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The contribution of the ipsilateral (nonaffected) hemisphere to recovery of motor function after stroke is controversial. Under the assumption that functionally relevant areas within the ipsilateral motor system should be tightly coupled to the demand we used fMRI and acoustically paced movements of the right index finger at six different frequencies to define the role of these regions for recovery after stroke. Eight well-recovered patients with a chronic striatocapsular infarction of the left hemisphere were compared with eight age-matched participants. As expected the hemodynamic response increased linearly with the frequency of the finger movements at the level of the left supplementary motor cortex (SMA) and the left primary sensorimotor cortex (SMC) in both groups. In contrast, a linear increase of the hemodynamic response with higher tapping frequencies in the right premotor cortex (PMC) and the right SMC was only seen in the patient group. These results support the model of an enhanced bihemispheric recruitment of preexisting motor representations in patients after subcortical stroke. Since all patients had excellent motor recovery contralesional SMC activation appears to be efficient and resembles the widespread, bilateral activation observed in healthy participants performing complex movements, instead of reflecting maladaptive plasticity. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Skilled spoken language production requires fast and accurate coordination of up to 100 muscles. A long-standing concept—tracing ultimately back to Paul Broca—assumes posterior parts of the inferior frontal gyrus to support the orchestration of the respective movement sequences prior to innervation of the vocal tract. At variance with this tradition, the insula has more recently been declared the relevant “region for coordinating speech articulation”, based upon clinico-neuroradiological correlation studies. However, these findings have been criticized on methodological grounds. A survey of the clinical literature (cerebrovascular disorders, brain tumours, stimulation mapping) yields a still inconclusive picture. By contrast, functional imaging studies report more consistently hemodynamic insular responses in association with motor aspects of spoken language. Most noteworthy, a relatively small area at the junction of insular and opercular cortex was found sensitive to the phonetic-linguistic structure of verbal utterances, a strong argument for its engagement in articulatory control processes. Nevertheless, intrasylvian hemodynamic activation does not appear restricted to articulatory processes and might also be engaged in the adjustment of the autonomic system to ventilatory needs during speech production: Whereas the posterior insula could be involved in the cortical representation of respiration-related metabolic (interoceptive) states, the more rostral components, acting upon autonomic functions, might serve as a corollary pathway to “voluntary control of breathing” bound to corticospinal and -bulbar fiber tracts. For example, the insula could participate in the implementation of task-specific autonomic settings such as the maintenance of a state of relative hyperventilation during speech production. [ABSTRACT FROM AUTHOR]

Abstract: Functional imaging studies have delineated a “minimal network for overt speech production”, encompassing mesiofrontal structures (supplementary motor area, anterior cingulate gyrus), bilateral pre- and postcentral convolutions, extending rostrally into posterior parts of the inferior frontal gyrus (IFG) of the language-dominant hemisphere, left anterior insula as well as bilateral components of the basal ganglia, the cerebellum, and the thalamus. In order to further elucidate the specific contribution of these cerebral regions to speech motor planning, subjects were asked to read aloud visually presented bisyllabic pseudowords during functional magnetic resonance imaging (fMRI). The test stimuli systematically varied in onset complexity (CCV versus CV) and frequency of occurrence (high-frequency, HF versus low-frequency, LF) of the initial syllable. A cognitive subtraction approach revealed a significant main effect of syllable onset complexity (CCV versus CV) at the level of left posterior IFG, left anterior insula, and both cerebellar hemispheres. Conceivably, these areas closely cooperate in the sequencing of subsyllabic aspects of the sound structure of verbal utterances. A significant main effect of syllable frequency (LF versus HF), by contrast, did not emerge. However, calculation of the time series of hemodynamic activation within the various cerebral structures engaged in speech motor control revealed this factor to enhance functional connectivity between Broca’s area and ipsilateral anterior insula. [Copyright &y& Elsevier]

Abstract: Recent functional MRI (fMRI) studies have revealed an increased task-related activation in older subjects during a variety of cognitive or perceptual tasks, which may signal beneficial compensatory activity to counteract structural and neurochemical changes associated with aging. Under the assumption that incremental movement rates are associated with an increased functional demand on the motor system, we used fMRI and acoustically paced movements of the right index finger at six different frequencies (2.0, 2.5, 3.0, 4.0, 5.0 and 6.0 Hz) to investigate the behavioral significance of additionally recruited brain regions in a group of healthy, older subjects (mean age 66 ± 8 years) compared with a group of young (mean age 23 ± 7 years) subjects. The actual tapping frequency (F(1,14) = 0.049, P = 0.829), the tapping interval (F(1,14) = 0.043, P = 0.847), and the error rates (F(1,14) = 0.058, P = 0.743) did not differ significantly between both groups, whereas there was a significant increase in reaction time in the older subjects (F(1,14) = 281.786, P ≤ 0.001). At all frequencies, the older subjects demonstrated significant overactivation within the ipsilateral sensorimotor and premotor cortex. However, we did not observe an increased age-related overactivation during higher movements rates in these or other motor regions. Moreover, the magnitude of the hemodynamic response in overactivated regions remained constant across all frequencies. In contrast to cognitive tasks, these findings indicate that an age-related overactivation within the motor system is not related to the functional demand and does not necessarily reflect reorganization to compensate for the neurobiological changes of aging. [Copyright &y& Elsevier]

Abstract: So far, only sparse data on the cerebral organization of speech motor control are available. In order to further delineate the neural basis of articulatory functions, fMRI measurements were performed during self-paced syllable repetitions at six different frequencies (2–6 Hz). Bilateral hemodynamic main effects, calculated across all syllable rates considered, emerged within sensorimotor cortex, putamen, thalamus and cerebellum. At the level of the caudatum and the anterior insula, activation was found restricted to the left side. The computation of rate-to-response functions of the BOLD signal revealed a negative linear relationship between syllable frequency and response magnitude within the striatum whereas cortical areas and cerebellar hemispheres exhibited an opposite activation pattern. Dysarthric patients with basal ganglia disorders show unimpaired or even accelerated speaking rate whereas, in contrast, cerebellar dysfunctions give rise to slowed speech tempo which does not fall below a rate of about 3 Hz. The observed rate-to-response profiles of the BOLD signal thus might help to elucidate the pathophysiological mechanisms of dysarthric deficits in central motor disorders. [Copyright &y& Elsevier]

Based on clinical and functional imaging data, the left anterior insula has been assumed to support prearticulatory functions of speech motor control such as the “programming” of vocal tract gestures. In order to further elucidate this model, a recent functional magnetic resonance imaging (fMRI) study of our group () investigated both overt (aloud) and covert (silent) production of highly overlearned word strings (“automatic speech”), based on the suggestion that “inner speech” might provide a “window” into preparatory motor activities (). As a control condition, subjects were asked to reproduce a nonlyrical tune. In contrast to hemodynamic responses within motor cortex and cerebellum, activation of the intrasylvian cortex turned out to be bound to overt task performance. Rather than prearticulatory processes, these findings suggest the left insula to contribute to the actual coordination of the up to 100 muscles engaged in articulation and phonation. Conceivably, the association of speech production with intrasylvian cortex might have evolved within the framework of phylogenetically older connections between the insula and limbic structures, on the one hand, and nonspeech functions of the upper midline musculature such as swallowing, on the other. Whereas (overt) speech tasks predominantly elicit activation within left anterior insula, reproduction of a nonlyrical tune yielded an opposite response pattern. Conceivably, the opposite distributional pattern of speaking and singing at the level of intrasylvian cortex reflects operation of the two hemispheres across different time domains (“double filtering by frequency theory”: left hemisphere=segmental information, right hemisphere=intonation contours of verbal utterances and musical melodies; ). In line with this suggestion, a further study of our group () provided first evidence that differential hemispheric filtering might be bound to insular cortex. [Copyright &y& Elsevier]

A multitude of functional imaging studies revealed a mass activation effect at the level of the sensorimotor cortex during repetitive finger-tapping or finger-to-thumb opposition tasks in terms of either a stepwise or a monotonic relationship between movement rate and hemodynamic response. With respect to subcortical structures of the centralmotor system, there is, by contrast, some preliminary evidence for nonlinear rate/response functions within basal ganglia and cerebellum. To further specify these hemodynamic mechanisms, functional magnetic resonance imaging (fMRI) was performed during a finger-tapping task in response to acoustic stimuli (six different frequencies: 2.0, 2.5, 3.0, 4.0, 5.0 and 6.0 Hz; applied via headphones). Passive listening to the same auditory stimuli served as a control condition. Statistical evaluation of the obtained data considered two approaches: categorical and parametric analysis. As expected, the magnitude of the elicited hemodynamic response within left sensorimotor cortex (plateau phase at frequencies above 4 Hz) and mesiofrontal cortex paralleled movement rate. The observed bipartite mesial response pattern, most presumably, reflects functional compartmentalization of supplementary motor area (SMA) in a rostral component (pre-SMA) and in a caudal (SMA proper) component. At the level of the cerebellum, two significant hemodynamic responses within the hemisphere ipsilateral to the hand engaged into finger tapping (anterior/posterior quadrangular lobule and posterior quadrangular lobule) could be observed. Both activation foci exhibited a stepwise rate/response function. In accordance with clinical data, these data indicate different cerebellar contributions to motor control at frequencies below or above about 3 Hz, respectively. Caudate nucleus, putamen, and external pallidum of the left hemisphere displayed, by contrast, a negative linear rate/response relationship. The physiological significance of these latter findings remains to be clarified. [Copyright &y& Elsevier]

Rhythm in terms of the modulation of syllable durations represents an information-bearing feature of verbal utterances contributing both to the meaning of a sentence (linguistic prosody) as well as a speaker''s emotional expression (affective prosody). In order to delineate the neural structures subserving rhythmic shaping of speech production, functional magnetic resonance imaging (fMRI) was performed during (a) isochronous syllable repetitions and (b) production of syllable triplets with lengthening either of the initial or final unit. A cognitive subtraction approach (rhythmic versus isochronous iterations) revealed activation of right-sided perisylvian areas (superior temporal gyrus, Broca analogue and adjacent premotor cortex) as well as contralateral subcortical structures (putamen and thalamus). Presumably, these responses reflect a right-hemisphere rehearsal mechanism of rhythmic patterns and left-hemisphere monitoring of verbal output. [Copyright &y& Elsevier]

A letter to the editor discussing a case of 36-year-old man with late onset vanishing white matter disease is presented.

A letter to the editor is presented dealing with the issue of cerebellar hemorrhage after angioplasty.

Different motor neuron disorders (MND s) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projection s to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Diffusion tensor imaging (DTI) provides comprehensive information about quantitative diffusion and connectivity in the human brain. Transformation into stereotactic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The objective of the present study was to optimize technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. Methods: Different averaging methods for mean diffusion-weighted images containing DTI information were compared, i.e., region of interest-based fractional anisotropy (FA) mapping, fiber tracking (FT) and corresponding tractwise FA statistics (TFAS). The novel technique of intersubject FT that takes into account directional information of single data sets during the FT process was compared to standard FT techniques. Application of the methods was shown in the comparison of normal subjects and subjects with defined white matter pathology (alterations of the corpus callosum). Results: Fiber tracking was applied to averaged data sets and showed similar results compared with FT on single subject data. The application of TFAS to averaged data showed averaged FA values around 0.4 for normal controls. The values were in the range of the standard deviation for averaged FA values for TFAS applied to single subject data. These results were independent of the applied averaging technique. A significant reduction of the averaged FA values was found in comparison to TFAS applied to data from subjects with defined white matter pathology (FA around 0.2). Conclusion: The applicability of FT techniques in the analysis of different subjects at the group level was demonstrated. Group comparisons as well as FT on group averaged data were shown to be feasible. The objective of this work was to identify the most appropriate method for intersubject averaging and group comparison which incorporates intersubject variability of the directional information. [Copyright &y& Elsevier]

A classical tenet of clinical neurology proposes that cerebellar disorders may give rise to speech motor disorders (ataxic dysarthria), but spare perceptual and cognitive aspects of verbal communication. During the past two decades, however, a variety of higher-order deficits of speech production, e.g., more or less exclusive agrammatism, amnesic or transcortical motor aphasia, have been noted in patients with vascular cerebellar lesions, and transient mutism following resection of posterior fossa tumors in children may develop into similar constellations. Perfusion studies provided evidence for cerebello-cerebral diaschisis as a possible pathomechanism in these instances. Tight functional connectivity between the language-dominant frontal lobe and the contralateral cerebellar hemisphere represents a prerequisite of such long-distance effects. Recent functional imaging data point at a contribution of the right cerebellar hemisphere, concomitant with language-dominant dorsolateral and medial frontal areas, to the temporal organization of a prearticulatory verbal code ('inner speech'), in terms of the sequencing of syllable strings at a speaker's habitual speech rate. Besides motor control, this network also appears to be engaged in executive functions, e.g., subvocal rehearsal mechanisms of verbal working memory, and seems to be recruited during distinct speech perception tasks. Taken together, thus, a prearticulatory verbal code bound to reciprocal right cerebellar/left frontal interactions might represent a common platform for a variety of cerebellar engagements in cognitive functions. The distinct computational operation provided by cerebellar structures within this framework appears to be the concatenation of syllable strings into coarticulated sequences. [ABSTRACT FROM AUTHOR]

Functional imaging demonstrated hemodynamic activation within specific brain areas that contribute to frequency-dependent movement control. Previous investigations demonstrated a linear relationship between movement and hemodynamic response rates within cortical regions, whereas the basal ganglia displayed an inverse neural activation pattern. We now investigated neural correlates of frequency-related finger movements in patients with Parkinson's disease (PD) to further elucidate the neurofunctional alterations in cortico-subcortical networks in that disorder. We studied ten PD patients (under dopaminergic medication) and ten healthy subjects using a finger-tapping task at three different frequencies (1-4 Hz), implemented in an event-related, sparse sampling fMRI design. FMRI data were analyzed by means of a parametric approach to relate movement rates and regional BOLD signal alteration. Compared to healthy controls, PD patients showed higher tapping response rates only during the lower 1 Hz condition. FMRI analysis revealed a rate-dependent neural activity within the supplemental motor area, primary sensorimotor cortex, thalamus and the cerebellum with higher neural activity at higher frequency conditions in both groups. Within the putamen/pallidum, an inverse neural activity and frequency response correlation could be observed in healthy subjects with higher BOLD signal responses in slow frequencies, whereas this relationship was not evident in PD patients. We could demonstrate similar behavioral responses and neural activation patterns at the level both of frontal and cerebellar areas in PD compared to healthy controls, whereas regions like the putamen/pallidum appear to be still dysfunctional under medication regarding frequency-related neural activation. These findings may, potentially, serve as a neural signature of basal ganglia dysfunctions in frequency-related task requirements. [ABSTRACT FROM AUTHOR]

Abstract: This fMRI study investigated phonological vs. auditory temporal processing in developmental dyslexia by means of a German vowel length discrimination paradigm (). Behavioral and fMRI data were collected from dyslexics and controls while performing same-different judgments of vowel duration in two experimental conditions. In the temporal, but not in the phonological condition, hemodynamic brain activation was observed bilaterally within the anterior insular cortices in both groups and within the left inferior frontal gyrus (IFG) in controls, indicating that the left IFG and the anterior insular cortices are part of a neural network involved in temporal auditory processing. Group subtraction analyses did not demonstrate significant effects. However, in a subgroup analysis, participants performing low in the temporal condition (all dyslexic) showed decreased activation of the insular cortices and the left IFG, suggesting that this processing network might form the neural basis of temporal auditory processing deficits in dyslexia. [Copyright &y& Elsevier]

Abstract: Behavioral and electrophysiological data indicate compromised stimulus suppression in schizophrenia. The physiological basis of this effect and its contributions to the etiology of the disease are poorly understood. We examined neural and metabolic measures of P50 suppression in 12 patients with schizophrenia and controls. First, whole-head magnetoencephalography (MEG) assessed amplitudes of left- and right-hemispheric evoked responses and induced oscillations. Secondly, functional magnetic resonance imaging (fMRI) measured the hemodynamic responses to pairs of beeps with a short interval (500ms) as compared with those with a long interval (1500ms). The suppression of alpha power (8–13Hz) time-locked to the stimuli was negatively correlated with the suppression of evoked components and the hemodynamic measures. Remarkably, the suppression of alpha power was reduced in the patients already prior to stimulus onset. Conceivably, alpha oscillations play a central role in stimulus adaptation of neuronal networks and reflect an active mechanism for sensory suppression. The reduced stimulus suppression in schizophrenia seems to be in part due to impaired generation of alpha oscillations in the auditory cortex, resulting in higher metabolic demand as detected by fMRI. Delayed recovery of alpha rhythm may reflect an impaired gating function and contribute to sensory and cognitive deficits in schizophrenia. [Copyright &y& Elsevier]

INTRODUCTION In order to obtain detailed information on disease-associated changes in the integrity of cerebral white matter (WM), complementary image analysis (CIA) was applied to patients with amyotrophic lateral sclerosis (ALS) and controls. METHODS Both diffusion tensor imaging and T1-weighted 3-dimensional data were analyzed with respect to WM microstructure and T1 signal intensity alterations, respectively, in a sample of 19 ALS patients. Covariate information was added in the form of clinical parameters. All results were obtained in one common analysis software environment (Tensor Imaging and Fiber Tracking). RESULTS Complementary analysis and display were performed for WM directionality and structure. Significant WM differences between ALS patients and controls were observed both in the motor system, that is, the bilateral corticospinal tracts, and in extramotor brain areas, in part correlating with clinical parameters. The performance of all analyses in one software environment enabled the synopsis of results obtained from various analyses. DISCUSSION/CONCLUSION Within the application of CIA to a neurodegenerative disease for the whole brainbased analysis of WM alterations together with clinical characteristics, it could be demonstrated that ALS was associated with WM changes within and outside the motor system. [ABSTRACT FROM AUTHOR]

Abstract: Clinical data indicate that the brain network of speech motor control can be subdivided into at least three functional–neuroanatomical subsystems: (i) planning of movement sequences (premotor ventrolateral–frontal cortex and/or anterior insula), (ii) preparedness for/initiation of upcoming verbal utterances (supplementary motor area, SMA), and (iii) on-line innervation of vocal tract muscles, i.e., motor execution (corticobulbar system, basal ganglia, cerebellum). Using an event-related design, this functional magnetic resonance imaging (fMRI) study sought to further delineate the contribution of SMA to pre-articulatory processes of speech production (preceding the innervation of vocal tract muscles) during an acoustically paced syllable repetition task forewarned by a tone signal. Hemodynamic activation across the whole brain and the time courses of the responses in five regions of interest (ROIs) were computed. First, motor preparation was associated with a widespread bilateral activation pattern, encompassing brainstem structures, SMA, insula, premotor ventrolateral–frontal areas, primary sensorimotor cortex (SMC), basal ganglia, and the superior cerebellum. Second, calculation of the time courses of BOLD (“blood oxygenation level-dependent”) signal changes revealed the warning stimulus to elicit synchronous onset of hemodynamic activation in these areas. However, during 4-s intervals of syllable repetitions SMA and cerebellum showed opposite temporal activation patterns in terms of a shorter (SMA) and longer (cerebellum) latency of the entire BOLD response—as compared to SMC, indicating different pacing mechanisms during the initial and the ongoing phase of the task. Nevertheless, the contribution of SMA was not exclusively restricted to the preparation/initiation of verbal responses since the extension of mesiofrontal activation varied with task duration. [Copyright &y& Elsevier]

Developmental dyslexia has been assumed to arise from general auditory deficits, compromising rapid temporal integration both of linguistic and nonlinguistic acoustic stimuli. Because the effort of auditory temporal processing of speech and nonspeech test materials may depend on presentation rate, fMRI measurements were performed in dyslexics and controls during passive listening to series of syllable and click sounds, using a parametric approach. Controls showed a decrease of hemodynamic brain activation within the right and an increase within the left anterior insula as a function of the presentation rate both of click as well as syllable trains. By contrast, dyslexics exhibited this profile of hemodynamic responses under the nonspeech condition only. As concerns syllables, activation in dyslexics did not depend on presentation rate. Moreover, a subtraction analysis of hemodynamic main effects across conditions and groups revealed decreased activation both of the left and right anterior insula in dyslexics compared to controls during application both of click and syllables. These results indicate, in line with preceding studies, that the insula of both hemispheres is involved in auditory temporal processing of nonlinguistic auditory stimuli and demonstrate, furthermore, that these operations of intrasylvian cortex also extend to the linguistic domain. In addition, our data suggest that the anterior insula represents an important neural correlate of deficient temporal processing of speech and nonspeech sounds in dyslexia. Hum Brain Mapp 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. Bulbar symptoms such as dysphagia and dysarthria are frequent features of ALS and can result in reductions in life expectancy and quality of life. These dysfunctions are assessed by clinical examination and by use of instrumented methods such as fiberendoscopic evaluation of swallowing and videofluoroscopy. Laryngospasm, another well-known complication of ALS, commonly comes to light during intubation and extubation procedures in patients undergoing surgery. Laryngeal and pharyngeal complications are treated by use of an array of measures, including body positioning, compensatory techniques, voice and breathing exercises, communication devices, dietary modifications, various safety strategies, and neuropsychological assistance. Meticulous monitoring of clinical symptoms and close cooperation within a multidisciplinary team (physicians, speech and language therapists, occupational therapists, dietitians, caregivers, the patients and their relatives) are vital. [ABSTRACT FROM AUTHOR]

Abstract: Isolated severe weakness of the paraspinal musculature, either at the cervical level leading to a “dropped head syndrome” or at the thoracic level leading to a “bent-spine syndrome”, is a rare disorder. Etiologically it may be present in a variety of neurological diseases including Parkinson''s disease, multiple system atrophy, neuromuscular or motor neuron diseases, as well as non-inflammatory, inflammatory, dystrophic or metabolic myopathies. We present a previously healthy 74-year-old man with a 2-month history of progressive difficulty in lifting his chin off his chest. Magnetic resonance imaging and skeletal muscle biopsy revealed an isolated myositis of the neck extensor and trapezius muscles, which responded well to steroid therapy. This case and other rare reports obtained from a systematic review of the literature indicate that in a subgroup of patients “dropped head syndrome” or “bent spine syndrome” is caused by a myositis, which emphasizes the necessity to obtain a MRI examination, as well as a muscle biopsy to diagnose this potentially treatable disease. [Copyright &y& Elsevier]

Abstract: As part of the frontotemporal dementias, primary progressive aphasia (PPA) is typically characterized by nonfluent speech with paraphasias, but there is growing evidence that also a fluent variant of PPA exists. We describe a patient suffering from PPA who adds to the broad clinical spectrum of this disorder. Moreover, we report for the first time that PPA may be associated with severe impairment in meaningful nonverbal sound recognition (environmental sound agnosia). These neuropsychological findings were found to be associated with distinct focal alterations in functional and structural neuroimaging. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial," by L. Kalra and colleagues in the 2015 issue.