mTOR Modulates Methamphetamine-Induced Toxicity through Cell Clearing Systems.
Methamphetamine (METH) is abused worldwide, and it represents a threat for public health. METH exposure induces a variety of detrimental effects. In fact, METH produces a number of oxidative species, which lead to lipid peroxidation, protein misfolding, and nuclear damage. Cell clearing pathways such as ubiquitin-proteasome (UP) and autophagy (ATG) are involved in METH-induced oxidative damage. Although these pathways were traditionally considered to operate as separate metabolic systems, recent studies demonstrate their interconnection at the functional and biochemical level. Very recently, the convergence between UP and ATG was evidenced within a single organelle named autophagoproteasome (APP), which is suppressed by mTOR activation. In the present research study, the occurrence of APP during METH toxicity was analyzed. In fact, coimmunoprecipitation indicates a binding between LC3 and P20S particles, which also recruit p62 and alpha-synuclein. The amount of METH-induced toxicity correlates with APP levels. Specific markers for ATG and UP, such as LC3 and P20S in the cytosol, and within METH-induced vacuoles, were measured at different doses and time intervals following METH administration either alone or combined with mTOR modulators. Western blotting, coimmunoprecipitation, light microscopy, confocal microscopy, plain transmission electron microscopy, and immunogold staining were used to document the effects of mTOR modulation on METH toxicity and the merging of UP with ATG markers within APPs. METH-induced cell death is prevented by mTOR inhibition, while it is worsened by mTOR activation, which correlates with the amount of autophagoproteasomes. The present data, which apply to METH toxicity, are also relevant to provide a novel insight into cell clearing pathways to counteract several kinds of oxidative damage.


[Neurophysiologic mechanisms of face recognition].
During the last three decades, the mechanisms implicated in face perception and recognition, have been investigated with an interdisciplinary approach. On one hand, in psychology, models of cognitive architectures have been developed in which the different kinds of mental operations in the processing of face have been identified. On the other hand, a lot of studies in neuropsychology have analyzed the deficits in visual processing of face, specifically due to lesions or dysfunctions of the central nervous system. Finally, research in neurophysiology (cellular recording in animal and functional cerebral imagery in man) have tried to highlight the complex assembly of cerebral areas implicated in these different operations. Besides a short summary of the principal data collected in this interdisciplinary approach, we present in this contribution results obtained in our laboratory and in the context of an "Action de recherche concertée", in the fields of neuropsychology and cerebral functional imagery.


Factors affecting intestinal absorption of cholesterol and plant sterols and stanols.
Various factors affect intestinal absorption of cholesterol and plant sterols and stanols. Plant sterols and stanols are generally less absorptive than cholesterol. Differential absorption rates among various plant sterols and stanols have been also reported. Although it was suggested that differential absorption among cholesterol and various plant sterols was determined by difference in excretion rates of sterols and stanols through ATP-binding cassette transporter (ABC) G5/ABCG8 of intestinal cells, our study suggests that affinity for and solubility in bile salt micelles can be important determinants for differential absorption of plant sterols and stanols. It was also suggested that plant sterols were transiently incorporated into intestinal cells and then excreted to intestinal lumen through ABCG5/ABCG8. However, in a rat study, transient incorporation of sitosterol into intestinal cells was not observed, suggesting that sitosterol is differentiated from cholesterol at the incorporation site of intestinal cells. It is well established that plant sterols inhibit intestinal absorption of cholesterol and exert a hypocholesterolemic activity. Plant sterols are solubilized in bile salt micelles as cholesterol. Our study clearly showed that because the sterol-solubilizing capacity of bile salt micelles was limited, plant sterols solubilized in micelles reduced the solubility of cholesterol. This can be the major cause of inhibition of cholesterol absorption by plant sterols. Pancreatic cholesterol esterase accelerates intestinal absorption of unesterified cholesterol. Although it was suggested that cholesterol esterase accelerated esterification of cholesterol incorporated into intestinal cells and acted as a transporter at the surface of intestinal cells, our research revealed that the accelerated cholesterol absorption was caused by hydrolysis of phosphatidylcholine in bile salt micelles. It is thought that hydrolysis of phosphatidylcholine reduces the affinity of cholesterol for the micelles and accelerates the incorporation of cholesterol released from the micelles into intestinal cells.


Pterygium surgery by double-sliding flaps procedure: Comparison between primary and recurrent pterygia.
This study aimed to evaluate the surgical outcomes of pterygial excision for primary and recurrent pterygia by a single method of pterygia excision combined with two conjunctival flaps. This retrospective study divided 193 cases of pterygium into the primary (140 cases) and recurrent (53 cases) pterygium groups. Following double-sliding conjunctival transposition flap operation and surgical excision of the pterygium, the success and recurrence rates of pterygial surgery were assessed based on visual acuity and corneal and total astigmatism during follow-up at least 6 months. Both primary and recurrent pterygium groups showed significant improvements in visual acuity and astigmatism (corneal and total) between before and after this procedure. Total astigmatism and success rate of primary pterygium were significantly better than those for recurrent pterygium. Two cases (1.4%) of primary pterygium and four cases (7.5%) of recurrent pterygium developed recurrence, corresponding to a rate of 3.1% (6/193 cases). The success rates significantly make a difference between primary and recurrent groups but did not differ significantly between the first recurrent and over twice recurrent pterygium. However, visual acuity, cornea, and total astigmatism improved significantly after surgery in first recurrent group but not in over twice recurrent group. The double-sliding conjunctival flaps surgery appeared to be a useful method, with a better success rate and lower pterygial recurrence in pterygium surgery. Especially, when pterygium is larger or recurrent type, this technique can be easily covered the bare sclera, as compared to any transposition conjunctival flap operation.


Tumor-Agnostic Treatment for Cancer: When How is Better than Where.
In the evolving landscape of precision oncology, genomic characterization of tumor has become crucial in order to move toward a molecular-based therapy for the vast majority of cancers. Recently, translational research has offered new perspectives in systemic cancer treatment thanks to the identification of novel oncogenic targets and the development of new targeted therapies, followed by the latest applications of genomic sequencing. Simultaneously, next-generation sequencing (NGS) has expanded its accessibility, being incorporated into clinical studies at the time of the initial screening, disease progression, and often in longitudinal monitoring of molecular changes. Consequently, new potentially targetable molecular alterations have been identified in several different types of tumors, leading to the development of tumor-agnostic treatments. Being highly selective for specific molecular alterations, these drugs are active against different subtypes of oncogene-addicted cancers. Three of these drugs-pembrolizumab [an anti-programmed death 1 (PD-1) monoclonal antibody (MAb)], larotrectinib [a pan-tropomyosin receptor tyrosine kinase (TRK) inhibitor], and entrectinib [a pan-TRK, anaplastic lymphoma kinase (ALK) and ROS-1 inhibitor]-received US FDA approval in 2017, 2018, and 2019, respectively. In this article, we critically review the clinical studies responsible for FDA approval and the most recently updated results. We then discuss the benefits and limitations of these new methodological approaches, paying particular attention to the largest precision medicine master protocol, NCI-MATCH. Among the benefits, there are the increased chances of offering targeted therapies for patients with specific alterations identified in different types of tumors. Among the limitations, we highlight that the same driver mutation may require different therapeutic strategies in different types of cancers. Additionally, the complex study design undeniably requires a dynamic strategy to enroll patients with considerable economic and managerial efforts.


Oral Lymphatic Malformations: A 21-Year Retrospective Study in a Single Institution.
Introduction. Oral lymphatic malformations are uncommon lesions. This study assessed the clinicopathological and sociodemographic features of oral lymphatic malformations in a Brazilian oral pathology service. Methods. Between 2000 and 2021, all oral lymphatic malformations diagnosed in a single oral pathology service were selected for the study. Clinical data, such as age, sex, site of the lesion, clinical presentation, diagnosis clinical, and the type of biopsy were recorded from the patient's clinical charts. Results. From 7554 oral lesions, 17 (0.22%) were oral lymphatic malformations. This lesion similarly affected both sexes, and the mean age of the patients was 16.5 years. The tongue was the most common site (n = 13; 76%). The mean size of the lesions was 17 mm. Oral lymphatic malformations were asymptomatic for 29% of the patients. Clinically, most lesions appeared as a reddish, sessile nodule, with a pebbly surface. In addition, the clinical and histopathological diagnoses agreed for most lesions (n = 11; 64%). The type of biopsy performed was excisional in 41% of lesions. Conclusions. In summary, oral lymphatic malformations present a low prevalence among the oral lesions diagnosed in an oral pathology service. Moreover, they affect equally both sexes, especially young patients, and usually appear as an asymptomatic or symptomatic nodular swelling on the tongue.


Independent prescribing by advanced physiotherapists for patients with low back pain in primary care: protocol for a feasibility trial with an embedded qualitative component.
Low back pain (LBP) is the most prevalent musculoskeletal condition in the UK. Guidelines advocate a multimodal approach, including prescription of medications. Advanced physiotherapy practitioners (APPs) are well placed to provide this care in primary care. Physiotherapist independent prescribing remains novel, with the first prescribers qualifying in 2014. This feasibility trial aims to evaluate the feasibility, suitability and acceptability of assessing the effectiveness of independent prescribing by APPs for patients with LBP in primary care, to inform the design of a future definitive stepped-wedged cluster trial. METHOD AND ANALYSIS: (1) Trial component. An APP (registered prescriber) will complete the initial participant consultation. If prescription drugs are required within the multimodal physiotherapeutic context, these will be prescribed. Patient-reported outcome measures will be completed prior to initial assessment and at 6 and 12 weeks to assess feasibility of follow-up and data collection procedures. Accelerometers will be fitted for 7 days to assess physical activity, sedentary behaviour and feasibility of use. (2) Embedded qualitative component. A focus group and semistructured interviews will be used to evaluate the views and experiences of the participants and APPs respectively, about the feasibility, suitability and acceptability of the proposed full trial. A Consolidated Standards of Reporting Trials diagram will be used to analyse feasible eligibility, recruitment and follow-up rates. Descriptive analysis of the data will be completed to evaluate procedures. Thematic analysis will be used to analyse and synthesise the qualitative data. This feasibility trial is approved by the Health Research Authority (HRA). Ethical approval was sought and granted via the Integrated Research Application System (IRAS) ID 250734.Data will be disseminated via publication in peer reviewed journal and conference presentation. It is anticipated that the results of this study will be used in conjunction with ethical evaluation, economic and risk analyses, as well as consultation with key stakeholders including the British health consumer when contemplating change, enhancement or redesign of the essential full randomised controlled trial. ISRCTN15516596, Pre-results.


Characteristics of biofilm on tunneled cuffed hemodialysis catheters in the presence and absence of clinical infection.
Biofilm occurring on the surface of tunneled hemodialysis (HD) catheters is difficult to eradicate and often is associated with recurrent bacteremia. We studied biofilm formation on catheters from patients with and without bacteremia to identify the location of bacterial growth and measure biofilm thickness. Prospective observational study. 76 adult HD patients; 26 had HD catheters removed for bacteremia and 50 had catheters removed for reasons other than infection. Segment of catheter, reason for catheter removal. Microbiological growth and biofilm thickness on the outer and luminal surfaces of extravascular and intravascular catheter segments. Catheter cultures were positive in 16 (62%) patients with bacteremia and 15 (30%) when the catheter was removed for non-infection-related reasons. In catheters with positive cultures, the outer surface of the extravascular segment was the most common site of bacterial growth (15/16 [94%] and 11/15 [73%] for bacteremic and nonbacteremic patients, respectively). Bacteremic patients had significantly thicker biofilm on all catheter surfaces, and in bacteremic patients, the biofilm was significantly thicker on the outer compared with the luminal surface for both extravascular (14.53 ± 6.17 vs 11.97 ± 5.01 μm; P < 0.001) and intravascular (12.21 ± 5.3 vs 9.46 ± 3.71 μm; P < 0.001) segments. Extravascular segments had significantly thicker biofilm compared with intravascular segments on both the outer (P < 0.001) and luminal (P < 0.001) surfaces. Similarly, in patients for whom the catheter was removed for non-infection-related reasons, the catheter had thicker biofilm on the outer compared with the inner surface in both extravascular (2.19 ± 2.84 vs 1.62 ± 2.33 μm; P < 0.001) and intravascular (1.92 ± 2.62 vs 1.29 ± 2.33 μm; P < 0.001) segments. Similar to catheters from bacteremic patients, the outer and luminal surfaces of the extravascular segments of the catheters had significantly thicker biofilm compared with their corresponding surfaces on the intravascular segments. Observational study. The outer surface of the extravascular segment of tunneled dialysis catheters in both bacteremic and nonbacteremic HD patients has the thickest biofilm and highest microbiological yield, and biofilm is thicker in patients with bacteremia. This knowledge is important for designing preventive strategies and also in the management of patients with catheter infection.


Nitroso-Redox Balance and Modulation of Basal Myocardial Function: An Update from the Italian Society of Cardiovascular Research (SIRC).
Reactive oxygen species and reactive nitrogen species are produced endogenously by cardiomyocytes and are fundamental signaling molecules that regulate cellular function. Production of ROS and RNS is finely tuned to maintain proper myocardial function, but is altered in many pathophysiological conditions, therefore contributing to worsening myocardial dysfunction and ultimately heart failure. Indeed, an excess of ROS and RNS is central in many pathways leading to cardiac hypertrophy and failure, and the correct regulation of the nitroso-redox balance is fundamental for the function of the main components of the EC-coupling machinery. Broad antioxidant therapies have been proposed to improve myocardial function, but these therapies blunt even physiological ROS and RNS signaling, bringing limited, if any, beneficial effect. On the other hand, more targeted interventions on specific sources or pathways may produce promising results.


Breathing exercises for adults with asthma.
Breathing exercises have been widely used worldwide as a complementary therapy to the pharmacological treatment of people with asthma. To evaluate the evidence for the efficacy of breathing exercises in the management of patients with asthma. The search for trials led review authors to review the literature available in The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and AMED and to perform handsearching of respiratory journals and meeting abstracts. Trial registers and reference lists of included articles were also consulted.The literature search has been updated to January 2013. We included randomised controlled trials of breathing exercises in adults with asthma compared with a control group receiving asthma education or, alternatively, with no active control group. Two review authors independently assessed trial quality and extracted data. RevMan software was used for data analysis based on the fixed-effect model. Continuous outcomes were expressed as mean differences (MDs) with confidence intervals (CIs) of 95%. Heterogeneity was assessed by inspecting the forest plots. The Chi(2) test was applied, with a P value of 0.10 indicating statistical significance. The I(2) statistic was implemented, with a value greater than 50% representing a substantial level of heterogeneity. A total of 13 studies involving 906 participants are included in the review. The trials were different from one another in terms of type of breathing exercise performed, number of participants enrolled, number and duration of sessions completed, outcomes reported and statistical presentation of data. Asthma severity in participants from the included studies ranged from mild to moderate, and the samples consisted solely of outpatients. The following outcomes were measured: quality of life, asthma symptoms, number of acute exacerbations and lung function. Eleven studies compared breathing exercise with inactive control, and two with asthma education control groups. All eight studies that assessed quality of life reported an improvement in this outcome. An improvement in the number of acute exacerbations was observed by the only study that assessed this outcome. Six of seven included studies showed significant differences favouring breathing exercises for asthma symptoms. Effects on lung function were more variable, with no difference reported in five of the eleven studies that assessed this outcome, while the other six showed a significant difference for this outcome, which favoured breathing exercises. As a result of substantial heterogeneity among the studies, meta-analysis was possible only for asthma symptoms and changes in the Asthma Quality of Life Questionnaire (AQLQ). Each meta-analysis included only two studies and showed a significant difference favouring breathing exercises (MD -3.22, 95% CI -6.31 to -0.13 for asthma symptoms; MD 0.79, 95% CI 0.50 to 1.08 for change in AQLQ). Assessment of risk of bias was impaired by incomplete reporting of methodological aspects of most of the included trials. Even though individual trials reported positive effects of breathing exercises, no reliable conclusions could be drawn concerning the use of breathing exercises for asthma in clinical practice. This was a result of methodological differences among the included studies and poor reporting of methodological aspects in most of the included studies. However, trends for improvement are encouraging, and further studies including full descriptions of treatment methods and outcome measurements are required.


Sleep Efficiency and Naturalistically-Observed Social Behavior Following Marital Separation: The Critical Role of Contact with an Ex-partner.
Marital disruption is associated with increased risk for a range of poor health outcomes, including disturbed sleep. This report examines trajectories of actigraphy-assessed sleep efficiency following marital separation as well as the extent to which daily social behaviors and individual differences in attachment explain variability in these trajectories over time. One hundred twenty-two recently-separated adults (N = 122) were followed longitudinally for three assessment periods over five months. To objectively assess daily social behaviors and sleep efficiency, participants wore the Electronically Activated Recorder (EAR) during the day (for one weekend at each assessment period) and an actiwatch at night (for seven days at each assessment period). Greater time spent with an ex-partner, as assessed by the EAR, was associated with decreased sleep efficiency between participants (p = .003). Higher attachment anxiety was also associated with decreased sleep efficiency (p = .03), as was the EAR-observed measure of "television on." The latter effect operated both between (p = .004) and within participants (p = .005). Finally, study timepoint moderated the association between EAR-observed measure of "television on" and sleep efficiency (p = .007). The current findings deepen our understanding of sleep disturbances following marital separation and point to contact with an ex-partner and time spent with the television on as behavioral markers of risk.


The Bali STD/AIDS study: human papillomavirus infection among female sex workers.
Female sex workers in low priced brothel areas in Denpasar, Bali, Indonesia participated in an intervention study designed to promote condom use and sexually transmitted disease (STD)/AIDS prevention. The intervention provided educational sessions for sex workers, STD treatment for sex workers, condom distribution, and media for clients. The brothel areas were divided into high and low areas for programme effort. The high effort areas received a more intensive behavioural intervention than the low effort areas. A clinic was available for STD treatment in both areas. Behavioural surveys and STD testing were used to evaluate the programmes. About 600 were evaluated for several STDs and completed personal interviews at enrolment and at six-month intervals during the 18-month study. About 50% of women were new to the study at each round. Human papillomavirus (HPV) testing of cervical swabbed specimens, using polymerase chain reaction methodology, was performed at the beginning of the study and 18 months later. Human papillomavirus infection was initially high in these women (38.3%) and declined to 29.7% after 18 months (P <0.01). The prevalence of HPV infection declined with age (P <0.01). HPV infection was associated with a number of STD symptoms that were reported in personal interviews. These associations were stronger in the first time period. Infection with Neisseria gonorrhoeae was associated with HPV infection at baseline (P =0.03). HPV infection declined in the study area with the more intensive educational programme (P <0.01). The prevalence of HPV infection declined over time and was associated with study area and age of woman.


Molecular targeted therapy of gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that occur predominantly in the stomach and the small bowel. Their pathogenesis is generally based on primary activating mutations in the KIT or PDGFRα genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib, first designed to competitively inhibit the ATP-binding pocket of the BCR-ABL tyrosin kinase exhibits inhibition also in the KIT and PDGFRα tyrosine kinases, which revolutionized the therapy of gastrointestinal stromal tumors, a disease without any systemic treatment options prior to imatinib. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease with a median progression-free survival of 19 to 26 months and an overall survival approaching 5 years. Disease progression results from different mechanisms of resistance most frequently involving the emergence of secondary mutations in KIT exons 13, 14, or 17. Several newer drugs have been studied in patients failing or being intolerant to imatinib, including the multitargeted agent sunitinib as well as other KIT targeting tyrosine kinase inhibitors like nilotinib or agents targeting alternative pathways like anti-angiogenic agents, mTOR-, RAF kinase- and chaperone inhibitors.


Hyperbaric oxygen therapy for postoperative ischemic bronchitis after resection of lung cancer.
Hyperbaric oxygen therapy (HBOT) has been used successfully in the treatment of specific ischemic injuries, but has been a little evaluated specifically in postoperative ischemic bronchitis (POIB). The purpose of this study was to evaluate the effect of HBOT when used for POIB after resection of lung cancer. From January 1999 to December 2016, 1,100 patients underwent lymph node dissection (LND) and either anatomic pulmonary resection or lung resection with bronchoplasty for lung cancer. POIB was diagnosed by bronchoscopy. HBOT was administered after POIB was diagnosed. HBOT comprised one 60-minute session daily in the hyperbaric chamber at 2.0 absolute atmospheres with 100% oxygen. We retrospectively analyzed the clinical course, timing of onset of POIB, outcomes, and any adverse events. Seven patients were identified to have had POIB treated with HBOT, all of whom were men with a smoking history and a median age of 65 years (range, 57-72 years). The operative procedures included three lung resections with bronchoplasty, three right lower lobectomies, and one right middle lobectomy performed owing to torsion of the middle lobe after right upper sleeve lobectomy. All 7 patients underwent subcarinal LND. POIB was diagnosed at a median of 11 days (range, 4-41 days) postoperatively. The median duration of an HBOT session was 7 days (range, 3-11 days). POIB resolved in 5 patients but worsened in 2, both of whom required further surgery. Prospective clinical trials are now needed to confirm the potential benefits of HBOT in POIB.


Short-Term Effects of Normocapnic Hyperpnea and Exercise Training in Patients With Chronic Obstructive Pulmonary Disease: A Pilot Study.
The aim of the study was to evaluate the short-term physiologic effects of respiratory muscle training with normocapnic hyperpnea added to standard exercise training on respiratory muscle endurance/strength and exercise tolerance in patients with chronic obstructive pulmonary disease. The study used a randomized controlled trial. Patients referred for rehabilitation were randomly assigned to 20 sessions (twice daily 5 d/wk) of either normocapnic hyperpnea (group 1, n = 12) or sham maneuvers (group 2, n = 10) in addition to individualized cycle training and abdominal, upper, and lower limb muscle exercise. At baseline and end of study, patients underwent evaluation of respiratory muscle endurance, maximum voluntary ventilation, maximal inspiratory, and expiratory pressures, and 6-min walking distance. After training, a significant improvement was found only for group 1 in respiratory muscle endurance time (by 654 [481] secs versus 149 [216] secs for group 2, P = 0.0108) and maximal inspiratory (group 1: from 81.2 [21.9] cmH2O to 107.6 [23.0] cmH2O, P = 0.018 versus group 2: from 75.4 [13.8] cmH2O to 81.3 [18.9] cmH2O, P = 0.139). The difference between groups for 6-min walking distance, maximum voluntary ventilation, and expiratory pressures was not significant. Short-term normocapnic hyperpnea training added to standard exercise, compared with exercise training alone, improves respiratory muscle endurance and strength but not exercise tolerance in patients with chronic obstructive pulmonary disease.


Cranial diameter pulsations measured by non-invasive ultrasound decrease with tilt.
Intracranial pressure (ICP) may play a significant role in physiological responses to microgravity by contributing to the nausea associated with microgravity exposure. However, effects of altered gravity on ICP in astronauts have not been investigated, primarily due to the invasiveness of currently available techniques. We have developed an ultrasonic device that monitors changes in cranial diameter pulsation non-invasively so that we can evaluate ICP dynamics in astronauts during spaceflight. This study was designed to demonstrate the feasibility of our ultrasound technique under the physiological condition in which ICP dynamics are changed due to altered gravitational force. Six healthy volunteers were placed at 60 degrees head-up, 30 degrees headup, supine, and 15 degrees head-down positions for 3 min at each angle. We measured arterial blood pressure (ABP) with a finger pressure cuff, and cranial diameter pulsation with a pulsed phase lock loop device (PPLL). Analysis of covariance demonstrated that amplitudes of cranial diameter pulsations were significantly altered with the angle of tilt (p < 0.001). The 95% confidence interval for linear regression coefficients of the cranial diameter pulsation amplitudes with tilt angle was 0.862 to 0.968. However, ABP amplitudes did not show this relationship. Our noninvasive ultrasonic technique reveals that the amplitude of cranial diameter pulsation decreases as a function of tilt angle, suggesting that ICP pulsation follows the same relationship. It is demonstrated that the PPLL device has a sufficient sensitivity to detect changes non-invasively in ICP pulsation caused by altered gravity.


[Migraine with aura and patent foramen ovale. A different clinical entity].
This work has aimed to evaluate the prevalence of patent foramen ovale in subjects with migraine with aura by transcranial contrast doppler and to describe the clinical and risk profile of these patients. We performed a transcranial contrast doppler in 94 consecutive out-patients with migraine with aura (MWA) in a neurology outpatient clinic. They were divided into two groups according to the presence of patent foramen ovale: MWA_RLsh (with right-to-left shunt) and MWA_RLNsh (without right-to-left shunt). Differences between the groups were analyzed according to endpoints of age, gender, clinical severity, aura type and attacks frequency, comorbility, cardiovascular risk factors (CVRFs), neuroimaging findings, severity of shunt and treatment. n=94; MWA_RLsh: 47 (54%). MWA_RLNsh: 40 (46%). Age: 33.13; standard desviation (SD): 10.8 vs 33.496; SD: 11.2; p=0.728. Female: 66 vs 72.5%; p=0.511. Visual aura: 73.9% vs 78.9%; p=0.921. There were no significant differences in regards to the risk factors studied or to the comorbid diseases that are associated to migraine. The patients with patent foramen ovale have an odds ratio (OR) of ischemic stroke: 1.189 (95% confidence interval [CI]: 0.226 to 6.248; p=0.840), OR for subclinical brain lesions in cranial magnetic resonance imaging (MRI): 0.589 (95% CI: 0.193 to 1.799; p=0.35) and OR for combined previous ischemic stroke and subclinical brain lesions: 0.745 (95% CI: 0.261 to 2.129; p=0.58). Migraine attack frequency >1 per month: 27.9 vs 36.4; p=0.464. Need for prophylaxis therapy: 44.7 vs 57.7%; p=0.284. Both groups are similar regarding their clinical profile. We did not find a greater prevalence of stroke or silent brain lesions in the group with positive shunt..


Systematic Review of International Colposcopy Quality Improvement Guidelines.
The American Society for Colposcopy and Cervical Pathology Colposcopy Standards Committee organized multiple working groups to draft colposcopy standards for the United States. As part of this project, international quality assurance and improvement measures were examined. The quality improvement working group performed a systematic review of the literature to collate international guidelines related to quality improvement. Source guidelines were collected using searches in Medline, Google Scholar, the International Federation of Cervical Pathology and Colposcopy Web site, other regional colposcopy group's Web sites, and communications with International Federation of Cervical Pathology and Colposcopy board of directors' members and other expert members of various national groups. Once identified, the sources were reviewed by multiple workgroup members for potential guideline materials. Fifty-six unique documents were identified, of which 18 met inclusion criteria and contributed data to the analysis. Information was abstracted and grouped by related subject. Wide variation exists in colposcopy guidance and quality indicators from regional and national colposcopy societies. Abstracted international guidelines are presented.


Volumetric growth of the different regions of the fetal spine.
The Author analysed the volumetric growth of the spine ("centra" + intervertebral discs) from the 13th week to term of prenatal life. The data were obtained from the osteological collection of the Department of Human Anatomy and Physiology (University of Turin), by means of a geometric procedure. The growth rate was compared with the observations of other Authors on the growth of the linear measures and with the results of previous works on the anteroposterior curvatures of the developing spine. The analysis of the growth in volume of the various spinal regions, seems to admit temporo-spatial relationships only between the growth velocity of the lumbar region and the appearance of the lumbar lordosis.


High-dose cyclophosphamide, carboplatin, and etoposide with autologous stem cell rescue in patients with breast cancer.
This study was designed to establish the toxicity and response rates o observed with a combination of high-dose cyclophosphamide, carboplatin, and etoposide with stem cell rescue in patients with breast carcinoma. Eligibility criteria included metastatic or locally advanced breast carcinoma ; aged < or equal to 60 years; performance status Eastern Cooperative Oncology Group (ECOG) 0-1; and creatinine clearance > or equal to 65 ml/min. Chemotherapy consisted of cyclophosphamide 25 mg/kg i.v. X 4 days, etoposide 400 mg/m(2) i.v. X 4 days, and carboplatin 375 mg/m(2) X 4 days. Bone marrow or peripheral blood stem cells were reinfused 48 h after completion of chemotherapy. Seventeen patients were treated in this study. The major toxicity was gastrointestinal (grades I and II). Fevers associated with neutropenia were observed in all the patients, but no episodes of bacteremia were documented. Hematopoietic toxicities were acceptable. No toxic deaths were observed. Six patients had chemotherapy-sensitive disease at time of transplant, nine had refractory disease, and two were untested. A response rate of 62% with 18% complete response (CR) was achieved. Two patients are free of disease at +7 and +9 months after transplantation. The combination of high-dose cyclophosphamide, carboplatin, and etoposide is well tolerated with a response rate comparable to previously reported high-dose chemotherapy regimens. However, in a poor prognostic risk group, namely patients with chemoinsensitive disease, this therapeutic approach seems to be of no advantage over standard chemotherapy.


Acetate and glycerol are not uniquely suited for the evolution of cross-feeding in E. coli.
The evolution of cross-feeding among individuals of the same species can help generate genetic and phenotypic diversity even in completely homogeneous environments. Cross-feeding Escherichia coli strains, where one strain feeds on a carbon source excreted by another strain, rapidly emerge during experimental evolution in a chemically minimal environment containing glucose as the sole carbon source. Genome-scale metabolic modeling predicts that cross-feeding of 58 carbon sources can emerge in the same environment, but only cross-feeding of acetate and glycerol has been experimentally observed. Here we use metabolic modeling to ask whether acetate and glycerol cross-feeding are especially likely to evolve, perhaps because they require less metabolic change, and thus perhaps also less genetic change than other cross-feeding interactions. However, this is not the case. The minimally required metabolic changes required for acetate and glycerol cross feeding affect dozens of chemical reactions, multiple biochemical pathways, as well as multiple operons or regulons. The complexity of these changes is consistent with experimental observations, where cross-feeding strains harbor multiple mutations. The required metabolic changes are also no less complex than those observed for multiple other of the 56 cross feeding interactions we study. We discuss possible reasons why only two cross-feeding interactions have been discovered during experimental evolution and argue that multiple new cross-feeding interactions may await discovery.


Probabilistic estimation of respiratory rate using Gaussian processes.
The presence of respiratory information within the electrocardiogram (ECG) signal is a well-documented phenomenon. We present a Gaussian process framework for the estimation of respiratory rate from the different sources of modulation in a single-lead ECG. We propose a periodic covariance function to model the frequency- and amplitude-modulation time series derived from the ECG, where the hyperparameters of the process are used to derive the respiratory rate. The approach is evaluated using data taken from 40 healthy subjects each with 2 hours of monitoring, containing ECG and respiration waveforms. Results indicate that the accuracy of our proposed method is comparable with that of existing methods, but with the advantages of a principled probabilistic approach, including the direct quantification of the uncertainty in the estimation.


Recurrent Hemarthrosis due to Iatrogenic AVF Treated With Onyx Embolization.
A 78-year-old gentleman presented with recurrent symptomatic hemarthrosis after total knee arthroplasty. His workup revealed an iatrogenic arteriovenous fistula (iAVF). The iAVF was embolized with the Onyx Liquid Embolization System with resolution of his symptoms up to 10 months of follow-up. This is the first description to our knowledge of an iatrogenic hemarthrosis after total knee arthroplasty successfully treated with Onyx solution embolization.


Viremia in experimental Creutzfeldt-Jakob disease.
Inoculation of the buffy coat of blood from guinea pigs infected with Creutzfeldt-Jakob disease resulted in passage of this disease to recipient animals. This demonstrates that there is a viremia in experimental Creutzfeldt-Jakob disease. These findings suggest that the hematogenous route may be implicated in the human infection and that the disease may possibly be transmitted by blood transfusions.


An expert-based job exposure matrix for large scale epidemiologic studies of primary hip and knee osteoarthritis: the Lower Body JEM.
When conducting large scale epidemiologic studies, it is a challenge to obtain quantitative exposure estimates, which do not rely on self-report where estimates may be influenced by symptoms and knowledge of disease status. In this study we developed a job exposure matrix (JEM) for use in population studies of the work-relatedness of hip and knee osteoarthritis. Based on all 2227 occupational titles in the Danish version of the International Standard Classification of Occupations (D-ISCO 88), we constructed 121 job groups comprising occupational titles with expected homogeneous exposure patterns in addition to a minimally exposed job group, which was not included in the JEM. The job groups were allocated the mean value of five experts' ratings of daily duration (hours/day) of standing/walking, kneeling/squatting, and whole-body vibration as well as total load lifted (kg/day), and frequency of lifting loads weighing ≥20 kg (times/day). Weighted kappa statistics were used to evaluate inter-rater agreement on rankings of the job groups for four of these exposures (whole-body vibration could not be evaluated due to few exposed job groups). Two external experts checked the face validity of the rankings of the mean values. A JEM was constructed and English ISCO codes were provided where possible. The experts' ratings showed fair to moderate agreement with respect to rankings of the job groups (mean weighted kappa values between 0.36 and 0.49). The external experts agreed on 586 of the 605 rankings. The Lower Body JEM based on experts' ratings was established. Experts agreed on rankings of the job groups, and rankings based on mean values were in accordance with the opinion of external experts.


Two cases of annular skin defects repaired with quadruple fan flaps (o-x flap).
Nowadays, patients have high expectations when it comes to minimization of postoperative scarring after dermatologic surgical procedures. When an annular lesion is being excised, normal skin should be excised, as well, to prevent a dog ears resulting in a long scar. We introduce a new flap reducing the scar length in annular defects. In order to avoid a long scar, we designed a quadruple fan flap (O-X flap) that is a variation of the rotation flap. It consists of four rotation flaps arranged like fans, with open and closed configuration. We suggest that the quadruple fan flap (O-X flap) is a viable option for treating annular skin defects, because it shortens the scar line, preserves normal tissue, and provides a cosmetically favorable outcome.


HIV-1 transmission and function of virus-infected monocytes/macrophages.
Monocyte/macrophages (MM) were isolated from HIV-1 seronegative individuals, infected with HIV-1 and examined for their ability to infect autologous T lymphocytes with and without concomitant presentation of exogenous Ag. HIV-1-infected MM presented tetanus toxin (TT) and streptokinase to T cells (as measured by [3H]thymidine incorporation) comparable to presentation by uninfected MM. In these studies, it was observed that HIV-1-infected MM without additional exogenous Ag stimulated autologous T lymphocytes, however, to a lesser degree than with TT and streptokinase. Virus production in T cells appeared to be relative to the degree of stimulation with the highest levels of stimulation and infection observed when T cells were exposed to HIV-1-infected TT-presenting MM. Studies were carried out to examine some of the restricting elements in MM-mediated infection of T lymphocytes with and without TT presentation. Antibodies to CD4, as well as soluble immunopurified gp120, blocked cell-mediated infection indicating that infection of T cells was through the CD4 molecule as has been demonstrated with cell-free virus. In addition, soluble gp120 inhibited Ag presentation by HIV-1-infected and uninfected MM. mAb to MHC class II Ag HLA-DR and -DP blocked T cell infection by HIV-1-infected MM with and without presentation of TT. No effect was observed with mAb to MHC class I Ag. These results indicate that virus transmission to T lymphocytes can be mediated by HIV-1-infected MM and that these cells maintain their function as APC. Activation of T cells appears to be important in the process of T cell infection in this system inasmuch as antibodies that block Ag presentation and thus a T cell proliferative signal inhibit infection.


Vimentin interacts with heterogeneous nuclear ribonucleoproteins and dengue nonstructural protein 1 and is important for viral replication and release.
Our previous study using expression proteomics demonstrated that many proteins, particularly five forms of heterogeneous nuclear ribonucleoproteins (hnRNPs), were up-regulated in human endothelial cells upon dengue virus infection. To address functional significance of these proteins in response to dengue virus infection, we performed a functional proteomics study to identify hnRNPs-interacting proteins in the infected EA.hy926 cells. Immunoprecipitation followed by 2-D PAGE and mass spectrometric analyses revealed 18 and 13 interacting partners of hnRNP C1/C2 and hnRNP K, respectively. Interestingly, vimentin was a common partner for both hnRNP C1/C2 and K. The interaction between vimentin and these hnRNPs was confirmed by reciprocal immunoprecipitation followed by Western blot analysis and also by double immunofluorescence staining. Disruption of vimentin intermediate filament by acrylamide not only dissociated these complexes but also reduced nuclear hnRNPs expression, whereas cytosolic hnRNPs expression was unchanged. We also demonstrated that vimentin was strongly associated with dengue non-structural protein 1 (NS1). Disruption of vimentin intermediate filament not only dissociated this complex but also reduced dengue NS1 expression, as well as viral replication and release. Our data report for the first time that vimentin interacts with hnRNPs and dengue NS1, and plays a crucial role in replication and release of dengue virus.


Prevention of retinoic acid-induced osteoporosis in mice by isoflavone-enriched soy protein.
A novel soy protein aggregate enriched with isoflavones (SPA-IS), a mixture of soy protein and isoflavones (Mix), isoflavones (IS), and the soy protein were obtained to investigate the preventive effects on osteoporosis induced by retinoic acid in Kunming mice. The serum osteocalcin levels in the Mix and SPA-IS groups decreased compared with the model group (mice showing retinoic acid-induced osteoporosis) (P < 0.05). The trabecular analysis results showed an increased preventive effect of the SPA-IS group over the Mix group, the IS group, and the soy protein group. The results of both left tibial maximum load and the 4th lumbar structural strength differ between the IS and the SPA-IS groups. The SPA-IS exhibited obvious oestrogenic activities on retinoic acid-induced osteoporosis in Kunming mice compared to Mix, IS, and soy protein. The results suggest that there is a potential use for SPA-IS in the treatment of osteoporosis induced by intake of retinoic acid. The improvement of bone indicators might be attributed to the formation of aggregate particles and the improvement of IS solubility.


Endogenous siRNA and miRNA targets identified by sequencing of the Arabidopsis degradome.
MicroRNAs (miRNAs) regulate the expression of target mRNAs in plants and animals [1]. Plant miRNA targets have been predicted on the basis of their extensive and often conserved complementarity to the miRNAs [2-4], as well as on miRNA overexpression experiments [5]; many of these target predictions have been confirmed by isolation of the products of miRNA-directed cleavage. Here, we present a transcriptome-wide experimental method, called "degradome sequencing," to directly detect cleaved miRNA targets without relying on predictions or overexpression. The 5' ends of polyadenylated, uncapped mRNAs from Arabidopsis were directly sampled, resulting in an empirical snapshot of the degradome. miRNA-mediated-cleavage products were easily discerned from an extensive background of degraded mRNAs, which collectively covered the majority of the annotated transcriptome. Many previously known Arabidopsis miRNA targets were confirmed, and several novel targets were also discovered. Quantification of cleavage fragments revealed that those derived from TAS transcripts, which are unusual in their production of abundant secondary small interfering RNAs (siRNAs), accumulated to very high levels. A subset of secondary siRNAs are also known to direct cleavage of targets in trans[6]; degradome sequencing revealed many cleaved targets of these trans-acting siRNAs (ta-siRNAs). This empirical method is broadly applicable to the discovery and quantification of cleaved targets of small RNAs without a priori predictions.


Effects of Movement-Based Mind-Body Interventions on Physical Fitness in Healthy Older Adults: A Meta-Analytical Review.
Declines in physical fitness can notably affect healthy aging of older adults. Multimodal exercise training regimen such as mind-body interventions (MBIs) has been reported to mitigate these aging-related declines of physical function. This meta-analytical review aimed at pooling the effects of MBIs on physical fitness indices compared to active control (AC) and inactive control (IC) conditions in healthy older adults. The literature search was conducted in 3 databases using search terms with Boolean conjunctions. Randomized controlled trials applying MBIs focusing on improving physical fitness parameters in healthy seniors over 65 years of age were screened for eligibility. Eligibility and study quality were assessed by 2 researchers using the PEDro scale. Standardized mean differences (SMD) adjusted for small sample sizes (Hedges' g) served as main outcomes for the comparisons of MBIs versus IC and MBIs versus AC. Thirty trials with 2,792 healthy community dwellers (mean age: 71.2 ± 4.7 years) were included. Large overall effects were found for strength (p < 0.001, SMD: 0.87 [90% CI: 0.43, 1.30], I2 = 94%), medium effects were observed for functional mobility (p = 0.009, SMD: 0.55 [90% CI: 0.20, 0.89], I2 = 83%), and small overall effects were found for static balance (p = 0.02, SMD: 0.35 [90% CI: 0.10, 0.60], I2 = 77%), endurance (p = 0.0001, SMD: 0.44 [90% CI: 0.25, 0.62], I2 = 0%), and flexibility (p = 0.003, SMD: 0.46 [90% CI: 0.21, 0.72], I2 = 54%) in favor of MBIs compared to IC. Small effects of strength slightly favoring AC (p = 0.08, SMD: -0.22 [90% CI: -0.43, -0.01], I2 = 52%) were found, whereas static balance moderately improved in favor of MBIs (p < 0.001, SMD: 0.46 [90% CI: 0.16, 0.76], I2 = 73%). MBIs induce small to moderate effects in relevant domains of physical fitness in healthy older adults. Strength should be better targeted with traditional resistance training routines, whereas balance seems to sufficiently benefit from MBIs. However, large variability between the studies was observed due to differences in methodology, intervention content, and outcomes that affect conclusive evidence.


The effects of exercise on cardiovascular biomarkers in patients with chronic heart failure.
Exercise training is recommended for chronic heart failure (HF) patients to improve functional status and reduce risk of adverse outcomes. Elevated plasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin T (cTnT) are associated with increased risk of adverse outcomes in this patient population. Whether exercise training leads to improvements in biomarkers and how such improvements relate to clinical outcomes are unclear. Amino-terminal pro-brain natriuretic peptide, hs-CRP, and cTnT levels were assessed at baseline and 3 months in a cohort of 928 subjects from the HF-ACTION study, a randomized clinical trial of exercise training versus usual care in chronic HF patients with reduced left ventricular ejection fraction (<35%). Linear and logistic regressions were used to assess 3-month biomarker levels as a function of baseline value, treatment assignment (exercise training vs usual care), and volume of exercise. Linear regression and Cox proportional hazard modeling were used to evaluate the relations between changes in biomarker levels and clinical outcomes of interest that included change in peak oxygen consumption (peak VO2), hospitalizations, and mortality. Exercise training was not associated with significant changes in levels of NT-proBNP (P = .10), hs-CRP (P = .80), or detectable cTnT levels (P = .83) at 3 months. Controlling for baseline biomarker levels or volume of exercise did not alter these findings. Decreases in plasma concentrations of NT-proBNP, but not hs-CRP or cTnT, were associated with increases in peak VO2 (P < .001) at 3 months and decreased risk of hospitalizations or mortality (P ≤ .04), even after adjustment for a comprehensive set of known predictors. Exercise training did not lead to meaningful changes in biomarkers of myocardial stress, inflammation, or necrosis in patients with chronic HF. Only improvements in NT-proBNP translated to reductions in peak VO2 and reduced risk of clinical events.


Rheumatoid arthritis and cancer risk[BULLET OPERATOR]results from the Greek European prospective investigation into cancer and nutrition cohort.
To investigate the relative risk of cancer development in rheumatoid arthritis (RA) patients in Greece after taking into consideration treatment modalities. The present analysis used data on the medical history of 26 331 participants in the Greek arm of the European Prospective Investigation into Cancer and Nutrition that were collected at enrollment and thereafter during active follow-up. A history of RA and of drug treatment for the disease, as reported at baseline examination, was linked to cases of cancer reported during follow-up. A total of 91 (9.9%) patients with RA developed a cancer compared with 1542 (6.1%) patients without RA. The overall hazard ratios of all cancers increased 25% [95% confidence interval (CI): 1-54] among participants with prevalent RA, and almost all the site-specific incident cancer sites considered had rate ratios above unity. In terms of the contribution of RA medication, the hazard ratios of patients treated with salicylates was close to unity (1.07, 95% CI: 0.69-1.65), whereas those who were not treated with salicylates had a 31% (95% CI: 3-67) increased risk for cancer incidence compared with those without RA at baseline. RA patients have excess cancer risk because of either underlying complex disease pathways or treatment agents targeting immune function. Administration of salicylates appears to reduce the risk of developing malignancies.


Favorable impact of low-dose fludarabine plus epirubicin and cyclophosphamide regimen (FLEC) as treatment for low-grade non-Hodgkin's lymphomas.
In recent years, conventional dose of fludarabine (FLU) alone or in combination with other drugs has been reported to be effective in the treatment of low-grade non-Hodgkin's lymphomas (LG-NHL). In particular, FLU and cyclophosphamide (CY) or FLU and mitoxantrone or idarubicin combined regimens have shown considerable therapeutic activity both as first line and salvage therapies, producing overall response rates ranging from 40-50% in previously treated patients and up to 70-90% in untreated ones. However severe neutropenia and infective complications have been reported in a significant number of patients. Based on these premises we evaluated the efficacy and toxicity of a new regimen combining low-doses of FLU with epirubicin (EPI) and CY (FLEC) in a group of advanced treatment-requiring LG-NHL patients. The aim of this study was to evaluate a strategy aimed at lowering therapy-related toxic effects without affecting the reported good response rate. Thirty patients with de novo, relapsed or refractory LG-NHL entered the study. FLEC regimen was as follows: EPI 60 mg/m(2) i.v. on day one, plus FLU 15 mg/m(2)/day i.v. (max 25 mg) and CY 250 mg/m(2)/day i.v. for four days. All 30 patients were evaluable for response, 13 (43%) fulfilled the criteria for CR and 11 (36%) for PR with an overall response rate of 79%. None of the 13 patients who achieved CR had relapsed after a follow-up of 2 to 23 months (median duration 13 months). With regard to age, 13/14 older patients (>/= 70 years) responded to the treatment and 9 of them maintained their response after a median of 13 months (range 2-22); six of the 14 (43%) obtained a CR. Therapy-related toxicity was mild regardless of age, neutropenia (43%) and fever of undetermined origin (26%) being the major side effects. Remarkably, a documented infection was recorded only in 2/30 (6%) patients. A low-dose FLU-based FLEC regimen appeared to be effective for advanced treatment-requiring LG-NHL, reproducing a similar overall response rate (79%) reported to have been achieved with other FLU based combination therapies. Toxic side effects were negligible and in particular documented infections were remarkably uncommon even in the group of elderly patients.


Clonal B-cell populations in patients with idiopathic thrombocytopenic purpura.
Idiopathic thrombocytopenic purpura (ITP) may be associated with other autoimmune diseases and the development of lymphoproliferative malignancies. In Sjögren's disease, Graves' disease, and essential mixed cryoglobulinemia, which are also associated with the development of B-cell neoplasia, clonal B-cell expansions have been detected. Eleven patients with ITP were investigated for the presence of a clonal excess (CE) using kappa-lambda flow cytometry and DNA analysis for rearrangement of immunoglobulin heavy and light chain genes in blood and/or spleen lymphocytes. In 10 of 11 patients, clonal B-cell populations were found by one or both tests. In three of these patients, oligoclonal B-cell populations were suggested by the combined findings. In all four patients with a small paraproteinemia, the isotype was confirmed by either flow cytometry or DNA rearrangement analysis. Our data suggest that the oligoclonal expansions are not restricted to CD5+ B cells, as in the majority of patients this subset was below the detection level of flow cytometry or DNA rearrangement analysis. None of the patients developed clinical manifestations of malignant lymphoma during a follow-up period of 10 to 44 months after sampling. We conclude that clonal excess populations of B cells are not a unique feature of malignant lymphoma, but may occur in autoimmune diseases, suggesting a benign (oligo)clonal B-cell proliferation.


Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models.
The development of biomimetic chemistry based on the NAD(P)H with hydrogen gas as terminal reductant is a long-standing challenge. Through rational design of the chiral and regenerable NAD(P)H analogues based on planar-chiral ferrocene, a biomimetic asymmetric reduction has been realized using bench-stable Lewis acids as transfer catalysts. A broad set of alkenes and imines could be reduced with up to 98 % yield and 98 % ee, likely enabled by enzyme-like cooperative bifunctional activation. This reaction represents the first general biomimetic asymmetric reduction (BMAR) process enabled by chiral and regenerable NAD(P)H analogues. This concept demonstrates catalytic utility of a chiral coenzyme NAD(P)H in asymmetric catalysis.


Regional non-nodal metastases of cutaneous melanoma.
The authors studied the prognosis of patients with so called local recurrences, satellites and in-transit metastases from cutaneous melanoma on the basis of 291 patients. These are the 19.3% of the 1503 patients with stage I and II melanoma originally submitted to surgical treatment at the National Cancer Institute of Milano (Italy). The majority of patients were males (M/F = 0.7): 102 had local recurrence, 99 in-transit metastases, 24 satellites and 66 both local and in-transit metastases. Regional non-nodal metastases were not related with the site of origin, and inadequate treatment of primary. These metastases were more frequently observed in patients who were submitted to regional node dissection no matter whether in discontinuity or in continuity with primary tumor. The frequency of regional non-nodal metastases was found to increase with increasing thickness of primary melanoma or, in stage II patients, with the number of involved nodes. Local and in-transit metastases were related with prognostic criteria in the same way. The overall survival was very close between in-transit and local metastases. Similar survival rates were observed comparing regional non-nodes and disseminated cutaneous and subcutaneous metastases. The authors conclude that the distinction between local recurrences, satellites and in-transit metastases is artificial and that these metastatic events are not prognostically dissimilar from metastases in distant skin areas.


A new flexible plug and play scheme for modeling, simulating, and predicting gastric emptying.
In-silico models that attempt to capture and describe the physiological behavior of biological organisms, including humans, are intrinsically complex and time consuming to build and simulate in a computing environment. The level of detail of description incorporated in the model depends on the knowledge of the system's behavior at that level. This knowledge is gathered from the literature and/or improved by knowledge obtained from new experiments. Thus model development is an iterative developmental procedure. The objective of this paper is to describe a new plug and play scheme that offers increased flexibility and ease-of-use for modeling and simulating physiological behavior of biological organisms. This scheme requires the modeler (user) first to supply the structure of the interacting components and experimental data in a tabular format. The behavior of the components described in a mathematical form, also provided by the modeler, is externally linked during simulation. The advantage of the plug and play scheme for modeling is that it requires less programming effort and can be quickly adapted to newer modeling requirements while also paving the way for dynamic model building. As an illustration, the paper models the dynamics of gastric emptying behavior experienced by humans. The flexibility to adapt the model to predict the gastric emptying behavior under varying types of nutrient infusion in the intestine (ileum) is demonstrated. The predictions were verified with a human intervention study. The error in predicting the half emptying time was found to be less than 6%. A new plug-and-play scheme for biological systems modeling was developed that allows changes to the modeled structure and behavior with reduced programming effort, by abstracting the biological system into a network of smaller sub-systems with independent behavior. In the new scheme, the modeling and simulation becomes an automatic machine readable and executable task.


Nutrient effects on the genetic and functional diversity of aquatic bacterial communities.
Studies on the effects of biodiversity on ecosystem functioning have generally revealed a positive asymptotic relationship between biodiversity and single functions, suggesting species redundancy with respect to these functions. However, most research was performed on specific processes and did not consider ecosystem 'multifunctionality'. There is also little information on the relationship between genetic and functional diversity. To analyze this relationship, we performed a microcosm experiment on a complex lake assemblage of decomposers, in the presence of the green alga Scenedesmus obliquus, which acted as carbon source for decomposers. By manipulating nutrient enrichment and the N : P input ratio, we observed that the structures of particle-associated and free bacterial assemblages were highly predictable in response to stoichiometric constraints. For a given treatment, the taxonomic compositions of free and particle-associated bacterial communities appeared close to each other only when phosphorus was not depleted. A coinertia analysis revealed a clear coupling between the genetic diversity of the microbial community, assessed using PCR-denatured gradient gel electrophoresis, and its potential functional diversity, studied with Biolog Ecoplates. This suggests that an ecologically relevant fraction of bacterial communities is characterized by lower level of redundancy than frequently thought, highlighting the necessity of exploring further the role of biodiversity in multifunctionality within ecosystems.


[The positional isomers of palmitic and oleic triglycerides, lipolysis, conformation of apoB-100, formation of apoE/B-100 ligand and absorption of lipoproteins of very low density by insulin-dependent cells under action of statins.]
The study was carried out to trace back quantitative alterations of positional isomers, oleic and palmitic triglycerides and individual fatty acids in blood serum. After two weeks of taking of Simvastatin (40, 80 mg), analysis of blood serum established decreasing of content of Рhosphatidylcholine and more reliable decreasing of amount of non-etherized alcohol cholesterol. No alterations of content of particular fatty acids were detected. In apoB-100, Рhosphatidylcholine and non-etherized alcohol cholesterol form polar mono-layer; it covers mass of oleic and palmitic triglycerides that was bound by apoB-100 in oleic and palmitic lipoproteins of very low density disturbing bio-availability of substrate (oleic and palmitic triglycerides) for post-heparin lipase. This very pool of non-etherized alcohol cholesterol is inhibited by statins activating lipolysis in oleic and palmitic lipoproteins of very low density. In blood was detected amount of palmitic positional isomersin oleic and palmitic triglycerides (palmitoyl-palmitoyl-palmitate and palmitol-palmitoyl-oleate) and oleic positional isomers (oleyl-oleyl-palmitate and oleyl-oleyl-oleate). The significant difference was marked in content of positional isomers both of oleyl-oleyl-oleate and oleyl-oleyl-palmitate; their content is less in blood of patients of experimental group as compared with healthy people. In case of treatment with Simvastatin (40 mg) the level of palmitic positional isomers and palmitol-palmitoyloleate is decreased. In case of treatment with Simvastatin (80 mg) significant decreasing of positional isomers-palmitolpalmitoyl-oleate and oleyl-oleyl-palmitate as compared with data before treatment. The detection of content of positional isomers triglycerides permits: a) to characterize disorders of metabolism of palmitic fatty acid, oleic fatty acid, oleic and palmitic triglycerides and oleic and palmitic lipoproteins of very low density of the same name; b) to form individual diet therapy; c) to obtain objective information concerning compliance of prescribed recommendations b y patient. The basis of primary prevention of atherosclerosis and atheromatosis is in decreasing up to physiological level in food the content of longchained saturated fatty acids mainly palmitic acid.


Early hominins evolved within non-analog ecosystems.
Present-day African ecosystems serve as referential models for conceptualizing the environmental context of early hominin evolution, but the degree to which modern ecosystems are representative of those in the past is unclear. A growing body of evidence from eastern Africa's rich and well-dated late Cenozoic fossil record documents communities of large-bodied mammalian herbivores with ecological structures differing dramatically from those of the present day, implying that modern communities may not be suitable analogs for the ancient ecosystems of hominin evolution. To determine when and why the ecological structure of eastern Africa's herbivore faunas came to resemble those of the present, here we analyze functional trait changes in a comprehensive dataset of 305 modern and fossil herbivore communities spanning the last ∼7 Myr. We show that nearly all communities prior to ∼700 ka were functionally non-analog, largely due to a greater richness of non-ruminants and megaherbivores (species >1,000 kg). The emergence of functionally modern communities precedes that of taxonomically modern communities by 100,000s of years, and can be attributed to the combined influence of Plio-Pleistocene C4 grassland expansion and pulses of aridity after ∼1 Ma. Given the disproportionate ecological impacts of large-bodied herbivores on factors such as vegetation structure, hydrology, and fire regimes, it follows that the vast majority of early hominin evolution transpired in the context of ecosystems that functioned unlike any today. Identifying how past ecosystems differed compositionally and functionally from those today is key to conceptualizing ancient African environments and testing ecological hypotheses of hominin evolution.


Prognostic factors and survival according to tumor subtype in newly diagnosed breast cancer with liver metastases: A competing risk analysis.
Population-based study for predicting the prognosis for breast cancer liver metastasis (BCLM) is lacking at present. Therefore, the present study aimed to evaluate newly diagnosed BCLM patients of different tumor subtypes and assess potential prognostic factors for predicting the survival for BCLM patients. Specifically, data were collected from the Surveillance, Epidemiology and End Results program from 2010 to 2014, and were assessed, including the data of patients with BCLM. Differences in the overall survival (OS) among patients was compared via Kaplan-Meier analysis. Other prognostic factors of OS were determined using the Cox proportional hazard model. In addition, the breast cancer-specific mortality was assessed using the Fine and Gray's competing risk model. A nomogram was also constructed on the basis of the Cox model for predicting the prognosis of BCLM cases. A total of 2,098 cases that had a median OS of 20.0 months were included. The distribution of tumor subtypes was as follows: 42.2% with human epidermal growth factor receptor 2 (Her2; -)/hormone receptor (HR; +), 12.8% with Her2(+)/HR(-), 19.1% with Her2(+)/HR(+) and 13.5% with triple negative breast cancer (TNBC). Kaplan-Meier analysis revealed that older age (>64 years), unmarried status, larger tumor, higher grade, no surgery, metastases at other sites, and TNBC subtype were associated with shorter OS. Additionally, multivariate analysis revealed that older age (>64 years), unmarried status, no surgery, bone metastasis, brain metastasis and TNBC subtype were significantly associated with worse prognosis. Thus, age at diagnosis, marital status, surgery, bone metastasis, brain metastasis and tumor subtype were confirmed as independent prognosis factors from a competing risk model. We also constructed a nomogram, which had the concordance index of internal validation of 0.685 (0.650-0.720). This paper had carried out the population-based prognosis prediction for BCLM cases. The survival of BCLM differed depending on the tumor subtype. More independent prognosis factors were age at the time of diagnosis, surgery, marital status, bone metastasis, as well as brain metastasis, in addition to tumor subtype. Notably, the as-constructed nomogram might serve as an efficient approach to predict the prognosis for individual patients.


Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma.
Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin.


Multicriteria Decision Analysis Applied to the Clinical Use of Pharmacotherapy for Overactive Bladder Symptom Complex.
The nonspecific storage symptom complex overactive bladder (OAB) is an important clinical condition in functional urology. Until recently, pharmacological therapy comprised antimuscarinic drugs, but more recently beta 3 agonists have added to the available agents. Traditional reporting of efficacy and safety of these agents relies upon regulatory placebo-controlled studies. There remains no head-to-head comparison of existing agents in the contemporary literature. Contemporary conclusions on comparative efficacy and safety drawn from the use of these agents are based on systematic reviews of the literature and associated meta-analyses. In this study, we used the analytical model of multicriteria decision analysis (MCDA) to compare contemporary pharmacotherapy for OAB. Efficacy and safety data from published, randomised, placebo-controlled trials of antimuscarinic antagonists, the beta 3 agonist, and the combination of an antimuscarinic and beta 3 agonist were used to populate the MCDA model. Experts assessed weights of the relative importance of favourable and unfavourable effects, which provided a common measure of benefits and safety that were combined in the MCDA model to give an overall ranking of the OAB drugs. When benefits are judged as more important than safety, fesoterodine 4 or 8mg used in a flexible dosing pattern provides the most favourable therapeutic option, over a wide sensitivity analysis relating to benefits and harms. In our analysis using an MCDA model, in both the flexible dosing pattern of fesoterodine and the solifenacin combination with mirabegron, the benefit-safety balance is better in terms of benefits and/or safety than any of the other available OAB drugs. Caution in interpretation of the data has to be expressed as the fesoterodine data are based on a flexible dosing regimen, which adds an additional dimension of personalising therapy. Overactive bladder (OAB) is a common condition with a significant impact on the quality of life. Possible symptoms include the following: (1) urgency-a compelling desire to urinate, which is difficult to defer; (2) urgency urinary incontinence-urgency leading to incontinence episodes; (3) frequency-increased frequency of wanting to pass urine; and (4) nocturia-increase in instances of getting up at night to urinate. To date, the mainstay of therapy for OAB has been antimuscarinic drugs and, more recently, the beta 3 agonist mirabegron. Ten international experts in urology, obstetrics, gynaecology, healthy ageing, and data analysis compared the benefit-risk balance of 14 OAB drugs licensed in Europe. The experts considered the importance of a favourable effect on the above four symptoms and also potential for side effects, but only three of these side effects, constipation, dry mouth, and dizziness, showed clinically relevant differences among the six drugs they considered. The observations recorded here suggest interesting differences between drugs across a wide range of possible trade-offs between benefit and safety. The different recruitment criteria used for each study may influence the results seen, so they need to be treated with caution. Comparison of flexibly dosed fesoterodine studies with fixed-dose fesoterodine studies introduces an additional potential bias; definitive conclusions can be drawn only if enough comparable placebo-controlled flexible dosing studies with other drugs were available.


Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling.
The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.


Inflammation and Thrombophilia in Pregnancy Complications: Implications for Risk Assessment and Clinical Management.
In Italy, each year 500,000 couples refer to specialized centers due to reproductive problems. Among them, recurrent pregnancy loss (RPL) represents a problem of great importance, given that it affects up to 5% of women of childbearing age. Infertility, on the other hand, is a condition that currently covers 10-20% of couples of reproductive age, being idiopathic in 20% of cases. Accumulating evidence support the concept that changes of blood coagulation, generically defined as the presence of a thrombophilic state (congenital or acquired), are the basis of 40-70% of cases of multiple abortions or infertility. Several evidences support the hypothesis that endothelial dysfunction, a hallmark of a condition of low-grade inflammation, is one of the earliest manifestations of thrombotic phenomena. To date, it's believed that, while the antiinflammatory Th2 cytokines (i.e. interleukin-10) can exert a protective role in pregnancy, the pro-inflammatory Th1 ones (i.e. interferon-γ, tumor necrosis factor-α,) have deleterious effects on pregnancy outcome, including fertilization and implantation failure. Moreover, development of many pregnancy complications, first and foremost venous thromboembolism (VTE), recognizes similar mechanism(s). As VTE is the main preventable cause of mortality during pregnancy, thromboprophylaxis is mandatory according to individual VTE risk, influenced by the presence of thrombophilic conditions. In this review, we will analyze the relationship between thrombophilia and pregnancy complications, with particular focus on the role of inflammation. Subsequently, we will consider some issues related to the thromboembolic risk in pregnancy. Finally, the role of thromboprophylaxis in pregnancy will be discussed.


Failed development and vulnerability to climate change in central Asia: implications for food security and health.
This article presents results of research undertaken to identify factors that affect the vulnerability of rural Mongolian herders to climate change. Findings suggest that models of market development instituted since 1990 have failed to recognize and support key elements of the pastoralist adaptive strategy. A retreating state presence has led to the collapse of regulatory regimes needed to safeguard critical common resources. This in turn has produced considerable social differentiation in the countryside, a breakdown in cooperative institutions, and conflicts over water and pasture. In a context of climate change, these changes seriously threaten the sustainability of the rural economy, leading to livelihood insecurity, growing rural poverty, and increasing rates of migration to shantytowns surrounding the capital city of Ulaanbaatar. The newly vulnerable poor are at higher risk for poor health and malnutrition.


Effect of long-term application of Crataegus oxyacantha on ischemia and reperfusion induced arrhythmias in rats.
The effect of long-term application of Crataegus oxyacantha on ischemia and reperfusion induced arrhythmias was investigated in Wistar rats on the heart in situ and on Langendorff preparations. Seventeen rats were fed for 8 weeks with 0.5 g/kg b.w. Crataegus extract per day, standardised to 2.2% flavonoids. Twenty age-matched untreated rats served as controls. In the hearts in situ as well as in the Langendorff preparations the left anterior descending coronary artery (LAD) was ligated for 20 min and subsequently reperfused for 30 min. ECG was continuously recorded and the time spent between start of ischemia and onset of arrhythmias was measured. In addition, during ischemia and reperfusion the number of ventricular premature beats and bigemini and the duration of salvos and ventricular flutter and fibrillation were determined. The ischemic area was evaluated in all experiments and coronary flow was measured in Langendorff preparations. In the present experiments, no cardioprotective effects of Crataegus oxyacantha could be detected, neither in the heart in situ nor in the Langendorff preparations. Although the ischemic areas were identical, arrhythmias occurred even earlier in the Crataegus collectives than in the controls. Also the number and duration of ischemia and reperfusion induced arrhythmias tended to occur longer and more frequently in the Crataegus collectives, whilst coronary flow remained unchanged. The phenomenon that Crataegus rather aggravates than prevents arrhythmias may be reduced to a Crataegus induced increase in intracellular Ca(2+)-concentration proven true for the positive inotropic effects of Crataegus.


Physical activity benefits and needs in adults with intellectual disabilities: systematic review of the literature.
Regular physical activity is vital for adult individuals with intellectual disabilities. The purpose of this review was to assess critically the evidence on effectiveness of physical activity interventions for adults with intellectual disability. An electronic database search was conducted. Research was then assessed for methodological rigor, and strength of the evidence was determined. Eleven clinical studies met inclusion criteria. Interventions studied included a variety of physical activity modes. Critical review revealed moderate to strong evidence that physical activity positively affected balance, muscle strength, and quality of life in individuals with intellectual disability. The authors also found that the research in this area needs to be translated into practice, specifically the development of physical activity programs that are adaptable to the needs of individuals with intellectual disability.


Imaging in myopia: potential biomarkers, current challenges and future developments.
Myopia is rapidly increasing in Asia and around the world, while it is recognised that complications from high myopia may cause significant visual impairment. Thus, imaging the myopic eye is important for the diagnosis of sight-threatening complications, monitoring of disease progression and evaluation of treatments. For example, recent advances in high-resolution imaging using optical coherence tomography may delineate early myopic macula pathology, optical coherence tomography angiography may aid early choroidal neovascularisation detection, while multimodal imaging is important for monitoring treatment response. However, imaging the eye with high myopia accurately has its challenges and limitations, which are important for clinicians to understand in order to choose the best imaging modality and interpret the images accurately. In this review, we present the current imaging modalities available from the anterior to posterior segment of the myopic eye, including the optic nerve. We summarise the clinical indications, image interpretation and future developments that may overcome current technological limitations. We also discuss potential biomarkers for myopic progression or development of complications, including basement membrane defects, and choroidal atrophy or choroidal thickness measurements. Finally, we present future developments in the field of myopia imaging, such as photoacoustic imaging and corneal or scleral biomechanics, which may lead to innovative treatment modalities for myopia.


Anti-infectives-induced adverse drug reactions in hospitalized patients.
To assess the rate and seriousness of adverse drug reactions (ADRs) attributable to anti-infective agents in hospitalized patients; to estimate the likelihood of experiencing anti-infectives-induced ADRs at different length of drug usage in the hospital; to compare different classes of anti-infectives in inducing ADRs; to determine the impact of age and sex on anti-infectives-induced ADRs. Prospective cohort study. Patients admitted to the infectious diseases department at a university teaching hospital, on Sunday to Wednesday, over a 9 months period, who received at least one anti-infective agent were eligible to enter the study. Any suspected noxious and untoward medical events, including laboratory tests abnormalities following anti-infective therapy. All patients admitted have received at least one anti-infective drug. Anti-infective agents induced ADRs were detected by interviewing patients and daily chart review. The seriousness, causality, and type of reactions were classified based on World Health Organization (WHO) definitions. Chi-square analysis was performed to assess the influence of sex and age on occurring ADRs. Both Kaplan-Meier and life table method were used to estimate the time to occur the ADR in anti-infective users. To compare the estimated risk of ADRs induced by different classes of anti-infectives, odds ratios were estimated. In all classes of anti-infectives, the odds ratio of each class was estimated with regard to anti-tuberculosis agents, which had the highest prevalence of ADRs. During the study period, 460 patients were entered the study. During the same period, 38 ADRs were recognized of which 20 (42%) were serious. The most recognized ADRs were suspected to be induced by anti-tuberculosis agents (29.8%). However in comparing with anti-tuberculosis agents, anti-fungal agents were associated with the highest ADR rate (odds ratio [OR], 4.21; 95% confidence interval [CI], 1.41-1.256) whereas cephalosporines were associated with the lowest rate, (OR, 0.1; 95%CI, 0.04-0.26). The survival analysis shows that the likelihood of experiencing an ADR was increased at first 14 days of drug therapy. Also Chi-square analysis shows that greater risk of anti-infectives-induced ADRs was observed in women. The rate of ADRs induced by anti-infective agents in this study was 8.2%. This is higher than a standard (5%) which has been reported in other studies. This study also shows that some of the classes of anti-infective agents like anti-fungals need more attention.


Multiple meiotic drive systems in the Drosophila melanogaster male.
The behaviour of two "meiotic drive" systems, Segregation-Distorter (SD) and the sex chromosome sc(4)sc(8) has been examined in the same meiocyte. It has been found that the two systems interact in a specific way. When the distorting effects of SD and sc(4)sc(8) are against each other, there is no detectable interaction. Each system is apparently oblivious to the presence of the other, gametes being produced according to independence expectations. However when the affected chromosomes are at the same meiotic pole an interaction occurs; the survival probability of the gamete containing both distorted chromosomal products is increased, rather than being decreased by the combined action of two systems.


Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis.
Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries. Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to identify those risk factors with strong levels of evidence which could be easily assessed by physicians or ophthalmologists to implement preventive interventions or address current behaviours. A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point estimates of each risk factor and associated 95% confidence intervals (CI) were calculated. Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease, and serum total and HDL cholesterol and triglyceride levels. Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons at risk of AMD.


Contextual factors influencing U.S. college students' decisions to drink responsibly.
This mixed-methods study qualitatively (n = 13-convenience) explored contextual factors influencing decisions to drink responsibly, and quantitatively (n = 729-random) assessed the prevalence of these factors and whether they varied as a function of sex and binge-drinking status. Data were collected in 2007 among Texas college students. The constant comparison model was used to analyze the qualitative data, while one-way ANOVAs and logistic regression were employed to assess the quantitative data. Effect sizes are reported for all significant ANOVA interactions. Psychometric properties are supplied for all quantitative scales. Implication and limitations are noted, and future research directions discussed.


Pretransplant Hepatitis C Virus Treatment Decreases Access to High-quality Livers.
Despite the revolutionary role of direct-acting antivirals for hepatitis C virus (HCV), the treatment timing for liver transplant candidates remains controversial. We hypothesize that deferring treatment until after liver transplantation improves access to a larger and higher-quality donor pool without a detrimental impact on post-liver transplantation outcomes. This single-center study includes recipients that underwent deceased-donor liver transplant with HCV as the primary indication January 1, 2014, to December 31, 2018. For recipients that were untreated (n = 87) versus treated (n = 42) pre-LT, we compared post-LT mortality using Cox regression with inverse probability of treatment-weighted data. Among pre-LT untreated recipients, 95% were willing to accept an HCV+ donor, and 44.8% received a positive HCV antibody and nucleic acid amplification test (NAT) liver. Among pre-LT treated recipients, 5% were willing to accept an HCV+ donor, and 100% received a negative HCV antibody and NAT liver. The median calculated model for end-stage liver disease at transplant was similar between pre-LT untreated (13, IQR = 9-22) and treated recipients (11, IQR = 8-14) (P = 0.1). Pre-LT treated recipients received livers from older (47 y old versus 37, P < 0.01) and higher body mass index donors (30.2 versus 26.6; P = 0.04) and spent longer on the waiting list (319 d 180, P < 0.001). Unadjusted post-LT mortality at 1 year was higher in the pre-LT treated recipients (14.6% versus 3.5%, P = 0.02). After adjusting for recipient factors, pre-LT treated recipients trended toward a 3.9 times higher risk of mortality compared with the pre-LT untreated recipients (adjusted hazard ratio = 0.973.8615.4) (P = 0.06). Deferring HCV treatment improves access to higher-quality donors and may improve post-LT survival.


Using Touch Screen Audio-CASI to Obtain Data on Sensitive Topics.
This paper describes a new interview data collection system that uses a laptop personal computer equipped with a touch-sensitive video monitor. The touch-screen-based audio computer-assisted self-interviewing system, or touch screen audio-CASI, enhances the ease of use of conventional audio CASI systems while simultaneously providing the privacy of self-administered questionnaires. We describe touch screen audio-CASI design features and operational characteristics. In addition, we present data from a recent clinic-based experiment indicating that the touch audio-CASI system is stable, robust, and suitable for administering relatively long and complex questionnaires on sensitive topics, including drug use and sexual behaviors associated with HIV and other sexually transmitted diseases.


Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.
The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged <90 days with LOS. NeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.


Evaluation of an enzyme immunoassay for serum gentamicin.
The EMIT (Enzyme Multiplied Immunoassay Technique) for serum gentamicin determination was evaluated by a standard procedure. The precision, accuracy, and specificity were assessed and proved satisfactory. Comparison with a bioassay was done, and results for patient samples showed a correlation coefficient of 0.95 between the two methods. Advantages of the enzyme immunoassay system were the provision of results within 15 min of receipt of blood in the laboratory, a requirement of minimal technical expertise, and an applicability to both large and small workloads. The EMIT proved during evaluation to be a practical alternative to current bioassays for the determination of serum gentamicin concentrations.


Assessment of the nutrition environment in rural counties in the Deep South.
The nutrition environment, including food store type, may influence dietary choices, which in turn can affect risk of obesity and related chronic diseases such as CHD, diabetes and cancer. The objective of the present study was to elucidate the extent to which healthy foods are available and affordable in various rural food outlets. A subset of the nutrition environment was assessed using the Nutrition Environment Measures Survey in Stores (NEMS-S). The NEMS-S instrument assessed the availability and price of healthy foods (e.g. low-fat/non-fat milk, lean meats and reduced-fat dinner entrées) compared with less healthy counterparts (e.g. whole milk, non-lean meats and regular dinner entrées). The NEMS-S also assessed the quality of fresh fruits and vegetables. Availability, prices and quality of healthy foods were compared between grocery stores (n 24) and convenience stores (n 67) in nine rural counties in Alabama. Mean availability subscale score (possible range 0 to 30; higher score indicates a greater number of healthier foods were available) for grocery stores was 22·6 (sd 8·1), compared with 6·6 (sd 5·2) in convenience stores (P < 0·0001); and mean price subscale score (possible range -9 to 18; higher score indicates that healthier options were less expensive than the less healthy options) for grocery stores was 2·4 (sd 2·7), compared with 0·7 (sd 1·2) in convenience stores (P = 0·0080). Mean total NEMS-S score (possible range -9 to 54) in grocery stores was 29·8 (sd 10·9) compared with 7·3 (sd 7·1) in convenience stores (P < 0·0001). Both grocery and convenience stores could be strategic points of intervention to improve the nutrition environment in the counties that were surveyed.