Synthesis of a Vocal Sound from the 3,000 year old Mummy, Nesyamun 'True of Voice'.

The sound of a 3,000 year old mummified individual has been accurately reproduced as a vowel-like sound based on measurements of the precise dimensions of his extant vocal tract following Computed Tomography (CT) scanning, enabling the creation of a 3-D printed vocal tract. By using the Vocal Tract Organ, which provides a user-controllable artificial larynx sound source, a vowel sound is synthesised which compares favourably with vowels of modern individuals.

The role of neuroticism in self-harm and suicidal ideation: results from two UK population-based cohorts.

BACKGROUND: Self-harm is common, debilitating and associated with completed suicide and increased all-cause mortality, but there is uncertainty about its causal risk factors, limiting risk assessment and effective management. Neuroticism is a stable personality trait associated with self-harm and suicidal ideation, and correlated with coping styles, but its value as an independent predictor of these outcomes is disputed. METHODS: Prior history of hospital-treated self-harm was obtained by record-linkage to administrative health data in Generation Scotland:Scottish Family Health Study (N = 15,798; self-harm cases = 339) and by a self-report variable in UK Biobank (N = 35,227; self-harm cases = 772). Neuroticism in both cohorts was measured using the Eysenck Personality Questionnaire-Short Form. Associations of neuroticism with self-harm were tested using multivariable regression following adjustment for age, sex, cognitive ability, educational attainment, socioeconomic deprivation, and relationship status. A subset of GS:SFHS was followed-up with suicidal ideation elicited by self-report (n = 3342, suicidal ideation cases = 158) and coping styles measured by the Coping Inventory for Stressful Situations. The relationship of neuroticism to suicidal ideation, and the role of coping style, was then investigated using multivariable logistic regression. RESULTS: Neuroticism was positively associated with hospital-associated self-harm in GS:SFHS (per EPQ-SF unit odds ratio 1.2 95% credible interval 1.1-1.2, pFDR 0.0003) and UKB (per EPQ-SF unit odds ratio 1.1 95% confidence interval 1.1-1.2, pFDR 9.8 × 10-17). Neuroticism, and the neuroticism-correlated coping style, emotion-oriented coping (EoC), were also associated with suicidal ideation in multivariable models. CONCLUSIONS: Neuroticism is an independent predictor of hospital-treated self-harm risk. Neuroticism and emotion-orientated coping styles are also predictive of suicidal ideation.

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117).

Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10-23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766).

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.

Assessing the presence of shared genetic architecture between Alzheimer's disease and major depressive disorder using genome-wide association data.

Major depressive disorder (MDD) and Alzheimer's disease (AD) are both common in older age and frequently co-occur. Numerous phenotypic studies based on clinical diagnoses suggest that a history of depression increases risk of subsequent AD, although the basis of this relationship is uncertain. Both illnesses are polygenic, and shared genetic risk factors could explain some of the observed association. We used genotype data to test whether MDD and AD have an overlapping polygenic architecture in two large population-based cohorts, Generation Scotland's Scottish Family Health Study (GS:SFHS; N=19 889) and UK Biobank (N=25 118), and whether age of depression onset influences any relationship. Using two complementary techniques, we found no evidence that the disorders are influenced by common genetic variants. Using linkage disequilibrium score regression with genome-wide association study (GWAS) summary statistics from the International Genomics of Alzheimer's Project, we report no significant genetic correlation between AD and MDD (rG=-0.103, P=0.59). Polygenic risk scores (PRS) generated using summary data from International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium were used to assess potential pleiotropy between the disorders. PRS for MDD were nominally associated with participant-recalled AD family history in GS:SFHS, although this association did not survive multiple comparison testing. AD PRS were not associated with depression status or late-onset depression, and a survival analysis showed no association between age of depression onset and genetic risk for AD. This study found no evidence to support a common polygenic structure for AD and MDD, suggesting that the comorbidity of these disorders is not explained by common genetic variants.

Evaluation of voice and quality of life after transoral endoscopic laser resection of early glottic carcinoma.

OBJECTIVE: This study aimed to evaluate voice and quality of life after transoral laser resection of early glottic carcinoma. METHODS: We studied 19 patients undergoing transoral laser resection of tumour stage (T) one or T2 glottic carcinoma. Laryngeal function was evaluated by video-stroboscopy, vocal function by the Voice Symptom Scale, the grade-roughness-breathiness-asthenia-strain scale and objective phoniatric assessment, and quality of life by the University of Washington Quality of Life questionnaire. RESULTS: Patients' glottic carcinoma tumour-node-metastasis (TNM) staging was T1 N0 M0 in 14 patients and T2 N0 M0 in five. Overall voice grade, roughness and breathiness were mild to moderate in 84 per cent; asthenia and voice strain were more uniformly distributed, with 15 per cent of patients having normal voice quality. Eight patients developed a glottic web post-operatively; anterior commissure web was significantly associated with worse voice grade (p = 0.05). Seven patients (47 per cent) had a 'mucosal wave' on the operated vocal fold; this was significantly associated with less strain on phonation (p = 0.05). Voice Symptom Scale score was low overall (15 patients (78.9 per cent) scored less than 30). The fundamental frequency and frequency irregularity were normal in nine patients (47.3 per cent); the closed quotient was normal in six (31.5 per cent). The averaged quality of life score was ≥ 90 in 14 patients (73.7 per cent); 18 (94.7 per cent) felt their health-related quality of life was either the same or better post-operatively; and overall quality of life was positive in all. CONCLUSION: Transoral laser resection of T1 and T2 glottic carcinoma enables adequate tumour tissue excision with preservation of acceptable vocal function. Most patients' post-operative quality of life is very good. Anterior commissure web formation is associated with poorer vocal function.

Voice source changes of child and adolescent subjects undergoing singing training--a preliminary study.

Many vocal practitioners have strong beliefs regarding the age at which singing training of a child should begin, and the different ways in which male and female children should be treated. These beliefs are not substantiated by any scientific research, leading to considerable dispute between vocal coaches and choral directors. The singing voices of over 127 child singers and non-singers aged 8-18 were analysed using electrolaryngographic measures. Analysis particularly concentrated on the laryngographically derived vocal fold closed quotient (CQ). Results indicated that the voice source characteristics of subjects could be divided into groups according to age, gender and the level of vocal training received. Female subjects in particular exhibited a marked development of voice source production according to the length of training received, while male subjects exhibited patterning according to both age (and related pubertal development), and training received. It was concluded that the process of training a young voice has a quantifiable effect upon the singing voice production of the child, and in particular on the female voice, while pubertal development also creates measurable effects on the voice source production of the male child.

Endemic melioidosis in tropical northern Australia: a 10-year prospective study and review of the literature.

In a prospective study of melioidosis in northern Australia, 252 cases were found over 10 years. Of these, 46% were bacteremic, and 49 (19%) patients died. Despite administration of ceftazidime or carbapenems, mortality was 86% (43 of 50 patients) among those with septic shock. Pneumonia accounted for 127 presentations (50%) and genitourinary infections for 37 (15%), with 35 men (18%) having prostatic abscesses. Other presentations included skin abscesses (32 patients; 13%), osteomyelitis and/or septic arthritis (9; 4%), soft tissue abscesses (10; 4%), and encephalomyelitis (10; 4%). Risk factors included diabetes (37%), excessive alcohol intake (39%), chronic lung disease (27%), chronic renal disease (10%), and consumption of kava (8%). Only 1 death occurred among the 51 patients (20%) with no risk factors (relative risk, 0.08; 95% confidence interval, 0.01-0.58). Intensive therapy with ceftazidime or carbapenems, followed by at least 3 months of eradication therapy with trimethoprim-sulfamethoxazole, was associated with decreased mortality. Strategies are needed to decrease the high mortality with melioidosis septic shock. Preliminary data on granulocyte colony-stimulating factor therapy are very encouraging.

The epidemiology of melioidosis in Australia and Papua New Guinea.

Melioidosis was first described in Australia in an outbreak in sheep in 1949 in north Queensland (22 degrees S). Human melioidosis was first described from Townsville (19 degrees S) in 1950. Melioidosis is hyperendemic in the Top End of the Northern Territory (NT) and as in parts of northeastern Thailand it is the commonest cause of fatal community-acquired septicemic pneumonia. In the 9 years since 1989 the prospective NT melioidosis study at Royal Darwin Hospital (12 degrees S) has documented 206 culture confirmed cases of melioidosis, with an average annual incidence of 16.5/100,000. Melioidosis is also seen in the north of Western Australia and north Queensland, including the Torres Strait Islands, but is uncommon in adjacent Papua New Guinea. Serological studies suggest that infection is rare in the Port Moresby region, but there is emerging evidence of melioidosis from Western Province. The NT study has documented inoculating events in 52 (25%) of cases, with an incubation period of 1-21 days (mean 9 days); 84% of cases had acute disease from presumed recent acquisition and 13% had chronic disease (sick, > 2 months). In 4% there was evidence of possible reactivation from a latent focus; 28 of 153 (18%) males had prostatic abscesses. The overall mortality was 21% (43 cases), with a mortality rate in septicemic cases (95) of 39% and in non-septicemic cases (103) of 4%. Pneumonia was the commonest presentation in both groups and, in addition, eight patients (two deaths) presented with melioidosis encephalomyelitis. Melioidosis clusters in temperate Australia are attributed to animals imported from the north. Molecular typing of Burkholderia pseudomallei isolates from temperate southwest Western Australia showed clonality over 25 years. In this outbreak and in studies from the NT, some soil isolates are molecularly identical to epidemiologically related animal and human isolates. Molecular typing has implicated the water supply in two clonal outbreaks in remote aboriginal communities in northern Australia. Further prospective collaborative studies are required to evaluate whether there are truly regional differences in clinical features of melioidosis and to better understand how B. pseudomallei is acquired from the environment.

Neurological melioidosis.

Neurological abnormalities have long been recognised in animals with melioidosis, including laboratory rodents and sheep in the first Australian outbreak in 1949. Autopsies in animals have shown microabscesses and lymphocytic infiltration to be present on occasion in the same animal, but Burkholderia pseudomallei is usually able to be grown from central nervous system (CNS) tissue. In humans CNS melioidosis is unusual, but both macroscopic brain abscesses and encephalitis occur. There has been a recently recognised syndrome of meningoencephalitis with varying involvement of brainstem, cerebellum and spinal cord. The prospective melioidosis study at Royal Darwin Hospital has documented 12 cases of CNS melioidosis over 9 years out of a total of 232 cases of melioidosis (5%). Prominent features on presentation were unilateral limb weakness (6), predominant cerebellar signs (2), mixed cerebellar and brainstem features with peripheral weakness (2) and flaccid paraparesis (2). Eight patients had unilateral VIIth nerve palsy and six bulbar palsy, with five requiring prolonged ventilation. Brain CT scans are usually normal initially, but MRI shows dramatic changes. Three patients died and only three made a full recovery. In two patients with predominant mononuclear CSF pleocytosis, B. pseudomallei was cultured from CSF and autopsy in one of these showed necrotising encephalitis with microabscesses. Although it has been postulated that a neurotropic exotoxin may account for melioidosis encephalomyelitis, the recent findings and comparison with the animal data suggest that direct organism spread within the CNS may be primarily responsible. Preliminary molecular typing of isolates shows no evidence of a specific strain of B. pseudomallei responsible for CNS melioidosis end further studies are required to determine if the apparent higher rate of CNS disease in Australia is due to true regional differences or is from increased ascertainment.

A real-time interface for a formant speech synthesizer.

This paper describes a multi-parametric user interface based around the Musical Instrument Digital Interface (MIDI) Creator system developed at York which provides MIDI data in response to changing pressures on five strain gauge sensors to control the fundamental frequency, first three formants and the overall amplitude of synthesized speech. Vocal synthesis is achieved by means of a freely available time domain formant synthesis system running on a standard PC compatible machine. The result is a novel hand-controlled speech synthesizer which is not command/phoneme based, but is rather more like a continually controlled musical instrument where the speech sounds are shaped in real-time.

A job-satisfaction measure for internal medicine residency program directors.

PURPOSE: To develop a job-satisfaction measure that encompasses the multifaceted job of internal medicine residency program directors. METHOD: Questions were devised to measure program directors satisfaction with various facets of their jobs. In 1996, the authors surveyed all non-military internal medicine program directors in the United States. RESULTS: Of the program directors surveyed, 301 (78%) responded. More respondents than non-respondents held the title of department chairperson in addition to the title of program director (22% vs 7%). Factor analysis and correlation analysis yielded a multifaceted measure (termed PD-Sat) composed of 20 questions and six facets (work with residents, colleague relationships, resources, patient care, pay, and promotion) that made sense based on literature review and discussions with program directors (face validity). The PD-Sat had good internal reliability (Cronbach's alpha = .88), as had each of its six facets (Cronbach's alphas = .60-.90). The six facets correlated modestly with one another (Pearson's r2 = .12-.67), suggesting they were measuring different aspects of a common concept. The PD-Sat correlated significantly with an established four-question global job-satisfaction scale used in previous studies (Pearson's r2 = .33) demonstrating concurrent validity. Scores on the PD-Sat predicted whether program directors were considering, seeking, or making a job change (predictive validity). The PD-Sat performed comparably well in subsets of program directors who were and were not department chairs, suggesting that it might be applicable to different populations of program directors. CONCLUSION: The authors have developed a new facet-specific job-satisfaction measure that is reliable and valid for assessing the job satisfaction of internal medicine program directors. Because job descriptions for program directors in other specialties are similar, it may also be useful in these populations.

Attributes of excellent attending-physician role models.

BACKGROUND: Although effective role models are important in medical education, little is known about the characteristics of physicians who serve as excellent clinical role models. We therefore conducted a case-control study to identify attributes that distinguish such physicians from their colleagues. METHODS: We asked members of the internal-medicine house staff at four teaching hospitals to name physicians whom they considered to be excellent role models. A total of 165 physicians named by one or more house-staff members were classified as excellent role models (these served as the case physicians in our study). A questionnaire was sent to them as well as to 246 physicians who had residency-level teaching responsibilities but who were not named (controls). Of these 411 physicians, 341 (83 percent) completed questionnaires while unaware of their case-control status. RESULTS: Of the 341 attending physicians who responded, 144 (42 percent) had been identified as excellent role models. Having greater assigned teaching responsibilities was strongly associated with being identified as an excellent role model. In the multivariate analysis, five attributes were independently associated with being named as an excellent role model: spending more than 25 percent of one's time teaching (odds ratio, 5.12; 95 percent confidence interval, 1.81 to 14.47), spending 25 or more hours per week teaching and conducting rounds when serving as an attending physician (odds ratio, 2.48; 95 percent confidence interval, 1.15 to 5.37), stressing the importance of the doctor-patient relationship in one's teaching (odds ratio, 2.58; 95 percent confidence interval, 1.03 to 6.43), teaching the psychosocial aspects of medicine (odds ratio, 2.31; 95 percent confidence interval, 1.23 to 4.35), and having served as a chief resident (odds ratio, 2.07; 95 percent confidence interval, 1.07 to 3.98). CONCLUSIONS: These data suggest that many of the attributes associated with being an excellent role model are related to skills that can be acquired and to modifiable behavior.

Long-term study of litter decomposition on a Pennine peat bog: which regression?

It is estimated that in the northern hemisphere one-third of the world pool of soil carbon is contained in peat resulting from an incomplete decomposition of plant remains. The time course for the decomposition of the predominant plant litters on a Pennine moorland in northern England is reported for a study extending over 23 years. Spatial variation of the weight remaining of decomposing litters increased with time. This experimental study gave an age for the upper layers of the bog and a curve for long-term decay based on direct observation rather than inferred from profile samples or from short-term observations. It showed that short-term observations can give misleading results in the long term, with a variety of litters with differing early decay rates ultimately making a similar contribution to accumulation. Spatial variation of the weight remaining of the decomposing litters increased with time, so that variation within micro-environments, or within apparantly uniform substrates, may contribute significantly to organic matter accumulation. An asymptotic curve best described the long-term course of decomposition leading to the accumulation of peat. The use of the model for the three litter types, Calluna vulgaris, Eriophorum vaginatum and Rubus chamaemorus, is described and the implication of the results for modelling of organic matter accumulation are then discussed.

ALBERT: a real-time visual feedback computer tool for professional vocal development.

This paper considers the nature of real-time visual feedback for vocal analysis and development and presents a new software tool, called ALBERT (acoustic and laryngeal biofeedback enhancement in real time), designed for use with those developing their voices professionally. This tool embodies several important issues in the provision of real-time visual feedback, including: (a) support for user-configurable visual displays, (b) the ability to use colour as a complementary or sole medium for the presentation of information, (c) the ability to combine algorithmically any number of vocal parameters to create a new single parameter representative of some aspect of vocal measurement which may be displayed and updated in real time, and (d) a rate of information update which may be altered by the user at any point for the most appropriate use according to the context of the feedback task. Several examples of system use are given, including the real-time display of fundamental frequency, jitter, and larynx closed quotient (CQ) parameters in a variety of visual configurations. Several examples are given relating to developing professional voice users, including the derivation of a new parameter which reflects the measure of progress of subjects along a linear correlation line between CQ and the level of energy in the singer's formant region.

Voice development under training with and without the influence of real-time visually presented biofeedback.

This paper describes an investigation into the developmental nature of the voice under training with and without the influence of real-time visually presented biofeedback. Two subjects who had not previously experienced any form of vocal training took six singing lessons. One was taught conventionally, while the other was taught with the aid of a system known as Acoustic and Laryngeal Biofeedback Enhancement Real Time (ALBERT). Real-time biofeedback was presented based upon measures of (i) larynx closed quotient (CQ), (ii) spectral amplitude in the singer's formant frequency band relative to the spectral amplitude of the full band (ratio), and (iii) both parameters combined in a manner based on previously observed correlations between them. Results indicate generally increased sound pressure levels (SPL) of acoustic output and generally consistent increases in the level of CQ and ratio across consecutive lessons for both subjects.

Variation of electrolaryngographically derived closed quotient for trained and untrained adult female singers.

The derivation of larynx closed quotient (CQ) measures from the electrolarynogograph output is discussed and data are presented for a group of trained and untrained adult female singers (N = 26) for a sung two-octave G major scale. Statistically significant trends are observed between the trained and untrained groups that suggest for the trained group: (a) CQ tends to be lower for pitches below D4 and higher for pitches above B4, and (b) the gradient [CQ/log(F0)] tends to correlate positively with the number of years singing training/experience. These data are compared with those reported previously for an adult male group, and it is suggested that CQ could be a useful parameter to include in a real-time visual display for singing training.

Double-blind, randomized, multicenter study of doxacurium vs. pancuronium in intensive care unit patients who require neuromuscular-blocking agents.

OBJECTIVE: To compare the neuromuscular-blocking and hemodynamic effects of doxacurium vs. pancuronium administered by intermittent bolus to intensive care unit (ICU) patients who required neuromuscular block to facilitate mechanical ventilation for > or = 24 hrs. DESIGN: A multicenter, prospective, double-blind, randomized study comparing doxacurium, a new benzylisoquinolone neuromuscular-blocking agent, with pancuronium. SETTING: ICUs of three tertiary care hospitals. PATIENTS: Forty critically ill patients (29 male, 11 female) with an average age of 52.5 yrs (range 19 to 80). INTERVENTIONS: With approval of our Institutional Review Boards and after obtaining informed consent, 40 critically ill patients were entered into the study. Histories and the results of physical examinations were recorded, laboratory data were collected, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated during the 8 hrs before the start of the study medication. Patients received either doxacurium (initial dose of 0.04 mg/kg) or pancuronium (initial dose of 0.07 mg/kg) by bolus injection with continuous measurement of vital signs every minute for 15 mins. We measured the degree of neuromuscular blockade using a peripheral-nerve stimulator to measure the Train-of-Four count. Patients were rebolused (doxacurium dose of 0.025 mg/kg, pancuronium dose of 0.05 mg/kg) based on clinical criteria, which were substantiated by measurement of the Train-of-Four count. The neuromuscular-blocking drugs were stopped when the patient no longer required paralysis or after 5 days of therapy, whichever came first. Group comparisons were made using repeated measures analysis of variance, Fisher's exact test, and two sample t-tests, when appropriate. Spearman's rank-correction coefficients were calculated to assess the relationship of onset time and recovery time with all baseline laboratory values and the APACHE II scores. A p < .05 was used to establish statistical significance. MEASUREMENTS AND MAIN RESULTS: There were no differences between the two groups with respect to age, gender, or APACHE II scores. There were no differences between groups in terms of adverse experiences, nor with respect to time of onset of block, number of doses, or the duration of neuromuscular blockade (2.6 vs. 2.2 days for doxacurium vs. pancuronium, respectively). There was a statistically significant increase in heart rate after the initial dose of pancuronium (120 +/- 23 vs. 109 +/- 22 beats/min postinjection vs. preinjection, respectively; p < .05) without any differences noted after doxacurium (107 +/- 21 vs. 109 +/- 21 beats/min, respectively). Furthermore, once neuromuscular block was discontinued, the pancuronium group had a more prolonged and variable recovery time (279 +/- 229 mins) compared with the doxacurium group (138 +/- 46 mins, p < .05). CONCLUSIONS: In critically ill patients requiring neuromuscular block for > 24 hrs, doxacurium was well tolerated without evidence of tachycardia and with a relatively prompt recovery profile.