The Gut Microbiome Modulates Body Temperature Both in Sepsis and Health.

Rationale: Among patients with sepsis, variation in temperature trajectories predicts clinical outcomes. In healthy individuals, normal body temperature is variable and has decreased consistently since the 1860s. The biologic underpinnings of this temperature variation in disease and health are unknown. Objectives: To establish and interrogate the role of the gut microbiome in calibrating body temperature. Methods: We performed a series of translational analyses and experiments to determine whether and how variation in gut microbiota explains variation in body temperature in sepsis and in health. We studied patient temperature trajectories using electronic medical record data. We characterized gut microbiota in hospitalized patients using 16S ribosomal RNA gene sequencing. We modeled sepsis using intraperitoneal LPS in mice and modulated the microbiome using antibiotics, germ-free, and gnotobiotic animals. Measurements and Main Results: Consistent with prior work, we identified four temperature trajectories in patients hospitalized with sepsis that predicted clinical outcomes. In a separate cohort of 116 hospitalized patients, we found that the composition of patients' gut microbiota at admission predicted their temperature trajectories. Compared with conventional mice, germ-free mice had reduced temperature loss during experimental sepsis. Among conventional mice, heterogeneity of temperature response in sepsis was strongly explained by variation in gut microbiota. Healthy germ-free and antibiotic-treated mice both had lower basal body temperatures compared with control animals. The Lachnospiraceae family was consistently associated with temperature trajectories in hospitalized patients, experimental sepsis, and antibiotic-treated mice. Conclusions: The gut microbiome is a key modulator of body temperature variation in both health and critical illness and is thus a major, understudied target for modulating physiologic heterogeneity in sepsis.

In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes.

BACKGROUND: Critically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. However, in other disease states and animal models, gut anaerobes are protective against pneumonia, organ failure and mortality. We therefore designed a translational series of analyses and experiments to determine the effects of anti-anaerobic antibiotics on the risk of adverse clinical outcomes among critically ill patients. METHODS: We conducted a retrospective single-centre cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared intensive care unit outcomes (ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival) in all patients and changes in gut microbiota in a subcohort of 116 patients. In murine models, we studied the effects of anaerobe depletion in infectious (Klebsiella pneumoniae and Staphylococcus aureus pneumonia) and noninfectious (hyperoxia) injury models. RESULTS: Early administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (hazard ratio (HR) 1.24, 95% CI 1.06-1.45), infection-free survival (HR 1.22, 95% CI 1.09-1.38) and overall survival (HR 1.14, 95% CI 1.02-1.28). Patients who received anti-anaerobic antibiotics had decreased initial gut bacterial density (p=0.00038), increased microbiome expansion during hospitalisation (p=0.011) and domination by Enterobacteriaceae spp. (p=0.045). Enterobacteriaceae were also enriched among respiratory pathogens in anti-anaerobic-treated patients (p<2.2×10-16). In murine models, treatment with anti-anaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia (p<0.05) and increased the lethality of hyperoxia (p=0.0002). CONCLUSIONS: In critically ill patients, early treatment with anti-anaerobic antibiotics is associated with increased mortality. Mechanisms may include enrichment of the gut with respiratory pathogens, but increased mortality is incompletely explained by infections alone. Given consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered.

SNIKT: sequence-independent adapter identification and removal in long-read shotgun sequencing data.

SUMMARY: Here, we introduce SNIKT, a command-line tool for sequence-independent visual confirmation and input-assisted removal of adapter contamination in whole-genome shotgun or metagenomic shotgun long-read sequencing DNA or RNA data. AVAILABILITY AND IMPLEMENTATION: SNIKT is implemented in R and is compatible with Unix-like platforms. The source code, along with documentation, is freely available under an MIT license at https://github.com/piyuranjan/SNIKT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cat-astrophic effects of sudden interruptions on spatial auditory attention.

Salient interruptions draw attention involuntarily. Here, we explored whether this effect depends on the spatial and temporal relationships between a target stream and interrupter. In a series of online experiments, listeners focused spatial attention on a target stream of spoken syllables in the presence of an otherwise identical distractor stream from the opposite hemifield. On some random trials, an interrupter (a cat "MEOW") occurred. Experiment 1 established that the interrupter, which occurred randomly in 25% of the trials in the hemifield opposite the target, degraded target recall. Moreover, a majority of participants exhibited this degradation for the first target syllable, which finished before the interrupter began. Experiment 2 showed that the effect of an interrupter was similar whether it occurred in the opposite or the same hemifield as the target. Experiment 3 found that the interrupter degraded performance slightly if it occurred before the target stream began but had no effect if it began after the target stream ended. Experiment 4 showed decreased interruption effects when the interruption frequency increased (50% of the trials). These results demonstrate that a salient interrupter disrupts recall of a target stream, regardless of its direction, especially if it occurs during a target stream.

Attentional modulation of neural dynamics in tactile perception of complex regional pain syndrome patients.

Body perceptual disturbances are an increasingly acknowledged set of symptoms and possible clinical markers of complex regional pain syndrome (CRPS), but the neurophysiological and neurocognitive changes that underlie them are still far from being clear. We adopted a multivariate and neurodynamical approach to the analysis of EEG modulations evoked by touch to highlight differences between patients and healthy controls, between affected and unaffected side of the body, and between "passive" (i.e., no task demands and equiprobable digit stimulation) and "active" tactile processing (i.e., where a digit discrimination task was administered and spatial probability manipulated). When correct identifications are considered, an early reduction in cortical decodability (28-56 ms) distinguishes CRPS patients from healthy volunteers. However, when error trials are included in the classifier's training, there is an unexpected increased decodability in the CRPS group compared with healthy volunteers (280-320 ms). These group differences in neural processing seemed to be driven by the affected rather than the unaffected side. We corroborated these findings with several exploratory analyses of neural representation dynamics and behavioural modelling, highlighting the need for single participant analyses. Although several limitations impacted the robustness and generalizability of these comparisons, the proposed analytical approach yielded promising insights (as well as possible biomarkers based on neural dynamics) into the relatively unexplored alterations of tactile decision-making and attentional control mechanisms in chronic CRPS.

Lung Microbiota Predict Clinical Outcomes in Critically Ill Patients.

Rationale: Recent studies have revealed that, in critically ill patients, lung microbiota are altered and correlate with alveolar inflammation. The clinical significance of altered lung bacteria in critical illness is unknown.Objectives: To determine if clinical outcomes of critically ill patients are predicted by features of the lung microbiome at the time of admission.Methods: We performed a prospective, observational cohort study in an ICU at a university hospital. Lung microbiota were quantified and characterized using droplet digital PCR and bacterial 16S ribosomal RNA gene quantification and sequencing. Primary predictors were the bacterial burden, community diversity, and community composition of lung microbiota. The primary outcome was ventilator-free days, determined at 28 days after admission.Measurements and Main Results: Lungs of 91 critically ill patients were sampled using miniature BAL within 24 hours of ICU admission. Patients with increased lung bacterial burden had fewer ventilator-free days (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88), which remained significant when the analysis was controlled for pneumonia and severity of illness. The community composition of lung bacteria predicted ventilator-free days (P = 0.003), driven by the presence of gut-associated bacteria (e.g., species of the Lachnospiraceae and Enterobacteriaceae families). Detection of gut-associated bacteria was also associated with the presence of acute respiratory distress syndrome.Conclusions: Key features of the lung microbiome (bacterial burden and enrichment with gut-associated bacteria) predict outcomes in critically ill patients. The lung microbiome is an understudied source of clinical variation in critical illness and represents a novel therapeutic target for the prevention and treatment of acute respiratory failure.

A highly reproducible method for the measurement of [6-O-methyl-11 C]diprenorphine and its radio-metabolites based on solid-phase extraction and radio-high-pressure liquid chromatography.

Described here is a method for the measurement of the radio-metabolites of the positron emission tomography radiotracer [6-O-methyl-11 C]diprenorphine ([11 C]diprenorphine) using in-line solid-phase extraction (SPE) combined with radio-high-pressure liquid chromatography analysis. We believe that this method offers a reliable and reproducible approach to [11 C]diprenorphine metabolite analysis. In addition, different SPE stationary phases are assessed for their efficiency for loading, retention and elution of the parent molecule and its metabolites. Having assessed C4, phenyl and C18 stationary phase, we concluded that a C18 SPE was optimal for our method. Finally, in silico predictions of diprenorphine metabolism were compared with in vivo metabolism of [11 C]diprenorphine induced by hepatic microsomal digestion and analysed by matrix-assisted laser desorption/ionisation mass spectrometry. It was found that there was a high degree of agreement between the two methods and in particular the formation of the diprenorphine-3-glucuronide metabolite.

A neurophysiological investigation of anticipation to pain in Parkinson's disease.

Chronic pain is common in people with Parkinson's disease and is often considered to be caused by the motor impairments associated with the disease. Altered top-down processing of pain characterises several chronic pain conditions and occurs when the cortex modifies nociceptive processing in the brain and spinal cord. This contrasts with bottom-up modulation of pain whereby nociceptive processing is modified on its way up to the brain. Although several studies have demonstrated altered bottom-up pain processing in Parkinson's, the contribution of enhanced anticipation to pain and atypical top-down processing of pain has not been fully explored. During the anticipation to noxious stimuli, EEG source localisation reported an increased activation in the midcingulate cortex and supplementary motor area in the Parkinson's disease group compared to the healthy control group during mid [-1,500 -1,000]-and late anticipation [-500 0], indicating enhanced cortical activity before noxious stimulation. The Parkinson's disease group was also more sensitive to the laser and required a lower voltage level to induce pain. This study provides evidence supporting the hypothesis that enhanced top-down processing of pain may contribute to the development of chronic pain in Parkinson's. Additional research to establish whether the altered anticipatory response is unique to noxious stimuli is required as no control stimulus was used within the current study. With further research to confirm these findings, our results inform a scientific rationale for novel treatment strategies of pain in Parkinson's disease, including mindfulness, cognitive therapies and other approaches targeted at improving top-down processing of pain.

Distinct patterns of default mode and executive control network circuitry contribute to present and future executive function in older adults.

Executive function (EF) performance in older adults has been linked with functional and structural profiles within the executive control network (ECN) and default mode network (DMN), white matter hyperintensities (WMH) burden and levels of Alzheimer's disease (AD) pathology. Here, we simultaneously explored the unique contributions of these factors to baseline and longitudinal EF performance in older adults. Thirty-two cognitively normal (CN) older adults underwent neuropsychological testing at baseline and annually for three years. Neuroimaging and AD pathology measures were collected at baseline. Separate linear regression models were used to determine which of these variables predicted composite EF scores at baseline and/or average annual change in composite ΔEF scores over the three-year follow-up period. Results demonstrated that low DMN deactivation, high ECN activation and WMH burden were the main predictors of EF scores at baseline. In contrast, poor DMN and ECN WM microstructure and higher AD pathology predicted greater annual decline in EF scores. Subsequent mediation analysis demonstrated that DMN WM microstructure uniquely mediated the relationship between AD pathology and ΔEF. These results suggest that functional activation patterns within the DMN and ECN and WMHs contribute to baseline EF while structural connectivity within these networks impact longitudinal EF performance in older adults.

Neural representations of aversive value encoding in pain catastrophizers.

Chronic pain is exacerbated by maladaptive cognition such as pain catastrophizing (PC). Biomarkers of PC mechanisms may aid precision medicine for chronic pain. Here, we investigate EEG biomarkers using mass univariate and multivariate (machine learning) approaches. We test theoretical notions that PC results from a combination of augmented aversive-value encoding ("magnification") and persistent expectations of pain ("rumination"). Healthy individuals with high or low levels of PC underwent an experimental pain model involving nociceptive laser stimuli preceded by cues predicting forthcoming pain intensity. Analysis of EEG acquired during the cue and laser stimulation provided event-related potentials (ERPs) identifying spatially and temporally-extended neural representations associated with pain catastrophizing. Specifically, differential neural responses to cues predicting high vs. low intensity pain (i.e. aversive value encoding) were larger in the high PC group, largely originating from mid-cingulate and superior parietal cortex. Multivariate spatiotemporal EEG patterns evoked from cues with high aversive value selectively and significantly differentiated the high PC from low PC group (64.6% classification accuracy). Regression analyses revealed that neural patterns classifying groups could be partially predicted (R2 = 28%) from those neural patterns classifying the aversive value of cues. In contrast, behavioural and EEG analyses did not provide evidence that PC modifies more persistent effects of prior expectation on pain perception and nociceptive responses. These findings support the hypothesis of magnification of aversive value encoding but not persistent expression of expectation in pain catastrophizers. Multivariate patterns of aversive value encoding provide promising biomarkers of maladaptive cognitive responses to chronic pain that have future potential for psychological treatment development and clinical stratification.

The Effects of Dynamic-range Automatic Gain Control on Sentence Intelligibility With a Speech Masker in Simulated Cochlear Implant Listening.

OBJECTIVES: "Channel-linked" and "multi-band" front-end automatic gain control (AGC) were examined as alternatives to single-band, channel-unlinked AGC in simulated bilateral cochlear implant (CI) processing. In channel-linked AGC, the same gain control signal was applied to the input signals to both of the two CIs ("channels"). In multi-band AGC, gain control acted independently on each of a number of narrow frequency regions per channel. DESIGN: Speech intelligibility performance was measured with a single target (to the left, at -15 or -30°) and a single, symmetrically-opposed masker (to the right) at a signal-to-noise ratio (SNR) of -2 decibels. Binaural sentence intelligibility was measured as a function of whether channel linking was present and of the number of AGC bands. Analysis of variance was performed to assess condition effects on percent correct across the two spatial arrangements, both at a high and a low AGC threshold. Acoustic analysis was conducted to compare postcompressed better-ear SNR, interaural differences, and monaural within-band envelope levels across processing conditions. RESULTS: Analyses of variance indicated significant main effects of both channel linking and number of bands at low threshold, and of channel linking at high threshold. These improvements were accompanied by several acoustic changes. Linked AGC produced a more favorable better-ear SNR and better preserved broadband interaural level difference statistics, but did not reduce dynamic range as much as unlinked AGC. Multi-band AGC sometimes improved better-ear SNR statistics and always improved broadband interaural level difference statistics whenever the AGC channels were unlinked. Multi-band AGC produced output envelope levels that were higher than single-band AGC. CONCLUSIONS: These results favor strategies that incorporate channel-linked AGC and multi-band AGC for bilateral CIs. Linked AGC aids speech intelligibility in spatially separated speech, but reduces the degree to which dynamic range is compressed. Combining multi-band and channel-linked AGC offsets the potential impact of diminished dynamic range with linked AGC without sacrificing the intelligibility gains observed with linked AGC.

Flexible 3D-Printed EEG Electrodes.

For electroencephalography (EEG) in haired regions of the head, finger-based electrodes have been proposed in order to part the hair and make a direct contact with the scalp. Previous work has demonstrated 3D-printed fingered electrodes to allow personalisation and different configurations of electrodes to be used for different people or for different parts of the head. This paper presents flexible 3D-printed EEG electrodes for the first time. A flexible 3D printing element is now used, with three different base mechanical structures giving differently-shaped electrodes. To obtain improved sensing performance, the silver coatings used previously have been replaced with a silver/silver-chloride coating. This results in reduced electrode contact impedance and reduced contact noise. Detailed electro-mechanical testing is presented to demonstrate the performance of the operation of the new electrodes, particularly with regards to changes in conductivity under compression, together with on-person tests to demonstrate the recording of EEG signals.

A meta-analytic review of the correlation between peripheral oxytocin and cortisol concentrations.

The stress dampening effects of exogenous oxytocin in humans have been well documented. However, the relation between endogenous oxytocin and cortisol is poorly understood. We conducted a meta-analysis on the correlation between oxytocin and cortisol levels measured at baseline (k=24, N=739). The effect size for the baseline correlation statistic was small (Pearson r=0.163, p=0.008), with high heterogeneity (I2=67.88%). Moderation analysis revealed that studies where participants anticipated an experimental manipulation evidenced a greater positive correlation compared to those that did not (Pearson r=0.318, p=0.006). A supplementary analysis including additional studies indicated that oxytocin levels in unextracted samples were 60 times higher when using this questionable practice. The findings suggest that the interplay between oxytocin and cortisol is dynamic and sensitive to the anticipation of stress or novelty. Furthermore, extraction of oxytocin appears to be an essential methodological practice.

Shifting Fundamental Frequency in Simulated Electric-Acoustic Listening: Effects of F0 Variation.

OBJECTIVE: Shifting the mean fundamental frequency (F0) of target speech down in frequency may be a way to provide the benefits of electric-acoustic stimulation (EAS) to cochlear implant (CI) users whose limited residual hearing precludes a benefit typically, even with amplification. However, previous study showed a decline in the amount of benefit at the greatest downward frequency shifts, and the authors hypothesized that this might be related to F0 variation. Thus, in the present study, the authors sought to determine the relationship between mean F0, F0 variation, and the benefits of combining electric stimulation from a CI with low-frequency residual acoustic hearing. DESIGN: The authors measured speech intelligibility in normal-hearing listeners using an EAS simulation consisting of a sine vocoder combined either with speech low-pass filtered at 500 Hz, or with a pure tone representing target F0. The authors used extracted target voice pitch information to modulate the tone, and manipulated both the frequency of the carrier (mean F0), as well as the standard deviation of the voice pitch information (F0 variation). RESULTS: A decline in EAS benefit was observed at the lowest mean F0 tested, but this decline disappeared when F0 variation was reduced to be proportional to the amount of the shift in frequency (i.e., when F0 was shifted logarithmically instead of linearly). CONCLUSION: Lowering mean F0 by shifting the frequency of a pure tone carrying target voice pitch information can provide as much EAS benefit as an unshifted tone, at least in the current simulation of EAS. These results may have implications for CI users with extremely limited residual acoustic hearing.

Reductions in co-contraction following neuromuscular re-education in people with knee osteoarthritis.

BACKGROUND: Both increased knee muscle co-contraction and alterations in central pain processing have been suggested to play a role in knee osteoarthritis pain. However, current interventions do not target either of these mechanisms. The Alexander Technique provides neuromuscular re-education and may also influence anticipation of pain. This study therefore sought to investigate the potential clinical effectiveness of the AT intervention in the management of knee osteoarthritis and also to identify a possible mechanism of action. METHODS: A cohort of 21 participants with confirmed knee osteoarthritis were given 20 lessons of instruction in the Alexander Technique. In addition to clinical outcomes EMG data, quantifying knee muscle co-contraction and EEG data, characterising brain activity during anticipation of pain, were collected. All data were compared between baseline and post-intervention time points with a further 15-month clinical follow up. In addition, biomechanical data were collected from a healthy control group and compared with the data from the osteoarthritis subjects. RESULTS: Following AT instruction the mean WOMAC pain score reduced by 56 % from 9.6 to 4.2 (P < 0.01) and this reduction was maintained at 15 month follow up. There was a clear decrease in medial co-contraction at the end of the intervention, towards the levels observed in the healthy control group, both during a pre-contact phase of gait (p < 0.05) and during early stance (p < 0.01). However, no changes in pain-anticipatory brain activity were observed. Interestingly, decreases in WOMAC pain were associated with reductions in medial co-contraction during the pre-contact phase of gait. CONCLUSIONS: This is the first study to investigate the potential effectiveness of an intervention aimed at increasing awareness of muscle behaviour in the clinical management of knee osteoarthritis. These data suggest a complex relationship between muscle contraction, joint loading and pain and support the idea that excessive muscle co-contraction may be a maladaptive response in this patient group. Furthermore, these data provide evidence that, if the activation of certain muscles can be reduced during gait, this may lead to positive long-term clinical outcomes. This finding challenges clinical management models of knee osteoarthritis which focus primarily on muscle strengthening. TRIAL REGISTRATION: ISRCTN74086288 , 4th January 2016, retrospectively registered.

Short Convergent Synthesis of the Mycolactone Core Through Lithiation-Borylation Homologations.

Using iterative lithiation-borylation homologations, the mycolactone toxin core has been synthesized in 13 steps and 17% overall yield. The rapid build-up of molecular complexity, high convergence and high stereoselectivity are noteworthy features of this synthesis.

'I didn't even know boys could get the vaccine': Parents' reasons for human papillomavirus (HPV) vaccination decision making for their sons.

OBJECTIVE: The study's objective was to examine parents' reasons for their decision to vaccinate their 9-16-year-old sons with the human papillomavirus (HPV) vaccine. METHODS: Using the precaution adoption process model (PAPM), parents were classified according to one of six stages of decision making: unaware, unengaged, undecided, decided not to vaccinate, decided to vaccinate, or vaccinated. Parents responded to an open-ended question: 'What would influence your decision to have your son vaccinated or not against HPV?' RESULTS: Three thousand one hundred and seventeen parents provided 2,874 interpretable narrative responses that were coded using thematic content analyses. The majority of parents were in the earlier precaution adoption process model stages, that is, unaware that the HPV vaccine could be given to boys (57.0%), unengaged (20.9%), or undecided (9.1%). Needing more information, vaccine cost, risks associated with vaccination, and wanting a doctor's recommendation influenced these earlier-staged parents' decisions. Parents who decided not to vaccinate their sons (6.8%) reported their decision was due to the risks, insufficient research, lack of confidence in vaccines, and/or no need for the vaccine (as their sons are not sexually active and/or too young). Parents who had decided to vaccinate their sons (5.0%) or who had vaccinated their sons (1.1%) reported that their decisions were based on protecting their sons' health and preventing disease. CONCLUSION: There are important differences in the factors that influence parents' decision depending on where they are along the decision-making trajectory. Assuring that parents are well informed about the importance of male vaccination, reducing vaccine cost, accurately communicating vaccine safety, and improving patient-provider communication may augment vaccine coverage and prevent HPV-associated cancers in Canada. Copyright © 2015 John Wiley & Sons, Ltd.

Spectral overlap and interaural time difference sensitivity: possible role of binaural interference.

A follow-up experiment to those conducted by Brown and Yost [(2011). J. Acoust. Soc. Am. 130, 358-364; (2013). Basic Aspects of Hearing: Physiology and Perception (Springer, London, UK)] examined interaural time difference (ITD) discrimination for a low-frequency target noise band flanked by monotic noise bands that were either lower-frequency than the target band, higher-frequency, or both. The flanking bands were either spectrally contiguous with the target band or spectrally separated. Significant interference in ITD processing occurred in the presence of the high-frequency flanking band. Results are discussed by way of a comparison of the conditions in the present study to those in studies of binaural interference. The possible role of attention is also discussed.

When the brain expects pain: common neural responses to pain anticipation are related to clinical pain and distress in fibromyalgia and osteoarthritis.

Supraspinal processes in humans can have a top-down enhancing effect on nociceptive processing in the brain and spinal cord. Studies have begun to suggest that such influences occur in conditions such as fibromyalgia (FM), but it is not clear whether this is unique to FM pain or common to other forms of chronic pain, such as that associated with osteoarthritis (OA). We assessed top-down processes by measuring anticipation-evoked potentials and their estimated sources, just prior (< 500 ms) to laser heat pain stimulation, in 16 patients with FM, 16 patients with OA and 15 healthy participants, by using whole-brain statistical parametric mapping. Clinical pain and psychological coping factors (pain catastrophizing, anxiety, and depression) were well matched between the patient groups, such that these did not confound our comparisons between FM and OA patients. For the same level of heat pain, insula activity was significantly higher in FM patients than in the other two groups during anticipation, and correlated with the intensity and extent of reported clinical pain. However, the same anticipatory insula activity also correlated with OA pain, and with the number of tender points across the two patient groups, suggesting common central mechanisms of tenderness. Activation in the dorsolateral prefrontal cortex was reduced during anticipation in both patient groups, and was related to less effective psychological coping. Our findings suggest common neural correlates of pain and tenderness in FM and OA that are enhanced in FM but not unique to this condition.