Alcoholism is characterized by a lack of control over excessive alcohol consumption despite significant negative consequences. This impulsive and compulsive behavior may be related to functional abnormalities within networks of brain regions responsible for how we make decisions. The abnormalities may result in strengthened networks related to appetitive drive—or the need to fulfill desires—and simultaneously weakened networks that exercise control over behaviors. Studies using functional magnetic resonance imaging (fMRI) in abstinent alcoholics suggest that abstinence is associated with changes in the tone of such networks, decreasing resting tone in appetitive drive networks, and increasing resting tone in inhibitory control networks to support continued abstinence. Identifying electroencephalographic (EEG) measures of resting tone in these networks initially identified using fMRI, and establishing in longitudinal studies that these abstinence-related changes in network tone are progressive would motivate treatment initiatives to facilitate these changes in network tone, thereby supporting successful ongoing abstinence. A person with alcoholism engages in risky or dangerous drinking despite experiencing serious negative physical and social consequences. Such persistence in pursuing damaging behaviors suggests that the short-term “appetitive” results of drinking (such as intoxication and losing one’s inhibitions) have greater control over the alcoholic’s behavior than do the negative consequences. From a neurobiological perspective, this pattern implies weak “top-down”—or knowledge-driven—executive control over impulsive and compulsive urges to consume alcohol and a strong “bottom-up”—or stimulus-driven—appetitive drive to consume alcohol, both impulsively and compulsively.Research using functional magnetic resonance imaging (fMRI) has identified networks of disparate brain regions involved in executive control and others involved in appetitive drive. Studies in alcoholics have demonstrated differences in activity in these networks compared with nondrinkers, implying that the networks can contribute to the poor decisionmaking and risky behaviors seen among alcoholics. This article reviews fMRI evidence that, compared with non–substance-abusing control subjects (NSACs), brain executive control networks are weakened or “tuned down” and appetitive drive networks are strengthened or “tuned up” in active alcoholism. Further, alcoholism correlates with changes in synchrony, or how well the brain regions within each network operate in concert. We also present cross-sectional fMRI data showing that abstinence maintenance is associated with compensatory changes in synchrony in these networks, such that the executive control network has greater synchrony and the appetitive drive network has reduced synchrony both in comparison to NSACs. The article proposes that electroencephalographic (EEG) analogs of these alcohol-related network differences exist and should be characterized. EEG could reveal different properties of these brain networks, such as timing of event processing, and may be more amenable than fMRI to active interventions such as neurofeedback. The article reviews a wide literature that supports the potential efficacy of an EEG neurofeedback intervention to mimic or augment the network changes seen in long-term abstinence. Finally, it presents a prototype showing that such neurofeedback is technically feasible.To understand what brain changes underlie behavior seen in alcoholism, researchers have focused on two networks believed to influence whether a person acts to fulfill a desire or to govern or control the desire when faced with a choice. These two networks are the appetitive drive and executive control networks see . During To determine how activity in these brain regions looks among alcoholics compared with control subjects, researchers use fMRI. fMRI measures brain activity by detecting the blood-oxygen-level–dependent (BOLD) contrast related to neural activity. Most fMRI experiments examine task-related patterns in the location and magnitude of the BOLD response, that is, the task activation of the brain. Many differences in activation in the executive control and appetitive drive networks have been observed in alcohol use, abuse, and dependence, suggesting that these networks and the multiple brain regions they encompass can contribute to the poor decisionmaking and risky behaviors seen in alcoholism  is associated with activation patterns different from those of control subjects in brain regions that are part of the executive control and appetitive drive networks. More recently, scientists have taken fMRI studies a step further to examine differences in how well such brain regions work together. Such work suggests that faulty co-activation or synchrony within brain networks, or an imbalance between opposing brain networks, is important in alcoholism.Various methodologies for detecting brain activity demonstrate that more than one region becomes activated at a time, both during task performance and while at rest. Imaging studies now have begun to parse how the regions work together and whether disturbances within networks are associated with identifiable patterns of behavior. Early fMRI studies primarily focused on changes in the magnitude of the BOLD response, assessing activation and de-activation of brain regions during a task. More recently, studies have shifted to using fMRI to probe the similarity or synchrony of the BOLD response across spatially disparate regions, especially while the brain is at rest. The work builds upon the EEG literature that long ago established the existence of spontaneously oscillating brain networks. EEG measures brain electrical activity. Oscillations detected with EEG at characteristic frequencies, or bands, represent the summed activity of thousands of neurons. Synchrony of oscillatory activity between brain regions is thought to support neural communication and plasticity  . The fMRA study of fronto-striatal functional connectivity in cocaine use disorders supports the model that a strong bottom-up appetitive drive network is active in addiction . FourteeThe above section suggests that current dependence and abuse is associated with exaggerated bottom-up and compromised top-down neural network functioning. The question then becomes whether abstinence from alcohol changes that neural network picture. Existing task studies suggest that compensatory mechanisms appear in long-term abstinence from nicotine and alcohol that may exert control over reward seeking and attenuate appetitive drive . To studCompared with NSAC subjects, LTAA subjects showed (1) decreased synchrony of limbic reward regions  with both bilateral NAcc and sgACC seeds  and (2) The lower synchrony of the limbic reward network in LTAA may reflect an ongoing compensatory effort to lower the induction of brain activity in regions known to be involved in reward processing. Increased synchrony between the NAcc and left DLPFC is consistent with literature showing that DLPFC input to the NAcc is involved in inhibition of behavior , as is tLTAA subjects with a shorter duration of abstinence had higher synchrony between sgACC and right DLPFC. The authors suggest that individuals with shorter duration of abstinence are more vulnerable to relapse than individuals with longer abstinence and thus may need more vigilant emotional regulation (reflected here by increased synchrony between sgACC and right DLPFC) to manage emotional situations and successfully avoid relapse. On the other hand, individuals with longer abstinence, who are at lower risk for relapse, may have a lower need for regulating emotion; hence, lower synchrony between sgACC and DLPFC in LTAA subjects was associated with longer (multiyear) abstinence durations. In total, the results here support the existence of compensatory mechanisms in LTAA subjects that are evident during rest, in which enhanced synchrony within the executive control networks and attenuated synchrony within appetitive drive networks may facilitate the behavioral control required to maintain abstinence.n = 35; 20 women, ages 47.9 ± 7.3 years; averaging 5.67 ± 4.80 years of abstinence), comparing them with 23 LTAA subjects without comorbid drug dependence  c. Using These studies indicate that active alcoholics exhibit lower top-down executive control network synchrony and higher bottom-up reward and appetitive drive network synchrony, and that these phenomena are more than reversed with successful abstinence. The observed “overcompensation” in network synchrony—that is, the greater executive control network synchrony observed in STAA and LTAA subjects compared with control subjects—may be necessary in order to inhibit the habitual response to alcohol. This is consistent with the authors’ 2013 paper showing that antisocial disposition does not change with long-term abstinence but that antisocial behavior is inhibited, with antisocial symptoms approaching zero in LTAA subjects . Given tSeveral fMRI task studies have demonstrated altered executive control network activation and connectivity in alcoholism, implying that the resting-state fMRI synchrony differences observed are present during task processing. Research to determine the association between resting state fMRI network synchrony and network performance during tasks that involve appetitive drive and executive control would help demonstrate how the brain’s readiness alters the brain’s response to a task. For example, in nicotine addicts, a modified Stroop task  has been used to assess appetitive drive and executive control networks . The stuJazmin Camchong developed an alcohol-cue analog of this task see . In a piTask studies, which can isolate elements of complex behaviors, could help show not only whether synchrony influences behavior but what synchrony changes mean in relation to what scientists know about how alcoholism disrupts normal functioning. For example, one way of conceptualizing the core problem in alcoholism and other addictions is that reinforcements consequent to behavior—such as becoming sick or hungover after drinking—do not appropriately guide future behavior. Adaptive learning involves computation by the brain of reward prediction errors (PEs), which reflect the difference between expected and actual outcomes. Normally, the PEs affect behavior by influencing higher-order executive functioning of the DLPFC, a region involved in goal-directed behavior. Alcoholic behaviors represent a shift away from regulation of behavior by the brain’s control and management functions  and toward influence by functions that process reward . Parts of the brain’s complex anatomy involved in each of these functions are spread far apart from one another. Nevertheless, they can act in concert to direct behaviors, and the balance between them turns out to have a profound impact in addiction and recovery. In the human brain, the appetitive drive and reward network—that is, the areas involved in forming and responding to appetites, drives, and desires—comprises mesocortico-limbic regions that mediate aspects of drug addiction such as responses to rewarding stimuli , memory of rewarding stimuli , and regulation of emotion and executive function  . The strThe subgenual anterior cingulate cortex (sgACC), a subdivision of the anterior cingulate cortex, plays a central role within the predominantly frontal cortical network underlying executive control . The ACCHere, images of the brain are labeled with some of the regions most important to the executive control and appetitive drive networks. The behaviors with which the regions are associated are also listed.See limbic system.Part of the striatum that influences goal-directed actions or behaviors.See limbic system.Implicated in inflexible, poor decisionmaking. Also involved in stress coping and cue responsivity, which are behavioral aspects of addiction.Part of the striatum with roles in reward and reinforcement learning as well as fear, impulsivity, and addiction.Involved in motivational behavior as well as emotion and social behavior. It receives and responds to primary sensory information. It is involved in the detection and processing of consequences of behavior, including the attachment of emotional valence to the negative consequences of behavior.Part of the default mode network see  and possInvolved in planning cognitive behavior, regulation of emotion, and executive function. Also part of the executive control network.Part of the striatum involved in mediating appetitive drive. The putamen regulates movement and has influence on habits and on learning related to stimulus response.See limbic system.Involved in response to rewarding stimuli.Connected with the cerebral cortex, thalamus, and brain stem. Involved in the control of voluntary movement, procedural learning, habits, cognition, and emotion.Parts of a salience network, a key mechanism by which the brain picks out details in its environment to focus on. Involved in learning and attention.Involved in goal-directed behavior. Includes the dorsolateral prefrontal cortex , involved in executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning.Encompasses the hippocampus, amygdala, and anterior thalamus. Implicated in both appetitive drive and executive control networks. An emotion, behavior, and motivation center.Connected with the lateral prefrontal cortex and with limbic system regions. Involved with emotion processing, learning, and memory.BerkingMMargrafMEbertDDeficits in emotion-regulation skills predict alcohol use during and after cognitive-behavioral therapy for alcohol dependenceJournal of Consulting and Clinical Psychology793307318201121534653BotvinickMMBraverTSBarchDMConflict monitoring and cognitive controlPsychology Review1083624652200117027226CooperMLFroneMRRussellMDrinking to regulate positive and negative emotions: A motivational model of alcohol useJournal of Personality and Social Psychology69599019957473043DrevetsWCPriceJLSimpsonJRSubgenual prefrontal cortex abnormalities in mood disordersNature386662782482719979126739ElliottRAgnewZDeakinJFHedonic and informational functions of the human orbitofrontal cortexCerebral Cortex201198204201019435707EverittBJRobbinsTWNeural systems of reinforcement for drug addiction: From actions to habits to compulsionNature Neuroscience81114811489200516251991FoxHCHongKASinhaRDifficulties in emotion regulation and impulse control in recently abstinent alcoholics compared with social drinkersAlcoholism: Clinical and Experimental Research332388394200818023295KellyAMDi MartinoAUddinLQDevelopment of anterior cingulate functional connectivity from late childhood to early adulthoodCerebral Cortex193640657200918653667PhanKLFitzgeraldDANathanPJNeural substrates for voluntary suppression of negative affect: A functional magnetic resonance imaging studyBiological Psychiatry573210219200515691521TahaSAFieldsHLInhibitions of nucleus accumbens neurons encode a gating signal for reward-directed behaviorJournal of Neuroscience261217222200616399690In another study, 20 non–treatment-seeking problem drinkers underwent fMRI during a stop-signal task (SST) to assess response inhibition, a subject’s ability to inhibit his own response to a stimulus . Weaker Other studies of network functioning in alcoholics during active tasks have also revealed abnormalities in networks other than the executive control and appetitive drive networks. For some tasks, alcoholics seemed to recruit additional brain regions (vs. controls) to accomplish a task, perhaps to overcome strong appetitive signals, or physical or functional degradation of brain networks used by controls for task performance. Within the DMN, for example, abstinent alcoholics show less resting-state synchrony between the posterior cingulate and cerebellar regions compared with control subjects but show greater left posterior cingulate-cerebellar synchrony during a spatial working-memory task. The finding suggests that alcoholics need more integration of inputs from multiple brain regions to achieve comparable task performance to controls . In addiIn later work , researcA study of 18 abstinent alcoholics and 17 healthy control subjects acquired fMRI data during an attentional Stroop task  and reveTask-related fMRI studies also may help identify characteristics of brain connectivity that can help predict whether or how readily an alcoholic will achieve abstinence. A cue-reactivity fMRI experiment with alcohol-associated and neutral stimuli was used to study 46 detoxified alcohol-dependent patients (19.74 ± 22.66 days abstinent) and 46 control subjects . Three mIn summary, fMRI functional connectivity or synchrony studies provide ample evidence that altered network synchrony exists in alcoholism and that plastic changes in network synchrony occur with abstinence. However, from cross-sectional studies alone, one cannot distinguish between brain synchrony actually changing in long-term abstinence b,c, versScientists understand little of how successful treatments such as behavioral therapies or 12-step programs work. They also understand little of the neurological mechanisms underlying reduction or cessation of drinking. Data reviewed here point to one such possible mechanism. They reveal network synchrony changes detected using fMRI that are graded with abstinence duration, suggesting that achieving and maintaining abstinence is associated with adaptive brain network synchrony changes that support reductions in bottom-up appetitive drive and increases in top-down executive inhibitory control. If longitudinal studies can confirm that the degree of the changes in the appetitive drive and executive control networks is associated with and predictive of successful abstinence, then such changes may underlie the success of behavior therapies. In addition, interventions that directly augment the network changes may provide another tool in the treatment toolbox.The idea of modifying brain network synchrony to promote abstinence is bolstered by the literature on using transcranial direct-current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) to treat alcohol craving. These noninvasive treatments are thought to reduce craving by modulating the activity and connectivity of brain networks. A case study by Direct currents and magnetic waves applied transcranially thus seem to influence brain synchrony and may help reduce symptoms such as craving in alcoholism. At the same time, people can achieve abstinence without them. A technique such as neurofeedback might help people with addictions directly strengthen the tone of their inhibitory networks or weaken the tone of their appetitive drive networks. Neurofeedback is a method built upon the idea that the mind and body are one, and that by training the mind or brain to achieve particular states indexed by some measured neurobiological signal (such as the BOLD response or EEG), the body will react in a more optimal way in order to improve emotional, cognitive, physical, and behavioral experiences. Neurofeedback that “feeds back” an auditory or visual signal that corresponds to the strength of brain network synchrony may promote network synchrony adaptations that support abstinence. For example, a neurofeedback protocol may instruct a patient to try to raise the pitch of a tone. A low-pitched tone is played when network synchrony is low, and the pitch increases with network synchrony. As the patient works to raise the tone, synchrony in the target network improves, training the network.Some technical challenges stand in the way of neurofeedback. First, it is neither practical nor economically feasible to use neurofeedback to modify fMRI-detected network synchrony directly. Furthermore, fMRI’s BOLD response cannot provide the time resolution necessary to allow real-time feedback to a patient about synchrony changes occurring in his or her brain. In contrast, EEG provides precise time resolution and generally is a more economical and efficient tool for use in treatment than fMRI.Since research on brain networks involved in alcoholism has used fMRI to date, scientists need to find EEG results that are analogous to the relevant fMRI-detected network phenomena to make EEG useful in neurofeedback. Fortunately, converging evidence suggests that the fMRI BOLD response reflects the summed neural activity of several oscillatory EEG networks  , 2007 toEEG neurofeedback in the treatment of substance use disorders dates to 1975 . Each time the subject chooses an item and receives negative feedback , a prediction error is generated. The learning rate counts the number of trials the subject goes through to figure out which stimulus leads to a positive outcome.Working memory actively holds multiple pieces of information in the mind where they can be manipulated. It includes subsystems that store and manipulate both visual images and verbal information. Tasks that test working memory require a subject to manipulate information as part of a goal-directed action while also being presented with distractions. The cognitive processes required to accomplish the task include executive control and attention, among others.Here, a subject is asked to respond as quickly as possible to a particular feature of a stimulus . In some instances, however, the stimulus is followed by another signal—such as an auditory tone—that tells the subject to withhold her planned response. This tests the subject’s ability to inhibit responses.This assesses whether a subject experiences interference in reaction time for completing a task. The classic Stroop test example involves looking at the names of colors spelled out in ink that is not the same color as the word . The subject is asked to name the color of the ink, and reaction time can indicate whether a person has problems with selective attention, cognitive flexibility, or processing speed.Technical challenges are inherent in a real-time EEG brain network synchrony neurofeedback system. However, the authors’ prototype for an EEG neurofeedback system uses a quad-core Intel i5 computer to acquire EEG and estimate network synchrony based on comparing the EEG of each possible pair of electrodes, and a second computer to display a movie as the feedback signal. Although the best estimates of EEG network synchrony likely will be derived from intracranial source estimates, the prototype has computational demands greater than those required to estimate intracranial source connectivity and thus is more than adequate to establish the feasibility of a future EEG network synchrony neurofeedback system. The prototype records 64 channels of scalp EEG, estimates pairwise cross-coherencies, and computes the contribution of the independent components (IC) that index executive control or appetitive drive network synchrony. First, the subject’s baseline network synchrony is estimated for use during training. During neurofeedback training, the system continuously records 64 channels of scalp EEG and analyzes the EEG to estimate network synchrony in real time. The real-time synchrony is compared with the subject’s baseline synchrony and the target distributions of synchrony for NSAC, STAA, and LTAA subjects. A degraded video stimulus feeds back to the subject if there is a large difference between the real-time estimate of synchrony and the target synchrony, whereas a clear video signal appears when the real-time synchrony estimate approaches the target synchrony. The prototype is fast enough to update the neurofeedback to the patient 10 times per second despite a computationally intensive method of reflecting EEG network synchrony. It is likely that a much simpler algorithm will sufficiently index EEG network synchrony once research clarifies which signals best represent key aspects of brain network synchrony in recovering alcoholics. For example, neurofeedback systems could eventually use cross-correlation of selected electrode pairs within one or two frequency bands, or correlation of estimated source activity or power between a small number of anatomical sources. The central research task that would enable development of an EEG neurofeedback system to treat alcoholism remains identifying the EEG measures of network function that change with abstinence and that correspond to the appetitive drive and inhibitory control fMRI networks.Alcoholism is characterized by a lack of control over excessive alcohol consumption despite significant negative consequences, a pattern of behavior that implies weak top-down executive control over impulsive and compulsive urges to consume alcohol, and a strong bottom-up appetitive drive that produces those urges. fMRI studies have identified multiple brain regions that contribute to the poor decisionmaking and risky behaviors seen in alcoholism. This chapter reviews fMRI network synchrony, or functional connectivity, studies suggesting that faulty coactivation or synchrony of multiple brain regions comprising networks, or an imbalance between opposing brain networks, is important in alcoholism. fMRI network studies in active alcoholics suggest that impulsive and compulsive behaviors are related to the ineffectiveness of brain networks, characterized by decreased synchrony in top-down executive control network and increased synchrony in the bottom-up appetitive drive network. Repeated high-volume alcohol exposure may compromise network integrity, as suggested by the relationship between synchrony and the severity and duration of alcohol use. Continued abstinence following alcoholism displays a different synchrony pattern. A series of studies in short- and long-term abstinent alcoholics observed decreased synchrony in appetitive drive networks and increased synchrony in inhibitory control networks, suggesting that the alcohol-induced imbalances in brain networks are reversed, helping individuals achieve and maintain abstinence by inhibiting behavior and reducing appetitive drive. Longitudinal studies of abstinent alcoholics at rest and during task performance would definitively establish whether plastic changes in the synchronous activity in brain networks reflects a crucial brain mechanism underlying the behavior changes in alcoholics that result in extended abstinence. Furthermore, the identification of EEG measures analogous to fMRI-executive control and appetitive drive network synchrony could potentially reveal the sequence and timing of mechanisms underlying the processing and inhibition of the brain’s response to alcohol cues that contribute to the maintenance of abstinence. Confirming the progressive network synchrony changes with longitudinal studies of abstinent alcoholics—together with identifying EEG networks—would support the treatment potential of interventions to augment these network changes. Neurofeedback of EEG alpha and theta rhythms has been a successful component of alcoholism treatment in some subjects, and feedback of a signal that indexes synchrony in specific brain networks holds great promise as an alcoholism treatment. A prototype for neurofeedback to alter measures of EEG network synchrony demonstrates the technical feasibility of this treatment approach. If longitudinal studies confirm that the adaptive changes in brain functional organization summarized in this article support ongoing abstinence, then EEG treatment to augment these changes is feasible and should be pursued.


Background: Patients with stage 5 chronic kidney disease (CKD) begin chronic hemodialysis with variable diuresis levels correlated to a comparable low glomerular filtration rate. Residual diuresis influences long-term evolution of the hemodialyzed patient, modifying the prognosis even if optimal Kt/ V is achieved. Aim of the study: The present study emphasizes the main determining factors of diuresis in a cohort of stage 5 CKD subjects at the beginning of hemodialysis.Material and methods: 216 patients with stage 5 CKD starting chronic hemodialysis were included in the study, and were grouped according to their residual diuresis: group A (urine output ≤ 500 mL/ day); group B (urine output between 500–1200 mL/ day); group C (urine output ≥ 1200 mL/ day).Results:Glomerular etiology, cardiac systolic dysfunction, severe malnutrition, emergency dialysis initiation and lack of permanent vascular access were proved to be associated with significant low diuresis. Age, gender, estimated glomerular filtration rate (GFR) and the presence of systemic hypertension did not influence the amount of daily diuresis.Conclusions: In CKD stage 5 patients, residual diuresis presents large variations in conditions of comparable low GFR. Factors influencing residual diuresis may be distinct from those that influence residual GFR. Preserved RRF is accompanied by multiple benefits: better removal of uremic toxins , increased phosphate urinary excretion and superior handling of secondary hyperparathyroidism , reduced cardiovascular complications and better volume control , improved nutritional markers , decreased need for erythropoiesis stimulating agents , reduced proinflammatory state , improved quality of life  and reduced all-cause mortality .Statistic data highlighted the importance of preserving residual renal function (RRF) at the beginning of dialysis. Increasing dialysis efficiency, in terms of increasing the dose of dialysis (Kt/ V) and/ or increasing intradialysis ultrafiltration is not associated with the same favorable effects [19]. Therefore, these two entities could have been considered similar. Additionally, several other researches emphasize the fact that in uremia, urine formation depends on several factors , being determined not only by GFR alone, but also by the tubular reabsorption activities and the osmotic loads in the blood [20-22]. Consequently, in advanced renal failure, accompanied by low residual GFR, patients might present different diuresis, from oligoanuria to polyuria. The studies that have been conducted used – as a measure for residual renal function – either the residual glomerular filtration rate (estimated with different formulas) (GFR), or the residual urine output . The equilibrium between GFR and tubular reabsorption is lost in advanced uremia, sometimes in earlier stages, depending on the concomitant complications as hypertension or/ and the primary renal diseases [21]. Preserving urine output in patients with chronic tubulointerstitial nephropathies supports the hypothesis that the tubular inability to reabsorb sodium and water is responsible for increased diuresis [21]. Later research revealed that the urine volume is less influenced by tubular inability to preserve sodium and water which may be reversed, at least partially, by low-sodium diet  and more by primary renal sodium retention with hypervolemia and by increased sanguine osmolarity as a result of urea and sodium retention . It was proven that, in advanced chronic renal failure, there is an alteration of concentration and dilution tubular capacity as well as a result of tubulointerstitial fibrosis  and an increased tubular resistance at ADH ; as a consequence, in uremia, increasing daily water intake has a minor effect on diuresis.In our research, we found no relationship between residual GFR and residual diuresis in patients with CKD stage 5 at the beginning of hemodialysis. This finding is in accordance with other studies which emphasize that, in uremic patients, diuresis is determined not only by residual GFR, but also by the rate of tubular reabsorption [29], as a consequence of associated senile changes in the kidney [29-32]. This discrepancy might be explained by the fact that not all the studies used only diuresis as a measure for RRF. Regarding gender, literature offers conflicting data .No relation between age or gender and residual urine output was found in the present study. Regarding age, our results are not in accordance with literature data in which, in the majority of cases, age was a strong predictor of diuresis and/ or RRF loss [25], in our study, diuresis was not lower in hypertensive patients when compared with normotensive subjects. This observation might have at least two explanations:Although systemic hypertension has proved to be one of the most important progression factors of CKD ; increased retention of sodium is followed by increased natriuresis and polyuria, as an adaptive mechanism for reducing hypertension ;- sodium retention and increased extracellular volume are the main cause of hypertension in advanced CKD .Presence of cardiac systolic dysfunction was significantly associated with lower urine output, as was severe hypoalbuminemia. Both these factors are associated with decreased renal flow secondary to reduced cardiac output in the first case and to lessened effective plasmatic volume in the second case. These observations are in accordance with literature data [Low GFR in CKD stage 5 patients is accompanied by different urine outputs. Systolic left ventricular dysfunction, glomerular etiology, malnutrition and late initiating of hemodialysis were proved to be associated with low residual diuresis in our study. Therefore, factors influencing residual diuresis may be distinct from those that influence residual GFR.Conflict of InterestsThe authors declare that there is no conflict of interests regarding the publication of this paper.


Authorship guidelines have established criteria to guide author selection based on significance of contribution and helped to define associated responsibilities and accountabilities for the published findings. However, low awareness, variable interpretation, and inconsistent application of these guidelines can lead to confusion and a lack of transparency when recognizing those who merit authorship. This article describes a research project led by the Medical Publishing Insights and Practices (MPIP) Initiative to identify current challenges when determining authorship for industry-sponsored clinical trials and develop an improved approach to facilitate decision-making when recognizing authors from related publications. A total of 498 clinical investigators, journal editors, publication professionals and medical writers were surveyed to understand better how they would adjudicate challenging, real-world authorship case scenarios, determine the perceived frequency of each scenario and rate their confidence in the responses provided. Multiple rounds of discussions about these results with journal editors, clinical investigators and industry representatives led to the development of key recommendations intended to enhance transparency when determining authorship. These included forming a representative group to establish authorship criteria early in a trial, having all trial contributors agree to these criteria and documenting trial contributions to objectively determine who warrants an invitation to participate in the manuscript development process. The resulting Five-step Authorship Framework is designed to create a more standardized approach when determining authorship for clinical trial publications. Overall, these recommendations aim to facilitate more transparent authorship decisions and help readers better assess the credibility of results and perspectives of the authors for medical research more broadly.http://www.biomedcentral.com/1741-7015/12/214.Please see related article: The online version of this article (doi:10.1186/s12916-014-0197-z) contains supplementary material, which is available to authorized users. The designation of authorship is essential for published research to be represented by those who provide significant intellectual contribution to its development and execution. More recently, authorship selection has evolved to confer not only the credit for the research but also accountability and responsibility for accuracy and integrity of the work. Yet, making this determination can be especially challenging due to the ambiguous nature of available authorship guidelines and the increasing complexity of clinical trial research . The mosImproving disclosure of authorship contributions and writing assistance was identified as one of ten recommendations to close the credibility gap in reporting industry-sponsored research by the Medical Publishing Insights and Practices (MPIP) Initiative , a collaIn early 2012, members of the MPIP Initiative’s Steering Committee collaborated with multiple respondent groups involved in publication of industry-sponsored clinical trials to identify authorship challenges arising from current guidelines. Following in-depth discussions with seven publication professionals , three journal editors and three clinical investigators, the MPIP Initiative Steering Committee and its academic collaborators converted these challenging situations into authorship case scenarios for further testing. An additional flow diagram provides a detailed overview of the authorship research project [see Additional file An online survey utilizing these authorship case scenarios was created to collect qualitative data regarding the rationale for adjudication of authorship decisions in individual cases . The survey also asked for confidence level in authorship decisions and perceived frequency of the situation described in the case. Respondents were asked to answer based on their professional experience, as cases did not mention any specific guidelines. At the end of the survey, respondents were also asked about their awareness of and reliance on specific authorship guidelines, as well as the time point during the clinical trial when they would agree on authorship criteria. The full survey [see Additional file The survey was sent via an email link (to avoid duplicate answers) to four respondent groups involved in the publication of clinical trial results: clinical investigators involved in industry-sponsored clinical trials (as of September 2012), editors of general or specialty journals who publish results from industry-sponsored clinical trials , publication professionals (as defined above) and medical writers employed or contracted by trial sponsors who collaborate with authors in drafting, revising and editing medical information for peer-reviewed journals and congresses. The last two groups were contacted through ISMPP, the American Medical Writers Association (AMWA), the European Medical Writers Association (EMWA) and the MPIP Initiative Steering Committee. Cases were presented randomly to minimize respondent fatigue. From a total of 498 responses, a sample of at least 96 participants per group enabled estimates with a 10% margin of error for the largest respondent group surveyed . The online survey remained open until all groups surpassed this sample size by at least 10%.Adjudications of cases, confidence in answers, and authorship practices of respondents were summarized as frequencies. The answers measuring respondents’ confidence and perceived frequency of scenarios were captured on 6 point scales and categorized into three groups: high confidence/frequency (score 1–2), moderate confidence/frequency (score 3–4) and low confidence/frequency (score 5–6). Open-ended explanations for adjudications were analyzed as qualitative data. Answers were summarized and analyzed using a general inductive approach . ParticiQuantitative survey results were discussed at two separate MPIP-hosted roundtable meetings: 10 U.S.-based editors and 15 MPIP members , and five European-based editors, one journal representative, and seven MPIP members . During these roundtables, a facilitator presented quantitative results from the survey-based study. Through an iterative process of discussion and consensus building, key themes were identified. Findings were further refined through analysis of qualitative survey answers and in-depth discussions with six clinical investigators who participated in the online survey and gave permission for follow-up conversations.Survey respondents (n = 498) included representation from all four target respondent groups: 145 clinical investigators (29% of respondents), 108 journal editors (22%), 132 publication professionals (26%) and 113 medical writers (23%) , followed by the Good Publication Practice (GPP2) guidelines  35% to . ClinicaFull descriptions of the seven hypothetical authorship case scenarios for industry-sponsored studies and answers by respondent group are presented in Figure Case 1 tests whether patient recruitment and trial site management were perceived to be significant enough contributions to merit an authorship invitation. Most of the respondents (49% to 68%) agreed that these contributions warranted an invitation to authorship. The rationale for this decision is illustrated by the response from a clinical investigator: ‘Recruiting patients is one of the most important tasks in a clinical trial, and the quality of the study depends on compliance with the inclusion and exclusion criteria. Therefore, this is probably one of the most important persons for the study, and should therefore take responsibility/be acknowledged as an author.’ This case was estimated by respondents to occur most frequently, and >73% of respondents in each group were confident in their answer. ICMJE criteria for authorship available at the time of the survey  were uncCase 2 explores the two issues: 1) whether a statistician who is believed to have made a substantial contribution but did not contribute to trial design or drafting of the manuscript merits an invitation to authorship; and 2) whether timing of authorship criteria fulfillment impacts the decision. More publication professionals supported consideration for authorship (72%) compared to clinical investigators (54%). Qualitative responses highlighted a lack of consensus between respondent groups. One editor commented that ‘Authorship on a manuscript needed to be decided before the writing of a first draft’, in contrast to a clinical investigator who wrote ‘Authorship should reflect a significant contribution to the substance of the study - it was an error not to include this person from the start.’ While respondents had generally high confidence in their answers , they reported moderate frequency for this case. ICMJE criteria in place at the time of the survey  providedCase 3 asks if a contribution from a medical writer could qualify the person as an author. In this case, a medical writer is hired to help draft the manuscript from a trial report and supports authors in manuscript development under the guidance of the authors to final acceptance. Nearly one quarter of journal editors (23%) and clinical investigators (25%) supported authorship in this case. Respondents were aware this choice was not concordant with guidelines, exemplified by a clinical investigator: ‘I believe medical writers should be listed as authors in those instances where they have contributed from the first draft through to submission. (I recognize that this would require revision of ICMJE guidelines).’ This case was estimated by respondents to be the second most frequent, and >76% of respondents in each group were confident in their answer. ICMJE guidelines at the time of survey  stated tFinally, Case 7 tests whether providing those who make a significant contribution the opportunity to serve as an author takes precedence over protection of proprietary information. In this scenario, respondents were asked if a clinician who leaves a trial sponsor company for a competitor after making a substantial contribution but prior to drafting the manuscript should be invited to contribute as an author. A majority of clinical investigators (61%) and journal editors (55%) were in favor of inviting the clinician to serve as an author versus publication professionals (26%) and medical writers (36%). As with other cases, respondents were more often concerned about what was fair and not what was prescribed, as noted by a publication professional: ‘Honestly speaking, I think the clinician should be recognized as an author, but he does not meet authorship criteria.’ More than 72% of respondents in each group were confident in their answer. This case was estimated to occur relatively infrequently.When considering answers from the cases as a whole, three overarching insights emerged. First, responses pertaining to granting authorship, acknowledgement, no recognition or other, varied not only across but within the four respondent groups for each case. This variability suggests limited agreement within peer groups as to how to determine authorship on challenging cases, as well as differences in opinion between the respondent groups. Second, a majority of respondents in all groups were confident in their answers regardless of the case subject, answer choice or perceived frequency. Finally, analysis of 2,841 out of 3,486 possible open-ended answers (81% response rate) highlighted key justifications underlying authorship decisions in the survey  and policies of the sponsor, and they should be finalized prior to first patient enrollment. Standardized language for those criteria should be included in written publication agreements and agreed to by all trial contributors, including those in the authorship working group.When determining these authorship criteria, trial activities meriting an invitation for authorship should be evaluated by their ability to impact broader trial outcomes compared to those serving a more narrow function. It is important to note that definitions for substantial contributions can differ between trials, provided external guidelines such as ICMJE are followed, since trial activities vary greatly across therapeutic areas, stages of development, sponsors and other dimensions. When considering large, multi-national trials, it is especially important to clearly determine substantial contribution criteria as early as possible in the trial, given the large number of contributors involved.In addition to setting the criteria for substantial contribution, the authorship working group should create a process for tracking and documenting all relevant trial contributions that meet the pre-defined criteria as substantial. This process should be made transparent in the written publication agreement, and trial contributors should be notified of the requirement to provide this information as part of ongoing trial responsibilities. To avoid creating new tasks and expense, tracking should be included among normal trial activities where possible.Once trial activities for a given manuscript are completed, the authorship working group should reconvene to apply the criteria to the documented contributions. All trial contributors, regardless of function, responsibility or relationship to trial sponsor(s), meeting the authorship criteria for substantial contribution determined in Step 2 should then be invited to draft/revise the manuscript. However, an invitation for authorship may be declined by a contributor. As part of our discussions with journal editors and clinical investigators, it was noted that while up-front participation is preferred, later contributions sometimes rise to the level of a substantial contribution. The authorship working group should have the responsibility to determine which potential authors made a substantial contribution based on the contribution data and adjudicate disagreements that arise from its decisions. Contributions which do not meet the standard for ‘substantial’ should be agreed to by all authors and noted in the acknowledgements.Those who accept an invitation to draft/revise the manuscript will serve as the initial author list. The final responsibility of the authorship working group is to ensure timely dissemination of findings that are consistent with the pre-specified aims of the clinical trial. Those in the author list should agree on their role prior to drafting the manuscript and all contributions should be fully documented. It is important that members of the author list fulfill the remaining authorship criteria beyond substantial contribution outlined in the written publication agreement. Changes to the author list can occur, either adding those who make a later substantial contribution or removing those who do not fulfill all authorship requirements. However, to maintain transparency, all authorship changes and the accompanying rationale should be documented and agreed to by the entire author list. At submission, the authors should consider providing a summary of the author list and their specific contributions to indicate how authorship was determined.Given the growing demand for increased transparency in publications for clinical trials -24, the Through discussions with journal editors, clinical investigators and industry representatives on the gaps in authorship decision-making that emerged from the survey, we identified key themes for improvement. These themes included defining the criteria for substantial contributions early in the trial, ensuring all trial contributors agree to these criteria and documenting contributions to ensure these criteria are met. Expanding on these key insights, the Five-step Authorship Framework was developed to provide a clear and flexible process to facilitate more transparent and consistent authorship decision-making.The success of the Five-Step Authorship Framework relies significantly on convening a working group early in the trial process to discuss which trial activities should be considered a substantial contribution in the context of current authorship guidelines. Given the wide diversity of trials undertaken and likely future changes in authorship guidelines, defining a comprehensive set of potential activities that meet the definition of ‘substantial’ for authorship is neither practical nor durable. Instead, utilizing the experience and judgment of a diverse group of core trial contributors in an open discussion format provides a transparent process for determining fair and comprehensive authorship criteria for a given trial. In addition, these authorship criteria should align with external guidelines, such as ICMJE and GPP2, to avoid potential bias in selection of criteria that exclude legitimate authorship. Documenting these definitions in authorship agreements ensures that all trial contributors are informed in advance and provides a basis for conflict resolution should a dispute arise. The flexibility of this framework permits authorship criteria specific to each trial, as some trial groups may define significant patient recruitment to be a substantial contribution while others may not (see Case 1). This adaptable format will help facilitate the continued movement away from patient recruitment as sole criteria for substantial contribution and place greater emphasis on intellectual contributions, thus better aligning with the evolving concept of authorship.The authorship working group should also be responsible for determining who has fulfilled the criteria of substantial contribution to help draft the manuscript, ensuring the results are consistent with the aims of the trial. The initial author list should be determined through matching the documented contributions of potential pre-specified authors to the authorship criteria. In this way, the authorship working group would have a data-driven approach to determine which potential authors fulfill criteria 1 of the ICMJE authorship recommendations . In addition, the pre-specified author criteria provide an objective basis for evaluating whether to add or remove an author as contributions come to light during manuscript development (see Cases 2 and 4). Given the importance of its responsibilities, the authorship working group should be a stand-alone group and not subsumed into the trial Steering Committee. As outlined, the authorship working group will not require substantial additional burden and, hence, convening such a group should be feasible.Our survey results identified divergent opinions both within and across respondent groups for how to adjudicate the cases, with varying awareness and reliance on authorship guidelines. Previous research has shown that authorship issues can be seen as either matters of defined rules or obligation . DecisioOur study has limitations related to its methodological approach, which was focused on collecting qualitative input from professional groups involved in industry-sponsored clinical trial publications rather than quantitative data, which can be difficult to collect via online surveys ,28. The The companies included in this publication will support implementation of this tool in their clinical trials to supplement best practice and would encourage other industry members to do so as well to ensure this framework is broadly embedded for maximum impact. Given the contribution from other stakeholders, such as journal editors, the authors will be reaching out to them and other organizations to ask for their help to foster awareness and uptake for the Five-step Framework.This research outlines an approach for manuscripts from industry-sponsored clinical trials that emphasizes early determination of substantial contribution by a diverse group of core participants, clear communication of authorship criteria to all participants and documentation of contributions that leads to less opaque authorship decisions. This Five-Step Authorship Framework has the potential to facilitate decision-making with improved transparency and consistency when recognizing authors for all clinical trial publications, not just those from industry-sponsored efforts.


To comprehensively investigate the types of driving errors and locations that are most problematic for older drivers with glaucoma compared to those without glaucoma using a standardized on-road assessment.Participants included 75 drivers with glaucoma (mean = 73.2±6.0 years) with mild to moderate field loss  and 70 age-matched controls without glaucoma (mean = 72.6 ± 5.0 years). On-road driving performance was assessed in a dual-brake vehicle by an occupational therapist using a standardized scoring system which assessed the types of driving errors and the locations where they were made and the number of critical errors that required an instructor intervention. Driving safety was rated on a 10-point scale. Self-reported driving ability and difficulties were recorded using the Driving Habits Questionnaire.Drivers with glaucoma were rated as significantly less safe, made more driving errors, and had almost double the rate of critical errors than those without glaucoma. Driving errors involved lane positioning and planning/approach, and were significantly more likely to occur at traffic lights and yield/give-way intersections. There were few between group differences in self-reported driving ability.Older drivers with glaucoma with even mild to moderate field loss exhibit impairments in driving ability, particularly during complex driving situations that involve tactical problems with lane-position, planning ahead and observation. These results, together with the fact that these drivers self-report their driving to be relatively good, reinforce the need for evidence-based on-road assessments for evaluating driving fitness. Glaucoma is a leading cause of visual field loss in older populations, affectinDriving is a key component in maintaining the independence of older adults, including those with glaucoma. However, older drivers with glaucoma report a number of driving difficulties, including problems with glare, night driving and tasks requiring peripheral vision and visual search, with avoA number of studies have reported elevated crash risk in drivers with glaucoma, however, the experimental design of these studies has been of variable quality. Earlier studies reported elevated crash rates in drivers with glaucoma,, 12 but The simulator-based driving performance of persons with glaucoma has been compared to those without glaucoma, involving small numbers of drivers with a variety of levels of glaucomatous visual field loss. One study found that drivers with glaucoma adjusted the position of the steering wheel more frequently (exhibited more jerky steering) than did the controls and were also poorer at detecting letters presented in the driving scene than controls, but there were no other between group differences, while a The specific nature of the driving difficulties of those with glaucoma on real roads has not been extensively studied, despite growing evidence that some drivers with glaucoma have an increased risk of motor vehicle collision involvement. The only studies that have assessed on-road driving in drivers with glaucoma have highlighted problems with lane-keeping, negotiating curves and anticipatory skills; and incrThe purpose of this study was to investigate which aspects of driving behavior and types of driving situation are most problematic for drivers with glaucoma. Compared to older adults without glaucoma, we hypothesized that lane control and skills involving observation and planning would be impaired in those with glaucoma; we included individuals with mild to moderate glaucomatous field loss, given they are more likely to be actively driving. This type of information regarding specific driving difficulties is essential to provide the basis for the design of interventions to improve the driving ability and safety of this population.Participants with glaucoma were recruited from the clinical records of the Queensland University of Technology (QUT) Optometry Clinic and private ophthalmology practices, and had been diagnosed as having glaucoma by their treating ophthalmologist. The age-matched control participants were recruited as a convenience sample from our existing database of normally-sighted volunteers as well as from the QUT Optometry Clinic. The participants with glaucoma and the controls were recruited simultaneously and tested in order of recruitment.Participants were excluded if they had any significant ocular or visual pathway disease leading to visual field loss, other than glaucoma; had Parkinson’s Disease; history of dizziness or vestibular disease; used a walking aid; or had signs of cognitive impairment . All partThe study adhered to the tenets of the Declaration of Helsinki and was approved by the Queensland University of Technology Human Research Ethics Committee. All participants were given a full explanation of the nature of the study and experimental procedures, and written informed consent was obtained. Participants attended two testing sessions including an assessment of visual function and self-reported driving, in addition to an assessment of on-road driving performance.2, using the letter-by-letter scoring method.[2, using the letter-by-letter scoring method.[All participants underwent an eye examination that included ophthalmoscopy, slit-lamp biomicroscopy, and fundus photography, to confirm eligibility for the study. Binocular visual acuity with the habitual driving correction was measured with the Early Treatment for Diabetic Retinopathy Study (ETDRS) chart at 5 m, at a luminance of 100 cd/mg method. Binoculag method. A +1.00 g method.Participants also completed the Driving Habits Questionnaire (DHQ), an instrument used to characterize driving habits, exposure, frequency, driving difficulties and provide a self-rating of driving quality. The degrA brief general health questionnaire was administered to record the presence of 15 chronic medical conditions. Hand griDriving performance was assessed under in-traffic conditions in an automatic, dual-brake vehicle using a previously validated technique.–37 An acParticipants drove along a 19.4 km route on the open road, which started with a short familiarization period and then progressed to driving along city and suburban streets, and involved simple and complex intersections for a range of traffic densities. The driving assessment was around 50 minutes in duration, except when the drive was terminated early if the driver was considered too unsafe to proceed. A large proportion of the drive (~75%) was conducted under directed instruction, where the driving instructor provided detailed instructions of the route, while the remaining drive (~25%) was conducted under self-directed navigation, where the participant had to find their own way to a given destination. The occupational therapist scored driving performance at a series of locations along the driving route in terms of driving behaviors (at an average of 149 locations) and scored overall driving safety on a 10 point scale based on driving standards criteria described elsewhere. The propAt each of the locations, several aspects of driving behavior were scored: general observation (scanning and attention), braking/acceleration (appropriate speed and braking), lane positioning, gap selection (gap selected when entering traffic or the gap between the driver and other vehicles) and approach to hazards (appropriate planning and preparation). ObservatEach of the locations was further allocated into one of six situation categories: traffic light controlled intersections, one-way traffic (straight and curved driving), two-way traffic (straight and curved driving), give-way , manoeuvring , and merging . For each situation, the total number of errors as a proportion of the total number of times that performance was assessed at that location was calculated for each participant.Driving errors that were considered by the occupational therapist to pose a significant risk to driving safety and required an instructor intervention to avoid an imminent safety issue (either through applying the brakes or taking control/correction of the steering wheel) were classified as critical errors (CE). Each CE was coded post-testing into one of four broad themes which described the predominant factor associated with the CE: Observation (failed to observe key information in the driving environment); Speed control (excessive or very slow speeds); Lane control (drifting over lanes or failing to keep in lane), and Vehicle control .Where drives were terminated early because of unsafe performance, driving behaviors and situation errors were scored as a proportion of number of locations assessed, and overall driving performance was scored accordingly.2 tests, where appropriate. Linear regression models were used to compare group differences in overall driving performance, driving behaviors and driving situations. For count outcome variables (CE and predominant CE factors), negative binomial regressions were used. All models were further adjusted for cognitive (MMSE score), motor (grip strength) and health status (number of co-morbidities) given that these factors have been shown to be associated with driving ability in previous research;[www.ibm.com). Analyses were two-tailed, and p<0.05 was considered statistically significant.Group differences for the vision and self-reported driving characteristics were examined using independent t-tests and χresearch; the inclParticipants included 75 older drivers aged 65 years and above with a diagnosis of glaucoma and 70 visually normal controls; their demographic and visual characteristics are presented in Participants’ self-reported driving characteristics as determined with the DHQ are shown in 12 = 0.016; p = 0.90).The on-road driving characteristics of the drivers with glaucoma and controls are presented in Blind-spot errors were the most common form of driving behaviour errors in both groups, however, there were no significant between group differences . The driThis study investigated which types of driving errors and driving situations are more problematic in a large sample of drivers with mild to moderate glaucomatous field loss compared to control drivers without glaucoma. Our data reveal that even drivers with mild to moderate field loss exhibit impaired driving performance compared to age-matched controls, being rated as less safe than the controls, having significantly more problems with observation, maintaining lane position and approach and planning than the controls, with driving errors being more common at traffic-light controlled or give-way intersections. The drivers with glaucoma were also significantly more likely to make one or more critical errors that required the driving instructor to intervene and these interventions were particularly associated with errors in observation. This finding that even mild to moderate glaucomatous field loss has important functional consequences supports other research that has shown impairments in activities of daily living such as eye-hand coordination , balanceThe types of driving errors made more often by the glaucomatous drivers included maintaining lane position, approach (including changing lanes and planning ahead) and observation, which suggest problems in appropriately observing the road environment and planning ahead. The finding of increased lane position errors supports the findings of the two small sample studies of drivers with binocular glaucomatous field loss,, 42 whicThe drivers with glaucoma made significantly more errors than controls at traffic light-controlled and give-way (yield) intersections. Importantly, the consequences of errors in these traffic situations are likely to involve multiple road users (vehicles and pedestrians) and have significant safety consequences. While crash data suggests that increasing age is a significant risk factor for the prevalence and severity of intersection crashes, this is The finding of self-reported problems with night-time driving concur with those of a large study by Janz et al and otheconditional licences that permit them to drive only within a limited radius of their home and/or during daylight hours. As for any study conducted under in-traffic conditions, there may be minor variations in weather and traffic, although assessments were only conducted in dry conditions and outside of peak hour traffic, and the occupational therapist took these variations into consideration when rating participants’ driving performance. Indeed, the fact that the study was also conducted outside of peak hour traffic may underestimate the potential driving problems of some of the participants when driving in busy traffic situations.The results of this study should be considered in terms of both its strengths and limitations. Strengths include a driving assessment under real traffic conditions in a wide variety of on-road environments using a standardized route that was both extensive in duration and length and included a variety of different driving challenges which allowed determination of both the type of errors and also the type of traffic locations that were more problematic. Furthermore, both the occupational therapist and driving instructor were masked to participants’ visual characteristics and whether they had glaucoma or not. Finally, we assessed drivers with a range of glaucomatous loss, from early to moderate loss, as these older adults are most likely to be driving on normal road systems, in addition to a representative sample of control drivers without glaucoma. A limitation, as in any study of this nature, is that the drivers were aware that they were being assessed and may have adjusted their driving performance accordingly. In addition, drivers were also assessed in an unfamiliar vehicle and in an unfamiliar driving environment that may have impacted on compensatory strategies; naturalistic studies of drivers with glaucoma in their own vehicles and in their own environments are therefore important for future research, given that many drivers with visual impairment are given In summary, this is the first on-road study to include a large sample of drivers with glaucoma enabling identification of the specific driving error types and driving locations that are most problematic for drivers with glaucoma compared to control drivers without glaucoma. We demonstrated that older drivers with mild to moderate glaucomatous field loss exhibited less safe overall driving performance, and made more errors involving specific driving behaviours and situations. Importantly, in a growing population of drivers with mild to moderate glaucoma, the impact of these differences on road safety will be critical, particularly as problem areas include situations such as traffic-light controlled intersections, where the consequences of errors can be fatal. Thus for older drivers with glaucoma early detection is important, not just to minimise or prevent progression of disease and its associated visual impairment, but also to ensure safe driving performance. We will explore the relationship between a range of standard and novel visual function tests and the driving outcome measures and safety in future papers, which will assist in the design of test batteries to better identify unsafe drivers. Future research will also use these results as a basis to explore potential interventions that can improve the driving ability and safety of this growing population.


Wound therapy improves every year by developing new wound treatment options or by advancing already existing wound materials, for example, adding self-releasing analgesic drugs or growth factors to wound dressings, or by binding and inactivating excessive proteases. Also new dressing materials based on silk fibers and enhanced methods to reduce bacterial burden, for example, cold argon plasma, might help to fasten wound healing. Optimal modern wound dressings should assure a moisture wound bed, help drainage, remove debris of the wound surface, provide optimal thermal stability, might be removed without trauma of the wound bed and wound edge, and be antiallergenic and without immunogenicity. But wound dressings have experienced continuous and significant changes over the years which emanate from a more detailed understanding of wound healing and improved technological, clinical, and scientific research in the field of wound healing. Now, wound dressings are getting more and more functionalized to a targeted therapy by including different pharmaceutical compounds . Those interactive additives might help optimize the healing process.Here, we want to present an overview about some of those new developments in topical wound therapy see also .Debridement is a basic necessity to reduce fibrin and bacterial burden on the wound surface and is therefore a kind of wound bed preparation to (re)induce wound healing. There are different mechanical debridements available , as well as autolytic debridements via hydrogels, enzymatic dressings, or honey, and a biosurgical debridement via larval debridement.Autolytic debridements are normally well tolerated because they cause no or only very little pain, but it takes much more time in contrast to mechanical debridement to reduce slough and fibrinous burden on the wound. Honey might be a little bit more painful in this context due to its osmotic action. On the other hand, honey might be additional antimicrobial effective by this osmotic dehydration, a low pH-value of 3.0–4.5, and the release of small amounts of hydrogen peroxide or methylglyoxal .Normally, mechanical debridement is easy and fast but on the other hand not very selective and for the patient sometimes very painful procedure. A recently induced more gentle method to reduce mechanically slough and fibrinous burden from the wound bed is a monofilament fibre product whose wound-contact side is fleecy and if wetted it has to be wiped over the surface of the wound for 2–4 minutes .Larvae debridement therapy is very selective to necrotic tissue, in most patients also painless, and due to the larval digestive juices secreted by the larvae antimicrobial effective and pH-modulating .Pain is a well-known problem in patients with chronic leg ulcers, especially for elderly patients where it may lead to reduced wound healing rates and reduced quality of life . Causes Beyond the possibility to add analgetics to wound dressings, the structure of the dressing itself can be used to reduce wound pain. Examples for this approach are silicone dressings which can be used to prevent dressing-related trauma or skin stripping while dressing change . DressinGrowth factors (GF) have been shown to promote wound healing in acute wounds by stimulating the growth of keratinocytes. Since the process of wound healing depends on the mitosis and migration of keratinocytes, reduction of GF represents a key factor for chronification of wounds. Application of GF implemented into topical wound dressings represents one possible attempt to face this problem. The in vivo use of a bilayer wound dressing containing epidermal growth factor- (EGF-) loaded microspheres decreased wound areas in a rabbit model in a dose-dependent manner much faster than wound dressings without EGF . InteresArtificial engineered scaffolds for wound healing are mimicking structure and functions to native extracellular matrix. These scaffolds can be created by, for example, bacteria producing cellulose , by cultured transgenic silkworms or by several electrospinning techniques. The last one is an efficient technique to produce a variety of polymeric nanofibers. Electrospun scaffolds for wound healing provide high surface area to volume ratio that promotes cell-matrix interaction at the nanoscale , 14, 15. Bombyx mori or Antheraea mylitta. The sericins ensure the cohesion of the cocoon by sticking the twin filaments together and constitute 25–30% of the weight of the fiber [Wound dressings can be composed of synthetic or biologic materials. One of those with biologic materials is wound dressings made of silk. Silkworm silk fibers are composed of two fibrous protein microfilaments (fibroins) embedded in a glue-like glycoprotein coating (sericin)  and can he fiber . Finallyhe fiber .Silk represents a new family of advanced biomaterials as a basis for wound dressings . It is gKanokpanont et al.  evaluateThe wax-coated silk fibroin fabrics showed improved mechanical properties less adhesive characteristics than the commercial wound dressing. The sericin-silk fibroin/gelatin spongy bioactive layers showed homogeneous porous structure and controllable biodegradation depending on the degree of cross-linking. Furthermore, they proved that fibroin can improve wound healing by supporting of attachment of epidermal cells and fibroblasts spreading and proliferation , 27. TheBombyx mori) that can combine their silk thread with human growth factors, for example, with epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), platelet derived growth factor (PDGF), or vascular endothelial growth factor (VEGF) [There exist transgenic silkworms (r (VEGF) . It has r (VEGF) .Also Schneider et al.  describeThey demonstrated that EGF is incorporated into the silk mats and is slowly released in a time-dependent manner (25% EGF release in 170 h) initiated by a burst effect on keratinocytes on the wound edge. This can be explained by the fact that the protein is not only inside the fiber but also at the surface. The first increase of EGF concentration is due to the ones on the surface of the silk fibers, and the second part of the release profile shows a more smooth increase, while EGF is released due to diffusion of the EGF molecules from inside the silk fibers to the fiber surface.So they could demonstrate in vivo with their human three-dimensional model that the biofunctionalized silk mats aid the healing by increasing the time of wound closure by the epidermal edge by 90%. Structure of the mats was preserved during the healing period.Gil et al.  comparedOne alternative method to transfer endogenous growth factors to the wound area is the production of autologous platelet-rich fibrin (PRF) that is prepared from a simple blood sample of the patient and is therefore a really low burden to the patient. PRF contains fibrin and high concentrations of different growth factors. Using autologous material decreases the risk of adverse events like allergenic reactions and delivers a cocktail of different growth factors in comparison with topically applied single heterologous growth factors. Large systematic reviews of this therapy exist, but while one meta-analysis in which studies about acute wounds were also included found a sufficient efficacy to stimulate healing even in long-lasting wounds  and diabWhile the deposition of GF on the wound area from external sources like wound dressings or via PRF could so far not sustain its position within standard wound treatments, the focus extended to the observation that chronic wounds have raised levels of protease activity and any GF that are applied to the wound are often subjected to proteolytic degradation which renders them inactive. In chronic wounds, matrix metalloproteinases (MMP) have been implicated by a number of studies as the major protease family responsible for the degradation of key factors critical to the ulcer's ability to heal . While, By binding and inactivating excessive proteases like MMP, endogenous growth factors are saved from degradation. For this reason, wound dressings with MMP inhibiting agents have recently been developed and are expected to improve the local treatment of these chronic wounds. Native bovine collagen type I was shown to bind proinflammatory cytokines and to decrease distinctively the concentration of MMP in wound fluids collected under treatment with a collagen-containing wound dressing . A woundIn another model, a nano-oligosaccharide factor (NOSF) was incorporated into a neutral Lipido-Colloid Technology (TLC) dressing and MMP inhibition by complex formation with TIMP could be demonstrated in vitro . In direIn vitro experiments showed that polyacrylate superabsorbers were capable of binding MMPs directly and additionally reduced the enzymatic activity of MMPs by competitive ion binding .Reducing protease activity in chronic wounds can only be one of several strategies in the treatment of stalling wounds. Proteases represent one of the best available biomarker to provide information about the status of a wound. Elevated protease levels in chronic wounds may not be characterized with other clinical criteria than presence of slough or fibrin. Therefore, diagnostic tests were generated, but additional research is recommended to evaluate the efficacy of such tests and the treatments and therapies applied when elevated protease levels are found , 51.Bacterial colonization of chronic wounds is common and a well-recognized factor contributing to impaired wound healing , 53. To Antiseptics are used extensively to reduce bacterial load on the wound surface. Limitations for some antiseptics might be their cytotoxic and their allergenic potential. The most frequently used antiseptics without significant cytotoxic or allergenic potential are polyhexanide, octenidine, or silver-containing wound dressings. PVP iodine is used very often, too, because it is very cheap and effective but contains a relevant allergenic potential.The broad antimicrobial effect of silver ions is based on complex formation with bacterial proteins leading to loss of function and structure of the bacterial membrane. Interaction with the enzymatic system and changes in the genetic information promote cell death. In vitro models showed a cytotoxic and wound healing delay in a mouse model. While the use of silver dressings has become very popular in standard wound care, a prospective randomized controlled trial (VULCAN) could not verify a significant effect on wound healing .Similar inconsistent results were found in an RCT analysing treatment of chronic lower leg ulcers with a polyhexamethylene biguanide (PHMB) coated foam compared to standard foam dressings. While a significant reduction of wound pain and bacterial burden can be achieved, reduction of wound area could not be fastened . AnotherIn addition to the use of antimicrobial wound dressings, other physical strategies to remove bacterial burden are in use. A new and promising method in this physical field is cold atmospheric plasma . In addiHigh-temperature plasmas are already in medical use for the sterilization of equipment, tissue destruction, cutting, and cauterizing. Cold atmospheric argon plasma has the same advantages as high-temperature plasmas but without heat production. An even plasma dose can be applied to different wound surfaces, and also larger wound areas (up to 6 cm diameter) can be treated within a single application .P < 10−6; 40%, P < 0.016) reduction of bacterial colonization in the plasma-treated wounds, regardless of the species of colonizing bacteria. No side-effects occurred and the treatment was well tolerated.Isbary et al. demonstrated that a 5-minute treatment in 38 wounds (291 treatments)  as well n  =  34) showed significantly improved healing compared with placebo-treated areas . Wound infection did not occur in any of the patients, and no relevant side effects were observed [To proof if cold plasma treatment can also improve wound healing, forty patients with skin graft donor sites (acute wounds) on the upper leg were enrolled in a placebo controlled study . The wouobserved .But not only in acute wounds but also in patients with chronic wounds, the effect of cold plasma application was evaluated . ChronicSometimes it is very difficult to treat especially chronic wounds properly due to missing options for diagnostic measurements on different wound parameters. At the moment there are few options available in wound surface diagnostics, but in most cases therapeutic conclusions are still missing.A few years ago, a new measurement tool to detect elevated protease activity on the wound surface and in the wound fluid was developed: the so-called “woundchek” . Unfortunately at the moment, further therapeutic options to reduce or inhibit measured increased protease activity are still missing.Normally, healing wounds show a lower pH-value in contrast to a more basic pH-value of chronic nonhealing wounds . VariatiIn a recent study the pH levels of 4 different wound dressings  were compared regarding their effect on pH-value. All dressings were found to have a low pH (below pH 4). The lowest was the protease modulating collage cellulose dressing with a pH of 2.3. By this, the acidic nature of the analyzed wound dressings might influence the healing process in the wound .Continuous in situ pH measurement on the wound surface is not possible at the moment due to a lack of suitable technologies. Normally, for pH monitoring, flat bottomed conventional glass pH probes are used. Recent innovations for wound pH sensing have developed a luminescent sensor spray with additional advantage of its applicability to uneven tissue surfaces due to its consistency. Images of the wound surface might result in pseudocolor pH maps of the area . A new tAll chronic wounds may be contaminated by microorganisms. But, in some cases, it is difficult to decide whether this wound is clinically infected or at least colonized with a critical bioburden of bacteria. Traditional criteria for wound infections are cellulitis and in most cases also abscess and development of pus.In all other cases suggestive of critical or initial infection, it might be possible to seek secondary signs of infection. Some of them might be for venous leg ulcers increase in local skin temperature, increase or change in ulcer pain, newly formed ulcers within flamed margins of preexisting ulcers, wound bed extension within inflamed margins, or delayed healing despite appropriate compression therapy . Those aWound treatment has come a long way since its beginning and this is largely due to improved understanding of the physical characteristics of wound healing and the availability of smart wound dressing materials. Nowadays, wound dressings should not only serve as exudate managers or absorbents, and they should also interact on a cellular level to treat imbalances in wound milieu to improve wound healing.Also new physical techniques and dressing materials like cold argon plasma or silk fibers found their way as innovative treatment options into wound therapy see .