Effects of Magnetically Guided, SPIO-Labeled, and Neurotrophin-3 Gene-Modified Bone Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury.
Despite advances in our understanding of spinal cord injury (SCI) mechanisms, there are still no effective treatment approaches to restore functionality. Although many studies have demonstrated that transplanting NT3 gene-transfected bone marrow-derived mesenchymal stem cells (BMSCs) is an effective approach to treat SCI, the approach is often low efficient in the delivery of engrafted BMSCs to the site of injury. In this study, we investigated the therapeutic effects of magnetic targeting of NT3 gene-transfected BMSCs via lumbar puncture in a rat model of SCI. With the aid of a magnetic targeting cells delivery system, we can not only deliver the engrafted BMSCs to the site of injury more efficiently, but also perform cells imaging in vivo using MR. In addition, we also found that this composite strategy could significantly improve functional recovery and nerve regeneration compared to transplanting NT3 gene-transfected BMSCs without magnetic targeting system. Our results suggest that this composite strategy could be promising for clinical applications.


The Role of Nutrition in Women with Benign Cyclic Mastalgia: A Case-Control Study.
Smoking, caffeine, oral contraception, and exercise are the most cited factors for premenstrual mastalgia in the literature, but remain controversial. In this study, we aimed to investigate the most often proposed nutritional factors for cyclic breast pain. Patients who met the criteria for participation in the mastalgia or control group were included in this case-control study. The age, body mass index, educational status, duration of breast pain, visual analog scale (VAS) pain score (0 to 10), number of births, use of oral contraception, exercise habits, drinking coffee, tea, alcohol and water, smoking history, and eating fast food and dessert were examined using a questionnaire. The mean age of mastalgia (n=256) and control (n=200) patients were 35.9±11.0 and 36.6±10.6 years, respectively. In the mastalgia group, the mean duration of cyclic breast pain time was 22.8±33.0 months and mean the VAS score 4.0±2.1. Body mass index and the mean number of births were higher in the mastalgia group than control group (p<0.005). There were no differences in smoking, oral contraceptive use, and drinking alcohol and tea (p>0.005). Compared to the mastalgia group, the control group ate more fast food and desserts, drank more water and coffee, and exercised less (p<0.005). The causes of mastalgia remain controversial. Our data supports some of the published studies, but not others. We propose that nutritional factors contribute less to the risk of mastalgia than is generally thought.


Playing with cardiac "redox switches": the "HNO way" to modulate cardiac function.
The nitric oxide (NO(•)) sibling, nitroxyl or nitrosyl hydride (HNO), is emerging as a molecule whose pharmacological properties include providing functional support to failing hearts. HNO also preconditions myocardial tissue, protecting it against ischemia-reperfusion injury while exerting vascular antiproliferative actions. In this review, HNO's peculiar cardiovascular assets are discussed in light of its unique chemistry that distinguish HNO from NO(•) as well as from reactive oxygen and nitrogen species such as the hydroxyl radical and peroxynitrite. Included here is a discussion of the possible routes of HNO formation in the myocardium and its chemical targets in the heart. HNO has been shown to have positive inotropic/lusitropic effects under normal and congestive heart failure conditions in animal models. The mechanistic intricacies of the beneficial cardiac effects of HNO are examined in cellular models. In contrast to β-receptor/cyclic adenosine monophosphate/protein kinase A-dependent enhancers of myocardial performance, HNO uses its "thiophylic" nature as a vehicle to interact with redox switches such as cysteines, which are located in key components of the cardiac electromechanical machinery ruling myocardial function. Here, we will briefly review new features of HNO's cardiovascular effects that when combined with its positive inotropic/lusitropic action may render HNO donors an attractive addition to the current therapeutic armamentarium for treating patients with acutely decompensated congestive heart failure.


A qualitative study of the post-treatment experiences and support needs of survivors of lymphoma.
To explore the post-treatment experiences and preferences for follow-up support of lymphoma survivors. Two focus groups were conducted with 17 participants to explore informational, psychological, emotional, social, practical and physical needs, 6-30 months post-treatment for lymphoma. Perceptions regarding a potential model of survivorship care were also elicited. Thematic content analysis revealed five key themes: Information; Loss and uncertainty; Family, support and post-treatment experience; Transition, connectivity and normalcy, and Person-centred post-treatment care. Participants described a sense of loss as they transitioned away from regular interaction with the hospital at the end of treatment, but also talked about the need to find a "new normal". Establishing post-treatment support structures that can provide individualised information, support, reassurance and referrals to community and peer support were identified as a helpful way to navigate the transition from patient to post-treatment survivor. Participants in our study articulated a need for a flexible approach to survivorship care, providing opportunities for individuals to access different types of support at different times post-treatment. Specialist post-treatment nurse care coordinators working across acute and community settings may offer one effective model of post-treatment support for survivors of haematological malignancies.


Computational modelling for cerebral aneurysms: risk evaluation and interventional planning.
Advanced computational techniques offer a new array of capabilities in the healthcare provision for cerebral aneurysms. In this paper information is provided on specific simulation methodologies that address some of the unanswered questions about intracranial aneurysm and their treatment. These include the evaluation of rupture risk, the thrombogenic characteristics of specific lesions and the efficacy assessment of particular interventional techniques and devices (e.g. endovascular coil embolisation and flow diversion using stents). The issues connected with ease-of-use and interactivity of computed simulations is discussed, and it is concluded, that the potential of these techniques to optimise planning of complex and multifaceted interventions is very significant, in spite of the fact that most of the methodologies described are still being developed and perfected.


Next-Generation Sequencing Analysis Reveals Differential Expression Profiles of MiRNA-mRNA Target Pairs in KSHV-Infected Cells.
Kaposi's sarcoma associated herpesvirus (KSHV) causes several tumors, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). Cellular and viral microRNAs (miRNAs) have been shown to play important roles in regulating gene expression. A better knowledge of the miRNA-mediated pathways affected by KSHV infection is therefore important for understanding viral infection and tumor pathogenesis. In this study, we used deep sequencing to analyze miRNA and cellular mRNA expression in a cell line with latent KSHV infection (SLKK) as compared to the uninfected SLK line. This approach revealed 153 differentially expressed human miRNAs, eight of which were independently confirmed by qRT-PCR. KSHV infection led to the dysregulation of ~15% of the human miRNA pool and most of these cellular miRNAs were down-regulated, including nearly all members of the 14q32 miRNA cluster, a genomic locus linked to cancer and that is deleted in a number of PEL cell lines. Furthermore, we identified 48 miRNAs that were associated with a total of 1,117 predicted or experimentally validated target mRNAs; of these mRNAs, a majority (73%) were inversely correlated to expression changes of their respective miRNAs, suggesting miRNA-mediated silencing mechanisms were involved in a number of these alterations. Several dysregulated miRNA-mRNA pairs may facilitate KSHV infection or tumor formation, such as up-regulated miR-708-5p, associated with a decrease in pro-apoptotic caspase-2 and leukemia inhibitory factor LIF, or down-regulated miR-409-5p, associated with an increase in the p53-inhibitor MDM2. Transfection of miRNA mimics provided further evidence that changes in miRNAs are driving some observed mRNA changes. Using filtered datasets, we also identified several canonical pathways that were significantly enriched in differentially expressed miRNA-mRNA pairs, such as the epithelial-to-mesenchymal transition and the interleukin-8 signaling pathways. Overall, our data provide a more detailed understanding of KSHV latency and guide further studies of the biological significance of these changes.


LINE-1 retrotransposition in the nervous system.
Long interspersed element-1 (LINE-1 or L1) is a repetitive DNA retrotransposon capable of duplication by a copy-and-paste genetic mechanism. Scattered throughout mammalian genomes, L1 is typically quiescent in most somatic cell types. In developing neurons, however, L1 can express and retrotranspose at high frequency. The L1 element can insert into various genomic locations including intragenic regions. These insertions can alter the dynamic of the neuronal transcriptome by changing the expression pattern of several nearby genes. The consequences of L1 genomic alterations in somatic cells are still under investigation, but the high level of mutagenesis within neurons suggests that each neuron is genetically unique. Furthermore, some neurological diseases, such as Rett syndrome and ataxia telangiectasia, misregulate L1 retrotransposition, which could contribute to some pathological aspects. In this review, we survey the literature related to neurodevelopmental retrotransposition and discuss possible relevance to neuronal function, evolution, and neurological disease.


Effect of Korean red ginseng on arterial stiffness in subjects with hypertension.
Korean red ginseng (KRG) improves endothelial function and lower blood pressure (BP), which may affect arterial stiffness. The present study evaluated whether KRG treatment could improve arterial stiffness in subjects with hypertension. Eighty (80) participants with hypertension who were treated with antihypertensive agents were randomly assigned to an active (KRG 3 g/day) or a placebo treatment group in a double-blind manner. Participants were not allowed to change their antihypertensive medications. Systolic BP (SBP) and diastolic BP (DBP) were measured at baseline, and at 1, 2, and 3 months. Arterial stiffness was assessed by the measurement of brachial-ankle pulse wave velocity (baPWV) at baseline, and at 1 and 3 months. Thirty (30) subjects in the active group (AG) and 34 subjects in the placebo group (PG) completed 3 months of treatment and then a per-protocol analysis was done. SBP and DBP at baseline, and at 1, 2, and 3 months were not different between the AG and PG (p>0.05). After 3 months of treatment, SBP of AG was not changed from SBP at baseline. However, DBP of AG, and SBP and DBP of PG after 3 months of treatment were significantly reduced (p<0.05). baPWV of both groups was significantly reduced at 1 and 3 months (p<0.05), but was not different between the groups at each time point. Analysis after adjustment for age, time-dependent mean arterial BP, heart rate, and levels of fasting blood glucose and triglycerides showed no significant difference between AG and PG in changes of baPWV from baseline to 1 and 3 months (p>0.05). Three (3) months' treatment with KRG did not improve arterial stiffness in subjects with hypertension.


Development of a Web-Based Resource for Parents of Young Children Newly Diagnosed With Autism: Participatory Research Design.
The internet provides an ideal avenue to share information, advice, and support regarding autism. However, many websites lack quality control and rarely provide a one-stop resource for families to access necessary, evidence-based information. This study aims to use participatory action research (PAR) with end users (ie, parents) and clinicians to develop a web-based resource (Pathways Beyond Diagnosis) to improve timely access to quality, evidence-based information, and support for families after their child is diagnosed with autism. The PAR approach involves 4 phases: (1) cooperative researcher-stakeholder planning, (2) cooperative researcher-stakeholder-based action, (3) stakeholder observation, and (4) cooperative researcher-stakeholder reflection. A total of 15 participants (parents, n=3; clinicians, n=9; and researchers, n=3) attended individual or group participatory design workshops. This was followed by the translation of knowledge and ideas generated during the workshops to produce mockups of webpages and content, rapid prototyping, and one-on-one consultations with end users to assess the usability of the website developed. A total of 3 participatory design workshops were held with the participants, each followed by a knowledge translation session. At the end of the PAR cycle, an alpha prototype of the website was built and a series of one-on-one end user consultation sessions were conducted. The PAR cycle revealed the importance of 6 key topic areas (understanding autism, accessing services, support, gaining funding, putting it all together, and looking into the future) associated with the time of diagnosis, which were incorporated into the beta version of the website. The development of the Pathways Beyond Diagnosis website using PAR ensures that families have ready access to practical and evidence-based information following a young child's diagnosis. The website guides families to access relevant, reputable, and evidence-based information in addition to summarizing key challenges encountered after diagnosis (ie, grief, sharing the diagnosis) and the importance of self-care.


Gut microbiota as an epigenetic regulator: pilot study based on whole-genome methylation analysis.
The core human gut microbiota contributes to the developmental origin of diseases by modifying metabolic pathways. To evaluate the predominant microbiota as an epigenetic modifier, we classified 8 pregnant women into two groups based on their dominant microbiota, i.e., Bacteroidetes, Firmicutes, and Proteobacteria. Deep sequencing of DNA methylomes revealed a clear association between bacterial predominance and epigenetic profiles. The genes with differentially methylated promoters in the group in which Firmicutes was dominant were linked to risk of disease, predominantly to cardiovascular disease and specifically to lipid metabolism, obesity, and the inflammatory response. This is one of the first studies that highlights the association of the predominant bacterial phyla in the gut with methylation patterns. Further longitudinal and in-depth studies targeting individual microbial species or metabolites are recommended to give us a deeper insight into the molecular mechanism of such epigenetic modifications. Epigenetics encompasses genomic modifications that are due to environmental factors and do not affect the nucleotide sequence. The gut microbiota has an important role in human metabolism and could be a significant environmental factor affecting our epigenome. To investigate the association of gut microbiota with epigenetic changes, we assessed pregnant women and selected the participants based on their predominant gut microbiota for a study on their postpartum methylation profile. Intriguingly, we found that blood DNA methylation patterns were associated with gut microbiota profiles. The gut microbiota profiles, with either Firmicutes or Bacteroidetes as a dominant group, correlated with differential methylation status of gene promoters functionally associated with cardiovascular diseases. Furthermore, differential methylation of gene promoters linked to lipid metabolism and obesity was observed. For the first time, we report here a position of the predominant gut microbiota in epigenetic profiling, suggesting one potential mechanism in obesity with comorbidities, if proven in further in-depth studies.


Method for the location of primary wear scars from retrieved metal on metal hip replacements.
Retrieved metal-on-metal acetabular cups are valuable resources in investigating the wear behaviour of failed hip implants, but adequate methods to do so are lacking. To further contribute to addressing this issue, we developed a method to detect the in vivo location of the primary wear scar of an explanted cup. We proposed a new method in which thirteen patients with failed metal hip resurfacings were recruited, and their acetabular components retrieved. A 3D wear map was generated and the precise location of the primary wear scar in each cup was identified using a coordinate measuring machine. This wear scar location was noted in relation to the features on the acetabular cup. Having identified the location of the wear scar, this 3D positional map was co-registered to the implant on the patient's pelvic 3D CT scan. Using our proposed technique, we were able to demonstrate that the in vivo position of the primary wear scar in explanted metal acetabular cups can be variable. This method has utilised existing techniques to better understand the three-dimensional properties of wear behaviour, and may be a method which can be used in further studies to investigate variables that affect the position of the primary wear scar.


Adverse drug reaction profile of microtubule-damaging antineoplastic drugs: A focused pharmacovigilance study in India.
The aim of the study was to analyze the adverse drug reaction (ADR) profile of microtubule-damaging antineoplastic drugs (taxanes and vinca alkaloids) and to look for unexpected ADRs among the local population. Focused study on these drugs, rampantly used in oncology department for a wide variety of tumors including early and advanced malignancies, would enable better treatment care by physicians. Data on ADRs were collected from the cancer patients belonging to both gender and of all ages, on taxanes- or vinca-based cancer chemotherapy and reported in the Indian Pharmacopoeia Commission form. Causality was assessed using the WHO criteria and Naranjo's Algorithm. Preventability and severity of ADRs were also assessed. A total of 97 ADRs were reported among 488 patients on microtubule-damaging anticancer drugs admitted over a period of 1 year. The incidence rate was 19.87%. Gastrointestinal system (40.2%) was the most affected followed by bone marrow (33%) and skin (8.2%). The highest incidence of ADRs was reported among paclitaxel (54.6%), and vincristine (39.2%). Most of the reported ADRs were of milder nature and preventable. The WHO causality assessment scale indicated 71.1% possible reactions. This study showed that most ADRs are preventable with effective ADR monitoring. There is a great need to create awareness among healthcare professionals regarding the importance of the pharmacovigilance system. Judicious use of the preventive measures will lead to a reduction in the incidence of ADRs due to the drug armamentarium, thereby enabling additional economic benefit to the patient and society.


Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy.
Current anti-VEGF therapies for colorectal cancer (CRC) provide limited survival benefit, as tumors rapidly develop resistance to these agents. Here, we have uncovered an immunosuppressive role for nonclassical Ly6Clo monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following VEGF signaling blockade, resulting in recruitment of CX3CR1+Ly6Clo monocytes into the tumor. We also found that treatment with VEGFA reduced expression of CX3CL1 in endothelial cells in vitro. Intravital microscopy revealed that CX3CR1 is critical for Ly6Clo monocyte transmigration across the endothelium in murine CRC tumors. Moreover, Ly6Clo monocytes recruit Ly6G+ neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6Clo monocyte or Ly6G+ neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, a gene therapy using a nanoparticle formulated with an siRNA against CX3CL1 reduced Ly6Clo monocyte recruitment and improved outcome of anti-VEGFR2 therapy in mouse CRCs. Our study unveils an immunosuppressive function of Ly6Clo monocytes that, to our knowledge, has yet to be reported in any context. We also reveal molecular mechanisms underlying antiangiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies.


CD24-triggered caspase-dependent apoptosis via mitochondrial membrane depolarization and reactive oxygen species production of human neutrophils is impaired in sepsis.
Apoptosis is the most common pathway of neutrophil death under both physiological and inflammatory conditions. In this study, we describe an apoptotic pathway in human neutrophils that is triggered via the surface molecule CD24. In normal neutrophils, CD24 ligation induces death through depolarization of the mitochondrial membrane in a manner dependent on caspase-3 and caspase-9 and reactive oxygen species. Proinflammatory cytokines such as TNF-α, IFN-γ, and GM-CSF upregulated the expression of CD24 in vitro, favoring the emergence of a new CD16(high)/CD24(high) subset of cultured neutrophils. We observed that CD24 expression (at both mRNA and protein levels) was significantly downregulated in neutrophils from sepsis patients but not from patients with systemic inflammatory response syndrome. This downregulation was reproduced by incubation of neutrophils from healthy controls with corticosteroids or with plasma collected from sepsis patients, but not with IL-10 or TGF-β. Decreased CD24 expression observed on sepsis neutrophils was associated with lack of functionality of the molecule, because cross-ligation of CD24 failed to trigger apoptosis in neutrophils from sepsis patients. Our results suggest a novel aspect of CD24-mediated immunoregulation and represent, to our knowledge, the first report showing the role of CD24 in the delayed/defective cell death in sepsis.


L-arginine causes amelioration of cerebrovascular dysfunction and brain inflammation during experimental heatstroke.
Cerebrovascular dysfunction ensuing from severe heatstroke includes intracranial hypertension, cerebral hypoperfusion, and brain inflammation. We attempted to assess whether L-arginine improves survival during experimental heatstroke by attenuating these reactions. Anesthetized rats, 70 min after the start of heat stress (43 degrees C), were divided into two major groups and given the following: vehicle solution (1 mL/kg body weight) or L-arginine (50-250 mg/kg body weight) intravenously. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. Their physiological and biochemical parameters were continuously monitored. When the vehicle-treated rats underwent heat stress, their survival time values were found to be 20 to 26 min. Treatment with i.v. doses of L-arginine significantly improved the survival rate during heatstroke (54-245 min). As compared with those of normothermic controls, all vehicle-treated heatstroke animals displayed higher levels of core temperature, intracranial pressure, and NO metabolite, glutamate, glycerol, lactate-pyruvate ratio, and dihydroxybenzoic acid in hypothalamus. In addition, hypothalamic levels of IL-1beta and TNF-alpha were elevated after heatstroke onset. In contrast, all vehicle-treated heatstroke animals had lower levels of MAP, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of oxygen. Administration of L-arginine immediately after the onset of heatstroke significantly reduced the intracranial hypertension and the increased levels of NO metabolite, glutamate, glycerol, lactate-pyruvate ratio, and dihydroxybenzoic acid in the hypothalamus that occurred during heatstroke. The heatstroke-induced increased levels of IL-1beta and TNF-alpha in the hypothalamus were suppressed by L-arginine treatment. In contrast, the hypothalamic levels of IL-10 were significantly elevated by L-arginine during heatstroke. The results suggest that L-arginine may cause attenuation of heatstroke by reducing cerebrovascular dysfunction and brain inflammation.


No improvement in endurance performance after a single dose of beetroot juice.
Dietary nitrate supplementation has received much attention in the literature due to its proposed ergogenic properties. Recently, the ingestion of a single bolus of nitrate-rich beetroot juice (500 ml, ~6.2 mmol NO3-) was reported to improve subsequent time-trial performance. However, this large volume of ingested beetroot juice does not represent a realistic dietary strategy for athletes to follow in a practical, performance-based setting. Therefore, we investigated the impact of ingesting a single bolus of concentrated nitrate-rich beetroot juice (140 ml, ~8.7 mmol NO3-) on subsequent 1-hr time-trial performance in well-trained cyclists. Using a double-blind, repeated-measures crossover design (1-wk washout period), 20 trained male cyclists (26 ± 1 yr, VO(2peak) 60 ± 1 ml · kg(-1) · min(-1), Wmax 398 ± 7.7 W) ingested 140 ml of concentrated beetroot juice (8.7 mmol NO3-; BEET) or a placebo (nitrate-depleted beetroot juice; PLAC) with breakfast 2.5 hr before an ~1-hr cycling time trial (1,073 ± 21 kJ). Resting blood samples were collected every 30 min after BEET or PLAC ingestion and immediately after the time trial. Plasma nitrite concentration was higher in BEET than PLAC before the onset of the time trial (532 ± 32 vs. 271 ± 13 nM, respectively; p < .001), but subsequent time-trial performance (65.5 ± 1.1 vs. 65 ± 1.1 s), power output (275 ± 7 vs. 278 ± 7 W), and heart rate (170 ± 2 vs. 170 ± 2 beats/min) did not differ between BEET and PLAC treatments (all p > .05). Ingestion of a single bolus of concentrated (140 ml) beetroot juice (8.7 mmol NO3-) does not improve subsequent 1-hr time-trial performance in well-trained cyclists.


Frontal filament morphogenesis in the salmon louse Lepeophtheirus salmonis.
The objective of the present study was to understand how and when the frontal filament (FF) in the salmon louse Lepeophtheirus salmonis is produced by examining the sequence of morphological changes leading to FF production in the copepodid and early chalimus stages. Atlantic salmon (Salmo salar) were heavily infested with newly molted copepodids. Sea lice were sampled prior to infestation and at 1, 2, 3, 4, 5, 6, 7, 8, and 9 days postinfestation. FF morphogenesis from newly molted copepodid to chalimus II, i.e., through 2 molts, was studied using high-resolution light microscopy of serial transverse and sagittal resin sections. Three groups of cells, identified as A, B, and C, are thought to be involved in the production of the secretions (S1 and S2) that form the filament material. The amount and shape of S1 and S2 and their association with B- and C-group cells, respectively, changed with the molt cycle. The following scenario for FF development is proposed: the first secretion to form after the molt for both copepodid and chalimus stages is S1, and it is formed by B-group cells and becomes the basal plate of the external FE C-group cells produce S2 during mid-intermolt to premolt stage. The S2 becomes the stem of the external FE In premolt larvae, S1 and S2 were contained within a cuticle-lined invagination that had a form similar to that of the extruded filament. The axial duct present in both copepodid and chalimus originates from the A-group cells and probably carries a secretion used to attach the filament to the host. This study provides strong evidence that L. salmonis produces a new filament with each molt, creating the possibility of using a sea lice control method based on interference with filament production more feasible.


Prick-prick with fresh foods in patients with latex allergy.
The quick spread of AIDS and other contagious infectious diseases has resulted in what was first voluntary, and subsequently recommended and compulsory, use of protection from contact with blood or bodily fluids. This protection has been especially widespread in the healthcare field. In the in vivo diagnosis of food allergy, it has been proven that the skin prick-prick test is sometimes more sensitive than skin prick test with commercial extracts. The aim of our study was to prove that handling fresh foods prepared for the prick-prick test with latex gloves can tamper with the results in patients with latex allergy. Statistically significant differences were found (p <0.001) between patients and controls in the prick-prick tests against the different foods after handling with latex gloves. No significant differences were found in controls for each prick-prick test for food with or without manipulation with latex gloves. Significant differences were found in the group of patients when performing prick-prick with the different foods before and after manipulation with latex gloves. We also observed that there were significant differences in prick-prick test between patients with latex sensitization and nonsensitized controls, and that the results of prick-prick test varied for each patient depending on whether or not foods had been handled with latex gloves.


Breastfeeding and postpartum amenorrhea in a traditional society: a hazards model analysis.
There is considerable variation in the length of the postpartum amenorrhea during which breastfeeding suppresses fertility, both within and between societies. In this paper, we investigate the association between breastfeeding and the resumption of menses and the impact of various biological and social covariates thereon, using data from two retrospective surveys in India. We use both univariate life table and multivariate time-dependent hazards techniques to analyze the data. Most prior investigations related the impact of breastfeeding to postpartum amenorrhea by taking duration of breastfeeding as a fixed covariate. However, breastfeeding beyond the resumption of menstruation cannot affect the duration of menses. Accordingly, the present study has a methodological focus in the sense that breastfeeding is treated as a time-dependent covariate. We found that breastfeeding, age of mother at child's birth, social status, level of income, religion and caste (subcaste), and residential status have significant effects on return of menses in Indian traditional society.


The role of facemasks and hand hygiene in the prevention of influenza transmission in households: results from a cluster randomised trial; Berlin, Germany, 2009-2011.
Previous controlled studies on the effect of non-pharmaceutical interventions (NPI) - namely the use of facemasks and intensified hand hygiene - in preventing household transmission of influenza have not produced definitive results. We aimed to investigate efficacy, acceptability, and tolerability of NPI in households with influenza index patients. We conducted a cluster randomized controlled trial during the pandemic season 2009/10 and the ensuing influenza season 2010/11. We included households with an influenza positive index case in the absence of further respiratory illness within the preceding 14 days. Study arms were wearing a facemask and practicing intensified hand hygiene (MH group), wearing facemasks only (M group) and none of the two (control group). Main outcome measure was laboratory confirmed influenza infection in a household contact. We used daily questionnaires to examine adherence and tolerability of the interventions. We recruited 84 households (30 control, 26 M and 28 MH households) with 82, 69 and 67 household contacts, respectively. In 2009/10 all 41 index cases had a influenza A (H1N1) pdm09 infection, in 2010/11 24 had an A (H1N1) pdm09 and 20 had a B infection. The total secondary attack rate was 16% (35/218). In intention-to-treat analysis there was no statistically significant effect of the M and MH interventions on secondary infections. When analysing only households where intervention was implemented within 36 h after symptom onset of the index case, secondary infection in the pooled M and MH groups was significantly lower compared to the control group (adjusted odds ratio 0.16, 95% CI, 0.03-0.92). In a per-protocol analysis odds ratios were significantly reduced among participants of the M group (adjusted odds ratio, 0.30, 95% CI, 0.10-0.94). With the exception of MH index cases in 2010/11 adherence was good for adults and children, contacts and index cases. Results suggest that household transmission of influenza can be reduced by the use of NPI, such as facemasks and intensified hand hygiene, when implemented early and used diligently. Concerns about acceptability and tolerability of the interventions should not be a reason against their recommendation. The study was registered with ClinicalTrials.gov (Identifier NCT00833885).


Anticipation of distress after discontinuation of mechanical ventilation in the ICU at the end of life.
A considerable number of patients admitted to the intensive care unit (ICU) die following withdrawal of mechanical ventilation. After discontinuation of ventilation without proper preparation, excessive respiratory secretion is common, resulting in a 'death rattle'. Post-extubation stridor can give rise to the relatives' perception that the patient is choking and suffering. Existing protocols lack adequate anticipatory preparation to respond to all distressing symptoms. We analyzed existing treatment strategies in distressing symptoms after discontinuation of mechanical ventilation. The actual period of discontinuation of mechanical ventilation can be very short, but thoughtful anticipation of distressing symptoms takes time. There is an ethical responsibility to anticipate and treat (iatrogenic) symptoms such as pain, dyspnea-associated respiratory distress, anxiety, delirium, post-extubation stridor, and excessive broncho-pulmonary secretions. This makes withdrawal of mechanical ventilation in ICU patients a thoughtful process, taking palliative actions instead of fast terminal actions. We developed a flowchart covering all possible distressing symptoms that can occur after withdrawal of mechanical ventilation and extubation. We recommend a two-phase process. Six hours before extubation, enteral feeding should be stopped and parenteral fluids reduced, overhydrated patients should be dehydrated with furosemide, administration of sedatives (for distress) and opioids (for pain and/or dyspnea) should be continued or started and methylprednisolone should be given in anticipation of stridor after extubation. Thirty minutes before extubation, Butylscopolamine should be given and methylprednisolone repeated. After this the patient should be extubated to secure a dying process as natural as possible with the lowest burden due to distress.


Determinants of changes in blood glucose response to short-term exercise training in patients with Type 2 diabetes.
The aim of the present study was to determine the effects of a 4-week exercise training intervention on blood glucose, insulin sensitivity, BMI (body mass index) and cardiorespiratory fitness in patients with Type 2 diabetes, and to identify and establish criteria for patients who are more likely to improve their blood glucose from short-term exercise training. A randomized, controlled trial of exercise training, comprising two supervised and one non-supervised sessions of individualized cardiorespiratory and resistance exercise per week, was performed in 132 healthy patients with Type 2 diabetes (exercise training group, n=68), with the aim of accumulating a minimum of 150 min of moderate-intensity exercise for 4 weeks. BMI, waist circumference, blood pressure, blood lipid profile, blood glucose, insulin, insulin sensitivity [calculated by HOMA(IR) (homoeostasis model assessment of insulin resistance) and QUICKI (quantitative insulin check index)], beta-cell function (calculated by HOMA(beta-Cell)), HbA(1c) (glycated haemoglobin) and VO(2max) (maximal oxygen consumption) were measured at baseline and at 4 weeks. The exercise training group had significant improvements in VO(2max), BMI and triacylglycerols (triglycerides). There were no significant changes in blood glucose, HOMA(IR), QUICKI or HOMA(beta-Cell). Decreases in blood glucose were significantly predicted by baseline blood glucose and HbA(1c), with these variables accounting for 15.9% of the change in blood glucose (P<0.001). ROC (receiver operator characteristic) curve analysis revealed that patients with a blood glucose >8.85 mmol/l (sensitivity=73%, specificity=78%) and HbA(1c) >7.15% (sensitivity=79%, specificity=60%) were more likely to achieve a clinically significant decrease in blood glucose. In conclusion, in apparently healthy patients with Type 2 diabetes, a 4-week exercise intervention improved cardiorespiratory fitness, BMI and triacylglycerols. Elevated blood glucose and HbA(1c) predicted improvements in blood glucose.


Supergene Evolution Triggered by the Introgression of a Chromosomal Inversion.
Supergenes are groups of tightly linked loci whose variation is inherited as a single Mendelian locus and are a common genetic architecture for complex traits under balancing selection [1-8]. Supergene alleles are long-range haplotypes with numerous mutations underlying distinct adaptive strategies, often maintained in linkage disequilibrium through the suppression of recombination by chromosomal rearrangements [1, 5, 7-9]. However, the mechanism governing the formation of supergenes is not well understood and poses the paradox of establishing divergent functional haplotypes in the face of recombination. Here, we show that the formation of the supergene alleles encoding mimicry polymorphism in the butterfly Heliconius numata is associated with the introgression of a divergent, inverted chromosomal segment. Haplotype divergence and linkage disequilibrium indicate that supergene alleles, each allowing precise wing-pattern resemblance to distinct butterfly models, originate from over a million years of independent chromosomal evolution in separate lineages. These "superalleles" have evolved from a chromosomal inversion captured by introgression and maintained in balanced polymorphism, triggering supergene inheritance. This mode of evolution involving the introgression of a chromosomal rearrangement is likely to be a common feature of complex structural polymorphisms associated with the coexistence of distinct adaptive syndromes. This shows that the reticulation of genealogies may have a powerful influence on the evolution of genetic architectures in nature.


Spinal pilocytic astrocytoma in an elderly patient.
Astrocytomas are the most common intramedullary spinal cord tumor in pediatric and adolescent patients and the incidence decreases with age. There are very few cases of spinal pilocytic astrocytomas (World Health Organization grade 1) reported after the fourth decade. We report the oldest known case of a pathologically confirmed spinal pilocytic astrocytoma. A 78-year-old woman presented with 12 months of bilateral lower extremity numbness. Magnetic resonance imaging revealed cord edema extending from C6 to T4. There was a 12-mm enhancing intramedullary lesion at the C7-T1 level with an associated cyst. Several years prior, she had seen a neurologist for lower extremity numbness and was diagnosed with peripheral neuropathy. She underwent C7-T1 laminectomy with partial resection of the spinal cord tumor and drainage of the cyst. Pathologic examination demonstrated a mildly cellular proliferation of astrocytes set in an eosinophilic fibrillar background. There were numerous Rosenthal fibers and prominent vasculature. There were no malignant features. The pathologic diagnosis was consistent with pilocytic astrocytoma, World Health Organization grade 1. The patient returned to her baseline function after several weeks and the imaging remained stable at the 4-month follow-up. Spinal pilocytic astrocytomas constitute 90% of intramedullary spinal cord tumors in patients younger than 10 years and 60% of those in adolescent patients. There are very few reported cases in patients older than 50 years. Our patient had an indolent course, cervical-thoracic location, imaging characteristics, and pathology that all support a diagnosis of pilocytic astrocytoma. This case highlights that low-grade lesions can occur in elderly patients and an aggressive approach may not be indicated.


Effect of filgotinib on health-related quality of life in active psoriatic arthritis: a randomized phase 2 trial (EQUATOR).
To examine the effects of filgotinib, an oral, selective Janus kinase 1 inhibitor, on health-related quality of life (HRQoL) using the Psoriatic Arthritis Impact of Disease (PsAID)9 questionnaire in active PsA. Patients were randomized 1 : 1 to filgotinib 200 mg or placebo once daily for 16 weeks in EQUATOR, a multicentre, double-blind, phase 2 randomized controlled trial. HRQoL was assessed with PsAID9 at Weeks 4 and 16. Change from baseline in total and individual domain scores, plus the proportions of patients achieving minimal clinically important improvement (MCII; ⩾3 points) and patient-accepted symptom status (PASS; score <4), were evaluated. Correlation with the 36-item short-form health survey (SF-36) was investigated. One hundred and thirty-one patients were randomized to filgotinib or placebo. Filgotinib effects on PsAID9 were observed from Week 4. At Week 16, mean (s.d.) change from baseline in PsAID9 was -2.3 (1.8) and -0.8 (2.2) for filgotinib and placebo, respectively (least-squares mean of group difference -1.48 [95% CI -2.12, -0.84], P < 0.0001), with significant improvements in all domains vs placebo. Significantly more patients on filgotinib achieved MCII (group difference 25.4% [95% CI 8.92, 39.99], P = 0.0022) and PASS (group difference 29.6% [95% CI 10.65, 45.60], P = 0.0018) at Week 16 vs placebo. Similar improvements in SF-36 were observed, with moderate to strong negative correlation between PsAID9 and SF-36. Filgotinib significantly improved HRQoL vs placebo in patients with active PsA, as measured by PsAID9. To our knowledge, EQUATOR is the first randomized controlled trial to evaluate PsAID9. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show, NCT03101670.


New characterisation method of electrical and electronic equipment wastes (WEEE).
Innovative separation and beneficiation techniques of various materials encountered in electrical and electronic equipment wastes (WEEE) is a major improvement for its recycling. Mechanical separation-oriented characterisation of WEEE was conducted in an attempt to evaluate the amenability of mechanical separation processes. Properties such as liberation degree of fractions (plastics, metals ferrous and non-ferrous), which are essential for mechanical separation, are analysed by means of a grain counting approach. Two different samples from different recycling industries were characterised in this work. The first sample is a heterogeneous material containing different types of plastics, metals (ferrous and non-ferrous), printed circuit board (PCB), rubber and wood. The second sample contains a mixture of mainly plastics. It is found for the first sample that all aluminium particles are free (100%) in all investigated size fractions. Between 92% and 95% of plastics are present as free particles; however, 67% in average of ferromagnetic particles are liberated. It can be observed that only 42% of ferromagnetic particles are free in the size fraction larger than 20mm. Particle shapes were also quantified manually particle by particle. The results show that the particle shapes as a result of shredding, turn out to be heterogeneous, thereby complicating mechanical separation processes. In addition, the separability of various materials was ascertained by a sink-float analysis and eddy current separation. The second sample was separated by automatic sensor sorting in four different products: ABS, PC-ABS, PS and rest product. The fractions were characterised by using the methodology described in this paper. The results show that the grade and liberation degree of the plastic products ABS, PC-ABS and PS are close to 100%. Sink-float separation and infrared plastic identification equipment confirms the high plastic quality. On the basis of these findings, a global separation flow sheet is proposed to improve the plastic separation of WEEE.


Signaling and interplay mediated by phospholipases A2, C, and D in LA-N-1 cell nuclei.
Phospholipids are integral components of the nuclear membranes and intranuclear domains. Alterations in phospholipid metabolism occur during cellular differentiation, proliferation, and apoptosis, but the molecular mechanism involved in the above processes remains unknown. We propose that the coordinated expression of different genes responsible for the expression of transcription factors, neurotrophins, and cytokines, along with lipid mediators generated by the action of phospholipases A2, C, and D (PLA2, PLC, and PLD), play a very important role in differentiation, proliferation, and apoptosis. The purpose of this minireview is to discuss recent developments in PLA2, PLC, and PLD-mediated signaling in the nucleus of LA-N-1 neuroblastoma cell cultures. In brain tissue, arachidonic acid is mainly released by the action of PLA2 and phospholipase C/diacylglycerol lipase (PLC/DAG-lipase) pathways. We have used LA-N-1 cell cultures to study activities of PLA2, C, and D during retinoic acid (RA)-mediated differentiation. The treatment of LA-N-1 cells with RA produces an increase in PLA2 activity in the nuclear fraction. This increase in PLA2 activity can be prevented with BMS493, a pan retinoic acid receptor antagonist, suggesting that RA-induced stimulation of PLA2 activity is a RA receptor-mediated process. The treatment of LA-N-1 cells with 12-O-tetradecanoyl-phorbol-13 acetate (TPA) and RA increases diacylglycerol (DAG) levels indicating the stimulation of PLC activity. This stimulation is blocked by D609, tricyclodecan-9-yl potassium xanthate, a competitive PtdCho-specific PLC inhibitor. LA-N-1 cells also contain DAG-and monoacylglycerol (MAG) lipase activities. Two isoforms of PLD, oleate-dependent and TPA-dependent, are also present in LA-N-1 cell homogenates. RA stimulates the oleate-dependent isoform of PLD, whereas RA does not stimulate the TPA-dependent isoform. Our studies have indicated that lipid mediators generated by the action of PLA2, PLC, and PLD on nuclear phospholipids markedly affect neuritic outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that RA receptors coupled with PLA2, PLC, and PLD activities in the nucleus may play an important role in the redistribution of arachidonic acid and its metabolites and DAG in nuclear and non-nuclear neuronal membranes during differentiation and growth suppression.


The modulation function and realizing method of holographic functional screen.
The modulation function of holographic functional screen (HFS) in the real-time, large-size full-color (RLF), three-dimensional (3D) display system is derived from angular spectrum analysis. The directional laser speckle (DLS) method to realize the HFS is proposed. A HFS by the DLS method was fabricated and used in the experiment. Experimental results show that the HFS is valid in the RLF 3D display, and that the derived modulation function is valuable for the design of the HFS. The research results are important to realize the RLF 3D display system which will find many applications such as holographic video.


Telomeric repeats facilitate CENP-A(Cnp1) incorporation via telomere binding proteins.
The histone H3 variant, CENP-A, is normally assembled upon canonical centromeric sequences, but there is no apparent obligate coupling of sequence and assembly, suggesting that centromere location can be epigenetically determined. To explore the tolerances and constraints on CENP-A deposition we investigated whether certain locations are favoured when additional CENP-A(Cnp1) is present in fission yeast cells. Our analyses show that additional CENP-A(Cnp1) accumulates within and close to heterochromatic centromeric outer repeats, and over regions adjacent to rDNA and telomeres. The use of minichromosome derivatives with unique DNA sequences internal to chromosome ends shows that telomeres are sufficient to direct CENP-A(Cnp1) deposition. However, chromosome ends are not required as CENP-A(Cnp1) deposition also occurs at telomere repeats inserted at an internal locus and correlates with the presence of H3K9 methylation near these repeats. The Ccq1 protein, which is known to bind telomere repeats and recruit telomerase, was found to be required to induce H3K9 methylation and thus promote the incorporation of CENP-A(Cnp1) near telomere repeats. These analyses demonstrate that at non-centromeric chromosomal locations the presence of heterochromatin influences the sites at which CENP-A is incorporated into chromatin and, thus, potentially the location of centromeres.


Surfactant-free electrochemical synthesis of metallic nanoparticles via stochastic collisions of aqueous nanodroplet reactors.
Stochastic collisions of aqueous nanodroplets (AnDs) on a microelectrode were observed in situ by electrochemistry. Reduction of Cu2+ ions enclosed in the reacting AnDs resulted in surfactant-free synthesis of copper nanoparticles on the electrode surface. The particle size distribution was reasonably controllable by the modulation of electrode voltage. The versatility of the synthetic method was established by its application in synthesizing nanoparticles of silver and cobalt oxyhydroxide.


Implementation of a Pilot SMS-Based Crisis Support Service in Australia.
Background: Australia's first short message service (SMS) crisis support service was launched by Lifeline Australia in July 2018. The pilot program was independently evaluated over a 240-day period. Aims: We aimed to examine the experiences of key staff employed in the Lifeline Text pilot and identify the skills and types of support required to deliver a high-quality SMS-based crisis support service. Method: In total, 22 interviews were conducted with 14 Lifeline Text crisis supporters and in-shift supervisors (supervisors) at two time points in September 2018 and March 2019. A modified framework approach was adopted to undertake qualitative data analyses. Results: Delivering crisis support via text was initially challenging as a result of the need to translate skills from telephone crisis support to the SMS platform. This was compounded by the high degree of suicidality of help-seekers and volatility in demand for the service. Limitations: The independent evaluators were not involved in the design of the pilot. Conclusion: Lifeline text is providing an important and necessary service, using a novel mode of delivery in Australia. Maintaining service quality at peak demand, with many distressed and suicidal help-seekers, requires specialized training, experience, and exceptional skills.


Urinary 1H-NMR metabolomics can distinguish pancreatitis patients from healthy controls.
The characterization of the urinary metabolome may yield biomarkers indicative of pancreatitis. We establish a non-invasive technique to compare urinary metabolic profiles in patients with acute and chronic pancreatitis to healthy controls. Urine was obtained from healthy controls (HC, n=5), inpatients with mild acute pancreatitis (AP, n=5), and outpatients with chronic pancreatitis (CP, n=5). Proton nuclear magnetic resonance spectra were obtained for each sample. Metabolites were identified and quantified in each spectrum; resulting concentrations were normalized to account for differences in dilution among samples. Kruskal-Wallis test, post-hoc Mann-Whitney U tests, and principal component analysis were performed to identify metabolites that discriminate healthy controls, acute pancreatitis, and chronic pancreatitis. Sixty metabolites were identified and quantified; five were found to differ significantly (P<0.05) among the three groups. Of these, citrate and adenosine remained significant after validation by random permutation. Principal component analysis demonstrated that healthy control urine samples can be differentiated from patients with chronic pancreatitis or acute pancreatitis; chronic pancreatitis patients could not be distinguished from acute pancreatitis patients. This metabolomic investigation demonstrates that this non-invasive technique offers insight into the metabolic states of pancreatitis. Although the identified metabolites cannot conclusively be defined as biomarkers of disease, future studies will validate our findings in larger patient cohorts.


Two-dimensional statistical recoupling for the identification of perturbed metabolic networks from NMR spectroscopy.
The development of Statistical Total Correlation Spectroscopy (STOCSY), a representation of the autocorrelation matrix of a spectral data set as a 2D pseudospectrum, has allowed more reliable assignment of one- and two-dimensional NMR spectra acquired from the complex mixtures that are usually used in metabolomics/metabonomics studies, thus, improving precise identification of candidate biomarkers contained in metabolic signatures computed by multivariate statistical analysis. However, the correlations obtained cannot always be interpreted in terms of connectivities between metabolites. In this study, we combine statistical recoupling of variables (SRV) and STOCSY to identify perturbed metabolite systems. The resulting Recoupled-STOCSY (R-STOCSY) method provides a 2D correlation landscape based on the SRV clusters representing physical, chemical, and biological entities. This enables the identification of correlations between distant clusters and extends the recoupling scheme of SRV, which was previously limited to the association of neighboring clusters. This allows the recovery of only meaningful correlations between metabolic signals and significantly enhances the interpretation of STOCSY. The method is validated through the measurement of the distances between the metabolites involved in these correlations, within the whole metabolic network, which shows that the average shortest path length is significantly shorter for the correlations detected in this new way compared to metabolite couples randomly selected from within the entire KEGG metabolic network. This enables the identification without any a priori knowledge of the perturbed metabolic network. The R-STOCSY completes the recoupling procedure between distant clusters, further reducing the high dimensionality of metabolomics/metabonomics data set and finally allows the identification of composite biomarkers, highlighting disruption of particular metabolic pathways within a global metabolic network. This allows the perturbed metabolic network to be extracted through NMR based metabolomics/metabonomics in an automated, and statistical manner.


Assessing inter-rater reliability for rating scales: resolving some basic issues.
This paper extends the recent work of Hall (1974) by presenting the minimal sample sizes and the specific linear agreement weights required for assessing the reliability of rating scales commonly used in neuropsychiatric and other clinico-medical settings. The weights are shown to vary as a function of (a) whether or not the rating scale contains a point of 'absence', and (b) the number of ordinal points on the scale.


Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent.
Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies.


Human lymphocyte antigen reactivity modified by neuraminidase.
Human lymphocytes treated with neuraminidase (from Vibrio cholera) are more susceptible to lysis with antiserums directed against HL-A antigens in the cytotoxicity test than are the corresponding cells incubated in buffer. Enzymetreated cells are also lysed by antibodies other than those directed against HL-A, but control cells are not. The extra sensitivity to antibody disappears after 2 to 6 days in tissue culture.


Physicochemical code for quinary protein interactions in Escherichia coli.
How proteins sense and navigate the cellular interior to find their functional partners remains poorly understood. An intriguing aspect of this search is that it relies on diffusive encounters with the crowded cellular background, made up of protein surfaces that are largely nonconserved. The question is then if/how this protein search is amenable to selection and biological control. To shed light on this issue, we examined the motions of three evolutionary divergent proteins in the Escherichia coli cytoplasm by in-cell NMR. The results show that the diffusive in-cell motions, after all, follow simplistic physical-chemical rules: The proteins reveal a common dependence on (i) net charge density, (ii) surface hydrophobicity, and (iii) the electric dipole moment. The bacterial protein is here biased to move relatively freely in the bacterial interior, whereas the human counterparts more easily stick. Even so, the in-cell motions respond predictably to surface mutation, allowing us to tune and intermix the protein's behavior at will. The findings show how evolution can swiftly optimize the diffuse background of protein encounter complexes by just single-point mutations, and provide a rational framework for adjusting the cytoplasmic motions of individual proteins, e.g., for rescuing poor in-cell NMR signals and for optimizing protein therapeutics.


Establishment of cell lines of uveal melanoma. Methodology and characteristics.
Six continuous cell lines have been established from choroidal and ciliary body melanomas. These lines have been maintained in culture for at least 100 in vitro population doublings for periods over 1 year. They were established initially using a human diploid fibroblast strain MRC-5 as a feeder layer. Cells were grown in Ham's F-12 medium containing fetal bovine and horse sera and supplemented with glucose, cholera toxin, and epidermal growth factor. Culture doubling times ranged from 72-96 hr; cloning efficiencies ranged from 1-5% in the absence of a feeder layer. Six cell lines were studied in detail by electron microscopy, and all were found to have evidence of melanosomes and/or premelanosomes. The morphology of the cells was characteristic of melanomas as defined by the Callender classification, with cell types ranging from spindle A to epithelioid. Karyotypic studies revealed the presence of only human chromosomes with modal numbers ranging from 48-54 in the different lines.


What are the financial barriers to medical care among the poor, the sick and the disabled in the Special Administrative Region of China?
Although Hong Kong is one of the richest cities in the world and has some of the best health outcomes such as long life expectancy, little is known about the people who are unable to access healthcare due to lack of financial means. Cross-sectional data from a sample of 2,233 participants aged 18 or above was collected from the first wave of the "Trends and Implications of Poverty and Social Disadvantages in Hong Kong" survey. Socio-demographic factors, lifestyle factors, and physical and mental health conditions associated with people who were unable to seek medical services due to lack of financial means in the past year were examined using forward stepwise logistic regression analyses. Of the 2,233 participants surveyed, 8.4% did not seek medical care due to lack of financial means during the past year. They were more likely to be income-poor. With respect to physical and mental health, despite having less likelihood to have multimorbidity, they tended to have higher levels of both anxiety and stress, poorer physical and mental health-related quality of life, and suffer from more severe disability and pain symptoms affecting their daily activities, when compared to the rest of the Hong Kong population. People who were denied of medical care due to financial barriers are generally sicker than people in the general Hong Kong population, implying that those with greater healthcare needs may have financial difficulties in receiving timely and appropriate medical care. Our findings suggest that inequity in healthcare utilization remains a critical issue in Hong Kong.


High prevalence of astigmatism in the 40- to 64-year-old population of Shahroud, Iran.
The prevalence of astigmatism, its axis and determinants were determined in the 40- to 64-year-old population of Shahroud, Iran. Population-based cross sectional study. Using random cluster sampling, 6311 subjects were invited for eye examinations. Of 5190 participants (response rate=82.2%), data of 5020 were eligible for analysis. Participants received visual acuity measurement, manifest refraction and eye examinations. The prevalence of astigmatism based on cylinder powers of more than 0.5, 1 and 3 D were studied. The prevalence (and 95% confidence interval) of astigmatism based on a cylinder power worse than 0.5, 1, and 3 D was 49.1% (47.6-50.5), 24.1% (22.9-25.3), and 3.4% (2.9-3.9), respectively. In a multiple logistic regression model, the prevalence of astigmatism was higher in men (odds ratio=1.25) and increased with age (odds ratio for each 5 years=1.21). Higher education was found to be inversely correlated to astigmatism (P < 0.001). The prevalence of with-the-rule, against-the-rule and oblique astigmatism was 12.6%, 25.9% and 10.6%, respectively. Oblique astigmatism was significantly higher in women and the older age groups (P < 0.001). Against-the-rule astigmatism increased with age from 19.9% in the age group of 40-44 to 37.0% in the age group of 60-64 (P < 0.001). In comparison with those studies conducted in Iran and other countries, the prevalence of astigmatism was higher in this study. Astigmatism was higher in men and age had an important role in astigmatism and its axis. The prevalence of against-the-rule and oblique astigmatism increased with age.


Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype.
Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome among women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype among women with polycystic ovary syndrome are inconsistent. We sought to determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome, and hyperandrogenemia in women with polycystic ovarian syndrome. We conducted secondary data analysis of a prospective multicenter, double-blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18-40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories: non-Hispanic whites, non-Hispanic blacks, and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome, and hyperandrogenemia in the different racial/ethnic groups. Body mass index (35.1 ± 9.8 vs 35.7 ± 7.9 vs 36.4 ± 7.9 kg/m2) and waist circumference (106.5 ± 21.6 vs 104.9 ± 16.4 vs 108.7 ± 7.3 cm) did not differ significantly between non-Hispanic white, non-Hispanic black, and Hispanic women. Hispanic women with polycystic ovarian syndrome had a significantly higher prevalence of hirsutism (93.8% vs 86.8%), abnormal free androgen index (75.8% vs 56.5%), abnormal homeostasis model assessment (52.3% vs 38.4%), and hyperglycemia (14.8% vs 6.5%), as well as lower sex hormone binding globulin compared to non-Hispanic whites. Non-Hispanic black women had a significantly lower prevalence of metabolic syndrome (24.5% vs 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non-Hispanic whites (85.7 ± 37.3 vs 130.2 ± 57.0 vs 120.1 ± 60.5 mg/dL, P < .01), with a markedly lower prevalence of hypertriglyceridemia (5.1% vs 28.3% vs 30.5%, P < .01) compared to the other 2 groups. Hispanic women with polycystic ovarian syndrome have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non-Hispanic black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than non-Hispanic white women.


Dynamic Embedding Projection-Gated Convolutional Neural Networks for Text Classification.
Text classification is a fundamental and important area of natural language processing for assigning a text into at least one predefined tag or category according to its content. Most of the advanced systems are either too simple to get high accuracy or centered on using complex structures to capture the genuinely required category information, which requires long time to converge during their training stage. In order to address such challenging issues, we propose a dynamic embedding projection-gated convolutional neural network (DEP-CNN) for multi-class and multi-label text classification. Its dynamic embedding projection gate (DEPG) transforms and carries word information by using gating units and shortcut connections to control how much context information is incorporated into each specific position of a word-embedding matrix in a text. To our knowledge, we are the first to apply DEPG over a word-embedding matrix. The experimental results on four known benchmark datasets display that DEP-CNN outperforms its recent peers.


Gag-Specific CD4 and CD8 T-Cell Proliferation in Adolescents and Young Adults with Perinatally Acquired HIV-1 Infection Is Associated with Ethnicity - The ANRS-EP38-IMMIP Study.
The ANRS-EP38-IMMIP study aimed to provide a detailed assessment of the immune status of perinatally infected youths living in France. We studied Gag-specific CD4 and CD8 T-cell proliferation and the association between the proliferation of these cells, demographic factors and HIV disease history. We included 93 youths aged between 15 and 24 years who had been perinatally infected with HIV. Sixty-nine had undergone valid CFSE-based T-cell proliferation assays. Gag-specific proliferation of CD4 and CD8 T cells was detected in 12 (16%) and 30 (38%) patients, respectively. The Gag-specific proliferation of CD4 and CD8 T cells was more frequently observed in black patients than in patients from other ethnic groups (CD4: 32% vs. 4%, P = 0.001; CD8: 55% vs. 26%, P = 0.02). Among aviremic patients, the duration of viral suppression was shorter in CD8 responders than in CD8 nonresponders (medians: 54 vs. 20 months, P = 0.04). Among viremic patients, CD8 responders had significantly lower plasma HIV RNA levels than CD8 nonresponders (2.7 vs. 3.7 log10 HIV-RNA copies/ml, P = 0.02). In multivariate analyses including sex and HIV-1 subtype as covariables, Gag-specific CD4 T-cell proliferation was associated only with ethnicity, whereas Gag-specific CD8 T-cell proliferation was associated with both ethnicity and the duration of viral suppression. Both CD4 and CD8 responders reached their nadir CD4 T-cell percentages at younger ages than their nonresponder counterparts (6 vs. 8 years, P = 0.04 for both CD4 and CD8 T-cell proliferation). However, these associations were not significant in multivariate analysis. In conclusion, after at least 15 years of HIV infection, Gag-specific T-cell proliferation was found to be more frequent in black youths than in patients of other ethnic groups, despite all the patients being born in the same country, with similar access to care.


Analysing the effect of novel therapies on cytokine expression in experimental arthritis.
Type II collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis that has been used extensively to address questions of disease pathogenesis and to validate novel therapeutic targets. Susceptibility to CIA is strongly associated with major histocompatibility complex class II genes, and the development of arthritis is accompanied by a robust T- and B-cell response to type II collagen. The main pathological features of CIA include proliferative synovitis with infiltration of inflammatory cells, pannus formation, cartilage degradation, erosion of bone and fibrosis. Pro-inflammatory cytokines, such as tumour necrosis factor alpha and interleukin-1beta, are expressed in the arthritic joints in both murine CIA and human rheumatoid arthritis, and blockade of these molecules results in amelioration of disease. Hence, there is a great deal of interest in the development of small-molecular-weight inhibitors of pro-inflammatory cytokines. There is also interest in the development and testing of drugs with the capacity to modulate the immune pathways involved in driving the inflammatory response in arthritis. For these reasons, there is a need to monitor the effect of novel treatments on cytokine expression in vivo. In this review, we outline the various techniques used to detect cytokines in experimental arthritis and describe how these techniques have been used to quantify changes in cytokine expression following therapeutic intervention.


Unintended Patient Safety Risks Due to Wireless Smart Infusion Pump Library Update Delays.
Our previous study showed that the issue of drug library update delays on wireless intravenous (IV) infusion pumps of one major vendor was widespread and significant. However, the impact of such a delay was unclear. The objective of this study was to quantify the impact of pump library update delays on patient safety in terms of missed and false infusion programming alerts. The study data sets included infusion logs and drug libraries from three hospitals of one health system from January 2015 to December 2016. We identified limit setting changes of any two consecutive drug library versions. We quantified the impact of using outdated drug limit settings by missed and false infusion programming alerts. Twenty-five updates of the drug library were released within the health system during the 2-year period with an average interval of 28.8 days. After a new library version was issued, it took at least 6 days for 50% of all pumps to become up-to-date and 15 days or more to reach 80%. All three hospitals had at least 16% of all IV infusions programmed with outdated libraries. This resulted in 18%, 24.4%, and 27% of false alerts in the three hospitals, respectively. We identified two cases of missed alert infusions of high-risk medications, propofol, and potassium chloride, which could have negatively impacted patient safety. These findings support our assumption that potential serious harm can happen when IV infusions are administered with outdated drug limit settings due to delays in drug library updates on the pump.


Microbiological effects and recolonization patterns after adjunctive subgingival debridement with Er:YAG laser.
The objective of this study was to assess the microbiological effects and recolonization patterns after non-surgical periodontal treatment protocol based on the adjunctive use of erbium-doped yttrium aluminium garnet (Er:YAG) laser. Patients diagnosed with chronic periodontitis were randomly assigned to two different treatment protocols: test, full-mouth subgingival ultrasonic instrumentation followed by Er-YAG laser application 1 week later to sites with initial probing pocket depth ≥4.5 mm; and control, full-mouth ultrasonic subgingival instrumentation within 1 week. Clinical (at sampled sites) and microbiological (culture-based) parameters were recorded at baseline and 3 and 12 months. Microbiological variables included total counts, frequency of detection, proportions and counts of target species. Results from 19 test and 21 control patients were compared. Minor changes were observed for total colony-forming units, with no differences between groups. For the frequency of detection, a limited and similar impact in both groups was observed for the most prevalent (over 80 %) periodontal pathogens (Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum). For proportions, reductions in P. gingivalis occurred at 3 months, both in the test and control groups (from 16.3 to 10 % and 16 to 14.8 %, respectively), although these differences were not statistically significant. At 12 months, the test group showed a statistically significant greater reduction in probing depth for the sampled sites. The adjunctive use of Er:YAG laser when compared with conventional ultrasonic debridement did not provide a microbiological added benefit. Even though some clinical benefits with the adjunctive laser application were identified when comparing both treatment protocols, there were no differences in microbiological outcomes or in the bacterial recolonization patterns.


Expression of cytokeratins 7 and 20 in ovarian neoplasia.
To further delineate specific staining patterns and refine the differential usefulness of cytokeratin (CK) 7/20 staining, we studied multiple ovarian tumors and primary nongynecologic neoplasms likely to metastasize to the ovary. Immunohistochemical analysis with semiquantitative grading to give quartile scores (0-4) was performed on 127 cases. Subsequent analysis indicated that a more informative diagnostic segregation could be achieved with a biphasic grading system (>50% staining, positive; 50% or less, negative). Lower intestinal tumors were CK7- and usually CK20+, while upper gastrointestinal tumors, including those of pancreatobiliary origin, were mostly CK7+ and CK20-. Serous papillary ovarian tumors were all CK7+ and CK20-. Mucinous ovarian carcinomas were all CK7+ and slightly more often CK20-, whereas the small number of ovarian borderline mucinous tumors studied were the most problematic, with no clear pattern. Multiple different tumor types from all nonovarian gynecologic sites were fairly consistently CK7+ and almost always CK20-. Differential CK staining of mucinous tumors of the female genital tract using CK7 and CK20 is useful for predicting the site of origin, provided samples are adequate in size. The most specific usefulness is the identification of lower gastrointestinal vs "other" neoplasms.


Biosynthesis of Polyunsaturated Fatty Acids in Sea Urchins: Molecular and Functional Characterisation of Three Fatty Acyl Desaturases from Paracentrotus lividus (Lamark 1816).
Sea urchins are broadly recognised as a delicacy and their quality as food for humans is highly influenced by their diet. Lipids in general and the long-chain polyunsaturated fatty acids (LC-PUFA) in particular, are essential nutrients that determine not only the nutritional value of sea urchins but also guarantee normal growth and reproduction in captivity. The contribution of endogenous production (biosynthesis) of LC-PUFA in sea urchins remained unknown. Using Paracentrotus lividus as our model species, we aimed to characterise both molecularly and functionally the repertoire of fatty acyl desaturases (Fads), key enzymes in the biosynthesis of LC-PUFA, in sea urchins. Three Fads, namely FadsA, FadsC1 and FadsC2, were characterised. The phylogenetic analyses suggested that the repertoire of Fads within the Echinodermata phylum varies among classes. On one hand, orthologues of the P. lividus FadsA were found in other echinoderm classes including starfishes, brittle stars and sea cucumbers, thus suggesting that this desaturase is virtually present in all echinoderms. Contrarily, the FadsC appears to be sea urchin-specific desaturase. Finally, a further desaturase termed as FadsB exists in starfishes, brittle stars and sea cucumbers, but appears to be missing in sea urchins. The functional characterisation of the P. lividus Fads confirmed that the FadsA was a Δ5 desaturase with activity towards saturated and polyunsaturated fatty acids (FA). Moreover, our experiments confirmed that FadsA plays a role in the biosynthesis of non-methylene interrupted FA, a group of compounds typically found in marine invertebrates. On the other hand, both FadsC desaturases from P. lividus showed Δ8 activity. The present results demonstrate that P. lividus possesses desaturases that account for all the desaturation reactions required to biosynthesis the physiological essential eicosapentaenoic and arachidonic acids through the so-called "Δ8 pathway".


Exsanguinating hemorrhage following gastric erosion after laparoscopic adjustable gastric banding.
Laparoscopic adjustable gastric banding (LAGB) has become a common bariatric operation, because of its safety, laparoscopic friendliness, acceptable weight loss and absence of long-term adverse nutritional sequelae. Gastric erosion is one of the troublesome complications of gastric banding. The etiology and presentation of erosion remain obscure. We present a patient who complained of persistent pain 6 months after gastric banding. Endoscopy revealed the band to be normally situated, which was also confirmed on upper GI imaging. Despite this, the patient subsequently presented with massive GI hemorrhage and circulatory collapse due to erosion, which necessitated emergency laparotomy with retrieval of the band from within the gastric lumen. This case highlights the possible urgent presentation of erosion after gastric banding, which was hitherto considered to be a more insidious complication. A high index of clinical suspicion remains the mainstay of diagnosis.


Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice.
Although cancer tends to affect the elderly, most preclinical studies are carried out in young subjects. In this study, we developed a melanoma-specific cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age-specific tumor-associated immune dysfunction. Both young and aged CD4(+)CD25(hi) regulatory T cells (Treg) exhibited equivalent in vitro T-cell suppression and tumor-associated augmentation in numbers. However, denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved tumor-specific immunity and reduced tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSCs in young and aged mice following MC-38 tumor challenge, although effects were greater in aged mice. Anti-Gr-1 boosted DT effects in young but not aged mice. Aged antitumor immune effector cells are therefore competent to combat tumor when underlying tumor-associated immune dysfunction is appropriately mitigated, but this dysfunction varies with tumor, thus also varying responses to immunotherapy. By tailoring immunotherapy to account for age-related tumor-associated immune dysfunctions, cancer immunotherapy for aged patients with specific tumors can be remarkably improved.


Laws Restricting Access to Abortion Services and Infant Mortality Risk in the United States.
Since the US Supreme Court's 1973 Roe v. Wade decision legalizing abortion, states have enacted laws restricting access to abortion services. Previous studies suggest that restricting access to abortion is a risk factor for adverse maternal and infant health. The objective of this investigation is to study the relationship between the type and the number of state-level restrictive abortion laws and infant mortality risk. We used data on 11,972,629 infants and mothers from the US Cohort Linked Birth/Infant Death Data Files 2008-2010. State-level abortion laws included Medicaid funding restrictions, mandatory parental involvement, mandatory counseling, mandatory waiting period, and two-visit laws. Multilevel logistic regression was used to determine whether type or number of state-level restrictive abortion laws during year of birth were associated with odds of infant mortality. Compared to infants living in states with no restrictive laws, infants living in states with one or two restrictive laws (adjusted odds ratio (AOR) = 1.08; 95% confidence interval [CI] = 0.99-1.18) and those living in states with 3 to 5 restrictive laws (AOR = 1.10; 95% CI = 1.01-1.20) were more likely to die. Separate analyses examining the relationship between parental involvement laws and infant mortality risk, stratified by maternal age, indicated that significant associations were observed among mothers aged ≤19 years (AOR = 1.09, 95% CI = 1.00-1.19), and 20 to 25 years (AOR = 1.10, 95% CI = 1.03-1.17). No significant association was observed among infants born to older mothers. Restricting access to abortion services may increase the risk for infant mortality.


WNT5A-mediated β-catenin-independent signalling is a novel regulator of cancer cell metabolism.
WNT5A has been identified as an important ligand in the malignant progression of a number of tumours. Although WNT5A signalling is often altered in cancer, the ligand's role as either a tumour suppressor or oncogene varies between tumour types and is a contemporary issue for investigators of β-catenin-independent WNT signalling in oncology. Here, we report that one of the initial effects of active WNT5A signalling in malignant melanoma cells is an alteration in cellular energy metabolism and specifically an increase in aerobic glycolysis. This was found to be at least in part due to an increase in active Akt signalling and lactate dehydrogenase (LDH) activity. The clinical relevance of these findings was strengthened by a strong correlation (P < 0.001) between the expression of WNT5A and LDH isoform V in a cohort of melanocytic neoplasms. We also found effects of WNT5A on energy metabolism in breast cancer cells, but rather than promoting aerobic glycolysis as it does in melanoma, WNT5A signalling increased oxidative phosphorylation rates in breast cancer cells. These findings support a new role for WNT5A in the metabolic reprogramming of cancer cells that is a context- dependent event.


Happy People Have Children: Choice and Self-Selection into Parenthood.
There is mixed evidence in the existing literature on whether children are associated with greater subjective well-being, with the correlation depending on which countries and populations are considered. We here provide a systematic analysis of this question based on three different datasets: two cross-national and one national panel. We show that the association between children and subjective well-being is positive only in developed countries, and for those who become parents after the age of 30 and who have higher income. We also provide evidence of a positive selection into parenthood, whereby happier individuals are more likely to have children.


Arsenic in private drinking water wells: an assessment of jurisdictional regulations and guidelines for risk remediation in North America.
Arsenic is a known carcinogen found globally in groundwater supplies due to natural geological occurrence. Levels exceeding the internationally recognized safe drinking water standard of 10 μg/L have been found in private drinking water supplies in many parts of Canada and the United States. Emerging epidemiological evidence confirms groundwater arsenic to be a significant health concern, even at the low to moderate levels typically found in this region. These findings, coupled with survey data reporting limited public adherence to testing and treatment guidelines, have prompted calls for improved protective measures for private well users. The purpose of this review is to assess current jurisdictional provisions for private well water protection in areas where arsenic is known to naturally occur in groundwater at elevated levels. Significant limitations in risk management approaches are identified, including inconsistent and uncoordinated risk communication approaches, lack of support mechanisms for routine water testing and limited government resources to check that testing and treatment guidelines are followed. Key action areas are discussed that can help to build regulatory, community and individual capacity for improved protection of private well water supplies and enhancement of public health.


Individual Differences in Good Manners Rather Than Compassion Predict Fair Allocations of Wealth in the Dictator Game.
One of the most common tools for studying pro-sociality is the dictator game, in which allocations to one's partner are often described in terms of altruism. However, the motivations driving these allocations may represent either emotional concern for others (compassion), adherence to social norms regarding fairness (politeness), or both. In this article, we apply personality psychology to the study of behavior in the dictator game, in which we examine the discriminant validity of distinct pro-social constructs from the Big Five and HEXACO models in relation to allocations of wealth. Across four studies (Study 1: N = 192; Study 2: N = 212; Study 3: N = 304; Study 4: N = 90) utilizing both hypothetical and incentivized designs, we found that the politeness-but not compassion-aspect of Big Five Agreeableness, as well as HEXACO Honesty-Humility, uniquely predicted dictator allocations within their respective personality models. These findings contribute to a growing literature indicating that the standard dictator game measures "good manners" or adherence to norms concerning fairness, rather than pure emotional concern or compassionate motives, and have important implications for how this paradigm is used and interpreted in psychological research.


Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells.
Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 μg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces.


Food and mental health: relationship between food and perceived stress and depressive symptoms among university students in the United Kingdom.
The current study assessed, by university and sex, the association between nutritional behaviour (twelve independent variables), and stress and depressive symptoms (dependent variables) in a sample from three UK countries. A cross-sectional survey was undertaken among undergraduates enrolled across seven universities in England, Wales and Northern Ireland (N = 3,706). Self-administered questionnaires included a 12-item food frequency questionnaire, Cohen's Perceived Stress Scale and modified Beck Depression Inventory. Sex and university comparisons were undertaken. Univariable and multivariable regression analyses were computed for each of the two outcomes--perceived stress and depressive symptoms. The frequencies of consuming of the various food groups differed by university and sex, as did depressive symptoms and perceived stress. Multivariable regression analyses indicated that consuming 'unhealthy' foods (e.g. sweets, cookies, snacks, fast food) was significantly positively associated with perceived stress (females only) and depressive symptoms (both males and females). Conversely, consuming 'healthy' foods (e.g. fresh fruits, salads, cooked vegetables) was significantly negatively associated with perceived stress and depressive symptoms scores for both sexes. There was significant negative association between consuming fish/sea food and depressive symptoms among males only. For males and for females, consuming lemonade/soft drinks, meat/sausage products, dairy/dairy products, and cereal/cereal products were not associated with either perceived stress or depressive symptoms. The associations between consuming 'unhealthy' foods and higher depressive symptoms and perceived stress among male and female students as well as the associations between consuming 'healthy' foods and lower depressive symptoms and perceived stress among male and female students in three UK countries suggest that interventions to reduce depressive symptoms and stress among students could also result in the consumption of healthier foods and/or vice versa.


The Bethesda System. A proposal for reporting abnormal cervical smears based on the reproducibility of cytopathologic diagnoses.
In the Bethesda System, noninvasive squamous abnormalities are classified as atypical squamous cells of undetermined significance (ASQUS), low-grade squamous intraepithelial lesions, and high-grade squamous intraepithelial lesions. The Bethesda System eliminates two diagnostic distinctions that are made in the dysplasia/carcinoma in situ and cervical intraepithelial neoplasia (CIN) classifications, CIN1 vs koilocytotic atypia and CIN2 vs CIN3, and maintains three others, negative vs ASQUS, ASQUS vs koilocytotic atypia, and CIN1 vs CIN2. To determine whether the diagnostic distinctions preserved in the Bethesda System are made more consistently than those eliminated, we analyzed the interobserver reproducibility of two cytopathologists in classifying 257 smears. The findings indicate that the distinctions retained in the Bethesda System are more reproducible than those eliminated. Specifically, cases classified as koilocytotic atypia were distinguished from CIN1 no more reproducibly than predicted by chance, whereas CIN2 and CIN3 were distinguished as consistently as any other pair of diagnoses examined. In 13 cases in which there was interobserver discordance, one reviewer classified the smear as ASQUS and the other reviewer diagnosed CIN2 or CIN3. The findings in this study suggest that smears showing koilocytotic atypia and/or CIN1 may be reported as low-grade squamous intraepithelial lesions without further specification. In contrast, smears showing high-grade squamous intraepithelial lesions may be further classified as CIN2 or CIN3 in accordance with the Bethesda guidelines. Since the diagnosis of ASQUS is applied to smears showing a wide spectrum of changes, management of patients with the diagnosis of ASQUS will be facilitated by providing an explanatory note and/or recommendations when appropriate.


Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.


Happy aged people are all alike, while every unhappy aged person is unhappy in its own way.
Aging of the world's population represents one of the most remarkable success stories of medicine and of humankind, but it is also a source of various challenges. The aim of the collaborative cross-cultural European study of adult well being (ESAW) is to frame the concept of aging successfully within a causal model that embraces physical health and functional status, cognitive efficacy, material security, social support resources, and life activity. Within the framework of this project, we show here that the degree of heterogeneity among people who view aging in a positive light is significantly lower than the degree of heterogeneity of those who hold a negative perception of aging. We base this conclusion on our analysis of a survey involving 12,478 people aged 50 to 90 from six West European countries. We treat the survey database as a bipartite network in which individual respondents are linked to the actual answers they provide. Taking this perspective allows us to construct a projected network of respondents in which each link indicates a statistically validated similarity of answers profile between the connected respondents, and to identify clusters of individuals independently of demographics. We show that mental and physical well-being are key factors determining a positive perception of aging. We further observe that psychological aspects, like self-esteem and resilience, and the nationality of respondents are relevant aspects to discriminate among participants who indicate positive perception of aging.


Coexistence of sarcoidosis and Hashimoto thyroiditis.
Sarcoidosis is a chronic, inflammatory disease with unknown cause characterized by non-caseating granuloma formations. It can present with bilateral hilar lymphadenopathy, skin lesions, eye involvement and locomotor system findings. Hashimoto thyroiditis is an organ-specific autoimmune disease characterized by increased autoantibody synthesis. Sarcoidosis can involve different endocrine glands. Thyroid gland involvement may lead to increased thyroid function disorders and autoantibodies. Herein, we report an 80-year-old female patient with sarcoidosis and Hashimoto coexistence.


Quantifying seasonal population fluxes driving rubella transmission dynamics using mobile phone data.
Changing patterns of human aggregation are thought to drive annual and multiannual outbreaks of infectious diseases, but the paucity of data about travel behavior and population flux over time has made this idea difficult to test quantitatively. Current measures of human mobility, especially in low-income settings, are often static, relying on approximate travel times, road networks, or cross-sectional surveys. Mobile phone data provide a unique source of information about human travel, but the power of these data to describe epidemiologically relevant changes in population density remains unclear. Here we quantify seasonal travel patterns using mobile phone data from nearly 15 million anonymous subscribers in Kenya. Using a rich data source of rubella incidence, we show that patterns of population travel (fluxes) inferred from mobile phone data are predictive of disease transmission and improve significantly on standard school term time and weather covariates. Further, combining seasonal and spatial data on travel from mobile phone data allows us to characterize seasonal fluctuations in risk across Kenya and produce dynamic importation risk maps for rubella. Mobile phone data therefore offer a valuable previously unidentified source of data for measuring key drivers of seasonal epidemics.