Synchronizing Automatic Gain Control in Bilateral Cochlear Implants Mitigates Dynamic Localization Deficits Introduced by Independent Bilateral Compression.

OBJECTIVES: The independence of left and right automatic gain controls (AGCs) used in cochlear implants can distort interaural level differences and thereby compromise dynamic sound source localization. We assessed the degree to which synchronizing left and right AGCs mitigates those difficulties as indicated by listeners' ability to use the changes in interaural level differences that come with head movements to avoid front-back reversals (FBRs). DESIGN: Broadband noise stimuli were presented from one of six equally spaced loudspeakers surrounding the listener. Sound source identification was tested for stimuli presented at 70 dBA (above AGC threshold) for 10 bilateral cochlear implant patients, under conditions where (1) patients remained stationary and (2) free head movements within ±30° were encouraged. These conditions were repeated for both synchronized and independent AGCs. The same conditions were run at 50 dBA, below the AGC threshold, to assess listeners' baseline performance when AGCs were not engaged. In this way, the expected high variability in listener performance could be separated from effects of independent AGCs to reveal the degree to which synchronizing AGCs could restore localization performance to what it was without AGC compression. RESULTS: The mean rate of FBRs was higher for sound stimuli presented at 70 dBA with independent AGCs, both with and without head movements, than at 50 dBA, suggesting that when AGCs were independently engaged they contributed to poorer front-back localization. When listeners remained stationary, synchronizing AGCs did not significantly reduce the rate of FBRs. When AGCs were independent at 70 dBA, head movements did not have a significant effect on the rate of FBRs. Head movements did have a significant group effect on the rate of FBRs at 50 dBA when AGCs were not engaged and at 70 dBA when AGCs were synchronized. Synchronization of AGCs, together with head movements, reduced the rate of FBRs to approximately what it was in the 50-dBA baseline condition. Synchronizing AGCs also had a significant group effect on listeners' overall percent correct localization. CONCLUSIONS: Synchronizing AGCs allowed for listeners to mitigate front-back confusions introduced by unsynchronized AGCs when head motion was permitted, returning individual listener performance to roughly what it was in the 50-dBA baseline condition when AGCs were not engaged. Synchronization of AGCs did not overcome localization deficiencies which were observed when AGCs were not engaged, and which are therefore unrelated to AGC compression.

Right cardiac involvement in lung diseases: a multimodality approach from diagnosis to prognostication.

Lung diseases are amongst the main healthcare issues in the general population, having a high burden of morbidity and mortality. The cardiovascular system has a key role in patients affected by respiratory disorders. More specifically, the right ventricle (RV) enables the impaired lung function to be overcome in an initial stage of disease process, reducing the severity of dyspnoea. In addition, two of the main causes of death in this setting are RV failure and sudden cardiac death (SCD). Echocardiography is regarded as a useful and easily available tool in assessing RV function. Several noninvasive echocardiographic parameters of elevated pulmonary pressures and RV function have been proposed. The combination of different parameters and imaging methods is paramount and researches regarding RV impairment using these indices has been specifically addressed in relation to the chronic obstructive and restrictive lung disease in order to guide the clinicians in the management of these patients. Cardiac involvement in lung diseases is often observed, and RV changes are reported also in early stages of pulmonary diseases. The role of right ventricle in chronic respiratory disease patients has to be evaluated in detail to describe the response to therapy and the degree of disease progression through multimodality and advanced imaging techniques. The aim of this review is to describe the different pathophysiological mechanisms of cardiac impairment in primary lung disease (such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and sarcoidosis) and to summarize the role of cardiac multimodality imaging in the diagnosis and the prognosis of these diseases.

Self-Induced Glassy Phase in Multimodal Cavity Quantum Electrodynamics.

We provide strong evidence that the effective spin-spin interaction in a multimodal confocal optical cavity gives rise to a self-induced glassy phase, which emerges exclusively from the peculiar Euclidean correlations and is not related to the presence of disorder as in standard spin glasses. As recently shown, this spin-spin effective interaction is both nonlocal and nontranslational invariant, and randomness in the atoms' positions produces a spin glass phase. Here we consider the simplest feasible disorder-free setting, where atoms form a one-dimensional regular chain and we study the thermodynamics of the resulting effective Ising model. We present extensive results showing that the system has a low-temperature glassy phase. The model depends on the adimensional parameter α=(a/w_{0})^{2}, a being a lattice spacing and w_{0} an interaction length scale. Notably, for rational values of α=p/q, the number of metastable states at low temperature grows exponentially with q and the problem of finding the ground state rapidly becomes computationally intractable, suggesting that the system develops high-energy barriers and ergodicity breaking occurs.

Time-dependent cognitive and somatic symptoms of depression as predictors of new cardiac-related events in at-risk patients: the UPBEAT-UK cohort.

BACKGROUND: Evidence suggests that somatic rather than cognitive depressive symptoms are risk factors for recurrent cardiac events in at-risk patients. However, this has never been explored using a time-dependent approach in a narrow time-frame, allowing a cardiac event-free time-window. METHODS: The analysis was performed on 595 participants [70.6% male, median age 72 (27-98)] drawn from the UPBEAT-UK heart disease patient cohort with 6-monthly follow-ups over 3 years. Depressive symptomatology was measured using the Patient Health Questionnaire-9 (PHQ-9) (four somatic, five cognitive items). New cardiac events (NCEs) including cardiac-related mortality were identified by expert examination of patient records. Analyses were performed using Cox proportional hazard models with delayed entry, with time-dependent depressive dimensions and covariates measured 12-18 months (median: 14.1, IQR: 3.5) prior to the event, with a 12-month cardiac event-free gap. RESULTS: There were 95 NCEs during the follow-up [median time-to-event from baseline: 22.3 months (IQR: 13.4)]. Both the somatic (HR 1.12, 95% CI 1.05-1.20, p = 0.001) and cognitive dimensions (HR 1.11, 95% CI 1.03-1.18, p = 0.004) were time-dependent risk factors for an NCE in the multi-adjusted models. Specific symptoms (poor appetite/overeating for the somatic dimension, hopelessness and feeling like a failure for the cognitive dimension) were also significantly associated. CONCLUSION: This is the first study of the association between depressive symptom dimensions and NCEs in at-risk patients using a time-to-event standardised approach. Both dimensions considered apart were independent predictors of an NCE, along with specific items, suggesting regular assessments and tailored interventions targeting specific depressive symptoms may help to prevent NCEs in at-risk populations.

Effects of Head Movements on Sound-Source Localization in Single-Sided Deaf Patients With Their Cochlear Implant On Versus Off.

OBJECTIVES: We investigated the ability of single-sided deaf listeners implanted with a cochlear implant (SSD-CI) to (1) determine the front-back and left-right location of sound sources presented from loudspeakers surrounding the listener and (2) use small head rotations to further improve their localization performance. The resulting behavioral data were used for further analyses investigating the value of so-called "monaural" spectral shape cues for front-back sound source localization. DESIGN: Eight SSD-CI patients were tested with their cochlear implant (CI) on and off. Eight normal-hearing (NH) listeners, with one ear plugged during the experiment, and another group of eight NH listeners, with neither ear plugged, were also tested. Gaussian noises of 3-sec duration were band-pass filtered to 2-8 kHz and presented from 1 of 6 loudspeakers surrounding the listener, spaced 60° apart. Perceived sound source localization was tested under conditions where the patients faced forward with the head stationary, and under conditions where they rotated their heads between (Equation is included in full-text article.). RESULTS: (1) Under stationary listener conditions, unilaterally-plugged NH listeners and SSD-CI listeners (with their CIs both on and off) were nearly at chance in determining the front-back location of high-frequency sound sources. (2) Allowing rotational head movements improved performance in both the front-back and left-right dimensions for all listeners. (3) For SSD-CI patients with their CI turned off, head rotations substantially reduced front-back reversals, and the combination of turning on the CI with head rotations led to near-perfect resolution of front-back sound source location. (4) Turning on the CI also improved left-right localization performance. (5) As expected, NH listeners with both ears unplugged localized to the correct front-back and left-right hemifields both with and without head movements. CONCLUSIONS: Although SSD-CI listeners demonstrate a relatively poor ability to distinguish the front-back location of sound sources when their head is stationary, their performance is substantially improved with head movements. Most of this improvement occurs when the CI is off, suggesting that the NH ear does most of the "work" in this regard, though some additional gain is introduced with turning the CI on. During head turns, these listeners appear to primarily rely on comparing changes in head position to changes in monaural level cues produced by the direction-dependent attenuation of high-frequency sounds that result from acoustic head shadowing. In this way, SSD-CI listeners overcome limitations to the reliability of monaural spectral and level cues under stationary conditions. SSD-CI listeners may have learned, through chronic monaural experience before CI implantation, or with the relatively impoverished spatial cues provided by their CI-implanted ear, to exploit the monaural level cue. Unilaterally-plugged NH listeners were also able to use this cue during the experiment to realize approximately the same magnitude of benefit from head turns just minutes after plugging, though their performance was less accurate than that of the SSD-CI listeners, both with and without their CI turned on.

The impact of peripheral mechanisms on the precedence effect.

When two similar sounds are presented from different locations, with one (the lead) preceding the other (the lag) by a small delay, listeners typically report hearing one sound near the location of the lead sound source-this is called the precedence effect (PE). Several questions about the underlying mechanisms that produce the PE are asked. (1) How might listeners' relative weighting of cues at onset versus ongoing stimulus portions affect perceived lateral position of long-duration lead/lag noise stimuli? (2) What are the factors that influence this weighting? (3) Are the mechanisms invoked to explain the PE for transient stimuli applicable to long-duration stimuli? To answer these questions, lead/lag noise stimuli are presented with a range of durations, onset slopes, and lag-to-lead level ratios over headphones. Monaural, peripheral mechanisms, and binaural cue extraction are modeled to estimate the cues available for determination of perceived laterality. Results showed that all three stimulus manipulations affect the relative weighting of onset and ongoing cues and that mechanisms invoked to explain the PE for transient stimuli are also applicable to the PE, in terms of both onset and ongoing segments of long-duration, lead/lag stimuli.

Individual listener differences in azimuthal front-back reversals.

Thirty-two listeners participated in experiments involving five filtered noises when listeners kept their eyes open or closed, for stimuli of short or long duration, and for stimuli that were presented at random locations or in a largely rotational procession. Individual differences in the proportion of front-back reversals (FBRs) were measured. There were strong positive correlations between the proportion of FBRs for any one filtered noise, but not when FBRs were compared across different filtered-noise conditions. The results suggest that, for each individual listener, the rate of FBRs is stable for any one filtered noise, but not across filtered noises.

The relative size of auditory scenes of multiple talkers.

Normal hearing listeners discriminated a change in the number of talkers speaking consonant-vowel pairs between two auditory scenes. The number of talkers (n = 2, 4, 6, or 8) in one scene was incremented by Δn talkers (Δn = 1-8 talkers, depending on n) in the other scene. The perceptual size of the auditory scene seems to be small, as discrimination performance reached an approximate 0.75 proportion correct asymptote for n > 4. The independent variable of overall level differences affected performance, but both spatial configuration and talker similarity had very little effect.

Sound-source localization as a multisystem process: The Wallach azimuth illusion.

Wallach [J. Exp. Psychol. 27, 339-368 (1940)] described a "2-1" rotation scenario in which a sound source rotates on an azimuth circle around a rotating listener at twice the listener's rate of rotation. In this scenario, listeners often perceive an illusionary stationary sound source, even though the actual sound source is rotating. This Wallach Azimuth Illusion (WAI) was studied to explore Wallach's description of sound-source localization as a required interaction of binaural and head-position cues (i.e., sound-source localization is a multisystem process). The WAI requires front-back reversed sound-source localization. To extend and consolidate the current understanding of the WAI, listeners and sound sources were rotated over large distances and long time periods, which had not been done before. The data demonstrate a strong correlation between measures of the predicted WAI locations and front-back reversals (FBRs). When sounds are unlikely to elicit FBRs, sound sources are perceived veridically as rotating, but the results are listener dependent. Listeners' eyes were always open and there was little evidence under these conditions that changes in vestibular function affected the occurrence of the WAI. The results show that the WAI is a robust phenomenon that should be useful for further exploration of sound-source localization as a multisystem process.

Discrimination of changes in spatial configuration for multiple, simultaneously presented sounds.

Listeners discriminated changes in the spatial configuration of two-to-eight consonant-vowel (CV) stimuli spoken by different talkers, all simultaneously presented from different loudspeakers in various azimuthal spatial configurations. The number of CVs, spatial configuration of the sound sources, and similarity of the talkers speaking the CVs were varied. Experiment I used a same-different procedure to determine the discriminability of different spatial configurations of multiple sound sources. In experiment II, listeners determined the direction (clockwise or counterclockwise) of sound source rotation over eight rotational steps. In both experiments, performance declined as the number of sound sources increased beyond two.

Head Movements Allow Listeners Bilaterally Implanted With Cochlear Implants to Resolve Front-Back Confusions.

OBJECTIVES: We report on the ability of patients fit with bilateral cochlear implants (CIs) to distinguish the front-back location of sound sources both with and without head movements. At issue was (i) whether CI patients are more prone to front-back confusions than normal hearing listeners for wideband, high-frequency stimuli; and (ii) if CI patients can utilize dynamic binaural difference cues, in tandem with their own head rotation, to resolve these front-back confusions. Front-back confusions offer a binary metric to gain insight into CI patients' ability to localize sound sources under dynamic conditions not generally measured in laboratory settings where both the sound source and patient are static. DESIGN: Three-second duration Gaussian noise samples were bandpass filtered to 2 to 8 kHz and presented from one of six loudspeaker locations located 60° apart, surrounding the listener. Perceived sound source localization for seven listeners bilaterally implanted with CIs, was tested under conditions where the patient faced forward and did not move their head and under conditions where they were encouraged to moderately rotate their head. The same conditions were repeated for 5 of the patients with one implant turned off (the implant at the better ear remained on). A control group of normal hearing listeners was also tested for a baseline of comparison. RESULTS: All seven CI patients demonstrated a high rate of front-back confusions when their head was stationary (41.9%). The proportion of front-back confusions was reduced to 6.7% when these patients were allowed to rotate their head within a range of approximately ± 30°. When only one implant was turned on, listeners' localization acuity suffered greatly. In these conditions, head movement or the lack thereof made little difference to listeners' performance. CONCLUSIONS: Bilateral implantation can offer CI listeners the ability to track dynamic auditory spatial difference cues and compare these changes to changes in their own head position, resulting in a reduced rate of front-back confusions. This suggests that, for these patients, estimates of auditory acuity based solely on static laboratory settings may underestimate their real-world localization abilities.

Binaural detection of a Gaussian noise target in the presence of a lead/lag masker.

Masked detection thresholds were measured for a noise target in the presence of a masker composed of (1) a lead/lag noise pair with the lead interaural time difference (ITD) set the same or opposite to the target, (2) a diotic masker, and (3) a dichotic pair of decorrelated noises. If the precedence effect actually eliminates a second, later arriving stimulus, a spatial release from masking would be expected when the lead ITD is opposite that of the target. Results for a range of lead/lag delays suggest that the precedence effect is not the result of a perceptual removal of the lag.

Loudness of an auditory scene composed of multiple talkers.

Normal hearing listeners judged loudness differences between two complex speech sounds, one consisting of "n" consonant-vowel (CV) pairs each spoken by a different talker and one consisting of "2n" CV pairs. When n was less than four, listeners' judgments of loudness differences between the two sounds was based on the level of the individual CVs within each sound, not the overall level of the sounds. When n was four or more, listeners' judgments of loudness differences between the two sounds was based on the overall level of the two sounds consisting of n or 2n CVs.

The influence of signal type on perceived reverberance.

Currently, architectural room acoustic metrics make no real distinction between a room impulse response and the auditory system's internal representation of a room. These metrics are generally based on impulse responses, and indirectly assume that the internal representation of the acoustic features of a room is independent of the sound source. However, while a room can be approximated as a linear, time-invariant system, auditory processing is highly non-linear and varies a great deal over time in response to different acoustic inputs. Listeners were presented with various signals (clicks, long-duration noise, music, and speech) convolved with impulse responses consisting of Gaussian noises with different rates of exponential decay. Listeners were asked to adjust the reverberation time of one of the signals to match the other. Analyses of the data show that the source signal has a significant influence on perceived reverberance. Also, listeners were less accurate when matching reverberation times between different signals than they were with identical signals, suggesting that predicting subjective measures of reverberance from room impulse responses faces severe limitations that cannot be neglected. Results further suggest that the auditory system does not have a well-developed temporal representation of the diffuse reverb tail.

The import of within-listener variability to understanding the precedence effect.

The purpose of this study was to gather behavioral data concerning the precedence effect as manifested by the localization-dominance of the leading elements of compound stimuli. This investigation was motivated by recent findings of Shackleton and Palmer [(2006). J. Assoc. Res. Otolaryngol. 7, 425-442], who measured the electro-physiological responses of single units in the inferior colliculus of the guinea pig. The neural data from Shackleton and Palmer indicated that processing of binaural cues like those relevant to understanding localization dominance is greatly affected by internal, neural noise. In order to evaluate the generality of their physiological results to human perception, the present study measured localization dominance so that behavioral responses within and across sets of samples (i.e., tokens) of frozen noises could be compared. Conceptually consistent with Shackleton and Palmer's neural data, the variability of perceived intracranial lateral positions produced by repeated presentations of the same tokens of noise was greater than the variability of intracranial lateral positions measured across different tokens of noise. This was true for each of the four individual listeners and for each of the 72 stimulus conditions studied. Thus, measured either neuro-physiologically (Shackleton and Palmer, 2006) or behaviorally (this study), the import of within-listener variability appears to be a general, intrinsic aspect of binaural information processing.

The precedence effect with increased lag level.

When a pair of sounds arrive from different directions with a sufficiently short delay between them, listeners hear a perceptually fused image with a perceived location that is dominated by the first arriving sound. This is called the precedence effect. To test the limits of this phenomenon, 200-ms noise stimuli were presented over headphones to model a temporally overlapping direct sound (lead) with a single reflection (lag) at inter-stimulus intervals (ISIs) of 0-5 ms. Lag intensity exceeded that of the lead by 0-10 dB. Results for 16 listeners show that lateralization shifted from the position of the lead towards the lag as lag level increased. Response variability also increased with lag level. An oscillatory pattern emerged across ISIs as lag level increased, to a degree that varied greatly between listeners. Analysis of modeled binaural cues suggests that these oscillatory patterns are correlated with ILDs produced by the physical interference of lead and lag during the ongoing portion of the stimulus, especially in the 764-Hz frequency band. Different listeners apparently weighted cues from the onset versus ongoing portions of the stimulus differently, as evidenced by the varying degree of influence the ongoing ILD cues had on listeners' perceived lateralization.

Spatial Hearing in Children With and Without Hearing Loss: Where and What the Speech Is Matters for Local Speech Intelligibility.

PURPOSE: This study examined children's ability to perceive speech from multiple locations on the horizontal plane. Children with hearing loss were compared to normal-hearing peers while using amplification with and without advanced noise management. METHOD: Participants were 21 children with normal hearing (9-15 years) and 12 children with moderate symmetrical hearing loss (11-15 years). Word recognition, nonword detection, and word recall were assessed. Stimuli were presented randomly from multiple discrete locations in multitalker noise. Children with hearing loss were fit with devices having separate omnidirectional and noise management programs. The noise management feature is designed to preserve audibility in noise by rapidly analyzing input from all locations and reducing the noise management when speech is detected from locations around the hearing aid user. RESULTS: Significant effects of left/right and front/back lateralization occurred as well as effects of hearing loss and hearing aid noise management. Children with normal hearing experienced a left-side advantage for word recognition and a right-side advantage for nonword detection. Children with hearing loss demonstrated poorer performance overall on all tasks with better word recognition from the back, and word recall from the right, in the omnidirectional condition. With noise management, performance improved from the front compared to the back for all three tasks and from the right for word recognition and word recall. CONCLUSIONS: The shape of children's local speech intelligibility on the horizontal plane is not omnidirectional. It is task dependent and shaped further by hearing loss and hearing aid signal processing. Front/back shifts in children with hearing loss are consistent with the behavior of hearing aid noise management, while the right-side biases observed in both groups are consistent with the effects of specialized speech processing in the left hemisphere of the brain.

Heart transplantation and biomarkers: a review about their usefulness in clinical practice.

Advanced heart failure (AdvHF) can only be treated definitively by heart transplantation (HTx), yet problems such right ventricle dysfunction (RVD), rejection, cardiac allograft vasculopathy (CAV), and primary graft dysfunction (PGD) are linked to a poor prognosis. As a result, numerous biomarkers have been investigated in an effort to identify and prevent certain diseases sooner. We looked at both established biomarkers, such as NT-proBNP, hs-troponins, and pro-inflammatory cytokines, and newer ones, such as extracellular vesicles (EVs), donor specific antibodies (DSA), gene expression profile (GEP), donor-derived cell free DNA (dd-cfDNA), microRNA (miRNA), and soluble suppression of tumorigenicity 2 (sST2). These biomarkers are typically linked to complications from HTX. We also highlight the relationships between each biomarker and one or more problems, as well as their applicability in routine clinical practice.

Speckle tracking echocardiography in plasma cell disorders: The role of advanced imaging in the early diagnosis of AL systemic cardiac amyloidosis.

INTRODUCTION: Amyloid light-chain amyloidosis is a rare condition characterized by the abnormal production of immunoglobulin light chain that misshape and form amyloid fibrils. Over time, these amyloid deposits can accumulate slowly, causing dysfunction in organs and tissues. Early identification is crucial to ensure optimal treatment. We aim to identify a better marker of cardiac amyloidosis, using advanced echocardiography, to improve diagnosis and the timing of available treatments. MATERIALS AND METHODS: 108 consecutive hematological patients (32, 30% female and 76, 70% male) with a plasma cell disorder referred to our Cardiological center underwent ECG, first and second-level echocardiography (Speckle Tracking) and complete biochemical profile. The best predictors of ALCA (AUC ≥ 0.8) were included in a further analysis stratified by AL score. RESULTS: At ROC analysis, the best bio-humoral predictors for the diagnosis of ALCA were Nt-pro-BNP (AUC: 0.97; p < 0.01) and Hs-Tn (AUC: 0.87; p < 0.01). Regarding echocardiography, the best diagnostic predictors were left atrial stiffness (LAS) (AUC: 0.83; p < 0.01) for the left atrium; free wall thickness for the right ventricle (AUC: 0.82; <0.01); left ventricular global longitudinal strain (LVGLS) (AUC: 0.92; p < 0.01) and LVMi (AUC 0.80; p < 0.001) for the left ventricle; and AL-score (AUC 0.83 p < 0.01). In patients with AL-SCORE < 1, LAS (AUC 0.86 vs AUC 0.79), LVGLS (AUC 0.92 vs AUC 0.86) and LV mass (AUC 0.91 vs AUC 0.72) had better diagnostic accuracy than patients with higher AL-score (AL SCORE ≥ 1). CONCLUSION: Multi-parametric imaging approach with LVGLS and LAS may be helpful for detecting early cardiac involvement in AL amyloidosis.

Reference values of strain-derived myocardial work indices in heart transplant patients.

Aims: Myocardial work (MW) is a relatively novel non-invasive echocardiographic method with increasing fields of application. Normal reference ranges of MW indices in patients who have undergone a heart transplant (HTx) have not been determined yet. The aim of this study was to obtain the reference ranges for 2D echocardiographic indices of MW for adult HTx patients and to compare them with the results of the European Association of Cardiovascular Imaging (EACVI) Normal Reference Ranges for Echocardiography (NORRE) study. Methods and results: All consecutive HTx patients admitted at our institution (University Hospital of Siena, Italy) between September 2019 and May 2022 who underwent endomyocardial biopsy (EMB) were considered. Patients with a history of rejection, a history of coronary artery vasculopathy, either acute cellular rejection or acute antibody-mediated rejection at EMB, and donor-specific antibodies were excluded. MW retrospectively performed for the included patients was retrieved, and the results were compared with those from the EACVI NORRE study. Out of 176 HTx patients who underwent EMB, 94 patients were excluded. The study population consisted of 82 HTx patients [68.3% male, median age 53 (46-62) years]. The median duration from HTx was 5 (2-22) months. The main MW indices such as global work efficiency (GWE, 84 ± 8%), global work index (GWI, 1447 ± 409 mmHg%), global constructive work (GCW, 2067 ± 423 mmHg%), and global wasted work [GWW, 310 (217-499) mmHg%] did not differ according to gender. Each of these indices significantly differed from those reported in the EACVI NORRE study (P-value <0.001), with lower GWI, GCW, and GWE and higher GWW values in the HTx population. Conclusion: This study provides reference ranges for MW indices in an adult HTx population free from transplant-related complications which proved to be different from those previously reported in healthy volunteers.