Evaluating the effectiveness of early vaccination in the control and eradication of equine influenza--a modelling approach.
In August 2007, Australia which had previously been free of equine influenza, experienced a large outbreak that lasted approximately 4 months before it was eradicated. The outbreak required a significant national response by government and the horse industries. The main components of the response were movement controls, biosecurity measures, risk-based zoning and, subsequently, vaccination to contain the outbreak. Although not initially used, vaccination became a key element in the eradication program, with approximately 140000 horses vaccinated. Vaccination is recognised as a valuable tool for managing EI in endemically infected countries but there is little experience using it in situations where the objective is disease eradication. Vaccination was undoubtedly an important factor in 2007 as it enabled movements of some horses and associated industry activities to recommence. However, its contribution to containment and eradication is less clear. A premises-level equine influenza model, based on an epidemiological analysis of the 2007 outbreak, was developed to evaluate effectiveness of the mitigation strategies used and to investigate whether vaccination, if applied earlier, would have had an effect on the course of the outbreak. The results indicate that early use of strategic vaccination could have significantly reduced the size of the outbreak. The four vaccination strategies evaluated had, by 1 month into the control program, reduced the number of new infections on average by 60% and the size of the infected area by 8-9%. If resources are limited, a 1 km suppressive ring vaccination around infected premises gave the best results, but with greater vaccination capacity, a 3 km ring vaccination was the most effective strategy. The findings suggest that as well as reducing clinical and economic impacts, vaccination when used with biosecurity measures and movement controls could play an important role in the containment and eradication of equine influenza.


Endoscopic transantral and transnasal repair of orbital floor fracture with the ballooning technique, and classification and characterization of orbital floor fractures.
The level of difficulty during an endoscopic approach for an inferior orbital fracture depends on the fracture pattern and the presence of a ruptured membrane (orbital periosteum and sinus mucosa). The purpose of our study was to examine fracture patterns according to age group and to determine the relationship between the type of fracture and the type of membrane injury. We reviewed the records of 30 patients who, from 2006 to 2010, underwent endoscopic transantral and transnasal approach with a balloon catheter technique to repair orbital floor fracture. The procedure was done through middle or inferior meatal antrostomy and two small antrostomies made in the anterior wall of the maxillary sinus by using an endoscope and specially designed curved dissectors. There were 3 linear, 20 trapdoor-type and 7 blowout fractures. There was a tendency toward a higher incidence of linear fractures at younger ages and of blowout fractures in older patients. All linear fractures had rupture of both membranes, whereas both membranes were intact in 15 of the 20 patients with trapdoor fractures. Among blowout fractures, there was no membrane rupture in five and both membranes were ruptured in two patients. No patient reported diplopia after fracture repair. Rupture of the periosteum, which makes visualization and reduction of orbital tissue difficult for the surgeon during endoscopic repair of the orbital floor fracture, was observed in 3 of 3 linear fractures and 5 of 20 trapdoor fractures. We found that linear fractures were more common in pediatric patients. Care of pediatric orbital floor fracture requires particular caution.


Epistasis in the expression of relevant traits in cassava (Manihot esculenta Crantz) for subhumid conditions.
There is limited knowledge on the inheritance of agronomic traits in cassava and the importance of epistasis for most crops. A nine-parent diallel study was conducted in subhumid environments. Thirty clones were obtained from each F1 cross. Each clone was represented by six plants, which were distributed in three replications at two locations. Therefore the same 30 genotypes of each F1 cross were planted in the three replications at the two locations. Analysis of variance suggested significant genetic effects for all variables analyzed (reaction to thrips, fresh root and foliage yields, harvest index, dry matter content, and root dry matter yield). Significant epistatic effects were observed for all variables, except harvest index. Dominance variance was always significant, except for dry matter content and dry matter yield. Additive variance was significant only for reaction to thrips. Results suggested that dominance plays an important role in complex traits such as root yield. The significance of epistasis can help us understand the difficulties of quantitative genetics models and QTLs in satisfactorily explaining phenotypic variation in traits with complex inheritance. Significant epistasis would justify the production of inbred parental lines to fix favorable allele combinations in the production of hybrid cassava cultivars.


In situ examination of a charged amino acid-induced structural change in lipid bilayers by sum frequency generation vibrational spectroscopy.
The interactions between amino acids (AAs) and membranes represent various short-range and long-range interactions for biological phenomena; however, they are still poorly understood. In this study, we used cationic lysine and arginine as AA models, and systematically investigated the interactions between charged AAs and lipid bilayers using sum frequency generation vibrational spectroscopy (SFG-VS) in situ and in real time. The AA-induced dynamic structural changes of the lipid bilayer were experimentally monitored using the spectral features of CD2, CD3, the lipid head phosphate, and carbonyl groups in real time. Time-dependent SFG changes in the structure of the lipid bilayer provide direct evidence for the different interactions of lysine and arginine with the membrane. It was found that the discrepancy between lysine and arginine in binding with the lipid bilayer is due to the nature of the terminal functional groups. Arginine exhibits a more drastic impact on the membrane than lysine. SFG responses of the acyl chains, phosphate groups, and carbonyl groups provide evidence that the interaction between AAs and the membrane most likely follows an electrostatics and hydrogen bond-induced defect model. This work presents an exemplary method for comprehensive investigations of interactions between membranes and other functionally significant substances.


A hybrid electroabsorption modulator device for generation of high spectral-efficiency optical modulation formats.
We report a novel hybrid integrated optic device consisting of AlGaInAs/InP electroabsorption modulators and a four-arm silica-on-silicon planar lightwave circuit optical interferometer. The device is designed for generation of high spectral efficiency optical modulation formats. We demonstrate generation of 21.4 Gb/s quadrature phase shift keyed optical signals with electrical data drives of 2V(pp) amplitudes, achieving a bit error rate of 10(-9) with the required optical signal to noise ratio of ~18 dB in a 0.1 nm resolution bandwidth.


New food for an old mouth: new enzyme for an ancient archaea.
As a multifunctional group of enzymes, glutathione S-transferases (GSTs) are capable of inactivation, degradation or excretion of wide range of compounds catalytically or non-catalytically. However, to date, no study has been addresses the presence of GSTs in archaea based on their enzymatic functions. In this study, beside glutathione (GSH) amount measurement, the determination of GST activity in halophilic archaeon called Haloarcula hispanica ATCC 33960 were aimed. According to the results, specific activity was determined as 19.68 nmol min⁻¹ mg⁻¹ protein and GSH content were found to be as 194 μg g⁻¹ K(m) and V(max) values for CDNB and GSH calculated from Lineweaver-Burk plot were 0.46 mM and 27.93 nmol min⁻¹ mg⁻¹, 0.13 mM and 22.03 nmol min⁻¹ mg⁻¹, respectively. Hanes-Woolf and Eadie-Hofstee plots for CDNB and GSH were also found to be in co-relation with the results obtained from Lineweaver-Burk plot. To the best of our knowledge, GST enzymes have not been identified in archaea yet, at least based on their catalytic activities. Therefore, it is the first report on this area.


A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver.
Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.


From Smoking-Permitted to Smokefree Prisons: A 3-Year Evaluation of the Changes in Occupational Exposure to Second-Hand Smoke Across a National Prison System.
Prisons in Scotland were one of the few workplaces exempt from the 2006 comprehensive smoking ban in indoor public places, excluding the prison workforce from the health benefits of smokefree workplaces. The November 2018 introduction of comprehensive restrictions on smoking in Scottish prisons aimed to protect prison staff and people in custody from the harmful impacts of second-hand smoke (SHS) exposure. This study presents SHS exposure data gathered after smokefree policy implementation and compares these with data gathered during and before policy development. Dylos DC1700 monitors were used to measure concentrations of fine particulate matter (PM2.5) derived from SHS across Scotland's 15 prisons. Six days of fixed-site monitoring (09.00 22 May 2019 to 09.00 28 May 2019) were conducted in residential halls in each prison 6 months post-smokefree policy implementation. Prison staff task-based measurements were conducted to assess concentrations of SHS in various locations (e.g. gyms and workshops) and during specific activities (e.g. cell searches, maintenance, and meal service). Utilizing the fixed-site monitoring data, typical daily PM2.5 exposure profiles were constructed for the prison service and time-weighted average (TWA) exposure concentrations were estimated for the typical shift patterns of residential staff pre- and post-smokefree policy implementation. Staff perceptions of changes to SHS exposure were assessed using online surveys. Analysis of both fixed-site and mobile task-based PM2.5 measurements showed the smokefree policy implementation was successful in reducing SHS exposures across the Scottish prison estate. Measured PM2.5 in residential halls declined markedly; median fixed-site concentrations reduced by more than 91% compared with measures in 2016 before policy announcement. The changes in the TWA concentrations across shifts (over 90% decrease across all shifts) and task-based measurements (89% average decrease for high-exposure tasks) provide evidence that prison staff exposure to SHS has significantly reduced. Following smokefree policy implementation, the majority of staff reported no longer being exposed to SHS at work. To our knowledge, this is the first comprehensive international study to objectively measure SHS levels before, during, and after implementation of a smokefree policy across a country's prison system. The findings confirm that such a policy change can be successfully implemented to eliminate occupational exposures to SHS. The results are highly relevant for other jurisdictions considering changes to prison smoking legislation.


The dynamics of the CHO host cell protein profile during clarification and protein A capture in a platform antibody purification process.
Recombinant protein products such as monoclonal antibodies (mAbs) for use in the clinic must be clear of host cell impurities such as host cell protein (HCP), DNA/RNA, and high molecular weight immunogenic aggregates. Despite the need to remove and monitor HCPs, the nature, and fate of these during downstream processing (DSP) remains poorly characterized. We have applied a proteomic approach to investigate the dynamics and fate of HCPs in the supernatant of a mAb producing cell line during early DSP including centrifugation, depth filtration, and protein A capture chromatography. The primary clarification technique selected was shown to influence the HCP profile that entered subsequent downstream steps. MabSelect protein A chromatography removed the majority of contaminating proteins, however using 2D-PAGE we could visualize not only the antibody species in the eluate (heavy and light chain) but also contaminant HCPs. These data showed that the choice of secondary clarification impacts upon the HCP profile post-protein A chromatography as differences arose in both the presence and abundance of specific HCPs when depth filters were compared. A number of intracellularly located HCPs were identified in protein A elution fractions from a Null cell line culture supernatant including the chaperone Bip/GRP78, heat shock proteins, and the enzyme enolase. We demonstrate that the selection of early DSP steps influences the resulting HCP profile and that 2D-PAGE can be used for monitoring and identification of HCPs post-protein A chromatography. This approach could be used to screen cell lines or hosts to select those with reduced HCP profiles, or to identify HCPs that are problematic and difficult to remove so that cell-engineering approaches can be applied to reduced, or eliminate, such HCPs.


Does the Length of Disability between Injury and Functional Restoration Program Entry Affect Treatment Outcomes for Patients with Chronic Disabling Occupational Musculoskeletal Disorders?
Purpose Functional restoration programs (FRPs), for patients with chronic disabling occupational musculoskeletal disorders (CDOMDs), have consistently demonstrated positive socioeconomic treatment outcomes, including decreased psychosocial distress and increased work return. The pre-treatment length of disability (LOD), or time between injury and treatment admission, has been shown to influence FRP work outcomes. Some studies have found that shorter LOD is associated with better work outcomes. However, few studies have actually examined cohorts with LOD duration longer than 18 months. This present study evaluated the effects of extended LOD (beyond 18 months) on important treatment outcomes. Methods A total cohort of 1413 CDOMD patients entered an FRP. Of those, 312 did not complete the program, so they were eliminated from outcome analyses. The 1101 patients who completed the FRP were classified based on LOD: Late Rehabilitation (LR, 3-6 months, n = 190); Chronic Disability (CD, 7-17 months, n = 494); and Late Chronic Disability (LCD). The LCD, in turn, consisted of four separate subgroups: 18-23 months (LCD-18, n = 110); 24-35 months (LCD-24, n = 123); 36-71 months (LCD-36, n = 74); and 72+ months (LCD-72, n = 110). Patients were evaluated upon admission and were reassessed at discharge. Those patients who chose to pursue work goals post-treatment (n = 912) were assessed 1-year later. Results Longer LOD was associated with less likelihood of completing the FRP (p < .001). Compared to the other LOD groups, a relatively large percentage of patients (47%) in the longest- disability group were receiving social security disability benefits. Associations were found between longer LOD and more severe patient-reported pain, disability, and depressive symptoms at treatment admission. At discharge, symptom severity decreased for these patient-reported variables in all LOD groups (p < .001). Using binary logistic regressions, it was found that LOD significantly predicted work-return (Wald = 11.672, p = .04) and work-retention (Wald = 11.811, p = .04) after controlling for covariates. Based on the LOD groups, the percentage of patients returning to, and retaining work, ranged from 75.6 to 94.1%, and from 66.7 to 86.3%, respectively. The odds of LCD-24 and LCD-72 patients returning to work were 2.9, and 7.4, respectfully, less likely, compared to LR patients. Furthermore, the odds of LCD-24 and LCD-72 patients retaining work were 3.3 and 3.8 times, respectively, less likely, compared to LR patients. Conclusions Long LOD was a risk factor for FRP non-completion, and was associated with more severe patient-reported variables, including pain intensity and perceived disability. Furthermore, long LOD was a significant predictor for work outcomes at 1 year following FRP discharge. Nevertheless, a large percentage of longer LOD (>24 months) patients had returned to work within the year after discharge (above 85%), and had retained at least part-time work 1-year later (above 66%). These results support the effectiveness of the FRP in mitigating the effects of extended LOD in a large percentage of long-term LOD patients.


Increased Risk of Developing Breast Cancer after a False-Positive Screening Mammogram.
Women with a history of a false-positive mammogram result may be at increased risk of developing subsequent breast cancer. Using 1994 to 2009 Breast Cancer Surveillance Consortium data, we included women ages 40 to 74 years with a screening mammogram that resulted in a false-positive with recommendation for additional imaging, false-positive with recommendation for biopsy, or true-negative with no cancer within one year following the examination. We used partly conditional Cox proportional hazards survival models to assess the association between a false-positive mammogram result and subsequent breast cancer, adjusting for potential confounders. Adjusted survival curves stratified by breast density and false-positive result were used to evaluate changes in risk over time. During 12,022,560 person-years of follow-up, 48,735 cancers were diagnosed. Compared with women with a true-negative examination, women with a false-positive with additional imaging recommendation had increased risk of developing breast cancer [adjusted HR (aHR) = 1.39; 95% confidence interval (CI), 1.35-1.44] as did women with a false-positive with a biopsy recommendation (aHR = 1.76; 95% CI,1.65-1.88). Results stratifying by breast density were similar to overall results except among women with almost entirely fatty breasts in which aHRs were similar for both the false-positive groups. Women with a false-positive result had persistently increased risk of developing breast cancer 10 years after the false-positive examination. Women with a history of a false-positive screening mammogram or biopsy recommendation were at increased risk of developing breast cancer for at least a decade, suggesting that prior false-positive screening may be useful in risk prediction models.


Structures of pseudo-decagonal approximants in Al-Co-Ni.
Quasi-crystals shocked the crystallographic world when they were reported in 1984. We now know that they are not a rare exception, and can be found in many alloy systems. One of the richer systems for quasi-crystals and their approximants is Al-Co-Ni. A large series of pseudo-decagonal (PD) approximants have been found. Only two of them, PD4 and PD8, have been solved by X-ray crystallography. We report here the structures of PD1, PD2, PD3 and PD5, solved from the limited information that is provided by electron diffraction patterns, unit cell dimensions and high-resolution electron microscopy images.


Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children.
Complications of Epstein-Barr virus (EBV) infection are diverse and include a number of neurologic manifestations such as meningitis, meningoencephalitis, cerebellitis, cranial neuritis and others. In general encephalitis caused by EBV in pediatric patients has been considered a self-limited illness with few or no sequelae. Charts were reviewed from all patients < 18 years of age admitted to or discharged from the State University of New York Health Science Center at Syracuse between 1982 and 1992 with a diagnosis of encephalitis or meningo-encephalitis. Eleven cases of EBV encephalitis diagnosed during a 10-year period were reviewed to characterize the clinical and laboratory findings in the acute setting and the extent of neurologic sequelae on follow-up. Acute neurologic manifestations were diverse and included combative behavior (55%), seizures (36%), headache (36%) and evidence of focal involvement (27%). Classic findings of infectious mononucleosis were noted infrequently; 18% each had pharyngitis, adenopathy, positive heterophile antibody tests or atypical lymphocytosis. Two patients (18%) had abnormal neuroimaging studies, one in the acute stage and the other at the time of follow-up. Seven patients (64%) had abnormal electroencephalograms (EEGs) in the acute setting; of these three had persistent abnormalities on follow-up. Forty percent developed persistent neurologic abnormalities including global impairment, perseverative autistic-like behavior and persistent left upper extremity paresis. Classic signs, symptoms and laboratory findings in infectious mononucleosis may be absent in Epstein-Barr virus encephalitis. Neurologic sequelae occur in a substantial number of patients.


Identification of neural stem cell differentiation repressor complex Pnky-PTBP1.
Splicing increases immensely the complexity of gene products expressed in the cell. The precise regulation of splicing is critical for the development, homeostasis, and function of all tissues in the body, including those comprising the neural system. Ramos et al. recently identified Pnky as a long noncoding RNA expressed selectively in neural tissues that was implicated in the transition of neural stem cells (NSCs) to mature neurons. Pnky actions appeared to be mediated by its interaction with the splicing factor and RNA-binding protein (RBP) polypyrimidine tract-binding protein (PTBP1), as silencing either Pnky or PTBP1 modulated in similar ways the patterns of spliced and expressed mRNAs in the cell. Strikingly, lowering the expression levels of Pnky or PTBP1 in NSCs actually enhanced neurogenesis, suggesting that the Pnky-PTBP1 complex elicited a splicing program of suppression of neurogenesis. With rapid progress in the design and delivery of RNA-based therapies, interventions to reduce Pnky levels may prove beneficial towards enhancing neurogenesis in disease states characterized by aberrant neuronal loss.


Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility.
The role of the gut microbiome in arresting pathogen colonization and growth is important for protection against Clostridium difficile infection (CDI). Observational studies associate proton pump inhibitor (PPI) use and CDI incidence. We hypothesized that PPI use affected the distal gut microbiome over time, an effect that would be best explored by time-longitudinal study of healthy subjects on PPI in comparison to treatment-naïve CDI subjects. This study enrolled nine healthy human subjects and five subjects with treatment-naïve CDI. After random assignment to a low (20 mg/day) or high (2× 20 mg/day) dose group, fecal samples were collected from the nine healthy subjects before, during, and after 28 days of PPI use. This was done in conjunction with pre-treatment fecal collection from CDI subjects. High-throughput sequencing (16S rRNA) was performed on time-longitudinal samples to assess changes to the healthy gut microbiome associated with prolonged PPI usage. The healthy samples were then compared to the CDI subjects to explore changes over time to the gut microbiome associated with PPI use and potentially related to CDI. We report that PPI usage at low and high dosages, administered for 28 days, resulted in decreases to observed operational taxonomic unit (OTU) counts after both 1 week and 1 month. This decrease resulted in observed OTU levels that were similar to those found in treatment-naïve CDI patients, which was partly reversible after a 1 month recovery period. We did not detect a dose-dependent difference in OTU levels nor did we detect significant changes in taxa previously reported to be affected by PPI treatment. While our observation of diminishing observed OTU counts during PPI therapy is a preliminary finding in a small cohort, our hypothesis that PPIs disrupt the healthy human gut microbiome is supported in this group. We conclude that decreases in observed species counts were reversible after cessation of PPI usage within 1 month. This finding may be a potential explanation for the association between prolonged PPI usage and CDI incidence.


The impact of anthropomorphic indices on clinical outcomes in patients with acute ST-elevation myocardial infarction.
Multiple studies have focused on the relationship of body anthropometric measures with clinical events in ST-elevation myocardial infarction (STEMI) patients, highlighting the 'obesity paradox'. However, the relative prognostic importance of these measures over other baseline variables is less known. We performed a retrospective analysis of 94,108 STEMI patients from seven clinical trials evaluating various reperfusion strategies to study the relationship and prognostic importance of height, weight, body mass index (BMI), and body surface area (BSA) with 30-day death and in-hospital cardiogenic shock, major bleeding, and stroke. Main outcome measures of interest included 30-day death and in-hospital cardiogenic shock, major bleeding, and stroke. Weight, BMI, and BSA were inversely and independently related to all clinical events. Despite being statistically significant (P<0.0001), the prognostic information contributed by weight beyond that conferred by baseline clinical factors was minimal (<1% of total prognostic information) making it of limited clinical relevance for predicting 30-day death and cardiogenic shock. In contrast, weight accounted for 8.4% and 4.3% of the prognostic information in the logistic regression models for major bleeding and for stroke. BMI or BSA added little incremental value over simple measure of weight. Although statistically significantly related to most outcomes in patients with STEMI including death and shock, body weight provided clinically relevant prognostic information only for the risk of major bleeding and of stroke. Furthermore, BMI or BSA contributed little incremental prognostic information beyond that provided by weight alone. Thus, the existing large body of information concerning the strong prognostic importance of anthropometric measures with outcomes after STEMI should be interpreted in the context of other more important risk factors.


Complementary and alternative medicine use among diabetic patients in Africa: a Kenyan perspective.
Complementary and alternative medicine (CAM) use is common among patients with chronic diseases in developing countries. The rising use of CAM in the management of diabetes is an emerging public health concern given the potential adverse effects, drug interactions and benefits associated with its use. Herbal medicine, dietary supplements, prayers and relaxation techniques are some of the most frequently used CAM modalities in Kenya. Cited reasons for CAM use as adjuvant therapy include dissatisfaction and inaccessibility of allopathic medicine, and recommendations by family and friends. This article explores the pattern of CAM use in Kenya and other developing countries. It also identifies some constraints to proper CAM control, and offers suggestions on what can be done to ensure safe and regulated CAM use.


Chronic coronary artery stenosis induces impaired function of remote myocardium: MRI and spectroscopy study in rat.
Our purpose was to study morphological, functional, and metabolic changes induced by chronic ischemia in myocardium supplied by the stenotic vessel and in the remote area by MR techniques. A new technique of image fusion is proposed for analysis of coronary artery stenosis involving coronary MR angiography and spectroscopic imaging. Cine-MRI was performed 2 wk after induction of coronary stenosis. Global heart function and regional wall thickening were determined in 11 Wistar rats with stenosis and compared with 7 control rats. Two weeks after stenosis was induced, spin-labeling MRI for measurement of perfusion was performed in 14 isolated hearts. In eight isolated hearts with coronary stenosis, MR spectroscopy was performed, followed by angiography. 31P metabolite maps were fused with three-dimensional coronary angiograms. Induction of stenosis led to reduced segmental wall thickening (control: 75 +/- 9%, ischemic region: 9 +/- 3%, P < 0.05 vs. control) but also to impaired function of the remote region and lower cardiac output. Perfusion was reduced by 74.9 +/- 4.0% within ischemic segments compared with a septal control region. The phosphocreatine (PCr)/ATP ratio as a marker of ischemia was reduced in the region associated with stenosis (1.09 +/- 0.09) compared with remote (1.27 +/- 0.08) and control hearts (1.43 +/- 0.08; P < 0.05). The histological fraction of fibrosis within the ischemic region (12.8 +/- 1.4%) correlated to ATP signal reduction from remote to the ischemic region (r = 0.71, P < 0.05), but not to reduced wall thickening. Coronary narrowing caused declining function accompanied by diminished PCr/ATP, indicating impaired energy metabolism. Neither decline of function nor PCr signal decline correlated to fraction of fibrosis in histology. In contrast, reduction of ATP correlated to fibrosis and therefore to loss of viability. Impaired function within the ischemic region is associated with decreased PCr. Function of the remote region was affected as well. The fusion of PCr metabolite maps and the coronary angiogram may help to assess coronary morphology and resulting metabolic changes simultaneously.


Tachykinins in endocrine tumors and the carcinoid syndrome.
A new antibody, active against the common tachykinin (TK) C-terminal, was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs). TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients. All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels. We found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is, to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.


MicroRNA-1280 inhibits invasion and metastasis by targeting ROCK1 in bladder cancer.
MicroRNAs (miRNAs) are non-protein-coding sequences that can function as oncogenes or tumor suppressor genes. This study documents the tumor suppressor role of miR-1280 in bladder cancer. Quantitative real-time PCR and in situ hybridization analyses showed that miR-1280 is significantly down-regulated in bladder cancer cell lines and tumors compared to a non-malignant cell line or normal tissue samples. To decipher the functional significance of miR-1280 in bladder cancer, we ectopically over-expressed miR-1280 in bladder cancer cell lines. Over-expression of miR-1280 had antiproliferative effects and impaired colony formation of bladder cancer cell lines. FACS (fluorescence activated cell sorting) analysis revealed that re-expression of miR-1280 in bladder cancer cells induced G2-M cell cycle arrest and apoptosis. Our results demonstrate that miR-1280 inhibited migration and invasion of bladder cancer cell lines. miR-1280 also attenuated ROCK1 and RhoC protein expression. Luciferase reporter assays demonstrated that oncogene ROCK1 is a direct target of miR-1280 in bladder cancer. This study also indicates that miR-1280 may be of diagnostic and prognostic importance in bladder cancer. For instance, ROC analysis showed that miR-1280 expression can distinguish between malignant and normal bladder cancer cases and Kaplan-Meier analysis revealed that patients with miR-1280 high expression had higher overall survival compared to those with low miR-1280 expression. In conclusion, this is the first study to document that miR-1280 functions as a tumor suppressor by targeting oncogene ROCK1 to invasion/migration and metastasis. Various compounds are currently being used as ROCK1 inhibitors; therefore restoration of tumor suppressor miR-1280 might be therapeutically useful either alone or in combination with these compounds in the treatment of bladder cancer.


Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation.
Co-milling of gamma-indomethacin and ranitidine hydrochloride form 2 at various weight ratios (1:2, 1:1 and 2:1) was investigated with a particular interest in the physicochemical properties and the stability of the milled mixed amorphous form. Co-milling was carried out using an oscillatory ball mill for various periods of time up to 60 min in a cold room (4 degrees C). The maximum temperature of the solid material was 42 degrees C during co-milling in a cold room. Results showed that both indomethacin and ranitidine hydrochloride were fully converted into the amorphous state after 60 min of co-milling. In contrast individually milled drugs remained partially crystalline after co-milling under the same conditions. During co-milling, the XRPD characteristic peaks of indomethacin were found to decrease faster than those of ranitidine hydrochloride. DSC results were in agreement with XRPD, and T(g)s of the fully converted amorphous mixtures of 29.3, 32.5 and 34.3 degrees C were measured for the 1:2, 1:1 and 2:1 mixtures, respectively. These T(g) values were in good agreement with the predicted T(g)s of the mixtures using the Gordon-Taylor equation. DRIFTS spectra of the co-milled amorphous samples showed peaks at 1610, 1679 and 1723 cm(-1), that were not present in the individually milled samples and that are indicative of an interaction at the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (N=CO) of the indomethacin molecule with the aci-nitro (C=N) of ranitidine hydrochloride. Upon 30 days of storage, the 1:2 mixtures were found to crystallize; however, the amorphous 2:1 and 1:1 mixtures were stable when milled for 60 min and stored at 4 degrees C (for the 2:1 mixture) and at 4 and 25 degrees C (for the 1:1 mixture), respectively. Although XRPD, DSC and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between indomethacin and ranitidine hydrochloride.


Cervimycin-Resistant Staphylococcus aureus Strains Display Vancomycin-Intermediate Resistant Phenotypes.
Resistance to antibiotics is an increasing problem and necessitates novel antibacterial therapies. The polyketide antibiotics cervimycin A to D are natural products of Streptomyces tendae HKI 0179 with promising activity against multidrug-resistant staphylococci and vancomycin-resistant enterococci. To initiate mode of action studies, we selected cervimycin C- and D-resistant (CmR) Staphylococcus aureus strains. Genome sequencing of CmR mutants revealed amino acid exchanges in the essential histidine kinase WalK, the Clp protease proteolytic subunit ClpP or the Clp ATPase ClpC, and the heat shock protein DnaK. Interestingly, all characterized CmR mutants harbored a combination of mutations in walK and clpP or clpC. In vitro and in vivo analyses showed that the mutations in the Clp proteins abolished ClpP or ClpC activity, and the deletion of clpP rendered S. aureus but not all Bacillus subtilis strains cervimycin-resistant. The essential gene walK was the second mutational hotspot in the CmR S. aureus strains, which decreased WalK activity in vitro and generated a vancomycin-intermediate resistant phenotype, with a thickened cell wall, a lower growth rate, and reduced cell lysis. Transcriptomic and proteomic analyses revealed massive alterations in the CmR strains compared to the parent strain S. aureus SG511, with major shifts in the heat shock regulon, the metal ion homeostasis, and the carbohydrate metabolism. Taken together, mutations in the heat shock genes clpP, clpC, and dnaK, and the walK kinase gene in CmR mutants induced a vancomycin-intermediate resistant phenotype in S. aureus, suggesting cell wall metabolism or the Clp protease system as primary target of cervimycin. IMPORTANCE Staphylococcus aureus is a frequent cause of infections in both the community and hospital setting. Resistance development of S. aureus to various antibiotics is a severe problem for the treatment of this pathogen worldwide. New powerful antimicrobial agents against Gram-positives are needed, since antibiotics like vancomycin fail to cure vancomycin-intermediate resistant S. aureus (VISA) and vancomycin-resistant enterococci (VRE) infections. One candidate substance with promising activity against these organisms is cervimycin, which is an antibiotic complex with a yet unknown mode of action. In our study, we provide first insights into the mode of action of cervimycins. By characterizing cervimycin-resistant S. aureus strains, we revealed the Clp system and the essential kinase WalK as mutational hotspots for cervimycin resistance in S. aureus. It further emerged that cervimycin-resistant S. aureus strains show a VISA phenotype, indicating a role of cervimycin in perturbing the bacterial cell envelope.


Prevalence of ulcerative colitis and Crohn's disease in Japan.
The prevalence of inflammatory bowel diseases is much lower in Asian countries, including Japan, than in Western countries, but it is rapidly increasing. However, no recent reports describe the current prevalence of these diseases in Japan, so we performed a descriptive epidemiological study to remedy this situation and to elucidate various characteristics of inflammatory bowel diseases in this country. Japan has a nationwide registration system of patients with intractable diseases, including ulcerative colitis and Crohn's disease. To calculate the age-standardized prevalence, we used this registration system to collect patient data, and we obtained detailed population data from the Japanese government's population estimates made in 2003 and 2004 and from the 2005 population census. In addition, information about the characteristics of ulcerative colitis and Crohn's disease patients was collected through the registration system. The age-standardized prevalence of ulcerative colitis in Japan in 2005 was 63.6 per 100,000 persons, and that of Crohn's disease was 21.2. Patient numbers have been steadily increasing with time. The age distribution was found to differ between the two diseases, with Crohn's disease affecting mainly younger people. In both diseases, more than 50% of the patients were male, and over 80% of the patients were classified as mild to moderate in terms of severity. The prevalence of inflammatory bowel diseases in Japan is still much lower than in Western countries. Surveillance should be continued, and research to clarify their etiologies in association with the increasing number of patients in Japan is needed.


Effect of skin-to-skin contact on parents' sleep quality, mood, parent-infant interaction and cortisol concentrations in neonatal care units: study protocol of a randomised controlled trial.
Separation after preterm birth is a major stressor for infants and parents. Skin-to-skin contact (SSC) is a method of care suitable to use in the neonatal intensive care unit (NICU) to minimise separation between parents and infants. Less separation leads to increased possibilities for parent-infant interaction, provided that the parents' sleep quality is satisfactory. We aimed to evaluate the effect of continuous SSC on sleep quality and mood in parents of preterm infants born <33 weeks of gestation as well as the quality of parent-infant interaction and salivary cortisol concentrations at the time of discharge. A randomised intervention study with two arms-intervention versus standard care. Data will be collected from 50 families. Eligible families will be randomly allocated to intervention or standard care when transferred from the intensive care room to the family-room in the NICU. The intervention consists of continuous SSC for four consecutive days and nights in the family-room. Data will be collected every day during the intervention and again at the time of discharge from the hospital. Outcome measures comprise activity tracker (Actigraph); validated self-rated questionnaires concerning sleep, mood and bonding; observed scorings of parental sensitivity and emotional availability and salivary cortisol. Data will be analysed with pairwise, repeated measures, Mann Whitney U-test will be used to compare groups and analysis of variance will be used to adjust for different hospitals and parents' gender. The study is approved by the Regional Research Ethics Board at an appropriate university (2016/89-31). The results will be published in scientific journals. We will also use conferences and social media to disseminate our findings. NCT03004677.


Cytomegalovirus post kidney transplantation: prophylaxis versus pre-emptive therapy?
Cytomegalovirus is the most important pathogen causing opportunistic infections in kidney allograft recipients. The occurrence of CMV disease is associated with higher morbidity, higher incidence of other opportunistic infections, allograft loss and death. Therefore, an efficient strategy to prevent CMV disease after kidney transplantation is required. Two options are currently available: pre-emptive therapy based on regular CMV PCR monitoring and generalized antiviral prophylaxis during a defined period. In this review, we describe those two approaches, highlight the distinct advantages and risks of each strategy and summarize the four randomized controlled trials performed in this field so far. Taken this evidence together, pre-emptive therapy and anti-CMV prophylaxis are both equally potent in preventing CMV-associated complications; however, the pre-emptive approach may have distinct advantages in allowing for development of long-term anti-CMV immunity. We propose a risk-adapted use of these approaches based on serostatus, immunosuppressive therapy and availability of resources at a particular transplant centre.


Peripheral Refraction and Contrast Detection Sensitivity in Pseudophakic Patients Implanted With a New Meniscus Intraocular Lens.
To evaluate peripheral refraction and contrast detection sensitivity in pseudophakic patients implanted with a new type of inverted meniscus intraocular lens (IOL) (Art25; Voptica SL) that was designed to provide better peripheral optics. One month after cataract surgery, in 87 eyes implanted with the Art25 IOL, peripheral contrast detection sensitivity was measured psychophysically at 40° visual angle, both horizontally and vertically, and compared with a control group of 51 eyes implanted with standard biconvex IOLs. Thirty-one eyes with the Art25 IOL and 28 eyes from the control group were randomly selected to also measure peripheral refraction using a scanning Hartmann-Shack wavefront sensor along 80° in the horizontal meridian. Most patients achieved emmetropia and good visual acuity, and no significant adverse events were observed after cataract surgery with Art25 IOLs. Peripheral contrast detection sensitivity was significantly better (P < .01) in the group with the Art25 IOL in both directions (7.78 ± 3.24 vs 5.74 ± 2.60 vertical, 10.98 ± 5.09 vs 7.47 ± 3.96 horizontal), which was in agreement with the optical quality improvement in the periphery due to a reduction of defocus (1.97 and 1.21 diopters [D] at 40° temporal and nasal sides) and astigmatism (1.17 and 0.37 D at 40° temporal and nasal sides) that was statistically significant (P < .01) from 20° of eccentricity. Patients implanted with a new inverted meniscus IOL present a reduced amount of peripheral defocus and astigmatism compared to patients implanted with standard biconvex IOLs. This improvement in optical quality leads to better contrast detection sensitivity measured at 40° of eccentricity. [J Refract Surg. 2022;38(4):229-234.].


Origins and diversification of a complex signal transduction system in prokaryotes.
The molecular machinery that controls chemotaxis in bacteria is substantially more complex than any other signal transduction system in prokaryotes, and its origins and variability among living species are unknown. We found that this multiprotein "chemotaxis system" is present in most prokaryotic species and evolved from simpler two-component regulatory systems that control prokaryotic transcription. We discovered, through genomic analysis, signaling systems intermediate between two-component systems and chemotaxis systems. Evolutionary genomics established central and auxiliary components of the chemotaxis system. While tracing its evolutionary history, we also developed a classification scheme that revealed more than a dozen distinct classes of chemotaxis systems, enabling future predictive modeling of chemotactic behavior in unstudied species.


Targeting of Runx2 by miR-135 and miR-203 Impairs Progression of Breast Cancer and Metastatic Bone Disease.
Progression of breast cancer to metastatic bone disease is linked to deregulated expression of the transcription factor Runx2. Therefore, our goal was to evaluate the potential for clinical use of Runx2-targeting miRNAs to reduce tumor growth and bone metastatic burden. Expression analysis of a panel of miRNAs regulating Runx2 revealed a reciprocal relationship between the abundance of Runx2 protein and two miRNAs, miR-135 and miR-203. These miRNAs are highly expressed in normal breast epithelial cells where Runx2 is not detected, and absent in metastatic breast cancer cells and tissue biopsies that express Runx2. Reconstituting metastatic MDA-MB-231-luc cells with miR-135 and miR-203 reduced the abundance of Runx2 and expression of the metastasis-promoting Runx2 target genes IL11, MMP-13, and PTHrP. In addition, tumor cell viability was decreased and migration suppressed in vitro. Orthotopic implantation of MDA-MB-231-luc cells delivered with miR-135 or miR-203, followed by an intratumoral administration of the synthetic miRNAs, reduced the tumor growth and spontaneous metastasis to bone. Furthermore, intratibial injection of these miRNA-delivered cells impaired tumor growth in the bone environment and inhibited bone resorption. Importantly, reconstitution of Runx2 in MDA-MB-231-luc cells delivered with miR-135 and miR-203 reversed the inhibitory effect of the miRNAs on tumor growth and metastasis. Thus, we have identified that aberrant expression of Runx2 in aggressive tumor cells is related to the loss of specific Runx2-targeting miRNAs and that a clinically relevant replacement strategy by delivery of synthetic miRNAs is a candidate for a therapeutic approach to prevent metastatic bone disease by this route.


Effect of prometryne on early life stages of marbled crayfish (Procambarus fallax f. virginalis).
The aim of this study is to assess the toxicity of prometryne in early life stages of marbled crayfish (Procambarus fallax f. virginalis) on the basis of mortality, early ontogeny, growth rate, and histopathology during and at the end of the test. The early life stages of marbled crayfish were exposed to prometryne at four concentrations, 0.51, (reported concentration in Czech rivers), 144, 1440, and 4320 μg x l(-1) for 53 days and compared to crayfish in a non-treated control group. RESU LTS: Prometryne in concentration 144, 1444 and 4320 μg x l(-1) caused decrease of weight and specific growth rates of crayfish. Crayfish exposed the highest concentration 4320 μg x l(-1) showed delay in ontogeny development. All crayfish groups exposed to prometryne showed histopathological changes in gill. On the basis of histopathological changes the values of LOEC = 0.51 μg x l(-1) and NOEC = for 0.10 μg x l(-1) of prometryne for marbled crayfish juveniles was estimated. Chronic exposure of prometryne on early life stages of crayfish has affected their mortality, growth rate, and histology. Some of the changes were observed only at higher exposures (144, 1444 and 4320 μg x l(-1)), but histopathological changes in gills were observed also in crayfish exposed to the real environmental concentration in Czech rivers (i.e. 0.51 μg x l(-1)), which is about 9 times lower than maximal concentration (4.40 μg x l(-1)) reported in surface waters of Greece. Concentrations of prometryne in World rivers have been reported to generally vary in the range of 0.1-4.40 μg x l(-1).


Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry.
Although many reports have described the abnormal structures of O-glycan in the IgA1 hinge region in IgA nephropathy (IgAN), the specific glycopeptide that can be used as a diagnostic biomarker for IgAN has not yet been identified. To pursue this diagnostic approach, we used mass spectrometric analysis to search for specific structures in IgA1 hinge glycopeptides in 30 IgAN patients contrasted with 30 healthy controls. IgA1 hinge glycopeptides were individually purified from the sera of 30 biopsy-proven IgAN patients and 30 healthy controls. The structure of each glycopeptide was analyzed by ion trap mass spectrometry. Sugar conformations in each glycopeptide were estimated by collision-induced dissociation tandem mass spectrometry. Furthermore, to search for specific O-glycans in IgAN patients with a statistical significance, the identified hinge glycopeptides were analyzed by Fisher exact test. A total of 57 hinge glycopeptides were identified from each of the 2 sample groups. Among the structures of the hinge glycopeptides identified, statistical significance was found for 6 glycopeptides (O-glycan compositions were 33-mer hinge core peptides + xGalNAc + yGal + zNeu5Ac; x:y:z = 5:3:3, 5:3:0, 5:2:1, 4:2:2, 3:1:1, 3:1:0) by Fisher exact test (p<0.05). In these 6 O-glycan compositions, 3 compositions (x:y:z = 4:2:2, 3:1:1, 3:1:0) were only observed in IgAN patients and were absent in the 30 controls. Statistically specific O-glycans were identified in 30 IgAN patients compared with 30 controls. These results open the possibility for preparation of lectin and/or antibodies binding to specific glycopeptides in IgAN.


Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer.
Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization. Ten tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype. The multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine.


Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation.
Runx2 is a bone-specific transcription factor that plays a critical role in bone development, postnatal bone formation, and chondrocyte maturation. The protein levels of Runx2 are regulated by the ubiquitin-proteasome pathway. In previous studies we discovered that E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) induces Runx2 degradation in a ubiquitin-proteasome-dependent manner, and Smurf1 plays an important role in osteoblast function and bone formation. In the present studies we investigated the molecular mechanism of Smurf1-induced Runx2 degradation. Smurf1 interacts with the PY motif of substrate proteins, and a PY motif has been identified in the C terminus of the Runx2 protein. To determine whether Smurf1 induces Runx2 degradation through the interaction with the PY motif of Runx2, we created a mutant Runx2 with a PY motif deletion and found that Smurf1 retained some of its ability to induce the degradation of the mutant Runx2, suggesting that Smurf1 could induce Runx2 degradation through an indirect mechanism. Smurf1 has been shown to interact with Smads 1, 5, 6, and 7, and Smads 1 and 5 also interact with Runx2. In the present studies we found that Smads 1 and 5 had no effect on Smurf1-induced Runx2 degradation. Although Smads 6 and 7 bind Smurf1, it is not known if Smads 6 or 7 interacts with Runx2 and mediate Runx2 degradation. We performed immunoprecipitation assays and found that Smad6 but not Smad7 interacts with Runx2. Smad6 enhances Smurf1-induced Runx2 degradation in an ubiquitin-proteasome-dependent manner. These results demonstrate that in addition to its interaction with the PY motif of Runx2, Smurf1 induces Runx2 degradation in a Smad6-dependent manner. Smurf1-induced Runx2 degradation serves as a negative regulatory mechanism for the BMP-Smad-Runx2 signaling pathway.


Molecular Detection of Taeniid Eggs in Beetles Collected in an Area Endemic for Taenia solium.
The aim of this study was to demonstrate the presence of Taenia solium eggs in beetles collected from sources within the natural environment through molecular techniques. Fifty-four pools of beetles were collected in three villages in Piura, Peru. DNA was extracted using the FastDNA spin kit for soil. Molecular identification of Taenia species was then performed through partial amplification of the mitochondrial cytochrome C oxidase subunit I gene. Finally, positive samples were sequenced to determine the tapeworm species. Seven positive samples were obtained through polymerase chain reaction amplification. Sequencing confirmed that two samples were from T. solium and three samples were from Taenia hydatigena. The other two samples could not be specifically identified. Our findings demonstrate that dung beetles ingest T. solium and T. hydatigena eggs under natural conditions and suggest that beetles may play a role in the dynamics of transmission of these cestodes.


Hybridization is a recurrent evolutionary stimulus in wild yeast speciation.
Hybridization can result in reproductively isolated and phenotypically distinct lineages that evolve as independent hybrid species. How frequently hybridization leads to speciation remains largely unknown. Here we examine the potential recurrence of hybrid speciation in the wild yeast Saccharomyces paradoxus in North America, which comprises two endemic lineages SpB and SpC, and an incipient hybrid species, SpC*. Using whole-genome sequences from more than 300 strains, we uncover the hybrid origin of another group, SpD, that emerged from hybridization between SpC* and one of its parental species, the widespread SpB. We show that SpD has the potential to evolve as a novel hybrid species, because it displays phenotypic novelties that include an intermediate transcriptome profile, and partial reproductive isolation with its most abundant sympatric parental species, SpB. Our findings show that repetitive cycles of divergence and hybridization quickly generate diversity and reproductive isolation, providing the raw material for speciation by hybridization.


First International Symposium, Uniportal VATS-International Course Uniportal VATS, Buenos Aires, Argentina.
This is a report of the first three days Uniportal VATS International Meeting. The conference included oral presentations at the Universidad Catolica Argentina (UCA), on the first day. Live Surgery from Shanghai Pulmonary Hospital, Tongji University, China, and Clinica San Camilo. Bs As, Argentina on the second day and a Wet lab in Fundación Triada Mininvasiva, Fatima Pilar on the final day.


A systematic review of associations between spiritual well-being and quality of life at the scale and factor levels in studies among patients with cancer.
The purpose of this systematic review was to examine the literature for associations between spiritual well-being and quality of life (QOL) among adults diagnosed with cancer. A systematic literature search was conducted in the PubMed and CINAHL databases on descriptive correlational studies that provided bivariate correlations or multivariate associations between spiritual well-being and QOL. A total of 566 citations were identified; 36 studies were included in the final review. Thirty-two studies were cross-sectional and four longitudinal; 27 were from the United States. Sample size ranged from 44 to 8805 patients. A majority of studies reported a positive association (ranges from 0.36 to 0.70) between overall spiritual well-being and QOL, which was not equal among physical, social, emotional, and functional well-being. The 16 studies that examined the Meaning/Peace factor and its association with QOL reported a positive association for overall QOL (ranges from 0.49 to 0.70) and for physical (ranges from 0.25 to 0.28) and mental health (ranges from 0.55 to 0.73), and remained significant after controlling for demographic and clinical variables. The Faith factor was not consistently associated with QOL. This review found consistent independent associations between spiritual well-being and QOL at the scale and factor (Meaning/Peace) levels, lending support for integrating Meaning/Peace constituents into assessment of QOL outcomes among people with cancer; more research is needed to verify our findings. The number of studies conducted on spiritual well-being and the attention to its importance globally emphasizes its importance in enhancing patients' QOL in cancer care.


Hippocampal volume and integrity as predictors of cognitive decline in intact elderly.
The risk of Alzheimer's disease can be predicted by volumetric analyses of MRI data in the medial temporal lobe. The present study compared a volumetric measurement of the hippocampus with a novel measure of hippocampal integrity (HI) derived from the ratio of parenchyma volume over total volume. Participants were cognitively intact and aged 60 years or older at baseline, and were tested twice, roughly 3 years apart. Participants had been recruited for a study on late-life major depression (LLMD) and were evenly split between depressed patients and controls. Linear regression models were applied to the data with a cognitive composite score as the outcome, and HI and volume, together or separately, as predictors. Subsequent cognitive performance was predicted well by models that included an interaction between HI and LLMD status, such that lower HI scores predicted more cognitive decline in depressed patients. More research is needed, but tentative results from this study appear to suggest that the newly introduced measure HI is an effective tool for the purpose of predicting future changes in general cognitive ability, and especially so in individuals with LLMD.


Shifts of tundra bacterial and archaeal communities along a permafrost thaw gradient in Alaska.
Understanding the response of permafrost microbial communities to climate warming is crucial for evaluating ecosystem feedbacks to global change. This study investigated soil bacterial and archaeal communities by Illumina MiSeq sequencing of 16S rRNA gene amplicons across a permafrost thaw gradient at different depths in Alaska with thaw progression for over three decades. Over 4.6 million passing 16S rRNA gene sequences were obtained from a total of 97 samples, corresponding to 61 known classes and 470 genera. Soil depth and the associated soil physical-chemical properties had predominant impacts on the diversity and composition of the microbial communities. Both richness and evenness of the microbial communities decreased with soil depth. Acidobacteria, Verrucomicrobia, Alpha- and Gamma-Proteobacteria dominated the microbial communities in the upper horizon, whereas abundances of Bacteroidetes, Delta-Proteobacteria and Firmicutes increased towards deeper soils. Effects of thaw progression were absent in microbial communities in the near-surface organic soil, probably due to greater temperature variation. Thaw progression decreased the abundances of the majority of the associated taxa in the lower organic soil, but increased the abundances of those in the mineral soil, including groups potentially involved in recalcitrant C degradation (Actinomycetales, Chitinophaga, etc.). The changes in microbial communities may be related to altered soil C sources by thaw progression. Collectively, this study revealed different impacts of thaw in the organic and mineral horizons and suggests the importance of studying both the upper and deeper soils while evaluating microbial responses to permafrost thaw.


EGb 761: ginkgo biloba extract, Ginkor.
EGb 761 [Ginkgo biloba extract EGb 761, Rökan, Tanakan, Tebonin] is a standardised extract of Ginkgo biloba leaves and has antioxidant properties as a free radical scavenger. A standardised extract of Ginkgo biloba leaves is a well defined product and contains approximately 24% flavone glycosides (primarily quercetin, kaempferol and isorhamnetin) and 6% terpene lactones (2.8-3.4% ginkgolides A, B and C, and 2.6-3.2% bilobalide). Ginkgolide B and bilobalide account for about 0.8% and 3% of the total extract, respectively. Other constituents include proanthocyanadins, glucose, rhamnose, organic acids, D-glucaric and ginkgolic acids. EGb 761 promotes vasodilation and improves blood flow through arteries, veins and capillaries. It inhibits platelet aggregation and prolongs bleeding time. EGb 761, which was originated by Dr Willmar Schwabe Pharmaceuticals (Dr Willmar Schwabe Group), has been available in Europe as a herbal extract since the early 1990s. However, products containing EGb 761 are not approved for use by the US FDA. As a dietary supplement, Nature's Way in the US distributes and markets a standardised extract of Ginkgo biloba leaves (the EGb 761 Formula) under the name Gingold Nature's Way. The French company Beaufour-Ipsen and its German subsidiary Ipsen Pharma are co-developing EGb 761 with Dr Willmar Schwabe Group. Beaufour-Ipsen (France) is developing EGb 761 as Tanakan, Dr Willmar Schwabe Pharmaceuticals (Germany) as Tebonin and Ipsen Pharma (Germany) as Rökan. Intersan was formerly developing EGb 761 in Germany, but Intersan appears to have been merged into Ipsen Pharma. However, there has been no recent development for these indications. In the UK and other European countries, the cardioprotective effects of EGb 761 in myocardial ischaemia and reperfusion are being investigated in preclinical studies. The psychological and physiological benefits of ginkgo are said to be based on its primary action of regulating neurotransmitters and exerting neuroprotective effects in the brain, protecting against or retarding nerve cell degeneration. Ginkgo also benefits vascular microcirculation by improving blood flow in small vessels and has antioxidant activity. There has been conflicting evidence about the benefits of ginkgo, e.g. the ginkgo clinical trial published in August 2002 in JAMA concluded that a leading ginkgo supplement did not produce measurable benefits for memory in healthy adults over 60, although a month earlier, another study concluded that the same ginkgo extract is effective in helping normal healthy older adults in memory and concentration. However, in December 2002, the Cochrane Collaboration, the world's most respected scientific reviewer of clinical trials in medicine, concluded that the published literature strongly supports the safety and potential benefits of ginkgo in treating memory loss and cognitive disorders associated with age- related dementia. A phase II study of EGb 761 in combination with fluorouracil is in progress in Germany in patients with pancreatic cancer. German researchers are investigating the potential of EGb 761 for the treatment of sudden deafness and tinnitus in clinical studies. EGb 761 was undergoing preclinical development for the potential treatment of diabetes in France, diabetic neuropathies in Russia, and cancer in Brazil. However, there has been no recent development for these indications. Beaufour-Ipsen has expressed the intention to license out its diabetes projects that may include EGb 761.


The influence of aerobic fitness on obesity and its parent-offspring correlations in a cross-sectional study among German families.
Overweight/obesity is an important public health burden worldwide, increasing the risk for the development of cardiovascular diseases or the metabolic syndrome. This risk may be reduced by a good aerobic fitness (AF) that can be improved by physical activity but is also influenced by genetic factors. The aim of this study was to test for familial aggregation of AF measured by maximal oxygen uptake (VO2max) and to estimate its heritability. Furthermore, an exploratory analysis of the association between overweight/obesity and AF was performed. In contrast to previous studies, all analyses were adjusted for additional environmental and behavioral factors, in particular for objectively measured physical activity (PA) in addition to body mass index (BMI). 79 families (157 parents, 132 children) performed a maximum exercise test (spiroergometry) to assess maximum oxygen uptake. PA was measured by accelerometry. Familial aggregation of AF was determined using a two-step design: AF was adjusted for age, sex and age*sex using linear regression. Afterwards, the residuals were used to determine the intraclass correlation coefficient (ICC) by ANOVA. Heritability and associations were estimated by generalized linear mixed models. Familial aggregation of AF (ICC = 0.22, p < 0.001) was significant but decreased when adjusted for PA or BMI. Its heritability was estimated as 40% (adjusted for PA) using the mid-parent-offspring design. Relative to the middle quintile of AF residuals, the odds of being overweight/obese were three- to tenfold reduced in the upper quintile (adjusted for age, sex, age*sex, PA). AF clustered in families after controlling for PA, BMI and parental smoking. Heritability was stronger for mother-child pairs as compared to father-child pairs after controlling for PA and BMI. Above average AF was negatively associated with overweight/obesity.


The vulnerability of men to virologic failure during antiretroviral therapy in a public routine clinic in Burkina Faso.
Gender differences in antiretroviral therapy (ART) outcomes are critical in sub-Saharan Africa. We assessed the association between gender and virologic failure among adult patients treated in a public routine clinic (one of the largest in West Africa) in Burkina Faso. We performed a case-control study between July and October 2012 among patients who had received ART at the Bobo Dioulasso Day Care Unit. Patients were eligible if they were 15 years or older, positive for HIV-1 or HIV-1+2, and on first-line ART for at least six months. Cases were all patients with two consecutive HIV loads >1000 copies/mL (Biocentric Generic or Abbott Real Time assays), or one HIV load >1000 copies/mL associated with immunologic or clinical failure criteria. Controls were all patients who only had HIV loads <300 copies/mL. The association between gender and virologic failure was assessed using a multivariate logistic regression, adjusted on age, level of education, baseline CD4+ T cell count, first and current antiretroviral regimens and time on ART. Of 2303 patients (74.2% women; median age: 40 years; median time on ART: 34 months), 172 had virologic failure and 2131 had virologic success. Among the former, 130 (75.6%) had confirmed virologic failure, 38 (22.1%) had viro-immunologic failure, and four (2.3%) had viro-clinical failure. The proportion of men was significantly higher among the cases than among the controls (37.2% vs. 24.9%; p<0.001). Compared to controls, cases were also younger, more immunodeficient at ART initiation, less likely to receive a protease inhibitor-based antiretroviral regimen and had spent a longer period of time on ART. After adjustment, male gender remained strongly associated with virologic failure (odds ratio 2.52, 95% CI: 1.77-3.60; p<0.001). Men on ART appeared more vulnerable to virologic failure than women. Additional studies are needed to confirm the poorer prognosis of men in this setting and to determine the causes for their vulnerability in order to optimize HIV care. From now on, efforts should be made to support the adherence of men to ART in the African setting.


DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer.
DNA methylation profiles can be used to define molecular cancer subtypes that may better inform disease etiology and clinical decision-making. This investigation aimed to create DNA methylation profiles of bladder cancer based on CpG methylation from almost 800 cancer-related genes and to then examine the relationship of those profiles with exposures related to risk and clinical characteristics. DNA, derived from formalin-fixed paraffin-embedded tumor samples obtained from incident cases involved in a population-based case-control study of bladder cancer in New Hampshire, was used for methylation profiling on the Illumina GoldenGate Methylation Bead Array. Unsupervised clustering of those loci with the greatest change in methylation between tumor and non-diseased tissue was performed to defined molecular subgroups of disease, and univariate tests of association followed by multinomial logistic regression was used to examine the association between these classes, bladder cancer risk factors and clinical phenotypes. Membership in the two most methylated classes was significantly associated with invasive disease (P < 0.001 for both class 3 and 4). Male gender (P = 0.04) and age >70 years (P = 0.05) was associated with membership in one of the most methylated classes. Finally, average water arsenic levels in the highest percentile predicted membership in an intermediately methylated class of tumors (P = 0.02 for both classes). Exposures and demographic associated with increased risk of bladder cancer specifically associate with particular subgroups of tumors defined by DNA methylation profiling and these subgroups may define more aggressive disease.


Supporting evidence for a human reservoir of invasive non-Typhoidal Salmonella from household samples in Burkina Faso.
Salmonella Typhimurium and Enteritidis are major causes of bloodstream infection in children in sub-Saharan Africa. This study assessed evidence for their zoonotic versus human reservoir. Index patients were children with blood culture confirmed Salmonella infection recruited during a microbiological surveillance study in Nanoro, rural Burkina between May 2013 and August 2014. After consent, their households were visited. Stool from household members and livestock (pooled samples per species) as well as drinking water were cultured for Salmonella. Isolates with identical serotype obtained from index patient and any household sample were defined as "paired isolates" and assessed for genetic relatedness by multilocus variable number tandem-repeat analysis (MLVA) and whole-genome sequencing (WGS). Twenty-nine households were visited for 32/42 (76.2%) eligible index patients: two households comprised two index patients each, and in a third household the index patient had a recurrent infection. Among the 32 index patients, serotypes were Salmonella Typhimurium (n = 26), Salmonella Enteritidis (n = 5) and Salmonella Freetown (n = 1). All Typhimurium isolates were sequence type (ST)313. Median delay between blood culture sampling and household visits was 13 days (range 6-26). Salmonella was obtained from 16/186 (8.6%) livestock samples (13 serotypes) and 18/290 (6.2%) household members (9 serotypes). None of the water samples yielded Salmonella. Paired Salmonella Typhimurium isolates were obtained from three households representing four index patients. MLVA types were identical in two pairs and similar in the third (consisting of two index patients and one household member). WGS showed a strong genetic relatedness with 0 to 2 core genome SNPs difference between pairs on a household level. Livestock samples did not yield any Salmonella Typhimurium or Salmonella Enteritidis, and the latter was exclusively obtained from blood culture. Other serotypes shared by human and/or livestock carriers in the same household were Salmonella Derby, Drac, Tennessee and Muenster. The current study provides further evidence of a human reservoir for invasive non-Typhoidal Salmonella (iNTS) in sub-Saharan Africa.


Determinants of two-year mortality among HIV positive patients with Cryptococcal meningitis initiating standard antifungal treatment with or without adjunctive dexamethasone in Uganda.
Globally, early initiation of antiretroviral therapy for HIV led to a reduction in the estimated mortality from cryptococcal meningitis (CCM) from 624,700 in 2009 to 181,100 in 2014. However, CCM remains one of the leading causes of mortality among HIV infected patients especially in sub-Saharan Africa where 75% of the deaths occur. Most of the studies evaluating mortality have reported short-term mortality (at or before 10 weeks of therapy). We determined mortality and associated factors among patients treated for CCM in the CryptoDex trial (ISRCTN59144167) in Uganda, and the effect of dexamethasone adjunctive therapy on mortality at two years. We conducted a retrospective cohort study between May 2017 and July 2017 to determine the long term survival (up to 2 years post-randomization) of all patients who had been enrolled into the CryptoDex trial in Uganda. The CryptoDex trial recruited between April 2013 and February 2015. We estimated mortality rates and determined factors affecting mortality at two years using Cox regression. The study followed up 211 participants, 127 (60.2%) of whom were male. Sixteen participants (7.58%) were diagnosed with HIV at the same admission when CCM was diagnosed. By two years following randomization 127 (60%) participants had died, a mortality rate of 67 deaths per 100 person-years. Mortality was associated with Glasgow coma score (GCS) below 15 (adjusted Hazard ratio (aHR) 1.77, 95% CI: 1.02-2.44), p = 0.040; weight (aHR 0.97, per 1 Kg increase; 95% CI: 0.94-0.99), p = 0.003; and presence of convulsions (aHR 2.31, 95% CI: 1.32-4.04), p = 0.004, while dexamethasone use and fungal burden had no effect. Long-term mortality in CCM patients remains high even among patients receiving recommended therapy. Strategies to improve long-term survival in CCM patients are urgently needed, especially targeting those with reduced GCS, low weight, and convulsions.


A physical map of a BAC clone contig covering the entire autosome insertion between ovine MHC Class IIa and IIb.
The ovine Major Histocompatibility Complex (MHC) harbors genes involved in overall resistance/susceptibility of the host to infectious diseases. Compared to human and mouse, the ovine MHC is interrupted by a large piece of autosome insertion via a hypothetical chromosome inversion that constitutes ~25% of ovine chromosome 20. The evolutionary consequence of such an inversion and an insertion (inversion/insertion) in relation to MHC function remains unknown. We previously constructed a BAC clone physical map for the ovine MHC exclusive of the insertion region. Here we report the construction of a high-density physical map covering the autosome insertion in order to address the question of what the inversion/insertion had to do with ruminants during the MHC evolution. A total of 119 pairs of comparative bovine oligo primers were utilized to screen an ovine BAC library for positive clones and the orders and overlapping relationships of the identified clones were determined by DNA fingerprinting, BAC-end sequencing, and sequence-specific PCR. A total of 368 positive BAC clones were identified and 108 of the effective clones were ordered into an overlapping BAC contig to cover the consensus region between ovine MHC class IIa and IIb. Therefore, a continuous physical map covering the entire ovine autosome inversion/insertion region was successfully constructed. The map confirmed the bovine sequence assembly for the same homologous region. The DNA sequences of 185 BAC-ends have been deposited into NCBI database with the access numbers HR309252 through HR309068, corresponding to dbGSS ID 30164010 through 30163826. We have constructed a high-density BAC clone physical map for the ovine autosome inversion/insertion between the MHC class IIa and IIb. The entire ovine MHC region is now fully covered by a continuous BAC clone contig. The physical map we generated will facilitate MHC functional studies in the ovine, as well as the comparative MHC evolution in ruminants.


The effect of an additional reflection in a precedence effect experiment.
Studies on the precedence effect typically utilize a two-source paradigm, which is not realistic relative to real world situations where multiple reflections exist. A step closer to multiple-reflection situations was studied using a three-source paradigm. Discrimination of interaural time differences (ITDs) was measured for one-, two-, and three-source stimuli, using clicks presented over headphones. The ITD was varied in either the first, second, or the third source. The inter-source intervals ranged from 0-130 ms. A perceptual weighting model was extended to incorporate the three-source stimuli and used to interpret the data. The effect of adding a third source could mostly, but not entirely, be understood by the interaction of effects observed in the precedence effect with two sources. Specifically, for delays between 1 and 8 ms, the ITD information of prior sources was typically weighted more heavily than subsequent sources. For delays greater than 8 ms, subsequent sources were typically weighted slightly more heavily than prior sources. However, there were specific conditions that showed a more complex interaction between the sources. These findings suggest that the two-source paradigm provides a strong basis for understanding how the auditory system processes reflections in spatial hearing tasks.


Potential Financial Conflict of Interest Among Physician Editorial Board Members of Orthopaedic Surgery Journals.
The practice of medicine is based on evidence from peer-reviewed literature. As can occur with author-related funding, the integrity of the process by which manuscripts are reviewed, edited, and approved for publication may be at risk due to financial conflict of interest. The purpose of our study was to assess potential financial conflict of interest among physician editorial board members of orthopaedic surgery journals. We identified the physician editorial board members of 15 orthopaedic surgery journals and searched the 2014 payments that were archived in the Centers for Medicare & Medicaid Services Open Payments system (mandated by the Physician Payments Sunshine Act). Total dollar values were calculated and tabulated in a multilevel fashion: nothing reported, >$0 and ≤$10,000, >$10,000, >$250,000, and >$950,000. We identified 908 physician editors of 15 orthopaedic surgery journals. Something of financial value was received by 78% (712 of 908) of these individuals. Rates of editorial board potential financial conflict of interest for individual journals ranged from 4% to 73% in the >$10,000 category. At the >$250,000 mark, rates ranged from 0% (2 journals) to 31%. When applying the >$950,000 criterion, physician potential conflict of interest ranged from 0% (5 journals) to 13%. Editor-related potential financial conflicts of interest exist in the orthopaedic surgery journals that we analyzed. These potential financial conflicts could possibly impact reviews.


Prestorage leukoreduction ameliorates the effects of aging on banked blood.
Previous studies have demonstrated that the transfusion of older blood is independently associated with higher rates of infectious complications, multiple organ failure, and mortality. Putative mechanisms implicate leukocytes in stored blood that generate immunomodulatory mediators as the stored blood ages. The purpose of this retrospective cohort study was to describe the effect of prestorage leukoreduction (PS-LR) on the detrimental clinical effects of increasing age on blood products used in trauma patients. All patients receiving >or=6 units of packed red cells and surviving >or=48 hours since May 1999 when institutional universal PS-LR was begun were identified. Transfusion requirements, demographic data, and causes of death were collected. Blood bank records were reviewed to determine the age of each unit of blood transfused. Multivariate logistic regression was used to determine the relationship between the age of PS-LR transfused blood and mortality after adjusting for total transfusion requirement, patient age, Injury Severity Score, head Abbreviated Injury Score, mechanism of injury, and gender. A subgroup analysis was performed excluding those patients in whom care was withdrawn at 48 hours to 72 hours postinjury for brain death or neurologic devastation. A total of 399 patients, receiving 6,603 units of blood, met inclusion criteria. Mortality analysis showed that increasing Injury Severity Score, patient age, head Abbreviated Injury Score, and number of units of packed red cells transfused were all independently associated with an increased risk of death. When mean age of blood was analyzed as a continuous variable, a significant reduction in the risk of death with increasing mean age of transfused PS-LR blood was noted (odds ratio [OR], 0.959; 95% confidence interval [CI], 0.924-0.996). Both of these findings persisted when the mean age of blood was dichotomized at 14 days (OR, 0.426; 95% CI, 0.182-0.998) and 21 days (OR, 0.439; 95% CI, 0.225-0.857). The area under the curve for the receiver operating characteristics of our mortality model was 0.90. After excluding 13 patients in whom care was withdrawn 48 hours to 72 hours postinjury for brain death or neurologic devastation, the mortality analysis still showed that increasing injury severity, number of units of packed red cells transfused, and age were all independently associated with an increased risk of death. The protective effect of receiving older blood seen in the all-cause mortality analysis disappeared because no association was found between odds of dying and increasing age of packed red blood cells units transfused. This was true whether the mean age of transfused blood was dichotomized at 14 days (OR, 0.93; CI, 0.30-2.83) or at 21 days (OR, 0.54; CI, 0.25-1.16). Our data suggest that the deleterious effects of aging on banked blood are ameliorated by PS-LR. We are currently conducting a prospective observational study in an effort to duplicate the findings of this retrospective investigation.


Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.
Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.


Identifying cardiac syncope based on clinical history: a literature-based model tested in four independent datasets.
We aimed to develop and test a literature-based model for symptoms that associate with cardiac causes of syncope. Seven studies (the derivation sample) reporting ≥2 predictors of cardiac syncope were identified (4 Italian, 1 Swiss, 1 Canadian, and 1 from the United States). From these, 10 criteria were identified as diagnostic predictors. The conditional probability of each predictor was calculated by summation of the reported frequencies. A model of conditional probabilities and a priori probabilities of cardiac syncope was constructed. The model was tested in four datasets of patients with syncope (the test sample) from Calgary (n=670; 21% had cardiac syncope), Amsterdam (n=503; 9%), Milan (n=689; 5%) and Rochester (3877; 11%). In the derivation sample ten variables were significantly associated with cardiac syncope: age, gender, structural heart disease, low number of spells, brief or absent prodrome, supine syncope, effort syncope, and absence of nausea, diaphoresis and blurred vision. Fitting the test datasets to the full model gave C-statistics of 0.87 (Calgary), 0.84 (Amsterdam), 0.72 (Milan) and 0.71 (Rochester). Model sensitivity and specificity were 92% and 68% for Calgary, 86% and 67% for Amsterdam, 76% and 59% for Milan, and 73% and 52% for Rochester. A model with 5 variables (age, gender, structural heart disease, low number of spells, and lack of prodromal symptoms) was as accurate as the total set. A simple literature-based Bayesian model of historical criteria can distinguish patients with cardiac syncope from other patients with syncope with moderate accuracy.


Dynamic modulation of inequality aversion in human interpersonal negotiations.
Negotiating with others about how finite resources should be distributed is an important aspect of human social life. However, little is known about mechanisms underlying human social-interactive decision-making in gradually evolving environments. Here, we report results from an iterative Ultimatum Game (UG), in which the proposer's facial emotions and offer amounts were sampled probabilistically based on the participant's decisions. Our model-free results confirm the prediction that both the proposer's facial emotions and the offer amount should influence acceptance rates. Model-based analyses extend these findings, indicating that participants' decisions in the UG are guided by aversion to inequality. We highlight that the proposer's facial affective reactions to participant decisions dynamically modulate how human decision-makers perceive self-other inequality, relaxing its otherwise negative influence on decision values. This cognitive model underlies how offers initially rejected can gradually become more acceptable under increasing affective load (predictive accuracy ~86%). Furthermore, modelling human choice behaviour isolated the role of the central arousal systems, assessed by measuring pupil size. We demonstrate that pupil-linked central arousal systems selectively encode a key component of subjective decision values: the magnitude of self-other inequality. Taken together, our results demonstrate that, under affective influence, aversion to inequality is a malleable cognitive process.


Target Molecules and Delivery Vehicles for Anti-HIV Drugs In vitro and In vivo.
Acquired Immune Deficiency Syndrome (AIDS) is the most serious stage of Human Immunodeficiency Virus (HIV) infection. The combinatorial Anti-Retroviral Therapy (cART) is widely used in suppressing HIV-1 infection and enhancing life span of infected patients to a significant level. However, delivery of therapeutic molecules is still a major challenge in vivo. The studies showed that the anti-HIV drugs delivered via nanocarriers could be selectively accumulated in infected cells accompanied by low side effects. On the other hand, HIV-1 infection kinetics is different in macrophages and T-cells suggesting various effects of antiretroviral drugs against HIV-1 in these target cells. Current anti-HIV therapeutic studies have focused on developing drug delivery systems targeted specifically to HIV-infected host cells. Indeed, the drug targeting can significantly lead to reduce in drug toxicity, drug dose, and increase in treatment efficacy through localizing its pharmacological activity to the site of interest. This review describes development of novel drug targeting systems used in suppressing the transmission and treatment of HIV infections.


Cluster headache and other TACs: Pathophysiology and neurostimulation options.
The trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders. There are several issues that remain unresolved in the understanding of the pathophysiology of the TACs, although activation of the trigeminal-autonomic reflex and ipsilateral hypothalamic activation both play a central role. The discovery of the central role of the hypothalamus led to its use as a therapeutic target. After the good results obtained with hypothalamic stimulation, other peripheral neuromodulation targets were tried in the management of refractory cluster headache (CH) and other TACs. This review is a summary both of CH pathophysiology and of efficacy of the different neuromodulation techniques. In chronic cluster headache (CCH) patients, hypothalamic deep brain stimulation (DBS) produced a decrease in attack frequency of more than 50% in 60% of patients. Occipital nerve stimulation (ONS) also elicited favorable outcomes with a reduction of more than 50% of attacks in around 70% of patients with medically intractable CCH. Stimulation of the sphenopalatine ganglion (SPG) with a miniaturized implanted stimulator produced a clinically significant improvement in 68% of patients (acute, preventive, or both). Vagus nerve stimulation (VNS) with a portable device used in conjunction with standard of care in CH patients resulted in a reduction in the number of attacks. DBS and ONS have been used successfully in some cases of other TACs, including hemicrania continua (HC) and short-lasting unilateral headache attacks (SUNHA). DBS has good results, but it is a more invasive technique and can generate serious adverse events. ONS has good results, but frequent and not serious adverse events. SPG stimulation (SPGS) is also efficacious in the acute and prophylactic treatment of refractory cluster headache. At this moment, ONS and SPG stimulation techniques are recommended as first line therapy in refractory cluster patients. New recent non-invasive approaches such as the non-invasive vagal nerve stimulator (nVNS) have shown efficacy in a few trials and could be an interesting alternative in the management of CH, but require more testing and positive randomized controlled trials.


Micro-droplet arrays for micro-compartmentalization using an air/water interface.
Here we present a water-in-air droplet platform for micro-compartmentalization for single molecule guided synthesis and analysis consisting of a flow-system hosting dense arrays of aqueous microdroplets on a glass surface surrounded by air. The droplets are formed in a few seconds by passing a waterfront over the array of hydrophilic spots surrounded by a hydrophobic coating, thus forming a micro-droplet array (MDA). The droplet volumes are tunable from approximately 50 femtoliter to 20 picoliter by adjusting the size of the hydrophilic spots. MDAs consisting of femtoliter volume droplets were stable for more than 24 hours in air at 37 °C in a reversibly sealed flow-system, thus allowing us to perform assays that require long incubations in the droplets. Using differently fluorescing liquids, it was further shown that droplets can be reformed on the same MDA several times by passing a new liquid plug over the surface, and that fluorescence from one reaction can be washed away with little to no carry-over, hence allowing for multistep reactions to be carried out on the system. The MDA created by an air/water interface supported digital immunoassays as was demonstrated by measuring the Aβ42 peptide in cerebrospinal fluid of Alzheimers patients and control patients. To demonstrate a two step droplet assay, first, histidine tagged peptides were expressed in the droplets and bound to the droplet-enclosed surface. Subsequently, the his-tagged peptides were detected using enzyme-conjugated antibodies in a second droplet generation step. As such, the chip demonstrates features necessary for library preparations for high throughput screening applications.


Quality of life in partners of patients with localised prostate cancer.
The diagnosis of prostate cancer and the following treatment does not only affect the patient, but also his partner. Partners often suffer even more severely from psychological distress than the patients themselves. This analysis aims to describe the quality of life (QoL) after the cancer diagnosis over time and to identify the effects of possible predictors of partners' quality of life in a German study population. Patients with localised prostate cancer and their partners were recruited from a prospective multicenter study in Germany, the Prostate Cancer, Sexuality, and Partnership (ProCaSP) Study. At five observation times during the follow-up period of 2 years after diagnosis, QoL (EORTC QLQ-C30) and personal, social, and cancer-related health factors as well as adaptation and coping factors of 293 couples were observed and analysed with mixed effects analysis. The men's prostate cancer diagnosis had a small, but significant impact on their partner's QoL. However, QoL of partners was most affected by the partners' own physical health and psychological condition, time, and their relationship quality. The finding that average QoL increased again 3 months after diagnosis and later should give partners faith and hope for the future. The identified most important predictors of partners' QoL are potentially susceptible to intervention, and further research on target groups in special need of support and on adequate interventions is needed.


The use of marker-assisted selection in animal breeding and biotechnology.
Improvement of livestock has focused on the selective breeding of individuals with superior phenotypes. With the development of increasingly advanced statistical methods that maximise selection for genetic gain, this simple approach has been extremely successful in increasing the quantity of agricultural output. However, information now available on the organisation and functioning of the genome could be used in breeding programmes to improve a range of traits. Many traits are under the control of several genetic loci, each of which contribute to the variation in the trait and hence are called quantitative trait loci (QTL). While genetic markers for QTL that are linked to the trait gene could be used to choose animals for selective breeding programmes, the most effective markers are the functional mutations within the trait genes. Strategies to identify markers for traits and the application of these markers are described by reference to examples of loci that control a range of different traits.