Natural language syntax complies with the free-energy principle.

Natural language syntax yields an unbounded array of hierarchically structured expressions. We claim that these are used in the service of active inference in accord with the free-energy principle (FEP). While conceptual advances alongside modelling and simulation work have attempted to connect speech segmentation and linguistic communication with the FEP, we extend this program to the underlying computations responsible for generating syntactic objects. We argue that recently proposed principles of economy in language design-such as "minimal search" criteria from theoretical syntax-adhere to the FEP. This affords a greater degree of explanatory power to the FEP-with respect to higher language functions-and offers linguistics a grounding in first principles with respect to computability. While we mostly focus on building new principled conceptual relations between syntax and the FEP, we also show through a sample of preliminary examples how both tree-geometric depth and a Kolmogorov complexity estimate (recruiting a Lempel-Ziv compression algorithm) can be used to accurately predict legal operations on syntactic workspaces, directly in line with formulations of variational free energy minimization. This is used to motivate a general principle of language design that we term Turing-Chomsky Compression (TCC). We use TCC to align concerns of linguists with the normative account of self-organization furnished by the FEP, by marshalling evidence from theoretical linguistics and psycholinguistics to ground core principles of efficient syntactic computation within active inference.

Diagnostic quality of ultrasound-guided fine-needle aspirates samples from the canine liver and spleen is not significantly affected by using 22-, 23-, and 25-gauge needles.

Ultrasound-guided fine-needle aspirates (FNA) of the liver and spleen for cytological analysis are a commonly performed procedure in canine veterinary practice. Based on our review of the literature, this is the first published study investigating whether needle size affects the diagnostic quality of hepatic and splenic samples. The aim of this prospective analytical study was to compare the diagnostic quality of ultrasound-guided FNA cytological samples of canine liver and spleen based on cellularity, blood contamination, and overall cell preservation between three different needle sizes (22-, 23-, and 25-gauge). A total of 282 splenic aspirates from 94 dogs and 348 hepatic aspirates from 116 dogs were enrolled in the study and examined by two board-certified veterinary clinical pathologists. In this study, no significant differences in diagnostic quality were identified between different needle gauge sizes when sampling canine liver and spleen. Blood contamination was higher using 22-gauge needles compared with 25-gauge needles (P = 0.024) when sampling the liver.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Difficulties with Speech-in-Noise Perception Related to Fundamental Grouping Processes in Auditory Cortex.

In our everyday lives, we are often required to follow a conversation when background noise is present ("speech-in-noise" [SPIN] perception). SPIN perception varies widely-and people who are worse at SPIN perception are also worse at fundamental auditory grouping, as assessed by figure-ground tasks. Here, we examined the cortical processes that link difficulties with SPIN perception to difficulties with figure-ground perception using functional magnetic resonance imaging. We found strong evidence that the earliest stages of the auditory cortical hierarchy (left core and belt areas) are similarly disinhibited when SPIN and figure-ground tasks are more difficult (i.e., at target-to-masker ratios corresponding to 60% rather than 90% performance)-consistent with increased cortical gain at lower levels of the auditory hierarchy. Overall, our results reveal a common neural substrate for these basic (figure-ground) and naturally relevant (SPIN) tasks-which provides a common computational basis for the link between SPIN perception and fundamental auditory grouping.

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.

Speech-evoked brain activity is more robust to competing speech when it is spoken by someone familiar.

When speech is masked by competing sound, people are better at understanding what is said if the talker is familiar compared to unfamiliar. The benefit is robust, but how does processing of familiar voices facilitate intelligibility? We combined high-resolution fMRI with representational similarity analysis to quantify the difference in distributed activity between clear and masked speech. We demonstrate that brain representations of spoken sentences are less affected by a competing sentence when they are spoken by a friend or partner than by someone unfamiliar-effectively, showing a cortical signal-to-noise ratio (SNR) enhancement for familiar voices. This effect correlated with the familiar-voice intelligibility benefit. We functionally parcellated auditory cortex, and found that the most prominent familiar-voice advantage was manifest along the posterior superior and middle temporal gyri. Overall, our results demonstrate that experience-driven improvements in intelligibility are associated with enhanced multivariate pattern activity in posterior temporal cortex.

Musicianship and melodic predictability enhance neural gain in auditory cortex during pitch deviance detection.

When listening to music, pitch deviations are more salient and elicit stronger prediction error responses when the melodic context is predictable and when the listener is a musician. Yet, the neuronal dynamics and changes in connectivity underlying such effects remain unclear. Here, we employed dynamic causal modeling (DCM) to investigate whether the magnetic mismatch negativity response (MMNm)-and its modulation by context predictability and musical expertise-are associated with enhanced neural gain of auditory areas, as a plausible mechanism for encoding precision-weighted prediction errors. Using Bayesian model comparison, we asked whether models with intrinsic connections within primary auditory cortex (A1) and superior temporal gyrus (STG)-typically related to gain control-or extrinsic connections between A1 and STG-typically related to propagation of prediction and error signals-better explained magnetoencephalography responses. We found that, compared to regular sounds, out-of-tune pitch deviations were associated with lower intrinsic (inhibitory) connectivity in A1 and STG, and lower backward (inhibitory) connectivity from STG to A1, consistent with disinhibition and enhanced neural gain in these auditory areas. More predictable melodies were associated with disinhibition in right A1, while musicianship was associated with disinhibition in left A1 and reduced connectivity from STG to left A1. These results indicate that musicianship and melodic predictability, as well as pitch deviations themselves, enhance neural gain in auditory cortex during deviance detection. Our findings are consistent with predictive processing theories suggesting that precise and informative error signals are selected by the brain for subsequent hierarchical processing.

How Long Does It Take for a Voice to Become Familiar? Speech Intelligibility and Voice Recognition Are Differentially Sensitive to Voice Training.

When people listen to speech in noisy places, they can understand more words spoken by someone familiar, such as a friend or partner, than someone unfamiliar. Yet we know little about how voice familiarity develops over time. We exposed participants (N = 50) to three voices for different lengths of time (speaking 88, 166, or 478 sentences during familiarization and training). These previously heard voices were recognizable and more intelligible when presented with a competing talker than novel voices-even the voice previously heard for the shortest duration. However, recognition and intelligibility improved at different rates with longer exposures. Whereas recognition was similar for all previously heard voices, intelligibility was best for the voice that had been heard most extensively. The speech-intelligibility benefit for the most extensively heard voice (10%-15%) is as large as that reported for voices that are naturally very familiar (friends and spouses)-demonstrating that the intelligibility of a voice can be improved substantially after only an hour of training.

Hypotonic challenge reduces human sperm motility through coiling and folding of the tail.

Human ejaculates collected for in vitro procedures show variably rapid increases in osmolality, depending on enzymatic degradation of compounds. Changes in osmolality can affect cell functions due to the energy consuming processes needed to control cell volume. The aim was to examine the effects of a hypotonic challenge for spermatozoa exposed to increased osmolality. Spermatozoa were selected by density gradient centrifugation and washed in media with different osmolalities. Osmolality was measured by freezing-point depression and sperm velocities by CASA. Swimming pattern observations and assessments of tail morphology of fixed spermatozoa were done with phase contrast microscopy. Increased osmolality did not change the curvilinear velocity (VCL), while decreased osmolality reduced or abolished VCL nonreversibly. For spermatozoa first exposed to 400 mOsm/kg, reversal of osmolality to 290 mOsm/kg reduced the VCL and the average path velocity (VAP) permanently. Hypotonic challenges increased sperm tail coiling and folding in a dose-response pattern. Spermatozoa once adjusted to high osmolality in the liquefied ejaculate are likely to suffer if exposed to a medium with a lower osmolality. For improved success of Assisted Reproductive Technologies (ART), it appears to be important to minimise the duration of sperm exposure to the ejaculate, by early dilution or sperm preparation.

Variational representational similarity analysis.

This technical note describes a variational or Bayesian implementation of representational similarity analysis (RSA) and pattern component modelling (PCM). It considers RSA and PCM as Bayesian model comparison procedures that assess the evidence for stimulus or condition-specific patterns of responses distributed over voxels or channels. On this view, one can use standard variational inference procedures to quantify the contributions of particular patterns to the data, by evaluating second-order parameters or hyperparameters. Crucially, this allows one to use parametric empirical Bayes (PEB) to infer which patterns are consistent among subjects. At the between-subject level, one can then assess the evidence for different (combinations of) hypotheses about condition-specific effects using Bayesian model comparison. Alternatively, one can select a single hypothesis that best explains the pattern of responses using Bayesian model selection. This note rehearses the technical aspects of within and between-subject RSA using a worked example, as implemented in the Statistical Parametric Mapping (SPM) software. En route, we highlight the connection between univariate and multivariate analyses of neuroimaging data and the sorts of analyses that are possible using component modelling and representational similarity analysis.

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects.

BACKGROUND: Smoking is a leading cause of numerous human disorders including pulmonary disease, cardiovascular disease, and cancer. Disease development is primarily caused by exposure to cigarette smoke constituents, many of which are known toxicants. Switching smokers to modified risk tobacco products (MRTPs) has been suggested as a potential means to reduce the risks of tobacco use, by reducing such exposure. METHODS: This randomized, controlled study investigated whether biomarkers of toxicant exposure (BoE) were reduced when smokers switched from smoking combustible cigarettes to using a novel (glo™/THP1.0) or in-market comparator (iQOS/THS) tobacco heating product (THP). One hundred eighty Japanese smokers smoked combustible cigarettes during a 2-day baseline period, followed by randomization to either continue smoking cigarettes, switch to using mentholated or non-mentholated variants of glo™, switch to using a non-mentholated variant of iQOS, or quit nicotine and tobacco product use completely for 5 days. Baseline and post-randomization 24-h urine samples were collected for BoE analysis. Carbon monoxide was measured daily in exhaled breath (eCO). RESULTS: On day 5 after switching, urinary BoE (excluding for nicotine) and eCO levels were significantly (p < .05) reduced by medians between 20.9% and 92.1% compared with baseline in all groups either using glo™ or iQOS or quitting tobacco use. Between-group comparisons revealed that the reductions in the glo™ groups were similar (p > .05) to quitting in many cases. CONCLUSIONS: glo™ or iQOS use for 5 days reduced exposure to smoke toxicants in a manner comparable to quitting tobacco use. THPs are reduced exposure tobacco products with the potential to be MRTPs. IMPLICATIONS: This clinical study demonstrates that when smokers switched from smoking combustible cigarettes to using tobacco heating products their exposure to smoke toxicants was significantly decreased. In many cases, this was to the same extent as that seen when they quit smoking completely. This may indicate that these products have the potential to be reduced exposure and/or reduced risk tobacco products when used by smokers whose cigarette consumption is displaced completely. CLINICAL TRIAL REGISTRATIONS: ISRCTN14301360 and UMIN000024988.

Possible factors influencing post-ejaculatory changes of the osmolality of human semen in vitro.

The human ejaculate is made up of secretions from the different accessory sex glands that empty in sequence at ejaculation. However, the different secretions only mix completely in vitro when the entire ejaculate is collected in a container and handled in the laboratory. At ejaculation, proteins from the seminal vesicles form a gel in the ejaculate and semen cannot be properly analysed and processed until the gel is liquefied. During and after liquefaction, there is continuous enzymatic activities and an ongoing increase in osmolality. The aim of this study was to investigate possible factors that influence the increase in semen osmolality in vitro. Osmolality was measured by freezing-point depression. Prostatic secretion was measured as zinc concentration. The presence of spermatozoa neither influenced the actual measurement of semen osmolality, nor the increase in osmolality. Enzymatic inhibitors reduced the increase in osmolality, and semen dilution prevented any increase in semen osmolality. However, the increase in osmolality covaried with the seminal zinc concentration, indicating that the observed increase was related to factors of prostatic origin. A simple and convenient procedure to reduce the risk for osmotic challenges for spermatozoa during handling for assisted reproductive technologies might be early dilution of semen.

Post-ejaculatory increase in human semen osmolality in vitro.

Spermatozoa prepared in vitro for assisted reproductive technology (ART) encounter other challenges than in vivo. One could be to survive and function despite varying extracellular osmolality. There is a lack of consistent knowledge of human semen osmolality and changes after liquefaction. The aim of this study was to investigate changes in semen osmolality that may occur in vitro after ejaculation and during sperm handling for ART. Osmolality was measured in 86 semen samples by freezing-point depression during storage in vitro at various times and temperatures. The freezing-point depression method was robust and reliable for measuring the osmolality of whole semen as shown by a low variability between repeats. At ejaculation, the osmolality was isotonic to cervical mucus and body fluids. There was a marked increase in osmolality after liquefaction, and the degree of increase varied greatly between samples. Osmolality rose with increasing temperature, and the progressive increase was blocked by denaturising temperature. Spermatozoa in each individual semen sample experienced a highly variable environment in vitro with respect to osmolality. This may be of importance regarding the handling of semen samples for the outcome of ART.

Using spatial release from masking to estimate the magnitude of the familiar-voice intelligibility benefit.

The ability to segregate simultaneous speech streams is crucial for successful communication. Recent studies have demonstrated that participants can report 10%-20% more words spoken by naturally familiar (e.g., friends or spouses) than unfamiliar talkers in two-voice mixtures. This benefit is commensurate with one of the largest benefits to speech intelligibility currently known-that which is gained by spatially separating two talkers. However, because of differences in the methods of these previous studies, the relative benefits of spatial separation and voice familiarity are unclear. Here, the familiar-voice benefit and spatial release from masking are directly compared, and it is examined if and how these two cues interact with one another. Talkers were recorded while speaking sentences from a published closed-set "matrix" task, and then listeners were presented with three different sentences played simultaneously. Each target sentence was played at 0° azimuth, and two masker sentences were symmetrically separated about the target. On average, participants reported 10%-30% more words correctly when the target sentence was spoken in a familiar than unfamiliar voice (collapsed over spatial separation conditions); it was found that participants gain a similar benefit from a familiar target as when an unfamiliar voice is separated from two symmetrical maskers by approximately 15° azimuth.

Familiar Voices Are More Intelligible, Even if They Are Not Recognized as Familiar.

We can recognize familiar people by their voices, and familiar talkers are more intelligible than unfamiliar talkers when competing talkers are present. However, whether the acoustic voice characteristics that permit recognition and those that benefit intelligibility are the same or different is unknown. Here, we recruited pairs of participants who had known each other for 6 months or longer and manipulated the acoustic correlates of two voice characteristics (vocal tract length and glottal pulse rate). These had different effects on explicit recognition of and the speech-intelligibility benefit realized from familiar voices. Furthermore, even when explicit recognition of familiar voices was eliminated, they were still more intelligible than unfamiliar voices-demonstrating that familiar voices do not need to be explicitly recognized to benefit intelligibility. Processing familiar-voice information appears therefore to depend on multiple, at least partially independent, systems that are recruited depending on the perceptual goal of the listener.

Semantic context improves speech intelligibility and reduces listening effort for listeners with hearing impairment.

OBJECTIVE: We investigated whether speech intelligibility and listening effort for hearing-aid users is affected by semantic context and hearing-aid setting. DESIGN: Participants heard target sentences spoken in a reverberant background of cafeteria noise and competing speech. Participants reported each sentence verbally. Eight participants also rated listening effort after each sentence. Sentence topic was either the same as, or different from, the previous target sentence. STUDY SAMPLE: Twenty participants with sensorineural hearing loss were fit binaurally with Signia receiver-in-the-canal hearing aids. Participants performed the task twice: once using the hearing aid's omnidirectional setting and once using the "Reverberant Room" setting, designed to aid listening in reverberant environments. RESULTS: Participants achieved better speech intelligibility for same-topic than different-topic sentences, and when they used the "Reverberant Room" than the omnidirectional hearing-aid setting. Participants who rated effort showed a reliable reduction in listening effort for same-topic sentences and for the "Reverberant Room" hearing-aid setting. The improvement in speech intelligibility from semantic context (i.e. same-topic compared to different-topic sentences) was greater than the improvement gained from changing hearing-aid setting. CONCLUSIONS: These findings highlight the enormous potential of cognitive (specifically, semantic) factors for improving speech intelligibility and reducing perceived listening effort in noise for hearing-aid users.

A randomised, controlled, two-Centre open-label study in healthy Japanese subjects to evaluate the effect on biomarkers of exposure of switching from a conventional cigarette to a tobacco heating product.

BACKGROUND: Smoking is a leading cause of numerous human disorders including lung cancer, chronic obstructive pulmonary disease, and atherosclerotic cardiovascular disease. The development of modified risk tobacco products (MRTPs) has been suggested as a possible way to reduce the risks of tobacco smoking by reducing exposure to cigarette smoke toxicants. This study is designed to investigate whether biomarkers of such exposure are reduced when smokers switch from smoking commercial cigarettes to using either a novel or a commercially-available tobacco heating product (THP). DESIGN AND METHODS: This study will assess biomarkers of exposure in current smokers who either remain smoking, switch to THP use, or quit all tobacco use completely, for 5 days. The study is an in-clinic (confinement) two-centre, randomised controlled clinical study with a forced-switching design. Subjects of either gender will be aged 23-55 years (minimum legal smoking age plus 3 years), of Japanese origin and with a verified smoking status (assessed by exhaled breath carbon monoxide and urinary cotinine levels). Subjects will have a usual brand cigarette within the International Organisation for Standardisation (ISO) tar band of 6-8 mg and will be judged to be healthy by medical history, physical examination, vital signs, electrocardiography (ECG), clinical biochemistry and lung function tests. The primary objective of this study is to assess changes within groups in selected biomarkers of exposure (BoE) and of biological effect (BoBE) after a forced switch from a commercial control cigarette to either a menthol or a non-menthol THP. Secondary objectives are to assess between-group differences, to determine nicotine pharmacokinetics for cigarettes and THPs, to assess subject's satisfaction with the study products, and to monitor additional endpoints related to safety and product use. DISCUSSION: Data from this study will advance our scientific understanding of the changes in exposure to cigarette smoke toxicants in smokers who switch to using a THP. TRIAL REGISTRATIONS: UMIN000024988 (25th November 2016); ISRCTN14301360 (14th December 2016).

HEMATOLOGY AND PLASMA CHEMISTRY OF THE PLOUGHSHARE TORTOISE (ASTROCHELYS YNIPHORA) IN A CAPTIVE BREEDING PROGRAM.

Blood samples from 172 captive and 40 wild, healthy, juvenile and adult, ploughshare tortoises ( Astrochelys yniphora ) were analyzed to determine hematological and biochemical reference intervals. Hematological analytes included packed cell volume (PCV), white blood cell count (WBC), and WBC differential estimates. Biochemical analysis included total protein measured by photometry (TP) and by refractometry (TPr), albumin (ALB), creatine kinase (CK), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), bile acids (BA), calcium (Ca), phosphorus (P), urea (UREA), and uric acid (UA). The jugular vein was identified as the preferred venipuncture site as subcarapacial vein venipuncture resulted in regular hemodilution. In due consideration of small sample sizes in some of the groups studied, adult tortoises had significantly higher plasma GLDH activity and TPr, TP, ALB, BA, and UREA concentrations and significantly lower AST activity and P concentration than juveniles. Captivity had a significant influence in some reference intervals, with captive adults presenting significantly higher WBC, and estimated counts of all white cell types as well as UREA and TPr than wild counterparts. Captive juveniles also showed significantly higher estimated monocyte and lower estimated eosinophil and basophil counts. Although these differences most likely reflect local environmental or dietary differences, without representing pathology or a deviation from the normal, they question the applicability of reference values from captive animals to wild animals and vice versa. Significant sex differences were only observed for PCV and UA. The reported reference intervals may serve as benchmarks for clinical assessment and conservation of this critically endangered species.

The effects of naturally occurring acids on the surface properties of chrysotile asbestos.

Chrysotile asbestos is considered an environmental health hazard. It is postulated that the surface of chrysotile, with its inherent positive charge and chemical content of trace transition metals within the mineral is a causative factor of the concern. Weathering may reduce the negative health effects of chrysotile asbestos, by alteration of the outer brucite layer of the chrysotile. To assess the changes in the surface properties of chrysotile asbestos by simulated weathering, chrysotile was treated with oxalic, hydrochloric, and carbonic acids. Naturally occurring chrysotile, from a mine site and serpentinitic stream sediments from the Sumas River were analyzed and compared. Oxalic acid, a chelating acid, was the most effective at extracting the majority of the trace elements present in the chrysotile, reducing their positive surface charge and producing visible changes at the surface of the fibers as shown by Field Emission Scanning Electron Microsopy (FESEM). Carbonic acid had little effect on the surface properties. Stream environments had minor detectable effects on the surface properties on the chrysotile stream sediments.