A multi-population approach supports common patterns in marine growth and maturation decision in Atlantic salmon (Salmo salar L.) from southern Europe.

This study provides a regional picture of long-term changes in Atlantic salmon growth at the southern edge of their distribution, using a multi-population approach spanning 49 years and five populations. We provide empirical evidence of salmon life history being influenced by a combination of common signals in the marine environment and population-specific signals. We identified an abrupt decline in growth from 1976 and a more recent decline after 2005. As these declines have also been recorded in northern European populations, our study significantly expands a pattern of declining marine growth to include southern European populations, thereby revealing a large-scale synchrony in marine growth patterns for almost five decades. Growth increments during their sea sojourn were characterized by distinct temporal dynamics. At a coarse temporal resolution, growth during the first winter at sea seemed to gradually improve over the study period. However, the analysis of finer seasonal growth patterns revealed ecological bottlenecks of salmon life histories at sea in time and space. Our study reinforces existing evidence of an impact of early marine growth on maturation decision, with small-sized individuals at the end of the first summer at sea being more likely to delay maturation. However, each population was characterized by a specific probabilistic maturation reaction norm, and a local component of growth at sea in which some populations have better growth in some years might further amplify differences in maturation rate. Differences between populations were smaller than those between sexes, suggesting that the sex-specific growth threshold for maturation is a well-conserved evolutionary phenomenon in salmon. Finally, our results illustrate that although most of the gain in length occurs during the first summer at sea, the temporal variability in body length at return is buffered against the decrease in post-smolt growth conditions. The intricate combination of growth over successive seasons, and its interplay with the maturation decision, could be regulating body length by maintaining diversity in early growth trajectories, life histories, and the composition of salmon populations.

Evaluation of a tiered opioid prescription algorithm in an ERAS pathway: exploring opportunities for further refinement.

BACKGROUND: Opioid over-prescription is wasteful and contributes to the opioid crisis. We implemented a personalized tiered discharge opioid protocol and education on opioid disposal to minimize over-prescription. OBJECTIVE: To evaluate the intervention by investigating opioid use post-discharge for women undergoing abdomino-pelvic surgery, and patient adherence to opioid disposal education. METHODS: We analyzed post-discharge opioid consumption among 558 patients. Eligible patients included those who underwent elective gynecologic surgery, were not taking scheduled opioids pre-operatively, and received discharge opioids according to a tiered prescribing algorithm. A survey assessing discharge opioid consumption and disposal safety knowledge was distributed on post-discharge day 21. Over-prescription was defined as >20% of the original prescription left over. Descriptive statistics were used for analysis. RESULTS: The survey response rate was 61% and 59% in the minimally invasive surgery and open surgery cohorts, respectively. Overall, 42.8% of patients reported using no opioids after hospital discharge, 45.2% in the minimally invasive surgery and 38.6% in the open surgery cohort. Furthermore, 74.9% of respondents were over-prescribed, with median age being statistically significant for this group (p=0.004). Finally, 46.4% of respondents expressed no knowledge regarding safe disposal practices, with no statistically significant difference between groups (p>0.99). CONCLUSION: Despite implementation of the tiered discharge opioid algorithm aimed to personalize opioid prescriptions to estimated need, we still over-prescribed opioids. Additionally, despite targeted education, nearly half of all patients who completed the survey did not know how to dispose of their opioid tablets. Additional efforts are needed to further refine the algorithm to reduce over-prescription of opioids and improve disposal education.

Effect of nodule size and stiffness on phonation threshold and collision pressures in a synthetic hemilaryngeal vocal fold model.

Synthetic vocal fold (VF) replicas were used to explore the role of nodule size and stiffness on kinematic, aerodynamic, and acoustic measures of voiced speech production. Emphasis was placed on determining how changes in collision pressure may contribute to the development of phonotrauma. This was performed by adding spherical beads with different sizes and moduli of elasticity at the middle of the medial surface of synthetic silicone VF models, representing nodules of varying size and stiffness. The VF models were incorporated into a hemilaryngeal flow facility. For each case, self-sustained oscillations were investigated at the phonation threshold pressure. It was found that increasing the nodule diameter increased the open quotient, phonation threshold pressure, and phonation threshold flow rate. However, these values did not change considerably as a function of the modulus of elasticity of the nodule. Nevertheless, the ratio of collision pressure to subglottal pressure increased significantly for both increasing nodule size and stiffness. This suggests that over time, both growth in size and fibrosis of nodules will lead to an increasing cycle of compensatory vocal hyperfunction that accelerates phonotrauma.

The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes.

OBJECTIVE: Low-grade serous carcinoma (LGSOC) is a rare epithelial ovarian/peritoneal cancer characterized by younger age at diagnosis, relative chemoresistance, prolonged overall survival (OS), and mutations in the mitogen activated protein kinase (MAPK) pathway compared to high-grade serous carcinoma. We describe the genomic profile of LGSOC by next generation sequencing (NGS) and evaluated its potential relationship to clinical outcomes. METHODS: The study included 215 women with LGSOC with: 1) pathologically confirmed LGSOC, 2) availability of NGS data, and 3) adequate clinical data. Clinical subgroups were compared for progression-free survival (PFS) and OS. Multivariable Cox regression analysis was performed. RESULTS: Median age at diagnosis was 46.6 years. The majority had a stage III ovarian primary. One or more mutations were identified in 140 (65.1%) cases; 75 (34.9%) had none. The most common mutations were KRAS (n = 71; 33.0%), NRAS (n = 24; 11.2%), and BRAF (n = 18; 8.4%). Patients with MAPK-mutated tumors (n = 113) (52.6%) had a significantly longer OS compared to those with tumors lacking MAPK pathway mutations (n = 102) (47.4%) [median OS, 147.8 months (95% CI,119.0-176.6) versus 89.5 months (95% CI, 61.4-117.7) (p = 0.01)], respectively. Median OS for patients with MAPK-mutated tumors was also significantly better than for patients whose tumors had no mutations (n = 75) [median OS, 147.8 months (95% CI, 119.0-176.6) versus 78.0 months (95% CI, 57.6-98.3)], respectively (p = 0.001). Median OS for patients with non-MAPK-mutated tumors (n = 27) was 125.1 months (95% CI, 83.9-166.3). In multivariable analysis, having a MAPK mutation was associated with improved OS. CONCLUSIONS: Patients with MAPK-mutated tumors have a significantly improved OS compared to those without MAPK-mutated tumors.

Triangular body-cover model of the vocal folds with coordinated activation of the five intrinsic laryngeal muscles.

Poor laryngeal muscle coordination that results in abnormal glottal posturing is believed to be a primary etiologic factor in common voice disorders such as non-phonotraumatic vocal hyperfunction. Abnormal activity of antagonistic laryngeal muscles is hypothesized to play a key role in the alteration of normal vocal fold biomechanics that results in the dysphonia associated with such disorders. Current low-order models of the vocal folds are unsatisfactory to test this hypothesis since they do not capture the co-contraction of antagonist laryngeal muscle pairs. To address this limitation, a self-sustained triangular body-cover model with full intrinsic muscle control is introduced. The proposed scheme shows good agreement with prior studies using finite element models, excised larynges, and clinical studies in sustained and time-varying vocal gestures. Simulations of vocal fold posturing obtained with distinct antagonistic muscle activation yield clear differences in kinematic, aerodynamic, and acoustic measures. The proposed tool is deemed sufficiently accurate and flexible for future comprehensive investigations of non-phonotraumatic vocal hyperfunction and other laryngeal motor control disorders.

Impact of a tiered discharge opioid algorithm on prescriptions and patient-reported outcomes after open gynecologic surgery.

OBJECTIVE: To compare discharge opioid refills, prescribed morphine equivalent dose and quantity, and longitudinal patient-reported outcomes before and after implementation of a tiered opioid prescribing algorithm among women undergoing open gynecologic surgery within an enhanced recovery after surgery program. METHODS: We compared opioid prescriptions, clinical outcomes, and patient-reported outcomes among 273 women. Post-discharge symptom burden was collected up to 42 days after discharge using the validated 27-item MD Anderson Symptom Inventory and analyzed using linear mixed effects models and Kaplan-Meier curves for symptom recovery. RESULTS: Among 113 pre-implementation and 160 post-implementation patients there was no difference in opioid refills (9.7% vs 11.3%, p=0.84). The post-implementation cohort had a significant reduction in median morphine equivalent dose (112.5 mg vs 225 mg, p<0.01), with no difference in median hospital length of stay (3 days vs 3 days, p=1.0) or 30-day readmission rate (9.4% vs 7.1%, p=0.66). There was no difference in patient-reported pain between the pre- and post-implementation cohorts on the day of discharge (severity 4.93 vs 5.14, p=0.53) or in any patient-reported symptoms, interference measures, or composite scores by post-discharge day 7. The median recovery time for most symptoms was 7 days, except for pain (14 days), fatigue (18 days), and physical interference (21 days), with no differences between cohorts. CONCLUSIONS: After implementation of a tiered opioid prescribing algorithm, the quantity and dose of discharge opioids prescribed decreased with no change in post-operative refills and without negatively impacting patient-reported symptom burden or interference, which can be used to educate and reassure patients and providers.

Sea lice infections on wild Atlantic salmon and sea trout in the River Tamar, UK: a temporal study.

Sea lice are amongst the most ecologically and economically damaging parasites of farmed salmonids globally. Spill-over from aquaculture can increase parasite pressure on wild fish populations, but quantifying this effect is challenging due to the relative paucity of data available on 'natural' salmonid louse burdens in the absence of aquaculture, particularly for Atlantic salmon Salmo salar. Here, wild Atlantic salmon and sea trout S. trutta were screened at the tidal limit of the River Tamar (UK) for the presence of sea lice. During 2013 and 2015, the prevalence of sea lice ranged from 41 (n = 361) to 60% (n = 275) and 55 (n = 882) to 58% (n = 800) in Atlantic salmon and sea trout, respectively. All sea lice collected were identified as Lepeophtheirus salmonis. Mean L. salmonis infection intensity across the study period was 5.84 (range: 1-66) in Atlantic salmon and 6.45 (range: 1-37) in sea trout. Infection intensity was positively correlated with the amount of external damage present for both fish species. Given that the fish were examined when returning to freshwater, the lice burdens obtained may represent an underestimate. Nevertheless, these data provide important baseline information on 'natural' sea louse infections in South West England, which has been proposed as a potential region for aquaculture development.

Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix.

OBJECTIVES: Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease. METHODS: Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40-100 moderate, and ≥100 high. RESULTS: Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%). CONCLUSIONS: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

Bayesian estimation of vocal function measures using laryngeal high-speed videoendoscopy and glottal airflow estimates: An in vivo case study.

This study introduces the in vivo application of a Bayesian framework to estimate subglottal pressure, laryngeal muscle activation, and vocal fold contact pressure from calibrated transnasal high-speed videoendoscopy and oral airflow data. A subject-specific, lumped-element vocal fold model is estimated using an extended Kalman filter and two observation models involving glottal area and glottal airflow. Model-based inferences using data from a vocally healthy male individual are compared with empirical estimates of subglottal pressure and reference values for muscle activation and contact pressure in the literature, thus providing baseline error metrics for future clinical investigations.

Ambulatory monitoring of Lombard-related vocal characteristics in vocally healthy female speakers.

Speakers typically modify their voice in the presence of increased background noise levels, exhibiting the classic Lombard effect. Lombard-related characteristics during everyday activities were recorded from 17 vocally healthy women who wore an acoustic noise dosimeter and ambulatory voice monitor. The linear relationship between vocal sound pressure level and environmental noise level exhibited an average slope of 0.54 dB/dB and value of 72.8 dB SPL at 50 dBA when correlation coefficients were greater than 0.4. These results, coupled with analyses of spectral and cepstral vocal function measures, provide normative ambulatory Lombard characteristics for comparison with patients with voice-use related disorders.

The difference between first and second harmonic amplitudes correlates between glottal airflow and neck-surface accelerometer signals during phonation.

Miniature high-bandwidth accelerometers on the anterior neck surface are used in laboratory and ambulatory settings to obtain vocal function measures. This study compared the widely applied L1-L2 measure (historically, H1-H2)-the difference between the log-magnitude of the first and second harmonics-computed from the glottal airflow waveform with L1-L2 derived from the raw neck-surface acceleration signal in 79 vocally healthy female speakers. Results showed a significant correlation (r = 0.72) between L1-L2 values estimated from both airflow and accelerometer signals, suggesting that raw accelerometer-based estimates of L1-L2 may be interpreted as reflecting glottal physiological parameters and voice quality attributes during phonation.

Automatic speech and singing classification in ambulatory recordings for normal and disordered voices.

Ambulatory voice monitoring is a promising tool for investigating phonotraumatic vocal hyperfunction (PVH), associated with the development of vocal fold lesions. Since many patients with PVH are professional vocalists, a classifier was developed to better understand phonatory mechanisms during speech and singing. Twenty singers with PVH and 20 matched healthy controls were monitored with a neck-surface accelerometer-based ambulatory voice monitor. An expert-labeled ground truth data set was used to train a logistic regression on 15 subject-pairs with fundamental frequency and autocorrelation peak amplitude as input features. Overall classification accuracy of 94.2% was achieved on the held-out test set.

Relationships between Challenge Tour golfers' clubhead velocity and force producing capabilities during a countermovement jump and isometric mid-thigh pull.

A number of field-based investigations have evidenced practically significant relationships between clubhead velocity (CHV), vertical jump performance and maximum strength. Unfortunately, whilst these investigations provide a great deal of external validity, they are unable to ascertain vertical ground reaction force (vGRF) variables that may relate to golfers' CHVs. This investigation aimed to assess if the variance in European Challenge Tour golfers' CHVs could be predicted by countermovement jump (CMJ) positive impulse (PI), isometric mid-thigh pull (IMTP) peak force (PF) and rate of force development (RFD) from 0-50 ms, 0-100 ms, 0-150 ms and 0-200 ms. Thirty-one elite level European Challenge Tour golfers performed a CMJ and IMTP on dual force plates at a tournament venue, with CHV measured on a driving range. Hierarchical multiple regression results indicated that the variance in CHV was significantly predicted by all four models (model one R2 = 0.379; model two R2 = 0.392, model three R2 = 0.422, model four R2 = 0.480), with Akaike's information criterion indicating that model one was the best fit. Individual standardised beta coefficients revealed that CMJ PI was the only significant variable, accounting for 37.9% of the variance in European Challenge Tour Golfers' CHVs.

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae.

Quorum sensing (QS) is a cell-cell communication mechanism that enables bacteria to assess their population density and alter their behavior upon reaching high cell number. Many bacterial pathogens utilize QS to initiate an attack on their host, thus QS has attracted significant attention as a potential antivirulence alternative to traditional antibiotics. Streptococcus pneumoniae, a notorious human pathogen responsible for a variety of acute and chronic infections, utilizes the competence regulon and its associated signaling peptide, the competence stimulating peptide (CSP), to acquire antibiotic resistance and establish an infection. In this work, we sought to define the binding pockets within the ComD1 receptor used for binding the hydrophobic side-chain residues in CSP1 through the introduction of highly-conservative point mutations within the peptide. Optimization of these binding interactions could lead to the development of highly potent CSP-based QS modulators while the inclusion of non-natural amino acids within the CSP sequence would confer resistance to protease degradation, a requirement for drug candidates.

Measuring vocal motor skill with a virtual voice-controlled slingshot.

Successful voice training (e.g., singing lessons) and vocal rehabilitation (e.g., therapy for a voice disorder) involve learning complex, vocal behaviors. However, there are no metrics describing how humans learn new vocal skills or predicting how long the improved behavior will persist post-therapy. To develop measures capable of describing and predicting vocal motor learning, a theory-based paradigm from limb motor control inspired the development of a virtual task where subjects throw projectiles at a target via modifications in vocal pitch and loudness. Ten subjects with healthy voices practiced this complex vocal task for five days. The many-to-one mapping between the execution variables pitch and loudness and resulting target error was evaluated using an analysis that quantified distributional properties of variability: Tolerance, noise, covariation costs (TNC costs). Lag-1 autocorrelation (AC1) and detrended-fluctuation-analysis scaling index (SCI) analyzed temporal aspects of variability. Vocal data replicated limb-based findings: TNC costs were positively correlated with error; AC1 and SCI were modulated in relation to the task's solution manifold. The data suggests that vocal and limb motor learning are similar in how the learner navigates the solution space. Future work calls for investigating the game's potential to improve voice disorder diagnosis and treatment.

Acoustic speech analysis of patients with decompensated heart failure: A pilot study.

This pilot study used acoustic speech analysis to monitor patients with heart failure (HF), which is characterized by increased intracardiac filling pressures and peripheral edema. HF-related edema in the vocal folds and lungs is hypothesized to affect phonation and speech respiration. Acoustic measures of vocal perturbation and speech breathing characteristics were computed from sustained vowels and speech passages recorded daily from ten patients with HF undergoing inpatient diuretic treatment. After treatment, patients displayed a higher proportion of automatically identified creaky voice, increased fundamental frequency, and decreased cepstral peak prominence variation, suggesting that speech biomarkers can be early indicators of HF.

Average Ambulatory Measures of Sound Pressure Level, Fundamental Frequency, and Vocal Dose Do Not Differ Between Adult Females With Phonotraumatic Lesions and Matched Control Subjects.

OBJECTIVES: Clinical management of phonotraumatic vocal fold lesions (nodules, polyps) is based largely on assumptions that abnormalities in habitual levels of sound pressure level (SPL), fundamental frequency (f0), and/or amount of voice use play a major role in lesion development and chronic persistence. This study used ambulatory voice monitoring to evaluate if significant differences in voice use exist between patients with phonotraumatic lesions and normal matched controls. METHODS: Subjects were 70 adult females: 35 with vocal fold nodules or polyps and 35 age-, sex-, and occupation-matched normal individuals. Weeklong summary statistics of voice use were computed from anterior neck surface acceleration recorded using a smartphone-based ambulatory voice monitor. RESULTS: Paired t tests and Kolmogorov-Smirnov tests resulted in no statistically significant differences between patients and matched controls regarding average measures of SPL, f0, vocal dose measures, and voicing/voice rest periods. Paired t tests comparing f0 variability between the groups resulted in statistically significant differences with moderate effect sizes. CONCLUSIONS: Individuals with phonotraumatic lesions did not exhibit differences in average ambulatory measures of vocal behavior when compared with matched controls. More refined characterizations of underlying phonatory mechanisms and other potentially contributing causes are warranted to better understand risk factors associated with phonotraumatic lesions.

Real-time estimation of aerodynamic features for ambulatory voice biofeedback.

The development of ambulatory voice monitoring devices has the potential to improve the diagnosis and treatment of voice disorders. In this proof-of-concept study, real-time biofeedback is incorporated into a smartphone-based platform that records and processes neck surface acceleration. The focus is on utilizing aerodynamic measures of vocal function as a basis for biofeedback. This is done using regressed Z-scores to compare recorded values to normative estimates based on sound pressure level and fundamental frequency. Initial results from the analysis of different voice qualities suggest that accelerometer-based estimates of aerodynamic parameters can be used for real-time ambulatory biofeedback.

OmpA-mediated rickettsial adherence to and invasion of human endothelial cells is dependent upon interaction with α2ß1 integrin.

Rickettsia conorii, a member of the spotted fever group (SFG) of the genus Rickettsia and causative agent of Mediterranean spotted fever, is an obligate intracellular pathogen capable of infecting various mammalian cell types. SFG rickettsiae express two major immunodominant surface cell antigen (Sca) proteins, OmpB (Sca5) and OmpA (Sca0). While OmpB-mediated entry has been characterized, the contribution of OmpA has not been well defined. Here we show OmpA expression in Escherichia coli is sufficient to mediate adherence to and invasion of non-phagocytic human endothelial cells. A recombinant soluble C-terminal OmpA protein domain (954-1735) with predicted structural homology to the Bordetella pertussis pertactin protein binds mammalian cells and perturbs R. conorii invasion by interacting with several mammalian proteins including ß1 integrin. Using functional blocking antibodies, small interfering RNA transfection, and mouse embryonic fibroblast cell lines, we illustrate the contribution of α2ß1 integrin as a mammalian ligand involved in R. conorii invasion of primary endothelial cells. We further demonstrate that OmpA-mediated attachment to mammalian cells is in part dependent on a conserved non-continuous RGD motif present in a predicted C-terminal 'pertactin' domain in OmpA.Our results demonstrate that multiple adhesin-receptor pairs are sufficient in mediating efficient bacterial invasion of R. conorii.

Modeling the effects of a posterior glottal opening on vocal fold dynamics with implications for vocal hyperfunction.

Despite the frequent observation of a persistent opening in the posterior cartilaginous glottis in normal and pathological phonation, its influence on the self-sustained oscillations of the vocal folds is not well understood. The effects of a posterior gap on the vocal fold tissue dynamics and resulting acoustics were numerically investigated using a specially designed flow solver and a reduced-order model of human phonation. The inclusion of posterior gap areas of 0.03-0.1 cm(2) reduced the energy transfer from the fluid to the vocal folds by more than 42%-80% and the radiated sound pressure level by 6-14 dB, respectively. The model was used to simulate vocal hyperfucntion, i.e., patterns of vocal misuse/abuse associated with many of the most common voice disorders. In this first approximation, vocal hyperfunction was modeled by introducing a compensatory increase in lung air pressure to regain the vocal loudness level that was produced prior to introducing a large glottal gap. This resulted in a significant increase in maximum flow declination rate and amplitude of unsteady flow, thereby mimicking clinical studies. The amplitude of unsteady flow was found to be linearly correlated with collision forces, thus being an indicative measure of vocal hyperfunction.