Channel modelling for indoor visible light communications.
Visible light communication (VLC) allows the dual use of light-emitting diodes (LEDs) for wireless communication purposes in addition to their primary purpose of illumination. As in any other communication system, realistic channel modelling is a key for VLC system design, analysis and testing. In this paper, we present a comprehensive survey of indoor VLC channel models. In order to set the background, we start with an overview of infrared (IR) channel modelling, which has received much attention in the past, and highlight the differences between visible and IR optical bands. In the light of these, we present a comparative discussion of existing VLC channel modelling studies and point out the relevant advantages and disadvantages. Then, we provide a detailed description of a site-specific channel modelling approach based on non-sequential ray tracing that precisely captures the optical propagation characteristics of a given indoor environment. We further present channel models for representative deployment scenarios developed through this approach that were adopted by the Institute of Electrical and Electronics Engineering (IEEE) as reference channel models. Finally, we consider mobile VLC scenarios and investigate the effect of receiver location and rotation for a mobile indoor user. This article is part of the theme issue 'Optical wireless communication'.


En bloc resection of a multilevel high-cervical chordoma involving C-2: new operative modalities: technical note.
En bloc resection of cervical chordomas has led to longer survival rates but has resulted in significant morbidities from the procedure, especially when the tumor is multilevel and located in the high-cervical (C1-3) region. To date, there have been only 5 reported cases of multilevel en bloc resection of chordomas in the high-cervical spine. In this technical report the authors describe a sixth case. A complete spondylectomy was performed at C-2 and C-3 with spinal reconstruction and stabilization, using several new modalities that were not used in the previous cases. The use of 1) preoperative endovascular sacrificing of the vertebral artery, 2) CT image-guidance, 3) an ultrasonic aspirator for skeletonizing the vertebral artery, and 4) the custom design of an anterior cage all contributed to absence of intraoperative or long-term (20 months) hardware failure and pseudarthrosis.


Simpler Procedure and Improved Performance for Pathogenic Bacteria Analysis with a Paper-Based Ratiometric Fluorescent Sensor Array.
Bacterial infections are the leading cause of morbidity and mortality in the world, particularly due to a delay in treatment and misidentification of the bacterial species causing the infection. Therefore, rapid and accurate identification of these pathogens has been of prime importance. The conventional diagnostic techniques include microbiological, biochemical, and genetic analyses, which are time-consuming, require large sample volumes, expensive equipment, reagents, and trained personnel. In response, we have now developed a paper-based ratiometric fluorescent sensor array. Environment-sensitive fluorescent dyes (3-hydroxyflavone derivatives) pre-adsorbed on paper microzone plates fabricated using photolithography, upon interaction with bacterial cell envelopes, generate unique fluorescence response patterns. The stability and reproducibility of the sensor array response were thoroughly investigated, and the analysis procedure was refined for optimal performance. Using neural networks for response pattern analysis, the sensor was able to identify 16 bacterial species and recognize their Gram status with an accuracy rate greater than 90%. The paper-based sensor was stable for up to 6 months after fabrication and required 30 times lower dye and sample volumes as compared to the analogous solution-based sensor. Therefore, this approach opens avenues to a state-of-the-art diagnostic tool that can be potentially translated into clinical applications in low-resource environments.


Lipids as key players in Alzheimer disease: alterations in metabolism and genetics.
Advances in Alzheimer Disease (AD) research suggest that central nervous system (CNS) lipids play a key role in the pathogenesis. This role is attributed to the rich lipid content of CNS structures and the presence of blood brain barrier which disables the exchange of lipids between CNS and plasma. Among these lipids, cholesterol is a unique molecule provided mainly by its de novo synthesis in the CNS. Special apolipoproteins used for its efficient recycling within the CNS and special oxysterols formed that are specific to brain all contribute to the unique properties of the molecule. Above all, the presence of cholesterol in the membrane enables it to function as a regulator of a number of protein related processes such as the beta-amyloid precursor protein cleavage. Cholesterol reducing agents such as statins are recently proposed to have a protective role in AD. This review will focus on the role of cholesterol metabolism and genetics in AD. Current literature investigating the relationship between cholesterol and AD will be evaluated from the pathophysiological perspective. Genetic studies concerning proteins which are involved in the CNS cholesterol metabolism will also be summarized in the hope that genomics may stimulate further studies and thus contribute to a more clear understanding of the molecular mechanisms in the pathophysiology of AD.


Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers.
Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.


It's all in the lens: differences in views on obesity prevention between advocates and policy makers.
Intervention strategies to reduce obesity include policy and environmental changes that are designed to provide opportunities, support, and cues to help people develop healthier behaviors. Policy changes at the state level are one way to influence access, social norms, and opportunities for better nutrition and increased physical activity among the population. Ten states were selected for a broad variance in obesity rates and number of enacted obesity prevention policies during the years of 2006-2009. Within the selected states, a purely qualitative study of attitudes of childhood obesity policy using semistructured telephone interviews was conducted. Interviews were conducted with state policy makers who serve on public health committees. A set of six states that had more than eight childhood obesity policies enacted were selected for subsequent qualitative interviews with a convenience sample of well-established advocates. Policy makers in states where there was more childhood obesity policy action believed in the evidence behind obesity policy proposals. Policy makers also varied in the perception of obesity as a constituent priority. The major differences between advocates and policy makers included a disconnect in information dissemination, opposition, and effectiveness of these policies. The findings from this study show differences in perceptions among policy makers in states with a greater number of obesity prevention bills enacted. There are differences among policy makers and advocates regarding the role and effectiveness of state policy on obesity prevention. This presents an opportunity for researchers and practitioners to improve communication and translation of evidence to policy makers, particularly in states with low legislation.


[Use of the aliphatic amine reaction with 2,5-dinitrophenol in antibiotic analysis].
Possible use of dinitrophenol reaction with amines in quantitative determination of amines and amino sugars in various antibiotics was investigated. It was found that the reaction with 2,5-dinitrophenol (2,5-DNP) in dimethylsulfoxide (DMSO) providing the highest batochromic shift in the electron spectra was most suitable. Selectivity of the 2,5-DNP reaction with respect to mycosamine contained in polyenic antibiotics was shown. With the method of PMR it was demonstrated that DMSO formed a complex with 2,5-DMP. The electron spectral of the complexes of glucosamine, N-methylgycosamine and levorin with 2,5-DNP were used for calculation of the complex stability constants, which were practically the same. This provided the use of glucosamine as a standard for plotting the calibration curves. A quantitative method for determination of amines in polyenic antibiotics based on the above reaction was developed.


Impacts of a Workplace-Based Weight-Control Intervention on Objective and Perceived Physical Activity among a Subgroup of Workers.
Physical activity (PA) has many benefits; however, groups facing barriers to health-promoting behaviors are less likely to be physically active. This may be addressed through workplace interventions. The current study employs objective (accelerometry) and perceived (International Physical Activity Questionnaire [IPAQ]) measures of PA among a subset of participants from the "Working for You" study, which tests a multi-level (work group and individual) workplace intervention targeted at workers with low-incomes. Linear mixed and hierarchical logistic regression models are used to determine the intervention's impact on moderate- to vigorous-PA (MVPA) and achieving the PA Guideline for Americans (≥150 minutes MVPA/week), respectively from baseline to 6- and 24-months, relative to a control group. Correlations (Spearman Rho) between perceived and objective PA are assessed. Of the 140 workers (69 control, 71 intervention) in the sub-study, 131 (94%) have valid data at baseline, 88 (63%) at 6-months, and 77 (55%) at 24-months. Changes in MVPA are not significantly different among intervention relative to control participants assessed by accelerometer or IPAQ at 6- or 24-months follow-up. The percent achieving the PA Guideline for Americans does not vary by treatment group by any measure at any time point (e.g., baseline accelerometry: [control: n=37 (57%); intervention: n=35 (53%)]). This study identifies limited agreement (correlation range: 0.04 to 0.42, all p>.05) between perceived and objective measures. Results suggest the intervention did not improve PA among the sub-study participants. Though agreement between objective and perceived MVPA is low, similar conclusions regarding intervention effectiveness are drawn.


Stress tolerance of misfolded carboxypeptidase Y requires maintenance of protein trafficking and degradative pathways.
The accumulation of aberrantly folded proteins can lead to cell dysfunction and death. Currently, the mechanisms of toxicity and cellular defenses against their effects remain incompletely understood. In the endoplasmic reticulum (ER), stress caused by misfolded proteins activates the unfolded protein response (UPR). The UPR is an ER-to-nucleus signal transduction pathway that regulates a wide variety of target genes to maintain cellular homeostasis. We studied the effects of ER stress in budding yeast through expression of the well-characterized misfolded protein, CPY*. By challenging cells within their physiological limits to resist stress, we show that the UPR is required to maintain essential functions including protein translocation, glycosylation, degradation, and transport. Under stress, the ER-associated degradation (ERAD) pathway for misfolded proteins is saturable. To maintain homeostasis, an "overflow" pathway dependent on the UPR transports excess substrate to the vacuole for turnover. The importance of this pathway was revealed through mutant strains compromised in the vesicular trafficking of excess CPY*. Expression of CPY* at levels tolerated by wild-type cells was toxic to these strains despite retaining the ability to activate the UPR.


[Extended-spectrum beta-lactamase production by Enterobacteriaceae isolates from urine cultures of outpatients: results of a 7-year follow-up].
The aim of the study was to evaluate the change of the frequency of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae isolates from urine samples of outpatients in years and to analyse the antibiotic resistance profiles for a rational drug use. The urine samples cultured in our laboratory from the patients who were admitted to outpatient clinics of our hospital between years 2007-2013 were included in this study. Enterobacteriaceae strains were isolated and identified by conventional methods and API 20E system (BioMérieux, France). The standard antimicrobial susceptibility tests were performed by Kirby Bauer disk diffusion method. ESBL production were screened by double-disk synergy method according to CLSI guidelines. E-test method (BioMérieux, France) were used for the verification of suspicious ESBL production. The identification and antimicrobial susceptibility testing were performed for a total of 12.535 isolates. Of the isolates 8716 were identified as Escherichia coli (69.3%), 1514 were Klebsiella pneumoniae/oxytoca (12.1%), 257 were Proteus mirabilis (2.1%), 345 were other Enterobacteriae members (8%), 411 were various non-fermentative gram-negative bacteria (3.3%) and 1292 were various gram-positive bacteria (10.3%). The total positivity rate of ESBL was found as 21.8% (2.283/10.487), and the ESBL positive rates for E.coli, K.pneumoniae/oxytoca and P.mirabilis were 21.2%, 28.2% and 4.7%, respectively. Other Enterobacteriaceae isolates were not evaluated because of the absence of standardized methods and breakpoint values. There was no statistically significant difference among ESBL producing isolates within seven years (p= 0.364). The antibiotic resistance rates of the ESBL-positive isolates were statistically higher than ESBL-negative isolates [amoxicillin-clavulanate (73.1%/11.3%), trimethoprim-sulfamethoxazole (63.1%/31.0%), nitrofurantoin (17.3%/8.6%), gentamicin (42.2%/10.1%), amikacin (3.5%/0.9%), tobramisin (56.8%/10.5%), imipenem (0.3%/0.1%), ofloxacin (66.8%/19.8%), ticarcillin-clavulanate (73.5%/19.8%), piperacillin-tazobactam (28.8%/5.0%)] (p< 0.05). Statistically significant variations were detected within the years for the resistance rates of amoxicillin-clavulanate (p= 0.001), tobramycin (p=0.003), ofloxacin (p= 0.001), ticarcillin-clavulanate (p= 0.001) and piperacillin-tazobactam (p= 0.001) were detected within the years. Although a quite high percentage of ESBL positivity in Enterobacteriaceae isolates was determined, there was a slight but not statistically significant increase of this value during the seven-year period. The stability of the percentage of ESBL positivity may indicate a positive change in the habit of the usage of beta-lactam antibiotics. According to the results of our study, the most effective drugs for ESBL-producing isolates were piperacillin-tazobactam among inhibitor combinations, amikacin among aminoglycosides and nitrofurantoin among orally-used drugs.


Asymmetric induction during Yang cyclization of alpha-oxoamides: the power of a covalently linked chiral auxiliary is enhanced in the crystalline state.
Gamma-hydrogen abstraction has been revealed to be the primary photoprocess in the crystalline state of alpha-oxoamides through photochemical and X-ray structural studies. The outstanding ability of a covalent chiral auxiliary in generating asymmetric induction in the photoproduct beta-lactam has been established with 10 examples. We have shown that the crystal lattice preorganizes the reactant molecules toward a single diastereomer of the beta-lactam and prevents large motions of the 1,4-diradical intermediate that would result in the loss of stereochemical memory. A rare single-crystal-to-single-crystal transformation path of one of the examples investigated establishes the direct correlation between the stereochemistries of the reactant and the product.


Does breastfeeding influence future sperm quality and reproductive hormones?
No human study has investigated the possible impact of breastfeeding on semen quality and levels of reproductive hormones, but a recent study of another hypothesis indicated an association with oligozoospermia. We investigated the association between breastfeeding, semen quality and levels of reproductive hormones. From a Danish pregnancy cohort established in 1984-1987, 347 sons were selected according to maternal smoking during pregnancy and followed up with questionnaires, semen analysis and blood sampling in 2005-2006. Complete data were available for 269 men aged 18-21 years. Breastfeeding was not statistically significantly associated with sperm concentration, total sperm count, sperm motility or morphology, oligozoospermia, follicle-stimulating hormone, inhibin B, luteinizing hormone, sex hormone-binding globulin (SHBG), the calculated level of free testosterone, free oestradiol, the free testosterone/free oestradiol ratio or the follicle-stimulating hormone/inhibin B ratio. Total testosterone and total oestradiol was 16% (p = 0.01) and 14% (p = 0.06), respectively, lower among men never breastfed in comparison with men breastfed exclusively for 1 month or longer. When taking SHBG into account, neither free testosterone nor free oestradiol was different between the two groups. This study shows no association between breastfeeding and sperm quality or reproductive hormones and a strong association is unlikely. A larger study would be needed to detect more subtle effects.


Chloride net efflux from intact erythrocytes under slippage conditions. Evidence for a positive charge on the anion binding/transport site.
Tracer chloride and potassium net efflux from valinomycin-treated human erythrocytes were measured into media of different chloride concentrations, Clo, at 25 degrees C and pH 7.8. Net efflux was maximal [45-50 mmol (kg cell solids)-1 min-1] at Clo = 0. It decreased hyperbolically with increasing Clo to 14-16 mmol (kg cell solids)-1 min-1. Half-maximal inhibition occurred at Clo = 3 mM. In the presence of the anion exchange inhibitor DNDS, net efflux was reduced to 5 mmol (kg cell solids)-1 min-1, independent of Clo. Of the three phenomenological components of net efflux, the Clo-inhibitable (DNDS-inhibitable) component was tentatively attributed to "slippage," that is, net transport mediated by the occasional return of the empty transporter. The Clo-independent (DNDS-inhibitable) component was tentatively attributed to movement of chloride through the anion transporter without the usual conformational change of the transport site on the protein ("tunneling"). These concepts of slippage and tunneling are shown to be compatible with a model that describes the anion transporter as a specialized single-site, two-barrier channel that can undergo conformational changes between two states. Net chloride efflux when the slippage component dominated (Clo = 0.7 mM) was accelerated by a more negative (inside) membrane potential. It appears that the single anion binding-and-transport site on each transporter has one net positive charge and that is neutralized when a chloride ion is bound.


Community healthcare appointments as an alternative to emergency department assessment: an exploration of family acceptability and preferences.
Pediatric emergency departments are overcrowded, in part due to many non-emergent visits. We aimed to assess the proportion of parents interested in leaving the pediatric emergency department (ED) prior to physician assessment if they could be offered a scheduled community healthcare appointment. We explored differences in care children received in the ED stratified by interest in a community healthcare appointment and parents' reasons when they were not interested. We conducted a 14-item survey within the pediatric ED at a Canadian tertiary care teaching hospital to assess parents' interest if a program offered community healthcare appointments and we determined preferred appointment characteristics. All parents presenting with children triaged as CTAS 2-5 who met eligibility criteria were approached by a research assistant prior to physician assessment. Surveys were paired with the medical chart outlining the care received. Descriptive statistics and a regression model were used to describe characteristics of families and care received among those who were and were not interested in a community healthcare appointment. In total, 403 surveys were completed. Overall, 236 participants (58.6%; 95% CI 53.8-63.4) were interested in a community healthcare appointment. In general, parents who were interested in a community healthcare appointment were younger and presented with younger children compared to those who were not interested. Among those interested, there was a preference to have the appointment with a pediatrician or family physician, timely access to an appointment, and appointments scheduled outside of regular business hours. Our study provides evidence that there is interest in an alternative care access model positioned to reduce pediatric ED congestion. We found that parents would be interested in leaving the pediatric ED in favor of a community healthcare appointment, provided it was with a physician and available in a timely manner.


Prasugrel: a novel platelet ADP P2Y(12) receptor antagonist.
Novel adenosine diphosphate (ADP) P2Y(12) antagonists such as prasugrel, ticagrelor, cangrelor, and elinogrel are in various phases of clinical development. These ADP P2Y(12) antagonists have advantages over clopidogrel ranging from faster onset to greater and less variable inhibition of platelet function. Novel ADP P2Y(12) antagonists are under investigation to determine whether their use can result in improved antiplatelet activity, faster onset of action, and/or greater antithrombotic effects than clopidogrel without an unacceptable increase in hemorrhagic or other side effects. Prasugrel (CS-747; LY-640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet ADP P2Y(12) receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower inter-individual variability in platelet response, and faster onset of activity compared to clopidogrel. Recent findings from large-scale phase-III testing show prasugrel to be more efficacious in preventing ischemic events in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI); however, this is achieved at the expense of an increased risk of bleeding. Prasugrel provides more rapid and consistent platelet inhibition than clopidogrel.


Anaesthesia for day case surgery: a survey of paediatric clinical practice in the UK.
In October 2000, we conducted a national postal survey of day case consultant anaesthetists in the UK to explore the range and variation in practice of anaesthetizing a patient for day case surgery (paediatrics, urology and orthopaedics). This paper reports the findings of this national survey of paediatric day case anaesthetic practice carried out as part of a major two-centre randomized controlled trial designed to investigate the costs and outcome of several anaesthetic techniques during day care surgery in paediatric and adult patients (cost-effectiveness study of anaesthesia in day case surgery). The survey used a structured postal questionnaire and collected data on the duration of surgical procedure; the use of premedication; the anaesthetic agents used for induction and maintenance; the fresh gas flow rates used for general anaesthesia; the use of antiemetics; and the administration of local anaesthesia and analgesia. The overall response rate for the survey was 74 and 63% for the paediatric section of the survey. Respondents indicated that 19% used premedication, 63% used propofol for induction, 54% used isoflurane for maintenance, 24% used prophylactic antiemetics and 85%, used a laryngeal mask. The findings of this national survey are discussed and compared with published evidence. This survey identifies the variation in clinical practice in paediatric day surgery anaesthesia in the UK.


Cardiac resynchronization therapy outcomes in patients with chronic heart failure: cardiac resynchronization therapy with pacemaker versus cardiac resynchronization therapy with defibrillator.
Cardiac resynchronization therapy (CRT) for chronic heart failure with left ventricular systolic dysfunction (LVSD) consistently improves survival against optimal medical therapy alone. Limited data exist comparing the outcomes between CRT with pacemaker (CRT-P) and with defibrillator (CRT-D). We aimed to investigate the long-term prognosis of patients who received CRT-P or CRT-D. Data were prospectively collected from consecutive patients with standard indications for CRT, who were implanted at a single large tertiary centre between 2008 and 2012. All-cause mortality was compared between those patients who received either CRT-P or CRT-D. A subgroup analysis was performed in patients with ischaemic cardiomyopathy. During the period in question, 795 patients received CRT devices: 544 (68.4%) CRT-P and 251 (31.6%) CRT-D. The mean follow-up was 1072 ± (SD 556) days. Overall, there was no survival benefit in those patients implanted with a CRT-D compared with CRT-P (hazard ratio 1.09, 95% confidence interval 0.84-1.41, P = 0.51). In patients with ischaemic chronic heart failure [n = 530 (66.7%)], there was a trend for improved survival with CRT-D; however, this was not significant after adjustment. In a subgroup analysis, there were no differences in mode-specific mortality in those patients implanted with CRT-D compared with CRT-P. In this large consecutive patient cohort, we did not find a survival benefit of CRT-D compared with CRT-P. Patients indicated for CRT devices may not reliably benefit from the addition of a defibrillator.


SetQuence & SetOmic: Deep set transformers for whole genome and exome tumour analysis.
In oncology, Deep Learning has shown great potential to personalise tasks such as tumour type classification, based on per-patient omics data-sets. Being high dimensional, incorporation of such data in one model is a challenge, often leading to one-dimensional studies and, therefore, information loss. Instead, we first propose relying on non-fixed sets of whole genome or whole exome variant-associated sequences, which can be used for supervised learning of oncology-relevant tasks by our Set Transformer based Deep Neural Network, SetQuence. We optimise this architecture to improve its efficiency. This allows for exploration of not just coding but also non-coding variants, from large datasets. Second, we extend the model to incorporate these representations together with multiple other sources of omics data in a flexible way with SetOmic. Evaluation, using these representations, shows improved robustness and reduced information loss compared to previous approaches, while still being computationally tractable. By means of Explainable Artificial Intelligence methods, our models are able to recapitulate the biological contribution of highly attributed features in the tumours studied. This validation opens the door to novel directions in multi-faceted genome and exome wide biomarker discovery and personalised treatment among other presently clinically relevant tasks.


The impact of the COVID-19 pandemic on cardiovascular disease prevention and corresponding geographical inequalities in England: interrupted time series analysis.
There has been disruption to the detection and management of those with hypertension and atrial fibrillation (AF) during the COVID-19 pandemic. This is likely to vary geographically and could have implications for future mortality and morbidity. We aimed to estimate the change in diagnosed prevalence, treatment and prescription indicators for AF and hypertension and assess corresponding geographical inequalities. Using the Quality and Outcomes Framework (2016/17 to 2021/22) and the English Prescribing Datasets (2018 to 2022), we described age standardised prevalence, treatment and prescription item rates for hypertension and AF by geography and over time. Using an interrupted time-series (ITS) analysis, we estimated the impact of the pandemic (from April 2020) on missed diagnoses and on the percentage change in medicines prescribed for these conditions. Finally, we described changes in treatment indicators against Public Health England 2029 cardiovascular risk targets. We observed 143,822 fewer (-143,822, 95%CI:-226,144, -61,500, p = 0.001) diagnoses of hypertension, 60,330 fewer (-60,330, 95%CI: -83,216, -37,444, p = 0.001) diagnoses of AF and 1.79% fewer (-1.79%, 95%CI: -2.37%, -1.22%), p < 0.0001) prescriptions for these conditions over the COVID-19 impact period. There was substantial variation across geography in England in terms of the indirect impact of the COVID-19 pandemic on the diagnosis, prescription, and treatment rates of hypertension and AF. 20% of Sub Integrated Care Boards account for approximately 62% of all missed diagnoses of hypertension. The percentage of individuals who had their hypertension controlled fell from 75.8% in 2019/20 to 64.1% in 2021/22 and the percentage of individuals with AF who were risk assessed fell from 97.2% to 90.7%. Hypertension and AF detection and management were disrupted during the COVID-19 pandemic. The disruption varied considerably across diseases and geography. This highlights the utility of administrative and geographically granular datasets to inform targeted efforts to mitigate the indirect impacts of the pandemic through applied secondary prevention measures.


A Comparative Review on Microbiota Manipulation: Lessons From Fish, Plants, Livestock, and Human Research.
During recent years the impact of microbial communities on the health of their host (being plants, fish, and terrestrial animals including humans) has received increasing attention. The microbiota provides the host with nutrients, induces host immune development and metabolism, and protects the host against invading pathogens (1-6). Through millions of years of co-evolution bacteria and hosts have developed intimate relationships. Microbial colonization shapes the host immune system that in turn can shape the microbial composition (7-9). However, with the large scale use of antibiotics in agriculture and human medicine over the last decades an increase of diseases associated with so-called dysbiosis has emerged. Dysbiosis refers to either a disturbed microbial composition (outgrowth of possible pathogenic species) or a disturbed interaction between bacteria and the host (10). Instead of using more antibiotics to treat dysbiosis there is a need to develop alternative strategies to combat disturbed microbial control. To this end, we can learn from nature itself. For example, the plant root (or "rhizosphere") microbiome of sugar beet contains several bacterial species that suppress the fungal root pathogen Rhizoctonia solani, an economically important fungal pathogen of this crop (11). Likewise, commensal bacteria present on healthy human skin produce antimicrobial molecules that selectively kill skin pathogen Staphylococcus aureus. Interestingly, patients with atopic dermatitis (inflammation of the skin) lacked antimicrobial peptide secreting commensal skin bacteria (12). In this review, we will give an overview of microbial manipulation in fish, plants, and terrestrial animals including humans to uncover conserved mechanisms and learn how we might restore microbial balance increasing the resilience of the host species.


The TGF-β profibrotic cascade targets ecto-5'-nucleotidase gene in proximal tubule epithelial cells and is a traceable marker of progressive diabetic kidney disease.
Progressive diabetic nephropathy (DN) and loss of renal function correlate with kidney fibrosis. Crosstalk between TGF-β and adenosinergic signaling contributes to the phenotypic transition of cells and to renal fibrosis in DN models. We evaluated the role of TGF-β on NT5E gene expression coding for the ecto-5`-nucleotidase CD73, the limiting enzyme in extracellular adenosine production. We showed that high d-glucose may predispose HK-2 cells towards active transcription of the proximal promoter region of the NT5E gene while additional TGF-β results in full activation. The epigenetic landscape of the NT5E gene promoter was modified by concurrent TGF-β with occupancy by the p300 co-activator and the phosphorylated forms of the Smad2/3 complex and RNA Pol II. Transcriptional induction at NT5E in response to TGF-β was earlier compared to the classic responsiveness genes PAI-1 and Fn1. CD73 levels and AMPase activity were concomitantly increased by TGF-β in HK-2 cells. Interestingly, we found increased CD73 content in urinary extracellular vesicles only in diabetic patients with renal repercussions. Further, CD73-mediated AMPase activity was increased in the urinary sediment of DN patients. We conclude that the NT5E gene is a target of the profibrotic TGF-β cascade and is a traceable marker of progressive DN.


Molecular and biological characteristics of H5 and H7 avian influenza viruses in live-bird markets of the northeastern United States, 1994-2001.
Surveillance for H5 and H7 subtypes of avian influenza virus (AIV) in the live-bird markets (LBMs) of the northeastern United States has been in effect since 1986 when the markets were first recognized as a potential reservoir for AIV. Long-term maintenance of AIV in the LBM system has been documented. However, little is known about the influence of successive cycles of replication in unnatural avian hosts (gallinaceous birds) on the genetics of the virus, especially in the region of the hemagglutinin (HA) gene that can influence pathogenicity. Isolation of low-pathogenicity H5 AIVs from the LBMs has been sporadic; however, in 1994 a low-pathogenicity H7N2 virus was isolated that has persisted in the LBMs for more than 7 yr. Efforts to eliminate the H7 virus from the markets have been unsuccessful. During the 7-yr period, several molecular changes have occurred at the hemagglutinin cleavage site of the H7 virus. These changes include substitutions of proline for threonine and lysine for asparagine, respectively, at the -2 and -5 positions of the HA1 protein. In addition, there has been a 24 nucleotide base-pair deletion in the receptor binding region of the HA1. The accumulation of an additional basic amino acid at the cleavage site is a cause for concern to regulatory authorities, and, therefore, efforts to eliminate the virus from the LBM system have been intensified.


Duplex ultrasound in the early diagnosis of acute mesenteric ischemia: a longitudinal cohort multicentric study.
Acute mesenteric ischemia (AMI) is a life-threatening condition requiring time-dependent treatment; thus, early recognition may improve outcomes. We hypothesized that clinician-performed mesenteric vessels duplex ultrasound (DUS) could facilitate early identification of patients with AMI in high-risk patients presenting with abdominal pain. This was a single-operator, observational, prospective cohort study. Patients aged at least 65 presenting to Emergency Departments with acute abdominal pain and no clear diagnosis after an initial work-up were enrolled. All patients underwent multidetector computed tomography and these findings provided the reference standard in this study. DUS of the celiac artery and superior mesenteric artery (SMA) were obtained to measure the peak systolic velocity (PSV) and were performed within 24 h of admission. PSVs outside the normal range were considered to indicate AMI. Of 49 patients identified, 47 were consented to enrollment and diagnostic images were obtained in 45 (96%). Fifteen patients (33%) had AMI (six occlusive, nine nonocclusive disease). Among these, 12 (80%) had abnormal DUS velocities. SMA PSV showed a sensitivity of 78.57% [95% confidence interval (CI): 49.2-95.34], a specificity of 64.52% (95% CI: 45.37-80.77), a positive predictive value of 50% (95% CI: 28.22-71.78), and a negative predictive value of 86.96% (95% CI: 66.41-97.22) for AMI. DUS had a sensitivity of 100%, a specificity of 64%, and a negative predictive value of 100% for occlusive AMI. Assessment of celiac artery PSV did not improve diagnostic performance. In this single-operator pilot study, mesenteric vessel DUS was performed successfully in the Emergency Department, with a high proportion of diagnostic images obtained. A normal SMA PSV was associated with a low risk of occlusive AMI.


The Effect of Improved Dysphagia Care on Outcome in Patients with Acute Stroke: Trends from 8-Year Data of a Large Stroke Register.
Early dysphagia screening and appropriate management are recommended by current guidelines to reduce complications and case fatality in acute stroke. However, data on the potential benefit of changes in dysphagia care on patient outcome are limited. Our objective was to assess the degree of implementation of dysphagia guidelines and determine the impact of modifications in dysphagia screening and treatment practices on disease complications and outcome in stroke patients over time. In this prospective register-based study ("Stroke Register of Northwestern Germany"), all adult stroke patients admitted to 157 participating hospitals between January, 2008 and December, 2015 were included (n = 674,423). Dysphagia incidence upon admission, the proportion of patients receiving a standardized swallowing screening, and the percentage of dysphagic patients being referred to a speech language therapist (SLT) for treatment were obtained per year. Pneumonia rate, modified Rankin Scale (mRS) at discharge, and in-hospital mortality were compared between groups of dysphagic vs. non-dysphagic patients over time. Screening proportions continuously increased from 47.2% in 2008 to 86.6% in 2015. But the proportion diagnosed with dysphagia remained stable with about 19%. The number of dysphagic patients receiving SLT treatment grew from 81.6 up to 87.0%. Pneumonia incidence was higher in dysphagic stroke cases (adjusted OR 5.4 [5.2-5.5], p < 0.001), accompanied by a worse mRS at discharge (adjusted OR for mRS ≥3: 3.1 [3.0-3.1], p < 0.001) and higher mortality (adjusted OR 3.1 [3.0-3.2], p < 0.001). The order of magnitude of these end points did not change over time. Although advances have been made in dysphagia care, prevalent screening and treatment practices remain insufficient to reduce pneumonia rate, improve functional outcome, and decrease case fatality in dysphagic stroke patients. More research is urgently needed to develop more effective swallowing therapies.


Development of a parent version of the Manchester-Minneapolis quality of life survey for use by parents and carers of UK children: MMQL-UK (PF).
Although it is now widely endorsed that children should as far as possible rate their own health related quality of life (HRQL), there are situations where proxy information on child HRQL may be useful, especially where a child is too ill or young to provide their own HRQL assessment. There is limited availability of generic HRQL scales that have a parallel child and parent version and that are reliable, valid, brief, comprehensible and suitable for use in UK populations. The aims of this study were therefore to develop and validate a parent version of the anglicised Manchester-Minneapolis Quality of Life child form (MMQL-UK (CF)) and to determine the level of association between the child and parent versions of this form. This study was undertaken concurrently with the anglicisation and validation of the MMQL, a measure of HRQL developed for use with children in North America. At that time, no parent version existed, so the MMQL form for children (MMQL-UK (CF)) was used as the basis for the development of the MMQL-UK parent form (PF). The sample included a control group of healthy children and their parents and five exemplar groups; children diagnosed with asthma, diabetes or inflammatory bowel disease and their parents, children in remission from cancer and their parents and children in public care and their carers. Consistency of the MMQL-UK (PF) components were assessed by calculating Cronbach's alpha. Validation of the parent questionnaire was undertaken by comparing MMQL-UK (PF) component scores with comparable components on the proxy PedsQLtrade mark quality of life scales, comparing MMQL-UK (PF) component scores between parents of healthy and chronic disease children and by comparison of component scores from children and their parents or carers. Reproducibility and responsiveness were assessed by retesting parents by follow-up questionnaires. A total of 874 children (completing MMQL-UK (CF)) and 572 parents or carers (completing MMQL-UK (PF)) took part in the study. The internal consistency of all the MMQL-UK (PF) components exceeding the accepted criterion of 0.70 and the construct validity was good with moderate correlations being evident between comparable components of the MMQL-UK (PF) and the proxy PedsQLtrade mark. Discriminant validity was demonstrated with significant differences being identified between parents of healthy children and those with chronic conditions. Intra-class correlations exceeded 0.65 for all MMQL-UK (PF) components demonstrating good reproducibility. Weak to moderate levels of responsiveness were demonstrated for all but social functioning. The MMQL-UK (PF) showed moderate parent-child correlation with the MMQL-UK (CF) for all components. The best correlations were seen for those components measuring the same construct (Pearson's r ranged from 0.31 to 0.61, p < 0.01 for equivalent components). The MMQL-UK (PF) showed moderate to good correlations with the MMQL-UK (CF) component scores. The MMQL-UK (PF) will be of use when comparing child and parent/carer perception of the impact of a child's condition on their HRQL or where the child is too ill or young to provide their own report.


Effect of SiO2 on immobilization of metals and encapsulation of a glass network in slag.
The final disposal of ash from an incinerator is of special concern because of the possibility of its releasing toxic substances. Melting/vitrification has been regarded as a prospective technology of ash treatment. The object of this investigation was to evaluate the effect of silica (SiO2) addition on the immobilization of hazardous metals and the encapsulation of a glass network during the vitrification process. Four specimens with SiO2/fly ash mixing ratios of 0, 0.1, 0.2, and 0.3, respectively, were tested. The mobility of metals in slag was then estimated by a sequential extraction procedure. X-ray diffraction analysis indicates that SiO2 leads to the polymerization of silicates. The encapsulation of aluminum, calcium, and magnesium would not be observed unless adequate amount of SiO2 was added. It was also found that SiO2 addition enhances the formation of a compact and interconnected glass network structure and, thus, contributes to the chemical stability of metals in slag. After vitrification, the mobility of cadmium, copper, iron, chromium, nickel, lead, and zinc was significantly reduced. However, there is no significant correlation between the immobilization of these metals and the addition of SiO2.


High prevalence of multidrug resistant ESBL- and plasmid mediated AmpC-producing clinical isolates of Escherichia coli at Maputo Central Hospital, Mozambique.
Epidemiological data of cephalosporin-resistant Enterobacterales in Sub-Saharan Africa is still restricted, and in particular in Mozambique. The aim of this study was to detect and characterize extended-spectrum β-lactamase (ESBL) - and plasmid-mediated AmpC (pAmpC)-producing clinical strains of Escherichia coli at Maputo Central Hospital (MCH), a 1000-bed reference hospital in Maputo, Mozambique. A total of 230 clinical isolates of E. coli from urine (n = 199) and blood cultures (n = 31) were collected at MCH during August-November 2015. Antimicrobial susceptibility testing was performed by the disc diffusion method and interpreted according to EUCAST guidelines. Isolates with reduced susceptibility to 3rd generation cephalosporins were examined further; phenotypically for an ESBL-/AmpC-phenotype by combined disc methods and genetically for ESBL- and pAmpC-encoding genes by PCR and partial amplicon sequencing as well as genetic relatedness by ERIC-PCR. A total of 75 isolates with reduced susceptibility to cefotaxime and/or ceftazidime (n = 75) from urine (n = 58/199; 29%) and blood (n = 17/31; 55%) were detected. All 75 isolates were phenotypically ESBL-positive and 25/75 (33%) of those also expressed an AmpC-phenotype. ESBL-PCR and amplicon sequencing revealed a majority of blaCTX-M (n = 58/75; 77%) dominated by blaCTX-M-15. All AmpC-phenotype positive isolates (n = 25/75; 33%) scored positive for one or more pAmpC-genes dominated by blaMOX/FOX. Multidrug resistance (resistance ≥ three antibiotic classes) was observed in all the 75 ESBL-positive isolates dominated by resistance to trimethoprim-sulfamethoxazole, ciprofloxacin and gentamicin. ERIC-PCR revealed genetic diversity among strains with minor clusters indicating intra-hospital spread. We have observed a high prevalence of MDR pAmpC- and/or ESBL-producing clinical E. coli isolates with FOX/MOX and CTX-Ms as the major β-lactamase types, respectively. ERIC-PCR analyses revealed genetic diversity and some clusters indicating within-hospital spread. The overall findings strongly support the urgent need for accurate and rapid diagnostic services to guide antibiotic treatment and improved infection control measures.


Tonic activation of group I mGluRs modulates inhibitory synaptic strength by regulating KCC2 activity.
The furosemide-sensitive potassium-chloride cotransporter (KCC2) plays an important role in establishing the intracellular chloride concentration in many neurons within the central nervous system. Consequently, modulation of KCC2 function will regulate the reversal potential for synaptic GABAergic inputs, thus setting the strength of inhibitory transmission. We show that tonic activation of group I metabotropic glutamate receptors (mGluR1s) regulates inhibitory synaptic strength via modulation of KCC2 function in pyramidal neurons of the hippocampal CA3 area. Specifically, group I mGluRs signal via activation of a protein kinase C-dependent pathway to alter KCC2 activity, thereby altering the intracellular chloride concentration, and thus inhibitory synaptic input. This interaction between the glutamatergic and chloride transport systems highlights a novel homeostatic mechanism whereby ambient glutamate levels directly regulate the inhibitory synaptic tone by setting the activity level of KCC2. Thus, mGluRs are poised to play a pivotal role in providing a direct interplay between the excitatory and inhibitory systems in the hippocampus.


PERV induces CXCL10 in human monocytes and monocyte-derived primary cells.
Pigs are suitable donor species for xenotransplantation and biological materials from these animals are used for this purpose for many years. A major risk of xenotransplantation is a zoonosis by transspecies transmission of animal viruses. In this regard Porcine Endogenous Retroviruses (PERVs) are of paramount importance because some of them are able to infect human cells and could induce innate immune responses. Using a replication competent polytropic PERV-A/C strain we have analysed induction of innate immune responses by this virus in human monocytes, Monocyte-Derived Macrophages (MDM) and Monocyte-Derived Dendritic Cells (MDDC). PERV-A/C elevates expression of the C-X-C motif chemokine 10 (CXCL10) up to 1000-fold in human monocytes and monocyte-derived primary cells. In comparison to CXCL10, the levels of interferon-β (IFN-β) and Interferon-Stimulated Gene 54 (ISG54) were almost unchanged. Heat-inactivated virus did not induce CXCL10 expression. Neither treatment with the reverse transcriptase inhibitors azidothymidine (AZT) and stavudine (d4T) nor treatment with the integrase inhibitor raltegravir (RAL) reduced the activation levels. Furthermore, depletion of SAM domain and HD domain-containing protein 1 (SAMHD1), a restriction factor that blocks PERV-A/C infection at the level of reverse transcription in these myeloid cells, had no significant effect on the CXCL10 induction level. These results imply that innate immune sensing leading to the strong CXCL10 response occurs at an early step of the replication process and does not require products of reverse transcription. Inhibition of Janus Kinases (JAKs) by AT9283 prevented the observed CXCL10 induction by the virus providing evidence that the JAK-STAT signalling pathway is involved in the CXCL10 response in theses myeloid cells. Our findings highlight PERVs as inducers of the pro-inflammatory chemokine CXCL10 and other innate immune responses in human monocytes and derived cells with potential implications in the context of xenotransplantation.


[Diagnosis of cytomegalovirus disease in biopsy and surgical material. Methods and clinical relevance].
Since the first description of cytomegaly as "disease with protozoan-like cells" more than 50 years have past until a definitive explanation of the viral aetiology was reached. In the eighties cytomegaly gained increasing importance in adults. This event was based upon the occurrence of cytomegaly especially in patients with organ transplantation, AIDS infection, chronic dialysis or chemotherapy of malignant tumours. With the development of immunohistochemistry (IHC), in situ hybridization (IHS) and polymerase chain reaction (PCR) new, more sensitive methods became available to detect CMV infections especially in biopsy specimens or cytological material. With IHC, ISH and PCR CMV verification is possible in seemingly normal cells without inclusion bodies. PCR can be used also on small biopsy particles of paraffin-embedded material and is characterized by high specificity and sensitivity. The parallel performance of IHC and ISH was proved to be useful in routine diagnostic work, whereas PCR should be used especially in diagnostically different cases. The methods of the evidence of CMV infection are analysed in the different organs.


Anti-PD1 does not improve pyroptosis induced by γδ T cells but promotes tumor regression in a pleural mesothelioma mouse model.
Mesothelioma is an aggressive tumor in the pleural cavity that is difficult to treat. Diagnosis is usually late with minimal treatment options available for the patients and with unfavorable outcomes. However, recent advances in immunotherapy using γδ T cells may have potential against mesothelioma, given its ample tumoricidal and tumor-migratory properties could allow its infiltration to the widespread tumor mass. Thus, we hypothesize that Vδ2 T cells can perform cytotoxic activities against mesothelioma especially when combined with immune checkpoint blocker against PD-1. Human Vδ2 T cells were expanded from peripheral blood mononuclear cells using Tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of Vδ2 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect Vδ2 T cells post adoptive transfer and characteristics of pyroptosis in ex vivo mesothelioma tissue sections. Indeed, our data demonstrated that Vδ2 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody in vitro, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of Vδ2 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of Vδ2 T cells into the tumor, especially to cells with BTN2A1 expression (a Vδ2 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by Vδ2 T cells. This was verified by Vδ2 T/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1β and IL-18. Vδ2 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing Vδ2 T cells in promoting pyroptosis. Taken together, our work demonstrated that Vδ2 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma.


[The algorith of preoperative cardiovascular therapy in high risk elderly oncology patients].
The study was based on 478 oncology patients (72.1 +/- 3.6 years old) with cardiovascular comorbidities operated from 1991 to 2008 in regards of abdominal and pelvic mainly 3rd stage tumors with multimodal general anesthesia (4.2 +/- 1.6 hours). In prospective group (n = 302) all patients received cardiovascular treatment, while in retrospective group (n = 176) only 48.9% received it. The evaluation of the cardiovascular therapy effect was based on the peri-operative and postoperative HR and BP dynamics. The occurrance of noticeable bradycardia and drop of BP lower than 90/60 mm Hg was considered as a deviation. It is revealed that the cardiovascular therapy with beta adrenoblockers and calcium antagonists leads to an intraoperative bradycardia in 59.8% and 73.7% of cases, while in patients without the aforementioned therapy in 26.6% and 46.4% of cases respectively (p < 0.05). Antiarrhythmics don't have a noticeable impact on the development of bradycardia (p = 0.204). Intraoperative hypotension on the basis of ATP inhibitor treatment developed in 92.2% of patients statistically significant (p < 0.01). Monotherapy with calcium antagonists or nitrates leads to the development of hypotension in 55.2% and 41.4% of cases respectively, though in patients without the given therapy a lot more often (p < 0.05). In the case of combined calcium antagonist/nitrate therapy hypotension develops in 55.5% of cases, and in 72.3% without the therapy (p < 0.05). For the means of prevention of cardiovascular complications during the surgical treatment it is appropriate to keep the therapy with nitrates, though vasodilatives should be canceled 12 hours before the surgery.


System-wide impacts of hospital payment reforms: evidence from Central and Eastern Europe and Central Asia.
While there is broad agreement that the way that health care providers are paid affects their performance, the empirical literature on the impacts of provider payment reforms is surprisingly thin. During the 1990s and early 2000s, many European and Central Asian (ECA) countries shifted from paying hospitals through historical budgets to fee-for-service (FFS) or patient-based payment (PBP) methods (mostly variants of diagnosis-related groups, or DRGs). Using panel data on 28 countries over the period 1990-2004, we exploit the phased shift from historical budgets to explore aggregate impacts on hospital throughput, national health spending, and mortality from causes amenable to medical care. We use a regression version of difference-in-differences (DID) and two variants that relax the DID parallel trends assumption. We find that FFS and PBP both increased national health spending, including private (i.e. out-of-pocket) spending. However, they had different effects on inpatient admissions (FFS increased them; PBP had no effect), and average length of stay (FFS had no effect; PBP reduced it). Of the two methods, only PBP appears to have had any beneficial effect on "amenable mortality", but we found significant impacts for only a couple of causes of death, and not in all model specifications.


Hip movement pathomechanics of patients with hip osteoarthritis aim at reducing hip joint loading on the osteoarthritic side.
This study aims at defining gait pathomechanics in patients with hip osteoarthritis (OA) and their effect on hip joint loading by combining analyses of hip kinematics, kinetics and contact forces during gait. Twenty patients with hip OA and 17 healthy volunteers matched for age and BMI performed three-dimensional gait analysis. Hip OA level was evaluated based on plane radiographs using the Tönnis classification. Hip joint kinematics, kinetics as well as hip contact forces were calculated. Waveforms were time normalized and compared between groups using statistical parametric mapping analysis. Patients walked with reduced hip adduction angle and reduced hip abduction and external rotation moments. The work generated by the hip abductors during the stance phase of gait was largely decreased. These changes resulted in a decrease and a more vertical and anterior orientation of the hip contact forces compared to healthy controls. This study documents alterations in hip kinematics and kinetics resulting in decreased hip loading in patients with hip OA. The results suggested that patients altered their gait to increase medio-lateral stability, thereby decreasing demand on the hip abductors. These findings support discharge of abductor muscles that may bear clinical relevance of tailored rehabilitation targeting hip abductor muscles strengthening and gait retraining.


Anisometropia in children: analysis of a hospital population.
In a hospital population of 1356 children 64 (4.7%) cases of anisometropia (at least 2 diopters in spherical or cylindrical power) were found. After the exclusion of all children with ocular lesions 53 remained. Twenty-seven (42%) of them had strabismus, which seemed to be related to accommodation effort rather than amount of anisometropia. Amblyopia was present in 17 (53%) of the patients with orthotropic anisometropia. Amblyopia increased with the amount of anisometropia. Therapy in the form of spectacle correction and part-time occlusion was successful in 47%. The success rate was related to the age of presentation.


[Riboflavin and lumiflavin analogs and alloxazine derivatives. I. Effect on riboflavin synthesis by and growth of Bacillus subtilis].
Effect of riboflavin, lumiflavin and a number of alloxazine derivatives is studied on the growth of three Bacillus subtilis strains with different genetic state of riboflavin operon as well as their ability to show coenzyme and regulating properties characteristic of vitamin B2. The fission of the ribityl chain of the riboflavin molecule results in the complete loss of both coenzyme and regulating properties of vitamin B2 (analogues of lumiflavin and alloxazine derivatives). Different types of esterification of hydroxyl groups of ribityl chain or its replacement by dulcityl chain results in the decrease of regulating properties characteristic of riboflavin as an end product of biosynthetic pathway (tetraacetylriboflavin and its derivatives, tetrapropionyl- and tetrabutyrylriboflavin) or to the loss of coenzyme and regulating activities (galactoflavin and tetrabenzoylriboflavin). The length increase of hydrocarbon chain under esterification of hydroxyl groups in ribityl chain results in enhancing vitamin B2 non-specific inhibitory effect on the growth of Bacillus subtilis strains studied. The replacement of 8-CH3 group in the riboflavin molecule by amino- or D-ribitylaminogroup results in the formation of specific antimetabolites, 8-amino(nor)riboflavin and 8-D-ribitylamino(nor)riboflavin respectively. Depending on the nature of other alterations or replacements of the 8-CH3 group of riboflavin molecule and their combinations with alterations of ribityl chain the reduction of the regulating activity (8-alpha-bromtetraacetylriboflavin) or a sharp decrease of coenzyme and regulating functions (analogues N 9 to N 15) takes place. The replacement of riboflavin-5-N-oxide and 2-thioriboflavin type did not affect the studied properties of riboflavin.


Attenuation of monocyte adhesion and oxidised LDL uptake in luteolin-treated human endothelial cells exposed to oxidised LDL.
Oxidative modification of LDL is causally involved in the development of atherosclerosis and occurs in vivo in the blood as well as within the vascular wall. The present study attempted to explore whether polyphenolic flavonoids influence monocyte-endothelium interaction and lectin-like oxidised LDL receptor 1 (LOX-1) expression involved in the early development of atherosclerosis. The flavones luteolin and apigenin inhibited THP-1 cell adhesion onto oxidised LDL-activated human umbilical vein endothelial cells (HUVEC), while the flavanols of (-)epigallocatechin gallate and (+)catechin, the flavonols of quercetin and rutin, and the flavanones of naringin, naringenin, hesperidin and hesperetin did not have such effects. Consistently, Western blot analysis revealed that the flavones at 25 microM dramatically and significantly abolished HUVEC expression of vascular cell adhesion molecule-1 and E-selectin evidently enhanced by oxidised LDL; these inhibitory effects were exerted by drastically down regulating mRNA levels of these cell adhesion molecules. In addition, quercetin and luteolin significantly attenuated expression of LOX-1 protein up regulated in oxidised LDL-activated HUVEC with a fall in transcriptional mRNA levels of LOX-1. In addition, quercetin and luteolin clearly blunted oxidised LDL uptake by HUVEC treated with oxidised LDL. The results demonstrate that the flavones luteolin and apigenin as well as quercetin were effective in the different initial steps of atherosclerosis process by inhibiting oxidised LDL-induced endothelial monocyte adhesion and/or oxidised LDL uptake. Therefore, certain flavonoids qualify as anti-atherogenic agents in LDL systems, which may have implications for strategies attenuating endothelial dysfunction-related atherosclerosis.


Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production.
Many cases of autosomal dominant early onset Alzheimer's disease (AD) result from mutations in the gene encoding presenilin-1 (PS-1). PS-1 is an integral membrane protein expressed ubiquitously in neurons throughout the brain in which it is located primarily in endoplasmic reticulum (ER). Although the pathogenic mechanism of PS-1 mutations is unknown, recent findings suggest that PS mutations render neurons vulnerable to apoptosis. Because increasing evidence indicates that mitochondrial alterations contribute to neuronal death in AD, we tested the hypothesis that PS-1 mutations sensitize neurons to mitochondrial failure. PC12 cell lines expressing a PS-1 mutation (L286V) exhibited increased sensitivity to apoptosis induced by 3-nitropropionic acid (3-NP) and malonate, inhibitors of succinate dehydrogenase, compared with control cell lines and lines overexpressing wild-type PS-1. The apoptosis-enhancing action of mutant PS-1 was prevented by antioxidants (propyl gallate and glutathione), zVAD-fmk, and cyclosporin A, indicating requirements of reactive oxygen species (ROS), caspases, and mitochondrial permeability transition in the cell death process. 3-NP induced a rapid elevation of [Ca2+]i, which was followed by caspase activation, accumulation of ROS, and decreases in mitochondrial reducing potential and transmembrane potential in cells expressing mutant PS-1. The calcium chelator BAPTA AM and agents that block calcium release from ER and influx through voltage-dependent channels prevented mitochondrial ROS accumulation and membrane depolarization and apoptosis. Our data suggest that by perturbing subcellular calcium homeostasis presenilin mutations sensitize neurons to mitochondria-based forms of apoptosis that involve oxidative stress.


[Chronic atrophic acrodermatitis].
All the 18 patients with acrodermatitis chronica atrophicans (ACA) showed the specific borrelia antibody at the indirect immunofluorescence assay. The patients exhibited a large spectrum of arthritic and neurologic complaints besides the typical cutaneous symptoms. Changes of proteins, of liver-typical parameters and of the electrocardiogram are also assigned to the Lyme-borreliosis. The penicillin therapy - three times accompanied by a Jarisch-Herxheimer-reaction - led to regression of the clinical changes. The secessions of borrelia-antibody-titers happens only very delayed. That is why it can not be used for the direct therapy control. The increased documented polysymptomatic of Lyme-borreliosis requires a wider knowledge and the country-wide possibility of specific diagnostic.


Cloning of the mouse insulin receptor substrate-3 (mIRS-3) promoter, and its regulation by p53.
The insulin receptor susbtrate-3 (IRS-3) is a member of a family of intermediate adapter proteins that function as major intracellular targets for phosphorylation by the activated insulin and IGF-I receptors. Among the four IRS proteins identified so far, IRS-3 exhibits a rather peculiar expression pattern during both the embryonic development and adult life, suggesting a different mechanism of regulation of its expression. In this study, we cloned the 5' flanking region of the mIRS-3 gene and analyzed its promoter activity. The mIRS-3 promoter is inhibited by wild-type p53, and this effect is completely abolished by cotransfection of a dominant negative p53. Tumor-derived p53 mutants show variable, but lower suppressing capability than wt p53. In addition, treatment with doxorubicin inhibits endogenous expression of mIRS-3 mRNA in C2C12 and 3T3-L1 cells. The DNA region spanning from nucleotides -287 and -178 in the mIRS-3 promoter is responsible for a 32.2% reduction of the mouse double minute 2 (MDM2) promoter activity, suggesting its involvement in the p53-mediated inhibitory effect. In conclusion, our study demonstrates that the mIRS-3 promoter is regulated by p53 at the transcriptional level. The inhibition of mIRS-3 promoter by wild-type p53, and its de-repression by tumor-derived p53 mutants, appears to be similar to that previously reported for the IGF-I receptor promoter, suggesting a common role of these two genes in p53-mediated cell growth and differentiation.


Evaluation of Clinical and Pathologic Risk Factors May Reduce the Rate of Multimodality Treatment of Early Cervical Cancer.
To assess the rate of postoperative adjuvant treatment in patients who underwent radical hysterectomy for early cervical cancer and to suggest criteria for the triage of patients who have a high probability of multimodality treatment. This was a multicenter retrospective study of 514 patients with FIGO stages IA2-IIA cervical cancer who underwent radical hysterectomy between 1999 and 2010. The patients were divided into 2 groups according to whether or not postoperative radiation was administered. The 2 groups were compared with regard to clinical and histopathologic variables divided into major and minor criteria (intermediate risk factors) based on lymph nodes status, parametrial involvement, tumor size, deep stromal invasion, and lymph-vascular space invasion. We identified 294 (57.2%) patients who received adjuvant postoperative radiotherapy (RT) or chemoradiation. Fifty-three percent of these patients who were treated by adjuvant radiation had only intermediate risk factors. Combining the various combinations of 2 out of 3 of the following criteria, we found that 89% of patients with tumors ≥2 cm and lymph-vascular space invasion received RT, 76% of patients with tumors ≥2 cm and depth of invasion >10 mm received RT, and 87% of patients with tumors depth of invasion >10 mm and lymph-vascular space invasion received RT. This study suggests that in patients with early cervical cancer, clinicopathologic evaluation of tumor size and lymph-vascular space invasion should be undertaken before performing radical hysterectomy. This approach can serve to tailor treatment, reducing the rate of employing both radical hysterectomy and chemoradiation.


Experimental assessment of bone mineral density using quantitative computed tomography in holstein dairy cows.
The aim of this study was to assess the measurement of bone mineral density (BMD) by quantitative computed tomography (QCT), comparing the relationships of BMD between QCT and dual-energy X-ray absorptiometry (DXA) and between QCT and radiographic absorptiometry (RA) in the metacarpal bone of Holstein dairy cows (n=27). A significant positive correlation was found between QCT and DXA measurements (r=0.70, P<0.01), and a significant correlation was found between QCT and RA measurements (r=0.50, P<0.01). We conclude that QCT provides quantitative evaluation of BMD in dairy cows, because BMD measured by QCT showed positive correlations with BMD measured by the two conventional methods: DXA and RA.


How do junior medical officers use online information resources? A survey.
Online information resources function dually as important learning tools and sources of the latest evidence-based recommendations for junior medical officers (JMOs). However, little is currently known about how JMOs utilise this information when providing care for their patients. This study aimed to examine the usage and experience of online information resources amongst JMOs in South Australia to ascertain (i) the type of resources accessed, (ii) the frequency, (iii) the intended purpose, and (iv) the perceived reliability. A survey instrument using multiple choices, five-point Likert scales and free-text comments was developed and distributed through SurveyMonkey to South Australian JMOs between 1 May 2014 and 30 June 2014. Of the 142 surveyed, 100 JMOs (70.4%) used online information resources as their first approach over all other resources available. JMOs overwhelmingly (94.4%, n = 134) used online information resources at least once per day, with the most frequent purpose for use being information regarding prescription medication (82.4%, n = 117, reported 'very frequent' use). JMOs stated online resources were necessary to perform their work and, of the different types of information accessed, they rated peer-reviewed resources as the most reliable. JMOs strongly rely upon online clinical information in their everyday practice. Importantly, provision of these resources assists JMOs in their education and clinical performance.


Debate: Recognising and responding to the mental health needs of young people in the era of COVID-19.
The COVID-19 pandemic is a 'perfect storm' for the mental health of young people, because of exposure to known risk factors for psychopathology and lack of support from the infrastructures that are normally in place to ensure safety and provide support. However, it is yet unclear if this 'perfect storm' will flood the Child & Adolescent Mental Health Services. The early, normative emotional responses observed may not lead to enduring psychopathology in most young people. Nevertheless, a minority of young people may show complex presentations, particularly in relation to bereavement. As epidemiology and clinical practice will reveal the actual needs of young people, the hope is that we will find the focus and determination to build new solutions to promote young people's mental health.


The role of membrane skeletal-associated alpha-globin in the pathophysiology of beta-thalassemia.
The beta-thalassemic mouse provides a useful model for testing hypotheses about the pathophysiology in human beta-thalassemia. The clinical picture of these mice and their red blood cell deformability characteristics are quite similar to those observed in human beta-thalassemia intermedia. The creation of transgenic mice that express human beta-globin (beta s) has provided an opportunity to study the effect of increasing the non-alpha-globin chain production on the thalassemic phenotype. A small increase in beta-globin production produces transgenic mice that are healthier, have almost normal hemoglobin values, and whose red blood cell deformability is increased. We quantified and characterized the membrane skeletal-associated globin in normal, transgenic thal/sickle, and thalassemic mice and showed that only alpha-globin was associated with the membrane skeleton in the pathologic red blood cells, and that the degree of rigidity as measured in the rheoscope correlated directly and closely with the amount of membrane skeletal-associated globin in these abnormal red blood cells.


[Psychological aspects of today's adolescents' sexuality].
Sexuality, particularly during adolescence, involves personality as a whole. During puberty, which starts the process of adolescence, adolescents are faced with the fact they have not chosen their body which sends them back to the experience of passivity of childhood. It arouses in the most vulnerable adolescents what remains of expectations or affective dependence regarding their family circle, and thus they are confronted with that basic human paradox, i.e. to be oneself one has to accept to receive and to feed upon others and at the same time to be different from them. Such a fear of being dependent on others may lead adolescents to deprive themselves of what they expect to receive from others. Sexuality and the body, through the emotions they summon, are particularly subject to aggressive or rejection behaviours which characterize that age.


A new species of Metagovea Rosas Costa, 1950 from Napo Province, Ecuador (Opiliones, Cyphophthalmi, Neogoveidae).
As a result of an expedition to Ecuador in 2014, a new species of mite harvestman was discovered. This new species belonging to the genus Metagovea Rosas Costa, 1950 - Metagovealigiae sp. n. - is described, based on male and female specimens from Napo Province, Ecuador. This is the fourth species described for the genus and the second from Ecuador. A simple terminology is proposed for the microtrichiae of the spermatopositor and genital characters in the family are discussed. The genus Brasiliogovea Martens, 1969 is consistently misspelled in the literature as Brasilogovea. The description of Metagovealigiae offered opportunity to discuss some aspects of systematics of the family.


Effects of increased temperature on plant communities depend on landscape location and precipitation.
Global climate change is affecting and will continue to affect ecosystems worldwide. Specifically, temperature and precipitation are both expected to shift globally, and their separate and interactive effects will likely affect ecosystems differentially depending on current temperature, precipitation regimes, and other biotic and environmental factors. It is not currently understood how the effects of increasing temperature on plant communities may depend on either precipitation or where communities lie on soil moisture gradients. Such knowledge would play a crucial role in increasing our predictive ability for future effects of climate change in different systems. To this end, we conducted a multi-factor global change experiment at two locations, differing in temperature, moisture, aspect, and plant community composition, on the same slope in the northern Mongolian steppe. The natural differences in temperature and moisture between locations served as a point of comparison for the experimental manipulations of temperature and precipitation. We conducted two separate experiments, one examining the effect of climate manipulation via open-top chambers (OTCs) across the two different slope locations, the other a factorial OTC by watering experiment at one of the two locations. By combining these experiments, we were able to assess how OTCs impact plant productivity and diversity across a natural and manipulated range of soil moisture. We found that warming effects were context dependent, with the greatest negative impacts of warming on diversity in the warmer, drier upper slope location and in the unwatered plots. Our study is an important step in understanding how global change will affect ecosystems across multiple scales and locations.


Spontaneous ovarian hyperstimulation syndrome and pituitary hyperplasia mimicking macroadenoma associated with primary hypothyroidism.
We report an unusual case of spontaneous ovarian hyperstimulation syndrome and pituitary hyperplasia mimicking macroadenoma in an adult, non-pregnant woman. Her condition was triggered by unrecognized primary hypothyroidism, which regressed after thyroid hormone replacement therapy. This case highlights the need for clinicians and radiologists to familiarize themselves with the clinical and imaging features detected in case of these complications of primary hypothyroidism, which are not well known in the medical and radiological profession. Such improved knowledge will help avoid delays in diagnosis, progression to life-threatening complications, and unnecessary surgery.


Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.
Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.


Growth in coculture stimulates metabolism of the phenylurea herbicide isoproturon by Sphingomonas sp. strain SRS2.
Metabolism of the phenylurea herbicide isoproturon by Sphingomonas sp. strain SRS2 was significantly enhanced when the strain was grown in coculture with a soil bacterium (designated strain SRS1). Both members of this consortium were isolated from a highly enriched isoproturon-degrading culture derived from an agricultural soil previously treated regularly with the herbicide. Based on analysis of the 16S rRNA gene, strain SRS1 was assigned to the beta-subdivision of the proteobacteria and probably represents a new genus. Strain SRS1 was unable to degrade either isoproturon or its known metabolites 3-(4-isopropylphenyl)-1-methylurea, 3-(4-isopropylphenyl)-urea, or 4-isopropyl-aniline. Pure culture studies indicate that Sphingomonas sp. SRS2 is auxotrophic and requires components supplied by association with other soil bacteria. A specific mixture of amino acids appeared to meet these requirements, and it was shown that methionine was essential for Sphingomonas sp. SRS2. This suggests that strain SRS1 supplies amino acids to Sphingomonas sp. SRS2, thereby leading to rapid metabolism of (14)C-labeled isoproturon to (14)CO(2) and corresponding growth of strain SRS2. Proliferation of strain SRS1 suggests that isoproturon metabolism by Sphingomonas sp. SRS2 provides unknown metabolites or cell debris that supports growth of strain SRS1. The role of strain SRS1 in the consortium was not ubiquitous among soil bacteria; however, the indigenous soil microflora and some strains from culture collections also stimulate isoproturon metabolism by Sphingomonas sp. strain SRS2 to a similar extent.


An exploratory comparative analysis of tyrosine kinase inhibitors or docetaxel in second-line treatment of EGFR wild-type non-small-cell lung cancer: a retrospective real-world practice review at a single tertiary care centre.
Treatment for advanced non-small-cell lung cancer (nsclc), especially in patients with wild-type EGFR, remains limited. Recently, erlotinib, a tyrosine kinase inhibitor (tki) targeting EGFR mutation, was approved as second-line treatment in EGFR wild-type nsclc. Despite evidence of better overall survival (os) with chemotherapy than with tki in second-line treatment, data on the use of tki in the real-life clinical setting remain limited. The present practice review of tki use for second- and third-line treatment in EGFR wild-type nsclc also compares clinical outcomes for tki and single-agent docetaxel as second-line treatment. Our retrospective cohort study included patients with EGFR wild-type nsclc treated at the Jewish General Hospital (Montreal, QC) between 2003 and 2013. Patients received a tki (erlotinib or gefitinib) in the second and third line or docetaxel in the second line. For each group, we determined os, disease control rate, progression-free survival (pfs), and event-free survival (efs). The tki group included 145 patients, with 92 receiving second-line treatment. In the control group, 53 patients received docetaxel as second-line therapy. In the tki group, os was 6.0 months; pfs, 2.7 months; and efs, 3.0 months. Comparing second-line treatments, os was 5.3 and 5.0 months respectively (p = 0.88), pfs was 2.5 and 1.8 months respectively (p = 0.041), and efs was 3.0 and 1.7 months respectively (p = 0.009). In our study cohort, second-line therapy for EGFR wild-type nsclc with tki (compared with docetaxel) was associated with statistically better pfs and efs and noninferior os. Those findings raise the question of whether efs should also be considered when choosing second-line treatment in this patient population.


The distribution of metals in the forest floor of aged conifer stands at a plantation in Northern England.
The distribution of the elements Cd, Cr, Cu, Mn, Ni, Pb, Sr, V and Zn has been examined in the horizons of soils under aged Sitka spruce (Picea sitchensis (Bong.) Carr.) stands at a plantation in Northern England. The stands are under first-generation cultivation and are up to 33 years old. Cadmium, Mn, Pb and Zn concentrations were consistently higher in the organic layers than in the underlying mineral soil. This contrasted with the situation for Sr and V. Cadmium, Pb and Zn all showed an increase in concentration in the L + F horizons with stand age and a corresponding increase in the difference between L + F horizon concentrations. Soil pH declined with increasing stand age. Cadmium, Cr, Pb and Zn were all present at higher concentrations in the F horizon than in any other, while Cu and Ni were relatively constant through all the horizons studied. For all nine elements, the H horizon was the largest store of the three organic layers. Calculated rates of accumulation of Cd, Pb and Zn in the L + F horizons gave good agreement with estimated regional atmospheric deposition rates. In comparison to atmospheric deposition, biological mobilisation and deposition of Cd, Pb and Zn make a relatively minor contribution to the surface soil metal burden. Cadmium appeared to be the most readily leached of these three metals from the forest floor, although some transfer of atmospherically-derived Pb to the H+ soil horizons was indicated.


X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation.
Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic anemias, and myelodysplastic syndromes. Here, we characterized a family with multiple female individuals who have macrocytic anemia. The proband was noted to have dyserythropoiesis and iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause of the disease, whole-exome sequencing of multiple family members revealed the presence of a mutation in the X chromosomal gene ALAS2, which encodes 5'-aminolevulinate synthase 2, in the affected females. We determined that this mutation (Y365C) impairs binding of the essential cofactor pyridoxal 5'-phosphate to ALAS2, resulting in destabilization of the enzyme and consequent loss of function. X inactivation was not highly skewed in wbc from the affected individuals. In contrast, and consistent with the severity of the ALAS2 mutation, there was a complete skewing toward expression of the WT allele in mRNA from reticulocytes that could be recapitulated in primary erythroid cultures. Together, the results of the X inactivation and mRNA studies illustrate how this X-linked dominant mutation in ALAS2 can perturb normal erythropoiesis through cell-nonautonomous effects. Moreover, our findings highlight the value of whole-exome sequencing in diagnostically challenging cases for the identification of disease etiology and extension of the known phenotypic spectrum of disease.


Induction of the SOS response in Escherichia coli inhibits Tn5 and IS50 transposition.
In response to DNA damage or the inhibition of normal DNA replication in Escherichia coli, a set of some 20 unlinked operons is induced through the RecA-mediated cleavage of the LexA repressor. We examined the effect of this SOS response on the transposition of Tn5 and determined that the frequency of transposition is reduced 5- to 10-fold in cells that constitutively express SOS functions, e.g., lexA(Def) strains. Furthermore, this inhibition is independent of recA function, is fully reversed by a wild-type copy of lexA, and is not caused by an alteration in the levels of the Tn5 transposase or inhibitor proteins. We isolated insertion mutations in a lexA(Def) background that reverse this transposition defect; all of these mapped to a new locus near 23 min on the E. coli chromosome.


Imaging patterns predict patient survival and molecular subtype in glioblastoma via machine learning techniques.
MRI characteristics of brain gliomas have been used to predict clinical outcome and molecular tumor characteristics. However, previously reported imaging biomarkers have not been sufficiently accurate or reproducible to enter routine clinical practice and often rely on relatively simple MRI measures. The current study leverages advanced image analysis and machine learning algorithms to identify complex and reproducible imaging patterns predictive of overall survival and molecular subtype in glioblastoma (GB). One hundred five patients with GB were first used to extract approximately 60 diverse features from preoperative multiparametric MRIs. These imaging features were used by a machine learning algorithm to derive imaging predictors of patient survival and molecular subtype. Cross-validation ensured generalizability of these predictors to new patients. Subsequently, the predictors were evaluated in a prospective cohort of 29 new patients. Survival curves yielded a hazard ratio of 10.64 for predicted long versus short survivors. The overall, 3-way (long/medium/short survival) accuracy in the prospective cohort approached 80%. Classification of patients into the 4 molecular subtypes of GB achieved 76% accuracy. By employing machine learning techniques, we were able to demonstrate that imaging patterns are highly predictive of patient survival. Additionally, we found that GB subtypes have distinctive imaging phenotypes. These results reveal that when imaging markers related to infiltration, cell density, microvascularity, and blood-brain barrier compromise are integrated via advanced pattern analysis methods, they form very accurate predictive biomarkers. These predictive markers used solely preoperative images, hence they can significantly augment diagnosis and treatment of GB patients.


The effect of cancellous autograft and novel plate design on radiographic healing and postoperative complications in tibial tuberosity advancement for cranial cruciate-deficient canine stifles.
To assess the effect of autogenous cancellous bone graft (autograft) and novel plate use on radiographic healing and complications in tibial tuberosity advancement (TTA) for treatment of cranial cruciate ligament (CrCL)-deficient stifles in dogs. Prospective clinical study. Consecutive dogs (n=125) with unilateral CrCL-deficient stifles. Four treatment groups: CPG, conventional plate with autograft; CPNG, conventional plate without autograft; NPG, novel plate with autograft; NPNG, novel plate without autograft were studied. Radiographs from 60 dogs were scored for healing at 6 and 10 weeks postoperatively; all 125 dogs were assessed for radiographic complications. Variables evaluated for relationship with healing scores and radiographic complications were age, weight, sex, cage and plate size, implant type, and graft use. Dogs with autograft had overall higher healing scores at 6 and 10 weeks. Radiographic complications occurred in 13 dogs (12 minor, 1 major), and were not influenced by graft or novel plate use. Autograft increases healing scores, but was not found to have a significant impact on the rate of complications in TTA. The novel plate was not found to have healing scores or radiographic complication rates significantly different from the conventional plate design.


Should research samples reflect the diversity of the population?
Recent research governance documents say that the body of research evidence must reflect population diversity. The response to this needs to be more sophisticated than simply ensuring minorities are present in samples. For quantitative research looking primarily at treatment effects of drugs and devices four suggestions are made. First, identify where the representation of minorities in samples matters-for example, where ethnicity may cause different treatment effects. Second, where the representation of a particular group matters then subgroup analysis of the results will usually be necessary. Third, ensuring representation and subgroup analysis will have costs; deciding on whether such representation is worthwhile will involve cost benefit analysis. Fourth, the representation of minorities should not be seen as mainly a locality issue. For qualitative research it is argued that the representation of diversity is often important. Given the small samples of many qualitative projects, however, the best way to ensure representation occurs is to allow a proliferation of such research, not to stipulate such representation in samples.


Hepatic perfusion imaging using factor analysis of contrast enhanced ultrasound.
Contrast enhanced ultrasound imaging provides a real-time tool for evaluating vasculature in the liver. Primary liver cancer is known to be perfused exclusively by blood from the hepatic artery, whereas normal liver is also supplied by the portal vein. Visual separation of two different phases of enhancement from the independent feeding vessels is important for diagnosis but remains a challenge. This paper presents a method of using factor analysis for extracting distinct time-intensity curves. A key component to this extraction is the clustering of measured bolus curves and their projection onto a positivity domain to obtain nonnegative curves. This technique provides complementary images representing spatial loadings on each curve. As little as 1% of the data is required to contain unmixed signals to extract time-intensity curves that correlate well with true curves. A method of combining this information to display a regional hepatic perfusion image is proposed, and results are tested on a set of 10 patients. Region of interest analysis suggests it is possible to detect changes in the hepatic perfusion index of liver lesions relative to normal liver parenchyma using contrast ultrasound.


Visuomotor process in movement correction: role of internal feedback loop.
This study examined the role of the internal feedback loop in movement correction during interceptive actions when what the performers expect to happen changes quickly. Eleven participants performed an interceptive task with a moving target under two conditions [Brief (8 m/s) or Long (4 m/s)]. We manipulated the probability of these target conditions to induce movement correction (20-80, 50-50, and 80-20%) and delivered transcranial magnetic stimulation before movement initiation to disrupt the prediction of the movement consequence in the supplementary motor area of the cerebral cortex. In the 20% probability condition, which requires movement correction, the transcranial magnetic stimulation pulse had a significant adverse effect on the temporal error in the Brief condition, but not in the Long condition. The present results indicate that the internal feedback loop is crucial for movement correction for relatively brief interceptions.


Innovative platforms for data aggregation, linkage and analysis in the context of pandemic and epidemic intelligence.
During the COVID-19 pandemic, open-access platforms that aggregate, link and analyse data were transformative for global public health surveillance. This perspective explores the work of three of these platforms: Our World In Data (OWID), Johns Hopkins University (JHU) COVID-19 Dashboard (later complemented by the Coronavirus Resource Center), and Global.Health, which were presented in the second World Health Organization (WHO) Pandemic and Epidemic Intelligence Innovation Forum. These platforms, operating mostly within academic institutions, added value to public health data that are collected by government agencies by providing additional real-time public health intelligence about the spread of the virus and the evolution of the public health emergency. Information from these platforms was used by health professionals, political decision-makers and members of the public alike. Further engagement between government and non-governmental surveillance efforts can accelerate the improvements needed in public health surveillance overall. Increasing the diversity of public health surveillance initiatives beyond the government sector comes with several benefits: technology innovation in data science, engagement of additional highly skilled professionals, greater transparency and accountability for government agencies, and new opportunities to engage with members of society.


Eosinophilic keratitis in 46 eyes of 27 horses in the Mid-Atlantic United States (2008-2012).
To review the signalment, clinical characteristics, treatment, and outcome of equine EK cases in the Mid-Atlantic United States; to evaluate the effects of topical or systemic corticosteroid treatment, oral cetirizine treatment and secondary corneal infection on disease duration; and to evaluate the association between corticosteroid and cetirizine treatment and likelihood of recurrence. Twenty-seven horses (47 eyes) diagnosed with EK from 2008 to 2012. Retrospective medical record review followed by phone interview to obtain recurrence data. Average age of affected horses was 8.2 years, SD 5.8 years. Eleven of 27 horses (41%) were diagnosed with EK in July. Twelve horses (44%) had been affected in previous years. Time to resolution averaged 3.7 months, SD 2.3 months. Ten horses (18 eyes) were treated with systemic dexamethasone, with a significantly shorter time to resolution, P = 0.03, averaging 2.23 months, SD 1.13 months, relative to horses not so treated, averaging 4.20 months, SD 1.47 months. Secondary infection led to a significant increase in time to resolution, P = 0.03, average 4.1 months, SD 1.7 months, relative to horses without secondary infection, average 3.0 months, SD 1.5 months. All eyes were visual at resolution. Horses treated with cetirizine were less likely to have recurrence during the follow-up period (1/13, or 8%) relative to horses not so treated (8/14, or 57%). Eosinophilic keratitis has a seasonal occurrence in summer in the Mid-Atlantic United States. Systemic but not topical corticosteroid treatment may decrease therapy duration. Treatment with cetirizine may be associated with a decreased risk of recurrence.