Magnified interaural level differences enhance spatial release from masking in bilateral cochlear implant users.

Bilateral cochlear implant (BiCI) usage makes binaural benefits a possibility for implant users. Yet, limited access to interaural time difference (ITD) cues and reduced saliency of interaural level difference (ILD) cues restricts perceptual benefits of spatially separating a target from masker sounds for BiCI users. Here, we explore whether magnifying ILD cues improves intelligibility of masked speech for BiCI listeners in a "symmetrical-masker" configuration, which controls for long-term positive target-to-masker ratio (TMR) at the ear nearer the target from naturally occurring ILD cues. We magnified ILDs by estimating moment-to-moment ITDs in 1-octave-wide frequency bands, and applying corresponding ILDs to the target-masker mixtures reaching the two ears at each time in each frequency band. We conducted two experiments, one with NH listeners using vocoded stimuli and one with BiCI users. ILD magnification significantly improved intelligibility in both experiments. BiCI listeners showed no benefit of spatial separation between target and maskers with natural ILDs, even for the largest target-masker separation. Because ILD magnification is applied to the mixed signals at each ear, the strategy does not alter the TMR in either ear at any time; improvements to masked speech intelligibility are thus likely from improved perceptual separation of the competing sources.

Profiling inflammatory outcomes of Candida albicans colonization and food allergy induction in the murine glandular stomach.

We investigated the effects of Candida albicans colonization on inflammatory responses in the murine glandular stomach, which is similar to the glandular mucosa of the human stomach. We also explored whether the presence of a food allergy could exacerbate C. albicans-induced inflammation or if C. albicans would amplify allergic inflammation in the glandular stomach. C. albicans successfully colonized the stomach of amoxicillin-pre-treated BALB/c mice and induced gastritis in the limiting ridge with minimal inflammation in the glandular stomach. There was significant upregulation of Il18, calprotectin (S100a8 and S100a9), and several antimicrobial peptides, but minimal induction of type 1, 2, or 3 responses in the glandular stomach. A robust type 2 response, inflammatory cell recruitment, and tissue remodeling occurred in the glandular stomach following oral ovalbumin challenges in sensitized mice. The type 2 response was not augmented by C. albicans colonization, but there was significant upregulation of Il1b, Il12a, Tnf, and Il17a in C. albicans-colonized food allergic mice. The presence of C. albicans did not affect the expression of genes involved in barrier integrity and signaling, many of which were upregulated during food allergy. Overall, our data indicate that C. albicans colonization induces minimal inflammation in the glandular stomach but augments antimicrobial peptide expression. Induction of a food allergy results in robust type 2 inflammation in the glandular stomach, and while C. albicans colonization does not exacerbate type 2 inflammation, it does activate a number of innate and type 3 immune responses amid the backdrop of allergic inflammation. IMPORTANCE: Food allergy continues to be a growing public health concern, affecting at least 1 in 10 individuals in the United States alone. However, little is known about the involvement of the gastric mucosa in food allergy. Gastrointestinal Candida albicans colonization has been reported to promote gastrointestinal inflammation in a number of chronic diseases. Using a mouse model of food allergy to egg white protein, we demonstrate regionalization of the inflammatory response to C. albicans colonization, induction of robust type 2 (allergic) inflammation in the stomach, and augmentation of innate and type 3 responses by C. albicans colonization during food allergy.

Morphometry of medial temporal lobe subregions using high-resolution T2-weighted MRI in ADNI3: Why, how, and what's next?

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

Automatic segmentation of medial temporal lobe subregions in multi-scanner, multi-modality MRI of variable quality.

Background: Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer's disease. However, image quality may vary in MRI. Poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images. Method: MRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimer's Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. To compare our proposed model with a baseline single-modality model in the full dataset with mixed high/poor image quality, we evaluated the ability of derived volume/thickness measures to discriminate Amyloid+ mild cognitive impairment (A+MCI) and Amyloid- cognitively unimpaired (A-CU) groups, as well as the stability of these measurements in longitudinal data. Results: The multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. Conclusion: The multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.

Height Fluctuations and Surface Gradients in Topographic Measurements.

Topographic maps are composed of pixels associated with coordinates (x, y, z) on a surface. Each pixel location (x, y) is linked with fluctuations in a measured height sample (z). Fluctuations here are uncertainties in heights estimated from multiple topographic measurements at the same position. Height samples (z) are measured at individual locations (x, y) in topographic measurements and compared with gradients on topographies. Here, gradients are slopes on a surface calculated at the scale of the sampling interval from inclination angles of vectors that are normal to triangular facets formed by adjacent height samples (z = z(x, y)). Similarities between maps of gradients logs and height fluctuations are apparent. This shows that the fluctuations are exponentially dependent on local surface gradients. The highest fluctuations correspond to tool/material interactions for turned surfaces and to regions of maximum plastic deformation for sandblasted surfaces. Finally, for abraded, heterogeneous, multilayer surfaces, fluctuations are dependent on both abrasion and light/sub-layer interactions. It appears that the natures of irregular surface topographies govern fluctuation regimes, and that regions which are indicative of surface functionality, or integrity, can have the highest fluctuations.

Top-down Determination of Fluctuations in Topographic Measurements.

A top-down method is presented and studied for quantifying topographic map height (z) fluctuations directly from measurements on surfaces of interest. Contrary to bottom-up methods used in dimensional metrology, this method does not require knowledge of transfer functions and fluctuations of an instrument. Fluctuations are considered here to be indicative of some kinds of uncertainties. Multiple (n), successive topographic measurements (z = z(x,y)) are made at one location without moving the measurand relative to the measurement instrument. The measured heights (z) at each position (x,y) are analyzed statistically. Fluctuation maps are generated from the calculated variances. Three surfaces were measured with two interferometric measuring microscopes (Bruker ContourGT™ and Zygo NewView™ 7300). These surfaces included an anisotropic, turned surface; an isotropic, sandblasted surface; and an abraded, heterogeneous, multilayer surface having different, complex, multiscale morphologies. In demonstrating the method, it was found that few non-measured points persisted for all 100 measurements at any location. The distributions of uncertainties are similar to those of certain features on topographic maps at the same locations, suggesting that topographic features can augment measurement fluctuations. This was especially observed on the abraded ophthalmic lens; a scratch divides the topographic map into two zones with different uncertainty values. The distributions of fluctuations can be non-Gaussian. Additionally, they can vary between regions within some measurements.

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.

Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method.

Involving research users in setting priorities for research is essential to ensure the outcomes are patient-centred and maximise its value and impact. The Musculoskeletal Disorders Research Advisory Group Versus Arthritis led a research priority setting exercise across musculoskeletal disorders. The Child Health and Nutrition Research Initiative (CHNRI) method of setting research priorities with a range of stakeholders was used, involving four stages and two surveys, to: (1) gather research uncertainties, (2) consolidate these, (3) score uncertainties against importance and impact, and (4) analyse scoring for prioritisation. 213 people responded to the first survey and 285 people to the second, representing clinicians, researchers, and people with musculoskeletal disorders. Key priorities included developing and testing new treatments, better treatment targeting, early diagnosis, prevention, and better understanding and management of pain, with an emphasis on understanding underpinning mechanisms. We present a call to action to researchers and funders to target these priorities.

Robust and Efficient Online Auditory Psychophysics.

Most human auditory psychophysics research has historically been conducted in carefully controlled environments with calibrated audio equipment, and over potentially hours of repetitive testing with expert listeners. Here, we operationally define such conditions as having high 'auditory hygiene'. From this perspective, conducting auditory psychophysical paradigms online presents a serious challenge, in that results may hinge on absolute sound presentation level, reliably estimated perceptual thresholds, low and controlled background noise levels, and sustained motivation and attention. We introduce a set of procedures that address these challenges and facilitate auditory hygiene for online auditory psychophysics. First, we establish a simple means of setting sound presentation levels. Across a set of four level-setting conditions conducted in person, we demonstrate the stability and robustness of this level setting procedure in open air and controlled settings. Second, we test participants' tone-in-noise thresholds using widely adopted online experiment platforms and demonstrate that reliable threshold estimates can be derived online in approximately one minute of testing. Third, using these level and threshold setting procedures to establish participant-specific stimulus conditions, we show that an online implementation of the classic probe-signal paradigm can be used to demonstrate frequency-selective attention on an individual-participant basis, using a third of the trials used in recent in-lab experiments. Finally, we show how threshold and attentional measures relate to well-validated assays of online participants' in-task motivation, fatigue, and confidence. This demonstrates the promise of online auditory psychophysics for addressing new auditory perception and neuroscience questions quickly, efficiently, and with more diverse samples. Code for the tests is publicly available through Pavlovia and Gorilla.

Effect of Titrated Exposure to Non-Traumatic Noise on Unvoiced Speech Recognition in Human Listeners with Normal Audiological Profiles.

Non-traumatic noise exposure has been shown in animal models to impact the processing of envelope cues. However, evidence in human studies has been conflicting, possibly because the measures have not been specifically parameterized based on listeners' exposure profiles. The current study examined young dental-school students, whose exposure to high-frequency non-traumatic dental-drill noise during their course of study is systematic and precisely quantifiable. Twenty-five dental students and twenty-seven non-dental participants were recruited. The listeners were asked to recognize unvoiced sentences that were processed to contain only envelope cues useful for recognition and have been filtered to frequency regions inside or outside the dental noise spectrum. The sentences were presented either in quiet or in one of the noise maskers, including a steady-state noise, a 16-Hz or 32-Hz temporally modulated noise, or a spectrally modulated noise. The dental students showed no difference from the control group in demographic information, audiological screening outcomes, extended high-frequency thresholds, or unvoiced speech in quiet, but consistently performed more poorly for unvoiced speech recognition in modulated noise. The group difference in noise depended on the filtering conditions. The dental group's degraded performances were observed in temporally modulated noise for high-pass filtered condition only and in spectrally modulated noise for low-pass filtered condition only. The current findings provide the most direct evidence to date of a link between non-traumatic noise exposure and supra-threshold envelope processing issues in human listeners despite the normal audiological profiles.

Contribution of the Microbiome, Environment, and Genetics to Mucosal Type 2 Immunity and Anaphylaxis in a Murine Food Allergy Model.

There is heterogeneity inherent in the immune responses of individual mice in murine models of food allergy, including anaphylaxis, similar to the clinical heterogeneity observed in humans with food allergies to a defined food. One major driver of this heterogeneity may be differences in the microbiome between sensitized individuals. Our laboratory and others have reported that disruption of the microbiome (dysbiosis) by broad spectrum antibiotics and/or yeast colonization can alter systemic immunity and favor the development of mucosal Type 2 immunity to aeroallergens. Our objective was to use a well-characterized murine model (Balb/c mice) of food allergies (chicken egg ovalbumin, OVA) and determine if antibiotic-mediated dysbiosis (including C. albicans colonization) could enhance the manifestation of food allergies. Furthermore, we sought to identify elements of the microbiome and host response that were associated with this heterogeneity in the anaphylactic reaction between individual food allergen-sensitized mice. In our dataset, the intensity of the anaphylactic reactions was most strongly associated with a disrupted microbiome that included colonization by C. albicans, loss of a specific Lachnoclostridium species (tentatively, Lachnoclostridium YL32), development of a highly polarized Type 2 response in the intestinal mucosa and underlying tissue, and activation of mucosal mast cells. Serum levels of allergen-specific IgE were not predictive of the response and a complete absence of a microbiome did not fully recapitulate the response. Conventionalization of germ-free mice resulted in Akkermansia muciniphila outgrowth and a higher degree of heterogeneity in the allergic response. C57BL/6 mice remained resistant even under the same dysbiosis-inducing antibiotic regimens, while changes in the microbiome markedly altered the reactivity of Balb/c mice to OVA, as noted above. Strikingly, we also observed that genetically identical mice from different rooms in our vivarium develop different levels of a Type 2 response, as well as anaphylactic reactions. The intestinal microbiome in these mice also differed between rooms. Thus, our data recapitulate the heterogeneity in anaphylactic reactions, ranging from severe to none, seen in patients that have circulating levels of food allergen-reactive IgE and support the concept that alterations in the microbiome can be one factor underlying this heterogeneity.

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.

Altered Pain Processing Associated with Administration of Dopamine Agonist and Antagonist in Healthy Volunteers.

Striatal dopamine dysfunction is associated with the altered top-down modulation of pain processing. The dopamine D2-like receptor family is a potential substrate for such effects due to its primary expression in the striatum, but evidence for this is currently lacking. Here, we investigated the effect of pharmacologically manipulating striatal dopamine D2 receptor activity on the anticipation and perception of acute pain stimuli in humans. Participants received visual cues that induced either certain or uncertain anticipation of two pain intensity levels delivered via a CO2 laser. Rating of the pain intensity and unpleasantness was recorded. Brain activity was recorded with EEG and analysed via source localisation to investigate neural activity during the anticipation and receipt of pain. Participants completed the experiment under three conditions, control (Sodium Chloride), D2 receptor agonist (Cabergoline), and D2 receptor antagonist (Amisulpride), in a repeated-measures, triple-crossover, double-blind study. The antagonist reduced an individuals' ability to distinguish between low and high pain following uncertain anticipation. The EEG source localisation showed that the agonist and antagonist reduced neural activations in specific brain regions associated with the sensory integration of salient stimuli during the anticipation and receipt of pain. During anticipation, the agonist reduced activity in the right mid-temporal region and the right angular gyrus, whilst the antagonist reduced activity within the right postcentral, right mid-temporal, and right inferior parietal regions. In comparison to control, the antagonist reduced activity within the insula during the receipt of pain, a key structure involved in the integration of the sensory and affective aspects of pain. Pain sensitivity and unpleasantness were not changed by D2R modulation. Our results support the notion that D2 receptor neurotransmission has a role in the top-down modulation of pain.

Application of Mass Finishing for Surface Modification of Copper Cold Sprayed Material Consolidations.

The surface roughness of additively manufactured (AM) components can have deleterious effects on the properties of the final part, such as corrosion resistance and fatigue life. Modification of the surface finish or parts produced by AM processes, such as cold spray, through methods such as mass finishing, can help to mitigate some of these issues. In this work, the surface evolution of as-produced copper cold sprayed material consolidations was studied through mass finishing. Three different copper powders attained by different production methods and of different sizes were used as feedstock. The surface topography of the cold spray deposits was measured as a function of the mass finishing time for the three copper cold spray samples and analyzed in terms of relative area and complexity, revealing an inverse correlation relating material removal rate and hardness/strength of the cold sprayed deposits. The material removal rate was also affected by the quality of the cold spray deposition, as defined by deposition efficiency (DE). Large initial drops in relative area and complexity are also likely due to the removal of loosely bonded powders at the start of mass finishing. Based on this study, the cold spray parameters that affect the rate of mass finishing have been explored.

Antibiotics cause metabolic changes in mice primarily through microbiome modulation rather than behavioral changes.

BACKGROUND: The microbiome is an important and increasingly-studied mediator of organismal metabolism, although how the microbiome affects metabolism remains incompletely understood. Many investigators use antibiotics to experimentally perturb the microbiome. However, antibiotics have poorly understood yet profound off-target effects on behavior and diet, including food and water aversion, that can confound experiments and limit their applicability. We thus sought to determine the relative influence of microbiome modulation and off-target antibiotic effects on the behavior and metabolic activity of mice. RESULTS: Mice treated with oral antibiotics via drinking water exhibited significant weight loss in fat, liver, and muscle tissue. These mice also exhibited a reduction in water and food consumption, with marked variability across antibiotic regimens. While administration of bitter-tasting but antimicrobially-inert compounds caused a similar reduction in water consumption, this did not cause tissue weight loss or reduced food consumption. Mice administered intraperitoneal antibiotics (bypassing the gastrointestinal tract) exhibited reduced tissue weights and oral intake, comparable to the effects of oral antibiotics. Antibiotic-treated germ-free mice did not have reduced tissue weights, providing further evidence that direct microbiome modulation (rather than behavioral effects) mediates these metabolic changes. CONCLUSIONS: While oral antibiotics cause profound effects on food and water consumption, antibiotic effects on organismal metabolism are primarily mediated by microbiome modulation. We demonstrate that tissue-specific weight loss following antibiotic administration is due primarily to microbiome effects rather than food and water aversion, and identify antibiotic regimens that effectively modulate gut microbiota while minimizing off-target behavioral effects.

Outcomes and Predictors of Severe Hyperoxemia in Patients Receiving Mechanical Ventilation: A Single-Center Cohort Study.

Rationale: Supplemental oxygen is among the most commonly administered therapies in intensive care units (ICUs). High supplemental oxygen exposure has been associated with harm in observational human studies and animal models, yet no consensus exists regarding which dose and duration of high oxygen constitutes harmful hyperoxemia, and little is known regarding the clinical factors that predict potentially injurious exposure. Objectives: To determine the dose and duration of the arterial partial pressure of oxygen (PaO2) associated with mortality among mechanically ventilated patients and to identify the clinical factors that predict this exposure. Methods: We performed a retrospective cohort study of patients who received invasive mechanical ventilation at a single academic institution in 2017 and 2018. We used a generalized additive model to visualize the relationship between the measured PaO2 via arterial blood gas measurements and 30-day mortality. We used multivariable logistic regression to identify patient- and hospital-level factors that predict exposure to harmful hyperoxemia. Results: We analyzed 2,133 patients with 33,310 arterial blood gas measurements obtained during mechanical ventilation. We identified a U-shaped relationship between PaO2 and mortality, in which PaO2 was positively correlated with mortality above a threshold of 200 mm Hg. A total of 1,184 patients (55.5%) had at least one PaO2 measurement above this threshold. If patients spent an entire day exposed to PaO2 > 200 mm Hg, they had 2.19 (95% confidence interval [CI], 1.33-3.60; P = 0.002) greater odds of 30-day mortality in an adjusted analysis. Any exposure to severe hyperoxemia (PaO2 > 200 mm Hg) was associated with mortality (odds ratio, 1.29; 95% CI, 1.04-1.59; P = 0.021). The strongest clinical predictor of severe hyperoxemia exposure was the identity of the ICU in which mechanical ventilation was delivered. Conclusions: Exposure to high arterial oxygen concentrations is common among mechanically ventilated patients, and the dose and duration of PaO2 ⩾ 200 mm Hg is associated with mortality. Severe hyperoxemia is highly variable across ICUs and is far more common in clinical practice than in recent randomized trials of oxygen-targeting strategies. Efforts to minimize this common and injurious exposure are needed.

Improving the efficiency and effectiveness of an industrial SARS-CoV-2 diagnostic facility.

On 11th March 2020, the UK government announced plans for the scaling of COVID-19 testing, and on 27th March 2020 it was announced that a new alliance of private sector and academic collaborative laboratories were being created to generate the testing capacity required. The Cambridge COVID-19 Testing Centre (CCTC) was established during April 2020 through collaboration between AstraZeneca, GlaxoSmithKline, and the University of Cambridge, with Charles River Laboratories joining the collaboration at the end of July 2020. The CCTC lab operation focussed on the optimised use of automation, introduction of novel technologies and process modelling to enable a testing capacity of 22,000 tests per day. Here we describe the optimisation of the laboratory process through the continued exploitation of internal performance metrics, while introducing new technologies including the Heat Inactivation of clinical samples upon receipt into the laboratory and a Direct to PCR protocol that removed the requirement for the RNA extraction step. We anticipate that these methods will have value in driving continued efficiency and effectiveness within all large scale viral diagnostic testing laboratories.