Open to the public: paywalls and the public rationale for open access medical research publishing.
Public voices have largely been absent from the discussions about open access publishing in medical research. Yet the public have a strong interest in ensuring open access of medical research findings because of their roles as funders, advocates, research participants, and patients. By limiting access to research outputs, the current publishing system makes it more difficult for research to be held accountable to the public. Paywalls undermine the work of public advocacy, which requires open access in order to lobby for policy changes and research funding. Research participants generously give their time and energy to research studies with the assumption that the results will be broadly disseminated. Finally, members of the public have a stake in open access publishing as a resource for health information and decision-making. This commentary explores these crucial roles of the public in order to develop a public rationale for open access medical research. We outline a critique of the current academic publishing ecosystem, re-focus the open access debate from a public perspective, and respond to some of the arguments against public open access. Although open access to medical research is not a panacea, removing paywalls and other barriers to public access is essential. The public are critical stakeholders of medical research data.


Personalized Text Messages and Automated Calls for Improving Vaccine Coverage Among Children in Pakistan: Protocol for a Community-Based Cluster Randomized Clinical Trial.
A major reason for poor childhood vaccine coverage in developing countries is the lack of awareness among parents and caregivers regarding the need for immunization and the importance of completing the entire series of vaccines. Short message service (SMS)-based interventions have been quite effective in different programs such as smoking cessation, treatment adherence, health care scheduled appointment attendance, antenatal care attendance, and compliance to immunization. However, there are limited data from low- and middle-income countries on the role of SMS and automated call-based messages and interventions to improve routine immunization (RI) coverage. The primary objective of this study is to evaluate whether automated mobile phone-based personalized messages (SMS or automated call) can improve RI uptake at 6, 10, and 14 weeks of age per the expanded program immunization schedule, compared with a usual care control group. Secondary objectives include assessing the effects of different types of automated SMS text or calls on RI coverage at 20 weeks of age. This is a mixed methods study using a clustered randomized controlled trial with 4 intervention arms and 1 control arm, augmented by qualitative interviews for personalizing the message. The study is being conducted in Pakistan (an urban site in Karachi and a rural site Matiari). In Karachi, 250 administrative structures are taken as 1 cluster, whereas in Matiari, a catchment area of 4 Lady Health Workers is considered as 1 cluster. The intervention targets families to receive weekly 1-way or 2-way (interactive) personalized automated SMS or automated phone call messages regarding vaccination. Possible barriers to vaccination are assessed in each family at the time of inclusion to determine the type of personalized messages that should be sent to the family to increase the chance of a positive response. Finally, in-depth interviews using purposive sampling are conducted before and after the trial to determine the family's vaccination experience and related factors. All study participants for the cluster randomized trial were enrolled by January 14, 2019. Study exit interviews at 20-weeks follow-up visits will be completed by June 2019. The results of this study will be useful to understand the respective effects of SMS text messages versus automated phone-based communication to improve RI coverage and timelines. Moreover, information regarding families' perceptions of vaccination and the daily life challenges for timely visits to the vaccine clinic will be used for developing more complex interventions that use mobile phone messages and possibly other approaches to overcome barriers in the uptake of correct and timely immunization practices. ClinicalTrials.gov NCT03341195; https://clinicaltrials.gov/ct2/show/NCT03341195 (Archived by WebCite at http://www.webcitation.org/78EWA56Uo). DERR1-10.2196/12851.


Are you in or out? Recruitment of adolescent smokers into a behavioral smoking cessation intervention.
Even though many adolescent smokers want to quit, it is difficult to recruit them into smoking cessation interventions. Little is known about which adolescent smokers are currently reached by these measures. In this study we compare participants of a group-based, cognitive behavioral smoking cessation intervention with adolescent smokers who decided against participating. Within a non-randomized controlled trial, data of 1053 smokers (aged 11-19) from 42 German secondary schools were analyzed. Of these smokers, 272 were recruited into 47 courses of the intervention. An in-class information session, individually addressing potential participants, and incentives were used as means of recruitment. Personal predictors of participation were analyzed using regression analyses and multivariate path analyses to test for mediation. In the path analysis model, nicotine dependence, quit motivation, and a previous quit attempt were directly positively related to participation. Heavier smoking behavior was indirectly positively associated with participation through nicotine dependence and negatively through quit motivation, yielding an overall positive indirect effect. The positive effect of a previous quit attempt on participation was partially mediated through nicotine dependence and quit motivation. The proportion of smoking friends were indirectly positively related to participation, mediated through nicotine dependence. Since adolescents with heavier smoking behavior and stronger nicotine dependence are less likely to undertake a successful unassisted quit attempt, the reach of these young smokers with professional cessation interventions is desirable. Further measures to improve the recruitment of those currently not motivated to quit have to be examined in future studies.


3D numerical simulation of coronary blood flow and its effect on endothelial cell activation.
The goal of the present study was to develop a physiologically realistic 3D computational fluid dynamics (CFD) model of the left coronary artery under normal and disease conditions to estimate blood flow induced shear stress, and then use the computed shear stress to stimulate vascular endothelial cells in vitro. A 3D geometry of the left coronary artery was built in ProE and the CFD analysis of the flow field was carried out in Fluent (v 6.23) under normal, 30%, 60% and 80% stenosis conditions. The transient blood flow velocity and shear stress were solved using a k-omega turbulence model. 3 typical shear stresses at normal, 80% stenosis and recirculation zone levels were applied to vascular endothelial cells in a cone and plate shearing device. Endothelial cell activation and injury induced by shear stress were measured by cell surface ICAM-1 and tissue factor expression, using fluorescence microscopy. Results demonstrated that oscillatory low shear stress present in the recirculation zones can significantly activate endothelial cells by enhancing ICAM-1 expression; while elevated shear stress at stenosis can induce endothelial cell damage by enhancing tissue factor expression. This study demonstrated that the combination of CFD and in vitro studies provided an efficient way to investigate the mechanism of blood flow induced mechanical stress on cardiovascular disease development in vivo.


Disruption of gastrulation and oral-aboral ectoderm differentiation in the Lytechinus pictus embryo by a dominant/negative PDGF receptor.
Little is known about the cell signaling involved in forming the body plan of the sea urchin embryo. Previous work suggested that PDGF-like and EGF-like receptor-mediated signaling pathways are involved in gastrulation and spiculogenesis in the Lytechinus pictus embryo. Here we show that expression of the human PDGF receptor-beta lacking the cytoplasmic domain disrupted development in a manner consistent with a dominant/negative mechanism. The truncated PDGF receptor-beta inhibited gut and spicule formation and differentiation along the oral-aboral axis. The most severely affected embryos arrested at a developmental stage resembling mesenchyme blastula. Coinjection into eggs of RNA encoding the entire human PDGF receptor-beta rescued development. The truncated PDGF receptor-beta caused the aboral ectoderm-specific genes LpS1 and LpC2 to be repressed while an oral ectoderm-specific gene, Ecto-V, was expressed in all ectoderm cells. The results support the hypothesis that a PDGF-like signaling pathway plays a key role in the intercellular communication required for gastrulation and spiculogenesis, and in cell commitment and differentiation along the oral-aboral axis.


The added risk of opioid problem use among treatment-seeking youth with marijuana and/or alcohol problem use.
To determine the added risk of opioid problem use (OPU) in youth with marijuana/alcohol problem use (MAPU). A total of 475 youth (ages 14-21 years) with OPU + MAPU were compared to a weighted sample of 475 youth with MAPU only (i.e. no OPU) before and after propensity score matching on gender, age, race, level of care and weekly use of marijuana/alcohol. Youth were recruited from 88 drug treatment sites participating in eight Center for Substance Abuse Treatment-funded grants. At treatment intake, participants were administered the Global Appraisal of Individual Need to elicit information on demographic, social, substance, mental health, human immunodeficiency virus (HIV), physical and legal characteristics. Odds ratios with confidence intervals were calculated. The added risk of OPU among MAPU youth was associated with greater comorbidity; higher rates of psychiatric symptoms and trauma/victimization; greater needle use and sex-related HIV risk behaviours; and greater physical distress. The OPU + MAPU group was less likely to be African American or other race and more likely to be aged 15-17 years, Caucasian; report weekly drug use at home and among peers; engage in illegal behaviors and be confined longer; have greater substance abuse severity and polydrug use; and use mental health and substance abuse treatment services. These findings expand upon the existing literature and highlight the substantial incremental risk of OPU on multiple comorbid areas among treatment-seeking youth. Further evaluation is needed to assess their outcomes following standard drug treatment and to evaluate specialized interventions for this subgroup of severely impaired youth.


[Enteral tube feeding after planned operations on organs of the abdominal cavity].
The enteral probe feeding was used in 60 patients operated on organs of the abdominal cavity in planned order. The individual nutrition media were composed with special reference to metabolic disorders and the functional state of the gastro-intestinal tract. It helped to make an adequate correction of metabolic disorders and facilitated early normalization of motor activity of the gastro-intestinal tract.


Complete mesocolic malposition of the gallbladder: An unusual case report with literature's review.
Anatomic variations and congenital anomalies involving the gallbladder position, shape, and number are frequently encountered on routine abdominal imagings and at surgery. However, most have no clinical significance, but their recognition is important because they may predispose to gallbladder diseases, serve as a potential source of confusion and diagnostic pitfalls for radiologists and surgeons, and increase the risk of inadvertent injury during biliary tract surgery or intervention. We observed an intra-mesocolic gallbladder found unexpectedly during the cholecystectomy in a 65-year-old male patient who was being operated on for acute calculous cholecystitis. An abdominal ultrasonography and computed tomography scan reported no anomalous or malpositioned gallbladder pre-operatively. As the location of this organ could not be definitely clarified in his previous operation elsewhere, we performed an explorative lapa-rotomy. There was no gallbladder at the normal position. The organ was found embedded deeply within the proximal portion of the transverse mesocolon, and then it was successfully excised. We established the diagnosis of an ectopic gallbladder in mesocolic position.


Updating memory after mild traumatic brain injury and orthopedic injuries.
Few studies have examined the trajectory of recovery of executive function (EF) after mild TBI (mTBI). Therefore, consensus has not been reached on the incidence and extent of EF impairment after mTBI. The present study investigated trajectory of change in executive memory over 3 months after mTBI on 59 right-handed participants with mTBI, as defined by Centers for Disease Control criteria, ages 14-30 years, recruited within 96 hours post-injury and tested <1 week (baseline), 1 month, and 3 months after injury. Also included were 58 participants with orthopedic injury (OI) and 27 typically developing (TD) non-injured participants with similar age, socioeconomic status, sex, and ethnicity. MRI data were acquired at baseline and 3 months. Although criteria included a normal CT scan, lesions were detected by MRI in 19 mTBI patients. Participants completed the KeepTrack task, a verbal recall task placing demands on goal maintenance, semantic memory, and memory updating. Scores reflected items recalled and semantic categories maintained. The mTBI group was divided into two groups: high (score ≥12) or low (score <12) symptoms based on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). Mixed model analyses revealed the trajectory of change in mTBI patients (high and low RPQ), OI patients, and TD subjects were similar over time (although the TD group differed from other groups at baseline), suggesting no recovery from mTBI up to 90 days. For categories maintained, differences in trajectory of recovery were discovered, with the OI comparison group surprisingly performing similar to those in the mTBI group with high RPQ symptoms, and different from low RPQ and the TD groups, bringing up questions about utility of OIs as a comparison group for mTBI. Patients with frontal lesions (on MRI) were also found to perform worse than those without lesions, a pattern that became more pronounced with time.


[Interrelationship between the thiamine content, thiamine diphosphate-dependent enzyme activity and reduced glutathione level in the rat liver].
Changes in the amount of thiamine, reduced glutathione, thiamine diphosphate-dependent dehydrogenase activity has been traced after thiamine injection to thiamine-deficient rats and oxythiamine to normal rats. The obtained data show that a drop in reduced glutathione level was a primary reason of the alpha-keto-acid dehydrogenase activity reduction under conditions of the thiamine deficiency. The existence of immediate connection between thiamine and glutathione metabolism is supposed.


A Comparative Analysis of Master Casts Obtained using Different Surface Treatments on Impression Copings for Single Tooth Implant Replacement -An In vitro Study.
Minor rotation of impression coping secured in the impression is an avoidable error that needs to be minimized to ensure precise positioning of implant analog in master cast. The aim of the study was to compare the precision in obtaining master casts by improving the stability of impression copings in the impression with the use of tray adhesive along various surface treatments to increase surface area and by mechanical locking. A total of 60 samples were made (15 samples for each group). A total of 15 samples for Group I were prepared with untreated impression copings, 15 samples for Group II with impression copings treated and modified by application of tray adhesive only. Group III includes 15 samples which were fabricated with impression copings modified by making four vertical grooves on surface of impression coping and coated with adhesive. Group IV had 15 samples which were fabricated with impression copings sandblasted with 50 μm aluminum oxide powder and coated with adhesive. Profile projector was used to evaluate the rotational accuracy of the implant analogs by comparing Molar Implant Angle (MIA) and Premolar Implant Angle (PIA) of test samples with reference model. One-way ANOVA and Student t-test were used to analyze the data. One-way ANOVA didn't show any significant differences for both MIA and PIA between the Groups I, II, III and IV. Student's unpaired t-test revealed no significant difference in the mean MIA and mean PIA. Conclusion: Though results were statistically non-significant, all types of surface treatments of the impression copings showed more accurate transfer than those with no treatment. Sandblasted and adhesive coated impression copings showed minimum amount of rotation followed by those with vertical slots and adhesive coated impression copings.


Acetylcholine and noradrenaline enhance foraging optimality in humans.
Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist nicotine, a noradrenaline reuptake inhibitor reboxetine, or a preferential dopamine reuptake inhibitor methylphenidate, and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.


Iatrogenic tracheal tear.
Large post intubation tracheal tears are usually detected intra-operatively due to unstable signs namely impaired ventilation and mediastinal emphysema and often require surgical management. Smaller tracheal tears are often missed during anaesthesia and recognized during the postoperative period. Conservative management should be considered in these latter cases.


Dynamic T 2 * relaxometry of hyperpolarized [1-13 C]pyruvate MRI in the human brain and kidneys.
This study aimed to quantify T 2 * $$ {T}_2^{\ast } $$ for hyperpolarized [1-13 C]pyruvate and metabolites in the healthy human brain and renal cell carcinoma (RCC) patients at 3 T. Dynamic T 2 * $$ {T}_2^{\ast } $$ values were measured with a metabolite-specific multi-echo spiral sequence. The dynamic T 2 * $$ {T}_2^{\ast } $$ of [1-13 C]pyruvate, [1-13 C]lactate, and 13 C-bicarbonate was estimated in regions of interest in the whole brain, sinus vein, gray matter, and white matter in healthy volunteers, as well as in kidney tumors and the contralateral healthy kidneys in a separate group of RCC patients. T 2 * $$ {T}_2^{\ast } $$ was fit using a mono-exponential function; and metabolism was quantified using pyruvate-to-lactate conversion rate maps and lactate-to-pyruvate ratio maps, which were compared with and without an estimated T 2 * $$ {T}_2^{\ast } $$ correction. The T 2 * $$ {T}_2^{\ast } $$ of pyruvate was shown to vary during the acquisition, whereas the T 2 * $$ {T}_2^{\ast } $$ of lactate and bicarbonate were relatively constant through time and across the organs studied. The T 2 * $$ {T}_2^{\ast } $$ of lactate was similar in gray matter (29.75 ± 1.04 ms), white matter (32.89 ± 0.9 ms), healthy kidney (34.61 ± 4.07 ms), and kidney tumor (33.01 ± 2.31 ms); and the T 2 * $$ {T}_2^{\ast } $$ of bicarbonate was different between whole-brain (108.17 ± 14.05 ms) and healthy kidney (58.45 ± 6.63 ms). The T 2 * $$ {T}_2^{\ast } $$ of pyruvate had similar trends in both brain and RCC studies, reducing from 75.56 ± 2.23 ms to 22.24 ± 1.24 ms in the brain and reducing from 122.72 ± 9.86 ms to 57.38 ± 7.65 ms in the kidneys. Multi-echo dynamic imaging can quantify T 2 * $$ {T}_2^{\ast } $$ and metabolism in a single integrated acquisition. Clear differences were observed in the T 2 * $$ {T}_2^{\ast } $$ of metabolites and in their behavior throughout the timecourse.


Challenges of Developing Robust AI for Intrapartum Fetal Heart Rate Monitoring.
Background: CTG remains the only non-invasive tool available to the maternity team for continuous monitoring of fetal well-being during labour. Despite widespread use and investment in staff training, difficulty with CTG interpretation continues to be identified as a problem in cases of fetal hypoxia, which often results in permanent brain injury. Given the recent advances in AI, it is hoped that its application to CTG will offer a better, less subjective and more reliable method of CTG interpretation. Objectives: This mini-review examines the literature and discusses the impediments to the success of AI application to CTG thus far. Prior randomised control trials (RCTs) of CTG decision support systems are reviewed from technical and clinical perspectives. A selection of novel engineering approaches, not yet validated in RCTs, are also reviewed. The review presents the key challenges that need to be addressed in order to develop a robust AI tool to identify fetal distress in a timely manner so that appropriate intervention can be made. Results: The decision support systems used in three RCTs were reviewed, summarising the algorithms, the outcomes of the trials and the limitations. Preliminary work suggests that the inclusion of clinical data can improve the performance of AI-assisted CTG. Combined with newer approaches to the classification of traces, this offers promise for rewarding future development.


Antibiotic prescribing for common infections in UK general practice: variability and drivers.
To examine variations across general practices and factors associated with antibiotic prescribing for common infections in UK primary care to identify potential targets for improvement and optimization of prescribing. Oral antibiotic prescribing for common infections was analysed using anonymized UK primary care electronic health records between 2000 and 2015 using the Clinical Practice Research Datalink (CPRD). The rate of prescribing for each condition was observed over time and mean change points were compared with national guideline updates. Any correlation between the rate of prescribing for each infectious condition was estimated within a practice. Predictors of prescribing were estimated using logistic regression in a matched patient cohort (1:1 by age, sex and calendar time). Over 8 million patient records were examined in 587 UK general practices. Practices varied considerably in their propensity to prescribe antibiotics and this variance increased over time. Change points in prescribing did not reflect updates to national guidelines. Prescribing levels within practices were not consistent for different infectious conditions. A history of antibiotic use significantly increased the risk of receiving a subsequent antibiotic (by 22%-48% for patients with three or more antibiotic prescriptions in the past 12 months), as did higher BMI, history of smoking and flu vaccinations. Other drivers for receiving an antibiotic varied considerably for each condition. Large variability in antibiotic prescribing between practices and within practices was observed. Prescribing guidelines alone do not positively influence a change in prescribing, suggesting more targeted interventions are required to optimize antibiotic prescribing in the UK.


Effect of interferon on systemic herpesvirus infections.
The studies reviewed here are encouraging in that HSV is moderately sensitive to the action of interferon and that infections in experimental animals clearly may be altered by exogenous interferon and interferon inducers. On the other hand it is apparent that the potential of this approach to treatment of herpesvirus infections is limited by the levels of interferon that can be passively administered or induced, the development of hyporeactivity which prevents maintaining high levels of interferon in infected animals after inoculation of inducers, and the failure to alter the course of HSV infection once the virus is established in target organs.


Partial rescue of epithelial phenotype in integrin beta4 null mice by a keratin-5 promoter driven human integrin beta4 transgene.
Integrin beta4 null mice exhibit extensive epidermal detachment, reminiscent of the human skin blistering disease junctional epidermolysis bullosa associated with pyloric atresia. Hemidesmosomes, the stable adhesion structures of squamous epithelia, are not formed in the absence of alpha6beta4. Null mutant mice die shortly after birth, but apart from their striking epithelial phenotype, no obvious developmental defects have been observed. To elucidate the cause of death in these mice, we generated transgenic mice with a heterologous construct consisting of the squamous epithelial-specific keratin-5 promoter and a human integrin beta4 subunit cDNA. The transgene was not expressed in the presence of endogenous beta4, probably as a result of competition for a limited pool of alpha6 subunits. In a beta4 null background, however, the transgene was expressed, and its expression pattern followed that of squamous epithelial-specific keratins. These rescued pups appeared healthy and ultrastructural analysis revealed that the interspecies heterodimer alpha6(mouse)/beta4(human) was sufficient to trigger the assembly of hemidesmosomes. After a variable period of up to 48 hours after birth these animals began to exhibit haemorrhages at the plantar and palmar areas. We observed the formation of small blisters and found that the transgene was not detectably expressed in this region, which is devoid of hair follicles. The rescued neonates became increasingly cyanotic and died soon after the onset of this phenomenon. We performed a developmental study of the expression of beta4 in the complete respiratory tract, but we found no correlation between the spatiotemporal distribution of beta4 and the onset of the respiratory insufficiency. It became clear, however, that there was a gradual detachment of squamous epithelia in the oral and nasal cavities which led to obstruction of the respiratory tract, suggesting that in beta4 null and rescued mice, neonatal death was a direct consequence of decreased adhesion properties of hairless squamous epithelia, rather than a developmental defect of the lungs.


Cancer and Aging - the Inflammatory Connection.
Aging and cancer are highly correlated biological phenomena. Various cellular processes such as DNA damage responses and cellular senescence that serve as tumor suppressing mechanisms throughout life result in degenerative changes and contribute to the aging phenotype. In turn, aging is considered a pro-tumorigenic state, and constitutes the single most important risk factor for cancer development. However, the causative relations between aging and cancer is not straight forward, as these processes carry contradictory hallmarks; While aging is characterized by tissue degeneration and organ loss of function, cancer is a state of sustained cellular proliferation and gain of new functions. Here, we review the molecular and cellular pathways that stand in the base of aging related cancer. Specifically, we deal with the inflammatory perspective that link these two processes, and suggest possible molecular targets that may be exploited to modify their courses.


Healthy universities--time for action: a qualitative research study exploring the potential for a national programme.
Despite the absence of national or international steers, there is within England growing interest in the Healthy University approach. This article introduces Healthy Universities; reports on a qualitative study exploring the potential for a national programme contributing to health, well-being and sustainable development; and concludes with reflections and recommendations. The study used questionnaires and interviews with key informants from English higher education institutions and national stakeholder organizations. The findings confirmed that higher education offers significant potential to impact positively on the health and well-being of students, staff and wider communities through education, research, knowledge exchange and institutional practice. There was strong support for extending the healthy settings approach beyond schools and further education, through a National Healthy Higher Education Programme that provides a whole system Healthy University Framework. Informants argued that although there are important public health drivers, it will also be necessary to show how a Healthy Universities can help achieve core business objectives and contribute to related agendas such as sustainability. Two models were discussed: an accreditation scheme with externally assessed standardized achievement criteria; and a flexible and light-touch framework focusing on change-related processes and utilizing self-assessment. While highlighting the appeal of league tables, many informants feared that a top-down approach could backfire, generating resistance and resulting in minimal compliance. In contrast, the majority felt that a process-focused aspirational model would be more likely to win hearts and minds and facilitate system-level change. Key recommendations relate to national programme development, research and evaluation and international collaboration and networking.


Factors affecting study efficiency and item non-response in health surveys in developing countries: the Jamaica national healthy lifestyle survey.
Health surveys provide important information on the burden and secular trends of risk factors and disease. Several factors including survey and item non-response can affect data quality. There are few reports on efficiency, validity and the impact of item non-response, from developing countries. This report examines factors associated with item non-response and study efficiency in a national health survey in a developing Caribbean island. A national sample of participants aged 15-74 years was selected in a multi-stage sampling design accounting for 4 health regions and 14 parishes using enumeration districts as primary sampling units. Means and proportions of the variables of interest were compared between various categories. Non-response was defined as failure to provide an analyzable response. Linear and logistic regression models accounting for sample design and post-stratification weighting were used to identify independent correlates of recruitment efficiency and item non-response. We recruited 2012 15-74 year-olds (66.2% females) at a response rate of 87.6% with significant variation between regions (80.9% to 97.6%; p < 0.0001). Females outnumbered males in all parishes. The majority of subjects were recruited in a single visit, 39.1% required multiple visits varying significantly by region (27.0% to 49.8% [p < 0.0001]). Average interview time was 44.3 minutes with no variation between health regions, urban-rural residence, educational level, gender and SES; but increased significantly with older age category from 42.9 minutes in the youngest to 46.0 minutes in the oldest age category. Between 15.8% and 26.8% of persons did not provide responses for the number of sexual partners in the last year. Women and urban residents provided less data than their counterparts. Highest item non-response related to income at 30% with no gender difference but independently related to educational level, employment status, age group and health region. Characteristics of non-responders vary with types of questions. Informative health surveys are possible in developing countries. While survey response rates may be satisfactory, item non-response was high in respect of income and sexual practice. In contrast to developed countries, non-response to questions on income is higher and has different correlates. These findings can inform future surveys.


Relapsing polychondritis.
Relapsing polychondritis (RP) is a rare, inflammatory disease with multisystem involvement and it should be considered in the aetiology of sudden respiratory distress. A 49-year-old woman was admitted to the emergency service of Osmangazi Hospital in acute respiratory distress. She had a tracheostomy following a diagnosis of laryngeal stenosis 10 years earlier. She was managed thereafter at another hospital with a diagnosis of asthma. At admission she was in respiratory distress, had arthralgias, bilateral subconjunctival hyperaemia, periorbital oedema and skin lesions. A thoracic CT showed tracheal wall thickening. Calcification of the auricular regions were noted bilaterally. Bronchi, conjunctiva and skin lesions were biopsied with a provisional diagnosis of RP. The diagnosis of RP in this patient was based on clinical, pathological and radiological findings. Steroid therapy was begun and she was referred to a surgical centre for stenting. This case report emphasizes the need to consider the possibility of RP as a cause of sudden respiratory distress.


Clinical pharmacy services in Brazil, particularly cardiometabolic diseases: a systematic scoping review and meta-analyses.
To map the clinical pharmacy services conducted in Brazil, their characteristics, outcomes, and process measures in general population, as well as the assessment of the clinical impact on people with cardiometabolic diseases (cardiovascular diseases and metabolic diseases). A systematic scoping review and meta-analysis were conducted. The electronic searches were re-run in March 2020. To the clinical impact assessment, meta-analyses of cardiometabolic outcomes (i.e., change of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, total cholesterol, glycated hemoglobin (HbA1c), fasting glycemia, LDL-, and HDL-cholesterol) were led. The risk of bias was assessed with the Cochrane Collaboration tools. 71 studies were identified (7,402 patients), being the majority quasi-experimental studies (n=41) and published by research groups of Southeast Brazil (n=33). Medication therapy management (n=62) was the most frequent clinical pharmacy service, performed on outpatient setting (n=45), with adults or elderly people (n=58) with hypertension (n=18) or diabetes (n=10). Process measures (n=58) (e.g. resolution of drug related-problem) were widely used as indicator, followed by clinical (n=44) (e.g. change in SBP), humanistic (n=12) (e.g. change in quality-of-life score assessed by Short-Form 36 Health Survey Questionnaire), and economic outcomes (n=3) (incremental cost-effectiveness ratio for reduction in HbA1c). Regarding the assessment of clinical impact of the services, 20 studies were included in meta-analyses, showing improvement in most cardiometabolic outcomes when considered individual studies. However, the evidence presents high risk of bias, high heterogeneity (median 67-90%) and imprecision, contributing to wide prediction intervals and low reliability. A predominance of studies on cardiometabolic diseases, process measures, and clinical outcomes were identified. Considering the assessment of the clinical impact of clinical pharmacy services in cardiometabolic diseases, an improvement in most cardiometabolic outcomes was showed, however, with low confidence and wide prediction interval. Therefore, development of larger studies with low risk of bias and major homogeneity is necessary for a better comprehension of clinical pharmacy service characteristics, benefits, and the population groups most benefited.


Similar nucleotide excision repair capacity in melanocytes and melanoma cells.
Sunlight UV exposure produces DNA photoproducts in skin that are repaired solely by nucleotide excision repair in humans. A significant fraction of melanomas are thought to result from UV-induced DNA damage that escapes repair; however, little evidence is available about the functional capacity of normal human melanocytes, malignant melanoma cells, and metastatic melanoma cells to repair UV-induced photoproducts in DNA. In this study, we measured nucleotide excision repair in both normal melanocytes and a panel of melanoma cell lines. Our results show that in 11 of 12 melanoma cell lines tested, UV photoproduct repair occurred as efficiently as in primary melanocytes. Importantly, repair capacity was not affected by mutation in the N-RAS or B-RAF oncogenes, nor was a difference observed between a highly metastatic melanoma cell line (A375SM) or its parental line (A375P). Lastly, we found that although p53 status contributed to photoproduct removal efficiency, its role did not seem to be mediated by enhanced expression or activity of DNA binding protein DDB2. We concluded that melanoma cells retain capacity for nucleotide excision repair, the loss of which probably does not commonly contribute to melanoma progression.


Influencing factors of early childhood teachers' disaster preparedness.
The risk of disasters and infectious diseases continues to persist in modern times. Children are a vulnerable group in disaster prevention and management due to their limited ability to cope on their own. Hence, the role and disaster preparedness capacity of early childhood teachers (ECTs) is vital for children's protection. This study aims to explore how ECTs can improve their personal resilience to adapt to and overcome disasters as part of early childhood education and care (ECEC). To this end, this study examined the effects of ECTs' self-efficacy, resilience, disaster awareness, COVID-19 stress, and work-related stress on their disaster preparedness. According to the outcomes of disaster preparedness of ECTs based on their general and job characteristics, full-time employees and principals scored significantly higher in work-related disaster preparedness (WrDP) compared to part-time workers and general and assistant teachers, respectively. Resilience and WrDP were identified as influencing factors of general disaster preparedness (GdP), with an explanatory power of 26.4%. GdP and self-efficacy were identified as influencing factors of WrDP, with an explanatory power of 25.7%. According to the findings, ECTs' self-efficacy and GdP must be improved, followed by developing strategies to strengthen their resilience and WrDP. Doing so would ensure the safety and disaster preparedness of ECTs and infants who have low self-care capacity.


Stratified entomological sampling in preparation for an area-wide integrated pest management program: the example of Glossina palpalis gambiensis (Diptera: Glossinidae) in the Niayes of Senegal.
The riverine tsetse species Glossina palpalis gambiensis Vanderplank 1949 (Diptera: Glossinidae) inhabits riparian forests along river systems in West Africa. The government of Senegal has embarked on a project to eliminate this tsetse species, and African animal trypanosomoses, from the Niayes area using an area-wide integrated pest management approach. A stratified entomological sampling strategy was therefore developed using spatial analytical tools and mathematical modeling. A preliminary phytosociological census identified eight types of suitable habitat, which could be discriminated from LandSat 7 ETM+ satellite images and denominated wet areas. At the end of March 2009, 683 unbaited Vavoua traps had been deployed, and the observed infested area in the Niayes was 525 km2. In the remaining area, a mathematical model was used to assess the risk that flies were present despite a sequence of zero catches. The analysis showed that this risk was above 0.05 in 19% of this area that will be considered as infested during the control operations. The remote sensing analysis that identified the wet areas allowed a restriction of the area to be surveyed to 4% of the total surface area (7,150 km2), whereas the mathematical model provided an efficient method to improve the accuracy and the robustness of the sampling protocol. The final size of the control area will be decided based on the entomological collection data. This entomological sampling procedure might be used for other vector or pest control scenarios.


Luminescent Platinum(II) Complexes with Terdentate N∧C∧C Ligands.
The synthesis, structure, and luminescence of Pt(II) complexes of the type [Pt(N∧C∧C)(L)] are reported, where N∧C∧C is a terdentate ligand resulting from the cycloplatination of 2-(3,5-diphenoxyphenyl)pyridine or 2-(4,4″-dimethyl-[1,1':3',1″-terphenyl]-5'-yl)pyridine, and L represents a monodentate ancillary ligand, which can be γ-picoline, 4-pyridinecarboxaldehyde, PPh3, n-butyl or 2,6-dimethylphenyl isocyanide, CO, or the N-heterocyclic carbenes 1-butyl-3-methylimidazol-2-ylidene or 4-butyl-3-methyl-1-phenyl-1H-1,2,3-triazol-5-ylidene. Derivatives bearing CO, isocyanides, or carbenes showed the highest stabilities in solution, whereas the pyridine and PPh3 derivatives establish ligand-exchange equilibria in acetonitrile. Different supramolecular structures are observed in the solid state, which largely depend on the nature of the ancillary ligand. Isocyanides and CO favor π interactions between the aromatic rings, metallophilic Pt···Pt contacts, or a combination of both. In contrast, pyridine ligands may lead to bimolecular assemblies driven by C-H···O, C-H···Pt, or C-H/π hydrogen bonds. Luminescence was examined in fluid solution, poly(methyl methacrylate) matrices, and the solid state at 298 K, and in 2-methyltetrahydrofuran glasses at 77 K. The majority of derivatives show highly efficient emissions from 3ILCT/MLCT or 3ILCT/MLCT/LLCT excited states of monomeric species. The formation of excimers and different types of emissive aggregates are demonstrated, which lead to red-shifted emissions of different origins and characteristics depending on the involved noncovalent interactions.


Protonation thermochemistry of alpha-aminoacids bearing a basic residue.
The proton affinity, PA, and protonation entropy, Delta(p)S degree, of glycine (Gly), 1, aspartic acid (Asp), 2, asparagine (Asn), 3, histidine (His), 4, lysine (Lys), 5, glutamic acid (Glu), 6, and glutamine (Gln), 7, have been reinvestigated by the extended kinetic method, using the "isothermal point" method and the orthogonal distance regression, ODR, technique. The proton affinity values of a-aminoacids bearing a basic residue (PA = 926.8; 965.2; 996.0; 993.9; 981.8 and 988.1 kJ.mol(-1) for 2-7, respectively) show significant deviation from the tabulated values. As expected from the effect of a strong intramolecular hydrogen bond in the protonated forms of these peculiar aminoacids, negative protonation entropies are detected (Delta(p)S degree = 36; 43; 37; 29; 95 and 55 J mol(-1) K(-1) for for 27 respectively).


Molecular diagnostic criteria of myeloproliferative neoplasms.
Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by the driver mutations JAK2, CALR, and MPL. These mutations cause constitutive activation of JAK-STAT signaling, which is central to pathogenesis of MPNs. Next-generation sequencing has further expanded the molecular landscape allowing for improved diagnostics, prognostication, and targeted therapy. This review aims to address current understanding of the molecular diagnosis of MPN not only through improved awareness of the driver mutations but also the disease modifying mutations. In addition, other genetic factors such as clonal hematopoiesis of indeterminate potential (CHIP), order of mutation, and mutation co-occurrence are discussed and how these factors influence disease initiation and ultimately progression. How this molecular information is incorporated into risk stratification models allowing for earlier intervention and targeted therapy in the future will be addressed further. The genomic landscape of the MPN has evolved in the last 15 years with integration of next-generation sequencing becoming the gold standard of MPN management. Although diagnostics and prognostication have become more personalized, additional studies are required to translate these molecular findings into targeted therapy therefore improving patient outcomes.


Temperature dependence of local density augmentation for acetophenone N,N,N',N'-tetramethylbenzidine exciplex in supercritical water.
Local density augmentation around exciplex between acetophenone and N,N,N',N'-tetramethylbenzidine in supercritical water was measured by observing the peak shift of transient absorption spectrum at temperatures from 380 to 410 degrees C and at pressures from 6 to 37 MPa. Large local density augmentation was observed at lower solvent densities. Local density augmentation was evaluated by the excess density, which was defined as the difference between local density and bulk density, and the density enhancement factor, which was defined by the ratio of the local density to the bulk density. The number of solvating molecules was estimated with a Langmuir adsorption model. The excess density was found to exhibit a maximum at approximately 0.15 g cm(-3), which decreased with increasing temperature. The density enhancement factor was found to decrease with increasing temperature; however, its value was much greater than unity at 410 degrees C, which provides evidence that exciplex-water interactions still exist at these conditions. The temperature dependence of local density augmentation around the exciplex in supercritical water was comparable with that in supercritical carbon dioxide, which suggests that the ratios of the solute-solvent and solvent-solvent interactions are comparable between these two systems.


Dendrimers with Oligospiroketal (OSK) Building Blocks: Synthesis and Properties.
The development of novel dendrimers containing oligospiroketal (OSK) rods as building blocks is described. The linkage between the core unit (CU), branching units (BU), and OSK rods relies on the CuAAC reaction between terminal alkynes and azides. Two different strategies of dendrimer synthesis were investigated and it was found that the convergent approach is clearly superior to the divergent one. SAXS measurements and MD simulations indicate that the obtained dendrimer features a globular structure with very low density. Obviously, the OSK rods stabilize a rather loose mass-fractal structure.


Chapter 5: Pediatric rhinosinusitis: Definitions, diagnosis and management-An overview.
Rhinosinusitis is common in the pediatric population; however, diagnostic and management techniques often differ when compared with adult rhinosinusitis. Multidisciplinary guidelines have outlined the diagnostic criteria for pediatric rhinosinusitis. Although acute rhinosinusitis is a more infectious phenomenon, chronic sinusitis involves a more multifactorial etiology. This article outlines some of the definitions of rhinosinusitis, diagnosis and management of pediatric sinusitis, and the complications of rhinosinusitis seen in the pediatric population.


Raising the voice of reason.
In the current economic climate, even the best known charities are facing reduced income and need to raise their profiles to ensure continued support. FRAME has always been well known among scientific organisations, but is less familiar to the public. The traditional sources of funding are drying up, and FRAME needs to promote itself to new audiences, if it is to succeed for another 40 years.


The influence of human leukocyte antigen matching on outcomes in pediatric heart transplantation.
Previous adult heart transplantation studies have demonstrated that donor-recipient human leukocyte antigen (HLA) matching results in reduced graft failure and improved patient survival. No study has examined these effects in children. This study investigated the effect of HLA matching on outcomes in pediatric heart transplantation. All pediatric heart transplantation data for patients 0-18 years of age available from the United Network for Organ Sharing Transplant Registry from 1987 to 2009 were analyzed retrospectively. Donor-recipient HLA matching at loci A, B, and DR (0-6) was compared with graft survival and recipient survival. For this study, 3,751 pediatric cardiac transplantation events with complete HLA matching data were identified and grouped as having 0 to 2 matches (3,416 events) or 3 to 6 matches (335 events). The 3- to 6-match group had less graft failure than the 0- to 2-match group (28.7% vs 34.4%; p = 0.035) and greater patient survival by 5 years (81% vs 72%; p = 0.045) and 10 years (66% vs 55%; p = 0.005) after transplantation. The HLA-DR matching alone resulted in less graft failure (p = 0.038) and improved patient survival (p = 0.017). A higher degree of HLA matching in pediatric heart transplantation is associated with decreased graft failure and improved patient survival. In this study, decreased graft failure rates and superior survival also were seen with DR matching alone.


Strong SARS-CoV-2 T-Cell Responses after One or Two COVID-19 Vaccine Boosters in Allogeneic Hematopoietic Stem Cell Recipients.
A full exploration of immune responses is deserved after anti-SARS-CoV-2 vaccination and boosters, especially in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although several reports indicate successful humoral responses in such patients, the literature is scarce on cellular specific immunity. Here, both B- (antibodies) and T-cell responses were explored after one (V3 n = 40) or two (V4 n = 12) BNT162b2 mRNA vaccine boosters in 52 allo-HSCT recipients at a median of 755 days post-transplant (<1 year n = 9). Results were compared with those of 12 controls who had received only one booster (BNT162b2 n = 6; mRNA-1273 n = 6). All controls developed protective antibody levels (>250 BAU/mL) and anti-spike T-cell responses. Similarly, 81% of the patients developed protective antibody levels, without difference between V3 and V4 (82.5% vs. 75%, p = 0.63), and 85% displayed T-cell responses. The median frequency of anti-spike T cells did not differ either between controls or the whole cohort of patients, although it was significantly lower for V3 (but not V4) patients. COVID-19 infections were solely observed in individuals having received only one booster. These results indicate that four vaccine injections help to achieve a satisfactory level of both humoral and cellular immune protection in allo-HSCT patients.


[The effect of cyclooxygenase inhibitors on ion and water transport in the human kidney and frog skin and bladder].
In the frog urinary bladder and skin, block of cyclooxygenase with diclofenac (voltaren) resulted in an increase in the water permeability and a decrease in the potential difference and short-circuit current. Addition of 0.01 mumole of prostaglandine E2 decreased the osmotic water permeability to initial values and increased the transepithelial ion transport in the frog skin. In the kidney of children with nocturnal enuresis there was an increase in the night diuresis and in excretion of osmotically active substances. Voltaren by reducing the endogenous autacoid production, restored the kidney function and symptoms of enuresis disappeared. The results obtained indicate an important role of the rate of the endogenous autacoid production in regulation of the water and ion transport in the osmoregulating organs studied.


Immunosuppressive effect of quercetin on dendritic cell activation and function.
Dendritic cells (DCs) play a crucial role in linking innate and adaptive immunity. Thus, DCs have been regarded as a major target of immunosuppressants for the control of harmful immune responses. In this study, we examined the effect of quercetin, a natural flavonoid found in many vegetables and fruits, on the activation and function of mouse DCs. Quercetin effectively inhibited LPS-induced DC activation by reducing the production of proinflammatory cytokines/chemokines and the expression levels of MHC class II and costimulatory molecules. In addition, quercetin uniquely blocked endocytosis by DCs and the LPS-induced DC migration was diminished by quercetin treatment. Furthermore, quercetin abrogated the ability of LPS-stimulated DCs to induce Ag-specific T cell activation, both in vitro and in vivo. Remarkably, coadministration of quercetin with 2,4-dinitro-1-fluorobenzene prevented 2,4-dinitro-1-fluorobenzene-induced contact hypersensitivity, indicating the potential of quercetin for treating delayed-type hypersensitive diseases. Blockage of LPS-induced ERK, JNK, Akt, and NF-kappaB activation contributed to the inhibitory effect of quercetin on DCs. These results strongly suggest that quercetin may be a potent immunosuppressive agent and could be used in the prevention and therapy of chronic inflammation, autoimmunity, and transplantation via the abolishment of DC activation and function.


A Parameterised Complexity Analysis of Bi-level Optimisation with Evolutionary Algorithms.
Bi-level optimisation problems have gained increasing interest in the field of combinatorial optimisation in recent years. In this paper, we analyse the runtime of some evolutionary algorithms for bi-level optimisation problems. We examine two NP-hard problems, the generalised minimum spanning tree problem and the generalised travelling salesperson problem in the context of parameterised complexity. For the generalised minimum spanning tree problem, we analyse the two approaches presented by Hu and Raidl ( 2012 ) with respect to the number of clusters that distinguish each other by the chosen representation of possible solutions. Our results show that a (1+1) evolutionary algorithm working with the spanning nodes representation is not a fixed-parameter evolutionary algorithm for the problem, whereas the problem can be solved in fixed-parameter time with the global structure representation. We present hard instances for each approach and show that the two approaches are highly complementary by proving that they solve each other's hard instances very efficiently. For the generalised travelling salesperson problem, we analyse the problem with respect to the number of clusters in the problem instance. Our results show that a (1+1) evolutionary algorithm working with the global structure representation is a fixed-parameter evolutionary algorithm for the problem.


[Health research in Chile].
An analysis of health research in Chile is made, considering factors like exaggerated professional training during undergraduate studies and clinical residencies, and displacement of professionals from academic activities to more remunerative positions. Additionally, the limited role of the Ministry of Health in research promotion, evidenced by the almost absent participation of public hospitals in clinical research is discussed. Research investment, among a 0.6 to 0.8% of the GNP, is far from developed countries and Chile has not defined relevant health problems where a search effort would have an impact in public health. The marked centralism of the country attempts against regional application to financed projects. The following suggestions are made: to increase the financing for investigation, to reassign resources allowing the access of regional institutions, to financing, to discuss in the Chilean Association of Medical Faculties (ASOFAMECH) the creation of an academic degree by means of a thesis during the professional studies and to give facilities to develop research during clinical residencies. Also, the Ministry of Health should be involved, creating a national agenda or research priorities and increasing its association with Universities. Also training programs for professionals with a special interest in investigation should be devised.


Effects of intravenous iron therapy on mortality and hospitalization of hemodialysis patients: A prospective cohort study in Korea.
Iron replacement therapy is necessary for anemia treatment in patients with advanced chronic kidney disease. Intravenous (IV) iron therapy is an efficient method for iron replacement. However, there are concerns regarding its considerable side effects, including increased risks of infection or major adverse cardiovascular events (MACE). This is a longitudinal study from a multicenter prospective cohort study conducted in the Korean end-stage renal disease population. All-cause mortality, death due to infection or MACE, hospitalization due to infection or MACE, and all adverse event of death or hospitalization due to infection or MACE were compared according to the iron replacement methods during the first 3 months of enrollment. Among 1,680 hemodialysis patients, 29.3% of patients received IV iron therapy, and 38% of patients received oral iron therapy. During the median 632 days follow-up, all-cause mortality, mortality or hospitalization due to infection or MACE, and all adverse events did not differ among iron replacement groups. There were significant differences related to the risk of all adverse events among iron replacement therapies in the log-rank test and univariate Cox regression analysis only in the prevalent dialysis patients; however, the significance was lost in multivariate Cox regression analysis. Similar results were observed in the 1-year short-term outcome analysis. High-dose IV iron did not increase adverse outcomes. All-cause mortality or all adverse events due to infection or MACE were not higher with the current clinical regimen of IV iron replacement therapy than with oral or no iron therapy in Korean hemodialysis patients.


Spontaneous locomotor activity and pharmacokinetics of intravenous methamphetamine and its metabolite amphetamine in the rat.
The purpose of these studies was to better understand the behavioral effects and pharmacokinetics of an i.v. bolus dose of (+)-methamphetamine [(+)-METH] in a rat model of (+)-METH abuse. We characterized the behavioral effects after increasing (+)-METH doses (0.1, 0.3, and 1.0 mg/kg) and the pharmacokinetics of (+)-METH (and its metabolite (+)-amphetamine [(+)-AMP)]) at the lowest and highest of these doses in adult male Sprague-Dawley rats. The doses and route of administration were selected to mimic aspects of human use on a dose/body weight basis. Although the 0.1 mg/kg dose did not cause statistically significant increases in locomotor activity compared with saline controls, the higher doses (0.3 and 1.0 mg/kg) caused statistically significant increases in locomotor activity (p <.05), which lasted for up to 3 h at the highest dose. After the 1.0 mg/kg dose, the volume of distribution at steady state was 9.0 liters/kg, the total clearance was 126 ml/min/kg, and the average distribution and elimination half-lives were 9.2 and 63.0 min, respectively. Because the pharmacokinetic values after the 0.1 mg/kg dose were not different from those after the 1.0 mg/kg dose, the pharmacokinetics of (+)-METH were considered to be independent of the dose over this 10-fold range. (+)-AMP serum concentrations after the 1.0 mg/kg dose peaked from 10 to 30 min, and exhibited a T(1/2lambdaz) of 98.5 min. The statistically longer T(1/2lambdaz) of (+)-AMP (p <.05) suggested that the (+)-AMP terminal elimination rate and not the (+)-AMP metabolic formation rate is the rate-limiting step in (+)-AMP elimination following i.v. (+)-METH dosing.


Mesophotic fishes of the Abrolhos Shelf, the largest reef ecosystem in the South Atlantic.
Fishes inhabiting rhodolith beds and reefs at mesophotic depths on the Abrolhos Shelf, which encompasses the largest and richest coral reef formation in the South Atlantic Ocean, were assessed through technical diving and remotely operated vehicles (ROVs). A total of 74 fish species were recorded, including at least one new species, one new record for the south-western Atlantic and six new records for the Abrolhos region. Overfishing, mining and port activities are already threatening many endangered and commercially important species recorded on the mesophotic reefs of Abrolhos Shelf, and the establishment of marine protected areas and off-reserve fisheries regulations are urgently needed.


Interaction between extracellular matrix molecules and microbial pathogens: evidence for the missing link in autoimmunity with rheumatoid arthritis as a disease model.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation followed by tissue rebuilding or fibrosis. A failure by the body to regulate inflammation effectively is one of the hallmarks of RA. The interaction between the external environment and the human host plays an important role in the development of autoimmunity. In RA, the observation of anti-cyclic citrullinated peptide antibodies (ACPA) to autoantigens is well recognized. Citrullination is a post-translational modification mediated by peptidyl arginine deiminases, which exist in both mammalian and bacterial forms. Previous studies have shown how proteins expressed in the human extracellular matrix (ECM) acquire properties of damage-associated molecular patterns (DAMPs) in RA and include collagens, tenascin-C, and fibronectin (FN). ECM DAMPs can further potentiate tissue damage in RA. Recent work has shown that citrullination in RA occurs at mucosal sites, including the oral cavity and lung. Mucosal sites have been linked with bacterial infection, e.g., periodontal disease, where exogenous pathogens are implicated in the development of autoimmunity via an infectious trigger. Proteases produced at mucosal sites, both by bacteria and the human host, can induce the release of ECM DAMPs, thereby revealing neoepitopes which can be citrullinated and lead to an autoantibody response with further production of ACPA. In this perspectives article, the evidence for the interplay between the ECM and bacteria at human mucosal surfaces, which can become a focus for citrullination and the development of autoimmunity, is explored. Specific examples, with reference to collagen, fibrinogen, and FN, are discussed.


Preliminary heritability of complete rotation large colon volvulus in Thoroughbred broodmares.
Large colon volvulus (LCV) is a life-threatening form of colic that occurs when the large colon rotates 360° or more on its axis, resulting in colonic distention and ischaemia. Any horse can suffer from LCV, but the risk is greatest for periparturient Thoroughbred broodmares; the objective of this study was to estimate the heritability of LCV in these horses. The criteria for classification as an LCV case were being a Thoroughbred broodmare from one of three farms in central Kentucky and having had surgical correction for LCV. Controls were identified as Thoroughbred broodmares present on the same farms with no history of surgical colic. Thirty-nine cases and 191 controls were identified. Age of the LCV cases at the time of incident was significantly younger than that of the controls at the time of the study (P<0.0001). A total of 2223 horses were present when the five-generation pedigrees of the 230 study horses were combined. Heritability of LCV was estimated at 0.311±0.383 from the fit of a logit sire model with binomial data including year of birth and farm as fixed effects. Further data on broodmares from these and other farms will help to improve this estimate, which suggests the LCV is moderately heritable.


Sepsis and the heart.
Septic shock, the most severe complication of sepsis, accounts for approximately 10% of all admissions to intensive care. Our understanding of its complex pathophysiology remains incomplete but clearly involves stimulation of the immune system with subsequent inflammation and microvascular dysfunction. Cardiovascular dysfunction is pronounced and characterized by elements of hypovolaemic, cytotoxic, and distributive shock. In addition, significant myocardial depression is commonly observed. This septic cardiomyopathy is characterized by biventricular impairment of intrinsic myocardial contractility, with a subsequent reduction in left ventricular (LV) ejection fraction and LV stroke work index. This review details the myocardial dysfunction observed in adult septic shock, and discusses the underlying pathophysiology. The utility of using the regulatory protein troponin for the detection of myocardial dysfunction is also considered. Finally, options for the management of sepsis-induced LV hypokinesia are discussed, including the use of levosimendan.


Peptidyl inverse esters of p-methoxybenzoic acid: a novel class of potent inactivator of the serine proteases.
A series of novel synthetic peptides, containing a C-terminal beta-amino alcohol linked to p-methoxybenzoic acid via an ester linkage, have been prepared and tested as inhibitors against typical members of the serine protease family. For example, the sequences Ac-Val-Pro-NH-CH-(CH2-C6H5)-CH2O-CO-C6H4-OCH3 (I) and Ac-Val-Pro-NH-CH-[CH-(CH3)2]-CH2O-CO-C6H4-OCH3 (II), which fulfil the known primary and secondary specificity requirements of chymotrypsin and elastase respectively, have been found to behave as exceptionally potent irreversible inactivators of their respective target protease. Thus I was found to inactivate chymotrypsin with an overall second-order rate constant (k2/Ki) of approx. 6.6x10(6) M-1. s-1, whereas II is an even more potent inactivator of human neutrophil elastase, exhibiting a second-order rate constant of inactivation of approx. 1.3x10(7) M-1.s-1. These values represent the largest rate constants ever reported for the inactivation of these proteases with synthetic peptide-based inactivators. On prolonged incubation in substrate-containing buffers, samples of the inactivated proteases were found to regain activity slowly. The first-order rate constants for the regeneration of enzymic activity from chymotrypsin and human neutrophil elastase inactivated by I and II respectively were determined to be approx. 5.8x10(-5) s-1 and approx. 4.3x10(-4) s-1. We believe that the most likely mechanism for the inactivation and regeneration of enzymic activity involves the formation and subsequent slow hydrolysis of long-lived acyl enzyme intermediates.


Abnormal white matter integrity in young children with autism.
This study investigated white matter integrity in young children with autism using diffusion tensor imaging (DTI). Twenty-two children with autism, mean age 3:2 years, and 32 controls, mean age 3:4 years, participated in the study. Tract-based spatial statistics (TBSS) revealed white matter abnormalities in several distinct clusters within the genu and body of the corpus callosum (CC), left superior longitudinal fasciculus (SLF) and right and left cingulum (Cg). TBSS-VOIs analysis was performed in the clusters where differences in fractional anisotropy (FA) were detected to investigate the relationship between changes in FA and diffusivity indices. In all VOIs, increase in FA was caused by a decrease in radial diffusivity (Dr), while no changes in axial diffusivity (Da) or mean diffusivity (MD) were observed. Tractography analysis was applied to further study the CC, SLF, and Cg. Witelson parcellation scheme was used for the CC. Significant increase in FA was seen in children with autism in the mid-body of the CC as well as in the left Cg. It is suggested that such abnormal white matter integrity in young children with autism may adversely affect connectivity between different brain regions and may be linked to some of the behavioral impairments apparent in autism.


Hemocyte migration during inflammatory-like reaction of Ciona intestinalis (Tunicata, ascidiacea).
Following an injuring factor such as the injection of erythrocytes into the tunic of Ciona intestinalis, an inflammatory-like response occurs and blood cells are massively involved in these mechanisms. Electron microscope observations illustrate the infiltration and migration of blood cells throughout the mantle epithelium into the tunic and show several prominent morphological changes.


Chemical and in situ characterization of macromolecular components of the cell walls from the green seaweed Codium fragile.
A comprehensive analysis of the carbohydrate-containing macromolecules from the coencocytic green seaweed Codium fragile and their arrangement in the cell wall was carried out. Cell walls in this seaweed are highly complex structures composed of 31% (w/w) of linear (1-->4)-beta-D-mannans, 9% (w/w) of pyruvylated arabinogalactan sulfates (pAGS), and low amounts of hydroxyproline rich-glycoprotein epitopes (HRGP). In situ chemical imaging by synchrotron radiation Fourier transform infrared (SR-FTIR) microspectroscopy and by immunolabeling using antibodies against specific cell wall carbohydrate epitopes revealed that beta-d-mannans and pAGS are placed in the middle part of the cell wall, whereas HRGP epitopes (arabinogalactan proteins (AGPs) and extensins) are located on the wall boundaries, especially in the utricle apical zone. pAGS are sulfated at C-2 and/or C-4 of the 3-linked beta-L-arabinopyranose units and at C-4 and/or C-6 of the 3-linked beta-D-galactopyranose residues. In addition, high levels of ketals of pyruvic acid were found mainly at 3,4- of some terminal beta-D-Galp units forming a five-membered ring. Ramification was found at some C-6 of the 3-linked beta-D-Galp units. In agreement with the immunolabeled AGP epitopes, a nonsulfated branched furanosidic arabinan with 5-linked alpha-L-Araf, 3,5-linked alpha-L-Araf, and terminal alpha-L-Araf units and a nonsulfated galactan structure composed of 3-(3,6)-linked beta-D-Galp residues, both typical of type-II AG glycans were found, suggesting that AGP structures are present at low levels in the cell walls of this seaweed. Based on this study, it is starting to emerge that Codium has developed unique cell wall architecture, when compared, not only with that of vascular plants, but also with other related green seaweeds and algae.


The effect of treating people with reversible ischaemic attacks of the brain and eye on the incidence of stroke in Australia.
Reversible ischaemic attacks of the brain or eye (RIA) are a risk factor for stroke. Strategies of stroke prevention include vascular risk factor control, antithrombotic therapy, and carotid surgery. To determine the effectiveness, risks and costs of each stroke prevention strategy for patients with RIA and the Australian community, and the effect of treating people with RIA on the incidence of stroke in Australia. Review of data from prospective community-based studies to determine the prevalence of RIA, the incidence of stroke, and the proportion of stroke patients who report a RIA before their stroke; and data from randomised trials to determine the effectiveness, risks and costs of treatments for RIA. About 111,000 Australians have had a prior RIA. Each year, about 37,000 Australians suffer a stroke, of whom up to 8000 (22%) have had a prior ('warning') RIA. Targeting effective stroke prevention strategies to RIA patients with relevant treatable conditions may reduce the individual's stroke risk by two-thirds (individual strategies) and possibly further (combination strategies). However, because the attributable risk of RIA for stroke is only about 22% (and may be less, given the role of other causal risk factors for stroke), strategies of stroke prevention in RIA patients can only reduce stroke incidence by up to 15% (from 22% to 7%). The potential benefits of the 'high risk' approach to stroke prevention appear to be less than the 'population' approach, but both approaches are necessary and complementary. Indeed, the cost of implementing the 'high risk' approach may be less than the cost of the strokes prevented ($255 million; i.e. 15% of $1.7 billion).


Evolution of the spider homeobox gene repertoire by tandem and whole genome duplication.
Gene duplication generates new genetic material that can contribute to the evolution of gene regulatory networks and phenotypes. Duplicated genes can undergo subfunctionalisation to partition ancestral functions and/or neofunctionalisation to assume a new function. We previously found there had been a whole genome duplication (WGD) in an ancestor of arachnopulmonates, the lineage including spiders and scorpions but excluding other arachnids like mites, ticks, and harvestmen. This WGD was evidenced by many duplicated homeobox genes, including two Hox clusters, in spiders. However, it was unclear which homeobox paralogues originated by WGD versus smaller-scale events such as tandem duplications. Understanding this is key to determining the contribution of the WGD to arachnopulmonate genome evolution. Here we characterised the distribution of duplicated homeobox genes across eight chromosome-level spider genomes. We found that most duplicated homeobox genes in spiders are consistent with an origin by WGD. We also found two copies of conserved homeobox gene clusters, including the Hox, NK, HRO, Irx, and SINE clusters, in all eight species. Consistently, we observed one copy of each cluster was degenerated in terms of gene content and organisation while the other remained more intact. Focussing on the NK cluster, we found evidence for regulatory subfunctionalisation between the duplicated NK genes in the spider Parasteatoda tepidariorum compared to their single-copy orthologues in the harvestman Phalangium opilio. Our study provides new insights into the relative contributions of multiple modes of duplication to the homeobox gene repertoire during the evolution of spiders and the function of NK genes.


Grandmaternal smoking, asthma and lung function in the offspring: the Lifelines cohort study.
Limited research exists regarding the association between grandmaternal smoking during pregnancy and the risk for asthma and altered lung function in grandchildren. This study aimed to investigate this association in a three-generation design. 37 291 participants (25 747 adults and 11 544 children) were included from the Lifelines study, a prospective longitudinal three generation cohort study in The Netherlands. Spirometry was available in 69.5% and 61.1% of the included adults and children. Logistic and linear regression were used to analyse the association between grandmaternal smoking during pregnancy and (1) asthma, (2) early childhood asthma (ie, onset before 6 years) and (3) lung function level. Maternal and paternal grandmaternal smoking were studied separately and the analyses were stratified by adult/child and by gender. The analyses were adjusted for gender, current smoking, birth variables and socioeconomic status. In the adult population, maternal grandmaternal smoking during pregnancy was associated with a higher risk for asthma (OR (95% CI): 1.38 (1.06 to 1.79)), early childhood asthma (1.49 (95% CI 1.06 to 2.11)) and a lower FEV1/FVC% predicted (B (95% CI): -1.04 (-1.91 to -0.16) in men. These findings were not observed in a separate analysis of children that participated in this study. There was also no significant association between paternal grandmaternal smoking and asthma/lung function. Maternal grandmaternal smoking during pregnancy is associated with higher asthma risk and lower lung function in male grandchildren and a reverse effect in male grandchildren of subsequent generations. Our study highlights the deep-rooted effects of tobacco smoking across generations.


Human body donation programs in Sri Lanka: Buddhist perspectives.
Considerable attention is being given to the availability of bodies for anatomical education. This raises the question of the manner in which they are obtained, that is, whether they are unclaimed or donated. With increasing emphasis upon the ethical desirability of using body bequests, the spotlight tends to be focused on those countries with factors that militate against donations. However, little attention has been paid to cultures where donations are readily available. One such country is Sri Lanka where the majority of the Buddhist population follows Theravada Buddhism. Within this context, the expectation is that donations will be given selflessly without expecting anything in return. This is because donation of one's body has blessings for a better outcome now and in the afterlife. The ceremonies to honor donors are outlined, including details of the "Pirith Ceremony." The relevance for other cultures of these features of body donation is discussed paying especial attention to the meaning of altruism and consent, and justification for the anonymization of cadavers. The degree to which anatomy is integrated into the surrounding culture also emerges as significant.


The effect of different diets including those containing soya-bean products, on digesta movement and water and nitrogen absorption in the small intestine of the pre-ruminant calf.
1. Preruminant calves, fistulated in the abomassum and distal ileum, were given by infusion into the abomasum, at intervals of 2-3 d, single experimental feeds of cow's milk or a synthetic milk diet in which the protein source was casein or a soya-bean product. Polyethylene glycol (PEG) and phenol red were included as markers. 2. After infusion of the experimental feed, measurements were made of transit time from proximal duodenum to distal ileum and mean ileal flow-rates for the first 3 and 21 h after food residues reached the distal ileum. PEG recoveries for these two periods and net nitrogen absorption up to the distal ileum were also determined. In some experiments sodium, potassium and magnesium concentrations and numbers of viable bacteria in ileal digesta were determined. 3. Measurements of passage of digesta, recovery of marker and net N absorption did not differ greatly between calves given cow's milk and the synthetic milk diet containing casein. Compared to the casein-based diet, a diet based on heated soya-bean flour given to a calf for the first or second time produced a somewhat higher ileal flow-rate and a significantly lower net N absorption. Net N absorption was even lower when a calf received a diet containing unheated soya-bean flour. 4. Calves given the diet containing heated soya-bean flour on several occasions appeared to develop a sensitivity to the flour, and after further feeds containing it they had significantly higher rates of ileal flow (accompanied by correspondingly high rates of Na and K flow), lower small intestine transit times and lower net N absorption values than similarly fed unsensitized calves. They also had significantly lower rates of passage of marker in the first few hours after food residues reached the ileum, indicating inhibition of abomasal emptying. Over all, the changes indicated a severe disturbance in digestive function which was not caused by abnormal bacterial growth and may have been due to a gastrointestinal allergy. 5. Diets prepared from water-extracted flour and from soya-bean-protein isolate also led to digestive disturbances in sensitized calves, but those containing concentrates prepared by extracting soya-bean meal with hot aqueous ethanol did not.


Strategies to Promote Long-Distance Optic Nerve Regeneration.
Mammalian retinal ganglion cells (RGCs) in the central nervous system (CNS) often die after optic nerve injury and surviving RGCs fail to regenerate their axons, eventually resulting in irreversible vision loss. Manipulation of a diverse group of genes can significantly boost optic nerve regeneration of mature RGCs by reactivating developmental-like growth programs or suppressing growth inhibitory pathways. By injury of the vision pathway near their brain targets, a few studies have shown that regenerated RGC axons could form functional synapses with targeted neurons but exhibited poor neural conduction or partial functional recovery. Therefore, the functional restoration of eye-to-brain pathways remains a greatly challenging issue. Here, we review recent advances in long-distance optic nerve regeneration and the subsequent reconnecting to central targets. By summarizing our current strategies for promoting functional recovery, we hope to provide potential insights into future exploration in vision reformation after neural injuries.


Factors related to pediatric obstructive sleep apnea-hypopnea syndrome in children with attention deficit hyperactivity disorder in different age groups.
This study aimed to retrospectively investigate the factors related to pediatric obstructive sleep apnea-hypopnea syndrome (OSAHS) with attention deficit hyperactivity disorder (ADHD) in children younger than 6 years and those older than 6 years.A total of 437 children who were hospitalized due to OSAHS between January 2014 and December 2014 were retrospectively reviewed. The children were further divided into OSAHS group and OSAHS + ADHD group. The general characteristics, OSA-18 quality of life, intention-hyperactivity score, and polysomnographic parameters (apnea-hypopnea index and the lowest oxygen saturation) were collected and compared between groups.There were 298 boys and 139 girls with the male to female ratio of 2.14:1. ADHD was found in 146 children including 105 boys and 41 girls with the male to female ratio of 2.56:1. Of these children, 31.62% and 35.46% had concomitant ADHD in children aged 4 to 5 years and those aged 6 to 11 years, respectively. In children aged 4 to 5 years, the incidence of allergic rhinitis was significantly higher (P = .016) and the adenoid hypertrophy was more severe (P = .001) in those with concomitant ADHD. In children aged 6 to 11 years, the tonsil hypertrophy was more severe in those with concomitant ADHD (P = .019). In children with concomitant ADHD, OSA-18 score was higher than in those with OSAHS alone (P < .001). Higher frequency of respiratory events (P < .001) and more severe hypoxia (P < .001) were found in children with concomitant ADHD than in those with OSAHS alone.As high as 30% of OSAHS children have concomitant ADHD, and the incidence of ADHD in OSAHS children is increasing over age. Boys are more likely to develop OSAHS and incidence of ADHD in OSAHS boys is higher than in OSAHS girls. In addition, risk factors of ADHD also vary between age groups. The ADHD is related to the severity of allergic rhinitis and adenoid hypertrophy in children aged 4 to 5 years, and to the severity of tonsil hypertrophy in children aged 6 to 11 years. Hypoxia may be an important factor causing ADHD. OSAHS should be treated as early as possible to reduce the incidence of ADHD in children.


Bio-interfactants as double-sided tapes for graphene oxide.
We present a versatile and highly substrate-independent approach for preparing multisandwich layers based on thermally reduced Graphene Oxide (rGO) which gets strongly attached by bio-interfactants using a layer-by-layer (LBL) aqueous dipping and rinsing process. The process allows for the deposition of homogeneous ultra-thin films (∼5.5 nm) in distinct surface topographies, thicknesses and compositions by varying the bio-interfactant layer(s). The layers formed on quartz or other semi conductive material are electrically conductive, flexible, and transparent. The here-developed approach could be applied for the fabrication of wearables, sensors, and antistatic transparent films.


Muscle Atrophy Due to Nerve Damage Is Accompanied by Elevated Myofibrillar Protein Synthesis Rates.
Muscle loss is a severe complication of many medical conditions such as cancer, cardiac failure, muscular dystrophies, and nerve damage. The contribution of myofibrillar protein synthesis (MPS) to the loss of muscle mass after nerve damage is not clear. Using deuterium oxide (D2O) labeling, we demonstrate that MPS is significantly increased in rat m.tibialis anterior (TA) compared to control (3.23 ± 0.72 [damaged] to 2.09 ± 0.26%∗day-1 [control]) after 4 weeks of nerve constriction injury. This is the case despite substantial loss of mass of the TA (350 ± 96 mg [damaged] to 946 ± 361 mg [control]). We also show that expression of regulatory proteins involved with MPS (p70s6k1: 2.4 ± 0.3 AU [damaged] to 1.8 ± 0.2 AU [control]) and muscle protein breakdown (MPB) (MAFbx: 5.3 ± 1.2 AU [damaged] to 1.4 ± 0.4 AU [control]) are increased in nerve damaged muscle. Furthermore, the expression of p70s6k1 correlates with MPS rates (r2 = 0.57). In conclusion, this study shows that severe muscle wasting following nerve damage is accompanied by increased as opposed to decreased MPS.


The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory.
Previous research has suggested that migraineurs show higher levels of oxidative stress (lipid peroxides) between migraine attacks and that migraine triggers may further increase brain oxidative stress. Oxidative stress is transduced into a neural signal by the TRPA1 ion channel on meningeal pain receptors, eliciting neurogenic inflammation, a key event in migraine. Thus, migraines may be a response to brain oxidative stress. In this article, a number of migraine components are considered: cortical spreading depression, platelet activation, plasma protein extravasation, endothelial nitric oxide synthesis, and the release of serotonin, substance P, calcitonin gene-related peptide, and brain-derived neurotrophic factor. Evidence is presented from in vitro research and animal and human studies of ischemia suggesting that each component has neuroprotective functions, decreasing oxidant production, upregulating antioxidant enzymes, stimulating neurogenesis, preventing apoptosis, facilitating mitochondrial biogenesis, and/or releasing growth factors in the brain. Feedback loops between these components are described. Limitations and challenges to the model are discussed. The theory is presented that migraines are an integrated defensive, neuroprotective response to brain oxidative stress.


Augmentation of primary influenza A virus-specific CD8+ T cell responses in aged mice through blockade of an immunoinhibitory pathway.
Immune responses diminish with age resulting in an increased susceptibility of the elderly to infectious agents and an inability to mount protective immune responses to vaccines. Immunosenescence affects multiple aspects of the immune system, including CD8(+) T cells, which control viral infections and are assumed to prevent the development of cancers. In this study, we tested if CD8(+) T cell responses in aged mice could be enhanced through a vaccine that concomitantly expresses Ag and a molecule that blocks an immunoinhibitory pathway. Specifically, we tested a vaccine based on a replication-defective chimpanzee-derived adenovirus vector expressing the nucleoprotein (NP) of influenza A virus as a fusion protein with the HSV type 1 glycoprotein D, which through binding to the herpes virus entry mediator, blocks the immunoinhibitory herpes virus entry mediator B and T lymphocyte attenuator/CD160 pathways. Our results show that the vaccine expressing a fusion protein of NP and glycoprotein D induces significantly higher NP-specific CD8(+) T cell responses in young and aged mice compared with the vaccine expressing NP only.


Brain volumes and cognitive function in very-low-birth-weight (VLBW) young adults.
Preterm born very-low-birth-weight (VLBW: birth weight ≤1500 g) survivors have increased risk of perinatal brain injury that may cause deviant brain development and later neuroimpairments, including reduced cognitive functioning. In this long-term follow up study of three year-cohorts (birth years 1986-88) of VLBW subjects and term born controls with normal birth weight, the aim was to examine differences in brain volumes at age 20 years. In addition, the relationships between brain volumes and cognitive abilities and perinatal variables were explored. Forty-four VLBW subjects and 60 controls were assessed with cognitive testing (Wechsler Adult Intelligence Scale - WAIS-III) and structural MRI at 1.5 T, using the FreeSurfer 5.1 software for volumetric analysis. A subpopulation had MRI performed also at age 15, and for this group changes in brain volumes with age were examined. The VLBW subjects had smaller brain volumes, especially of thalamus, globus pallidus and parts of the corpus callosum, and larger lateral ventricles than controls at age 20. However, no significant group differences in longitudinal change from age 15 to 20 were observed. The most immature and smallest VLBW subjects at birth, and those with the highest perinatal morbidity, showed most pronounced volume deviations. Positive associations between several brain volumes and full IQ, as well as three of four IQ indices in the VLBW group, were observed. Reduced volumes of grey and white matter and ventricular dilatation in VLBW young adults may indicate permanent effects on brain development from perinatal brain injury with influence on later cognitive function.


Genetic variability in enzymes of metabolic pathways conferring protection against non-enzymatic glycation versus diabetes-related morbidity and mortality.
We hypothesized that genetic variability in genes encoding enzymes metabolizing glycolytic intermediates produced in excess under hyperglycemic conditions [i.e., transketolase (TKT), transaldolase, TKT-like protein 1, fructosamine 3-kinase (FN3K), glyoxalase 1 and glucose-6-phosphate dehydrogenase] could influence progression of diabetic nephropathy (DN) and diabetes-related morbidity and mortality. A total of 19 single nucleotide polymorphisms (SNPs) in six candidate genes were studied in 314 type 2 diabetic subjects with variable stage of kidney disease (normo- and microalbuminuria, proteinuria, end-stage renal disease). SNP selection criteria were based on known functional effect and gene coverage. SNPs were detected using polymerase chain reaction based methods. Subjects were followed up for median of 38 months. Time-to-event analysis considered three end-points: 1) DN progression by at least one stage; 2) major cardiovascular event; and 3) all-cause mortality. We found combined effect of TKT SNP rs11130362 and FN3K SNP rs1056534 on DN progression (p<0.01). Additionally, TKT rs3736156 alone and also in combination with the previous two SNPs exhibited significant effect on incidence of major cardiovascular events (p<0.01 and p=0.01, respectively). Genetic variability in rate-limiting enzymes of pathways proposed to confer hypothetical protection against hyperglycemia might act as an important determinant of hyperglycemia toxicity in long-standing diabetes.


Pneumococcal responses are similar in Papua New Guinean children aged 3-5 years vaccinated in infancy with pneumococcal polysaccharide vaccine with or without prior pneumococcal conjugate vaccine, or without pneumococcal vaccination.
In an earlier trial, Papua New Guinean (PNG) children at high risk of pneumococcal disease were randomized to receive 0 or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7), followed by a single dose of 23-valent pneumococcal polysaccharide vaccine (PPV23) at 9 months of age. We here studied in a non-randomized follow-up trial the persistence of pneumococcal immunity in these children at 3-5 years of age (n = 132), and in 121 community controls of a similar age with no prior pneumococcal vaccination. Circulating IgG antibody titers to all PCV7 and PPV23-only serotypes 2, 5 and 7F were measured before and after challenge with 1/5th of a normal PPV23 dose. Serotype-specific memory B-cells were enumerated at 10 months and 3-5 years of age for a subgroup of study children. Serotype-specific IgG antibody titers before and after challenge were similar for children who received PCV7/PPV23, PPV23 only, or no pneumococcal vaccines. Before challenge, at least 89% and 59% of children in all groups had serotype-specific titers ≥ 0.35μg/ml and ≥ 1.0 μg/ml, respectively. Post-challenge antibody titers were higher or similar to pre-challenge titers for most children independent of pneumococcal vaccination history. The rise in antibody titers was significantly lower when pre-challenge titers were higher. Overall the relative number of serotype-specific memory B-cells remained the same or increased between 10 months and 3-5 years of age, and there were no differences in serotype-specific memory B-cell numbers at 3-5 years of age between the three groups. Immunity induced by PCV7 and/or PPV23 immunization in infancy does not exceed that of naturally acquired immunity in 3-5-year-old children living in a highly endemic area. Also, there was no evidence that PPV23 immunization in the first year of life following PCV7 priming induces longer-term hypo-responsiveness. Clinicaltrials.gov NCT01414504 and NCT00219401.


Regional variation in health care utilization and mortality.
Geographic variation in health care utilization has raised concerns of possible inefficiencies in health care supply, as differences are often not reflected in health outcomes. Using comprehensive Norwegian microdata, we exploit cross-region migration to analyze regional variation in health care utilization. Our results indicate that place factors account for half of the difference in utilization between high and low utilization regions, while the rest reflects patient demand. We further document heterogeneous impacts of place across socioeconomic groups. Place factors account for 75% of the regional utilization difference for high school dropouts, and 40% for high school graduates; for patients with a college degree, the impact of place is negligible. We find no statistically significant association between the estimated place effects and overall mortality. However, we document a negative association between place effects and utilization-intensive causes of death such as cancer, suggesting high-supply regions may achieve modestly improved health outcomes.


BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes.
There have been significant advances with regard to BRAF-targeted therapies against metastatic melanoma. However, the majority of patients receiving BRAF inhibitors (BRAFi) manifest disease progression within a year. We have recently shown that melanoma patients treated with BRAFi exhibit an increase in melanoma-associated antigens and in CD8+ tumor-infiltrating lymphocytes in response to therapy. To characterize such a T-cell infiltrate, we analyzed the complementarity-determining region 3 (CDR3) of rearranged T-cell receptor (TCR) β chain-coding genes in tumor biopsies obtained before the initiation of BRAFi and 10-14 d later. We observed an increase in the clonality of tumor-infiltrating lymphocytes in 7 of 8 patients receiving BRAFi, with a statistically significant 21% aggregate increase in clonality. Over 80% of individual T-cell clones detected after initiation of BRAFi treatment were new clones. Interestingly, the comparison of tumor infiltrates with clinical responses revealed that patients who had a high proportion of pre-existing dominant clones after the administration of BRAFi responded better to therapy than patients who had a low proportion of such pre-existing dominant clones following BRAFi. These data suggest that although the inhibition of BRAF in melanoma patients results in tumor infiltration by new lymphocytes, the response to treatment appears to be related to the presence of a pre-existing population of tumor-infiltrating T-cell clones.


Semi-automatic segmentation for 3D motion analysis of the tongue with dynamic MRI.
Dynamic MRI has been widely used to track the motion of the tongue and measure its internal deformation during speech and swallowing. Accurate segmentation of the tongue is a prerequisite step to define the target boundary and constrain the tracking to tissue points within the tongue. Segmentation of 2D slices or 3D volumes is challenging because of the large number of slices and time frames involved in the segmentation, as well as the incorporation of numerous local deformations that occur throughout the tongue during motion. In this paper, we propose a semi-automatic approach to segment 3D dynamic MRI of the tongue. The algorithm steps include seeding a few slices at one time frame, propagating seeds to the same slices at different time frames using deformable registration, and random walker segmentation based on these seed positions. This method was validated on the tongue of five normal subjects carrying out the same speech task with multi-slice 2D dynamic cine-MR images obtained at three orthogonal orientations and 26 time frames. The resulting semi-automatic segmentations of a total of 130 volumes showed an average dice similarity coefficient (DSC) score of 0.92 with less segmented volume variability between time frames than in manual segmentations.


An integrative affect regulation process model of internalized weight bias and intuitive eating in college women.
The present study extended the weight stigma and well-being process model (Tylka et al., 2014) by examining three affect regulation pathways that may help simultaneously explain the predicted inverse association between internalized weight bias and intuitive eating. A weight-diverse sample of 333 college women completed an online survey assessing internalized weight stigma, intuitive eating, body shame, body image flexibility, and self-compassion. Self-reported height and weight were used to calculate body mass index (BMI). Non-parametric bootstrap resampling procedures were computed to ascertain the presence of the indirect effects of internalized weight bias on intuitive eating via the three hypothesized mediators controlling for BMI in a combined model. Results demonstrated that body image flexibility significantly and self-compassion marginally contributed unique variance in accounting for this relationship. Our preliminary cross-sectional findings contribute to a nascent body of scholarship seeking to provide a theoretically-driven understanding of how negative and positive forms of experiencing and relating to the body may co-occur within individuals. Results also point to potential target variables to consider incorporating in later-stage efforts to promote more adaptive ways of eating amidst internalized weight stigma.