Can REDD+ help the conservation of restricted-range island species? Insights from the endemism hotspot of São Tomé.
REDD+ aims to offset greenhouse gas emissions through "Reduced Emissions from Deforestation and forest Degradation". Some authors suggest that REDD+ can bring additional benefits for biodiversity, namely for the conservation of extinction-prone restricted-range species. Here, we assess this claim, using São Tomé Island (Democratic Republic of São Tomé and Príncipe) as a case study. We quantified the abundance of bird and tree species, and calculated the aboveground carbon stocks across a gradient of land-use intensity. We found a strong spatial congruence between carbon and the presence and abundance of endemic species, supporting the potential of REDD+ to protect these taxa. We then assessed if REDD+ could help protect the forests of São Tomé and Príncipe. To do so, we used OSIRIS simulations to predict country-level deforestation under two different REDD+ designs. These simulations showed that REDD+ could promote the loss of forests in São Tomé and Príncipe through leakage. This happened even when additional payments for biodiversity were included in the simulations, and despite São Tomé and Príncipe having the fourth highest carbon stocks per land area and the second highest biodiversity values according to the OSIRIS database. These results show weaknesses of OSIRIS as a planning tool, and demonstrate that the benefits that REDD+ might bring for biodiversity are strongly dependent on its careful implementation. We recommend that payment for ecosystem services programmes such as REDD+ develop safeguards to ensure that biodiversity co-benefits are met and perverse outcomes are avoided across all tropical countries. In particular, we advise specific safeguards regarding the conservation of extinction-prone groups, such as island restricted-range species.


3D Fluid-Structure Interaction Simulation of Aortic Valves Using a Unified Continuum ALE FEM Model.
Due to advances in medical imaging, computational fluid dynamics algorithms and high performance computing, computer simulation is developing into an important tool for understanding the relationship between cardiovascular diseases and intraventricular blood flow. The field of cardiac flow simulation is challenging and highly interdisciplinary. We apply a computational framework for automated solutions of partial differential equations using Finite Element Methods where any mathematical description directly can be translated to code. This allows us to develop a cardiac model where specific properties of the heart such as fluid-structure interaction of the aortic valve can be added in a modular way without extensive efforts. In previous work, we simulated the blood flow in the left ventricle of the heart. In this paper, we extend this model by placing prototypes of both a native and a mechanical aortic valve in the outflow region of the left ventricle. Numerical simulation of the blood flow in the vicinity of the valve offers the possibility to improve the treatment of aortic valve diseases as aortic stenosis (narrowing of the valve opening) or regurgitation (leaking) and to optimize the design of prosthetic heart valves in a controlled and specific way. The fluid-structure interaction and contact problem are formulated in a unified continuum model using the conservation laws for mass and momentum and a phase function. The discretization is based on an Arbitrary Lagrangian-Eulerian space-time finite element method with streamline diffusion stabilization, and it is implemented in the open source software Unicorn which shows near optimal scaling up to thousands of cores. Computational results are presented to demonstrate the capability of our framework.


High Intensity Interval Training (HIIT) Improves Cardiorespiratory Fitness (CRF) in Healthy, Overweight and Obese Adolescents: A Systematic Review and Meta-Analysis of Controlled Studies.
Background: High Intensity Interval Training (HIIT) is a sustainable and effective method for improving Cardiorespiratory Fitness (CRF) in adolescents. HIIT is proven to produce equal or greater improvements in CRF when compared to moderate intensity continuous exercise (MICE) in adolescents. Methods: The studies included were considered eligible if: (1) Participants were adolescents (11-18 years old); (2) Examined changes in CRF measured either directly or indirectly; (3) Included a non-exercising control group or MICE comparison group; (4) Participants were matched at enrolment; (5) Reported HIIT protocol information; (6) Provided HIIT intensity. A meta-analysis was conducted to determine the effect of HIIT on CRF. Meta-regression and moderator analyses were performed out to quantitatively examine moderators of protocol design on CRF improvements. Results: HIIT displays a moderate effect to improve CRF (g = 0.86, 95% CI 0.518-1.106, p < 0.001). Neither study duration (weeks), nor total or weekly accumulated HIIT volume (min) displayed any significant moderation effect on pooled improvement on CRF (p > 0.05). Conclusions: HIIT is an effective method to improve CRF in adolescents, irrespective of body composition. Notably, meta regression analysis identified that prolonged high volume HIIT programs are similarly effective to short term low volume HIIT programs. This becomes of particular interest for those involved in school curricula, where short HIIT exercise may provide a pragmatic adjunct to the health benefits of Physical Education (PE) lessons.


Comment on "Post-wildfire logging hinders regeneration and increases fire risk".
Donato et al. (Brevia, 20 January 2006, p. 352) concluded that logging after wildfire kills natural regeneration and increases fire risk. We argue that their paper lacks adequate context and supporting information to be clearly interpreted by scientists, resource managers, policy-makers, and the public.


Using intervention mapping to promote the receipt of clinical preventive services among women with physical disabilities.
This article describes the development of Promoting Access to Health Services (PATHS), an intervention to promote regular use of clinical preventive services by women with physical disabilities. The intervention was developed using intervention mapping (IM), a theory-based logical process that incorporates the six steps of assessment of need, preparation of matrices, selection of theoretical methods and strategies, program design, program implementation, and evaluation. The development process used methods and strategies aligned with the social cognitive theory and the health belief model. PATHS was adapted from the workbook Making Preventive Health Care Work for You, developed by a disability advocate, and was informed by participant input at five points: at inception through consultation by the workbook author, in conceptualization through a town hall meeting, in pilot testing with feedback, in revision of the curriculum through an advisory group, and in implementation by trainers with disabilities. The resulting PATHS program is a 90-min participatory small-group workshop, followed by structured telephone support for 6 months.


Antimicrobial photodynamic therapy as an adjunct for treatment of deep carious lesions-A systematic review.
For deep carious lesions, a more conservative treatment modality ("selective caries removal") has been proposed, where only the heavily contaminated dentine is removed. In this regard, effective adjuncts for cavity disinfection such as the antimicrobial photodynamic therapy (aPDT) can be valuable clinically prior to definitive restoration. Therefore, the aim of this study was to systematically assess clinical studies on the effectiveness of aPDT as a supplementary tool in the treatment of deep caries lesions. Searches were performed in four databases (PubMed, EMBASE, ISI Web of Science, ClinicalTrials.gov) from 1st January, 2011 until 21st June, 2016 for search terms relevant to the observed parameters, pathological condition, intervention and anatomic entity. The pooled information was evaluated according to PRISMA guidelines. At first, 1651 articles were recovered, of which 1249 full-text articles were evaluated, 270 articles thereof were reviewed for eligibility and finally 6 articles met all inclusion criteria. The aPDT protocols involved Methylene Blue, Toluidine Blue and aluminium-chloride-phthalocyanine as photosensitizers and diode lasers, light-emitting diodes and halogen light-sources. The data from five reports, utilizing both culture-dependent and -independent methods, disclosed significant reduction of cariogenic bacterial load after mechanical caries removal with adjunct aPDT. As these studies exhibit some methodological limitations, e.g. lack of positive controls, this systematic review can support the application of aPDT to a limited extent only in terms of reducing the microbial load in deep carious lesions before restorative treatment.


Thiopurine therapy: when to start and when to stop.
The thiopurines azathioprine and 6-mercaptopurine are effective both for active disease and for maintaining remission in both Crohn's disease and ulcerative colitis. This review describes criteria for starting thiopurines (two or more courses of steroids in a calendar year, relapse as prednisolone is reduced below 15 mg/day, within 6 weeks of stopping steroids) and the benefits of continuing treatment for up to 5 years. Challenging issues, such as thiopurine intolerance, relative merits of azathioprine, 6-mercaptopurine, monitoring therapy and thiopurines in pregnancy are addressed.


Residual health status after Guillain-Barré syndrome.
To study the extent to which patients experience residual problems in daily functioning several years after having Guillain-Barré syndrome (GBS) a survey of 123 patients who had had Guillain-Barré syndrome three to six years previously was performed, using the sickness impact profile (SIP) for measuring functional health status and a functional assessment scale (F score) for measuring physical condition. The patients were diagnosed according to the international criteria for Guillain-Barré syndrome and were at the time of diagnosis unable to walk more than 10 metres without support. The physical SIP score correlated positively with final physical recovery (Pearson's r = 0.79). The psychosocial SIP score indicated impairment in all patient groups compared with matched normal control values; they included the group with no, or mild, residual symptoms (P < 0.05). No relation was found between clinical variables related to the severity or duration of Guillain-Barré syndrome and residual psychosocial dysfunctioning, except for a relation with disturbance of sensation in the arms. In conclusion, in many patients with Guillain-Barré syndrome, psychosocial functioning is still seriously affected, even when they have physically recovered, or show only mild residual signs.


Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms.
Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPARβ/δ in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPARβ/δ. Expression of PPARβ/δ caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPARβ/δ-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPARβ/δ competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARα-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPARβ/δ mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPARβ/δ inhibits RAR/RXR dimerization and represents a new therapeutic strategy.


Plasmonic propagations distances for interferometric surface plasmon resonance biosensing.
A surface plasmon resonance (SPR) scheme is proposed in which the local phase modulations of the coupled plasmons can interfere and yield phase-sensitive intensity modulations in the measured signal. The result is an increased traceability of the SPR shifts for biosensing applications. The main system limitation is the propagation distance of the coupled plasmon modes. This aspect is therefore studied for thin film microstructures operating in the visible and near-infrared spectral regions. The surface roughness of the substrate layer is examined for different dielectrics and deposition methods. The Au layer, on which the plasmonic modes are propagating and the biosensing occurs, is also examined. The surface roughness and dielectric values for various deposition rates of very thin Au films are measured. We also investigate an interferometric SPR setup where, due to the power flux transfer between plasmon modes, the specific choice of grating coupler can either decrease or increase the plasmon propagation length.


Ionized calcium and magnesium: the effect of septic shock in the baboon.
Ionized calcium (Ca2+) and ionized magnesium (Mg2+) are important intracellular "second messengers" and control exictation-contraction coupling, excitation-secretion, oxidative phosphorylation, and mitochondrial acid-base balance. The present study examines the effect of septic shock on serum (Ca2+) and (Mg2+). Five adult female baboons were subjected to live E. coli septic shock and then resuscitated. Three baboons served as controls. Ca2+ was measured by the Orion SS-20 flow-through calcium electrode and Mg2+ calculated by the method of Killen. Other measurements included: total calcium, bound calcium, total magnesium, bound magnesium, phosphate, albumin, globulin, hemotocrit, and total protein. This study shows that there are significant disturbances of Ca2+ and Mg2+ during septic shock in the baboon. These disturbances may in part explain cellular dysfunction during shock including: decreased myocardial contractility, inappropriate secretion of endocrine cells, decrease in oxidative phosphorylation, and mitochondrial acidosis.


The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder.
This article describes the development of consensus medication algorithms for the treatment of patients with major depressive disorder in the Texas public mental health system. To the best of our knowledge, the Texas Medication Algorithm Project (TMAP) is the first attempt to develop and prospectively evaluate consensus-based medication algorithms for the treatment of individuals with severe and persistent mental illnesses. The goals of the algorithm project are to increase the consistency of appropriate treatment of major depressive disorder and to improve clinical outcomes of patients with the disorder. A consensus conference composed of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of major depressive disorder in the Texas mental health system. After a series of presentations and panel discussions, the consensus panel met and drafted the algorithms. The panel consensually agreed on algorithms developed for both nonpsychotic and psychotic depression. The algorithms consist of systematic strategies to define appropriate treatment interventions and tactics to assure optimal implementation of the strategies. Subsequent to the consensus process, the algorithms were further modified and expanded iteratively to facilitate implementation on a local basis. These algorithms serve as the initial foundation for the development and implementation of medication treatment algorithms for patients treated in public mental health systems. Specific issues related to adaptation, implementation, feasibility testing, and evaluation of outcomes with the pharmacotherapeutic algorithms will be described in future articles.


Is surgical intervention more effective than non-surgical treatment for carpal tunnel syndrome? A systematic review.
Carpal tunnel syndrome is a common disorder in hand surgery practice. Both surgical and conservative interventions are utilized for the carpal tunnel syndrome. Although certain indications would specifically indicate the need for surgery, there is a spectrum of patients for whom either treatment option might be selected. The purpose of this systematic review was to compare the efficacy of surgical treatment of carpal tunnel syndrome with conservative treatment. We included all controlled trials written in English, attempting to compare any surgical interventions with any conservative therapies. We searched Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2010), MEDLINE (1980 to June 2010), EMBASE (1980 to June 2010), PEDro (searched in June 2010), international guidelines, computer searches based on key words and reference lists of articles. Two reviewers performed study selection, assessment of methodological quality and data extraction independently of each other. Weighted mean differences and 95% confidence intervals for patient self-reported functional and symptom questionnaires were calculated. Relative risk (RR) and 95% confidence intervals for electrophysiological studies and complication were also calculated. We assessed seven studies in this review including 5 RCTs and 2 controlled trials. The methodological quality of the trials ranged from moderate to high. The weighted mean difference demonstrated a larger treatment benefit for surgical intervention compared to non surgical intervention at six months for functional status 0.35( 95% CI 0.22, 0.47) and symptom severity 0.43 (95% CI 0.29, 0.57). There were no statistically significant difference between the intervention options at 3 months but there was a benefit in favor of surgery in terms of function and symptom relief at 12 months (0.35, 95% CI 0.15, 0.55 and 0.37, 95% CI 0.19 to 0.56). The RR for secondary outcomes of normal nerve conduction studies was 2.3 (95% CI 1.2, 4.4), while RR was 2.03 (95% CI 1.28 to 3.22) for complication, both favoring surgery. Both surgical and conservative interventions had treatment benefit in carpal tunnel syndrome. Surgical treatment has a superior benefit, in symptoms and function, at six and twelve months. Patient underwent surgical release were two times more likely to have normal nerve conduction studies but also had complication and side effects as well. Given the treatment differential and potential for adverse effects and that conservative interventions benefitted a substantial proportion of patients, current practice of a trial of conservative management with surgical release for severe or persistent symptoms is supported by evidence.


The Sole Provider: Preparation for Deployment to a Medically Austere Theater.
The combat focus of the US Military over the past 15 years has primarily centered on the Iraq and Afghanistan areas of operation (AOs). Thus, much human and financial capital has been dedicated to the creation of a robust medical infrastructure to support those operations. However, Special Operation Forces (SOF) are often called upon to deploy in much more medically austere AOs. SOF medical providers operating in such environments face significant challenges due to the diversity of medical threats, extremely limited access to medical resupply, a material shortage of casualty evacuation platforms, lack of medical facilities, and limited access to higher-level care providers. This article highlights the challenges faced during a recent Special Forces deployment to such an austere environment. Many of these challenges can be mitigated with a specific approach to premission training and preparation.


Interacting with the public as a risk factor for employee psychological distress.
The 1-month prevalence of any mental disorder in employees ranges from 10.5% to 18.5%. Mental disorders are responsible for substantial losses in employee productivity in both absenteeism and presenteeism. Potential work related factors contributing to mental difficulties are of increasing interest to employers. Some data suggests that being sales staff, call centre operator, nurse or teacher increases psychological distress. One aspect of these occupations is that there is an interaction with the public. The aim of this study is to evaluate whether employees who interact with the public are at greater risk of psychological distress. Data was collected from two studies. In study one 11,259 employees (60% female; mean age 40-years +/- SD 10-years) from six employers responded to the Health and Work Performance Questionnaire (HPQ) which contained a measure of psychological distress, the Kessler 6 (K6). Employees were coded as to whether or not they interacted with the public. Binomial logistic regression was performed on this data to determine the odds ratio (OR) for moderate or high psychological distress in employees that interacted with the public. Study two administered the HPQ and K6 to sales employees of a large Australian bank (N = 2,129; 67% female; mean age 39-years SD 10-years). This questionnaire also probed how many contacts individuals had with the public in the past week. Analysis of variance was used to determine if the number of contacts was related to psychological distress. In study one the prevalence of psychological distress in those that interacted and did not interact with the public were 19% and 15% respectively (P < 0.001). Interacting with the public was associated with an increased OR of 1.3 (P < 0.001) for moderate to high levels of psychological distress. In study two employees with less than 25 contacts with the public per week had a lower K6 score than those who had > or = 25 contacts per week (P = 0.016). The results of the current study are indicative that interaction with the public increases levels of psychological distress. Employees dealing with the public may be an employee subgroup that could be targeted by employers with mental health interventions.


Effect of three apple rootstocks on the population of the small red-belted clearwing borer, Synanthedon myopaeformis.
Abstract Experiments were conducted in Ash-Shoubak area of Jordan from June 2003 to September 2005 to study the effect of three apple rootstocks on the development of the small red-belted clearwing borer, Synanthedon myopaeformis (Borkh.) (Lepidoptera: Sesiidae), under field conditions. Mondial Gala apple trees grafted on the dwarfing rootstock M9 and the semi-dwarfing rootstock M26 were equally infested, whereas those grafted on MM106 showed significantly lower infestation levels. S. myopaeformis bore into burr knots that develop below a graft union on rootstocks and girdle the tree. There was a significant effect of rootstock on the numbers of burrs present, and the percentage of burr knots infested by S. myopaeformis, with M106 having significantly fewer burrs, and a lower percent infested.


Common and cell-type specific responses to anti-cancer drugs revealed by high throughput transcript profiling.
More effective use of targeted anti-cancer drugs depends on elucidating the connection between the molecular states induced by drug treatment and the cellular phenotypes controlled by these states, such as cytostasis and death. This is particularly true when mutation of a single gene is inadequate as a predictor of drug response. The current paper describes a data set of ~600 drug cell line pairs collected as part of the NIH LINCS Program ( http://www.lincsproject.org/ ) in which molecular data (reduced dimensionality transcript L1000 profiles) were recorded across dose and time in parallel with phenotypic data on cellular cytostasis and cytotoxicity. We report that transcriptional and phenotypic responses correlate with each other in general, but whereas inhibitors of chaperones and cell cycle kinases induce similar transcriptional changes across cell lines, changes induced by drugs that inhibit intra-cellular signaling kinases are cell-type specific. In some drug/cell line pairs significant changes in transcription are observed without a change in cell growth or survival; analysis of such pairs identifies drug equivalence classes and, in one case, synergistic drug interactions. In this case, synergy involves cell-type specific suppression of an adaptive drug response.


Effects of scanning (routine health information exposure) on cancer screening and prevention behaviors in the general population.
Research on health information exposure focuses primarily on deliberate information-seeking behavior and its effects on health. By contrast, this study explores the complementary and perhaps more influential role of health information acquired through exposure to routinely used sources, called scanning. The authors hypothesized that scanning from nonmedical sources, both mediated and interpersonal, affects cancer screening and prevention decisions. The authors used a nationally representative longitudinal survey of 2,489 adults 40 to 70 years of age to analyze the effects of scanning on 3 cancer screening behaviors (mammography, prostate-specific antigen [PSA], and colonoscopy) and 3 prevention behaviors (exercising, eating fruits and vegetables, and dieting to lose weight). After adjustment for baseline behaviors and covariates, scanning at baseline predicted weekly exercise days 1 year later as well as daily fruit and vegetable servings 1 year later for those whose consumption of fruits and vegetables was already higher at baseline. Also, among those reporting timely screening mammogram behavior at baseline, scanning predicted repeat mammography. Scanning was marginally predictive of PSA uptake among those not reporting a PSA at baseline. Although there were strong cross-sectional associations, scanning did not predict dieting or colonoscopy uptake in longitudinal analyses. These analyses provide substantial support for a claim that routine exposure to health content from nonmedical sources affects specific health behaviors.


Betahistine for tinnitus.
Tinnitus is a symptom defined as the perception of sound in the absence of an external source. In England alone there are an estimated ¾ million general practice consultations every year where the primary complaint is tinnitus, equating to a major burden on healthcare services. Clinical management strategies include education and advice, relaxation therapy, tinnitus retraining therapy, cognitive behavioural therapy, sound enrichment using ear-level sound generators or hearing aids, and drug therapies to manage co-morbid symptoms such as sleep difficulties, anxiety or depression. As yet, no drug has been approved for tinnitus by a regulatory body. Nonetheless, over 100,000 prescriptions for betahistine are being filled every month in England, and nearly 10% of general practitioners prescribe betahistine for tinnitus. To assess the effects of betahistine in patients with subjective idiopathic tinnitus. The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL, via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 23 July 2018. Randomised controlled trials (RCTs) recruiting patients of any age with acute or chronic subjective idiopathic tinnitus were included. We included studies where the intervention involved betahistine and this was compared to placebo, no intervention or education and information. We included all courses of betahistine, regardless of dose regimens or formulations and for any duration of treatment. We used the standard methodological procedures expected by Cochrane. Our primary outcomes included tinnitus loudness and significant adverse effects (upper gastrointestinal discomfort). Our secondary outcomes included tinnitus symptom severity as measured by the global score on a multi-item tinnitus questionnaire, depressive symptoms, symptoms of generalised anxiety, health-related quality of life, other adverse effects (e.g. headache, drowsiness, allergic skin reactions (pruritis, rashes) and exacerbation of tinnitus) and tinnitus intrusiveness. We used GRADE to assess the quality of evidence for each outcome; this is indicated in italics. This review included five studies (with a total of 303 to 305 participants) comparing the effects of betahistine with placebo in adults with subjective idiopathic tinnitus. Four studies were parallel-group RCTs and one had a cross-over design. The risk of bias was unclear in all of the included studies.Due to heterogeneity in the outcomes measured and measurement methods used, very limited data pooling was possible. When we pooled the data from two studies for the primary outcome tinnitus loudness, the mean difference on a 0- to 10-point visual analogue scale at one-month follow-up was not significant between betahistine and placebo (-0.16, 95% confidence interval (CI) -1.01 to 0.70; 81 participants) (very low-quality evidence). There were no reports of upper gastrointestinal discomfort (significant adverse effect) in any study.As a secondary outcome, one study found no difference in the change in the Tinnitus Severity Index between betahistine and placebo (mean difference at 12 weeks 0.02, 95% CI -1.05 to 1.09; 50 participants) (moderate-quality evidence). None of the studies reported the other secondary outcomes of changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health-related quality of life as measured by a validated instrument, nor tinnitus intrusiveness.Other adverse effects that were reported were not treatment-related. There is an absence of evidence to suggest that betahistine has an effect on subjective idiopathic tinnitus when compared to placebo. The evidence suggests that betahistine is generally well tolerated with a similar risk of adverse effects to placebo treatments. The quality of evidence for the reported outcomes, using GRADE, ranged from moderate to very low.If future research into the effectiveness of betahistine in patients with tinnitus is felt to be warranted, it should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the development of validated, patient-centred outcome measures for research in the field of tinnitus.


Isolation of Leishmania Promastigote Flagella.
Eukaryotic flagella are conserved multifunctional organelles with roles in motility, intercellular interactions, and signal transduction. Leishmania possess a single flagellum at all stages of their life cycle. Flagella of promastigote forms in the fly are long and motile, with a canonical 9 + 2 microtubule axoneme and an extra-axonemal paraflagellar rod (PFR). This protocol describes a simple method for the isolation of Leishmania mexicana promastigote flagella, optimized to yield intact flagella that retain both the cytoskeletal elements (9 + 2 axoneme and PFR) and the surrounding membrane. The isolated flagella and deflagellated cell bodies are suitable for analysis by electron microscopy, protein mass spectrometry, and lipidomics.


Brain growth after surgical treatment for infant postinfectious hydrocephalus in Sub-Saharan Africa: 2-year results of a randomized trial.
Hydrocephalus in infants, particularly that with a postinfectious etiology, is a major public health burden in Sub-Saharan Africa. The authors of this study aimed to determine whether surgical treatment of infant postinfectious hydrocephalus in Uganda results in sustained, long-term brain growth and improved cognitive outcome. The authors performed a trial at a single center in Mbale, Uganda, involving infants (age < 180 days old) with postinfectious hydrocephalus randomized to endoscopic third ventriculostomy plus choroid plexus cauterization (ETV+CPC; n = 51) or ventriculoperitoneal shunt (VPS; n = 49). After 2 years, they assessed developmental outcome with the Bayley Scales of Infant Development, Third Edition (BSID-III), and brain volume (raw and normalized for age and sex) with CT scans. Eighty-nine infants were assessed for 2-year outcome. There were no significant differences between the two surgical treatment arms in terms of BSID-III cognitive score (p = 0.17) or brain volume (p = 0.36), so they were analyzed together. Raw brain volumes increased between baseline and 2 years (p < 0.001), but this increase occurred almost exclusively in the 1st year (p < 0.001). The fraction of patients with a normal brain volume increased from 15.2% at baseline to 50.0% at 1 year but then declined to 17.8% at 2 years. Substantial normalized brain volume loss was seen in 21.3% patients between baseline and year 2 and in 76.7% between years 1 and 2. The extent of brain growth in the 1st year was not associated with the extent of brain volume changes in the 2nd year. There were significant positive correlations between 2-year brain volume and all BSID-III scores and BSID-III changes from baseline. In Sub-Saharan Africa, even after successful surgical treatment of infant postinfectious hydrocephalus, early posttreatment brain growth stagnates in the 2nd year. While the reasons for this finding are unclear, it further emphasizes the importance of primary infection prevention and mitigation strategies along with optimizing the child's environment to maximize brain growth potential.


Co-administration of etomoxir and RU-486 mitigates insulin resistance in hepatic and muscular tissues of STZ-induced diabetic rats.
Insulin resistance is a condition of central importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary heart disease. Despite its association with numerous health problems, the mechanism responsible for the development of this phenomenon remains to be established. A novel theory has proposed that insulin resistance in diabetes stems, at least in part, from enhanced free fatty acid (FFA) oxidation and/or excessive production of glucocorticoids (GCs). Several key predictions of this premise were subjected to experimental testing using streptozotocin (STZ)-treated rats as a model for insulin-dependent diabetes mellitus and euglycemic-hyperinsulinemic clamp technique for the in vivo measurement of insulin actions. Euglycemic clamp studies with an insulin infusion index of 5 mU/kg/min were used to measure endogenous glucose production (EGP), glucose infusion rate (GIR), glucose disposal rate (GDR) and skeletal muscle glucose utilization index (GUI). Post-absorptive basal EGP and plasma levels of glucose and free fatty acids (FFA) were elevated in the STZ diabetic rats compared to their corresponding control values. In contrast, hypoinsulinemia was evident in these animals. Steady-state GIR and GDR during euglycemic-hyperinsulinemic clamp were markedly decreased in the STZ diabetic rats. Similarly, insulin-mediated suppression of EGP and plasma FFA concentration was also impaired in these animals. GUI, a measure of 2-deoxyglucose (2-DG) uptake, was increased in response to insulin in the order of white gastrocnemus (WG), red gastrocnemus (RG), extensor digitorum longus and soleus muscles. This parallels the percentage of red fibers in these muscles. Diabetes interferes with insulin's ability to increase 2-DG uptake in all of the above muscles with the exception of WG. Nullification of the associated hyperlipidemic and hypercortisolemic states of diabetes with etomoxir (hyperlipidemic) and the glucocorticoid receptor blocker RU-486 (hypercortisolemic) ameliorated the diabetes-related impairment of the in vivo insulin action. Overall these results together with those garnered from the literature support the notion that hypercortisolemia and the enhancement of FFA oxidation are involved, at least in part, in the development of hepatic and skeletal muscle insulin resistance in poorly controlled type I diabetes.


Rett syndrome: an eye-tracking study of attention and recognition memory.
The aim of this study was to examine attention and recognition memory for faces and patterns in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. Because Rett syndrome impairs speech and hand use, precluding most neuropsychological testing, the visual paired-comparison paradigm (VPC) was used, together with eye tracking. In the VPC, two identical stimuli are presented for familiarization. On test, the familiar stimulus and a new one are paired, and recognition inferred from preferential looking to the novel target. Attention is measured by looking time, gaze dispersion, and number/length of fixations. Twenty-seven female patients with Rett syndrome (mean age 10y 6mo; SD 6y 8mo, age range 2-22y) from the Rett clinic at a children's hospital were assessed in this study, along with 30 age- and sex-matched typically developing participants (outpatients from the same hospital). Although patients with Rett syndrome showed recognition of both faces and patterns, with novelty scores greater than chance (50%), their performance was significantly poorer than that of the typically developing comparison group. Their attention to both was less mature and marked by a more narrowly focused gaze, with fewer and longer fixations. When inspecting faces, attention to the eyes was similar in both groups; however, patients with Rett syndrome tended to ignore the nose and mouth. This is one of the first studies to characterize attention and memory in individuals with Rett syndrome. Visually based techniques, such as the VPC, open a new avenue for quantifying the cognitive phenotype associated with this syndrome.


Control of Pathogenic and Spoilage Microorganisms in Fresh-cut Fruits and Fruit Juices by Traditional and Alternative Natural Antimicrobials.
Traditional antimicrobials have been extensively used for many years. However, consumers are currently demanding wholesome, fresh-like, and safe foods without addition of chemically synthesized preservatives. The application of novel natural antimicrobials to assure safety of fresh-cut fruits and unpasteurized juices while preventing quality loss is a promising alternative. The effectiveness of these natural substances added to fruit derivatives has been studied by different researchers. Antimicrobials of animal (lactoperoxidase, lysozyme, and chitosan), plant (essential oils, aldehydes, esters, herbs, and spices), and microbial origin (nisin) can be used to effectively reduce pathogenic and spoilage microorganisms in fresh-cut fruits and fruit juices. Nevertheless, the use of these compounds at a commercial level is still limited due to several factors such as impact on sensory attributes or, in some cases, regulatory issues concerning their use. Therefore, extensive research on the effects of each antimicrobial on food sensory characteristics is still needed so that antimicrobial substances of natural origin can be regarded as feasible alternatives to synthetic ones.


Building a precise machine-specific time structure of the spot and energy delivery model for a cyclotron-based proton therapy system.
Objective. We proposed an experimental approach to build a precise machine-specific beam delivery time (BDT) prediction and delivery sequence model for standard, volumetric, and layer repainting delivery based on a cyclotron accelerator system.Approach. Test fields and clinical treatment plans' log files were used to experimentally derive three main beam delivery parameters that impacted BDT: energy layer switching time (ELST), spot switching time, and spot drill time. This derived machine-specific model includes standard, volumetric, and layer repainting delivery sequences. A total of 103 clinical treatment fields were used to validate the model.Main results. The study found that ELST is not stochastic in this specific machine. Instead, it is actually the data transmission time or energy selection time, whichever takes longer. The validation showed that the accuracy of each component of the BDT matches well between machine log files and the model's prediction. The average total BDT was about (-0.74 ± 3.33)% difference compared to the actual treatment log files, which is improved from the current commercial proton therapy system's prediction (67.22%±26.19%).Significance. An accurate BDT prediction and delivery sequence model was established for an cyclotron-based proton therapy system IBA ProteusPLUS®. Most institutions could adopt this method to build a machine-specific model for their own proton system.


Population-based survey of human sodium and potassium excretion.
1. During the 1989 National Heart Foundation Risk Factor Prevalence Survey a subsample in Hobart collected 24 h urine samples to measure electrolyte excretion. 2. The ranges were 30-344 mmol/24 h for Na+ excretion (mean 160 mmol/24 h for men, 124 mmol/24 h for women), and 25-119 mmol/24 h for K+ excretion (mean 77 mmol/24 h for men, 68 mmol/24 h for women). 3. As in other surveys, women excreted about 20-25% less Na+ and K+ than men, although there was no significant sex difference in the ratio of Na+/K+ excretion. 4. The recommended dietary intake (RDI) for Na+ and K+ was followed simultaneously by 19% of subjects, and 13% had a 24 h urinary Na+/K+ ratio less than or equal to 1.0. 5. Observance of the RDI limited the value of iodized salt for goitre prophylaxis. 6. Sodium excretion rates were outside the therapeutic range of thiazide diuretics in 22% of subjects. 7. Diet groups for long-term prospective cohort studies to test the prophylactic value of avoiding salt could apparently be recruited from existing subsamples of the population.


Embryo technology: implications for fertility in cattle.
During the past thirty years, basic and experimental studies on classical (superovulation; non-surgical recovery and transfer of cattle embryos) and advanced embryo technologies (in vitro embryo production; cloning by somatic cell nuclear transfer) have generated structural and functional information on oocyte development and quality, fertilisation and conceptus development. This information has provided new insight, not only into these technologies per se but also into the factors contributing to fertility in cattle. It is now known that the peripheral and follicular endocrine profiles have a profound influence on the subsequent developmental competence of the embryo. It is also well established that manipulation of the oocytes or embryos may adversely affect embryonic and foetal development, leading to the so-called 'large offspring syndrome'. Information from such studies has alerted scientists to the importance of epigenetics in cattle reproduction.


Real time detection of cell cycle regulator cyclin A on living tumor cells with europium emission.
Six water-soluble europium complexes (Eu-L1-P(n) and Eu-L2-P(n), n = 1, 2 and 3) with one antenna chromophore, two different linkers (L1 and L2) and three proposed cyclin A specific peptides (P1: -GAKRRLIF-NH2; P2: -GGAKRRLIF-NH2; P3: -Hex- GAKRRLIF-NH2) have been synthesized. With structural information available, comparisons of the cyclin grooves of cyclin A and the six europium complexes have been made, and insights have been gained into the determinants for peptide binding and the foundation of differential binding. Experiment-wise, the linear and two-photon induced photophysical properties of these conjugates were monitored in aqueous solution. Numerous in situ/in vitro biological assays have been carried out, such as responsive emission changes in situ/in vitro, Western blot and cellular uptake. As imaging agents, complexes with peptides P3: -Hex-GAKRRLIF-NH2 showed high selectivity to cyclin A in numerous cancer cells. When it comes to responsive optical signal changes, complex Eu-L2-P3 exhibited a threefold emission enhancement upon binding with cyclin A (100 nM cyclin A, ϕ = 8% to 21%, log KB = 5.83, detection limit = 5 nM), and this could be initiated by the shortened distance between the antenna and the lanthanide after they bind/get into cyclin A. It is promising that our compounds (especially compound Eu-L2-P3) could serve as the template for structure-guided efforts to develop potential imaging therapeutics on the basis of selective imaging of CDK2/cyclin A activity.


Nuclear accumulation of Smad complexes occurs only after the midblastula transition in Xenopus.
Activin and the Nodal-related proteins induce mesendodermal tissues during Xenopus development. These signals act through specific receptors to cause the phosphorylation, at their carboxyl termini, of Smad2 and Smad3. The phosphorylated Smad proteins form heteromeric complexes with Smad4 and translocate into the nucleus to activate the transcription, after the midblastula transition, of target genes such as Xbra and goosecoid (gsc). In this paper we use bimolecular fluorescence complementation (BiFC) to study complex formation between Smad proteins both in vivo and in response to exogenous proteins. The technique has allowed us to detect Smad2-Smad4 heteromeric interactions during normal Xenopus development and Smad2 and Smad4 homo- and heteromers in isolated Xenopus blastomeres. Smad2-Smad2 and Smad2-Smad4 complexes accumulate rapidly in the nuclei of responding cells following Activin treatment, whereas Smad4 homomeric complexes remain cytoplasmic. When cells divide, Smad2-Smad4 complexes associate with chromatin, even in the absence of ligand. Our observation that Smad2-Smad4 complexes accumulate in the nucleus only after the midblastula transition, irrespective of the stage at which cells were treated with Activin, may shed light on the mechanisms of developmental timing.


On-chip hydrodynamic chromatography of DNA through centimeters-long glass nanocapillaries.
This study demonstrates hydrodynamic chromatography of DNA fragments in a microchip. The microchip contains a highly regular array of nanofluidic channels (nanocapillaries) that are essential for resolving DNA in this chromatography mode. The nanocapillaries are self-enclosed robust structures built inside a doped glass layer on silicon using low-resolution photolithography and standard semiconductor processing techniques. Additionally, the unique nanocapillaries feature a cylindrical inner radius of 600 nm maintained over a length scale of 5 cm. The microchip with bare open nanocapillaries is shown to rapidly separate a digest of lambda DNA in free solution (<5 min under the elution pressure of 60 to 120 psi), relying entirely on pressure-driven flows and, in doing so, avoiding the field-induced DNA aggregations encountered in gel-free electrophoresis. The nanocapillaries, despite their relatively short length, are observed to fractionate DNA fragments reasonably well with a minimum resolvable size difference below 5 kbp. In the chromatograms obtained, the number of theoretical plates exceeds 105 plates per m for 3.5 and 21 kbp long DNA fragments. The relative mobility of fragments in relation to their size is found to be in excellent agreement with the simple quadratic model of hydrodynamic chromatography. The model is shown to estimate greater effective hydrodynamic radii than those of respective fragments being unconfined in bulk solution, implying increased drag forces and reduced diffusion coefficients, which is also a noticeable trend among diffusion coefficient estimates derived from the experimentally obtained plate heights. This robust mass-producible microchip can be further developed into a fully integrated bioanalytic microsystem.


Semi-solid Sucrose Stearate-Based Emulsions as Dermal Drug Delivery Systems.
Mild non-ionic sucrose ester surfactants can be employed to produce lipid-based drug delivery systems for dermal application. Moreover, sucrose esters of intermediate lipophilicity such as sucrose stearate S-970 possess a peculiar rheological behavior which can be employed to create highly viscous semi-solid formulations without any further additives. Interestingly, it was possible to develop both viscous macroemulsions and fluid nanoemulsions with the same chemical composition merely by slight alteration of the production process. Optical light microscopy and cryo transmission electron microscopy (TEM) revealed that the sucrose ester led to the formation of an astonishing hydrophilic network at a concentration of only 5% w/w in the macroemulsion system. A small number of more finely structured aggregates composed of surplus surfactant were likewise detected in the nanoemulsions. These discoveries offer interesting possibilities to adapt the low viscosity of fluid O/W nanoemulsions for a more convenient application. Moreover, a simple and rapid production method for skin-friendly creamy O/W emulsions with excellent visual long-term stability is presented. It could be shown by franz-cell diffusion studies and in vitro tape stripping that the microviscosity within the semi-solid formulations was apparently not influenced by their increased macroviscosity: the release of three model drugs was not impaired by the complex network-like internal structure of the macroemulsions. These results indicate that the developed semi-solid emulsions with advantageous application properties are highly suitable for the unhindered delivery of lipophilic drugs despite their comparatively large particle size and high viscosity.


Human transient receptor potential (TRP) channel expression profiling in carcinogenesis.
Despite the intensive research of the last three decades into Transient Receptor Potential (TRP) cation channels, no precise and complete profiling of these channels is yet available regarding their involvement in physiopathology and carcinogenesis in particular. TRP channel activity is crucial for all the essential hallmarks of carcinogenesis such as proliferation, apoptosis, migration and angiogenesis, which is the reason why these channels have been proposed not only as clinical markers, but also as promising targets for anti-cancer therapy. However, in the majority of studies, each channel has been considered as a separate molecular entity and studied independently from the other TRPs, while a complete "transportome" of the specific stages of carcinogenesis is required for the effective use of these targets. This review focuses on the partial TRP expression profiles found in the literature and the means by which a full TRP signature could be achieved.


Illuminating novel biological aspects and potential new therapeutic approaches for chronic myeloproliferative malignancies.
This review reflects the presentations and discussion at the 14th post-American Society of Hematology (ASH) International Workshop on Chronic Myeloproliferative Malignancies, which took place on the December 10 and 11, 2019, immediately after the 61st ASH Annual Meeting in Orlando, Florida. Rather than present a resume of the proceedings, we address some of the topical translational science research and clinically relevant topics in detail. We consider how recent studies using single-cell genomics and other molecular methods reveal novel aspects of hematopoiesis which in turn raise the possibility of new therapeutic approaches for patients with myeloproliferative neoplasms (MPNs). We discuss how alternative therapies could benefit patients with chronic myeloid leukemia who develop BCR-ABL1 mutant subclones following ABL1-tyrosine kinase inhibitor therapy. In MPNs, we focus on efforts beyond JAK-STAT and the merits of integrating activin receptor ligand traps, interferon-α, and allografting in the current treatment algorithm for patients with myelofibrosis.


Longitudinal Changes in and Modifiable Predictors of the Prevalence of Severe Depressive Symptoms for Family Caregivers of Terminally Ill Cancer Patients over the First Two Years of Bereavement.
Bereaved families endure tremendous grief. However, few studies have longitudinally investigated caregivers' bereavement grief for more than one year postloss and none is from family-oriented Asian countries. We explored longitudinal changes in and modifiable predictors of severe depressive symptoms for Taiwanese family caregivers of terminally ill cancer patients over the first two years postloss. For this descriptive, longitudinal study, severe depressive symptoms (Center for Epidemiological Studies Depression Scale score ≥16) were measured 1, 3, 6, 13, 18, and 24 months postloss. To identify modifiable factors (preloss depressive symptom levels, subjective caregiving burden, objective caregiving load, preparedness for patient death, and postloss social support) associated with postloss severe depressive symptoms, we used multivariate logistic regression modeling with the generalized estimating equation. Bereaved caregivers (N = 285) were recruited by convenience from a medical center in northern Taiwan. Bereaved family caregivers' prevalence of severe depressive symptoms peaked one month postloss (73.3%) and significantly decreased to 15.2% 24 months after the patient's death. After adjusting for confounders, bereaved caregivers were more likely to have severe depressive symptoms if they had heavy objective caregiving load and higher preloss depressive symptom levels. However, their likelihood of severe depressive symptoms was buffered by being better prepared for the patients' death and having greater social support. Bereaved family caregivers' severe depressive symptoms decreased significantly over the first two years postloss. Healthcare professionals should appropriately assess at-risk bereaved caregivers when patients are still alive and provide effective interventions to facilitate caregivers' return to normal life.


Practical management of chronic lymphocytic leukemia with acalabrutinib.
Treatment of chronic lymphocytic leukemia (CLL) has been transformed in the past two decades. The introduction of targeted therapies has improved patient outcomes and the deliverability of effective therapies. Making the best use of the next wave of Bruton's tyrosine kinase (BTK) inhibitors requires an understanding of the nuances that separate the drugs in this class of agents. This paper reviews the newer BTK inhibitors and provides practical guidance on the management of CLL using acalabrutinib. Acalabrutinib is a safe and efficacious BTKi in the treatment of CLL. While some side effects appear to be an "on-target" effect of BTK inhibition, the selectivity of second-generation covalent BTK inhibitors such as acalabrutinib may result in a favorable safety profile due to less off-target kinase inhibition. Acalabrutinib represents a well-tolerated and effective alternative to ibrutinib in the management of CLL.


Genetic control of the eighth component of complement.
Using isoelectric focusing in polyacrylamide gel and a hemolytic assay for development of patterns, extensive, structural polymorphism in human C8 has been delineated. Two alleles, C8A and C8B, have been identified in orientals, with gene frequencies of 0.655 and 0.345. In blacks, what appears to be a third common allele was found, so that frequencies were 0.692, 0.259, and 0.049 for C8A, C8B, and C8A1. In whites, C8A1 was rare with a frequency of 0.003, and frequencies for C8A and C8B were 0.649 and 0.349. Inheritance was autosomal codominant in family studies and the distribution of types in random unrelated populations fit the Hardy-Weinberg equilibrium in all groups. C8 allotypes have been determined for two previously studied families, each with a homozygous C8-deficient propositus. This study suggests that C8 deficiency is a silent or null allele of the C8 structural locus, and that half normal levels of C8 cannot be used as a single criterion for the establishment of heterozygous C8 deficiency. C8 allotypes, as well as 18 other autosomal markers, were also determined for 24 families. The C8 structural locus is not closely linked to these markers, including the human histocompatibility loci complex.


Transient expression of a winged-helix protein, MNF-beta, during myogenesis.
A novel winged-helix transcription factor, MNF-beta, is expressed coincidentally with cell cycle withdrawal and differentiation of skeletal myogenic cells. MNF-beta is closely related to the myocyte nuclear factor (MNF) protein previously described (now termed MNF-alpha), but expression of the two isoforms is differentially regulated, and they exhibit distinctive functional properties with respect to DNA binding in vitro and transcriptional regulatory activity in transient-transfection assays. A DNA sequence motif binding MNF-beta with high affinity was selected from a library of random oligonucleotides and was found to be similar to but distinct from the cognate binding site for HNF-3beta, a more distantly related winged-helix protein. The temporal pattern of MNF-beta expression and the presence of MNF binding motifs within conserved promoter elements of several genes that modulate cell cycle progression support a working hypothesis that MNF proteins may modulate proliferation of myogenic precursor cells during development and muscle regeneration.


Medical direction of wilderness and other operational emergency medical services programs.
Within a healthcare system, operational emergency medical services (EMS) programs provide prehospital emergency care to patients in austere and resource-limited settings. Some of these programs are additionally considered to be wilderness EMS programs, a specialized type of operational EMS program, as they primarily function in a wilderness setting (eg, wilderness search and rescue, ski patrols, water rescue, beach patrols, and cave rescue). Other operational EMS programs include urban search and rescue, air medical support, and tactical law enforcement response. The medical director will help to ensure that the care provided follows protocols that are in accordance with local and state prehospital standards, while accounting for the unique demands and needs of the environment. The operational EMS medical director should be as qualified as possible for the specific team that is being supervised. The medical director should train and operate with the team frequently to be effective. Adequate provision for compensation, liability, and equipment needs to be addressed for an optimal relationship between the medical director and the team.


Investigation of a genetic variation of a variable number tandem repeat polymorphism of interleukin-6 gene in patients with multiple sclerosis.
Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that the C allele of a variable number tandem repeat (vntr) polymorphism located in the 3'flanking region of the IL-6 gene ( IL-6) is associated with reduced activity of IL-6 in vivo. Since disease-modifying genes are likely to contribute to phenotypic differences in MS patients, we tested the hypothesis that the IL-6 C allele is associated with the clinical course of MS. The IL-6 C allele was equally distributed between 217 MS patients of German Caucasian origin and 111 age-mached healthy controls. Stratification of patients according to the course of disease revealed no significant difference of IL-6 C allele distribution between patients with primary progressive and those with either relapsing-remitting or secondary progressive MS although IL-6 C allele was more frequent in patients with RR-MS. Since IL-6 C allele has been associated with a benign course in Sardinian MS patients, we further analysed an independent sample of 125 Sardinian MS patients revealing that IL-6 C allele was much more frequent than in German MS patients. Taken together, a disease-modifying effect of IL-6 C allele could not be demonstrated in MS patients of German Caucasian descent.


A major lipid raft protein raftlin modulates T cell receptor signaling and enhances th17-mediated autoimmune responses.
The membrane microdomains known as lipid rafts have been shown to act as platforms for the initiation of various receptor signals. Through proteomic analysis, we have identified a novel protein termed Raftlin (raft-linking protein) as a major protein in lipid rafts. To determine the physiological and immunological functions of Raftlin in mammals, we generated Raftlin-deficient mice, as well as Raftlin-transgenic (Tg) mice. Although Raftlin was originally identified in B cells, we observe no severe abnormalities in the B cells of these mice, presumably due to a high expression of Raftlin-homologue (Raftlin-2). T cells, in contrast, expressed a substantial amount of Raftlin but no Raftlin-2. In Raftlin-deficient mice, T cell-dependent Ab production was reduced, and experimental autoimmune encephalomyelitis, a Th17-dependent autoimmune disease model, was ameliorated. In Raftlin-Tg mice, in contrast, Ab production was enhanced and experimental autoimmune encephalomyelitis was more severe. Cytokine production, especially that of IL-17, was reduced in Raftlin-deficient T cells, while it was enhanced in Raftlin-Tg T cells. We found that these changes were associated with the strength of the TCR-mediated signals. Importantly, localization of Lck protein in the lipid rafts was enhanced by Raftlin overexpression and reduced by Raftlin deficiency. These data indicate that Raftlin modulates TCR signals and is necessary for the fine-tuning of T cell-mediated immune responses.


Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial.
Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. UK Vaccine Taskforce and National Institute for Health Research.


Association of Surgeon-Patient Sex Concordance With Postoperative Outcomes.
Surgeon sex is associated with differential postoperative outcomes, though the mechanism remains unclear. Sex concordance of surgeons and patients may represent a potential mechanism, given prior associations with physician-patient relationships. To examine the association between surgeon-patient sex discordance and postoperative outcomes. In this population-based, retrospective cohort study, adult patients 18 years and older undergoing one of 21 common elective or emergent surgical procedures in Ontario, Canada, from 2007 to 2019 were analyzed. Data were analyzed from November 2020 to March 2021. Surgeon-patient sex concordance (male surgeon with male patient, female surgeon with female patient) or discordance (male surgeon with female patient, female surgeon with male patient), operationalized as a binary (discordant vs concordant) and 4-level categorical variable. Adverse postoperative outcome, defined as death, readmission, or complication within 30-day following surgery. Secondary outcomes assessed each of these metrics individually. Generalized estimating equations with clustering at the level of the surgical procedure were used to account for differences between procedures, and subgroup analyses were performed according to procedure, patient, surgeon, and hospital characteristics. Among 1 320 108 patients treated by 2937 surgeons, 602 560 patients were sex concordant with their surgeon (male surgeon with male patient, 509 634; female surgeon with female patient, 92 926) while 717 548 were sex discordant (male surgeon with female patient, 667 279; female surgeon with male patient, 50 269). A total of 189 390 patients (14.9%) experienced 1 or more adverse postoperative outcomes. Sex discordance between surgeon and patient was associated with a significant increased likelihood of composite adverse postoperative outcomes (adjusted odds ratio [aOR], 1.07; 95% CI, 1.04-1.09), as well as death (aOR, 1.07; 95% CI, 1.02-1.13), and complications (aOR, 1.09; 95% CI, 1.07-1.11) but not readmission (aOR, 1.02; 95% CI, 0.98-1.07). While associations were consistent across most subgroups, patient sex significantly modified this association, with worse outcomes for female patients treated by male surgeons (compared with female patients treated by female surgeons: aOR, 1.15; 95% CI, 1.10-1.20) but not male patients treated by female surgeons (compared with male patients treated by male surgeons: aOR, 0.99; 95% CI, 0.95-1.03) (P for interaction = .004). In this study, sex discordance between surgeons and patients negatively affected outcomes following common procedures. Subgroup analyses demonstrate that this is driven by worse outcomes among female patients treated by male surgeons. Further work should seek to understand the underlying mechanism.


Osteoclastogenic Differentiation of Macrophages in the Development of Abdominal Aortic Aneurysms.
Arterial calcification is common and contributes to the pathogenesis of occlusive vascular disease. Similar to the dynamics of bone, it is a tightly controlled process that maintains a balance between osteogenesis and osteolysis. However, whether calcium homeostasis plays a role in the development of aneurysms has not been explored. We hypothesized that macrophages differentiate into osteoclasts in aneurysmal arteries and that protease byproducts contribute to aneurysm pathophysiology. We performed histological and immunohistochemical analyses and showed that macrophages positive for several osteoclast markers, including tartrate acid phosphatase, occur in great numbers in the human aneurysmal aorta, but very few occur in the human stenotic aorta and none in the nondiseased human aorta. Moreover, in situ zymography showed elevated protease activity in these cells compared with undifferentiated macrophages. Tumor necrosis factor-α and calcium phosphate stimulated this osteoclastogenic differentiation process through nuclear factor-κB, mitogen-activated protein kinases, and intracellular calcium signaling but not the receptor activator of the nuclear factor-κB ligand. Inhibition of osteoclastogenic differentiation by bisphosphonate inhibits aneurysm development in a mouse model. These results suggest that differentiation of macrophages into osteoclasts contributes to the pathophysiology of aneurysmal disease.


CD44 and p53 immunoexpression patterns in NF1 neoplasms - indicators of malignancy and infiltration.
Neurofibromatosis type 1 (NF1) provides a unique system to evaluate the complete range of neoplastic expressions, from encapsulated benignity to invasiveness and malignancy. This study was aimed at determining whether CD44 and p53 may serve as indicators of malignant progression of neurofibroma. CD44, a transmembrane glycoprotein receptor for hyaluronic acid, and participates in cell-extracellular matrix interactions and migration. CD44 may play a vital role, either through under or overexpression, with invasion and metastases of tumors, altering their ability to infiltrate the adjacent tissue. The tumor suppressor gene, p53, has also been implicated in malignant progression of various human tumors including malignant peripheral nerve sheath tumors (MPNST). A total of 44 tumors from 33 patients with NF1 were evaluated with an anti-human CD44H, CD44 splice variant v6 and anti-p53 monoclonal antibodies. Morphologic expression patterns of expression were evaluated for CD44 while semiquantitative criteria were applied to assess, p53 nuclear positivity. Immunoexpression of p53 was markedly higher in 12 of 16 MPNST (75%). Thirteen of 28 (46%) benign neurofibroma also had some expression of p53 above 'normal level', although much lower than the MPNST. Plexiform neurofibroma did not differ from other benign lesions in their expression of p53. Our results suggest that p53 mutation as evidenced by immunohistochemical overexpression is a factor in malignant transformation and progression of neurofibroma. 70% of benign neurofibroma demonstrated some, usually focal, CD44 positivity. The pattern of CD44 expression in plexiform neurofibroma was revealing, as it was maximal in the 'nonencapsulated' portions of the tumors. Eight of 11 (72%) locally infiltrative cutaneous neurofibroma and 13 of 16 (81%) MPNST exhibited diffuse CD44 positivity. CD44v6 expression was positive in control tissues but was not identified in any of tumor samples. Also, within the confines of encapsulated tumors CD44 expression is limited, while in poorly circumscribed neurofibroma CD44 expression is upregulated. This is interpreted as a reflection of the interaction of CD44+ tumor cells with extracellular matrix, hence facilitating infiltrative behavior.


Clinical Evaluation, Hematology, and Serum Chemistry of Ocelots ( Leopardus pardalis ) in the Atlantic Forest of Brazil.
During the last three decades, much research has illustrated the potential impact of diseases on wild animal populations. However, few studies focused on establishing parameters to reliably differentiate healthy from sick animals. We present clinical, hematologic, and serum chemistry data from nine healthy ocelots ( Leopardus pardalis ) and one ill ocelot captured in 2012 and 2013 in Brazil. Laboratory results were compared to mean values of captive ocelots and reference ranges for domestic cats ( Felis catus ). Free-ranging ocelots had overall higher white blood cells, aspartate aminotransferase, creatine phosphokinase, lactate dehydrogenase, urea nitrogen, and triglycerides, probably due to handling. Free-ranging ocelots also presented hyperproteinemia, hyperglobulinemia, hypoalbuminemia, and hyperuricemia.


Task rules, working memory, and fluid intelligence.
Many varieties of working memory have been linked to fluid intelligence. In Duncan et al. (Journal of Experimental Psychology:General 137:131-148, 2008), we described limited working memory for new task rules: When rules are complex, some may fail in their control of behavior, though they are often still available for explicit recall. Unlike other kinds of working memory, load is determined in this case not by real-time performance demands, but by the total complexity of the task instructions. Here, we show that the correlation with fluid intelligence is stronger for this aspect of working memory than for several other, more traditional varieties-including simple and complex spans and a test of visual short-term memory. Any task, we propose, requires construction of a mental control program that aids in segregating and assembling multiple task parts and their controlling rules. Fluid intelligence is linked closely to the efficiency of constructing such programs, especially when behavior is complex and novel.


CLoSES: A platform for closed-loop intracranial stimulation in humans.
Targeted interrogation of brain networks through invasive brain stimulation has become an increasingly important research tool as well as therapeutic modality. The majority of work with this emerging capability has been focused on open-loop approaches. Closed-loop techniques, however, could improve neuromodulatory therapies and research investigations by optimizing stimulation approaches using neurally informed, personalized targets. Implementing closed-loop systems is challenging particularly with regard to applying consistent strategies considering inter-individual variability. In particular, during intracranial epilepsy monitoring, where much of this research is currently progressing, electrodes are implanted exclusively for clinical reasons. Thus, detection and stimulation sites must be participant- and task-specific. The system must run in parallel with clinical systems, integrate seamlessly with existing setups, and ensure safety features are in place. In other words, a robust, yet flexible platform is required to perform different tests with a single participant and to comply with clinical requirements. In order to investigate closed-loop stimulation for research and therapeutic use, we developed a Closed-Loop System for Electrical Stimulation (CLoSES) that computes neural features which are then used in a decision algorithm to trigger stimulation in near real-time. To summarize CLoSES, intracranial electroencephalography (iEEG) signals are acquired, band-pass filtered, and local and network features are continuously computed. If target features are detected (e.g. above a preset threshold for a certain duration), stimulation is triggered. Not only could the system trigger stimulation while detecting real-time neural features, but we incorporated a pipeline wherein we used an encoder/decoder model to estimate a hidden cognitive state from the neural features. CLoSES provides a flexible platform to implement a variety of closed-loop experimental paradigms in humans. CLoSES has been successfully used with twelve patients implanted with depth electrodes in the epilepsy monitoring unit. During cognitive tasks (N=5), stimulation in closed loop modified a cognitive hidden state on a trial by trial basis. Sleep spindle oscillations (N=6) and sharp transient epileptic activity (N=9) were detected in near real-time, and stimulation was applied during the event or at specified delays (N=3). In addition, we measured the capabilities of the CLoSES system. Total latency was related to the characteristics of the event being detected, with tens of milliseconds for epileptic activity and hundreds of milliseconds for spindle detection. Stepwise latency, the actual duration of each continuous step, was within the specified fixed-step duration and increased linearly with the number of channels and features. We anticipate that probing neural dynamics and interaction between brain states and stimulation responses with CLoSES will lead to novel insights into the mechanism of normal and pathological brain activity, the discovery and evaluation of potential electrographic biomarkers of neurological and psychiatric disorders, and the development and testing of patient-specific stimulation targets and control signals before implanting a therapeutic device.


Laser-based light barrier.
Design methods of a light barrier consisting of a reciprocally placed transmitter-receiver system with a continuous directional light beam are considered. An optical diagram is designed. Usage of multiple lasers in the transmitter is proposed to form a rectangular detection area. A sequential pulsed driving method is used. A detection method to find the detectors blocked by an object existing in the detection area is proposed. Light barrier detection area determination, line laser placements, photodetector array design principles, a common operation principle of sequentially pulsed lasers, reaction time obtainment, a simplified diagram, the structure of the light barrier using two line lasers, and the time diagrams explaining the operation principle are given.


Single nucleus multi-omics regulatory landscape of the murine pituitary.
To provide a multi-omics resource and investigate transcriptional regulatory mechanisms, we profile the transcriptome, chromatin accessibility, and methylation status of over 70,000 single nuclei (sn) from adult mouse pituitaries. Paired snRNAseq and snATACseq datasets from individual animals highlight a continuum between developmental epigenetically-encoded cell types and transcriptionally-determined transient cell states. Co-accessibility analysis-based identification of a putative Fshb cis-regulatory domain that overlaps the fertility-linked rs11031006 human polymorphism, followed by experimental validation illustrate the use of this resource for hypothesis generation. We also identify transcriptional and chromatin accessibility programs distinguishing each major cell type. Regulons, which are co-regulated gene sets sharing binding sites for a common transcription factor driver, recapitulate cell type clustering. We identify both cell type-specific and sex-specific regulons that are highly correlated with promoter accessibility, but not with methylation state, supporting the centrality of chromatin accessibility in shaping cell-defining transcriptional programs. The sn multi-omics atlas is accessible at snpituitaryatlas.princeton.edu.


Perception and attitude of pregnant women in a rural community north-west Nigeria to female genital mutilation.
Nigeria has the highest absolute number of residents who have undergone female genital mutilation (FGM) and most are carried out during infancy; however most reports on FGM are from urban based facilities hence we sought to know the perception and attitude of pregnant women residing in a rural community in northern Nigeria to FGM. A descriptive cross sectional study utilized a pretested structured interviewer administered questionnaire to assess the types of FGM known, reasons for performing it and willingness to support or perform FGM among 323 pregnant women attending antenatal care in two different health facilities. Of the 323 respondents, 256 (79.3%) were aware of the practice and the common varieties of FGM known to them were Gishiri cut in 137 (53.5%) and Angurya cut 113 (44.1). The notable reasons for carrying out FGM in the community were tradition 88 (34.4%), to ease difficulty in childbirth 69 (26.9%) and better marriage prospect in 55 (21.5%). Of the respondents that were aware of FGM; 100 (39.1%) have experienced it and 55 (21.5%) of those aware of it would subject their daughters to the procedure. There was statistically significant association between willingness to mutilate daughters by the respondents type of education (p = 0.014) and the type of facility they were receiving antenatal care (p = 0.001). FGM is prevalent in this community with Gishiri cut being the commonest variety. It is often associated with difficult childbirth and many women would subject their daughters to this practice. Female education and empowerment is crucial to discontinuation of this practice.


Erythropoietin regulation of red blood cell production: from bench to bedside and back.
More than 50 years of efforts to identify the major cytokine responsible for red blood cell (RBC) production (erythropoiesis) led to the identification of erythropoietin (EPO) in 1977 and its receptor (EPOR) in 1989, followed by three decades of rich scientific discovery. We now know that an elaborate oxygen-sensing mechanism regulates the production of EPO, which in turn promotes the maturation and survival of erythroid progenitors. Engagement of the EPOR by EPO activates three interconnected signaling pathways that drive RBC production via diverse downstream effectors and simultaneously trigger negative feedback loops to suppress signaling activity. Together, the finely tuned mechanisms that drive endogenous EPO production and facilitate its downstream activities have evolved to maintain RBC levels in a narrow physiological range and to respond rapidly to erythropoietic stresses such as hypoxia or blood loss. Examination of these pathways has elucidated the genetics of numerous inherited and acquired disorders associated with deficient or excessive RBC production and generated valuable drugs to treat anemia, including recombinant human EPO and more recently the prolyl hydroxylase inhibitors, which act partly by stimulating endogenous EPO synthesis. Ongoing structure-function studies of the EPOR and its essential partner, tyrosine kinase JAK2, suggest that it may be possible to generate new "designer" drugs that control selected subsets of cytokine receptor activities for therapeutic manipulation of hematopoiesis and treatment of blood cancers.


Guidelines of the International Headache Society for Clinic-Based Headache Registries, 1st edition.
Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., "common data elements"), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache.


Results of three to 10 year follow up of balloon dilatation of the pulmonary valve.
The results of immediate and short term follow up of balloon dilatation of the pulmonary valve have been well documented, but there is limited information on long term follow up. To evaluate the results of three to 10 year follow up of balloon dilatation of the pulmonary valve in children and adolescents. Tertiary care centre/university hospital. Retrospective study. 85 patients (aged between 1 day and 20 years, mean (SD) 7.0 (6.4) years) underwent balloon dilatation of the pulmonary valve during an 11 year period ending August 1994. There was a resultant reduction in the peak to peak gradient from 87 (38) to 26 (22) mm Hg. Immediate surgical intervention was not required. Residual gradients of 29 (17) mm Hg were measured by catheterisation (n = 47) and echo Doppler (n = 82) at intermediate term follow up (two years). When individual results were scrutinised, nine of 82 patients had restenosis, defined as a peak gradient of 50 mm Hg or more. Seven of these patients underwent repeat balloon dilatation of the pulmonary valve: peak gradients were reduced from 89 (40) to 38 (20) mm Hg. Clinical evaluation and echo Doppler data of 80 patients showed that residual peak instantaneous Doppler gradients were 17 (15) mm Hg at long term follow up (three to 10 years, median seven), with evidence for late restenosis in one patient (1.3%). Surgical intervention was necessary to relieve fixed infundibular stenosis in three patients and supravalvar pulmonary stenosis in one. Repeat balloon dilatation was performed to relieve restenosis in two patients. Actuarial reintervention free rates at one, two, five, and 10 years were 94%, 89%, 88%, and 84%, respectively. Pulmonary valve regurgitation was noted in 70 of 80 patients at late follow up, but neither right ventricular dilatation nor paradoxical interventricular septal motion developed. The results of late follow up of balloon dilatation of the pulmonary valve are excellent. Repeat balloon dilatation was performed in 11% of patients and surgical intervention for subvalvlar or supravalvar stenosis in 5%. Most patients had mild residual pulmonary regurgitation but right ventricular volume overload was not required. Balloon dilatation is the treatment of choice in the management of moderate to severe stenosis of the pulmonary valve. Further follow up studies should be undertaken to evaluate the significance of residual pulmonary regurgitation.


Relationship between strength characteristics and unweighted and weighted vertical jump height.
To investigate the relationship between maximum strength and differences in jump height during weighted and unweighted (body weight) static (SJ) and countermovement jumps (CMJ). Sixty-three collegiate athletes (mean +/- SD; age= 19.9 +/- 1.3 y; body mass = 72.9 +/- 19.6 kg; height = 172.8 +/- 7.7 cm) performed two trials of the SJ and CMJ with 0 kg and 20 kg on a force plate; and two trials of mid-thigh isometric clean pulls in a custom rack over a force plate (1000-Hz sampling). Jump height (JH) was calculated from flight time. Force-time curve analyses determined the following: isometric peak force (IPF), isometric force (IF) at 50, 90, and 250 ms, and isometric rates of force development (IRFD). Absolute and allometric scaled forces, [absolute force/(body mass(0.67))], were used in correlations. IPF, IRFD, F50(a), F50, F90, and F250 showed moderate/strong correlations with SJ and CMJ height percent decrease from 0 to 20 kg. IPF(a) and F250(a) showed weak/moderate correlations with percent height decrease. Comparing strongest (n = 6) to weakest (n = 6): t tests revealed that stronger athletes (IPF(a)) performed superior to weaker athletes. Data indicate the ability to produce higher peak and instantaneous forces and IRFD is related to JH and to smaller differences between weighted and unweighted jump heights. Stronger athletes jump higher and show smaller decrements in JH with load. A weighted jump may be a practical method of assessing relative strength levels.


Training the trainers: Finding new educational opportunities in the virtual world.
The COVID-19 pandemic has disrupted scientific gatherings and conferences, opening up opportunities for virtual learning platforms. Realizing the potential of online academic exchanges, the World Psychiatric Association (WPA) also developed virtual avenues and information systems for capacity building of mental health professionals across the world. Among its first such initiatives, the WPA organized a virtual Train the Trainers workshop, where 123 psychiatrists, psychiatric trainees, and educators from 45 countries participated. The innovative and interactive workshop allowed participants to get to know each other, exchange educational and professional experiences, and ask questions or receive advice from experts. Keynote speakers, including WPA President Prof. Afzal Javed and Prof. Norman Sartorius, stressed upon the importance of finding innovative solutions in psychiatry training and the need to improve teaching and training in the field of psychiatry, especially in the provision of leadership and communication skills. Online training methods can provide easy access to academics and students while reducing the organizational and logistical costs. They have the potential to improve educational equality and allow the voice of the underprivileged scientists to be heard across the globe. The devastating impact on access to mental health services during COVID-19 underscores the urgent need for online training, particularly in countries where the ratio of psychiatrists to patients is inadequate and doctors concentrate more on treatment than on research and education. Virtual educational interventions could prove incredibly useful in the future just as they are being successfully utilized in local and regional contexts during the pandemic.


Systematic identification of barriers to human iPSC generation.
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) holds enormous promise for regenerative medicine. To elucidate endogenous barriers limiting this process, we systematically dissected human cellular reprogramming by combining a genome-wide RNAi screen, innovative computational methods, extensive single-hit validation, and mechanistic investigation of relevant pathways and networks. We identify reprogramming barriers, including genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion. Specific a disintegrin and metalloproteinase (ADAM) proteins inhibit reprogramming, and the disintegrin domain of ADAM29 is necessary and sufficient for this function. Clathrin-mediated endocytosis can be targeted with small molecules and opposes reprogramming by positively regulating TGF-β signaling. Genetic interaction studies of endocytosis or ubiquitination reveal that barrier pathways can act in linear, parallel, or feedforward loop architectures to antagonize reprogramming. These results provide a global view of barriers to human cellular reprogramming.


Preventing perinatal transmission of HIV--costs and effectiveness of a recommended intervention.
To calculate the national costs of reducing perinatal transmission of human immunodeficiency virus through counseling and voluntary testing of pregnant women and zidovudine treatment of infected women and their infants, as recommended by the Public Health Service, and to compare these costs with the savings from reducing the number of pediatric infections. The authors analyzed the estimated costs of the intervention and the estimated cost savings from reducing the number of pediatric infections. The outcome measures are the number of infections prevented by the intervention and the net cost (cost of intervention minus the savings from a reduced number of pediatric HIV infections). The base model assumed that intervention participation and outcomes would resemble those found in the AIDS Clinical Trials Group Protocol 076. Assumptions were varied regarding maternal seroprevalence, participation by HIV-infected women, the proportion of infected women who accepted and completed the treatment, and the efficacy of zidovudine to illustrate the effect of these assumptions on infections prevented and net cost. Without the intervention, a perinatal HIV transmission rate of 25% would result in 1750 HIV-infected infants born annually in the United States, with lifetime medical-care costs estimated at $282 million. The cost of the intervention (counseling, testing, and zidovudine treatment) was estimated to be $ 67.6 million. In the base model, the intervention would prevent 656 pediatric HIV infections with a medical care cost saving of $105.6 million. The net cost saving of the intervention was $38.1 million. Voluntary HIV screening of pregnant women and ziovudine treatment for infected women and their infants resulted in cost savings under most of the assumptions used in this analysis. These results strongly support implementation of the Public Health Service recommendations for this intervention.


Cardiac resynchronization improves coronary blood flow.
Asynchronous ventricular activation, induced by left bundle branch block, is known to have deleterious effects on the systolic and diastolic functions of the left ventricle (LV). Cardiac resynchronization therapy (CRT) has been proposed as a complementary method to improve the LV systolic performance by restoring the synchronized contraction patterns in patients with advanced heart failure and left bundle branch block. However, the effect of CRT on myocardial blood flow is not well established. In the present study, we therefore examined the coronary blood flow in 20 patients with idiopathic dilated cardiomyopathy, implanted with a biventricular pacemaker according to the established CRT criteria. Color Doppler settings were adjusted for the optimal coronary flow imaging, and coronary flow velocities were obtained in all patients. Typical diastolic predominant phasic Doppler spectrum of the distal left anterior descending coronary artery (LAD) was recorded. Conventional echocardiographic variables, peak values of the diastolic and systolic LAD velocities, and the velocity time integrals were measured for three or five consecutive beats during CRT with pacemaker on and off. Successful CRT with biventricular pacing increased coronary blood flow velocities of the distal LAD in addition to its well-known benefits on the systolic and diastolic LV performance in patients with significant dyssynchrony. CRT decreased duration of mitral regurgitation and increased diastolic filling time. Peak diastolic velocities and velocity time integral of the distal LAD were increased significantly. In conclusion, successful CRT with biventricular pacing improves coronary blood flow velocities of the distal LAD.


Epidemiology of Sjögren's Syndrome-from an Oral Perspective.
Oral symptoms are among the most distressing manifestations for patients with Sjögren's syndrome (SS). The feeling of dry mouth is unpleasant, and hyposalivation may contribute to difficulty in speaking, chewing and swallowing and reduced quality of life. Reduced salivary flow increases the risk for dental caries and problems with prosthetic replacement. It seems that SS is not as frequently occurring as previously anticipated. Population-based prevalence studies on primary SS in Europe, conducted on large background populations and in accordance with the AECG criteria, reported of a prevalence of 1-9 cases per 10,000 people. This gives a combined prevalence of nearly 39/100,000 (~0.04 %). The cause of Sjögren's syndrome is even now not fully understood, and the treatment of oral symptoms is still mostly palliative. Hopefully, useful information will appear from the new methods that are now available for genome wide association studies, epigenetics, DNA methylation studies, and proteomics. Similarly, this is anticipated for the immunological side of the story. The interferon signature, the interferon γ/interferon α mRNA ratio, and CXCL13 are among the proposed biomarkers of active disease. In this review, we provide an update on oral aspects of Sjögren's syndrome with emphasis on the latest publications on these topics.