Pitch discrimination is better for synthetic timbre than natural musical instrument timbres despite familiarity

Pitch discrimination is better for complex tones than pure tones, but how pitch discrimination differs between natural and artificial sounds is not fully understood. This study compared pitch discrimination thresholds for flat-spectrum harmonic complex tones with those for natural sounds played by musical instruments of three different timbres (violin, trumpet, and flute). To investigate whether natural familiarity with sounds of particular timbres affects pitch discrimination thresholds, this study recruited non-musicians and musicians who were trained on one of the three instruments. We found that flautists and trumpeters could discriminate smaller differences in pitch for artificial flat-spectrum tones, despite their unfamiliar timbre, than for sounds played by musical instruments, which are regularly heard in everyday life (particularly by musicians who play those instruments). Furthermore, thresholds were no better for the instrument a musician was trained to play than for other instruments, suggesting that even extensive experience listening to and producing sounds of particular timbres does not reliably improve pitch discrimination thresholds for those timbres. The results show that timbre familiarity provides minimal improvements to auditory acuity, and physical acoustics (e.g., the presence of equal-amplitude harmonics) determine pitch discrimination thresholds more than does experience with natural sounds and timbre-specific training

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The role of the extended MNS in emotional and nonemotional judgments of human song.

In the present study, we examined the involvement of the extended mirror neuron system (MNS)-specifically, areas that have a strong functional connection to the core system itself-during emotional and nonemotional judgments about human song. We presented participants with audiovisual recordings of sung melodic intervals (two-tone sequences) and manipulated emotion and pitch judgments while keeping the stimuli identical. Mu event-related desynchronization (ERD) was measured as an index of MNS activity, and a source localization procedure was performed on the data to isolate the brain sources contributing to this ERD. We found that emotional judgments of human song led to greater amounts of ERD than did pitch distance judgments (nonemotional), as well as control judgments related to the singer's hair, or pitch distance judgments about a synthetic tone sequence. Our findings support and expand recent research suggesting that the extended MNS is involved to a greater extent during emotional than during nonemotional perception of human action

Beat perception ability and instructions to synchronize influence gait when walking to music-based auditory cues.

Synchronizing gait to music-based auditory cues (rhythmic auditory stimulation) is a strategy used to manage gait impairments in a variety of neurological conditions, including Parkinson\u27s disease. However, knowledge of how to individually optimize music-based cues is limited. The purpose of this study was to investigate how instructions to synchronize with auditory cues influences gait outcomes among healthy young adults with either good or poor beat perception ability. 65 healthy adults walked to metronome and musical stimuli with high and low levels of perceived groove (how much it induces desire to move) and familiarity at a tempo equivalent to their self-selected walking pace. Participants were randomized to instruction conditions: (i) synchronized: match footsteps with the beat, or (ii) free-walking: walk comfortably. Participants were classified as good or poor beat perceivers using the Beat Alignment Test. In this study, poor beat perceivers show better balance-related parameters (stride width and double-limb support time) when they are not instructed to synchronize their gait with cues (versus when synchronization was required). Good beat perceivers, in contrast, were better when instructed to synchronize gait (versus when no synchronization was required). Changes in stride length and velocity were influenced by musical properties, in particular the perceived \u27groove\u27 (greater stride length and velocity with high- versus low-groove cues) and, in some cases, this interacted with beat perception ability. The results indicate that beat perception ability and instructions to synchronize indeed influence spatiotemporal gait parameters when walking to music- and metronome-based rhythmic auditory stimuli. Importantly, these results suggest that both low groove cues and instructing poor beat perceivers to synchronize may interfere with performance while walking, thus potentially impacting both empirical and clinical outcomes

Hippocampal viscoelasticity and episodic memory performance in healthy older adults examined with magnetic resonance elastography

Episodic memory is particularly sensitive to normative aging; however, studies investigating the structure-function relationships that support episodic memory have primarily been limited to gross volumetric measures of brain tissue health. Magnetic resonance elastography (MRE) is an emerging non-invasive, high-resolution imaging technique that uniquely quantifies brain viscoelasticity, and as such, provides a more specific measure of neural microstructural integrity. Recently, a significant double dissociation between orbitofrontal cortex-fluid intelligence and hippocampal-relational memory structure-function relationships was observed in young adults, highlighting the potential of sensitive MRE measures for studying brain health and its relation to cognitive function. However, the structure-function relationship observed by MRE has not yet been explored in healthy older adults. In this study, we examined the relationship between hippocampal (HC) viscoelasticity and episodic memory in cognitively healthy adults aged 66–73 years (N = 11), as measured with the verbal-paired associates (VPA) subtest from the Wechsler Memory Scale (WMS-R). Given the particular dependence of verbal memory tasks on the left HC, unilateral HC MRE measurements were considered for the first time. A significant negative correlation was found between left HC damping ratio, ξ and VPA recall score (rs = −0.77, p = 0.009), which is consistent with previous findings of a relationship between HC ξ and memory performance in young adults. Conversely, correlations between right HC ξ with VPA recall score were not significant. These results highlight the utility of MRE to study cognitive decline and brain aging and suggest its possible use as a sensitive imaging biomarker for memory-related impairments