Exploring the Efficacy of Selected Allografts in Chronic Wound Healing: Evidence from Murine Models and Clinical Data for a Proposed Treatment Algorithm.

SIGNIFICANCE: Chronic wounds can lead to poor outcomes for patients, with risks including amputation and death. In the United States, chronic wounds affect 2.5% of the population and cost up to $28 billion per year in primary healthcare costs. RECENT ADVANCES: Allograft tissues (dermal, amnion, and amnion/chorion) have shown efficacy in improving healing of chronic, recalcitrant wounds in human patients, as evidenced by multiple clinical trials. Their mechanisms of actions have been relatively understudied, until recently. Research in murine models has shown dermal allografts promote re-epithelialization, amnion allografts promote granulation tissue formation and angiogenesis, and amnion/chorion allografts support all stages of wound healing. These findings not only confirm effectiveness, but they shed light on mechanisms of action responsible for their therapeutic utility in patients. CRITICAL ISSUES: Despite the promise of allografts in chronic wound care, a gap exists in understanding which allografts are most effective during each wound healing stage. The variable efficacy among each type of allograft suggests a mechanistic approach towards a proposed clinical treatment algorithm, based on wound characteristics and patient's needs, may be beneficial. FUTURE DIRECTIONS: Recent advances in allografts provide a framework for further investigations on how allograft selection can be based on specific needs of individual patients. This requires additional research to identify which allografts support the best outcomes during each stage of the wound healing process as well as utility in specific wound types. Longitudinal human studies investigating the long-term impacts of allografts, particularly in the remodeling phase, are also essential to developing a deeper understanding of their role in sustained wound repair and recovery.

Exploring a targeted approach for public health capacity restrictions during COVID-19 using a new computational model.

This work introduces the Queen's University Agent-Based Outbreak Outcome Model (QUABOOM). This tool is an agent-based Monte Carlo simulation for modelling epidemics and informing public health policy. We illustrate the use of the model by examining capacity restrictions during a lockdown. We find that public health measures should focus on the few locations where many people interact, such as grocery stores, rather than the many locations where few people interact, such as small businesses. We also discuss a case where the results of the simulation can be scaled to larger population sizes, thereby improving computational efficiency.

A Clinically Viable Medial Olivocochlear Reflex Assay Using Transient-Evoked Otoacoustic Emissions.

OBJECTIVES: The contralateral medial olivocochlear reflex (MOCR) strength may indicate various auditory conditions in humans, but a clinically viable assay and equipment are needed for quick, accurate, and reliable measurements. The first experiment compared an earlier version of the assay, which used a nonlinear-mode chirp stimulus, with a new assay using a linear-mode click stimulus, designed to give reliable MOCR measurements in most normal-hearing ears. The second experiment extended the improved assay on a purpose-built binaural hardware platform that used forward-pressure level (FPL) calibration for both the stimulus and the contralateral MOCR elicitor. DESIGN: Transient-evoked otoacoustic emission (TEOAE) tests were measured with and without a 60-dB SPL MOCR-evoking contralateral broadband noise. The normalized MOCR strength (MOCR%) was derived from the TEOAE responses for each trial pair using the complex pressure difference weighted by the TEOAE magnitude. Experiment 1 compared MOCR% within-subject and across-day using two TEOAE stimuli: nonlinear-mode chirps (50 dB SPL, bandpass 1-5 kHz, 14 ms window delayed by 2 ms) and linear-mode clicks (50 dB SPL, bandpass 0.5-2.5 kHz, 13 ms window delayed by 5 ms). TEOAE responses were analyzed in the 0.5 to 2.5 kHz band. Thirty adult participants with normal hearing (30 ears) completed the study. The TEOAE stimulus was calibrated in situ using spectral flattening, and the contralateral noise was calibrated in a coupler. Twelve TEOAE trial pairs were collected for each participant and condition. Experiment 2 used a purpose-built binaural system. The TEOAE stimuli were linear-mode clicks (50 dB SPL, bandpass 1-3 kHz, 13 ms window delayed by 5 ms), analyzed in the 1 to 3 kHz band over ~12 trial pairs. After a probe refit, an additional trial pair was collected for the two early-stopping signal-to-noise ratio criteria (15 and 20 dB). They were evaluated for single-trial reliability and test time. Nineteen adult participants with normal hearing (38 ears) completed the study. The TEOAE clicks and contralateral elicitor noise were calibrated in situ using FPL and delivered with automated timing. RESULTS: MOCR% for linear-mode clicks was distinguishable from measurement variability in 98% to 100% of participants' ears (both experiments), compared with only 73% for the nonlinear-mode chirp (experiment 1). MOCR detectability was assessed using the MOCR% across-subject/within-subject variance ratio. The ratio in experiment 1 for linear-mode clicks was higher (8.0) than for nonlinear-mode chirps (6.4). The ratio for linear-mode clicks (8.9) in experiment 2 was slightly higher than for the comparable linear-mode stimulus (8.0) in experiment 1. TEOAEs showed excellent reliability with high signal-to-noise ratios in both experiments, but reliability was higher for linear-mode clicks than nonlinear-mode chirps. MOCR reliability for the two stimuli was comparable. The FPL pressure response retest reliability derived from the SPL at the microphone was higher than the SPL retest reliability across 0.4 to 8 kHz. Stable results required 2 to 3 trial pairs for the linear-mode click (experiments 1 and 2) and three for the nonlinear-mode chirp (experiment 1), taking around 2 min on average. CONCLUSIONS: The linear-mode click assay produced measurable, reliable, and stable TEOAE and MOCR results on both hardware platforms in around 2 min per ear. The stimulus design and response window ensured that any stimulus artifact in linear mode was unlikely to confound the results. The refined assay is ready to produce high-quality data quickly for clinical and field studies to develop population norms, recognize diagnostic patterns, and determine risk profiles.

Nonstructural carbohydrates explain post-fire tree mortality and recovery patterns.

Trees use nonstructural carbohydrates (NSCs) to support many functions, including recovery from disturbances. However, NSC's importance for recovery following fire and whether NSC depletion contributes to post-fire delayed mortality are largely unknown. We investigated how fire affects NSCs based on fire-caused injury from a prescribed fire in a young Pinus ponderosa (Lawson & C. Lawson) stand. We assessed crown injury (needle scorch and bud kill) and measured NSCs of needles and inner bark (i.e., secondary phloem) of branches and main stems of trees subject to fire and at an adjacent unburned site. We measured NSCs pre-fire and at six timesteps post-fire (4 days-16 months). While all trees initially survived the fire, NSC concentrations declined quickly in burned trees relative to unburned controls over the same post-fire period. This decline was strongest for trees that eventually died, but those that survived recovered to unburned levels within 14 months post-fire. Two months post-fire, the relationship between crown scorch and NSCs of the main stem inner bark was strongly negative (Adj-R2 = 0.83). Our results support the importance of NSCs for tree survival and recovery post-fire and suggest that post-fire NSC depletion is in part related to reduced photosynthetic leaf area that subsequently limits carbohydrate availability for maintaining tree function. Crown scorch is a commonly measured metric of tree-level fire severity and is often linked to post-fire tree outcome (i.e., recovery or mortality). Thus, our finding that NSC depletion may be the mechanistic link between the fire-caused injury and tree outcome will help improve models of post-fire tree mortality and forest recovery.

Anti-fibrotic effects of statin drugs: A review of evidence and mechanisms.

Fibrosis is a pathological repair process common among organs, that responds to tissue damage by replacement with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs with a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may paint a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.

Haptic Communication of Language.

In this review, the development of communication systems and devices that convey language tactually is examined, first from an historical perspective focusing on the communities who use the tactile modality to substitute for impairments in vision and/or hearing. Then, the more recent developments in wearable tactile communication systems for conveying text and speech to those without sensory impairments are reviewed. The performance of tactile display technology developed for these user communities is discussed in the context of the proficiency achieved by skilled users of natural methods of tactile communication. In tracing the history of tactile devices used to convey language, it is evident that technological advances in other domains, such as screen readers and speech synthesizers for the visually impaired and cochlear implants for those with hearing loss, have had a profound impact on the requirements for effective tactile language systems. For some communities, such as the Deafblind, it is essential that the tactile communication platform is bi-directional so that the user can both send and receive language. Devices developed to address such needs have yet to achieve commercial success. Recent research on wearable tactile displays has highlighted the importance of extensive training for learning and retaining languages presented tactually.

Performance of a convolutional autoencoder designed to remove electronic noise from p-type point contact germanium detector signals.

We present a convolutional autoencoder to denoise pulses from a p-type point contact high-purity germanium detector similar to those used in several rare event searches. While we focus on training procedures that rely on detailed detector physics simulations, we also present implementations requiring only noisy detector pulses to train the model. We validate our autoencoder on both simulated data and calibration data from an 241 Am source, the latter of which is used to show that the denoised pulses are statistically compatible with data pulses. We demonstrate that our denoising method is able to preserve the underlying shapes of the pulses well, offering improvement over traditional denoising methods. We also show that the shaping time used to calculate energy with a trapezoidal filter can be significantly reduced while maintaining a comparable energy resolution. Under certain circumstances, our denoising method can improve the overall energy resolution. The methods we developed to remove electronic noise are straightforward to extend to other detector technologies. Furthermore, the latent representation from the encoder is also of use in quantifying shape-based characteristics of the signals. Our work has great potential to be used in particle physics experiments and beyond.

A set of Saccharomyces cerevisiae integration vectors for fluorescent dye labeling of proteins.

Protein fusions are frequently used for fluorescence imaging of individual molecules, both in vivo and in vitro. The SNAP, CLIP, HALO (aka HaloTag7), and DHFR protein tags can be linked to small molecule dyes that provide brightness and photo-stability superior to fluorescent proteins. To facilitate fluorescent dye tagging of proteins in the yeast Saccharomyces cerevisiae, we constructed a modular set of vectors with various combinations of labeling protein tags and selectable markers. These vectors can be used in combination to create strains where multiple proteins labeled with different colored dyes can be simultaneously observed.

Kiss1 expression in the hypothalamic arcuate nucleus is lower in dairy cows of reduced fertility†.

We tested the hypothesis that divergent genetic merit for fertility of dairy cows is due to aberrant reproductive neuroendocrine function. The kisspeptin status of non-pregnant cows of either positive (POS) or negative (NEG) breeding values (BVs) for fertility was studied in three groups (n = 8), based on their previous post-partum period: POS cows, which had spontaneous ovarian cycles (POS-CYC) and NEG cows, which either cycled (NEG-CYC) or did not cycle (NEG-NONCYC). Ovarian cycles were synchronized, blood samples were taken to define endocrine status, and the animals were slaughtered in an artificial follicular phase. The brains and the pituitary glands were collected for quantitative polymerase chain reaction (qPCR) and in situ hybridization of hypothalamic GNRH1, Kiss1, TAC3, and PDYN and pituitary expression of LHB and FSHB. Gonadotropin releasing hormone (GnRH) and kisspeptin levels were quantified in snap frozen median eminence (ME). GNRH1 expression and GnRH levels in the ME were similar across groups. Kiss1 expression in the preoptic area of the hypothalamus was also similar across groups, but Kiss1 in the arcuate nucleus was almost 2-fold higher in POS-CYC cows than in NEG groups. TAC3 expression was higher in POS-CYC cows. The number of pituitary gonadotropes and the level of expression of LHB and FSHB were similar across groups. We conclude that the lower levels of Kiss1 and TAC3 in NEG cows with low fertility status and may lead to deficient GnRH and gonadotropin secretion.

Changes in tree drought sensitivity provided early warning signals to the California drought and forest mortality event.

Climate warming in recent decades has negatively impacted forest health in the western United States. Here, we report on potential early warning signals (EWS) for drought-related mortality derived from measurements of tree-ring growth (ring width index; RWI) and carbon isotope discrimination (∆13 C), primarily focused on ponderosa pine (Pinus ponderosa). Sampling was conducted in the southern Sierra Nevada Mountains, near the epicenter of drought severity and mortality associated with the 2012-2015 California drought and concurrent outbreak of western pine beetle (Dendroctonus brevicomis). At this site, we found that widespread mortality was presaged by five decades of increasing sensitivity (i.e., increased explained variation) of both tree growth and ∆13 C to Palmer Drought Severity Index (PDSI). We hypothesized that increasing sensitivity of tree growth and ∆13 C to hydroclimate constitute EWS that indicate an increased likelihood of widespread forest mortality caused by direct and indirect effects of drought. We then tested these EWS in additional ponderosa pine-dominated forests that experienced varying mortality rates associated with the same California drought event. In general, drier sites showed increasing sensitivity of RWI to PDSI over the last century, as well as higher mortality following the California drought event compared to wetter sites. Two sites displayed evidence that thinning or fire events that reduced stand basal area effectively reversed the trend of increasing hydroclimate sensitivity. These comparisons indicate that reducing competition for soil water and/or decreasing bark beetle host tree density via forest management-particularly in drier regions-may buffer these forests against drought stress and associated mortality risk. EWS such as these could provide land managers more time to mitigate the extent or severity of forest mortality in advance of droughts. Substantial efforts at deploying additional dendrochronological research in concert with remote sensing and forest modeling will aid in forecasting of forest responses to continued climate warming.

Concept Inventories as a Complement to Learning Progressions.

Learning progressions (LPs) are descriptions of students' growing sophistication in the understanding of a particular construct through a curricular sequence. They are particularly useful for organizing complex constructs for which students do not necessarily connect concepts as taught in different courses. However, they are challenging to construct, because they attempt to linearize students' inherently nonlinear learning. As a result, it is essential to have methods to assess students' arrival at particular steps along the progression. One tool readily available to instructors is concept inventories (CIs). We have mapped published CIs to LPs for acid-base chemistry. The alignment not only provides an assessment that professors can use to pinpoint student learning, but also creates another tool to verify hypothetical LPs.  We have compared the types of questions asked on CIs in chemistry, biology, and biochemistry, as well as in some standardized test banks. The mapping of questions from CIs to steps on the LPs allows refinement of the LPs and reveals gaps in assessment tools for sophisticated concepts. This alignment is a novel addition to the cycle of validation of an LP.

Snake Effect: A Novel Haptic Illusion.

We present a novel, movement-based haptic illusion called the "snake effect." Unlike apparent motion or sensory saltation, the snake effect feels wavy and creepy as though the belly of a slithering snake is making and breaking contact with the skin. This illusion is achieved by modulating the amplitudes of vibrotactile pulses sent successively to an array of tactors. Pilot testing established the following signal parameters for creating the snake effect: a minimal pulse duration of 1.69 s, carrier frequency in the range of 200-300 Hz, amplitude modulation of the carrier with a sine, sine-squared or Gaussian waveform (shown to be more effective than a linear up-and-down ramp), and a peak amplitude of 30 dB above detection threshold. The main experiment examined the most effective signal onset asynchrony (SOA) ranges by estimating the upper and lower SOA thresholds using a one-up one-down adaptive procedure with interleaved ascending and descending series. The results indicate an optimal SOA range from 271.5 ms to 798 ms with a midpoint of 535 ms. The snake effect is a vivid illusion that can be used as a distinctive signal for encoding information and to enhance immersion and engagement in gaming and entertainment.

Few generalizable patterns of tree-level mortality during extreme drought and concurrent bark beetle outbreaks.

Tree mortality associated with drought and concurrent bark beetle outbreaks is expected to increase with further climate change. When these two types of disturbance occur in concert it complicates our ability to accurately predict future forest mortality. The recent extreme California USA drought and bark beetle outbreaks resulted in extensive tree mortality and provides a unique opportunity to examine questions of why some trees die while others survive these co-occurring disturbances. We use plot-level data combined with a three-proxy tree-level approach using radial growth, carbon isotopes, and resin duct metrics to evaluate 1) whether variability in stand structure, tree growth or size, carbon isotope discrimination, or defenses precede mortality, 2) how relationships between these proxies differ for surviving and now-dead trees, and 3) whether generalizable risk factors for tree mortality exist across pinyon pine (Pinus monophylla), ponderosa pine (P. ponderosa), white fir (Abies concolor), and incense cedar (Calocedrus decurrens) affected by the combination of drought and beetle outbreaks. We find that risk factors associated with mortality differ between species, and that few generalizable patterns exist when bark beetle outbreaks occur in concert with a particularly long, hot drought. We see evidence that both long-term differences in physiology and shorter-term beetle-related selection and variability in defenses influence mortality susceptibility for ponderosa pine, whereas beetle dynamics may play a more prominent role in mortality patterns for white fir and pinyon pine. In contrast, incense cedar mortality appears to be attributable to long-term effects of growth suppression. Risk factors that predispose some trees to drought and beetle-related mortality likely reflect species-specific strategies for dealing with these particular disturbance types. The combined influence of beetles and drought necessitates the consideration of multiple, species-specific risk factors to more accurately model forest mortality in the face of similar extreme events more likely under future climates.

Improving Tactile Codes for Increased Speech Communication Rates in a Phonemic-Based Tactile Display.

Previous research has shown evidence of tactile speech acquisition of up to 500 English words presented as tactile phonemic patterns using a 4-by-6 tactor array worn on the forearm. This article describes modifications to some of the tactile codes encoding the 39 English phonemes, and ten additional codes as abbreviated patterns for the ten most frequent phoneme pairs in spoken English. The re-design aimed to reduce the duration of phonemes and phoneme pairs that occur most frequently, with the goal to increase tactile speech transmission rates. Code identification experiments were conducted with ten participants over three weeks using a video game. The average identification rate of the 49 modified codes (39 phonemes plus 10 phoneme pairs) was 83.3% with an average learning time of 6.2 hours. The average identification rate of the 49 codes in a retention test with 7 of the 10 participants after more than 90 days of no exposure to the tactile codes was 75.7%. An analysis using ideal transmission rates showed a 58% increase in transmission rate with the modified tactile codes as compared to the original codes, demonstrating that the improved codes can speed up tactile speech communication.

Axial resin duct quantification in tree rings: A functional defense trait.

Resin ducts in the secondary xylem of tree rings are a measure of a tree's defense capacity from insects and pathogens. Because resin ducts are permanently embedded within the xylem, retrospective analysis can be performed to quantify changes in defense over time and determine factors that contribute to this change, such as climate and disturbance. Here, we provide methods on how to measure axial resin ducts in secondary xylem. These methods provide the necessary protocols for consistent quantification of xylem resin ducts and terminology, which will also allow easier cross-comparison among studies in the future. We describe:•Steps to prepare tree cores for resin duct measurements.•Procedure to obtain image and measure individual resin ducts.•Software code to compile duct measurements into a complete chronology with both standardized and unstandardized resin duct metrics for further analyses.

Infrared thermal imaging as a screening tool for paediatric wrist fractures.

Wrist injuries are common in paediatric trauma; however, only half of children evaluated with an x-ray for possible fractures will have one. Thermal imaging offers a possible non-ionising method of screening for fractures and thus reducing negative x-ray rates. One hundred five children attending the Emergency Department for wrist injuries were recruited. Two 30-s thermal videos were recorded from injured and uninjured wrists-in flat and 45° elevated positions. A region of interest (ROI) was defined on each wrist. Cases in which the ROI was covered or had ice applied were excluded, leaving 40 patients for analysis. Comparisons of ROI included (i) injured and uninjured wrists-flat and elevated positions; (ii) as in (i) with a reference region on the proximal forearm subtracted; (iii) injured wrist ROI-flat and elevated positions. Fractures and sprains increased the mean skin surface temperature by 1.519% (p = 0.008) and 0.971% (p = 0.055) respectively compared with the uninjured wrist. The mean temperature difference between flat and elevated positions for fractures was 0.268% and - 0.1291% for sprains. This difference was statistically significant for fracture (p = 0.004) but not sprain (p = 0.500). The temperature differences recorded by thermal imaging between fractured and sprained wrists may assist in differentiation of these injuries. Graphical abstract Operational stages involved from thermal video recording to generation of results.

Acquisition of 500 English Words through a TActile Phonemic Sleeve (TAPS).

Recently, a phonemic-based tactile speech communication system was developed with the goal to transmit speech through the skin for people with hearing impairments and those whose auditory and visual channels are overloaded or compromised. The display, called the TActile Phonemic Sleeve (TAPS), consisted of a 4-by-6 tactor array worn on the dorsal and volar surfaces of the forearm. Earlier work showed that people were able to learn the haptic symbols for 39 English phonemes and reach a mean phoneme recognition rate of 86% correct within one to four hours of training. The current research evaluated the acquisition of up to 500 words using TAPS. A total of 51 participants were trained and tested in three studies with increasing number of phonemes and vocabulary sizes. Individual achievements varied, but the results clearly demonstrate the potential of transmitting any English word using TAPS within a reasonable period of learning. Future work will include increasing the speech transmission rate with TAPS by improving the phonemic codes and reducing the inter-phoneme intervals, addressing the reception of words and sentences composed of strings of tactile phonemes, and assessing the performance of TAPS as a speech communication system for people with severe hearing impairments.

Incidental Categorization of Vibrotactile Stimuli.

Past research has demonstrated incidental learning of task-irrelevant visual and auditory stimuli. Motivated by the possibility of similar evidence in the tactile domain and potential applications in tactile speech communication systems, we investigated incidental categorization of vibrotactile stimuli through a visuomotor task of shape identification. Two experiments were conducted where participants were exposed to position-based or movement-based vibrotactile stimuli prior to performing a speeded response to one of two targets. The two experiments differed only in the particular sets of such stimuli employed. Unbeknownst to the participants, the vibrotactile stimuli and visual targets were initially correlated perfectly to facilitate the incidental learning of their associations, briefly uncorrelated to check the cost in reaction time, and correlated again to re-establish the initial association. Finally, participants were asked to predict visual targets from novel position-based and movement-based stimuli. The results from both experiments provided evidence of incidental categorization of vibrotactile stimuli. The percent-correct scores and sensitivity indices for the overt categorization of novel stimuli from both experiments were well above chance, indicating generalization of learning. And while both experiments showed an increase in reaction time when the association between vibrotactile stimuli and visual targets was disrupted, this reaction time cost was significant only for the stimuli used in the second experiment. Our finding of incidental categorization in the tactile domain has important implications for the effective acquisition of speech in tactile speech communication systems.

Exosomes from dairy cows of divergent fertility; Action on endometrial cells.

Abnormalities in endometrial function contribute to poor fertility and reproductive failure. Exosomes are small lipid vesicles that contain transferable bioactive substances; they participate in intercellular signaling and may have critical roles in reproductive mechanisms, including endometrial remodeling in preparation for pregnancy. In this study, we evaluated the effects of exosomes from heifers with high and low genetic merit for fertility on inflammatory mediator expression by bovine endometrial epithelial and stromal cell lines. Co-incubation of exosomes from low, compared with high, fertility heifers upregulated the gene expression of pro-inflammatory IL1A and IL8 (CXCL8) but downregulated IL4 gene expression in epithelial cells. In contrast, stromal cells co-incubated with exosomes from low, compared with high, fertility heifers downregulated the gene expression of CXCL9, CXCL10, and CX3CL1. Our findings demonstrated that circulating exosomes from high fertility heifers did not alter endometrial inflammatory mediator gene expression. In contrast, circulating exosomes from low fertility heifers enhanced endometrial expression of inflammatory mediators, which may contribute to aberrant inflammation, leading to a reduced fertility in low fertility heifers. However, an in-depth investigation is required to elucidate the role of exosomes in regulating endometrial remodeling events required for enhanced reproductive performance and fertility in dairy cows.