The uniform double layer model and myocardial infarction: forward solution consideration.
The Uniform Double Layer (UDL) model of the cardiac generator is often used for forward simulation of body surface potentials (BSPs). The model also proved to be very useful for the inverse computation of heart activation. However, for the purposes of Myocardial Infarction (MI) modelling mostly the Multiple Dipole (MD) models are used. In our study, the ability of UDL model to represent the activation of the heart with an old MI was examined. The finite element model of the heart was used to simulate electrical activation of the heart with an old MI. Different locations of endocardial MI were used. For each of them three cases were considered according to the scale of the infarcted area: small and medium endocardial and large transmural. For the further computation of the electric field within the torso volume conductor two types of UDL representation of the cardiac generator were used. For the first UDL model, supposing the scared tissue to be unexcitable, an "infarcted" surface (different from the "healthy" surface) of activated myocardium was generated for each case of MI. Times when activation wavefront reached particular nodes on the surface served as an input for the forward computation of BSPs. To be able to understand the behaviour of the UDL, we also created the second UDL model, where the "infarcted activation sequence" was approximated on the original "healthy" heart surface. The BSPs were computed for each case of MI using both UDL cardiac generators. The boundary element method with the inhomogeneous volume conductor was used for computations. The BSPs generated by both models for the same case of MI were compared using the correlation coefficient. The results show, that it is possible to find an approximation of the "infarcted activation sequence" on the "healthy" heart generator surface in a way that BSPs generated by both models have a correlation coefficient higher than 0.96 for the entire period of depolarisation. Visualisation of the epicardial isochrones might help to understand the UDL model behaviour under the MI conditions. It would be useful for the correct interpretation of the results when using the UDL model for inverse solution. (Fig. 7, Ref. 5.)


Evolutionary conservation of sequences directing chromosome breakage and rDNA palindrome formation in tetrahymenine ciliates.
Extensive, programmed chromosome breakage occurs during formation of the somatic macronucleus of ciliated protozoa. The cis-acting signal directing breakage has been most rigorously defined in Tetrahymena thermophila, where it consists of a 15-bp DNA sequence known as Cbs, for chromosome breakage sequence. We have identified sequences identical or nearly identical to the T. thermophila Cbs at sites of breakage flanking the germline micronuclear rDNA locus of six additional species of Tetrahymena as well as members of two related genera. Other general features of the breakage site are also conserved, but surprisingly, the orientation and number of copies of Cbs are not always conserved, suggesting the occurrence of germline rearrangement events over evolutionary time. At one end of the T. thermophila micronuclear rDNA locus, a pair of short inverted repeats adjacent to Cbs directs the formation of a giant palindromic molecule. We have examined the corresponding sequences from two other Tetrahymena species. We find the sequence to be partially conserved, as previously implied from analysis of macronuclear rDNA, but of variable length and organization.


Immunostimulatory and anti-inflammatory impact of Fragaria ananassa methanol extract in a rat model of cadmium chloride-induced pulmonary toxicity.
Cadmium is an extremely dangerous heavy metal that can lead to disastrous consequences in all organisms. Several natural remedies reduce the toxicities of experimentally generated metals in animals. Strawberry Fragaria ananassa contains several bioactive compounds that may mitigate heavy-metal toxicity. The study aim was to evaluate the ability of a strawberry fruit methanol extract (SE) to reduce Cd toxicity and to identify and quantify the active constituents of SE. Forty Wistar rats were classified into four groups: the control group- 1 ml saline IP; SE group- 100 mg of SE/kg rats orally; cadmium (Cd) group-2 mg CdCl2/kg body weight/IP daily; and treated group- SE given 1 hour before Cd administration. Administration of Cd induced several histopathological and immunohistochemical alterations in lung sections. Biochemical analysis of lung homogenates and mRNA levels of antioxidants and inflammatory cytokines indicated significant changes to the risk profile. SE administration significantly decreased the oxidative stress, inflammation, tissue damage, the mean area percentage of collagen fibers, and positive immuno-expressions of TNF-α and NF-κB induced by CdCl2. Moreover, the MDA, TNF-α, GM-CSF, and IL-1β levels in Cd-exposed rat lung tissue were significantly lower in the SE-treated group than in the Cd-group. SE significantly augmented lung GSH, SOD, HO-1, GPx-2, and Nrf2 levels in Cd-exposed rats. SE mitigated Cd-caused oxidative stress and lung inflammation. Therefore, regularly consuming a strawberry-rich diet could benefit general health and help prevent and treat diseases.


Video-assisted thoracoscopic surgery for right middle lobectomy in children.
This case-control study was designed to evaluate the potential advantages and disadvantages of video-assisted thoracoscopic surgery for right middle lobectomy in children. Ten children (6.1 +/- 3.0 yr, mean +/- SD) who underwent right middle lobectomy under videoscopy were compared with 10 controls matched for age (6.8 +/- 3.5 yr) and operated by thoracotomy (muscle-sparing technique) during the same period by the same surgeon. Operating time was significantly longer in the videoscopy group than in the thoracotomy group (146 +/- 28 mn vs 100 +/- 27 mn, P < 0.001). Minimum oxygen saturation values were significantly higher in the videoscopy group whereas oxygen requirements did not differ between groups. Incidence of postoperative respiratory complications (mainly atelectasis) was similar in the two groups. No difference in postoperative analgesic requirements in the postoperative period was demonstrated. No real benefit or disadvantage of videoscopy over standard thoracotomy could be observed in this retrospective case-control study.


Potential value of serum Aspergillus IgG antibody detection in the diagnosis of invasive and chronic pulmonary aspergillosis in non-agranulocytic patients.
At present, serum Aspergillus IgG and IgM antibody detection is mainly used in the diagnosis of chronic pulmonary aspergillosis (CPA), but its value in the diagnosis of invasive pulmonary aspergillosis (IPA) in non-agranulocytic patients is still unclear. IgM can be used as a marker of acute infection to help diagnose acute infection-related diseases. IgG is a marker of long-term infection and is used to assist in the diagnosis of pre-existing or chronic infection-related diseases. The aim of this study was to investigate and compare the value of serum Aspergillus IgG and IgM antibody detection in the diagnosis of IPA and CPA in non-agranulocytic patients. Fifty-eight cases of pulmonary aspergillosis (37 IPA and 21 CPA cases), 15 cases of community-acquired bacterial pneumonia and 50 cases in the healthy control group were collected. The serum (1,3)-β-D-glucan test (G test) was performed with a chromogenic method, and the galactomannan test (GM test) and Aspergillus IgG and IgM antibody detection were performed by commercial enzyme-linked immunosorbent assay (ELISA) in all patients. The sensitivity and specificity, cut-off value and area under the curve (AUC) of Aspergillus IgG and IgM antibodies were further obtained by receiver operating characteristic (ROC) curves. The positive rate of the G test, Aspergillus IgG antibody detection and the GM test also showed notable differences among the IPA, CPA, community-acquired bacterial pneumonia and healthy groups (P = 0.006, P < 0.001 and P = 0.217, respectively). Only the positive rate of the GM test showed a significant difference between the IPA and CPA groups (P = 0.04). ROC curves indicated that Aspergillus IgG antibody detection had a higher specificity in the IPA group than in the CPA group (0.952). The detection of Aspergillus IgG antibody can preferably distinguish IPA from community-acquired bacterial pneumonia and healthy controls (sensitivity = 0.923, specificity = 0.459, cut-off value = 134.46, AUC = 0.727). It can also distinguish CPA from community-acquired bacterial pneumonia and healthy controls (sensitivity = 0.952, specificity = 0.692, cut-off value = 75.46, AUC = 0.873). Serum Aspergillus IgG antibody detection may have certain clinical value in the diagnosis of IPA and CPA in non-agranulocytic patients.


Expression profiling and comparative analyses of seven midgut serine proteases from the yellow fever mosquito, Aedes aegypti.
Aedes aegypti utilizes blood for energy production, egg maturation and replenishment of maternal reserves. The principle midgut enzymes responsible for bloodmeal digestion are endoproteolytic serine-type proteases within the S1.A subfamily. While there are hundreds of serine protease-like genes in the A. aegypti genome, only five are known to be expressed in the midgut. We describe the cloning, sequencing and expression profiling of seven additional serine proteases and provide a genomic and phylogenetic assessment of these findings. Of the seven genes, four are constitutively expressed and three are transcriptionally induced upon blood feeding. The amount of transcriptional induction is strongly correlated among these genes. Alignments reveal that, in general, the conserved catalytic triad, active site and accessory catalytic residues are maintained in these genes and phylogenetic analysis shows that these genes fall within three distinct clades; trypsins, chymotrypsins and serine collagenases. Interestingly, a previously described trypsin consistently arose with other serine collagenases in phylogenetic analyses. These results suggest that multiple gene duplications have arisen within the S1.A subfamily of midgut serine proteases and/or that A. aegypti has evolved an array of proteases with a broad range of substrate specificities for rapid, efficient digestion of bloodmeals.


Regionalization of Stroke Systems of Care in the Stroke Belt States: The IMPROVE Stroke Care Quality Improvement Program.
Despites guidelines and strong evidence supporting intravenous thrombolysis and endovascular thrombectomy for acute stroke, access to these interventions remains a challenge. The objective of the IMPROVE stroke care program was to accelerate acute stroke care delivery by implementing best practices and improving the regional systems of care within comprehensive stroke networks. The IMPROVE Stroke Care program was a prospective quality improvement program based on established models used in acute coronary care. Nine hub hospitals (comprehensive stroke centers), their 52 regional/community referral hospitals (spokes), and over 100 emergency medical service agencies participated. Through 6 regional meetings, 49 best practices were chosen for improvement by the participating sites. Over a two-year period, progress was tracked and discussed weekly and performance reviews were disseminated quarterly. Data were collected on 21,647 stroke code activations of which 8502 (39.3%) activations had a final diagnosis of stroke. There were 7226 (85.0%) ischemic strokes, and thrombolytic therapy was administered 2814 times (38.9%). There was significant overall improvement in the proportion that received lytic therapy within 45 minutes (baseline of 44.6% to 60.4%). The hubs were more frequently achieving this at baseline, but both site types improved. A total of 1455 (17.1%) thrombectomies were included in the data of which 401 (27.6%) were transferred from a spoke. There was no clinically significant change in door-to-groin times for hub-presenting thrombectomy patients, however significant improvement occurred for transferred cases, 46 minutes (interquartile range (IQR) 36, 115.5) at baseline to 27 minutes (IQR 10, 59). The IMPROVE program approach was successful at improving delivery of thrombolytic intervention across the consortium at both spoke and hub sites through collaborative efforts to operationalize guideline-based care through iterative sharing of performance and best practices for implementation. Our approach allowed identification of both opportunities for improvement and operational best practices providing guidance on how best to create a regional stroke care network and operationalize the published acute stroke care guidelines.


Psychosocial influences on engagement in care among HIV-positive young black gay/bisexual and other men who have sex with men.
Young black gay/bisexual and other men who have sex with men (YB-GBMSM) living with HIV are at risk for poor engagement in HIV care. Relatively little is known about factors that impact engagement outcomes at various stages along the HIV care continuum in this specific population. The purpose of this analysis was to examine associations between various psychosocial factors and likelihood of engagement at each stage of the care continuum, among a geographically diverse sample of 132 YB-GBMSM living with HIV. Negative self-image, a component of HIV stigma, had an inverse association with early care seeking after HIV diagnosis (OR=1.05; 95% CI 1.01-1.10). Negative self-image was also inversely associated with adherence to medical appointments (OR=0.95; 95% CI 0.91-0.99), while employment (OR=0.30; 95% CI 0.12-0.75) and ethnic identity affirmation (OR=0.28; 95% CI 0.12-0.68) were both positively associated with appointment adherence. HIV-positive identity salience was associated with a higher likelihood of being on antiretroviral therapy (OR=1.06; 95% CI 1.02, 1.09). These findings highlight the importance of processes related to identity development, as both barriers and facilitators of engagement in care for HIV-positive YB-GBMSM.


Malaria in travelers: a review of the GeoSentinel surveillance network.
Malaria is a common and important infection in travelers. We have examined data reported to the GeoSentinel surveillance network to highlight characteristics of malaria in travelers. A total of 1140 malaria cases were reported (60% of cases were due to Plasmodium falciparum, 24% were due to Plasmodium vivax). Male subjects constituted 69% of the study population. The median duration of travel was 34 days; however, 37% of subjects had a travel duration of < or =4 weeks. The majority of travellers did not have a pretravel encounter with a health care provider. Most cases occurred in travelers (39%) or immigrants/refugees (38%). The most common reasons for travel were to visit friends/relatives (35%) or for tourism (26%). Three-quarters of infections were acquired in sub-Saharan Africa. Severe and/or complicated malaria occurred in 33 cases, with 3 deaths. Compared with others in the GeoSentinel database, patients with malaria had traveled to sub-Saharan Africa more often, were more commonly visiting friends/relatives, had traveled for longer periods, presented sooner after return, were more likely to have a fever at presentation, and were less likely to have had a pretravel encounter. In contrast to immigrants and visitors of friends or relatives, a higher proportion (73%) of the missionary/volunteer group who developed malaria had a pretravel encounter with a health care provider. Travel to sub-Saharan Africa and Oceania was associated with the greatest relative risk of acquiring malaria. We have used a global database to identify patient and travel characteristics associated with malaria acquisition and characterized differences in patient type, destinations visited, travel duration, and malaria species acquired.


Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study.
In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.


Blunt traumatic rupture of the main pulmonary vessels.
This report described a patient who, though exhibiting no physical signs of chest trauma, had fatal blunt traumatic rupture of the main pulmonary blood vessels, unaccompanied by bronchial injury. A high index of suspicion for such intrathoracic injury should prompt a chest x-ray film in any case of multiple trauma.


[Hygiene in endoscopy in the clinic and practice, 2003: Results of infection hygiene survey on endoscopy services in Frankfurt am Main by the public health service].
Guidelines for reprocessing flexible endoscopes have been published in many countries. Compliance to the German guidelines, published in 2002 by the Commission on Hospital Hygiene and Infection Prevention on the Robert Koch Institute is mandatory in all endoscopic units, in hospitals as well as in private practices. Here, a survey of current reprocessing practices in an urban region in Germany is published, covering all hospitals and private practices in this region. In summer 2003, all endoscopic units in Frankfurt/Main, Germany--15 hospitals and 23 private practices -- were visited by members of the public health service, using a checklist based on the recommendations of the German guideline. In these institutions, more than 70 000 endoscopic examinations per year are performed. 87 % (13 /15) of the hospitals and 43 % (10/23) of the practices, reported to conduct more than 1000 procedures per year. Great differences were found in hygienic quality comparing endoscopic units in hospitals and in private practices. In hospitals compliance with the guidelines was satisfactory. Main problems in the practices were: missing facilities for ultrasonic cleaning (74%) and sterilizing (43%), faults in reprocessing the bottle and tube for air/water-channel flushing (26%) which was filled in with water not sterilised (48%), storage of the endoscope with risk of recontamination (48%), missing routine-tests of the endoscopes after reprocessing (44%). Generally, hygienic conditions and procedures were worse in smaller units than in bigger ones. The data from Frankfurt hospitals are satisfactory. In private practices, however, especially in smaller ones, improvements are mandatory. Improvements should cover the quality of structure and process, i.e. specific education of the nurses, availability of ultrasonic cleaners and sterilizators and -- preferably -- automatic dishwashers, as well as implementation of a written protocol for hygiene in endoscopy, based on the German Guidelines.


Treating Wounds With an Avascular Component With a Dermal Regenerative Template.
Partially avascular wounds pose a challenge to wound care surgeons. The authors reviewed the literature and institutional results on the use of a dermal regenerative template (DRT) over partially avascular wounds to quantify the ability of the DRT to vascularize over these wounds. A review of the literature was performed using Ovid MEDLINE, Google Scholar, and Cochrane Library. Patient demographics, comorbidities, wound types, surface area of avascular tissues, and skin graft take were analyzed. A retrospective review of institutional cases was conducted. A total of 32 articles met inclusion criteria. The retrospective review included 26 patients with partially avascular wounds reconstructed with the DRT. Seventeen patients experienced 100% graft take, 6 experienced partial take, and 3 suffered complete loss. The percent and absolute size of avascular surface area in the wound was significantly lower in cases of complete graft take compared with partial take and complete loss (1.9% and 2.7 cm2; 9.3% and 10.0 cm2; 18.0% and 9.3 cm2, respectively, P ⟨ .001). Chronic wound status (P ⟨ .001) was significantly associated with less graft take. This literature review and retrospective study confirm the DRT is a viable option to provide vascularized coverage over wounds with avascular components. This study suggests the DRT is more reliable in wounds with less than 1.9% avascular tissues and less successful in chronic wounds.


Can post-acute care programmes for older people reduce overall costs in the health system? A case study using the Australian Transition Care Programme.
There is an increasing demand for acute care services due in part to rising proportions of older people and increasing rates of chronic diseases. To reduce pressure and costs in the hospital system, community-based post-acute care discharge services for older people have evolved as one method of reducing length of stay in hospital and preventing readmissions. However, it is unclear whether they reduce overall episode cost or expenditure in the health system at a more general level. In this paper, we review the current evidence on the likely costs and benefits of these services and consider whether they are potentially cost-effective from a health services perspective, using the Australian Transition Care Programme as a case study. Evaluations of community-based post-acute services have demonstrated that they reduce length of stay, prevent some re-hospitalisations and defer nursing home placement. There is also evidence that they convey some additional health benefits to older people. An economic model was developed to identify the maximum potential benefits and the likely cost savings from reduced use of health services from earlier discharge from hospital, accelerated recovery, reduced likelihood of readmission to hospital and delayed entry into permanent institutional care for participants of the Transition Care Programme. Assuming the best case scenario, the Transition Care Programme is still unlikely to be cost saving to a healthcare system. Hence for this service to be justified, additional health benefits such as quality of life improvements need to be taken into account. If it can be demonstrated that this service also conveys additional quality of life improvements, community-based programmes such as Transition Care could be considered to be cost-effective when compared with other healthcare programmes.


A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.
Two aldosterone inhibitors are currently licensed for heart failure (HF) in the UK: spironolactone and eplerenone. Recent clinical guidelines recommend eplerenone after an acute myocardial infarction (MI) for patients with symptoms and/or signs of HF and left ventricular dysfunction. The primary objective was to evaluate relative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone in patients with postMI HF and explore the possibility of conducting an indirect comparison of spironolactone and eplerenone. A second objective was to undertake value-of-information (VOI) analyses to determine the need for further research to identify research questions critical to decision-making and to help inform the design of future studies. Relevant databases including MEDLINE, EMBASE and CENTRAL were searched between September and December 2008. Randomised controlled trials (RCTs) of spironolactone, eplerenone, canrenone or potassium canrenoate were included if conducted in a postMI HF population. Trials of general HF patients with a subgroup of postMI HF patients were considered if they had at least 100 ischaemic participants per arm and the authors provided subgroup data when contacted. Adverse events summary data were sought from recognised reference sources and RCTs or observational studies in any population that recruited more than 100 participants. The comparative clinical effectiveness and cost-effectiveness of spironolactone and eplerenone was derived using Bayesian meta-regression drawing on a wider 'network' of aldosterone trials to those considered in the main clinical effectiveness review. An alternative scenario was also considered assuming a 'class effect' for the aldosterone antagonists in terms of major clinical events, but allowing for potential differences in side effect profiles. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) where appropriate. Uncertainty in cost-effectiveness results was also presented and used to inform future research priorities using VOI analyses based on expected value of perfect information (EVPI). A probabilistic decision analytic model was developed to estimate cost-effectiveness of spironolactone, eplerenone and standard care for management of postMI HF, provide estimates relevant to the NHS and explore alternative approaches to an indirect comparison between spironolactone and eplerenone. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life-years (QALYs) and costs from the NHS persepctive. In the base-case analysis, 2-year treatment duration was assumed, consistent with the follow-up in the main RCTs. Other scenarios were explored to examine the robustness of alternative assumptions including impact of different treatment durations. Searches yielded five RCTs: two spironolactone trials of poor methodological quality and three trials of which only one (of eplerenone) specifically examined postMI HF (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, EPHESUS). One trial of spironolactone (Randomised Aldactone Evaluation Study, RALES) and one of canrenone (Antiremodelling Effect of Aldosterone receptors blockade with canrenone In mild Chronic Heart Failure, AREA IN-CHF) comprised general HF, but data were available for an ischaemic subgroup. Structural similarity of spironolactone and eplerenone suggests that they may be interchangeable, but formal indirect comparison between the three trials was severely limited by trial differences. Relative safety data were limited from RCTs and observational sources. Hyperkalaemia rates varied, but were generally higher than for placebo; data were insufficient to assess discontinuation because of hyperkalaemia.Gynaecomastia rates were higher with spironolactone. Adverse event data were sparse. Systematic review of economic evidence identified three main published studies but none used a UK perspective or attempted to compare cost-effectiveness in postMI HF. The new decision model indicated that eplerenone was the most cost-effective strategy for postMI HF (ICER of eplerenone compared with standard care was 4457 pounds per QALY, increasing to 7893 pounds per QALY if treatment continued over the patient's lifetime); in neither scenario did spironolactone appear cost-effective. The ICER of eplerenone was consistently under the 20,000-30,000 pounds per QALY threshold used to establish value for money in the NHS. Uncertainty resulted in EVPI estimates between 820M pounds (base-case) and 1265M pounds (lifetime treatment duration scenario). When class effect for mortality and hospitalisations was assumed spironolactone emerged as the most cost-effective treatment and EVPI estimates were negligible. If class effect is considered more plausible than the results of the evidence synthesis model then there would be limited value in additional research. Exchangeability between trials was poor and there was a lack of robust data in RCTs. Only two good-quality trials of aldosterone inhibitors in the postMI HF population were found, but lack of exchangeability with respect to study populations, meant that a comparison between these drugs could not be done. It consistently emerged that, compared with usual care, use of an aldosterone antagonist appears to be a highly cost-effective strategy for the management of postMI HF patients in the NHS. An adequately powered, well-conducted RCT that directly compares spironolactone and eplerenone is required to provide more robust evidence on the optimal management of postMI HF patients.


Endothelium-derived relaxing factor is likely to modulate the tone of resistance arteries in rabbit hindlimb in vivo.
Vasodilation mediated by endothelium-derived relaxing factor (EDRF) has been demonstrated in large conduit arteries in vitro. In the present study we investigated whether the EDRF mechanism is also present in resistance arteries of a peripheral vascular bed, namely the hindlimb of the rabbit. The right femoral artery of anesthetized rabbits was cannulated and blood was supplied through a shunt from the carotid artery. Femoral arterial blood flow and pressure were measured in the shunt. Systemic pressure was measured in the abdominal aorta. The hemodynamic effects of endothelium-dependent and -independent vasodilators (infused into the shunt) were measured before and after treatment of the vascular bed with gossypol or p-bromophenacyl bromide (p-BPB). Gossypol, a polyphenolic antioxidant, is a selective and irreversible inhibitor of the EDRF-mediated vasodilation in isolated arteries; p-BPB is an alkylating agent and also produces irreversible inhibition of endothelium-mediated relaxations in vitro. During inhibitor treatment the hindlimb was temporarily isolated from the blood circulation and perfused with a cell-free medium; the venous effluent was drained off so that only minimal amounts of inhibitor reached the systemic circulation. The endothelium-dependent vasodilators acetylcholine (ACh) and substance P, and the endothelium-independent vasodilators prostaglandin E1 (PGE1) and glyceryl trinitrate (GTN) induced concentration-dependent increases in femoral arterial flow (and decreases in vascular resistance). Gossypol treatment had no direct effect on systemic blood pressure or femoral arterial flow. However, after gossypol, the effects of ACh and substance P on vascular resistance were almost abolished, but there was no significant effect on the responses to PGE1 and GTN.(ABSTRACT TRUNCATED AT 250 WORDS)


Methods for Gastrointestinal Endoscopy Quantification: A Focus on Hands and Fingers Kinematics.
Gastrointestinal endoscopy is a complex procedure requiring the mastery of several competencies and skills. This procedure is in increasing demand, but there exist important management and ethical issues regarding the training of new endoscopists. Nowadays, this requires the direct involvement of real patients and a high chance of the endoscopists themselves suffering from musculoskeletal conditions. Colonoscopy quantification can be useful for improving these two issues. This paper reviews the literature regarding efforts to quantify gastrointestinal procedures and focuses on the capture of hand and finger kinematics. Current technologies to support the capture of data from hand and finger movements are analyzed and tested, considering smart gloves and vision-based solutions. Manus VR Prime II and Stretch Sense MoCap reveal the main problems with smart gloves related to the adaptation of the gloves to different hand sizes and comfortability. Regarding vision-based solutions, Vero Vicon cameras show the main problem in gastrointestinal procedure scenarios: occlusion. In both cases, calibration and data interoperability are also key issues that limit possible applications. In conclusion, new advances are needed to quantify hand and finger kinematics in an appropriate way to support further developments.


Nucleic acid-binding polymers as anti-inflammatory agents.
Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be taken up by inflammatory cells and activate multiple nucleic acid-sensing toll-like receptors (TLR3, 7, 8, and 9). The inappropriate activation of these TLRs can engender a variety of inflammatory and autoimmune diseases. The redundancy of the TLR family encouraged us to seek materials that can neutralize the proinflammatory effects of any nucleic acid regardless of its sequence, structure or chemistry. Herein we demonstrate that certain nucleic acid-binding polymers can inhibit activation of all nucleic acid-sensing TLRs irrespective of whether they recognize ssRNA, dsRNA or hypomethylated DNA. Furthermore, systemic administration of such polymers can prevent fatal liver injury engendered by proinflammatory nucleic acids in an acute toxic shock model in mice. Therefore these polymers represent a novel class of anti-inflammatory agent that can act as molecular scavengers to neutralize the proinflammatory effects of various nucleic acids.


Neuronal nicotinic receptor beta2 and beta4 subunits confer large differences in agonist binding affinity.
We used equilibrium binding analysis to characterize the agonist binding properties of six different rat neuronal nicotinic receptor subunit combinations expressed in Xenopus laevis oocytes. The alpha4beta2 receptor bound [3H]cytisine with a Kdapp of 0.74 +/- 0. 14 nM. The rank order of Kiapp values of additional nicotinic ligands, determined in competition assays, was cytisine < nicotine < acetylcholine < carbachol < curare. These pharmacological properties of alpha4beta2 expressed in oocytes are comparable to published values for the high affinity cytisine binding site in rat brain (alpha4beta2), demonstrating that rat neuronal nicotinic receptors expressed in X. laevis oocytes display appropriate pharmacological properties. Use of [3H]epibatidine allowed detailed characterization of multiple neuronal nicotinic receptor subunit combinations. Kdapp values for [3H]epibatidine binding were 10 pM for alpha2beta2, 87 pM for alpha2beta4, 14 pM for alpha3beta2, 300 pM for alpha3beta4, 30 pM for alpha4beta2, and 85 pM for alpha4beta4. Affinities for six additional agonists (acetylcholine, anabasine, cytisine, 1, 1-dimethyl-4-phenylpiperazinium, lobeline, and nicotine) were determined in competition assays. The beta2-containing receptors had consistently higher affinities for these agonists than did beta4-containing receptors. Particularly striking examples are the affinities displayed by alpha2beta2 and alpha2beta4, which differ in 1,1-dimethyl-4-phenylpiperazinium, nicotine, lobeline, and acetylcholine affinity by 120-, 86-, 85-, and 61-fold, respectively. Although smaller differences in affinity could be ascribed to different alpha subunits, the major factor in determining agonist affinity was the nature of the beta subunit.


Continuous attractors of Lotka-Volterra recurrent neural networks with infinite neurons.
Continuous attractors of Lotka-Volterra recurrent neural networks (LV RNNs) with infinite neurons are studied in this brief. A continuous attractor is a collection of connected equilibria, and it has been recognized as a suitable model for describing the encoding of continuous stimuli in neural networks. The existence of the continuous attractors depends on many factors such as the connectivity and the external inputs of the network. A continuous attractor can be stable or unstable. It is shown in this brief that a LV RNN can possess multiple continuous attractors if the synaptic connections and the external inputs are Gussian-like in shape. Moreover, both stable and unstable continuous attractors can coexist in a network. Explicit expressions of the continuous attractors are calculated. Simulations are employed to illustrate the theory.


A new method for predicting SIRS after percutaneous transhepatic gallbladder drainage.
The occurrence of systemic inflammatory response after percutaneous transhepatic gallbladder drainage brings great risks to patients and is one of the challenges faced by clinicians. Therefore, it is of great significance to find a suitable prediction method for clinicians to intervene early and reduce the transformation of serious complications. Easy-to-obtain and objectively measured clinical features were screened, and logistic regression was used to construct a prediction model. The predictive ability of the model was evaluated by using the receiver operating characteristic curve and the decision curve in the validation set and the training set, respectively. Nine clinical features (CRP, Fever, DBIL, Obstruction, Bile properties, PCT, Length, Width, and Volume factor) were used to construct the prediction model, and the validation results showed that the prediction model had good performance in the training set (AUC = 0.83) and the validation set (AUC = 0.81). The decision curve also showed that the predictive ability of the model incorporating nine clinical features is better than that of a single clinical feature. The model we constructed can accurately predict the occurrence of SIRS, which can guide clinicians to take treatment measures and avoid the deterioration of complications.


Hydrophobic blocks facilitate lipid compatibility and translocon recognition of transmembrane protein sequences.
Biophysical hydrophobicity scales suggest that partitioning of a protein segment from an aqueous phase into a membrane is governed by its perceived segmental hydrophobicity but do not establish specifically (i) how the segment is identified in vivo for translocon-mediated insertion or (ii) whether the destination lipid bilayer is biochemically receptive to the inserted sequence. To examine the congruence between these dual requirements, we designed and synthesized a library of Lys-tagged peptides of a core length sufficient to span a bilayer but with varying patterns of sequence, each composed of nine Leu residues, nine Ser residues, and one (central) Trp residue. We found that peptides containing contiguous Leu residues (Leu-block peptides, e.g., LLLLLLLLLWSSSSSSSSS), in comparison to those containing discontinuous stretches of Leu residues (non-Leu-block peptides, e.g., SLSLLSLSSWSLLSLSLLS), displayed greater helicity (circular dichroism spectroscopy), traveled slower during sodium dodecyl sulfate-polyacrylamide gel electrophoresis, had longer reverse phase high-performance liquid chromatography retention times on a C-18 column, and were helical when reconstituted into 1-palmitoyl-2-oleoylglycero-3-phosphocholine liposomes, each observation indicating superior lipid compatibility when a Leu-block is present. These parameters were largely paralleled in a biological membrane insertion assay using microsomal membranes from dog pancreas endoplasmic reticulum, where we found only the Leu-block sequences successfully inserted; intriguingly, an amphipathic peptide (SLLSSLLSSWLLSSLLSSL; Leu face, Ser face) with biophysical properties similar to those of Leu-block peptides failed to insert. Our overall results identify local sequence lipid compatibility rather than average hydrophobicity as a principal determinant of transmembrane segment potential, while demonstrating that further subtleties of hydrophobic and helical patterning, such as circumferential hydrophobicity in Leu-block segments, promote translocon-mediated insertion.


Restricted gene flow and local adaptation highlight the vulnerability of high-latitude reefs to rapid environmental change.
Global climate change poses a serious threat to the future health of coral reef ecosystems. This calls for management strategies that are focused on maximizing the evolutionary potential of coral reefs. Fundamental to this is an accurate understanding of the spatial genetic structure in dominant reef-building coral species. In this study, we apply a genotyping-by-sequencing approach to investigate genome-wide patterns of genetic diversity, gene flow, and local adaptation in a reef-building coral, Pocillopora damicornis, across 10 degrees of latitude and a transition from temperate to tropical waters. We identified strong patterns of differentiation and reduced genetic diversity in high-latitude populations. In addition, genome-wide scans for selection identified a number of outlier loci putatively under directional selection with homology to proteins previously known to be involved in heat tolerance in corals and associated with processes such as photoprotection, protein degradation, and immunity. This study provides genomic evidence for both restricted gene flow and local adaptation in a widely distributed coral species, and highlights the potential vulnerability of leading-edge populations to rapid environmental change as they are locally adapted, reproductively isolated, and have reduced levels of genetic diversity.


Metric-Based Visual Acuity and Defocus Curve Simulation of Two Multifocal Intraocular Lens Models.
To predict clinical defocus curve performance of the PanOptix intraocular lens (IOL) model TFNT00, a population-based image quality metric was applied to a pseudophakic eye model. Visual acuity (VA) was simulated using a 2-surface reduced eye model. For each virtual eye, the derived corneal surface was combined with scaled IOL surface. Corneal power and aberration, anterior chamber depth, and pupil size were iterated using a Monte-Carlo approach. Image quality of the IOLs was assessed using the total aberration map to compute the amplitude point spread function. A diffraction-normalized light-in-the-bucket metric was calculated for each virtual eye for defocuses from -3.5 D to +1.0 D (step size 0.25 D) and transformed to VAs and defocus curves. Simulated VA for the ReSTOR +3.0 D lens was used to generate a calibration function by linear regression correlation of simulated data with clinical VA data. Simulated TFNT00 VA was then validated by comparing defocus curves to clinical TFNT00 data. From -3.5 D to +1.0 D, the simulated defocus curve was generally consistent with the defocus curve from the TFNT00 clinical trial. The mean absolute difference was 0.022 logMAR (~1 letter) for simulated VA versus clinical trial VA. IOL image quality can be assessed using a population-based virtual eye model to simulate VA and predict clinical performance. Computational modeling and simulation can be applied to future IOL development before clinical trials are conducted.


Ambient air pollution: health hazards to children.
Ambient (outdoor) air pollution is now recognized as an important problem, both nationally and worldwide. Our scientific understanding of the spectrum of health effects of air pollution has increased, and numerous studies are finding important health effects from air pollution at levels once considered safe. Children and infants are among the most susceptible to many of the air pollutants. In addition to associations between air pollution and respiratory symptoms, asthma exacerbations, and asthma hospitalizations, recent studies have found links between air pollution and preterm birth, infant mortality, deficits in lung growth, and possibly, development of asthma. This policy statement summarizes the recent literature linking ambient air pollution to adverse health outcomes in children and includes a perspective on the current regulatory process. The statement provides advice to pediatricians on how to integrate issues regarding air quality and health into patient education and children's environmental health advocacy and concludes with recommendations to the government on promotion of effective air-pollution policies to ensure protection of children's health.


The transcriptional response of Arabidopsis leaves to Fe deficiency.
Due to its ease to donate or accept electrons, iron (Fe) plays a crucial role in respiration and metabolism, including tetrapyrrole synthesis, in virtually all organisms. In plants, Fe is a component of the photosystems and thus essential for photosynthesis. Fe deficiency compromises chlorophyll (Chl) synthesis, leading to interveinal chlorosis in developing leaves and decreased photosynthetic activity. To gain insights into the responses of photosynthetically active cells to Fe deficiency, we conducted transcriptional profiling experiments on leaves from Fe-sufficient and Fe-deficient plants using the RNA-seq technology. As anticipated, genes associated with photosynthesis and tetrapyrrole metabolism were dramatically down-regulated by Fe deficiency. A sophisticated response comprising the down-regulation of HEMA1 and NYC1, which catalyze the first committed step in tetrapyrrole biosynthesis and the conversion of Chl b to Chl a at the commencement of Chl breakdown, respectively, and the up-regulation of CGLD27, which is conserved in plastid-containing organisms and putatively involved in xanthophyll biosynthesis, indicates a carefully orchestrated balance of potentially toxic tetrapyrrole intermediates and functional end products to avoid photo-oxidative damage. Comparing the responses to Fe deficiency in leaves to that in roots confirmed subgroup 1b bHLH transcription factors and POPEYE/BRUTUS as important regulators of Fe homeostasis in both leaf and root cells, and indicated six novel players with putative roles in Fe homeostasis that were highly expressed in leaves and roots and greatly induced by Fe deficiency. The data further revealed down-regulation of organ-specific subsets of genes encoding ribosomal proteins, which may be indicative of a change in ribosomal composition that could bias translation. It is concluded that Fe deficiency causes a massive reorganization of plastid activity, which is adjusting leaf function to the availability of Fe.


How populations differentiate despite gene flow: sexual and natural selection drive phenotypic divergence within a land fish, the Pacific leaping blenny.
Divergence between populations in reproductively important features is often vital for speciation. Many studies attempt to identify the cause of population differentiation in phenotype through the study of a specific selection pressure. Holistic studies that consider the interaction of several contrasting forms of selection are more rare. Most studies also fail to consider the history of connectivity among populations and the potential for genetic drift or gene flow to facilitate or limit phenotypic divergence. We examined the interacting effects of natural selection, sexual selection and the history of connectivity on phenotypic differentiation among five populations of the Pacific leaping blenny (Alticus arnoldorum), a land fish endemic to the island of Guam. We found key differences among populations in two male ornaments--the size of a prominent head crest and conspicuousness of a coloured dorsal fin--that reflected a trade-off between the intensity of sexual selection (male biased sex ratios) and natural selection (exposure to predators). This differentiation in ornamentation has occurred despite evidence suggesting extensive gene flow among populations, which implies that the change in ornament expression has been recent (and potentially plastic). Our study provides an early snapshot of divergence in reproductively important features that, regardless of whether it reflects genetic or plastic changes in phenotype, could ultimately form a reproductive barrier among populations.


Eight-year follow-up of the 90,000-person Haimen City cohort: I. Hepatocellular carcinoma mortality, risk factors, and gender differences.
In an 8-year follow-up of a prospective cohort study in Haimen City, China, we sought to identify hepatocellular carcinoma (HCC) risk factors in addition to hepatitis B virus (HBV) infection. Two cohorts of adults between ages 25 and 64 years at study entry were followed from 1992-1993 to 2000. The male cohort included 58,545 men, 15.0% of whom were HBV carriers. The female cohort included 25,340 women, 10.7% of whom were HBV carriers. 434,718 person-years of follow-up were accumulated, and 1092 deaths from HCC occurred. The relationship of potential risk factors measured at study entry to HCC mortality was analyzed using Cox proportional hazards models. For males, HCC mortality was significantly associated with HBV infection [relative risk (RR) 18.8; 95% confidence interval (CI), 15.7-22.5], history of acute hepatitis (RR, 2.3; 95% CI, 2.0-2.7), family history of HCC (RR, 2.3; 95% CI, 1.9-2.7), and occupation as a peasant (RR, 1.5; 95% CI, 1.3-1.8). For females, HCC mortality was significantly associated with HBV infection (RR, 33.5; 95% CI, 17.1-65.5) and acute hepatitis history (RR, 4.7; 95% CI, 3.0-7.5). HCC risk was not significantly associated with alcohol consumption, water source, or staple foods in either sex. There was no association with smoking in males, but there was a positive association for females. Environmental and genetic risk factors besides HBV infection play a significant role in HCC mortality in this extremely high-risk population. Gender differences in HCC mortality and known risk factors are substantial and warrant further study. Identification of risk factors amenable to intervention should be a high priority in the prevention of HCC.


Correlates of age at natural menopause in the cohorts of EPIC-Italy.
A large number of studies have investigated the factors correlated to age at natural menopause in several populations. However, information on genetics and life-style factors influencing the age of onset of menopause in different populations is of current scientific interest. Specifically, for Italian women there are no large population-based data. The EPIC-Italy collaboration is a source of data of this kind; moreover, the geographical distribution of the cohorts (recruited in northern, central and southern Italy) is an added value as regards the scientific interest of these data. A number of biological and life-style-related factors have been analyzed to evaluate their association to the age at natural menopause in 14,454 menopausal women of the EPIC-Italy collaboration. As regards life-style and environmental factors, the main results are: a) women living in different areas of the country have different ages of onset of natural menopause; b) educational level is significantly associated to this age and may explain part of the between-center difference; c) cigarette smoking appears as a major correlate and probably determinant of the age at natural menopause across all the Italian cohorts; d) alcohol consumption does not have any relationship with the age at natural menopause; e) the use of oral contraceptives may influence age at natural menopause. As regards biological factors, short cycles and low parity have been found associated with earlier menopause. Overall, the results concerning menstrual cycles, parity, and cigarette smoking are consistent with the hypothesis that the number of oocytes in the ovary is pre-determined and any acceleration or impairment of the ovarian function leads to reduce the duration of the reproductive life.


MicroRNA-206 Contributes to the Progression of Preeclampsia by Suppressing the Viability and Mobility of Trophocytes via the Inhibition of AGTR1.
The development of preeclampsia (PE) is associated with the impaired trophoblast motility. MicroRNAs (miRs) contribute to the modulation of trophoblast invasion. In the current study, the role of miR-206/AGTR1 in the TNF-alpha-induced invasion defect of trophoblasts was explored. The levels of miR-206 and ATGR1 in clinical placenta tissues were investigated. Trophoblasts were treated with TNF-alpha, and the levels of miR-206 and ATGR1 were modulated. Changes in cell viability, invasion, and inflammation in trophoblasts were detected. The level of miR-206 was induced, while the level of AGTR1 was suppressed in placenta tissues. In in vitro assays, TNF-alpha suppressed viability, induced inflammatory response, inhibited invasion, upregulated miR-206, and down-regulated AGTR1. The inhibited expression of miR-206 or the overexpression of AGTR1 counteracted the effects of TNF-alpha, indicating the key role of the miR-206/AGTR1 in progression of PE. Collectively, miR-206 suppressed viability, induced inflammatory response, and decreased invasion of trophoblasts by inhibiting AGTR1.


Prediction of Lignin Content in Different Parts of Sugarcane Using Near-Infrared Spectroscopy (NIR), Ordered Predictors Selection (OPS), and Partial Least Squares (PLS).
The building of multivariate calibration models using near-infrared spectroscopy (NIR) and partial least squares (PLS) to estimate the lignin content in different parts of sugarcane genotypes is presented. Laboratory analyses were performed to determine the lignin content using the Klason method. The independent variables were obtained from different materials: dry bagasse, bagasse-with-juice, leaf, and stalk. The NIR spectra in the range of 10 000-4000 cm-1 were obtained directly for each material. The models were built using PLS regression, and different algorithms for variable selection were tested and compared: iPLS, biPLS, genetic algorithm (GA), and the ordered predictors selection method (OPS). The best models were obtained by feature selection with the OPS algorithm. The values of the root mean square error prediction (RMSEP), correlation of prediction ( RP), and ratio of performance to deviation (RPD) were, respectively, for dry bagasse equal to 0.85, 0.97, and 2.87; for bagasse-with-juice equal to 0.65, 0.94, and 2.77; for leaf equal to 0.58, 0.96, and 2.56; for the middle stalk equal to 0.61, 0.95, and 3.24; and for the top stalk equal to 0.58, 0.96, and 2.34. The OPS algorithm selected fewer variables, with greater predictive capacity. All the models are reliable, with high accuracy for predicting lignin in sugarcane, and significantly reduce the time to perform the analysis, the cost and the chemical reagent consumption, thus optimizing the entire process. In general, the future application of these models will have a positive impact on the biofuels industry, where there is a need for rapid decision-making regarding clone production and genetic breeding program.


Pyometra in cats: 183 cases (1979-1984).
Pyometra was diagnosed in 183 cats. The most common signs detected by owners included vaginal discharge, anorexia, and lethargy. Main clinical findings on physical examination were vaginal discharge, abdominal distention, dehydration, palpable uterus, and pyrexia. Abdominal radiography revealed a large uterus in 138/169 cats. Most cats had leukocytosis with a left shift. Diagnosis of pyometra was confirmed at surgery in all cats on the basis of finding a large uterus containing purulent material. Clinical signs resolved in 168 cats after surgery; 15 cats (8%) died or were euthanatized. Postoperative complications in 20% generally resolved within 2 weeks after the cats were sent home. Signs detected by owners and results of physical examination in cats with pyometra were similar, but not as conspicuous as those reported in the dog. Mortality (8%) was similar to that seen in dogs.


Endoscopic endonasal middle clinoidectomy: anatomic, radiological, and technical note.
The middle clinoid is an osseous prominence that arises from the body of the sphenoid bone at the anterolateral margin of the sella. To illustrate the radiological and surgical anatomy of the middle clinoid and describe the technical nuances for endonasal endoscopic middle clinoid removal. The fine-cut head CT-angiogram scans of 100 patients and 50 anatomic specimens were examined. The middle clinoid was categorized as: absent, small, prominent, or caroticoclinoidal ring. Ten colored silicon-injected anatomic specimens were used to study the surgical anatomy for the endonasal middle clinoidectomy. Extensive surgical experience allowed for intraoperative observations regarding the surgical anatomy of the middle clinoid and the technical nuances for its removal. The middle clinoid was identifiable in 60% of scans (bilateral in 35%), and 20% had at least one caroticoclinoidal ring (bilateral in 6%). When present, the middle clinoid is located at the transition between the intracavernous internal carotid artery (ICA) and paraclinoidal ICA, and covers the anteromedial roof of the cavernous sinus. Endonasal removal of the middle clinoid improves access to the parasellar region. The middle clinoidectomy is completed exposing the following structures sequentially: sellar dura, anterior wall of the cavernous sinus, dura of the lateral tuberculum sella, and paraclinoidal ICA. When a caroticoclinoidal ring is identified, progressive reduction of the middle clinoid can be achieved without fracturing the ring. Recognition of the middle clinoid and caroticoclinoidal ring on preoperative imaging is critical for surgical planning and middle clinoid removal in endonasal skull base surgery.


Deep learning networks in the segmentation of the left atrial appendage in 2D ultrasound: A comparative analysis.
Left atrial appendage (LAA) is the major source of thromboembolism in patients with non-valvular atrial fibrillation. Currently, LAA occlusion can be offered as a treatment for these patients, obstructing the LAA through a percutaneously delivered device. Nevertheless, correct device sizing is a complex task, requiring manual analysis of medical images. This approach is sub-optimal, time-demanding, and highly variable between experts. Different solutions were proposed to improve intervention planning, but, no efficient solution is available to 2D ultrasound, which is the most used imaging modality for intervention planning and guidance. In this work, we studied the performance of recently proposed deep learning methods when applied for the LAA segmentation in 2D ultrasound. For that, it was created a 2D ultrasound database. Then, the performance of different deep learning methods, namely Unet, UnetR, AttUnet, TransAttUnet was assessed. All networks were compared using seven metrics: i) Dice coefficient; ii) Accuracy iii) Recall; iv) Specificity; v) Precision; vi) Hausdorff distance and vii) Average distance error. Overall, the results demonstrate the efficiency of AttUnet and TransAttUnet with dice scores of 88.62% and 89.28%, and accuracy of 88.25% and 86.30%, respectively. The current results demonstrate the feasibility of deep learning methods for LAA segmentation in 2D ultrasound.Clinical relevance- Our results proved the clinical potential of deep neural networks for the LAA anatomical analysis.


Reflex Hepatitis C Virus Viral Load Testing Following an Initial Positive Hepatitis C Virus Antibody Test: A Global Systematic Review and Meta-analysis.
Many people who have a positive hepatitis C virus (HCV) antibody (Ab) test never receive a confirmatory HCV RNA viral load (VL) test. Reflex VL testing may help address this problem. We undertook a systematic review to evaluate the effectiveness of reflex VL testing compared with standard nonreflex approaches on outcomes across the HCV care cascade. We searched 4 databases for studies that examined laboratory-based reflex or clinic-based reflex VL testing approaches, with or without a nonreflex comparator, and had data on the uptake of HCV RNA VL test and treatment initiation and turnaround time between Ab and VL testing. Both laboratory- and clinic-based reflex VL testing involve only a single clinic visit. Summary estimates were calculated using random-effects meta-analyses. Fifty-one studies were included (32 laboratory-based and 19 clinic-based reflex VL testing). Laboratory-based reflex VL testing increased HCV VL test uptake versus nonreflex testing (RR: 1.35; 95% CI: 1.16-1.58) and may improve linkage to care among people with a positive HCV RNA test (RR: 1.47; 95% CI: .81-2.67) and HCV treatment initiation (RR: 1.03; 95% CI: .46-2.32). The median time between Ab and VL test was <1 day for all laboratory-based reflex studies and 0-5 days for 13 clinic-based reflex testing. Laboratory-based and clinic-based HCV reflex VL testing increased uptake and reduced time to HCV VL testing and may increase HCV linkage to care. The World Health Organization now recommends reflex VL testing as an additional strategy to promote access to HCV VL testing and treatment. PROSPERO CRD42021283822.


The cost of eating more sustainable diets: A nutritional and environmental diet optimisation study.
We aim to identify the dietary changes to improve nutrition and reduce diet-related greenhouse gas emission (GHGE) simultaneously in Brazil, taking into account the heterogeneity in food habits and prices across the country. Food consumption and prices were obtained from two nationwide surveys (n = 55,970 households and 34,003 individuals). Linear programming models were performed to design optimised diets most resembling the observed diets, and meeting different sets of constraints: (i) nutritional, for preventing chronic diseases and meeting nutrient adequacy; (ii) socio-cultural: by respecting food preferences; and (iii) environmental: by reducing GHGE by steps of 10%. Moving toward a diet that meets nutritional recommendations led to a 14% to 24% cost increase and 10% to 27% GHGE reduction, depending on the stringency of the acceptability constraints. Stronger GHGE reductions were achievable (up to about 70%), with greater departure from the current diet, but not achieving calcium and potassium goals. Diet cost increment tended to be mitigated with GHGE reduction in most models, along with reductions in red meat, chicken, eggs, rice, and high-fat sugar sodium foods.


Impact of spexin on metabolic diseases and inflammation: An updated minireview.
Spexin (SPX) is a 14 amino acid length peptide hormone which was discovered using bioinformatic tools. It is extensively expressed in central and peripheral tissues and secreted into circulation in response to metabolic stress. Recent studies revealed that SPX acts as a multifunctional peptide in various metabolic processes such as body weight, food intake, energy balance, glucose and lipid metabolism, lipid storage, salt-water balance, and arterial blood pressure. Endogenous SPX is sensitive to metabolic changes, and circulating levels of SPX have been shown to be reduced in chronic diseases such as obesity, diabetes, and insulin resistance. Moreover, in fish and rodent models, systemic SPX treatment has positive effects on metabolism including reduced food intake, fat mass, lipid accumulation, and inflammation, improved insulin sensitivity, energy expenditure, and organ functions which are underlying mechanisms in diseases. Taken together, these findings suggest that SPX is a potential drug target for the development of new pharmacological strategies to cure metabolic diseases. This review focuses on metabolo-protective properties of SPX and discusses novel insights into the biology and mechanism of SPX in the pathogenesis of diabetes, obesity, non-alcoholic fatty liver disease, metabolic syndrome, polycystic ovary syndrome, cardiovascular diseases, and kidney diseases, which are considerable global health problems.


[Intravenous high-dose methylprednisolone efficacy for treatment of idiopathic thrombocytopenic purpura in adults].
To determine the efficacy of a short intravenous course of high-dose methylprednisolone compared with the standard treatment with prednisone for adult patients with idiopathic thrombocytopenic purpura (ITP). Retrospective. For all patients diagnosed with ITP between January 1st 1988 and January 1st 1998 in the University Hospital Vrije Universiteit, Amsterdam, the Netherlands, data were obtained until June 1st 1998. These patients had received a brief course of treatment with methylprednisolone i.v. (1 g per day on three successive days in the outpatient department) or the standard treatment (protracted oral treatment with prednisone). A response was defined as a rise in platelet count of > 50 x 10(9)/l. When a remission lasted more than a year a patient was defined as longterm responder. The results concerned 41 patients. The prednisone group comprised 7 males and 20 females, mean age 39 years, the methylprednisolone group comprised 2 males and 12 females, mean age 43 years. Initial treatment with prednisone or methylprednisolone resulted in equal response rates of, respectively, 63% (17/27 patients) and 64% (9/14 patients). The number of longterm responders was 8 of 27 patients in the prednisone group and 2 of 14 patients in the methylprednisolone group. At time of relapse 22 patients were treated with the other treatment modality. The response rate in the group of patients treated with prednisone after first-line treatment with methylprednisolone, was 67% (6/9), for methylprednisolone after first-line treatment with prednisone the response rate was 23% (3/13). A short intravenous course of high-dose methylprednisolone is effective as initial treatment of adults with ITP. Toxicity of longterm treatment with prednisone can be avoided in a number of patients with ITP. In patients refractory to treatment with methylprednisolone, the response rate to second-line treatment with prednisone was not negatively influenced, since two thirds of these relapsing patients subsequently responded to prednisone.


GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer's disease mouse model.
GV1001 protects neural cells from amyloid-β (Aβ) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aβ oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aβ oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.


Community-level determinants of stakeholder perceptions of community stigma toward people with opioid use disorders, harm reduction services and treatment in the HEALing Communities Study.
Community stigma toward people with opioid use disorder (OUD) can impede access to harm reduction services and treatment with medications for opioid use disorder (MOUD). Such community OUD stigma is partially rooted in community-level social and economic conditions, yet there remains a paucity of large-scale quantitative data examining community-level factors associated with OUD stigma. We examined whether rurality, social inequity, and racialized segregation across communities from four states in the HEALing Communities Study (HCS) were associated with 1) greater perceived community stigma toward people treated for OUD, 2) greater perceived intervention stigma toward MOUD, and 3) greater perceived intervention stigma toward naloxone by community stakeholders in the HCS. From November 2019-January 2020, a cross-sectional survey about community OUD stigma was administered to 801 members of opioid overdose prevention coalitions across 66 communities in four states prior to the start of HCS intervention activities. Bivariate analyses assessed pairwise associations between community rural/urban status and each of the three stigma variables, using linear mixed effect modeling to account for response clustering within communities, state, and respondent sociodemographic characteristics. We conducted similar bivariate analyses to assess pairwise associations between racialized segregation and social inequity. On average, the perceived community OUD stigma scale score of stakeholders from rural communities was 4% higher (β=1.57, SE=0.7, p≤0.05), stigma toward MOUD was 6% higher (β=0.28, SE=0.1, p≤0.05), and stigma toward naloxone was 10% higher (β=0.46, SE=0.1, p≤0.01) than among stakeholders from urban communities. No significant differences in the three stigma variables were found among communities based on racialized segregation or social inequity. Perceived community stigma toward people treated for OUD, MOUD, and naloxone was higher among stakeholders in rural communities than in urban communities. Findings suggest that interventions and policies to reduce community-level stigma, particularly in rural areas, are warranted.


Volumetric optoacoustic neurobehavioral tracking of epileptic seizures in freely-swimming zebrafish larvae.
Fast three-dimensional imaging of freely-swimming zebrafish is essential to understand the link between neuronal activity and behavioral changes during epileptic seizures. Studying the complex spatiotemporal patterns of neuronal activity at the whole-brain or -body level typically requires physical restraint, thus hindering the observation of unperturbed behavior. Here we report on real-time volumetric optoacoustic imaging of aberrant circular swimming activity and calcium transients in freely behaving zebrafish larvae, continuously covering their motion across an entire three-dimensional region. The high spatiotemporal resolution of the technique enables capturing ictal-like epileptic seizure events and quantifying their propagation speed, independently validated with simultaneous widefield fluorescence recordings. The work sets the stage for discerning functional interconnections between zebrafish behavior and neuronal activity for studying fundamental mechanisms of epilepsy and in vivo validation of treatment strategies.


Recommended intakes of vitamin D to optimise health, associated circulating 25-hydroxyvitamin D concentrations, and dosing regimens to treat deficiency: workshop report and overview of current literature.
Vitamin D is a fat-soluble hormone that traditionally has been linked to bone health. Recently, its involvement has been extended to other (extra-skeletal) disease areas, such as cancer, CVD, energy metabolism and autoimmune diseases. Vitamin D deficiency is a worldwide problem, and several recommendation-setting bodies have published guidelines for adequate vitamin D intake and status. However, recommendations from, for example, the Health Council of the Netherlands do not provide advice on how to treat vitamin D deficiency, a condition that is often encountered in the clinic. In addition, these recommendations provide guidelines for the maintenance of 'minimum levels', and do not advise on 'optimum levels' of vitamin D intake/status to further improve health. The NutriProfiel project, a collaboration between the Gelderse Vallei Hospital (Ede, the Netherlands) and the Division of Human Nutrition of Wageningen University (Wageningen, the Netherlands), was initiated to formulate a protocol for the treatment of vitamin deficiency and for the maintenance of optimal vitamin D status. To discuss the controversies around treatment of deficiency and optimal vitamin D status and intakes, a workshop meeting was organised with clinicians, scientists and dietitians. In addition, a literature review was conducted to collect recent information on optimal intake of vitamins, their optimal circulating concentrations, and effective dosing regimens to treat deficiency. This information has been translated into the NutriProfiel advice, which is outlined in this article.


Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine.
The discriminative stimulus effects of nicotine and cocaine were studied, alone and in combination, in rats. Two sets of rats were trained to press one lever when injected intraperitoneally (i.p.) with either nicotine (0.1 mg/kg = 0.6 micromol/kg, Set 1) or cocaine (8.9 mg/kg base = 29.4 micromol/kg, Set 2), and another lever when injected with saline. Rats learned to discriminate drug from saline, and maintained discriminative control throughout the study (at > 85% drug-appropriate responding). In accordance with most previous findings, cocaine only partially substituted for nicotine (maximum = 41% nicotine-lever responding). The nicotinic agonist, nornicotine, produced dose-related, near-full substitution for nicotine (maximum = 76% nicotine-lever responding), whereas the peripherally acting nicotinic agonist, methylcarbamylcholine, did not substitute for nicotine. The muscarinic receptor agonist pilocarpine also failed to substitute for nicotine. However, in the cocaine-trained rats, nicotine substituted fully for cocaine in a dose-dependent manner, demonstrating that cross-generalization between the two drugs is not symmetrical. Finally, administration of each drug as a pre-treatment to the other yielded inconsistent increases in each drug's discriminative stimulus effects. The results are congruent with the view that the discriminative stimulus effects of nicotine and cocaine share common features, but the asymmetric pattern of cross-generalization and the interactions revealed in the combination tests also suggest that there are important differences between them.


Endothelial dysfunction: a strategic target in the treatment of hypertension?
Endothelial dysfunction is a common feature of hypertension, and it results from the imbalanced release of endothelium-derived relaxing factors (EDRFs; in particular, nitric oxide) and endothelium-derived contracting factors (EDCFs; angiotensin II, endothelins, uridine adenosine tetraphosphate, and cyclooxygenase-derived EDCFs). Thus, drugs that increase EDRFs (using direct nitric oxide releasing compounds, tetrahydrobiopterin, or L-arginine supplementation) or decrease EDCF release or actions (using cyclooxygenase inhibitor or thromboxane A2/prostanoid receptor antagonists) would prevent the dysfunction. Many conventional antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation beta-blockers, possess the ability to reverse endothelial dysfunction. Their use is attractive, as they can address arterial blood pressure and vascular tone simultaneously. The severity of endothelial dysfunction correlates with the development of coronary artery disease and predicts future cardiovascular events. Thus, endothelial dysfunction needs to be considered as a strategic target in the treatment of hypertension.


Hazelnut as Ingredient in Dairy Sheep Diet: Effect on Sensory and Volatile Profile of Cheese.
The opportunity of replacing expensive feedstuffs with agro-industrial by-products in the diet of food producing animals is raising increasing interest while addressing global concern for the scarcity of natural resources and environmental impact of livestock farming. Hazelnut peels, rich in fiber and vitamins and characterized by a high concentration of fats, is considered a suitable ingredient to be included in the diet of ruminants. The aim of this research was to assess the effect of dietary hazelnut peels on the chemical and sensory properties of sheep cheese during refrigerated storage. To this purpose, 20 Comisana lactating ewes were randomly assigned to two experimental groups, control (C) and hazelnut peels (HP), balanced for parity, milk yield and body weight. Bulk milk collected from the 2 groups was used to produce 5 Pecorino cheeses for each group. After 40 d of aging, each cheese of each experimental group was divided into 3 pieces: 1 piece was sampled for analyses (C0, HP0) and 2 were wrapped in PVC film, simulating the condition of pre-wrapped products, and analyzed after 7 (C7, HP7) and 14 days of storage (C14, HP14) at 8°C with 80% moisture. The cheeses were analyzed for chemical and fatty acid composition, sensory analysis, odor active compounds and SmartNose. As expected, HP cheeses presented a higher lipid content compared to C, a lower content in SFA and PUFA, and a greater content in MUFA. A triangle test revealed a clear distinction between the 2 groups (α = 0.01) The sensory profile showed a significant effect on holes (P < 0.05) and a marginal production of off-flavors linked to spicy and acid attributes for HP cheeses The volatile profile of C and HP cheese samples showed a good similarity, partially explained by the short ripening time and the absence of 2-nonanone in HP7, suggesting a higher antioxidant protection grade of this cheese compared to the others. These results were confirmed by Smart Nose analysis. Further studies on vitamin content should be conducted in order to investigate the interactions between the presence of antioxidant volatile compounds and the oxidative stability of ewe cheese.


Alteration of murine mammary tumorigenesis by dietary enrichment with n-3 fatty acids in fish oil.
We and others have previously shown that dietary fat can alter the growth and metastasis of rodent mammary tumors. Few transplantable tumor models have been used to study the effects of dietary n-6 versus n-3 fatty acids on mammary tumorigenesis. Here we study the effects of fish oil and safflower oil on the growth and metastasis of an animal model that in several ways parallels the human disease. Tumor latency, growth and metastasis were studied in mice fed diets that contained either 10 or 20% total fat which was varied in the type of fat with either menhaden fish oil (FO), safflower oil (SO) or a 50/50 mixture of the two. Tumor latency was significantly longer and tumor growth was significantly slower in mice fed the 20% FO diet. When spontaneous metastasis was assessed, mice fed diets containing FO had significantly decreased numbers of pulmonary nodules and total metastatic load. Likewise, mice fed FO diets had a lower level of implantation and survival of pulmonary metastases. Thus, in our animal model, diets containing n-3 fatty acids in fish oil significantly decrease primary breast tumor growth and its metastasis.


The response-signal method reveals age-related changes in object working memory.
Sixteen healthy young adults (ages 18-32) and 16 healthy older adults (ages 67-81) completed a delayed response task in which they saw the following visual sequence: memory stimuli (2 abstract shapes; 3,000 ms), a blank delay (5,000 ms), a probe stimulus of variable duration (one abstract shape; 125, 250, 500, 1,000, or 2,000 ms), and a mask (500 ms). Subjects decided whether the probe stimulus matched either of the memory stimuli; they were instructed to respond during the mask, placing greater emphasis on speed than accuracy. The authors used D. L. Hintzman & T. Curran's (1994) 3-parameter compound bounded exponential model of speed-accuracy tradeoff to describe changes in discriminability associated with total processing time. Group-level analysis revealed a higher rate parameter and a higher asymptote parameter for the young adult group, but no difference across groups in x-intercept. Proxy measures of cognitive reserve (Y. Stern et al., 2005) predicted the rate parameter value, particularly in older adults. Results suggest that in working memory, aging impairs both the maximum capacity for discriminability and the rate of information accumulation, but not the temporal threshold for discriminability.


CRISPR/Cas9 and Genome Editing for Viral Disease-Is Resistance Futile?
Chronic viral infections remain a major public health issue affecting millions of people worldwide. Highly active antiviral treatments have significantly improved prognosis and infection-related morbidity and mortality but have failed to eliminate persistent viral forms. Therefore, new strategies to either eradicate or control these viral reservoirs are paramount to allow patients to stop antiretroviral therapy and realize a cure. Viral genome disruption based on gene editing by programmable endonucleases is one promising curative gene therapy approach. Recent findings on RNA-guided human immunodeficiency virus 1 (HIV-1) genome cleavage by Cas9 and other gene-editing enzymes in latently infected cells have shown high levels of site-specific genome disruption and potent inhibition of virus replication. However, HIV-1 can readily develop resistance to genome editing at a single antiviral target site. Current data suggest that cellular repair associated with DNA double-strand breaks can accelerate the emergence of resistance. On the other hand, a combination antiviral target strategy can exploit the same repair mechanism to functionally cure HIV-1 infection in vitro while avoiding the development of resistance. This perspective summarizes recent findings on the biology of resistance to genome editing and discusses the significance of viral genetic diversity on the application of gene editing strategies toward cure.


Trends in Cannabis-positive Urine Toxicology Test Results: US Veterans Health Administration Emergency Department Patients, 2008 to 2019.
This study aimed to examine trends in cannabis-positive urine drug screens (UDSs) among emergency department (ED) patients from 2008 to 2019 using data from the Veterans Health Administration (VHA) health care system, and whether these trends differed by age group (18-34, 35-64, and 65-75 years), sex, and race, and ethnicity. VHA electronic health records from 2008 to 2019 were used to identify the percentage of unique VHA patients seen each year at an ED, received a UDS, and screened positive for cannabis. Trends in cannabis-positive UDS were examined by age, race and ethnicity, and sex within age groups. Of the VHA ED patients with a UDS, the annual prevalence positive for cannabis increased from 16.42% in 2008 to 27.2% in 2019. The largest increases in cannabis-positive UDS were observed in the younger age groups. Male and female ED patients tested positive for cannabis at similar levels. Although the prevalence of cannabis-positive UDS was consistently highest among non-Hispanic Black patients, cannabis-positive UDS increased in all race and ethnicity groups. The increasing prevalence of cannabis-positive UDS supports the validity of previously observed population-level increases in cannabis use and cannabis use disorder from survey and administrative records. Time trends via UDS results provide additional support that previously documented increases in self-reported cannabis use and disorder from surveys and claims data are not spuriously due to changes in patient willingness to report use as it becomes more legalized, or due to greater clinical attention over time.


Visualization and characterization of cancer stem-like cells in cervical cancer.
Cancer stem cells (CSCs), defined by their differentiation capacity, self-renewal capacity, and maintenance of proliferation, have been identified in many tumors, including cervical cancer. Current studies identify CSCs by several specific biomarkers; however, it is difficult to monitor cervical CSCs in real-time in vitro and in vivo. Recent research reported the visualization of CSCs in breast cancer and gliomas using green fluorescent protein, ZsGreen, fused to a degron motif ornithine decarboxylase (ODC), which is destroyed by proteasomes. Accordingly, CSCs have low 26S proteasome activity, whereas non-CSCs have high 26S proteasome activity. Therefore, it is possible to observe CSCs by their accumulation of the fluorescent ZsGreen protein. In this study, we investigated optical imaging parameters to evaluate CSCs using two human cervical cancer cell lines: CaSki and HeLa. We defined populations as cell types having high- and low ZsGreen-cODC (high- and low-Zs, respectively) expression levels. The results of a sphere-forming assay revealed that the self-renewal ability of the high-Zs population was significantly higher than that of the low-Zs population. A tumorigenicity assay confirmed that the high-Zs population exhibited higher tumorigenic potential than the low-Zs population. The radioresistance of the high-Zs population of both HeLa and CaSki cells and the chemoresistance of the high-Zs population of CaSki cells were confirmed by a clonogenic survival assay and the tetrazolium dye assay, respectively. These results indicate that high-Zs populations of both the HeLa and CaSki cell lines possess CSC-like properties and therapeutic resistance. In conclusion, we successfully visualized CSC-like cells using a fluorescent protein system.


Prenatal cocaine and neonatal outcome: evaluation of dose-response relationship.
The aim of this study was to evaluate the hypothesis that prenatal cocaine exposure would negatively affect newborn behavior. A prospective observational study of term infants recruited from the low-risk nursery used a structured, standardized interview to obtain maternal data. Cocaine exposure was determined by radioimmunoassay of the infant's meconium stool. An examiner blinded to the infant's cocaine status administered the Brazelton Neonatal Behavioral Assessment Scales. The sample was composed of 23 exposed and 29 nonexposed infants. On six of the seven Brazelton Neonatal Behavioral Assessment Scale clusters, cocaine-exposed infants performed less well than control infants, with significant differences observed for autonomic stability. In addition, a dose-response relationship was suggested. Significant negative, within-group relationships were evident in the exposed group, indicating poorer performance with increasing meconium cocaine concentration for orientation (r = -.40) and regulation of state (r = -.40). Regression model testing of the influence of meconium cocaine concentration on neurobehavioral outcomes, after controlling for significant confounders, identified a significant independent, negative effect of meconium cocaine concentration on two clusters-motor and regulation of state. In otherwise healthy full-term infants, prenatal cocaine exposure identified by quantitative analysis of cocaine concentration in meconium had a significant, independent negative association with motor and regulation of state that remained after controlling for other significant confounders. A dose-response relationship was evident.


Estimating HIV/AIDS prevalence in countries with low-level and concentrated epidemics: the example of Honduras.
Estimates of HIV/AIDS prevalence are important, because they are the primary measure of the current state of the epidemic in a country. How estimates of HIV/AIDS are made depends on the level of the epidemic. For estimates of HIV/AIDS prevalence in low-level and concentrated epidemics it is necessary to disaggregate the total adult population into sub-groups based on the relative risk of infection. For each group, the major issues and questions are: identifying risk groups, estimating the size of the populations, and estimating HIV prevalence in these groups. The greatest difficulty in making estimates of prevalence in low-level and concentrated epidemics is often establishing the size of various populations. Because of the uncertainty inherent in making an estimate of population size for these groups at high risk, low and high estimates are used. In order to demonstrate the method the case of Honduras was used. The most recent HIV prevalence data and the estimates of population sizes were applied. It was estimated that Honduras, which has a total population of 6,575,000 (United Nations Population Division sources), has approximately 55,000 adults living with HIV/AIDS, with a range of uncertainty between 30,000 and 80,000. Estimations of the burden of HIV is a continuous process and should be updated on a regular basis according to the most recent and relevant information available.


Anogenital and Physical Injuries in Adolescent Sexual Assault Patients: The Role of Victim-Offender Relationship, Alcohol Use, and Memory Impairment.
Prior research has documented high rates of anogenital and physical injuries among adolescent sexual assault patients. Although a number of factors related to rates of injury detection in adolescents have been identified, there may be additional features of the assault that are disclosed in the patient history that could be important indicators of injury risk. The purpose of the current study was to expand this literature by examining whether factors that are salient in sexual assaults committed against adolescents-victim-offender relationship, substance use, and memory impairment-are associated with documented anogenital and physical injury rates. Results indicated that victim-offender relationship, substance use, and assault memory are significantly related to the number of anogenital injuries and, particularly, the number of physical injuries detected in adolescent sexual assault patients. These results highlight the importance of a comprehensive patient history, including assessment of alcohol and drug use and memory impairment, to guide the medical forensic examination.


Effect of black tea extract on herpes simplex virus-1 infection of cultured cells.
The purpose of this investigation was to determine if black tea extract (BTE), consisting primarily of flavanol compounds called theaflavins, could inhibit herpes simplex virus type-1 (HSV-1) infection in cultured A549 (human epithelial) and Vero cells. The effect of BTE both on A549 and Vero cultured cells and on HSV-1 was assessed by using phase contrast and fluorescent microscopy, and cell viability and proliferation assays. After establishing the maximum non-cytotoxic concentration of BTE, A549 and Vero cells and HSV-1 virions were treated with varying concentrations of BTE, respectively. A549 and Vero cells were infected with HSV-1 with green fluorescent protein (GFP) insert at the UL46 gene. The effect of infectivity was determined by viral DNA extraction followed by PCR, plaque assays, adsorption assays, and electrophoresis of PCR products. BTE was not cytotoxic to A549 and Vero cells, as confirmed by cell viability and proliferation assays, in which BTE treated groups paralleled the positive control group. For both cell lines, plaque assays and fluorescent microscopy indicated an inverse relationship between BTE concentration (from 0.14 μM - 1.4 mM) and HSV-1 infectivity. Specifically, PCR and electrophoresis showed a reduction in the viral genome following treatment with BTE. In addition, there was a noticeable decrease in the amount of viral plaques for BTE treated samples in the adsorption assays. BTE consisting primarily of theaflavins is not cytotoxic and can reduce or block the production of infectious HSV-1 virions in cultured A549 and Vero cells, thus inhibiting the infectivity of the virus by interfering in the attachment, penetration and viral DNA replication of HSV-1 particles. These findings indicate that BTE enriched with theaflavins has the potential to be developed as a safe, therapeutic antiviral agent to prevent the spread of HSV-1.


Differential signaling networks of Bcr-Abl p210 and p190 kinases in leukemia cells defined by functional proteomics.
The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p190, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p190 occurs in the majority of B-cell acute lymphoblastic leukemia. Differences in protein interactions and activated signaling pathways that may be associated with the different diseases driven by p210 and p190 are unknown. We have performed a quantitative comparative proteomics study of p210 and p190. Strong differences in the interactome and tyrosine phosphoproteome were found and validated. Whereas the AP2 adaptor complex that regulates clathrin-mediated endocytosis interacts preferentially with p190, the phosphatase Sts1 is enriched with p210. Stronger activation of the Stat5 transcription factor and the Erk1/2 kinases is observed with p210, whereas Lyn kinase is activated by p190. Our findings provide a more coherent understanding of Bcr-Abl signaling, mechanisms of leukemic transformation, resulting disease pathobiology and responses to kinase inhibitors.


Risk communication and prostate cancer: identifying which summary statistics are best understood by men.
The format in which risk is communicated influences how patients make health care decisions. The same statistical information may be summarized differently according to relative risk reduction, absolute risk reduction, number needed to treat, or odds ratio. A total of 76 men participated in focus groups exploring their understanding of information about prostate cancer treatments when framed across these different formats. Using thematic analysis, it was identified that the study participant best understood information when outcomes were framed as an absolute risk reduction and in a positive frame. Patient education materials about prostate cancer treatment options should be reported as an increase in probability of survivorship rather than decrease in risk of mortality and incorporate impact of treatment on patient-centered quality-of-life outcomes.


The DIalysis Symptom COntrol-Restless Legs Syndrome (DISCO-RLS) Trial: A Protocol for a Randomized, Crossover, Placebo-Controlled Blinded Trial.
Restless legs syndrome (RLS) affects approximately 30% of patients with end-stage kidney disease and is associated with impaired sleep and health-related quality of life. Medications used to treat RLS in patients receiving dialysis may have an increased risk of adverse events with dose titration, and residual RLS symptoms are common despite the use of effective treatments. Randomized controlled trials of monotherapy and combination pharmacologic therapy for RLS in hemodialysis are needed. To perform a randomized, crossover, placebo-controlled blinded trial of pharmacologic therapy for RLS in hemodialysis. The DIalysis Symptom COntrol-Restless Legs Syndrome (DISCO-RLS) trial is a randomized, crossover, placebo-controlled blinded trial of fixed low-dose pharmacologic therapy in patients receiving hemodialysis in 10 centers across Canada. It uses patient partners in its design, conduct, and reporting. Adults receiving thrice-weekly hemodialysis for at least 3 months with RLS of at least mild symptoms defined International Restless Legs Syndrome Study Group Rating Scale (IRLS) of 10 or more will enter a double placebo run-in period to exclude nonadherent participants and those unable to tolerate double placebo. Seventy-two participants who completed the run-in period will be randomized to 1 of 8 treatment sequences based on modeling with 4 treatment periods. Each treatment period lasts 4 weeks and consists of ropinirole 0.5 mg daily and gabapentin 100 mg daily, both together or neither with a double dummy placebo control for each treatment. The primary outcome is the difference in change scores of the IRLS between study treatments. Secondary outcomes are the differences in change scores of the Restless Legs Syndrome-6 Scale, patient global impression, 5-level EQ-5D version, and safety outcomes. This randomized, crossover, placebo-controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination of ropinirole and gabapentin in patients receiving hemodialysis with RLS. Patients with chronic kidney disease not on dialysis, kidney transplant recipients and those receiving peritoneal dialysis or home hemodialysis are not included. The intervention's long term safety and efficacy including the risk of augmentation is not captured. This randomized crossover placebo controlled blinded trial will evaluate the efficacy and safety of fixed low-dose combination ropinirole and gabapentin in patients receiving hemodialysis with RLS. ClinicalTrials.gov (NCT03806530).


Critical evaluation of Mirels' rating system for impending pathologic fractures.
This project examined the hypothesis that Mirels' rating system for impending pathologic fractures is reproducible, valid, and applicable across various experience levels and training backgrounds. Twelve true clinical histories and corresponding radiographs for patients with femoral metastatic lesions were reviewed by 53 participants from five experience levels: orthopaedic residents, musculoskeletal radiologists, orthopaedic attendings, fellowship-trained practicing orthopaedic oncologists, and radiation or medical oncologists. Each examiner provided individual and total Mirels' scores and independent determination of impending fracture using clinical judgment. A subset of seven histories without prophylactic fixation provided a natural history group. There was highly significant agreement across experience categories for overall Kappa and for the concordance for individual and overall scores. Kappa analysis showed good agreement for site, moderate agreement for type, and fair agreement for size and pain. There was no significant difference in overall scores across experience levels. The pooled odds ratio favored Mirels rating system over clinical judgment regardless of experience level. Overall sensitivity was 91% and specificity was 35%. Mirels' system seems to be reproducible, valid, and more sensitive than clinical judgment across experience levels. However, although the system is a valuable screening tool, more specific parameters are needed.