Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation.

Cytomegalovirus (CMV) continues to be one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes. Management of CMV varies considerably among transplant centers but has been become more standardized by publication of consensus guidelines by the Infectious Diseases Section of The Transplantation Society. An international panel of experts was reconvened in October 2012 to revise and expand evidence and expert opinion-based consensus guidelines on CMV management, including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues. The following report summarizes the recommendations.

European guidelines for sclerotherapy in chronic venous disorders.

AIM: Sclerotherapy is the targeted chemical ablation of varicose veins by intravenous injection of a liquid or foamed sclerosing drug. The treated veins may be intradermal, subcutaneous, and/or transfascial as well as superficial and deep in venous malformations. The aim of this guideline is to give evidence-based recommendations for liquid and foam sclerotherapy. METHODS: This guideline was drafted on behalf of 23 European Phlebological Societies during a Guideline Conference on 7-10 May 2012 in Mainz. The conference was organized by the German Society of Phlebology. These guidelines review the present state of knowledge as reflected in published medical literature. The regulatory situation of sclerosant drugs differs from country to country but this has not been considered in this document. The recommendations of this guideline are graded according to the American College of Chest Physicians Task Force recommendations on Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines. RESULTS: This guideline focuses on the two sclerosing drugs which are licensed in the majority of the European countries, polidocanol and sodium tetradecyl sulphate. Other sclerosants are not discussed in detail. The guideline gives recommendations concerning indications, contraindications, side-effects, concentrations, volumes, technique and efficacy of liquid and foam sclerotherapy of varicose veins and venous malformations.

Americans with Disabilities Act Accessibility Guidelines, 2001

Disabilities accessiblity guidelines for Americans produced by Department of Human Rights

Feasibility and clinical outcomes when using practice guidelines for evaluation of fever in returning travelers and migrants : a validation study.

BACKGROUND: Practice guidelines for examining febrile patients presenting upon returning from the tropics were developed to assist primary care physicians in decision making. Because of the low level of evidence available in this field, there was a need to validate them and assess their feasibility in the context they have been designed for. OBJECTIVES: The objectives of the study were to (1) evaluate physicians' adherence to recommendations; (2) investigate reasons for non-adherence; and (3) ensure good clinical outcome of patients, the ultimate goal being to improve the quality of the guidelines, in particular to tailor them for the needs of the target audience and population. METHODS: Physicians consulting the guidelines on the Internet (www.fevertravel.ch) were invited to participate in the study. Navigation through the decision chart was automatically recorded, including diagnostic tests performed, initial and final diagnoses, and clinical outcomes. The reasons for non-adherence were investigated and qualitative feedback was collected. RESULTS: A total of 539 physician/patient pairs were included in this study. Full adherence to guidelines was observed in 29% of the cases. Figure-specific adherence rate was 54.8%. The main reasons for non-adherence were as follows: no repetition of malaria tests (111/352) and no presumptive antibiotic treatment for febrile diarrhea (64/153) or abdominal pain without leukocytosis (46/101). Overall, 20% of diversions from guidelines were considered reasonable because there was an alternative presumptive diagnosis or the symptoms were mild, which means that the corrected adherence rate per case was 40.6% and corrected adherence per figure was 61.7%. No death was recorded and all complications could be attributed to the underlying illness rather than to adherence to guidelines. CONCLUSIONS: These guidelines proved to be feasible, useful, and leading to good clinical outcomes. Almost one third of physicians strictly adhered to the guidelines. Other physicians used the guidelines not to forget specific diagnoses but finally diverged from the proposed attitudes. These diversions should be scrutinized for further refinement of the guidelines to better fit to physician and patient needs.

EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy.

Food allergy can result in considerable morbidity, impact negatively on quality of life, and prove costly in terms of medical care. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group, building on previous EAACI position papers on adverse reaction to foods and three recent systematic reviews on the epidemiology, diagnosis, and management of food allergy, and provide evidence-based recommendations for the diagnosis and management of food allergy. While the primary audience is allergists, this document is relevant for all other healthcare professionals, including primary care physicians, and pediatric and adult specialists, dieticians, pharmacists and paramedics. Our current understanding of the manifestations of food allergy, the role of diagnostic tests, and the effective management of patients of all ages with food allergy is presented. The acute management of non-life-threatening reactions is covered in these guidelines, but for guidance on the emergency management of anaphylaxis, readers are referred to the related EAACI Anaphylaxis Guidelines.

Childhood obesity and walking: guidelines and challenges.

The development and maintenance of excess body mass in many children is partly attributable to levels of physical activity that are lower than the recommended 60 minutes/day. Walking is a recommended form of physical activity for obese children, due to its convenience and perceived ease of adoption. Unfortunately, studies that have used objective physical activity assessment continue to report low step counts and levels of physical activity in obese children. This may be due to physiological and/or biomechanical factors that make walking more difficult for obese children. The purpose of this review is to highlight the current recommended and measured levels of physical activity for children and to discuss the physiological and biomechanical challenges of walking for obese children that may help explain why these children are not meeting physical activity goals.

Blood pressure target attainment in the background of guidelines: the very elderly in Swiss primary care.

Background There are only a few trials for the very elderly population (>79 years). No consensus, which blood pressure (BP) goals and substances should be applied, has been found yet. This survey was undertaken to investigate how octogenarians are treated and attain BP targets in the Swiss primary care. Methods Data from 4594 hypertensive patients were collected within 7 days. Eight hundred and seventy-seven patients met the requirement to be >79 years. We assessed substances/combinations and investigated pulse pressure and target blood pressure attainment (TBPA) using three different recommendations [Canadian Hypertension Education Program (CHEP), Swiss Society of Hypertension (SSH), European Society of Hypertension-European Society of Cardiology (ESH-ESC)]. Secondarily, we compared TBPA attained by angiotensin-converting enzyme inhibitor (ACEI)/diuretic (D), angiotensin receptor blocker (ARB)/D and calcium channel blocker (CCB)/D with any other dual therapy and investigated whether Ds/beta-blockers (BBs) or Ds/renin angiotensin-converting enzyme inhibitors (RAAS-Is) lead to higher TBPA. Finally, we assessed the impact of drug administration, practical work experience, location and specialization of GPs on TBPA. Results Octogenarians attained target blood pressure (TBP) between 44% (ESH-ESC) and 74% (SSH). Optimal/normal BP was reached in 22.8% of patients. Pulse pressure <65 mmHg was shown in 66.4% of patients. Monotherapy was most commonly applied followed by dual single-pill combination with ARB/D (46.5%) or ACEI/D (36.0%). No benefit in TBPA was found comparing a RAASI/D and CCB/D treatment with any other dual combination. There was also no difference between BB/D and RAAS-I/D combination therapy and between single-pill combination and dual free combinations. Conclusions GPs adhere to the use of substances proven in outcome trials and attain high TBP. No difference in meeting BP goals could be found using different drug classes. There is an unmet need to harmonize recommendations and to add additional information for the treatment of octogenarians.

Guidelines for the Conversion of Urban Four-Lane Undivided Roadways to Three-Lane Two-Way Left-turn Lane Facilities, April 2001

Four-lane undivided roadways in urban areas can experience a degradation of service and/or safety as traffic volumes increase. In fact, the existence of turning vehicles on this type of roadway has a dramatic effect on both of these factors. The solution identified for these problems is typically the addition of a raised median or two-way left-turn lane (TWLTL). The mobility and safety benefits of these actions have been proven and are discussed in the “Past Research” chapter of this report along with some general cross section selection guidelines. The cost and right-of-way impacts of these actions are widely accepted. These guidelines focus on the evaluation and analysis of an alternative to the typical four-lane undivided cross section improvement approach described above. It has been found that the conversion of a four-lane undivided cross section to three lanes (i.e., one lane in each direction and a TWLTL) can improve safety and maintain an acceptable level of service. These guidelines summarize the results of past research in this area (which is almost nonexistent) and qualitative/quantitative before-and-after safety and operational impacts of case study conversions located throughout the United States and Iowa. Past research confirms that this type of conversion is acceptable or feasible in some situations but for the most part fails to specifically identify those situations. In general, the reviewed case study conversions resulted in a reduction of average or 85th percentile speeds (typically less than five miles per hour) and a relatively dramatic reduction in excessive speeding (a 60 to 70 percent reduction in the number of vehicles traveling five miles per hour faster than the posted speed limit was measured in two cases) and total crashes (reductions between 17 to 62 percent were measured). The 13 roadway conversions considered had average daily traffic volumes of 8,400 to 14,000 vehicles per day (vpd) in Iowa and 9,200 to 24,000 vehicles per day elsewhere. In addition to past research and case study results, a simulation sensitivity analysis was completed to investigate and/or confirm the operational impacts of a four-lane undivided to three-lane conversion. First, the advantages and disadvantages of different corridor simulation packages were identified for this type of analysis. Then, the CORridor SIMulation (CORSIM) software was used x to investigate and evaluate several characteristics related to the operational feasibility of a four-lane undivided to three-lane conversion. Simulated speed and level of service results for both cross sections were documented for different total peak-hour traffic, access densities, and access-point left-turn volumes (for a case study corridor defined by the researchers). These analyses assisted with the identification of the considerations for the operational feasibility determination of a four -lane to three-lane conversion. The results of the simulation analyses primarily confirmed the case study impacts. The CORSIM results indicated only a slight decrease in average arterial speed for through vehicles can be expected for a large range of peak-hour volumes, access densities, and access-point left-turn volumes (given the assumptions and design of the corridor case study evaluated). Typically, the reduction in the simulated average arterial speed (which includes both segment and signal delay) was between zero and four miles per hour when a roadway was converted from a four-lane undivided to a three-lane cross section. The simulated arterial level of service for a converted roadway, however, showed a decrease when the bi-directional peak-hour volume was about 1,750 vehicles per hour (or 17,500 vehicles per day if 10 percent of the daily volume is assumed to occur in the peak hour). Past research by others, however, indicates that 12,000 vehicles per day may be the operational capacity (i.e., level of service E) of a three-lane roadway due to vehicle platooning. The simulation results, along with past research and case study results, appear to support following volume-related feasibility suggestions for four-lane undivided to three-lane cross section conversions. It is recommended that a four-lane undivided to three-lane conversion be considered as a feasible (with respect to volume only) option when bi-directional peak-hour volumes are less than 1,500 vehicles per hour, but that some caution begin to be exercised when the roadway has a bi-directional peak-hour volume between 1,500 and 1,750 vehicles per hour. At and above 1,750 vehicles per hour, the simulation indicated a reduction in arterial level of service. Therefore, at least in Iowa, the feasibility of a four-lane undivided to three-lane conversion should be questioned and/or considered much more closely when a roadway has (or is expected to have) a peak-hour volume of more than 1,750 vehicles. Assuming that 10 percent of the daily traffic occurs during the peak-hour, these volume recommendations would correspond to 15,000 and 17,500 vehicles per day, respectively. These suggestions, however, are based on the results from one idealized case xi study corridor analysis. Individual operational analysis and/or simulations should be completed in detail once a four-lane undivided to three-lane cross section conversion is considered feasible (based on the general suggestions above) for a particular corridor. All of the simulations completed as part of this project also incorporated the optimization of signal timing to minimize vehicle delay along the corridor. A number of determination feasibility factors were identified from a review of the past research, before-and-after case study results, and the simulation sensitivity analysis. The existing and expected (i.e., design period) statuses of these factors are described and should be considered. The characteristics of these factors should be compared to each other, the impacts of other potentially feasible cross section improvements, and the goals/objectives of the community. The factors discussed in these guidelines include • roadway function and environment • overall traffic volume and level of service • turning volumes and patterns • frequent-stop and slow-moving vehicles • weaving, speed, and queues • crash type and patterns • pedestrian and bike activity • right-of-way availability, cost, and acquisition impacts • general characteristics, including - parallel roadways - offset minor street intersections - parallel parking - corner radii - at-grade railroad crossings xii The characteristics of these factors are documented in these guidelines, and their relationship to four-lane undivided to three-lane cross section conversion feasibility identified. This information is summarized along with some evaluative questions in this executive summary and Appendix C. In summary, the results of past research, numerous case studies, and the simulation analyses done as part of this project support the conclusion that in certain circumstances a four-lane undivided to three-lane conversion can be a feasible alternative for the mitigation of operational and/or safety concerns. This feasibility, however, must be determined by an evaluation of the factors identified in these guidelines (along with any others that may be relevant for a individual corridor). The expected benefits, costs, and overall impacts of a four-lane undivided to three-lane conversion should then be compared to the impacts of other feasible alternatives (e.g., adding a raised median) at a particular location.

Accessible Parking Spaces Guidelines, 2001

The Americans with Disabilities Act Accessibility Guidelines (ADAAG) and Chapter 321L of the Iowa Code.

Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation.

Invasive opportunistic fungal diseases (IFDs) are important causes of morbidity and mortality in paediatric patients with cancer and those who have had an allogeneic haemopoietic stem-cell transplantation (HSCT). Apart from differences in underlying disorders and comorbidities relative to those of adults, IFDs in infants, children, and adolescents are unique with respect to their epidemiology, the usefulness of diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of interventional phase 3 clinical trials for guidance of evidence-based decisions. To better define the state of knowledge on IFDs in paediatric patients with cancer and allogeneic HSCT and to improve IFD diagnosis, prevention, and management, the Fourth European Conference on Infections in Leukaemia (ECIL-4) in 2011 convened a group that reviewed the scientific literature on IFDs and graded the available quality of evidence according to the Infectious Diseases Society of America grading system. The final considerations and recommendations of the group are summarised in this manuscript.

Frequency and effects of meeting health-behavior guidelines among adolescents

Objective: To assess the relationship between overweight status and the concomitant adherence to physical activity, daily screen time, and nutritional guidelines. Methods: Data were derived from the Swiss HBSC survey 2006. Participants (n=8130, 48.7% girls) were divided into two groups: normal-weight (n=7215, 44.8% girls), and overweight (n=915, 34.8% girls), using self-reported height and weight. Groups were compared on adherence to physical activity, screen time and nutritional guidelines. Bivariate analyses were carried out followed by multivariate analyses using normal-weight individuals as the reference category. Results: Regardless of gender, overweight individuals reported more screen time, less physical activity, and less concomitant adherence to guidelines. For boys, the multivariate analysis showed that any amount exceeding screen time recommendations was associated with increased odds of being overweight (>2-4h: adjusted odds ratio (AOR)=l .40; >4-6h: AOR=l .48; >6h: AOR=l .83). A similar relation was found for any amount below physical activity recommendations (4-6 times a week: AOR=1.67; 2-3 times a week: AOR=1.87; once a week or less: AOR=2.1). For girls, not meeting nutritional guidelines was less likely among overweight individuals (0-2 recommendations: AOR=0.54). Regardless of weight status, more than half of adolescents did not comply with any guideline and less than 2% met all 3 at the same time. Conclusions: Meeting current nutritional, physical activity and screen time guidelines should be encouraged with respect to overweight. However, as extremely low rates of concomitant adherence were found regardless of weight status, their achievability is questionable (especially for nutrition) which warrants further research to better adapt them to adolescents.