenable to cytometric analysis. A qualified pathologist, well-trained technologist, and well-informed clinician all play crucial roles in the appropriate application of cytometric analysis of the clinical specimen. The wide variety of applications make flow cytometry a useful tool for all clinicians, regardless of practice location.


Developmental origin of a major difference in sensory patterning between zebrafish and bluefin tuna.
The posterior lateral line system (PLL) of teleost fish comprises a number of mechanosensory organs arranged in defined patterns on the body surface. Embryonic patterns are largely conserved among teleosts, yet adult patterns are highly diverse. Although changes in pattern modify the perceptual abilities of the system, their developmental origin remains unknown. Here we compare the processes that underlie the formation of the juvenile PLL pattern in Thunnus thynnus, the bluefin tuna, to the processes that were elucidated in Danio rerio, the zebrafish. In both cases, the embryonic PLL comprises five neuromasts regularly spaced along the horizontal myoseptum, but the juvenile PLL comprises four roughly parallel anteroposterior lines in zebrafish, whereas it is a simple dorsally arched line in tuna fish. We examined whether this difference involves evolutionary novelties, and show that the same mechanisms mediate the transition from embryonic to juvenile patterns in both species. We conclude that the marked difference in juveniles depends on a single change (dorsal vs. ventral migration of neuromasts) in the first days of larval life.


p120-Catenin Is Required for Dietary Calcium Suppression of Oral Carcinogenesis in Mice.
Previous studies have shown that dietary calcium suppresses oral carcinogenesis, but the mechanism is unclear. p120-catenin (p120) is a cytoplasmic protein closely associated with E-cadherin to form the E-cadherin-β-catenin complex and may function as a tumor suppressor in the oral epithelium. To determine whether p120 is involved in the mechanism by which dietary calcium suppresses oral carcinogenesis, The normal, low, or high calcium diet was fed control mice (designated as floxed p120 mice) or mice in which p120 was specifically deleted in the oral squamous epithelium during the adult stage (designated as p120cKO mice). All mice were exposed to a low dose of oral cancer carcinogen 4-nitroquinoline 1-oxide and rates of oral squamous cell carcinoma (OSCC) and proliferation and differentiation in the cancerous and non-cancerous oral epithelium of these mice were examined. The results showed that the low calcium diet increased rates of OSCC and proliferation of the non-cancerous oral epithelium and decreased differentiation of the non-cancerous oral epithelium, but had no effect on cancerous oral epithelium. In contrast, the high calcium diet had opposite effects. However, the effect of the dietary calcium on the rates of OSCC, proliferation, and differentiation of the non-cancerous epithelium were not seen in p120cKO mice. Based on these results, we conclude that p120 is required for dietary calcium suppression of oral carcinogenesis and oral epithelial proliferation and dietary calcium induction of oral epithelial differentiation. J. Cell. Physiol. 232: 1360-1367, 2017. © 2016 Wiley Periodicals, Inc.


Pedicle marrow signal hyperintensity on short tau inversion recovery- and t2-weighted images: prevalence and relationship to clinical symptoms.
Lumbar pedicle marrow hyperintense signal on T2- and STIR-weighted images is not an uncommon finding. We hypothesize that these marrow signal intensity changes and their behavior within the pedicle are associated with clinical symptoms and that their improvement or resolution correlates with clinical improvement. We investigated the prevalence of these pedicle marrow changes, associated morphologic abnormalities, and the relationship to symptoms over time. Prevalence was evaluated prospectively in 246 patients and retrospectively in 400 patients. To analyze the relationship between changes in signal intensity over time and symptoms, a third group of 30 patients was followed clinically for assessment of pain and functional limitation and with MR studies for 18 months or until signal intensity changes resolved. The prevalence of pedicle marrow hyperintensity on T2 and STIR-weighted sequences was 1.7%. Associated morphologic abnormalities were pars interarticularis and pedicle fractures and degenerative facets. In the longitudinal study, pedicle marrow signal hyperintensity on T2- and STIR-weighted images resolved in 17 patients and persisted in 5 patients. The extent, intensity, and resolution of signal intensity changes significantly related to the degree of functional limitation (P = .01). Resolution of pedicle marrow hyperintensity on T2 and STIR-weighted images was associated with improved functional testing and a trend toward decreased pain.


Transport of nonmetabolizable opines by Agrobacterium tumefaciens.
We have examined the uptake of [14C]octopine and [14C]nopaline by Agrobacterium tumefaciens strains containing the C58 chromosomal background in medium suitable for the induction of vir genes. All strains tested could transport both of these opines, regardless of the presence or type of Ti plasmid (octopine or nopaline) present in the bacterium. The transport of these opines required active cellular metabolism. Nonradioactive octopine, nopaline, and arginine competed effectively with [14C]octopine and [14C]nopaline for transport into A. tumefaciens A136, suggesting that the transport of these opines occurs via an arginine transport pathway not encoded by the Ti plasmid.


Measurement invariance tests of revisions to archaically worded items in the Mach IV scale.
The Machiavellian IV [1] instrument, developed almost 50 years ago to measure trait Machiavellianism and still in wide use in personality research, uses item wording that is not gender-neutral, makes use of idiomatic expressions, and includes archaic references. In this two-sample study, exploratory factor analysis (EFA) was conducted on one sample to examine the structure of responses to the Mach IV. In an independent second sample the resulting EFA structure was analyzed using confirmatory factor analysis-based measurement equivalence/invariance (ME/I) tests in a control group with the original archaic items and a treatment group with eight items rewritten in a more modern vernacular. Specific model testing steps [2] and statistical tests [3] were applied in a bottom-up approach [4] to ME/I tests on these two versions of the Mach IV. The two versions were found to have equal form, equal factor loadings, but unequal indicator error variances. Subsequent item-by-item tests of error invariance resulted in substantial decrements to fit for three revised items suggesting that the error associated with these items was not equal across the two versions.


Fluoride induces apoptosis via inhibiting SIRT1 activity to activate mitochondrial p53 pathway in human neuroblastoma SH-SY5Y cells.
There has been a great concern about the neurotoxicity of fluoride since it can pass through the blood-brain barrier and accumulate in the brain. It has been suggested that apoptosis plays a vital role in neurotoxicity of fluoride. However, whether p53-mediated apoptotic pathway is involved is still unclear. Our results showed that apoptosis was induced after treatment with 40 and 60 mg/L of NaF for 24 h in human neuroblastoma SH-SY5Y cells. Exposure to 60 mg/L of NaF for 24 h significantly upregulated the levels of p53 and apoptosis-related proteins including PUMA, cytochrome c (cyto c), cleaved caspase-3 and cleaved PARP, whereas downregulated Bcl-2 in SH-SY5Y cells. Meanwhile, fluoride increased p53 nuclear translocation, cyto c release from mitochondria to cytoplasm and mitochondrial translocation of Bax in SH-SY5Y cells. Fluoride-induced increases of apoptotic rates and apoptosis-related protein levels were significantly attenuated by inhibiting p53 transcriptional activity with pifithrin-α. In addition, fluoride inhibited the deacetylase activity of SIRT1 and increased p53 (acetyl K382) level in SH-SY5Y cells. Apoptosis and upregulation of cleaved caspase-3, cleaved PARP and p53 (acetyl K382) induced by fluoride could be ameliorated by SIRT1 overexpression or its activator resveratrol in SH-SY5Y cells. Taken together, our study demonstrates that fluoride induces apoptosis by inhibiting the deacetylase activity of SIRT1 to activate mitochondrial p53 pathway in SH-SY5Y cells, which depends on p53 transcriptional activity. Thus, SIRT1 may be a promising target to protect against neurotoxicity induced by fluoride.


The 2018 Inter-agency field manual on reproductive health in humanitarian settings: revising the global standards.
Since the 1990s, the Inter-agency field manual on reproductive health in humanitarian settings (IAFM) has provided authoritative guidance on reproductive health service provision during different phases of complex humanitarian emergencies. In 2018, the Inter-Agency Working Group on Reproductive Health in Crises will release a new edition of this global resource. In this article, we describe the collaborative and inter-sectoral revision process and highlight major changes in the 2018 IAFM. Key revisions to the manual include repositioning unintended pregnancy prevention within and explicitly incorporating safe abortion care into the Minimum Initial Service Package (MISP) chapter, which outlines a set of priority activities to be implemented at the outset of a humanitarian crisis; stronger guidance on the transition from the MISP to comprehensive sexual and reproductive health services; and the addition of a logistics chapter. In addition, the IAFM now places greater and more consistent emphasis on human rights principles and obligations, gender-based violence, and the linkages between maternal and newborn health, and incorporates a diverse range of field examples. We conclude this article with an outline of plans for releasing the 2018 IAFM and facilitating uptake by those working in refugee, crisis, conflict, and emergency settings.


Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond.
This review summarizes our current understanding of catechol-o-methyltransferase (COMT) and how it relates to brain function and schizophrenia. We begin by considering the COMT gene, its transcripts and proteins, and its relevance for central catecholamine function. We then describe how variation in COMT activity affects the function of the prefrontal cortex (PFC) and associated areas, reviewing evidence that COMT modulates executive function and working memory and highlighting recent data that also implicate it in emotional processing. Finally, we discuss briefly the genetic association between COMT and schizophrenia, focusing in particular on the complex interaction of functional loci within the gene that may underlie the mixed results of studies to date. We conclude by outlining preliminary data indicating that COMT is a promising therapeutic target for ameliorating the cognitive deficits associated with schizophrenia.


Probe-Directed Degradation (PDD) for Flexible Removal of Unwanted cDNA Sequences from RNA-Seq Libraries.
Most applications for RNA-seq require the depletion of abundant transcripts to gain greater coverage of the underlying transcriptome. The sequences to be targeted for depletion depend on application and species and in many cases may not be supported by commercial depletion kits. This unit describes a method for generating RNA-seq libraries that incorporates probe-directed degradation (PDD), which can deplete any unwanted sequence set, with the low-bias split-adapter method of library generation (although many other library generation methods are in principle compatible). The overall strategy is suitable for applications requiring customized sequence depletion or where faithful representation of fragment ends and lack of sequence bias is paramount. We provide guidelines to rapidly design specific probes against the target sequence, and a detailed protocol for library generation using the split-adapter method including several strategies for streamlining the technique and reducing adapter dimer content.


GeneTRACE-reconstruction of gene content of ancestral species.
While current computational methods allow the reconstruction of individual ancestral protein sequences, reconstruction of complete gene content of ancestral species is not yet an established task. In this paper, we describe GENETRACE, an efficient linear-time algorithm that allows the reconstruction of evolutionary history of individual protein families as well as the complete gene content of ancestral species. The performance of the method was validated with a simulated evolution program called SimulEv. Our results indicate that given a set of correct phylogenetic profiles and a correct species tree, ancestral gene content can be reconstructed with sensitivity and selectivity of more than 90%. SimulEv simulations were also used to evaluate performance of the reconstruction of gene content-based phylogenetic trees, suggesting that these trees may be accurate at the terminal branches but suffer from long branch attraction near the root of the tree.


Advancing Science Through Collaborative Data Sharing and Synthesis.
The demand for researchers to share their data has increased dramatically in recent years. There is a need to replicate and confirm scientific findings to bolster confidence in many research areas. Data sharing also serves the critical function of allowing synthesis of findings across trials. As innovative statistical methods have helped resolve barriers to synthesis analyses, data sharing and synthesis can help answer research questions that cannot be answered by individual trials alone. However, the sharing of data among researchers remains challenging and infrequent. This article aims to (a) increase support for data sharing and synthesis collaborations among researchers to advance scientific knowledge and (b) provide a model for establishing these collaborations using the example of the ongoing National Institute of Mental Health's Collaborative Data Synthesis on Adolescent Depression Trials. This study brings together datasets from existing prevention and treatment trials in adolescent depression, as well as researchers and stakeholders, to answer questions about "for whom interventions work" and "by what pathways interventions have their effects." This is critical to improving interventions, including increasing knowledge about intervention efficacy among minority populations, or what we call "scientific equity." The collaborative model described is relevant to fields with research questions that can only be addressed by synthesizing individual-level data.


Accidental cannabis poisoning in the elderly.
There are two main varieties of Cannabis sativa plant, namely, hemp which is cultivated for fiber and seeds and contains low amounts of psychoactive cannabinoids and the other which is cultivated for the drug cannabis or marijuana. Increasing popularity of hemp food products and alleged beneficial effects of cannabinoids in the drug variety of cannabis might lead to confusion in the lay population and unintentional ingestion of marijuana, as described in this case report. During a workshop on the use of hemp for medicinal purposes, there was a degustation of various hemp food products including also cookies that were brought by one of the attendees. Approximately 1 h after ingestion of cookies, people experienced nausea and vomiting, dizziness, sleepiness and difficulty walking. Twelve people were referred to emergency department, where two were admitted to intensive care because of central nervous system depression. They were all managed with supportive measures and were discharged home without health-related consequences.


A biomechanical approach to evaluate overload and specificity characteristics within physical preparation exercises.
An essential component of any physical preparation programme is the selection of training exercises to facilitate desired performance outcomes, with practitioners balancing the principles of sports training to inform exercise selection. This study aimed to advance biomechanical understanding of the principles of overload and specificity within exercise selection, utilising novel joint kinetic and intra-limb joint coordination analyses. Three-dimensional kinematic and kinetic data were obtained from six male sprinters (100 m PB, 10.64-11.00) performing block starts (competitive motor task) and seven training exercises that encompassed traditionally viewed general and more specific exercises. Results highlighted the challenging nature of exercise selection, with all exercises demonstrating capacity to overload relevant joint kinetic features of the block start. In addition, all exercises were able to promote the emergence of proximal and in-phase extension joint coordination patterns linked with block start execution, although traditionally viewed non-specific exercises elicited greater overall coordination similarity. The current research helps advance biomechanical understanding of overload and specificity within exercise selection, by demonstrating how exercise selection should not solely be based on perceived replication of a competitive motor task. Instead, practitioners must consider how the musculoskeletal determinants of performance are overloaded, in addition to promoting task specific coordination patterns.


Barriers to primary care responsiveness to poverty as a risk factor for health.
Poverty is widely recognized as a major determinant of poor health, and this link has been extensively studied and verified. Despite the strong evidentiary link, little work has been done to determine what primary care health providers can do to address their patients' income as a risk to their health. This qualitative study explores the barriers to primary care responsiveness to poverty as a health issue in a well-resourced jurisdiction with near-universal health care insurance coverage. One to one interviews were conducted with twelve experts on poverty and health in primary care in Ontario, Canada. Participants included family physicians, specialist physicians, nurse practitioners, community workers, advocates, policy experts and researchers. The interviews were analysed for anticipated and emergent themes. This study reveals provider- and patient-centred structural, attitudinal, and knowledge-based barriers to addressing poverty as a risk to health. While many of its findings reinforce previous work in this area, this study's findings point to a number of areas front line primary care providers could target to address their patients' poverty. These include a lack of provider understanding of the lived reality of poverty, leading to a failure to collect adequate data about patients' social circumstances, and to the development of inappropriate care plans. Participants also pointed to prejudicial attitudes among providers, a failure of primary care disciplines to incorporate approaches to poverty as a standard of care, and a lack of knowledge of concrete steps providers can take to address patients' poverty. While this study reinforces, in a well-resourced jurisdiction such as Ontario, the previously reported existence of significant barriers to addressing income as a health issue within primary care, the findings point to the possibility of front line primary care providers taking direct steps to address the health risks posed by poverty. The consistent direction and replicability of these findings point to a refocusing of the research agenda toward an examination of interventions to decrease the health impacts of poverty.