Effects of pollution-induced changes in oxygen conditions scaling up from individuals to ecosystems in a tropical river network.
Anthropogenic inputs of nutrients and organic matter are common in tropical lowland rivers while little is known about the pollution-induced changes in oxygen availability and respiratory performance of ectotherms in these high temperature systems. We investigated the effects of agriculture and urban land-use on river water oxygen levels (diel measurements), decomposition rates (Wettex) and macroinvertebrate assemblages (field studies), as well as the oxy-regulatory capacity of eight riverine macroinvertebrate taxa (laboratory study) from a tropical lowland river network in Myanmar. The highest decomposition rates (0.1-5.5 mg Wettex degree day-1) and oxygen stress (≤91% saturation deficits) were found in reaches draining degraded catchments with elevated concentrations of nutrients. All individual macroinvertebrate taxa investigated were to some extent able to regulate their respiration when placed under oxygen stress in the laboratory (regulation value of 0.74-0.89). The oxy-regulation capacity of macroinvertebrate assemblages in the river network were, as predicted, inversely related to diel oxygen stress (maximum deficit; lm, R2 = 0.69), where taxonomic richness and pollution sensitivity (ASPT metric) also declined sharply (lm, R2 ≥ 0.79). Our study shows that eutrophication and organic pollution induce oxygen deficits in tropical rivers but stimulate decomposition rates, which may further deplete oxygen levels. Furthermore, macroinvertebrate oxy-regulatory capacity predicts assemblage composition along gradients in oxygen stress at the ecosystem level. Our findings suggest that tropical lowland river systems could be highly sensitive to pollution by nutrients and organic matter leading to substantial impacts on ectotherm community composition and ecosystem functioning.


Medical students' relative immunity, or lack thereof, against COVID-19 emotional distress and psychological challenges; a descriptive study from Jordan.
Background: Emotional distress is a major impact of COVID-19 among not only the general public but also healthcare workers including medical students. This study aimed at describing self-reported changes in emotional reactions associated with COVID-19 among medical students in Jordan and to assessing the potential effect of social media utilization on emotional distress among this group. Methods: A cross-sectional design was utilized to collect data early on during the outbreak in Jordan. All medical students in Jordan were eligible to complete an online questionnaire assessing self-reported emotional reactions to COVID-19 that covered four main domains: negative emotion (anxiety, worry, depression, panic, loneliness, and nervousness), positive emotion (happiness, joy, and excitement), sleep disorders (insomnia, shallow sleep, nightmares, and insufficient sleep), and aggression (verbal argument and physical fighting). The frequency of social media utilization as a main source of COVID-19 information was also assessed. Results: 59.9% of participants were females, 64.9% were enrolled at the two major medical schools in Jordan, and 59.6% were in the pre-clinical stage (years). A significant proportion of participants self-reported increased negative emotional levels of anxiety (49.2%), worry (72.4%), depression (23.1%), panic (22.6%), and nervousness (38.2%) and decreased positive emotional levels of happiness (44.8%), joy (47.3%), and feelings of excitement (45.1%). Self-reported sleep disorders were not as common (less than 15% for any of the four items), while arguing with others was at 26.7%. Significant differences by gender and academic year were detected. Almost half of participants reported using social media as a main source of COVID-19 information "most/all-the-times" with a significant effect of such on reducing emotional distress. Conclusion: The results suggest a potential effect of COVID-19 on the emotional distress of medical students. Addressing and mitigating such effects is crucial. The potential buffering effect of social media should be further investigated.


From Denmark to Deep River: integrating care in small and rural communities in Ontario.
Integrating community-based health and social care for older persons is said to help individuals maintain high levels of independence, well-being and quality of life and contribute to health systems sustainability by moderating the demand for costly emergency services and inappropriate hospital care. Rural settings, however, pose challenges distinct from those in urban areas. Using North Renfrew Long-Term Care Services as a case study, this paper discusses the principles and practices of a small, rural community service agency located in Renfrew County, Ontario, that provides to its scattered populations a range of services across the care continuum. Services include community support programs, supportive housing and long-term care beds as well as an innovative 24-Hour Flexible In-Home Support Pilot program adapted from the ground breaking "night patrol" system in Denmark.


[Successful Boston keratoprosthesis in a patient with Lyell's syndrome].
We present the case of a woman readmitted to our service to receive treatment for severe ophthalmic manifestations due to Lyell's syndrome. This intense affectation of the ocular surface along with limbal stem cell deficiency are grounds for treatment with Boston type 1 keratoprosthesis, which provided a stable and very satisfactory functional result. As noted in this case report, the Boston Type 1 keratoprosthesis seems to be a viable option after multiple failed corneal grafts or in situations with a poor prognosis for primary penetrating keratoplasty because of limbal stem cell deficiency, such as Lyell's syndrome.


Regulation of rat renal alpha 2 B-adrenergic receptors by potassium depletion.
Potassium depletion and alpha 2-adrenergic receptor (alpha 2-AR) agonists produce similar physiological effects on renal function. Both stimuli increase Na-H exchange in proximal tubule cells, inhibit water transport in collecting tubule cells, and alter blood pressure regulation. The purpose of this study was to determine whether potassium depletion and renal alpha 2-AR subtype expression were linked. Kidney membrane proteins and RNA were harvested from anesthetized rats fed a potassium-deficient diet for 4-20 days (LK 4 to LK 20). Using a selective alpha 2-AR antagonist, [3H]MK-912, we observed that potassium depletion led to a dramatic increase in maximum binding (270% of control) without a change in dissociation constant. Competitive binding studies in LK 14 kidney membranes employing chlorpromazine, prazosin, and oxymetazoline suggested that the increase in alpha 2-ARs in response to potassium depletion was due primarily to an increase in the B subtype of alpha 2-AR. Northern blot analysis demonstrated that renal alpha 2B-AR mRNA levels increased (190% of control) after 4 or 14 days on a potassium-deficient diet. In contrast, there was no difference in steady-state alpha 2A-receptor protein levels by Western blot analysis. We conclude that potassium depletion selectively increases the expression of the B subtype of alpha 2-AR with no detectable effect on alpha 2A-AR expression.


Glyphosate toxicosis in domestic animals: a survey from the data of the Centre National d'Informations Toxicologiques Veterinaires (CNITV).
A retrospective study was conducted of 482 glyphosate calls recorded at the Centre National d'Informations Toxicologiques Veterinaires (CNITV) of France between 1991 and 1994. Most of the calls came from veterinary practitioners (83.8%) and were related to emergencies. In the majority of calls, the CNITV did not assess clinical observations as certain or highly probable glyphosate poisoning. Only 31 cases were assessed as certain or highly probable and were linked with direct ingestion of glyphosate concentrates or sprays in 25 dogs. The symptoms were most frequently described as vomiting, hypersalivation and diarrhea; prostration and paresis were not common. Symptomatic treatment resulted in rapid recovery without sequelae.


[Peripheral nerve entrapment syndrome in musicians].
This survey article discusses entrapment syndromes of nerves in instrumentalists. There is no specific susceptibility of musicians to peripheral nerve lesions. They are, however, very sensitive to symptoms caused by entrapment neuropathies. In pianists the right arm is more often affected and in violinists the left. Some typical syndromes are described such as the thoracic outlet syndrome, carpal tunnel syndrome, anterior and posterior interosseus syndrome, as well as ulnar neuropathies at elbow and wrist. The symptoms of peripheral nerve entrapment can interfere with playing the instrument in such a way that musicians have to give up their career. The results of conservative and surgical treatment are, however, favourable.


Effect of Psychoeducational Intervention on Donepezil Retention Rate and Analysis of Reasons for the Discontinuation in Patients with Alzheimer's Dementia: A Randomized Study.
Medication discontinuation for patients with Alzheimer's dementia (AD) influences treatment efficacy. This study aimed to evaluate the effect of psychoeducational intervention (PI) on donepezil retention rates and identify the factors associated with donepezil continuation in patients with AD. One hundred and seventeen patients with AD were randomly allocated to the PI (n = 58) or standard care (SC; n = 59) groups. All patients were prescribed donepezil for 48 weeks. Primary endpoints were the 48-week donepezil retention rate and the reasons for donepezil discontinuation in the PI and SC groups. The secondary endpoint was the predictive factors, among the baseline clinical variables, for donepezil continuation in all patients. The donepezil retention rate was 62.1% (36/58) in the PI group and 66.1% (39/59) in the SC group. The most common reason for discontinuation in both groups was adverse events (PI, 12.1%; SC, 10.2%). Logistic regression analysis revealed that the results of the pentagon copying test in the Mini-Mental State Examination administered at baseline was a significant predictor of donepezil continuation for all patients in both the groups (odds ratio: 0.359; 95% confidence interval: 0.154-0.839). There was no significant difference between the PI and SC groups concerning donepezil retention rate in patients with AD. Our results demonstrate that the pentagon copying test can significantly predict donepezil continuation in patients with AD, indicating that impaired visuospatial and executive functions may reflect medication discontinuation. UMIN-CTR:UMIN000012617.


LOCAL KERNEL CANONICAL CORRELATION ANALYSIS WITH APPLICATION TO VIRTUAL DRUG SCREENING.
Drug discovery is the process of identifying compounds which have potentially meaningful biological activity. A major challenge that arises is that the number of compounds to search over can be quite large, sometimes numbering in the millions, making experimental testing intractable. For this reason computational methods are employed to filter out those compounds which do not exhibit strong biological activity. This filtering step, also called virtual screening reduces the search space, allowing for the remaining compounds to be experimentally tested.In this paper we propose several novel approaches to the problem of virtual screening based on Canonical Correlation Analysis (CCA) and on a kernel-based extension. Spectral learning ideas motivate our proposed new method called Indefinite Kernel CCA (IKCCA). We show the strong performance of this approach both for a toy problem as well as using real world data with dramatic improvements in predictive accuracy of virtual screening over an existing methodology.


Genetic cause of immune dysregulation - one gene or two?
Some autoimmune disorders are monogenetic diseases; however, clinical manifestations among individuals vary, despite the presence of identical mutations in the disease-causing gene. In this issue of the JCI, Massaad and colleagues characterized a seemingly monogenic autoimmune disorder in a family that was linked to homozygous loss-of-function mutations in the gene encoding the endonuclease Nei endonuclease VIII-like 3 (NEIL3), which has not been previously associated with autoimmunity. The identification of an unrelated healthy individual with the same homozygous mutation spurred more in-depth analysis of the data and revealed the presence of a second mutation in a known autoimmune-associated gene. Animals lacking Neil3 had no overt phenotype, but were predisposed to autoantibody production and nephritis following exposure to the TLR3 ligand poly(I:C). Together, these results support further evaluation of the drivers of autoimmunity in supposedly monogenic disorders.


Detection of differentially expressed genes in an isogenic breast metastasis model using RNA arbitrarily primed-polymerase chain reaction coupled with array hybridization (RAP-array).
To facilitate the study of the mechanisms of breast cancer metastasis we have previously characterized a pair of breast tumor cell lines that originate from the same breast tumor cell line MDA-MB-435, but which have diametrically opposite metastatic capabilities. These cell lines constitute a stable and accessible experimental system for the identification of metastasis-related genes and for the study of their role in the process of metastasis. In this study, we used a combination of RNA arbitrarily primed-polymerase chain reaction (RAP-PCR) fingerprinting and cDNA arrays (here termed "RAP-array") to identify genes differentially expressed with respect to metastatic phenotype. RAP-PCR was used to generate radioactive probes of reduced complexity for hybridization to nylon membranes containing 588 cDNAs of known identity. Single RAP-PCR fingerprint probes hybridized from 61 (10.4%) to 116 (19.7%) of the filter array targets, with a signal detection overlap of approximately 21%. A total of 344 (57%) of the 588 target genes were detected by five single RAP-PCR fingerprints. The advantage of using reduced complexity probes was highlighted by the fact that the combination of RAP probes before hybridization compromised the overall detection rate by up to 40%. Sequential application of RAP-PCR probes allowed the screening of a greater, and an alternative fraction of the transcript population than was achieved with a radiolabeled total cDNA probe. Verification by quantitative reverse transcriptase-PCR confirmed significantly increased expression of keratin 9 (>100-fold) in nonmetastatic breast tumor cells and of CD70 (fivefold) in metastatic cells. The differential expression of keratin 9 and CD70 was maintained between cells grown as primary xenografts in athymic mice. The RAP-array method enabled the detection of genes not revealed using other screening methods and that are candidates for further investigation in the context of metastatic phenotype.


Effects of a supplementation of n-3 polyunsaturated fatty acids with or without fish gelatin on gene expression in peripheral blood mononuclear cells in obese, insulin-resistant subjects.
To investigate gene expression changes in peripheral blood mononuclear cells (PBMCs) following an n-3 polyunsaturated fatty acid (PUFA) and n-3 PUFA plus fish gelatin (+FG) supplementation. A transcriptome comparison of 8-week supplementation with n-3 PUFA and n-3 PUFA+FG was carried out in PBMCs of 16 obese insulin-resistant subjects. Erythrocyte n-3 PUFA concentration increased and plasma triglycerides decreased significantly without altering inflammatory parameters after both supplementations. n-3 PUFA supplementation changed the expression of 805 genes, whereas n-3 PUFA+FG supplementation altered the expression of 184 genes. Three genes were commonly changed: fatty acid desaturase 1, free fatty acid receptor 3, and ectodysplasin. Pathway analyses indicate changes in gene expression via the nuclear receptor peroxisome proliferator-activated receptor α pathway after both supplementations. Further, the extent of modifications in the expression of genes implicated in the inflammatory pathways - the oxidative stress response mediated by nuclear factor (erythroid-derived 2)-like 2, nuclear transcription factor κB, oxidative stress, and hypoxia-inducible factor signaling - was different after each supplementation. Although n-3 PUFA and n-3 PUFA+FG supplementations have a distinct impact on gene expression levels, the consequences on biochemical parameters and metabolic pathways were comparable after both supplementations.


Association Between Ibuprofen Use and Severity of Surgically Managed Posttonsillectomy Hemorrhage.
Ibuprofen used in postoperative management of pain after tonsillectomy has not been shown to increase the overall risk for posttonsillectomy hemorrhage (PTH). The severity of bleeding is difficult to quantify but may be a more important outcome to measure. To evaluate the association between ibuprofen use and severity of PTH using transfusion events as a marker of severity. This retrospective cohort study identified 8868 patients who underwent tonsillectomy from January 20, 2011, through June 30, 2014, at the tertiary academic Children's Hospital of Philadelphia. Of these patients, 6710 met the inclusion criteria. Data were collected using electronic database acquisition and query. Multivariate analysis was performed to identify independent prognostic factors for PTH and receipt of transfusion. Of the 6710 patients who met criteria for analysis (3454 male [51.5%] and 3256 female [48.5%]; median age, 5.4 years [interquartile range, 3.7-8.2 years]), 222 (3.3%) presented with PTH that required surgical control (sPTH). A total of 15 of the 8868 patients required transfusion for an overall risk for transfusion after tonsillectomy of 0.2%. Fifteen of 222 patients undergoing sPTH (6.8%) received transfusions. No significant independent increased risk for sPTH was associated with use of ibuprofen (adjusted odds ratio [OR], 0.90; 95% CI, 0.68-1.19). A significant independent association was found in the risk for sPTH in patients 12 years or older (adjusted OR, 2.74; 95% CI, 1.99-3.76) and in patients with a history of recurrent tonsillitis (adjusted OR, 1.52; 95% CI, 1.12-2.06). When using transfusion rates as a surrogate for severity of sPTH, transfusion increased by more than 3-fold among ibuprofen users compared with nonusers (adjusted OR, 3.16; 95% CI, 1.01-9.91), and the upper limit of the 95% CI suggests the difference could be nearly 10 times greater. The risk for sPTH is not increased with use of postoperative ibuprofen but is increased in patients 12 years or older and patients undergoing tonsillectomy with a history of recurrent tonsillitis. Hemorrhage severity is significantly increased with ibuprofen use when using transfusion rate as a surrogate marker for severity.


Evaluating imidacloprid exposure among grape field male workers using biological and environmental assessment tools: An exploratory study.
Imidacloprid is a neonicotinoid insecticide commonly injected through agricultural drip irrigation systems to reduce the population of vine mealybugs (P. ficus) in grape farms. There is a growing concern of potential human health effects of imidacloprid, however, there is limited information on the exposure to imidacloprid in farm workers. Imidacloprid exposure was evaluated in this exploratory study of 20 male migrant grape workers sampled five days after imidacloprid was injected in the irrigation system during winter and summer seasons. We administered a questionnaire on work activities, exposure characteristics, and socio-demographics and collected personal air, hand wipe, and spot urine samples. Heat exposure was also assessed. Spearman's correlation coefficients and Wilcoxon rank-sum tests were utilized to evaluate associations and differences in imidacloprid exposures with socio-demographic, occupational, and environmental characteristics. All participants had less than a high school education and about half identified an Indigenous language as their primary language. Although not detected in air samples, imidacloprid was detected in 85% of the hand wipes (median: 0.26: 0.41 μg/wipe, range: 0.05-7.10 μg/wipe). The majority of participants (75%) had detectable urinary concentrations of imidacloprid (median: 0.11 μg/g creatinine, range: 0.05-3.90 μg/g of creatinine), and nearly all (95%) had detectable urinary concentrations of 5-hydroxy-Imidacloprid (5-OH-IMI), a metabolite of imidacloprid (median: 1.28 μg/g creatinine, range: 0.20-27.89 μg/g creatinine). There was a significant correlation (p < 0.001) between imidacloprid in hand wipes and urinary imidacloprid and 5-OH-IMI (rs: 0.67 for imidacloprid and 0.80 for 5-OH-IMI). Hand temperature was significantly and positively correlated (p < 0.05) with imidacloprid concentration on hand wipes (rs: 0.70), and urinary biomarkers (rs: 0.68 for imidacloprid, and 0.60 for 5-OH-IMI) suggesting that working in high temperatures may influence the exposure and absorption of imidacloprid. Thus, research on farm workers would benefit in the future by evaluating imidacloprid exposure in relation to heat stress and other occupational factors.


Photocleavable core cross-linked polymeric micelles of polypept(o)ides and ruthenium(II) complexes.
Core cross-linking of polymeric micelles has been demonstrated to contribute to enhanced stability that can improve the therapeutic efficacy. Photochemistry has the potential to provide spatial resolution and on-demand drug release. In this study, light-sensitive polypyridyl-ruthenium(II) complexes were combined with polypept(o)ides for photocleavable core cross-linked polymeric micelles. Block copolymers of polysarcosine-block-poly(glutamic acid) were synthesized by ring-opening N-carboxyanhydride polymerization and modified with aromatic nitrile-groups on the glutamic acid side chain. The modified copolymers self-assembled into micelles and were cross-linked by cis-diaquabis(2,2'-bipyridine)-ruthenium(II) ([Ru(bpy)2(H2O)2]2+) or cis-diaquabis(2,2'-biquinoline)-ruthenium(II) ([Ru(biq)2(H2O)2]2+). Depending on the flexibility and hydrophobicity of the nitrile linker, either small spherical structures (Dh 45 nm, PDI 0.11) or worm-like micelles were obtained. The cross-linking reaction did not affect the overall size distribution but induced a change in the metal-to-ligand charge transfer peak from 482 to 420 nm and 592 to 548 nm. The cross-linked micelles displayed colloidal stability after incubation with human blood plasma and during gel permeation chromatography in hexafluoroisopropanol. Light-induced cleavage of [Ru(bpy)2(H2O)2]2+ was accomplished within 300 s, while [Ru(biq)2(H2O)2]2+ could not be completely released. Analysis in HuH-7 cells revealed increased cytotoxicity via micellar delivery of [Ru(bpy)2(H2O)2]2+ but mostly irradiation damage for [Ru(biq)2(H2O)2]2+. Further evaluation in ovo confirmed stable circulation pointing towards the future development of quick-release complexes.


Assessing the relationship between physical activity and the gut microbiome in a large, population-based sample of Wisconsin adults.
The gut microbiome is an important factor in human health and disease. While preliminary studies have found some evidence that physical activity is associated with gut microbiome richness, diversity, and composition, this relationship is not fully understood and has not been previously characterized in a large, population-based cohort. In this study, we estimated the association between several measures of physical activity and the gut microbiota in a cohort of 720 Wisconsin residents. Our sample had a mean age of 55 years (range: 18, 94), was 42% male, and 83% of participants self-identified as White. Gut microbial composition was assessed using gene sequencing of the V3-V4 region of 16S rRNA extracted from stool. We found that an increase of one standard deviation in weekly minutes spent in active transportation was associated with an increase in alpha diversity, particularly in Chao1's richness (7.57, 95% CI: 2.55, 12.59) and Shannon's diversity (0.04, 95% CI: 0.0008, 0.09). We identified interactions in the association between Inverse Simpson's diversity and physical activity, wherein active transportation for individuals living in a rural environment was associated with additional increases in diversity (4.69, 95% CI: 1.64, 7.73). We also conducted several permutational ANOVAs (PERMANOVA) and negative binomial regression analyses to estimate the relationship between physical activity and microbiome composition. We found that being physically active and increased physical activity time were associated with increased abundance of bacteria in the family Erysipelotrichaceae. Active transportation was associated with increased abundance of bacteria in the genus Phascolarctobacterium, and decreased abundance of Clostridium. Minutes in active transportation was associated with a decreased abundance of the family Clostridiaceae.


Leishmania infecting man and wild animals in Saudi Arabia. 9. The black rat (Rattus rattus) a probable reservoir of visceral leishmaniasis in Gizan province, south-west Saudi Arabia.
Twenty-two black rats (Rattus rattus) were captured in houses where parasitologically confirmed cases of human visceral leishmaniasis had been recorded in Al-Arda Emara, Gizan province, south-west Saudi Arabia. Four of the rats were found to be infected with Leishmania; isoenzyme characterization showed that 3 were infected with L. donovani sensu lato zymodeme LON42 and the fourth with L. infantum zymodeme LON49. L. donovani s.l. LON42 has also been isolated from human visceral leishmaniasis patients living in this area, while dogs, but not humans, have been found to be infected with L. infantum LON49 in this part of Saudi Arabia.


Bayesian genomic models boost prediction accuracy for survival to Streptococcus agalactiae infection in Nile tilapia (Oreochromus nilioticus).
Streptococcosis is a major bacterial disease in Nile tilapia that is caused by Streptococcus agalactiae infection, and development of resistant strains of Nile tilapia represents a sustainable approach towards combating this disease. In this study, we performed a controlled disease trial on 120 full-sib families to (i) quantify and characterize the potential of genomic selection for survival to S. agalactiae infection in Nile tilapia, and (ii) identify the best genomic model and the optimal density of single nucleotide polymorphisms (SNPs) for this trait. In total, 40 fish per family (15 fish intraperitoneally injected and 25 fish as cohabitants) were used in the challenge test. Mortalities were recorded every 3 h for 35 days. After quality control, genotypes (50,690 SNPs) and phenotypes (0 for dead and 1 for alive) for 2472 cohabitant fish were available. Genetic parameters were obtained using various genomic selection models (genomic best linear unbiased prediction (GBLUP), BayesB, BayesC, BayesR and BayesS) and a traditional pedigree-based model (PBLUP). The pedigree-based analysis used a deep 17-generation pedigree. Prediction accuracy and bias were evaluated using five replicates of tenfold cross-validation. The genomic models were further analyzed using 10 subsets of SNPs at different densities to explore the effect of pruning and SNP density on predictive accuracy. Moderate estimates of heritabilities ranging from 0.15 ± 0.03 to 0.26 ± 0.05 were obtained with the different models. Compared to a pedigree-based model, GBLUP (using all the SNPs) increased prediction accuracy by 15.4%. Furthermore, use of the most appropriate Bayesian genomic selection model and SNP density increased the prediction accuracy up to 71%. The 40 to 50 SNPs with non-zero effects were consistent for all BayesB, BayesC and BayesS models with respect to marker id and/or marker locations. These results demonstrate the potential of genomic selection for survival to S. agalactiae infection in Nile tilapia. Compared to the PBLUP and GBLUP models, Bayesian genomic models were found to boost the prediction accuracy significantly.


Influence of HPV16 E6/7 on the expression of FGF2 and FGFR type B in cervical carcinogenesis.
This study investigates the influence of fibroblast growth factor receptor type B (FGFRb) and fibroblast growth factor on cervical carcinogenesis associated with HPV16 E6/7 infection, using primary cancer cells isolated from Taiwanese patients with cervical cancer. Functional interaction between FGFRb in Cx cells and HPV16 E6/7 transfected Cx cells (CxWJ cells) following treatment with FGF-7, according to cell growth, invasive ability, and tumor growth in SCID mice. Our results indicate that the downregulation of FGFRb gene expression in CxWJ cells partially represses proliferation and the invasive ability provided by FGF-7 stimulation. In SCID mice, the FGF2 and FGFR1 gene expression ascend in CxWJ tumor nodule. These data provide evidence of a functional interaction between HPV16 E6/7 in FGFRb and FGF2, suggesting that cooperative stimulation of HPV E6/7 in inactivated FGFRb and the upregulation of FGF2 may be necessary to completely overcome the oncogenic function associated with the progression of cervical carcinogenesis.


The effect of cobaltous chloride on liver haem metabolism in the rat. Evidence for inhibition of haem synthesis and for increased haem degradation.
After a single dose of cobaltous chloride there was a marked inhibition of liver 5-aminolaevulinate (5-ALA) synthetase (at 1 h) and this was followed in turn by a stimulation of haem oxygenase (at 3 h) and by a return of the synthetase activity to normal or above normal (at 17 h). Bile cannulation experiments were performed 1 and 17 h after administration of CoCl2. At 1 h there was a marked decrease in bile porphyrin content, no change in bile concentration of bilirubin, but a decrease in the conversion of [14C]-5-ALA to bilirubin and to liver haem. At 17 h, an the other hand, the bile excretion of both porphyrins and bilirubin was significantly greater than in controls and more radioactivity (from [14C]-5-ALA) appeared in the bile as bilirubin. It is concluded that the effects of cobalt on liver haem metabolism are complex and time-dependent. There is first inhibition of liver haem synthesis at two different steps of the pathway (synthesis of 5-ALA and conversion of 5-ALA to haem), with diversion of [14C]-5-ALA into a relatively stable liver pool different from haem; and at a later stage there is also an increase in the rate of liver haem degradation.


Independence of bacteria on phytoplankton? Insufficient support for Fouilland & Mostajir's (2010) suggested new concept.
In a recent review, Fouilland & Mostajir questioned the direct dependence of bacterioplankton on phytoplankton based on a dataset of total primary production (particulate plus dissolved) and bacterial carbon demand (bacterial production plus respiration) estimated rates. We point out two problems for this interpretation. Firstly, there is considerable uncertainty in the authors' application of conversion factors to raw data and modelled rates so that the shape of the scatterplots can be substantially altered. Secondly, the current conceptual view of dissolved organic carbon lability and its temporal and spatial variations still provides enough support for the accepted paradigm.


Quantitative assessment of altered rectal mucosal permeability due to rectally applied nonoxynol-9, biopsy, and simulated intercourse.
Microbicide toxicity may reduce the efficacy of topical preexposure prophylaxis for human immunodeficiency virus (HIV) transmission. Noninvasive quantitative measures of microbicide toxicity would usefully inform microbicide development. Ten subjects received 3 one-time interventions: 5 mL of Normosol-R fluid alone (negative control), 5 mL of 2% nonoxynol-9 (N-9) gel, and 5 mL of Normosol-R with coital simulation and sigmoidoscopic biopsy (CS + BX). Each dose of N-9 and Normosol-R contained 500 µCi of (99m)technetium-diethylene triamine pentaacetic acid. Plasma and urine radioactivity was assessed over 24 hours. The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was 12.0 times (95% confidence interval [CI], 6.8-21.0) and 8.4 times (95% CI, 5.2-13.5) the mean concentration after Normosol-R control receipt and CS + BX receipt, respectively; paired differences persisted for 24 hours. After N-9 dosing, the urine isotope level was 3.6 times (95% CI, 1.1-11.4) the level observed 8 hours after Normosol-R control receipt and 4.0 times (95% CI, 1.4-11.4) the level observed 4 hours after CS + BX receipt. Permeability after CS + BX receipt was greater than that after Normosol-R control receipt in 0-2-hour urine specimens only (mean permeability, 2.4; 95% CI, 1.0-5.8) but was not greater in blood. Plasma sampling after rectal radioisotope administration provided quantitative estimates of altered mucosal permeability after chemical and mechanical stresses. Permeability testing may provide a useful noninvasive adjunct to assess the mucosal effects of candidate microbicides. Clinical Trials Registration. NCT00389311.


Xeroradiography in the evaluation of acquired airway abnormalities in children.
Xeroradiography of the neck was performed on 36 children with suggested or known acquired tracheal abnormalities. The information obtained from the lateral projection xeroradiograph was superior in selected cases to the conventional soft tissue roentgenogram. In these cases, the information obtained justified the increased (12-fold) radiation exposure and obviated the need for positive contrast examination. This procedure should be considered in any case in which a fluoroscopic contrast examination is indicated.


Mass Transfer Characteristics of Haemofiltration Modules-Experiments and Modeling.
Reliable mathematical models are important tools for design/optimization of haemo-filtration modules. For a specific module, such a model requires knowledge of fluid- mechanical and mass transfer parameters, which have to be determined through experimental data representative of the usual countercurrent operation. Attempting to determine all these parameters, through measured/external flow-rates and pressures, combined with the inherent inaccuracies of pressure measurements, creates an ill-posed problem (as recently shown). The novel systematic methodology followed herein, demonstrated for Newtonian fluids, involves specially designed experiments, allowing first the independent reliable determination of fluid-mechanical parameters. In this paper, the method is further developed, to determine the complete mass transfer module-characteristics; i.e., the mass transfer problem is modelled/solved, employing the already fully-described flow field. Furthermore, the model is validated using new/detailed experimental data on concentration profiles of a typical solute (urea) in counter-current flow. A single intrinsic-parameter value (i.e., the unknown effective solute-diffusivity in the membrane) satisfactorily fits all data. Significant insights are also obtained regarding the relative contributions of convective and diffusive mass-transfer. This study completes the method for reliable module simulation in Newtonian-liquid flow and provides the basis for extension to plasma/blood haemofiltration, where account should be also taken of oncotic-pressure and membrane-fouling effects.


Subsequent Development of Epithelial Ovarian Cancer After Ovarian Surgery for Benign Ovarian Tumor: A Population-Based Cohort Study.
The goal of the current study is to determine the risk of subsequent development of epithelial ovarian cancer (EOC) in women after ovarian surgery for benign ovarian tumors. We conducted the nationwide population-based historic cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan. Eleven thousand six hundred twenty women who underwent ovarian surgery for ovarian benign diseases were analyzed. The collected data included age, types of ovarian surgery, medical history by Charlson comorbidity index (CCI), infertility (yes/no), pelvic inflammatory disease (PID) (yes/no), tubal ligation (yes/no), total/subtotal hysterectomy (TH/STH) (yes/no), and endometrioma (yes/no). We used the Kaplan-Meier method and the Log-rank test to evaluate the risk factors. Cox proportional hazard methods were used to evaluate risk factors for the subsequent development of EOC. Multivariate analysis using Cox stepwise forward regression was conducted for the covariate selected in univariate analysis. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using the Wald test. Subsequent EOC incidence rate (IR, incidence per 10,000 person-years) of women after ovarian surgery for benign ovarian tumors was 2.98. Separating into four groups based on different age, IR of EOC was 1.57 (<30 years), 4.71 (30-39 years), 3.59 (40-49 years) and 0.94 (≥50 years), respectively. Univariate and multivariate analyses identified only high level of CCI (≥2 or more) as an independent risk factor for subsequent development of EOC in women after ovarian surgery for benign ovarian tumors (HR 59.17, 95% CI 7.50-466.80 in women with CCI level of 2 and HR 190.68, 95% CI 24.33-2494.19, in women with CCI level ≥3, respectively). Our results, if confirmed, suggest that women with other comorbidities (CCI) should be well informed that they may have a higher risk of subsequent development of EOC when ovarian surgery is planned even though the final pathology showed a benign ovarian tumor.


Caloric restriction counteracts chemotherapy-induced inflammation and increases response to therapy in a triple negative breast cancer model.
Triple negative breast cancer (TNBC) is a heterogeneous disease that has no available targeted therapies. Previously, we have shown that caloric restriction (CR) can augment the effects of radiation therapy in a TNBC mouse model. To build upon this, we now present data regarding the combination of chemotherapy and CR in the same 4T1 model. Chemotherapy can induce inflammation that breeds resistance to therapy. We propose CR as a mechanism to decrease chemotherapy-induced inflammation and increase efficacy of therapy. 12-week old Balb/c mice were orthotopically injected with a syngeneic triple negative breast cancer cell line (4T1) and were treated in one of six cohorts: ad lib fed (AL), 30% reduction in calorie intake (CR), cisplatin or docetaxol alone or a combination CR+cisplatin/docetaxol. Mice in the cohorts receiving chemotherapy+CR had longer overall survival (12 ± 2 days) as compared to the AL group. These mice also demonstrated less lung metastases at the final time point of in vivo imaging. In addition, downregulation of the IGF-1R and IRS signaling pathways were noted most significantly in those mice receiving combination therapy. Lastly, serum from these mice demonstrated an increase in inflammatory cytokines TNF-α and IL-1β in response to chemotherapy alone. This increase was dampened by the addition of CR. Taken together, these data suggest that while chemotherapy is effective in TNBC, it can cause inflammation, which can be a driver of resistance to therapy. This chemotherapy-induced inflammation can be reversed with the use of CR as a nontoxic adjunct to treatment.


Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women.
Levels of endogenous hormones have been associated with the risk of breast cancer among postmenopausal women. Little research, however, has investigated the association between hormone levels and tumor receptor status or invasive versus in situ tumor status. Nor has the relation between breast cancer risk and postmenopausal progesterone levels been investigated. We prospectively investigated these relations in a case-control study nested within the Nurses' Health Study. Blood samples were prospectively collected during 1989 and 1990. Among eligible postmenopausal women, 322 cases of breast cancer (264 invasive, 41 in situ, 153 estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [ER+/PR+], and 39 ER-negative and PR-negative [ER-/PR-] disease) were reported through June 30, 1998. For each case subject, two control subjects (n = 643) were matched on age and blood collection (by month and time of day). Endogenous hormone levels were measured in blood plasma. We used conditional and unconditional logistic regression analyses to assess associations and to control for established breast cancer risk factors. We observed a statistically significant direct association between breast cancer risk and the level of both estrogens and androgens, but we did not find any (by year) statistically significant associations between this risk and the level of progesterone or sex hormone binding globulin. When we restricted the analysis to case subjects with ER+/PR+ tumors and compared the highest with the lowest fourths of plasma hormone concentration, we observed an increased risk of breast cancer associated with estradiol (relative risk [RR] = 3.3, 95% confidence interval [CI] = 2.0 to 5.4), testosterone (RR = 2.0, 95% CI = 1.2 to 3.4), androstenedione (RR = 2.5, 95% CI = 1.4 to 4.3), and dehydroepiandrosterone sulfate (RR = 2.3, 95% CI = 1.3 to 4.1). In addition, all hormones tended to be associated most strongly with in situ disease. Circulating levels of sex steroid hormones may be most strongly associated with risk of ER+/PR+ breast tumors.


Cancer incidence among pharmaceutical workers.
A cluster of cancers at one plant in a pharmaceutical company in Sweden was the initiator for this work, which describes the cancer incidence among the laboratory and production workers at this company. The investigation is a retrospective cohort study. All employees with possible exposure to chemical, pharmacological, or biological agents and employment for at least six months at the company during 1960-1990 were included. Standardized incidence ratios (SIR) were calculated with the local county population as reference. The total cancer incidence was close to the expected. In a subcohort consisting of the highest exposed employees, an SIR of 3.5 [95% confidence interval (95% CI) 1.5-6.8] was found for urothelial tumors, while there were no urothelial tumors among the workers with the lowest exposure. An evaluation of the exposures among the subjects with urothelial tumors revealed no association with specific exposures in the workplaces. There was also a statistically significant increase in the risk for acute leukemia (SIR 4.5, 95% CI 1.2-12 ). With a 10-year induction-latency period in the calculations, the elevated risk was smaller and not significant. Although the numbers were small, there were also statistically significant overrisks for cancer of the peritoneum, the lip, and the pleura. A significant increase in the risk for urothelial tumors was found among pharmaceutical workers. All but one of those with urothelial tumors were smokers, but confounding from smoking could probably not explain the risk increase.


RGD targeted poly(L-glutamic acid)-cystamine-(Gd-DO3A) conjugate for detecting angiogenesis biomarker alpha(v) beta3 integrin with MRT, mapping.
Cyclic Arg-Gly-Asp-D-Phe-Lys [c(RGDfK)] targeted poly(L-glutamic acid) (PGA)-(Gd-DO3A) conjugate with a biodegradable cystamine spacer was prepared and evaluated for in vivo detection of an angiogenesis biomarker, alpha(v)beta3 integrin, in neoplastic tissues with T1 mapping, a quantitative magnetic resonance imaging (MRI) technique. The binding activity of the c(RGDfK) containing conjugate was investigated using in vitro vitronectin assay with human prostate carcinoma DU145 cell line and Kaposi's sarcoma SLK cell line. The peptide c(RGDfK) and PGA-cystamine-(Gd-DO3A) conjugate were used as controls. The binding affinity of polymer bound c(RGDfK) was slightly lower than free c(RGDfK) peptide. The RGD targeted conjugate had higher binding affinity to the DU145 cells than the SLK cells, which was consistent to free c(RGDfK). The imaging of alpha(v)beta3 integrin with targeted PGA-cystamine-(Gd-DO3A) was evaluated in nude mice bearing DU145 and SLK xenografts at a dose of 5 micromol-Gd/kg. The targeted conjugate demonstrated higher in vivo binding affinity to the DU145 xenografts than the SLK xenografts, resulting in a significant decrease of T1 values of water protons in the periphery of the DU145 tumors as shown in the MR T1 maps. No significant decrease of T1 values was observed in the SLK tumor with the targeted conjugate and in both tumors with the non-targeted conjugate. The targeted polymeric Gd(III) chelate conjugate with a degradable spacer has the potential to be a new paradigm for safe and effective probes in molecular imaging with quantitative MR T1 mapping.


Semi-quantitative assessment of salivary gland function in patients with differentiated thyroid carcinoma after radioiodine-131 treatment.
Sialadenitis and xerostomia are well-known side effects of high-dose radioactive iodine ((131)Iota) treatment in patients with differentiated thyroid carcinoma (DTC). This study was undertaken to determine salivary gland function semi-quantitatively in patients with DTC given (131)I for the treatment of the thyroid remnant and/or metastases. Thirty-six patients, 11 males and 25 females, mean age 53.5 years, range 22-73 years, were studied. Scintigraphy of the salivary glands was performed with (99m)Tc-pertechnetate and the salivary excretion fraction (SEF) of the parotid and the submandibular glands was calculated as a measure of their function. Measurements were performed before (131)I treatment as a baseline study, and three weeks and three months later. The patients were clinically evaluated by a standardized subjective questionnaire. Results were as follows: Mean SEF at three weeks and three months after (131)I treatment was reduced as compared to baseline measurements. The total mean baseline measurements, those of three weeks and those of three months later were: 54.9%, 47.2% and 46% respectively; P<0.05 for both measurements (Table 1). The SEF decrease of the parotid glands was greater than that of the submandibular glands (P<0.05 as compared for both salivary glands before and three weeks and three months after (131)I treatment). This confirmed the higher radiosensitivity of the parotid glands as compared to the submandibular glands. In 12 patients (33%) there was no significant decrease of SEF in the salivary glands after (131)I treatment. The relation between the decrease of SEF after three weeks and after three months and the dose of (131)I administered, was for the right and left submandibular glands significant (P=0.016 and P=0.002), while for the parotid glands it was insignificant (P=0.22 and P=0.27 respectively) (Table 4). Reduction of SEF in the parotid glands three months after (131)I treatment was greater than after three weeks. This difference, as regards the submandibular glands, was not significant. Our results show that high dose (131)I treatment in DTC patients induces a significant effect on salivary gland function, which is dose-related in the submandibular glands, and more prominent in the parotid glands.


The 36K polypeptide synthesized in Newcastle disease virus-infected cells possesses properties predicted for the hypothesized 'V' protein.
Newcastle disease virus (NDV) virions possess two proteins which react strongly with monoclonal antibody 688 following separation by high resolution two-dimensional (isoelectric focusing/SDS) PAGE and detection by Western blotting. One is the phosphorylated nucleocapsid-associated 53K [P (NAP)] protein, the other comigrates with the 36K protein detected by radiolabelling NDV-infected chick embryo fibroblasts. [35S]Cysteine/[3H]leucine dual-labelling experiments show that the 36K protein is very rich in cysteine compared to the P (NAP) protein. In the Beaudette C strain it comigrates on one-dimensional SDS-polyacrylamide gels with the matrix protein (M); however, it is resolved from the slower migrating M protein from the Ulster strain of NDV. The size, strain-specific isoelectric point, high cysteine content and antigenic relatedness to the P (NAP) protein suggest that the 36K protein is the 'V' protein of NDV, the counterpart of which is found in other Paramyxoviridae.


Collagen remodeling by phagocytosis is determined by collagen substrate topology and calcium-dependent interactions of gelsolin with nonmuscle myosin IIA in cell adhesions.
We examine how collagen substrate topography, free intracellular calcium ion concentration ([Ca(2+)]i, and the association of gelsolin with nonmuscle myosin IIA (NMMIIA) at collagen adhesions are regulated to enable collagen phagocytosis. Fibroblasts plated on planar, collagen-coated substrates show minimal increase of [Ca(2+)]i, minimal colocalization of gelsolin and NMMIIA in focal adhesions, and minimal intracellular collagen degradation. In fibroblasts plated on collagen-coated latex beads there are large increases of [Ca(2+)]i, time- and Ca(2+)-dependent enrichment of NMMIIA and gelsolin at collagen adhesions, and abundant intracellular collagen degradation. NMMIIA knockdown retards gelsolin recruitment to adhesions and blocks collagen phagocytosis. Gelsolin exhibits tight, Ca(2+)-dependent binding to full-length NMMIIA. Gelsolin domains G4-G6 selectively require Ca(2+) to interact with NMMIIA, which is restricted to residues 1339-1899 of NMMIIA. We conclude that cell adhesion to collagen presented on beads activates Ca(2+) entry and promotes the formation of phagosomes enriched with NMMIIA and gelsolin. The Ca(2+) -dependent interaction of gelsolin and NMMIIA in turn enables actin remodeling and enhances collagen degradation by phagocytosis.


Influence of uranium on bacterial communities: a comparison of natural uranium-rich soils with controls.
This study investigated the influence of uranium on the indigenous bacterial community structure in natural soils with high uranium content. Radioactive soil samples exhibiting 0.26% - 25.5% U in mass were analyzed and compared with nearby control soils containing trace uranium. EXAFS and XRD analyses of soils revealed the presence of U(VI) and uranium-phosphate mineral phases, identified as sabugalite and meta-autunite. A comparative analysis of bacterial community fingerprints using denaturing gradient gel electrophoresis (DGGE) revealed the presence of a complex population in both control and uranium-rich samples. However, bacterial communities inhabiting uraniferous soils exhibited specific fingerprints that were remarkably stable over time, in contrast to populations from nearby control samples. Representatives of Acidobacteria, Proteobacteria, and seven others phyla were detected in DGGE bands specific to uraniferous samples. In particular, sequences related to iron-reducing bacteria such as Geobacter and Geothrix were identified concomitantly with iron-oxidizing species such as Gallionella and Sideroxydans. All together, our results demonstrate that uranium exerts a permanent high pressure on soil bacterial communities and suggest the existence of a uranium redox cycle mediated by bacteria in the soil.


Patterns of genotoxicity and contaminant exposure: evidence of genomic instability in the marsh frogs (Rana ridibunda) of Sumgayit, Azerbaijan.
The wetlands of Sumgayit in the Azerbaijan Republic contain complex mixtures of contaminants, including polycyclic aromatic hydrocarbons (PAHs), mercury, organochlorine pesticides, and polychlorinated biphenyls. Marsh frogs (Rana ridibunda) were collected from several contaminated wetlands within the city as well as from two reference sites outside the city. Sediment samples revealed heterogeneous patterns of PAH and mercury concentrations throughout Sumgayit, with the highest levels occurring east of the Sumgayit River, within the industrial zone. Flow cytometry and micronucleus assay revealed elevated estimates of genetic damage in frogs from the wetlands east of the Sumgayit River compared to frogs from the reference sites. Flow cytometric data showed a significant correlation with sediment mercury concentrations, whereas population micronucleus frequencies were significantly correlated with high-molecular-weight PAHs.


Biological activities of yarrow species (Achillea spp.).
The genus Achillea consists of about 140 perennial herbs native to the Northern hemisphere. Traditional indications of their use include digestive problems, liver and gall-bladder conditions, menstrual irregularities, cramps, fever, wound healing. The Commission E approves its internal use for loss of appetite and dyspeptic ailments (gastric catarrh, spastic discomfort), externally it is used in form of sitz bath or as a compress against skin inflammation, slow healing wounds, bacterial or fungal infections. In the last decades, pharmacological studies became intensive, although human clinical investigations are still rare. Recent findings have confirmed several traditional uses. The largest number of data accumulated for antioxidant and anti-inflammatory effects. There are positive results on the analgesic, anti-ulcer, choleretic, hepatoprotective and wound healing activities. First results on other interesting therapeutical areas - antihypertensive, antidiabetic, antitumor, antispermatogenic activities -need confirmation. Yarrow can be used also as an insect repellent. Contact dermatitis as adverse effect may be connected to sesquiterpenes. The diversity and complexity of the effective compounds of yarrow species explains the broad spectrum of their activity. According to the literature the pharmacological effects are mainly due to the essential oil, proazulenes and other sesquiterpene lactones, dicaffeoylquinic acids and flavonoids. Synergistic actions of these and other compounds are also supposed. Achillea species have different chemical and therapeutical values. Despite of numerous data, correct evaluation of the results is difficult because of missing generally accepted taxonomical nomenclature. The used chemical-analytical methods and bio-assays are utmost diverse, making the comparison complicated. Further research on the activity is needed using exactly defined plant material, standardized methods and chemical analysis.


Prevalence and clinical features of asymptomatic peripheral artery disease in Japanese stroke patients.
A recent worldwide disease registration study has revealed a high prevalence of polyvascular diseases in stroke patients. However, although a poor clinical outcome of patients with polyvascular disease has been reported, there have been few reports on clinical features of peripheral artery disease (PAD) in stroke patients. We assessed the prevalence, demographics, characteristics, and risk factors of PAD in Japanese stroke patients. One hundred and one consecutive chronic stroke patients in an outpatient clinic underwent ankle-brachial index (ABI) screening tests. PAD was diagnosed when the ABI was <0.9. Abnormal ABI was found in 19 patients (18.8%). Eleven patients were asymptomatic, and 8 patients had symptoms of intermittent claudication. Gender, prevalence of hypertension, and dyslipidemia and alcohol intake were not different between the patients with PAD and those without PAD. Prevalence of diabetes mellitus (63.6%) was higher in the patients with asymptomatic PAD. Among the clinical subtypes of stroke, the patients with atherothrombotic infarction had a higher prevalence of PAD. The prevalence of PAD in stroke patients was 18.8%. Approximately 60% of the patients had no symptoms related to PAD. Diabetes mellitus was associated with higher prevalence of asymptomatic PAD among Japanese stroke patients.


An audit of ingested and aspirated foreign bodies in children at a university hospital in South Africa: The Pietermaritzburg experience.
The ingestion or aspiration of foreign bodies (FBs) by children is a common problem around the world. Our centre in Pietermaritzburg, South Africa, has a dedicated paediatric surgical service, and all patients with an ingested or aspirated FB are managed under the direct care of a paediatric surgeon. To review our centre's experience with this problem by means of a retrospective audit and use the data to develop and refine appropriate local management guidelines. Grey's Hospital has a hybrid electronic medical registry (HEMR) that captures patient data on admission, after a procedure and on discharge. The HEMR was reviewed and all patients with an appropriate International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) code indicating an ingested or aspirated FB were identified and retrieved for review. A total of 105 cases of FB ingestion or aspiration in children <12 years of age from January 2012 to December 2014 were identified from the HEMR. The patients' ages ranged from 4 months to 10 years (mean 3 years and 6 months), and 59.0% (n=62) were male and 41.0% (n=43) female. A total of 107 FBs were removed (two patients each had two coins removed). The commonest FBs were coins (n=77, 71.9%), followed by batteries (n=6, 5.6%), plastic toys (n=5, 4.7%), buttons (n=5, 4.7%), screws/washers (n=3, 2.8%), seeds (n=2, 1.9%), needles (n=2, 1.9%), bones (n=2, 1.9%), a marble (n=1, 0.9%), a rubber eraser (n=1, 0.9%), a curtain hook (n=1, 0.9%), a nail (n=1, 0.9%) and a wood speck (n=1, 0.9%). Of the FBs, 67 (62.6%) were in the oesophagus, 17 (15.9%) in the respiratory system, 14 (13%) in the intestine and 9 (8.4%) in the oral cavity. The average time from ingestion/aspiration to presentation was <48 hours. Of the FBs, 67 (62.6%) were removed via rigid oesophagoscopy and 13 (12.1%) via rigid bronchoscopy, 13 (12.1%) were passed rectally, and 9 (8.4%) were removed via grasping forceps in the oral cavity, 4 (3.7%) via thoracotomy and 1 (0.9%) via emergency laparotomy. A total of 15 complications included mucosal ulceration/slough (n=6, 40.0%), oesophageal perforation (n=3, 20.0%), aspiration pneumonia (n=3, 20.0%), and tracheal perforation, lung collapse and contact bleed (n=1 each, 6.7%). No patient presented in respiratory distress or needed emergency airway management, and there were no deaths. The development of a dedicated paediatric surgery service and the implementation of management protocols have resulted in excellent outcomes for this problem.


Response to an education program for parents about adult pertussis vaccination.
We designed a prospective study to evaluate the effectiveness of an educational intervention designed to increase awareness and knowledge of pertussis among parents and grandparents of newborns. We also evaluated its effect on their willingness to receive the tetanus toxoid-diphtheria toxoid-acellular pertussis vaccine. There was a statistically significant (P < .05) increase in participants' knowledge about pertussis and in their willingness to receive vaccination after our education program. However, follow-up several months after participants underwent the intervention revealed that only 12 (8%) of 150 participants had been vaccinated.


The immunological basis of tumor rejection: the absolute dependence of the effector arm on sensitized T cells after chemoimmunotherapy of a murine sarcoma.
The mechanisms of tumor rejection were investigated by using a therapeutic model system involving treatment of C57BL/6J (B6) mice bearing the syngeneic MCA/76-9 or the unrelated MCA/76-64 sarcomas with cytoxan and tumor-sensitized T lymphocytes. Separated tumor-associated T lymphocytes (TAL) and tumor-associated macrophages (TAM) isolated from the regressing tumors 8 to 10 days after combination therapy expressed relatively specific cytotoxicity in vitro, whereas the unseparated tumor-associated cells (TAC), consisting of a mixture of TAL and TAM, expressed nonspecific cytotoxicity. TAM-mediated cytotoxicity was not dependent on the presence of TAL, as shown by T cell depletion of TAM or TAC cultures with the use of monoclonal anti-Thy-1 or anti-Lyt-2 antibody and complement. In contrast, the nonspecific cytotoxicity was dependent on the presence of T cells. In vivo assays using the Winn test failed to confirm certain aspects of the in vitro data. Without exception, the TAC inhibited tumor growth in an immunologically specific manner, having no effect on the growth of the unrelated B6 sarcoma. T cell depletion completely abrogated in vivo cytotoxicity. Specificity of tumor growth inhibition was confirmed in a bystander experiment in which TAC were mixed with both tumor cell types and were injected into recipient B6 mice. Tumors grew under these conditions, but the tumor that grew consisted only of those tumor cells toward which TAC cytotoxicity was not specifically directed. A bioassay indicated that the specifically immune antitumor effects at the site of regression were initiated between days 3 and 7 after combination therapy. By days 7 and 9, few tumorigenic stem cells could be detected at the tumor site. However, T cell depletion of the TAC isolated on days 8 to 10 resulted in enhanced tumor growth when the depleted TAC were injected into recipient mice. The conclusions reached were that tumor rejection was absolutely dependent on T cell participation at the tumor site, and that if TAM were involved, they required the presence of TAL and did not express nonspecific antitumor cytotoxicity. Indeed, the accelerated tumor growth seen in the absence of TAL suggested the possibility that TAM were growth stimulatory.


High-sensitivity intrinsic fiber-optic Fabry-Perot pressure sensor.
A new configuration for a pressure sensor in which the motion of a diaphragm produces strain in a fiber Fabry-Perot interferometer (FFPI) is described. The single-mode fiber containing the interferometer is bonded at one end to the stainless-steel diaphragm. The fiber is also attached beyond the interferometer to the sensor housing in such a manner that it is always under tension and experiences a strain in proportion to the deflection of the diaphragm. An analysis relating the expected interferometer phase change to pressure is presented, and the dynamic response of the FFPI sensor to pressure changes produced by an air pump is in good agreement with that measured with a conventional pressure sensor.


Geographical distribution of Slovenian BRCA1/2 families according to family origin: implications for genetic screening.
Knowledge of the geographical distribution of highly recurrent mutations may be useful for efficient screening in cancer families. Since the cloning of the BRCA1/2 genes, it is known that the wide spectrum of deleterious mutations shows high ethnic and geographic heterogeneity. In this study, we have tested probands from 582 breast/ovarian cancer families and positioned all 156 BRCA1/2 families on the map according to the family origin. We observed that high-risk families with the same recurrent mutation present a typical geographical distribution and that different recurrent mutations may show different distribution patterns. We then evaluated the genetic screening implications of this heterogeneous prevalence of the most recurrent mutations found [300T>G(c.181T>G), 1806C>T(c.1687C>T), 969ins7(c.844_850dupTCATTAC), 5382insC(c.5266dupC), 235G>A(c.116G>A) in BRCA1 and IVS16-2A>G(c.7806-2A>G) in BRCA2]. On the basis of these results, specific testing procedures for new incident cases may be offered according to their family origins and, according to the information regarding clusters revealed in this study, the individuals (especially those at low risk), originating from regions with clusters, might be screened preferentially for cluster mutations and analysis may be simplified according to the family origin.


SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study.
To determine the rates of asymptomatic viral carriage and seroprevalence of SARS-CoV-2 antibodies in healthcare workers. A cross-sectional study of asymptomatic healthcare workers undertaken on 24/25 April 2020. University Hospitals Birmingham NHS Foundation Trust (UHBFT), UK. 545 asymptomatic healthcare workers were recruited while at work. Participants were invited to participate via the UHBFT social media. Exclusion criteria included current symptoms consistent with COVID-19. No potential participants were excluded. Participants volunteered a nasopharyngeal swab and a venous blood sample that were tested for SARS-CoV-2 RNA and anti-SARS-CoV-2 spike glycoprotein antibodies, respectively. Results were interpreted in the context of prior illnesses and the hospital departments in which participants worked. Proportion of participants demonstrating infection and positive SARS-CoV-2 serology. The point prevalence of SARS-CoV-2 viral carriage was 2.4% (n=13/545). The overall seroprevalence of SARS-CoV-2 antibodies was 24.4% (n=126/516). Participants who reported prior symptomatic illness had higher seroprevalence (37.5% vs 17.1%, χ2=21.1034, p<0.0001) and quantitatively greater antibody responses than those who had remained asymptomatic. Seroprevalence was greatest among those working in housekeeping (34.5%), acute medicine (33.3%) and general internal medicine (30.3%), with lower rates observed in participants working in intensive care (14.8%). BAME (Black, Asian and minority ethnic) ethnicity was associated with a significantly increased risk of seropositivity (OR: 1.92, 95% CI 1.14 to 3.23, p=0.01). Working on the intensive care unit was associated with a significantly lower risk of seropositivity compared with working in other areas of the hospital (OR: 0.28, 95% CI 0.09 to 0.78, p=0.02). We identify differences in the occupational risk of exposure to SARS-CoV-2 between hospital departments and confirm asymptomatic seroconversion occurs in healthcare workers. Further investigation of these observations is required to inform future infection control and occupational health practices.


[Etiology of deafness in children].
A retrospective etiological study of 112 files of deaf children is presented. A prenatal etiology is found in 42.8%, a perinatal in 19.6% and a postnatal in 13.4% of the cases. No cause was suspected in 30.3% of the cases. These results emphasise existing literature.


Microdamage analysis of single-use flexible ureteroscope immediately after lithotripsy use.
This prospective ex vivo study investigated microdamage to single-use flexible ureteroscopes (fURS) after ureteroscopy and endoscopic combined intrarenal surgery (ECIRS). The performance of 30 WiScope devices (OTU Medical, San Jose, CA, USA) was examined immediately after use, dividing them into three equal groups: ureteroscopy and ECIRS in the prone and supine positions. The overall scope of microdamage assessment included the scope deflection, bending radius, resolution, and water flow rate. Additionally, we analyzed the association between scope status and surgical parameters. The deflection, bending radius, and resolution remained similarly above the thresholds in all groups. However, the water flow rate was below the threshold in seven scopes (70%) in the ureteroscopy group and none in the ECIRS groups (P = 0.001). Univariate and multivariable logistic regression analyses demonstrated that basket wire catheter use was associated with an increased risk for overall scope microdamage (odds ratio [OR], 22.70; P = 0.006 and OR, 22.40; P = 0.019, respectively). Stone size, total laser energy, and surgical position were not associated with a risk for scope microdamage. In conclusion, ureteroscopy was more closely associated with scope damage than ECIRS, and basket wire catheter use seemed to inflict more damage to the fURS.


The risk of peri-prosthetic fracture after primary and revision total hip and knee replacement.
Peri-prosthetic fracture after joint replacement in the lower limb is associated with significant morbidity. The primary aim of this study was to investigate the incidence of peri-prosthetic fracture after total hip replacement (THR) and total knee replacement (TKR) over a ten-year period using a population-based linked dataset. Between 1 April 1997 and 31 March 2008, 52,136 primary THRs, 8726 revision THRs, 44,511 primary TKRs, and 3222 revision TKRs were performed. Five years post-operatively, the rate of fracture was 0.9% after primary THR, 4.2% after revision THR, 0.6% after primary TKR and 1.7% after revision TKR. Comparison of survival analysis for all primary and revision arthroplasties showed peri-prosthetic fractures were more likely in females, patients aged > 70 and after revision arthroplasty. Female patients aged > 70 should be warned of a significantly increased risk of peri-prosthetic fracture after hip or knee replacement. The use of adjuvant medical treatment to reduce the effect of peri-prosthetic osteoporosis may be a direction of research for these patients.


Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review on human and animal data.
The teratogenic effect of caffeine has been clearly demonstrated in rodents. The sensitivity of different animals species is variable. Malformations have been demonstrated in mice at 50-75 mg/kg of caffeine, whereas the lowest dose usually needed to induce malformations is 80 mg/kg in rats. However, when caffeine is administered in fractioned amounts during the day, 330 mg/kg/day are necessary to reach teratogenicity in rats. In rodents, the most frequently observed malformations are those of the limbs and digits, ectrodactyly, craniofacial malformations (labial and palatal clefts) and delays in ossification of limbs, jaw and sternum. Nevertheless, even in rodents, caffeine can be considered as a weak teratogenic agent, given the quite large quantities of caffeine necessary to induce malformations and the small number of animals affected. In humans, caffeine does not present any teratogenic risk. The increased risk of the most common congenital malformations entailed by moderate consumption of caffeine is very slight. However, caffeine potentiates the teratogenic effect of other substances, such as tobacco, alcohol, and acts synergistically with ergotamine and propranolol to induce materno-fetal vasoconstrictions leading to malformations induced by ischemia. Therefore, even though caffeine does not seem to be harmful to the human fetus when intake is moderate and spread out over the day, some associations, especially with alcohol, tobacco, and vasoconstrictive or anti-migraine medications should be avoided. Maternal consumption of caffeine affects brain composition, especially in case of a low-protein diet and also seems to interfere with zinc fixation in brain. Maternal exposure to caffeine induces also long-term consequences on sleep, locomotion, learning abilities, emotivity, and anxiety in rat offspring, whereas in humans, more studies are needed to ascertain long-term behavioral effects of caffeine ingestion by pregnant mothers.


The effect of reminder systems on patients' adherence to treatment.
Patient adherence is an important component of the treatment of chronic disease. An understanding of patient adherence and its modulating factors is necessary to correctly interpret treatment efficacy and barriers to therapeutic success. This meta-analysis aims to systematically review published randomized controlled trials of reminder interventions to assist patient adherence to prescribed medications. A Medline search was performed for randomized controlled trials published between 1968 and June 2011, which studied the effect of reminder-based interventions on adherence to self-administered daily medications. Eleven published randomized controlled trials were found between 1999 and 2009 which measured adherence to a daily medication in a group receiving reminder interventions compared to controls receiving no reminders. Medication adherence was measured as the number of doses taken compared to the number prescribed within a set period of time. Meta- analysis showed a statistically significant increase in adherence in groups receiving a reminder intervention compared to controls (66.61% versus 54.71%, 95% CI for mean: 0.8% to 22.4%). Self-reported and electronically monitored adherence rates did not significantly differ (68.04% versus 63.67%, P = 1.0). Eight of eleven studies showed a statistically significant increase in adherence for at least one of the reminder group arms compared to the control groups receiving no reminder intervention. The data are limited by imperfect measures of adherence due to variability in data collection methods. It is also likely that concomitant educational efforts in the study populations, such as instructions regarding proper administration and importance of correct dosing schedules, contributed to improved patient adherence, both in reminder and control arms. The search strategy could have missed relevant studies which were categorized by disease rather than adherence. Reminder-based interventions may improve adherence to daily medications. However, the interventions used in these studies, which included reminder phone calls, text messages, pagers, interactive voice response systems, videotelephone calls, and programmed electronic audiovisual reminder devices, are impractical for widespread implementation, and their efficacy may be optimized when combined with alternative adherence-modifying strategies. More practical reminder-based interventions should be assessed to determine their value in improving patient adherence and treatment outcomes.


The evolution of transposable elements in natural populations of self-fertilizing Arabidopsis thaliana and its outcrossing relative Arabidopsis lyrata.
Transposable Elements (TEs) make up the majority of plant genomes, and thus understanding TE evolutionary dynamics is key to understanding plant genome evolution. Plant reproductive systems are diverse and mating type variation is one factor among many hypothesized to influence TE evolutionary dynamics. Here, we collected a large TE-display data set in self-fertilizing Arabidopsis thaliana, and compared it to data gathered in outcrossing Arabidopsis lyrata. We analyzed seven TE families in four natural populations of each species to tease apart the effects of mating system, demography, transposition, and selection in determining patterns of TE diversity. Measures of TE band differentiation were largely consistent across TE families. However, patterns of diversity in A. thaliana Ac elements differed significantly from that other TEs, perhaps signaling a lack of recent transposition. Across TE families, we estimated higher allele frequencies and lower selection coefficients on A. thaliana TE insertions relative to A. lyrata TE insertions. The differences in TE distributions between the two Arabidopsis species represents a synthesis of evolutionary forces that include the transposition dynamics of individual TE families and the demographic histories of populations. There are also species-specific differences that could be attributed to the effects of mating system, including higher overall allele frequencies in the selfing lineage and a greater proportion of among population TE diversity in the outcrossing lineage.


Phase shift in skyrmion crystals.
The magnetic skyrmion crystal is a periodic array of a swirling topological spin texture. Since it is regarded as an interference pattern by multiple helical spin density waves, the texture changes with the relative phase shifts among the constituent waves. Although such a phase degree of freedom is relevant to not only magnetism but also transport properties, its effect has not been elucidated thus far. We here theoretically show that a phase shift in the skyrmion crystals leads to a tetra-axial vortex crystal and a meron-antimeron crystal, both of which show a staggered pattern of the scalar spin chirality and give rise to nonreciprocal transport phenomena without the spin-orbit coupling. We demonstrate that such a phase shift can be driven by exchange interactions between the localized spins, thermal fluctuations, and long-range chirality interactions in spin-charge coupled systems. Our results provide a further diversity of topological spin textures and open a new field of emergent electromagnetism by the phase shift engineering.


Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A.
Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator that is regulated by ambient tonicity. TonEBP protects the renal medulla from the deleterious effects of hyperosmolality and regulates the urinary concentration by stimulating aquaporin-2 and urea transporters. The therapeutic use of cyclosporin A (CsA) is limited by nephrotoxicity that is manifested by reduced GFR, fibrosis, and tubular defects, including reduced urinary concentration. It was reported recently that long-term CsA treatment was associated with decreased renal expression of TonEBP target genes, including aquaporin-2, urea transporter, and aldose reductase. This study tested the hypothesis that long-term CsA treatment reduces the salinity/tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of TonEBP. CsA treatment for 7 d did not affect TonEBP or renal function. Whereas expression of sodium transporters was altered, the medullary tonicity seemed unchanged. Conversely, 28 d of CsA treatment led to downregulation of TonEBP and overt nephrotoxicity. The downregulation of TonEBP involved reduced expression, cytoplasmic shift, and reduced transcription of its target genes. This was associated with reduced expression of active sodium transporters-sodium/potassium/chloride transporter type 2 (NKCC2), sodium/chloride transporter, and Na(+),K(+)-ATPase-along with increased sodium excretion and reduced urinary concentration. Infusion of vasopressin restored the expression of NKCC2 in the outer medulla as well as the expression and the activity of TonEBP. It is concluded that the downregulation of TonEBP in the setting of long-term CsA administration is secondary to the reduced tonicity of the renal medullary interstitium.


Childhood body mass index trajectories and associations with adult-onset chronic kidney disease in Denmark: A population-based cohort study.
Although excess adult adiposity is a strong risk factor for chronic kidney disease (CKD), evidence for associations with early life body size is limited. We investigated whether childhood body mass index (BMI) trajectories are associated with adult-onset CKD and end-stage kidney disease (ESKD) using a population-based cohort. Further, we examined the role of adult-onset type 2 diabetes (T2D) in these associations. We included 151,506 boys and 148,590 girls from the Copenhagen School Health Records Register, born 1930 to 1987 with information on measured weights and heights at ages 6 to 15 years. Five sex-specific childhood BMI trajectories were analyzed. Information on the main outcomes CKD and ESKD, as well as T2D, came from national health registers. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using Poisson regression adjusted for year of birth. During a median of 30.8 person-years of follow-up, 5,968 men and 3,903 women developed CKD and 977 men and 543 women developed ESKD. For both sexes, the rates of CKD and ESKD increased significantly with higher child BMI trajectories in comparison with the average BMI trajectory (40% to 43% of individuals) and the below-average BMI trajectory (21% to 23% of individuals) had the lowest rates. When including T2D, most associations were significant and men (IRR = 1.39, 95% CI: 1.13 to 1.72) and women (IRR = 1.54, 95% CI: 1.28 to 1.86) with the obese childhood BMI trajectory (2% of individuals) had significantly higher CKD rates than the average BMI trajectory, whereas for ESKD, the associations were positive, but nonsignificant, for men (IRR = 1.38, 95% CI: 0.83 to 2.31) but significant for women (IRR = 1.97, 95% CI: 1.25 to 3.11) with the obese BMI trajectory. A main study limitation is the use of only hospital-based CKD diagnoses. Individuals with childhood BMI trajectories above average had higher rates of CKD and ESKD than those with an average childhood BMI trajectory. When including T2D, most associations were significant, particularly with CKD, emphasizing the potential information that the early appearance of above-average BMI growth patterns provide in relation to adult-onset CKD beyond the information provided by T2D development.


Minimization of polymerization shrinkage effects on composite resins by the control of irradiance during the photoactivation process.
High levels of shrinkage stress caused by volumetric variations during the activation process are one of the main problems in the practical application of composite resins. The aim of this study is to reduce the shrinkage stress and minimize the effects caused by composite resin volumetric variation due to the photopolymerization. In this way, this work proposes a systematic study to determine the optimal dimming function to be applied to light curing processes. The study was performed by applying mathematical techniques to the optimization of nonlinear objective functions. The effectiveness of the dimming function was evaluated by monitoring the polymerization shrinkage stress during the curing process of five brands/models of composites. This monitoring was performed on a universal testing machine using two steel bases coupled in the arms of the machine where the resin was inserted and polymerized. The quality of the composites cured by the proposed method was analyzed and compared with the conventional photoactivation method by experiments to determine their degree of conversion (DC). Absorbance measurements were performed using Fourier-transform infrared spectroscopy (FT-IR). A T-test was performed on DC results to compare the photoactivation techniques. We also used scanning electron microscopy (SEM) to analyze in-vitro the adhesion interface of the resin in human teeth. Our results showed that the use of the optimal dimming function, named as exponential, resulted in the significant reduction of the shrinkage stress (~36.88% ±6.56 when compared with the conventional method) without affecting the DC (t=0.86, p-value=0.44). The SEM analyses show that the proposed process can minimize or even eliminate adhesion failures between the tooth and the resin in dental restorations. The results from this study can promote the improvement of the composite resin light curing process by the minimization of polymerization shrinkage effects, given an operational standardization of the photoactivation process.


African swine fever detection and transmission estimates using homogeneous versus heterogeneous model formulation in stochastic simulations within pig premises.
African swine fever (ASF) is one of the most important foreign animal diseases to the U.S. swine industry. Stakeholders in the swine production sector are on high alert as they witness the devastation of ongoing outbreaks in some of its most important trade partner countries. Efforts to improve preparedness for ASF outbreak management are proceeding in earnest and mathematical modeling is an integral part of these efforts. This study aimed to assess the impact on within-herd transmission dynamics of ASF when the models used to simulate transmission assume there is homogeneous mixing of animals within a barn. Barn-level heterogeneity was explicitly captured using a stochastic, individual pig-based, heterogeneous transmission model that considers three types of infection transmission, (1) within-pen via nose-to-nose contact; (2) between-pen via nose-to-nose contact with pigs in adjacent pens; and (3) both between- and within-pen via distance-independent mechanisms (e.g., via fomites). Predictions were compared between the heterogeneous and the homogeneous Gillespie models. Results showed that the predicted mean number of infectious pigs at specific time points differed greatly between the homogeneous and heterogeneous models for scenarios with low levels of between-pen contacts via distance-independent pathways and the differences between the two model predictions were more pronounced for the slow contact rate scenario. The heterogeneous transmission model results also showed that it may take significantly longer to detect ASF, particularly in large barns when transmission predominantly occurs via nose-to-nose contact between pigs in adjacent pens. The findings emphasize the need for completing preliminary explorations when working with homogeneous mixing models to ascertain their suitability to predict disease outcomes.


Circulating Epstein-Barr virus DNA in the serum of patients with gastric carcinoma.
We investigated the detectability of EBV DNA in the serum of gastric carcinoma patients in Hong Kong. Previous data have shown that approximately 10% of gastric carcinomas in Hong Kong are associated with EBV. We recruited 51 patients with gastric carcinoma, 30 patients with gastritis, and 197 apparently healthy controls. For gastric carcinoma patients, blood samples were obtained before surgery. After surgery, the resected tumor samples from the cancer cases were subjected to in situ hybridization for small EBV-encoded RNA (EBER). Serum EBV DNA in all cases was measured by real-time quantitative PCR. Serum EBV DNA was detectable in 5 of 5 (100%) EBER-positive gastric carcinoma cases (median concentration, 1063 copies/ml), in 13 of 14 (93%) EBER-negative gastric carcinoma cases with EBER-positive infiltrating lymphocytes (median concentration, 50 copies/ml), and in 0 of 32 (0%) EBER-negative cases. In the nontumor controls, serum EBV DNA was detectable in 7 of 30 (23%) gastritis cases (median concentration, 0 copies/ml) and in 7 of 197 (3.6%) apparently healthy individuals (median concentration, 0 copy/ml). Our data indicate that serum EBV DNA reflects tumoral EBER status and opens up the possibility that circulating EBV DNA may be used as a tumor marker for the EBER-positive gastric carcinomas. The biological and clinical significance of the presence of low levels of circulating EBV DNA in the minority of gastritis patients and healthy individuals remains to be elucidated.


Novel Approaches for the Recovery of Natural Pigments with Potential Health Effects.
The current increased industrial food production has led to a significant rise in the amount of food waste generated. These food wastes, especially fruit and vegetable byproducts, are good sources of natural pigments, such as anthocyanins, betalains, carotenoids, and chlorophylls, with both coloring and health-related properties. Therefore, recovery of natural pigments from food wastes is important for both economic and environmental reasons. Conventional methods that are used to extract natural pigments from food wastes are time-consuming, expensive, and unsustainable. In addition, natural pigments are sensitive to high temperatures and prolonged processing times that are applied during conventional treatments. In this sense, the present review provides an elucidation of the latest research on the extraction of pigments from the agri-food industry and how their consumption may improve human health.


Determining the long-term health burden and risk of sequelae for 14 foodborne infections in British Columbia, Canada: protocol for a retrospective population-based cohort study.
Over one in eight Canadians is affected by a foodborne infection annually; however, the long-term consequences, including the risks and costs of sequelae, are unclear. We aim to estimate the health burden and direct costs of 14 infections commonly transmitted by food, considering the acute illness and subsequent sequelae and mortality, for the population of British Columbia, Canada (~4.7 million). We will conduct a population-based retrospective cohort study of the British Columbia provincial population, over a 10-year study period (1 January 2005 to 31 December 2014). Exposure is defined as a provincially reported illness caused by Clostridium botulinum, Campylobacter, Cryptosporidium, Cyclospora, Giardia, hepatitis A virus, Listeria, non-typhoidal Salmonella spp, Salmonella Typhi, Salmonella Paratyphi, Shiga toxin-producing Escherichia coli, Shigella, Vibrio parahaemolyticus or Yersinia (excluding pestis). We will link individual-level longitudinal data from eight province-wide administrative health and reportable disease databases that include physician visits, hospitalisations and day surgeries, deaths, stillbirths, prescription medications (except those to treat HIV) and reportable foodborne diseases. Using these linked databases, we will investigate the likelihood of various sequelae and death. Hazard models will be used to estimate the risk of outcomes and their association with the type of foodborne infection. Epidemiological analyses will be conducted to determine the progression of illness and the fraction of sequelae attributable to specific foodborne infections. Economic analyses will assess the consequent direct healthcare costs. This study has been approved by a University of Waterloo Research Ethics Committee (no 30645), the University of British Columbia Behavioral Research Ethics Board (no H16-00021) and McGill University's Institutional Review Board (no A03-M12-19A). Results will be disseminated via presentations to academics, public health practitioners and knowledge users, and publication in peer-reviewed journals. Where such publications are not open access, manuscripts will also be available via the University of Waterloo's Institutional Repository (https://uwspace.uwaterloo.ca).


[Epidemiology of chronic rheumatic disease of heart among teenagers in the Republic of Dagestan].
The morbidity of rheumatic heart diseases (RHD) was studied, for the purpose of designing a set of measures to prevent them, among the teenagers in the Republic of Dagestan. The studies were based on the medical aid appealability, hospitalization data and clinical-and-epidemiological research made, with respect to climatic-and-geographic zones, in 3 rural areas and in the city of Makhachkala. A total of 1142 teenagers were questioned; laboratory-instrumental examinations were made for 234 teenagers. According to the data analysis, RHD and acute rheumatic fever (ARF) have been recently on the rise in the Republic, where the average morbidity figures are 4.5-fold higher versus those registered in whole Russia. The morbidity rate of RHD went up 1.8-fold, and that of ARF--1.5-fold, in Dagestan during 2000-2002. According to clinical-and-epidemiological examinations, RHD prevail among rural youth residing primarily in plains and, to a less extent, in highlands. Finally, measures are suggested, on the basis of research, for the prevention of RHD among youth.


Grading fecal consistency in an omnivorous carnivore, the brown bear: Abandoning the concept of uniform feces.
Grading the fecal consistency of carnivores is a frequently used tool for monitoring gut health and overall digestion. Several fecal consistency grading systems are available for mainly felids and canids. No such system exists for the brown bear (Ursus arctos Linnaeus, 1758). We aim at extending current fecal consistency grading systems with a scoring system for brown bears. The system was set up during a diet study with nine individuals fed a variety of diets including beef meat, rabbit, fruit, and grass-fruit-pellet mix in an incomplete crossover design. One additional individual was included opportunistically and was fed the typical zoo diet (vegetable-fruit-meat-pellet diet). All feces from the collection period were photographed, graded by "handling the feces" and visually inspected for dietary components. Based on a total of 446 feces, a six-point scale for uniform fecal consistencies was established. In 11% of all feces, two distinct consistencies could be distinguished, a feature that appears in other carnivore species as well. Hence, an additional grading system for dual consistencies was developed. The fecal consistency of brown bears is heavily dependent on the diet items processed before defecation with the general observation that the more vegetation or whole prey, the firmer the feces, and at certain proportions of the latter, the higher the chance for dual fecal consistencies to occur. The results indicate that in bears, diet may have a strong effect on fecal consistency, hampering animal health assessments without prior knowledge of the diet.


Building trust in real world evidence (RWE): moving transparency in RWE towards the randomized controlled trial standard.
The increasing use of RWE in regulatory and reimbursement decision-making indicates the significant progress that has been made in building trust in RWE through greater transparency. This review of the published literature and key online sources was conducted to provide an update on progress towards greater transparency in RWE, based on four key barriers to trust identified in a 2016 paper and applying learnings from transparency initiatives established for RCTs, such as the US FDA Amendments Act (FDAAA) 2007 Final Rule. Multiple initiatives from the US FDA, EMA and organizations such as the ISPOR-ISPE Joint Task Force have yielded new guidance documents and tools that enable greater transparency in RWE study methodology (STaRT-RWE and HARPER templates), data source selection and quality (SPIFD2 framework, REQueST tool), strategy (the Center for Open Science RWE Study Registry), and will therefore improve transparency in RWE study reporting. Programs such as the REPEAT Initiative and RWE DUPLICATE are investigating reproducibility of RWE studies and improving understanding of the circumstances when valid inference on treatment effects can be obtained from RWE studies. Further work is needed to embed and to implement the new tools and guidance that are available, and thus raise standards for RWE transparency towards the levels expected for RCTs.


The relative contribution of COVID-19 infection versus COVID-19 related occupational stressors to insomnia in healthcare workers.
Healthcare workers have experienced high rates of psychiatric symptom burden and occupational attrition during the COVID-19 pandemic. Identifying contributory factors can inform prevention and mitigation measures. Here, we explore the potential contributions of occupational stressors vs COVID-19 infection to insomnia symptoms in US healthcare workers. An online self-report survey was collected between September 2020 and July 2022 from N=594 US healthcare workers, with longitudinal follow-up up to 9 months. Assessments included the Insomnia Severity Index (ISI), the PTSD Checklist for DSM-5 (PCL-5), and a 13-item scale assessing COVID-19 related occupational stressors. Insomnia was common (45% of participants reported at least moderate and 9.2% reported severe symptoms at one or more timepoint) and significantly associated with difficulty completing work-related tasks, increased likelihood of occupational attrition, and thoughts of suicide or self-harm (all p<.0001). In multivariable regression with age, gender, and family COVID-19 history as covariates, past two-week COVID-related occupational stressors, peak COVID-related occupational stressors, and personal history of COVID-19 infection were all significantly related to past two-week ISI scores (β=1.7±0.14SE, β=0.08±0.03, and β=0.69±0.22 respectively). Although similar results were found for the PCL-5, when ISI and PCL-5 items were separated by factor, COVID-19 infection was significantly related only to the factor consisting of sleep-related items. Both recent occupational stress and personal history of COVID-19 infection were significantly associated with insomnia in healthcare workers. These results suggest that both addressing occupational stressors and reducing rates of COVID-19 infection are important to protect healthcare workers and the healthcare workforce.


New outpatient referrals to a tertiary paediatric cardiac centre: evidence of increasing workload and evolving patterns of referral.
To assess the volume and range of diagnosis in new patients referred to paediatric cardiac outpatient clinics. Data was collected prospectively, using a proforma completed at all outpatient clinics over a period of three months. There were 526 new referrals, representing an increase of almost one-fifth compared to 5 years ago. Of the referrals, 78 percent came from hospital doctors, and 22 percent from general practitioners, with 221 of those referred being infants. A heart murmur was the most common reason for referral, representing almost two-thirds of cases. In 372 patients referred (71 percent), the heart was discovered to be structurally normal. The proportion of patients with normal hearts referred by general practitioners and hospital doctors were 81 percent, and 68 percent, respectively (p less than 0.004). There was considerable variation in the pattern of referral between doctors working in different hospitals. New referrals to centres dealing with congenital cardiac malformations are increasing alarmingly, with the majority of the children referred having normal hearts. This increase in demand for specialist services has important implications for resources and training.


Structure and assembly of lipid-containing viruses, with special reference to bacteriophage PM2 as one type of model system.
The simpler lipid-containing viruses (influenza, Semliki Forest, PM2) may have a phospholipid bilayer sandwiched between an outer shell of protein and an internal nucleocapsid possessing helical or icosahedral symmetry. Extensive physical and chemical studies have enabled us to form a more detailed picture of the structure of bacteriophage PM2 and controlled stepwise degradation of the virion has helped us to localize the four viral proteins. The surface protein (II) of PM2 is basic and interacts with the acidic phosphatidylglycerol of the bilayer to stabilize the membrane. The nucleocapsid protein (III) has proteolipid characteristics and may interact with the phospholipids in a hydrophobic fashion. The spikes are formed from protein I and the fourth protein (IV) is closely associated with the DNA. It is possible to reassemble the virus by reversing the degradation steps. Assembly has been especially useful in revealing the processes whereby the proteins and lipids interact to form the bilayer. Furthermore, results of in vivo studies of phospholipid synthesis and both in vivo and in vitro studies of viral protein synthesis have enabled us to form a reasonably complete picture of the biosynthesis of PM2.