Strategies for improving outcomes in NSCLC: a look to the future.

Advances in the management of non-small cell lung cancer (NSCLC) over the past 30 years have led to small increases in 5-year survival rates across Europe, though further improvements may require new treatment strategies. In order to improve efficiency and reduce the cost of development, future trials for new targeted agents in NSCLC should aim to recruit patients on the basis of tumour biology rather than clinical characteristics. However, identification of predictive biomarkers is required to maximise the benefits of new approaches and expedite the drug development process. Nevertheless, the NSCLC landscape is changing rapidly, and recent improvements in our understanding of the molecular biology of the disease will help in the identification of novel targeted agents as well as assisting in the development of personalised strategies for the numerous small subsets of defined NSCLC. Progress in imaging and treatment delivery is also likely to improve outcomes for patients with the disease. This article outlines recent progress in the treatment of NSCLC, identifies current challenges and describes proposals for improving the future management of the disease. It is hoped that implementation of some of these strategies will go some way to improving the outlook for patients with NSCLC.

Consultoria del procés de logística interna del laboratori d'anàlisis clíniques a l'Hospital General de Vic

Com a resultat de les politiques i estratègies de col·laboració entre la universitat de Vic i de l’hospital i de la voluntat de realitzar activitats formatives conjuntes , s’estableix un línia de treball orientada a l’estudi i anàlisi de la situació logística interna actual del laboratori d’anàlisis clíniques de l’Hospital General de Vic. El treball es centra en el procés intern del laboratori i l’abast de l’estudi es troba limitat a les àrees especifiques d’hematologia i coagulació i bioquímica. D’aquestes dues àrees el treball realitza un estudi exhaustiu del seu procés intern, identifica les seves activitats i la seva metodologia de treball amb l’objectiu d’elaborar el Value Stream Map de cadascuna de les àrees. Les àrees de Microbiologia, Banc de Sang i Urgències resten fora d’aquest estudi exhaustiu tot i que són presents en el treball per la inevitable interacció que tenen en la globalitat del procés. El treball es centra bàsicament en els processos automatitzats tot i que els processos que es duen a terme en el laboratori són tant automatitzats com manuals. També es limita al sistema productiu intern del laboratori tot i la interacció que té aquest sistema intern amb altres centres productius del sistema com ara són els centres d’atenció primària, els diversos hospitals i centres d’atenció sociosanitària. El laboratori es troba immers en el moment de l’elaboració d’aquest treball en un situació de canvi i millora del seus processos interns que consisteixen principalment en la substitució de part la maquinària actual que obliguen a la definició d’un nou layout i d’una nova distribució de la producció a cada màquina. A nivell extern també s’estan produint millores en el sistema informàtic de gestió que afecten a part del seu procés. L’objectiu del treball és donar visibilitat total al procés de logística interna actual del laboratori, identificant clarament com són i quina seqüència tenen els processos logístics interns i els mètodes de treball actuals, tant de recursos màquina com recursos persona, per poder identificar sota una perspectiva de generació de valor, aquells punts concrets de la logística interna que poden ser millorats en quant a eficiència i productivitat amb l’objectiu que un cop identificats es puguin emprendre accions i/o projectes de millora. El treball finalitza amb un anàlisis final del procés logística interna des d’una òptica Lean. Per fer-ho, identifica aquelles activitats que no aporten valor al procés o MUDA i les classifica en set categories i es realitzen diverses propostes de millora com són la implantació d’un flux continu , anivellat i basat en un concepte pull , identifica activitats que poden ser estandarditzades i/o simplificades i proposa modificacions en les infraestructures físiques per donar major visibilitat al procés. L’aspecte humà del procés es planteja des d’un punt de vist de metodologia, formació, comunicació i aplicació de les 5S.

Haemodynamic consequences of changing bicarbonate and calcium concentrations in haemodialysis fluids.

BACKGROUND: In a previous study we demonstrated that mild metabolic alkalosis resulting from standard bicarbonate haemodialysis induces hypotension. In this study, we have further investigated the changes in systemic haemodynamics induced by bicarbonate and calcium, using non-invasive procedures. METHODS: In a randomized controlled trial with a single-blind, crossover design, we sequentially changed the dialysate bicarbonate and calcium concentrations (between 26 and 35 mmol/l for bicarbonate and either 1.25 or 1.50 mmol/l for calcium). Twenty-one patients were enrolled for a total of 756 dialysis sessions. Systemic haemodynamics was evaluated using pulse wave analysers. Bioimpedance and BNP were used to compare the fluid status pattern. RESULTS: The haemodynamic parameters and the pre-dialysis BNP using either a high calcium or bicarbonate concentration were as follows: systolic blood pressure (+5.6 and -4.7 mmHg; P < 0.05 for both), stroke volume (+12.3 and +5.2 ml; P < 0.05 and ns), peripheral resistances (-190 and -171 dyne s cm(-5); P < 0.05 for both), central augmentation index (+1.1% and -2.9%; ns and P < 0.05) and BNP (-5 and -170 ng/l; ns and P < 0.05). The need of staff intervention was similar in all modalities. CONCLUSIONS: Both high bicarbonate and calcium concentrations in the dialysate improve the haemodynamic pattern during dialysis. Bicarbonate reduces arterial stiffness and ameliorates the heart tolerance for volume overload in the interdialytic phase, whereas calcium directly increases stroke volume. The slight hypotensive effect of alkalaemia should motivate a probative reduction of bicarbonate concentration in dialysis fluid for haemodynamic reasons, only in the event of failure of classical tools to prevent intradialytic hypotension.

Invasive mould infections: a multi-disciplinary update.

Systemic fungal infections remain a significant cause of mortality in neutropenic and immunocompromised patients, despite advances in their diagnosis and treatment. The incidence of such infections is rising due to the use of intensive chemotherapy regimens in patients with solid tumours or haematological cancers, the increasing numbers of allogeneic haematopoietic stem cell and solid organ transplants, and the use of potent immunosuppressive therapy in patients with autoimmune disorders. In addition, the epidemiology of systemic fungal infections is changing, with atypical species such as Aspergillus terreus and zygomycetes becoming more common. Treatment has traditionally focused on empirical therapy, but targeted pre-emptive therapy in high-risk patients and prophylactic antifungal treatment are increasingly being adopted. New treatments, including lipid formulations of amphotericin B, second-generation broad-spectrum azoles, and echinocandins, offer effective antifungal activity with improved tolerability compared with older agents; the potential impact of these treatments is reflected in their inclusion in current treatment and prophylaxis guidelines. New treatment strategies, such as aerosolized lipid formulations of amphotericin B, may also reduce the burden of mortality associated with systemic fungal infections. The challenge is to identify ways of coupling potentially effective treatments with early and reliable identification of patients at highest risk of infection.

Application of a support system to the design of wastewater treatment plants

This paper presents a case study that explores the advantages that can be derived from the use of a design support system during the design of wastewater treatment plants (WWTP). With this objective in mind a simplified but plausible WWTP design case study has been generated with KBDS, a computer-based support system that maintains a historical record of the design process. The study shows how, by employing such a historical record, it is possible to: (1) rank different design proposals responding to a design problem; (2) study the influence of changing the weight of the arguments used in the selection of the most adequate proposal; (3) take advantage of keywords to assist the designer in the search of specific items within the historical records; (4) evaluate automatically thecompliance of alternative design proposals with respect to the design objectives; (5) verify the validity of previous decisions after the modification of the current constraints or specifications; (6) re-use the design records when upgrading an existing WWTP or when designing similar facilities; (7) generate documentation of the decision making process; and (8) associate a variety of documents as annotations to any component in the design history. The paper also shows one possible future role of design support systems as they outgrow their current reactive role as repositories of historical information and start to proactively support the generation of new knowledge during the design process

From radiobiology to technology: what is changing in radiotherapy for prostate cancer.

In the last decades, new technologies have been introduced in the daily clinical practice of the radiation oncologist: 3D-Conformal radiotherapy (RT) became almost universally available, thereafter, intensity modulated RT (IMRT) gained large diffusion, due to its potential impact in improving the clinical outcomes, and more recently, helical and volumetric arc IMRT with image-guided RT are becoming more and more diffused and used for prostate cancer patients. The conventional dose-fractionation results to be the best compromise between the efficacy and the safety of the treatment, but combining new techniques, modern RT allows to overcame one of the major limits of the 'older' RT: the impossibility of delivering higher total doses and/or high dose/fraction. The evidences regarding radiobiology, clinical and technological evolution of RT in prostate cancer have been reported and discussed.

Current developments in the radiotherapy approach to elderly and frail patients with glioblastoma multiforme.

The benefit of postoperative radiotherapy (RT) has been demonstrated in elderly patients aged 65 years or older with glioblastoma multiforme. Hypofractionated RT schedules can reduce the time and morbidity of treatment while maintaining comparable survival outcomes to lengthy conventional RT. Current international randomized clinical trials are studying the optimized hypofractionated RT regimens, hypofractionated RT in comparison with temozolomide chemotherapy and hypofractionated RT in comparison with the same RT plus temozolomide. Given the guarded prognosis of the elderly and frail patients, quality of life and side effects of treatment should be closely examined. As more than half of cancers in the world occur in developing countries, hypofractionated RT could be better utilized as a cost-effective treatment for this group of patients.

Simultaneous Optical Recording in Multiple Cells by Digital Holographic Microscopy of Chloride Current Associated to Activation of the Ligand-Gated Chloride Channel GABA(A) Receptor.

Chloride channels represent a group of targets for major clinical indications. However, molecular screening for chloride channel modulators has proven to be difficult and time-consuming as approaches essentially rely on the use of fluorescent dyes or invasive patch-clamp techniques which do not lend themselves to the screening of large sets of compounds. To address this problem, we have developed a non-invasive optical method, based on digital holographic microcopy (DHM), allowing monitoring of ion channel activity without using any electrode or fluorescent dye. To illustrate this approach, GABA(A) mediated chloride currents have been monitored with DHM. Practically, we show that DHM can non-invasively provide the quantitative determination of transmembrane chloride fluxes mediated by the activation of chloride channels associated with GABA(A) receptors. Indeed through an original algorithm, chloride currents elicited by application of appropriate agonists of the GABA(A) receptor can be derived from the quantitative phase signal recorded with DHM. Finally, chloride currents can be determined and pharmacologically characterized non-invasively simultaneously on a large cellular sampling by DHM.

Why Objective Monitoring of Compliance is Important in the Management of Hypertension.

Hypertensive patients often experience poor adherence to treatment, a frequent cause of uncontrolled blood pressure. In this study, we have evaluated whether or not the use of electronic monitoring for drug adherence is a useful approach to identify and correct compliance problems in hypertensive patients, which may ultimately enhance the effect of antihypertensive therapy. Sixty-nine treated patients with an office blood pressure greater than 140/90 mm Hg were enrolled in this study. With patient consent, current antihypertensive therapy was dispensed in electronic pillboxes that record the time and date of each opening without changing the drug regimen. The intention was to provide physicians with objective measurements of drug compliance. The monitoring of compliance per se without any other intervention induced a marked decrease of blood pressure in the whole group (from 159/104Â+/-23/12 mm Hg to 143/92Â+/-20/15, meansÂ+/-standard deviation, p less than 0.001). A complete normalization of blood pressure (less than 140/90 mm Hg) was obtained in one third of the patients (group 1, n=23) during the monitoring period. A significant improvement of blood pressure control was found in another third (group 2, n=23), whereas in the remaining patients (group 3, n=23) no change in blood pressure was observed. The distribution of individual compliance values, as well as the mean compliances was comparable in the three subgroups. Conversely, the compliance reports have identified several potentially overtreated patients in group 1, a large number of patients with a poor adherence to the prescribed therapy in all groups, and patients who clearly needed a change in pharmacotherapy mainly in group 3. Thus, our results suggest that electronic monitoring of compliance can considerably enhance the efficacy of antihypertensive therapy in patients with uncontrolled hypertension. This procedure should be used more extensively in clinical practice whenever the blood pressure response to therapy appears insufficient. (c)2000 by Le Jacq Communications, Inc.

MIGCLIM: Predicting plant distribution and dispersal in a changing climate

Many studies have forecasted the possible impact of climate change on plant distribution using models based on ecological niche theory. In their basic implementation, niche-based models do not constrain predictions by dispersal limitations. Hence, most niche-based modelling studies published so far have assumed dispersal to be either unlimited or null. However, depending on the rate of climatic change, the landscape fragmentation and the dispersal capabilities of individual species, these assumptions are likely to prove inaccurate, leading to under- or overestimation of future species distributions and yielding large uncertainty between these two extremes. As a result, the concepts of "potentially suitable" and "potentially colonisable" habitat are expected to differ significantly. To quantify to what extent these two concepts can differ, we developed MIGCLIM, a model simulating plant dispersal under climate change and landscape fragmentation scenarios. MIGCLIM implements various parameters, such as dispersal distance, increase in reproductive potential over time, barriers to dispersal or long distance dispersal. Several simulations were run for two virtual species in a study area of the western Swiss Alps, by varying dispersal distance and other parameters. Each simulation covered the hundred-year period 2001-2100 and three different IPCC-based temperature warming scenarios were considered. Our results indicate that: (i) using realistic parameter values, the future potential distributions generated using MIGCLIM can differ significantly (up to more than 95% decrease in colonized surface) from those that ignore dispersal; (ii) this divergence increases both with increasing climate warming and over longer time periods; (iii) the uncertainty associated with the warming scenario can be nearly as large as the one related to dispersal parameters; (iv) accounting for dispersal, even roughly, can importantly reduce uncertainty in projections.

Measures of health and disease in Africa: are current methods giving us useful information about trends in cardiovascular diseases?

An enormous burst of interest in the public health burden from chronic disease in Africa has emerged as a consequence of efforts to estimate global population health. Detailed estimates are now published for Africa as a whole and each country on the continent. These data have formed the basis for warnings about sharp increases in cardiovascular disease (CVD) in the coming decades. In this essay we briefly examine the trajectory of social development on the continent and its consequences for the epidemiology of CVD and potential control strategies. Since full vital registration has only been implemented in segments of South Africa and the island nations of Seychelles and Mauritius - formally part of WHO-AFRO - mortality data are extremely limited. Numerous sample surveys have been conducted but they often lack standardization or objective measures of health status. Trend data are even less informative. However, using the best quality data available, age-standardized trends in CVD are downward, and in the case of stroke, sharply so. While acknowledging that the extremely limited available data cannot be used as the basis for inference to the continent, we raise the concern that general estimates based on imputation to fill in the missing mortality tables may be even more misleading. No immediate remedies to this problem can be identified, however bilateral collaborative efforts to strength local educational institutions and governmental agencies rank as the highest priority for near term development.

Study Regarding Implementation of a Uniform Statewide System to Allow for Electronic Transactions for the Registration and Titling of Motor Vehicles

LEGISLATIVE STUDY – The 83rd General Assembly of the Iowa Legislature, in Senate File 2273, directed the Iowa Department of Transportation (DOT) to conduct a study of how to implement a uniform statewide system to allow for electronic transactions for the registration and titling of motor vehicles. PARTICIPANTS IN STUDY – As directed by Senate File 2273, the DOT formed a working group to conduct the study that included representatives from the Consumer Protection Division of the Office of the Attorney General, the Department of Public Safety, the Department of Revenue, the Iowa State County Treasurer’s Association, the Iowa Automobile Dealers Association, and the Iowa Independent Automobile Dealers Association. CONDUCT OF THE STUDY – The working group met eight times between June 17, 2010, and October 1, 2010. The group discussed the costs and benefits of electronic titling from the perspectives of new and used motor vehicle dealers, county treasurers, the DOT, lending institutions, consumers and consumer protection, and law enforcement. Security concerns, legislative implications, and implementation timelines were also considered. In the course of the meetings the group: 1. Reviewed the specific goals of S.F. 2273, and viewed a demonstration of Iowa’s current vehicle registration and titling system so participants that were not users of the system could gain an understanding of its current functionality and capabilities. 2. Reviewed the results of a survey of county treasurers conducted by the DOT to determine the extent to which county treasurers had processing backlogs and the extent to which county treasurers limited the number of dealer registration and titling transactions that they would process in a single day and while the dealer waited. Only eight reported placing a limit on the number of dealer transactions that would be processed while the dealer waited (with the number ranging from one to four), and only 11 reported a backlog in processing registration and titling transactions as of June 11, 2010, with most backlogs being reported in the range of one to three days. 3. Conducted conference calls with representatives of the American Association of Motor Vehicle Administrators (AAMVA) and representatives of three states -- Kansas, which has an electronic lien and titling (ELT) program, and Wisconsin and Florida, each of which have both an ELT program and an electronic registration and titling (ERT) program – to assess current and best practices for electronic transactions. In addition, the DOT (through AAMVA) submitted a survey to all U.S. jurisdictions to determine how, if at all, other states implemented electronic transactions for the registration and titling of motor vehicles. Twenty-eight states responded to the survey; of the 28 states that responded, only 13 allowed liens to be added or released electronically, and only five indicated allowing applications for registration and titling to be submitted electronically. DOT staff also heard a presentation from South Dakota on its ERT system at an AAMVA regional meeting. ELT information that emerged suggests a multi-vendor approach, in which vendors that meet state specifications for participation are authorized to interface with the state’s system to serve as a portal between lenders and the state system, will facilitate electronic lien releases and additions by offering lenders more choices and the opportunity to use the same vendor in multiple states. The ERT information that emerged indicates a multi-interface approach that offers an interface with existing dealer management software (DMS) systems and through a separate internet site will facilitate ERT by offering access that meets a variety of business needs and models. In both instances, information that emerged indicates that, in the long-term, adoption rates are positively affected by making participation above a certain minimum threshold mandatory. 4. To assess and compare functions or services that might be offered by or through a vendor, the group heard presentations from vendors that offer products or services that facilitate some aspect of ELT or ERT. 5. To assess the concerns, needs and interest of Iowa motor vehicle dealers, the group surveyed dealers to assess registration and titling difficulties experienced by dealers, the types of DMS systems (if any) used by dealers, and the dealers’ interest and preference in using an electronic interface to submit applications for registration and titling. Overall, 40% of the dealers that responded indicated interest and 57% indicated no interest, but interest was pronounced among new car dealers (75% were interested) and dealers with a high number of monthly transactions (85% of dealers averaging more than 50 sales per month were interested). The majority of dealers responding to the dealer survey ranked delays in processing and problems with daily limits on transaction as ―minor difficulty or ―no difficulty. RECOMMENDATIONS -- At the conclusion of the meetings, the working group discussed possible approaches for implementation of electronic transactions in Iowa and reached a consensus that a phased implementation of electronic titling that addressed first electronic lien and title transactions (ELT) and electronic fund transfers (EFT), and then electronic applications for registration and titling (ERT) is recommended. The recommendation of a phased implementation is based upon recognition that aspects of ELT and EFT are foundational to ERT, and that ELT and EFT solutions are more readily and easily attained than the ERT solution, which will take longer and be somewhat more difficult to develop and will require federal approval of an electronic odometer statement to fully implement. ELT – A multi-vendor approach is proposed for ELT. No direct costs to the state, counties, consumers, or dealers are anticipated under this approach. The vendor charges participating lenders user or transaction fees for the service, and it appears the lenders typically absorb those costs due to the savings offered by ELT. Existing staff can complete the programming necessary to interface the state system with vendors’ systems. The estimated time to implement ELT is six to nine months. Mandatory participation is not recommended initially, but should be considered after ELT has been implemented and a suitable number of vendors have enrolled to provide a fair assessment of participation rates and opportunities. EFT – A previous attempt to implement ELT and EFT was terminated due to concern that it would negatively impact county revenues by reducing interest income earned on state funds collected by the county and held until the monthly transfer to the state. To avoid that problem in this implementation, the EFT solution should remain revenue neutral to the counties, by allowing fees submitted by EFT to be immediately directed to the proper county account. Because ARTS was designed and has the capacity to accommodate EFT, a vendor is not needed to implement EFT. The estimated time to implement EFT is six to nine months. It is expected that EFT development will overlap ELT development. ERT – ERT itself must be developed in phases. It will not be possible to quickly implement a fully functioning, paperless ERT system, because federal law requires that transfer of title be accompanied by a written odometer statement unless approval for an alternate electronic statement is granted by the National Highway Traffic Safety Administration (NHTSA). It is expected that it will take as much as a year or more to obtain NHTSA approval, and that NHTSA approval will require design of a system that requires the seller to electronically confirm the seller’s identity, make the required disclosure to the buyer, and then transfer the disclosure to the buyer, who must also electronically confirm the buyer’s identity and electronically review and accept the disclosure to complete and submit the transaction. Given the time that it will take to develop and gain approval for this solution, initial ERT implementation will focus on completing and submitting applications and issuing registration applied for cards electronically, with the understanding that this process will still require submission of paper documents until an electronic odometer solution is developed. Because continued submission of paper documents undermines the efficiencies sought, ―full‖ ERT – that is, all documents necessary for registration and titling should be capable of approval and/or acceptance by all parties, and should be capable of submission without transmittal or delivery of duplicate paper documents .– should remain the ultimate goal. ERT is not recommended as a means to eliminate review and approval of registration and titling transactions by the county treasurers, or to place registration and titling approval in the hands of the dealers, as county treasurers perform an important role in deterring fraud and promoting accuracy by determining the genuineness and regularity of each application. Authorizing dealers to act as registration agents that approve registration and title applications, issue registration receipts, and maintain and deliver permanent metal license plates is not recommended. Although distribution of permanent plates by dealers is not recommended, it is recommended that dealers participating in ERT generate and print registration applied for cards electronically. Unlike the manually-issued cards currently in use, cards issued in this fashion may be queried by law enforcement and are less susceptible to misuse by customers and dealers. The estimated time to implement the electronic application and registration applied for cards is 12 to 18 months, to begin after ELT and EFT have been implemented. It is recommended that focus during this time be on facilitating transfers through motor vehicle dealers, with initial deployment focused on higher-volume dealers that use DMS systems. In the long term an internet option for access to ERT must also be developed and maintained to allow participation for lower-volume dealers that do not use a DMS system. This option will also lay the ground work for an ERT option for sales between private individuals. Mandatory participation in Iowa is not recommended initially. As with ELT, it is recommended that mandatory participation be considered after at least an initial phase of ERT has been implemented and a suitable number of dealers have enrolled to provide a fair assessment of participation rates and opportunities. The use of vendors to facilitate ERT is not initially proposed because 1) DOT IT support staff is capable of developing a system that will interact with DMS systems and will still have to develop a dealer and public interface regardless of whether a vendor acts as intermediary between the DMS systems, and 2) there is concern that the cost of the vendor-based system, which is funded by transaction-based payments from the dealer to the vendor, will be passed to the consumer in the form of additional documentation or conveyance fees. However, the DOT recommends flexibility on this point, as development and pilot of the system may indicate that a multi-vendor approach similar to that recommended for ELT may increase the adoption rate by larger dealers and may ultimately decrease the user management to be exercised by DOT staff. If vendors are used in the process, additional legislation or administrative rules may be needed to control the fees that may be passed to the consumer. No direct cost to the DOT or county treasurers is expected, as the DOT expects that it may complete necessary programming with existing staff. Use of vendors to facilitate ERT transactions by dealers using DMS systems would result in transaction fees that may ultimately be passed to consumers. LEGISLATION – As a result of the changes implemented in 2004 under Senate File 2070, the only changes to Iowa statutes proposed are to section 321.69 of the Iowa Code, ―Damage disclosure statement,and section 321.71, ―Odometer requirements.‖ In each instance, authority to execute these statements by electronic means would be clarified by authorizing language similar to that used in section 321.20, subsections ―2‖ and ―3,‖ which allows for electronic applications and directs the department to ―adopt rules on the method for providing signatures for applications made by electronic means.‖ In these sections, the authorizing language might read as follows: Notwithstanding contrary provisions of this section, the department may develop and implement a program to allow for any statement required by this section to be made electronically. The department shall adopt rules on the method for providing signatures for statements made by electronic means. Some changes to DOT administrative rules will be useful but only to enable changes to work processes that would be desirable in the long term. Examples of long term work processes that would be enabled by rule changes include allowing for signatures created through electronic means and electronic odometer certifications. The DOT rules, as currently written, do not hinder the ability to proceed with ELT, EFT, and ERT.