Performance evaluation of deep learning based stream nitrate concentration prediction model to fill stream nitrate data gaps at low-frequency nitrate monitoring basins.

Accurate and frequent nitrate estimates can provide valuable information on the nitrate transport dynamics. The study aimed to develop a data-driven modeling framework to estimate daily nitrate concentrations at low-frequency nitrate monitoring sites using the daily nitrate concentration and stream discharge information of a neighboring high-frequency nitrate monitoring site. A Long Short-Term Memory (LSTM) based deep learning (DL) modeling framework was developed to predict daily nitrate concentrations. The DL modeling framework performance was compared with two well-established statistical models, including LOADEST and WRTDS-Kalman, in three selected basins in Iowa, USA: Des Moines, Iowa, and Cedar River. The developed DL model performed well with NSE >0.70 and KGE >0.70 for 67% and 79% nitrate monitoring sites, respectively. DL and WRTDS-Kalman models performed better than the LOADEST in nitrate concentration and load estimation for all low-frequency sites. The average NSE performance of the DL model in daily nitrate estimation is 20% higher than that of the WRTDS-Kalman model at 18 out of 24 sites (75%). The WRTDS-Kalman model showed unrealistic fluctuations in the estimated daily nitrate time series when the model received limited observed nitrate data (less than 50) for simulation. The DL model indicated superior performance in winter months' nitrate prediction (60% of cases) compared to WRTDS-Kalman models (33% of cases). The DL model also better represented the exceedance days from the USEPA maximum contamination level (MCL). Both the DL and WRTDS-Kalman models demonstrated similar performance in annual stream nitrate load estimation, and estimated values are close to actual nitrate loads.

Bacteria Invade the Brain Following Sterile Intracortical Microelectrode Implantation.

Brain-machine interface performance is largely affected by the neuroinflammatory responses resulting in large part from blood-brain barrier (BBB) damage following intracortical microelectrode implantation. Recent findings strongly suggest that certain gut bacterial constituents penetrate the BBB and are resident in various brain regions of rodents and humans, both in health and disease. Therefore, we hypothesized that damage to the BBB caused by microelectrode implantation could amplify dysregulation of the microbiome-gut-brain axis. Here, we report that bacteria, including those commonly found in the gut, enter the brain following intracortical microelectrode implantation in mice implanted with single-shank silicon microelectrodes. Systemic antibiotic treatment of mice implanted with microelectrodes to suppress bacteria resulted in differential expression of bacteria in the brain tissue and a reduced acute inflammatory response compared to untreated controls, correlating with temporary improvements in microelectrode recording performance. Long-term antibiotic treatment resulted in worsening microelectrode recording performance and dysregulation of neurodegenerative pathways. Fecal microbiome composition was similar between implanted mice and an implanted human, suggesting translational findings. However, a significant portion of invading bacteria was not resident in the brain or gut. Together, the current study established a paradigm-shifting mechanism that may contribute to chronic intracortical microelectrode recording performance and affect overall brain health following intracortical microelectrode implantation.

In Vivo Characterization of Intracortical Probes with Focused Ion Beam-Etched Nanopatterned Topographies.

(1) Background: Intracortical microelectrodes (IMEs) are an important part of interfacing with the central nervous system (CNS) and recording neural signals. However, recording electrodes have shown a characteristic steady decline in recording performance owing to chronic neuroinflammation. The topography of implanted devices has been explored to mimic the nanoscale three-dimensional architecture of the extracellular matrix. Our previous work used histology to study the implant sites of non-recording probes and showed that a nanoscale topography at the probe surface mitigated the neuroinflammatory response compared to probes with smooth surfaces. Here, we hypothesized that the improvement in the neuroinflammatory response for probes with nanoscale surface topography would extend to improved recording performance. (2) Methods: A novel design modification was implemented on planar silicon-based neural probes by etching nanopatterned grooves (with a 500 nm pitch) into the probe shank. To assess the hypothesis, two groups of rats were implanted with either nanopatterned (n = 6) or smooth control (n = 6) probes, and their recording performance was evaluated over 4 weeks. Postmortem gene expression analysis was performed to compare the neuroinflammatory response from the two groups. (3) Results: Nanopatterned probes demonstrated an increased impedance and noise floor compared to controls. However, the recording performances of the nanopatterned and smooth probes were similar, with active electrode yields for control probes and nanopatterned probes being approximately 50% and 45%, respectively, by 4 weeks post-implantation. Gene expression analysis showed one gene, Sirt1, differentially expressed out of 152 in the panel. (4) Conclusions: this study provides a foundation for investigating novel nanoscale topographies on neural probes.

Reactive Amine Functionalized Microelectrode Arrays Provide Short-Term Benefit but Long-Term Detriment to In Vivo Recording Performance.

Intracortical microelectrode arrays (MEAs) are used for recording neural signals. However, indwelling devices result in chronic neuroinflammation, which leads to decreased recording performance through degradation of the device and surrounding tissue. Coating the MEAs with bioactive molecules is being explored to mitigate neuroinflammation. Such approaches often require an intermediate functionalization step such as (3-aminopropyl)triethoxysilane (APTES), which serves as a linker. However, the standalone effect of this intermediate step has not been previously characterized. Here, we investigated the effect of coating MEAs with APTES by comparing APTES-coated to uncoated controls in vivo and ex vivo. First, we measured water contact angles between silicon uncoated and APTES-coated substrates to verify the hydrophilic characteristics of the APTES coating. Next, we implanted MEAs in the motor cortex (M1) of Sprague-Dawley rats with uncoated or APTES-coated devices. We assessed changes in the electrochemical impedance and neural recording performance over a chronic implantation period of 16 weeks. Additionally, histology and bulk gene expression were analyzed to understand further the reactive tissue changes arising from the coating. Results showed that APTES increased the hydrophilicity of the devices and decreased electrochemical impedance at 1 kHz. APTES coatings proved detrimental to the recording performance, as shown by a constant decay up to 16 weeks postimplantation. Bulk gene analysis showed differential changes in gene expression between groups that were inconclusive with regard to the long-term effect on neuronal tissue. Together, these results suggest that APTES coatings are ultimately detrimental to chronic neural recordings. Furthermore, interpretations of studies using APTES as a functionalization step should consider the potential consequences if the final functionalization step is incomplete.

The effect of a Mn(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP) coating on the chronic recording performance of planar silicon intracortical microelectrode arrays.

Intracortical microelectrode arrays (MEAs) are used to record neural activity. However, their implantation initiates a neuroinflammatory cascade, involving the accumulation of reactive oxygen species, leading to interface failure. Here, we coated commercially-available MEAs with Mn(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP), to mitigate oxidative stress. First, we assessed the in vitro cytotoxicity of modified sample substrates. Then, we implanted 36 rats with uncoated, MnTBAP-coated ("Coated"), or (3-Aminopropyl)triethoxysilane (APTES)-coated devices - an intermediate step in the coating process. We assessed electrode performance during the acute (1-5 weeks), sub-chronic (6-11 weeks), and chronic (12-16 weeks) phases after implantation. Three subsets of animals were euthanized at different time points to assess the acute, sub-chronic and chronic immunohistological responses. Results showed that MnTBAP coatings were not cytotoxic in vitro, and their implantation in vivo improved the proportion of electrodes during the sub-chronic and chronic phases; APTES coatings resulted in failure of the neural interface during the chronic phase. In addition, MnTBAP coatings improved the quality of the signal throughout the study and reduced the neuroinflammatory response around the implant as early as two weeks, an effect that remained consistent for months post-implantation. Together, these results suggest that MnTBAP coatings are a potentially useful modification to improve MEA reliability.

Hydro-bio-geo-socio-chemical interactions and the sustainability of residential landscapes.

Residential landscapes are essential to the sustainability of large areas of the United States. However, spatial and temporal variation across multiple domains complicates developing policies to balance these systems' environmental, economic, and equity dimensions. We conducted multidisciplinary studies in the Baltimore, MD, USA, metropolitan area to identify locations (hotspots) or times (hot moments) with a disproportionate influence on nitrogen export, a widespread environmental concern. Results showed high variation in the inherent vulnerability/sensitivity of individual parcels to cause environmental damage and in the knowledge and practices of individual managers. To the extent that hotspots are the result of management choices by homeowners, there are straightforward approaches to improve outcomes, e.g. fertilizer restrictions and incentives to reduce fertilizer use. If, however, hotspots arise from the configuration and inherent characteristics of parcels and neighborhoods, efforts to improve outcomes may involve more intensive and complex interventions, such as conversion to alternative ecosystem types.

Antioxidant Dimethyl Fumarate Temporarily but Not Chronically Improves Intracortical Microelectrode Performance.

Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a brain-computer interface (BCI) system aimed at restoring function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5-11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (<12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals and assess its usefulness for specific applications.

Treatment of Refractory Low Back Pain Using Passive Recharge Burst in Patients Without Options for Corrective Surgery: Findings and Results From the DISTINCT Study, a Prospective Randomized Multicenter Controlled Trial.

OBJECTIVE: Spinal cord stimulation (SCS) is effective for relieving chronic intractable pain conditions. The Dorsal spInal cord STImulatioN vs mediCal management for the Treatment of low back pain study evaluates the effectiveness of SCS compared with conventional medical management (CMM) in the treatment of chronic low back pain in patients who had not undergone and were not candidates for lumbar spine surgery. METHODS AND MATERIALS: Patients were randomized to passive recharge burst therapy (n = 162) or CMM (n = 107). They reported severe pain and disability for more than a decade and had failed a multitude of therapies. Common diagnoses included degenerative disc disease, spondylosis, stenosis, and scoliosis-yet not to a degree amenable to surgery. The six-month primary end point compared responder rates, defined by a 50% reduction in pain. Hierarchical analyses of seven secondary end points were performed in the following order: composite responder rate (numerical rating scale [NRS] or Oswestry Disability Index [ODI]), NRS, ODI, Pain Catastrophizing Scale responder rate, Patient Global Impression of Change (PGIC) responder rate, and Patient-Reported Outcome Measure Information System-29 in pain interference and physical function. RESULTS: Intention-to-treat analysis showed a significant difference in pain responders on NRS between SCS (72.6%) and CMM (7.1%) arms (p < 0.0001). Of note, 85.2% of those who received six months of therapy responded on NRS compared with 6.2% of those with CMM (p < 0.0001). All secondary end points indicated the superiority of burst therapy over CMM. A composite measure on function or pain relief showed 91% of subjects with SCS improved, compared with 16% of subjects with CMM. A substantial improvement of 30 points was observed on ODI compared with a

Breast-Q sensory outcomes of non-neurotized, autologous, unilateral breast reconstruction with a minimum of 3-year follow-up.

INTRODUCTION: Sensory reinnervation of autologous breast tissue after free flap reconstruction is highly variable. There is no long-term follow-up data exploring spontaneous reinnervation and how this affects patients' quality of life nor the nerve-related symptoms they experience. To address this issue, we invited patients with a minimum of 3 years after non-neurotized, free flap breast reconstruction to complete patient-reported outcome measures exploring sensation, quality of life and breast-related symptoms. METHODS: We performed a retrospective cohort study of patients undergoing unilateral Muscle-Sparing Transverse Rectus Abdominus Muscle (MS-TRAM) or deep inferior epigastric artery perforator (DIEP) flap breast reconstruction between 01-01-2015 and 31-12-2019 in the Department of Plastic and Reconstructive Surgery at Manchester University NHS Foundation Trust. We invited participants to complete the recently developed Breast-Q© Breast Sensation Module. RESULTS: All patients had undergone unilateral immediate (n = 85) or delayed (n = 82) breast reconstruction after mastectomy using either a free DIEP (n = 150) or TRAM (n = 17) flap reconstruction a minimum of 3 years prior. The median age at operation was 48. Sensation after reconstruction was significantly reduced in the reconstructed breast compared with the contralateral breast (P < 0.0001) with a reduction in reported quality of life (immediate (68.0 [54.0, 89.0]) and delayed (68.0 [62.0, 83.8])). The sensation was significantly better in immediate vs delayed procedures (P = 0.024). Sensory scores after reconstruction increased with age (P = 0.036). DISCUSSION: Breast sensation after non-neurotized reconstruction with autologous tissue is significantly reduced at long-term follow-up with a reduction in quality of life. A minimum outcome set for quantification of breast sensation is required and future research into the cost-benefit of neurotized, autologous breast reconstruction is needed.

Factors affecting the placement of agricultural best management practices in the agricultural conservation planning framework (ACPF) toolbox in the mid-Atlantic region.

There has been a recent push to conduct spatially explicit landscape planning at finer hydrologic unit scales to mitigate diffuse pollution. The Agricultural Conservation and Planning Framework (ACPF) helps identify potential locations for agricultural conservation practices by using high-resolution soils and elevation data. This spatially explicit approach attempts to identify runoff and nutrient pathways, but output may be influenced by user-specified parameters and the properties of the digital elevation model (DEM) being used. Here we assess differences in the density and location of conservation practices sited by the ACPF toolbox across three DEM resolutions in three agricultural catchments, each in distinct physiographies (Ridge and Valley, Piedmont, Coastal Plain) of the United States mid-Atlantic region. Output frequency did not vary much for contour buffer strips or water and sediment control basins (WASCOBs) across DEM resolution, particularly compared with landscape type. The DEM resolution was crucial for the density of grassed waterways but of little consequence for contour buffer strips. Placement density of WASCOBs and contour buffer strips varied by region. Grassed waterways are sited based on either discrete values or statistical distributions of stream power index (SPI). A higher density of grassed waterways was placed in lower relief landscapes when a single standard deviation threshold was applied. Using discrete SPI values for the grassed waterway tool generated more consistent output across watersheds than output based on statistical distributions. These and other reported findings can help guide user decisions in future applications of the ACPF toolbox, particularly across different areas of study.

Biomechanical micromotion at the neural interface modulates intracellular membrane potentialsin vivo.

Objective. Respiration and vascular pulsation cause relative micromotion of brain tissue against stationary implants resulting in repetitive displacements of 2-4µm (due to vascular pulsation) and 10-30µm (due to breathing) in rats. However, the direct functional impact of such tissue micromotion on the cells at the neural interface remains unknown. This study aims to test the hypothesis that micromotion in brain tissue causes changes in membrane potentials (MPs) through the activation of mechanosensitive ion channels.Approach. Intracellular MPs were recorded from Aplysia ganglion cells (n= 8) and cortical cells (n= 15)in vivoinn= 7 adult rats. Cyclic stresses between 0.2 and 4 kPa repeated at 1 Hz were tested in Aplysia ganglion cells. For thein vivoexperiments, 30µM of gadolinium chloride (Gd3+), a non-selective blocker of mechanosensitive ion channels, was used to assess the role of such ion channels.Main results. In Aplysia ganglion cells, there were no MP changes for <1.5 kPa, and action potentials were observed at >3.1 kPa. Drug studies utilizing 5-HT showed an 80% reduction in firing frequency from controls. Inin vivoexperiments, periodic pulsations (1-10 mV) were observed in the MPs of cells that corresponded to breathing and heart-rate. In response to the addition of 30µM Gd3+, we observed a significant reduction (0.5-3 mV) in the periodic pulsations in MP in all cortical cells across four different rats, suggesting the role of mechanosensitive ion channels in mediating MP fluctuations due to tissue micromotion at the neural interface.Significance.Under chronic conditions, the tissue at the interface stiffens due to scar tissue formation, which is expected to increase the likelihood of recruiting stretch-receptors due to tissue micromotion. It is speculated that such chronic sub-threshold pulsations in MPs might trigger the immune response at the neural interface.

Best Management Practices for Diffuse Nutrient Pollution: Wicked Problems Across Urban and Agricultural Watersheds.

Extensive time and financial resources have been dedicated to address nonpoint sources of nitrogen and phosphorus in watersheds. Despite these efforts, many watersheds have not seen substantial improvement in water quality. The objective of this study is to review the literature and investigate key factors affecting the lack of improvement in nutrient levels in waterways in urban and agricultural regions. From 94 studies identified in the academic literature, we found that, although 60% of studies found improvements in water quality after implementation of Best Management Practices (BMPs) within the watershed, these studies were mostly modeling studies rather than field monitoring studies. For studies that were unable to find improvements in water quality after the implementation of BMPs, the lack of improvement was attributed to lack of knowledge about BMP functioning, lag times, nonoptimal placement and distribution of BMPs in the watershed, postimplementation BMP failure, and socio-political and economic challenges. We refer to these limiting factors as known unknowns. We also acknowledge the existence of unknown unknowns that hinder further improvement in BMP effectiveness and suggest that machine learning, approaches from the field of business and operations management, and long-term convergent studies could be used to resolve these unknown unknowns.

Leveraging Big Data Towards Functionally-Based, Catchment Scale Restoration Prioritization.

The persistence of freshwater degradation has necessitated the growth of an expansive stream and wetland restoration industry, yet restoration prioritization at broad spatial extents is still limited and ad-hoc restoration prevails. The River Basin Restoration Prioritization tool has been developed to incorporate vetted, distributed data models into a catchment scale restoration prioritization framework. Catchment baseline condition and potential improvement with restoration activity is calculated for all National Hydrography Dataset stream reaches and catchments in North Carolina and compared to other catchments within the river subbasin to assess where restoration efforts may best be focused. Hydrologic, water quality, and aquatic habitat quality conditions are assessed with peak flood flow, nitrogen and phosphorus loading, and aquatic species distribution models. The modular nature of the tool leaves ample opportunity for future incorporation of novel and improved datasets to better represent the holistic health of a watershed, and the nature of the datasets used herein allow this framework to be applied at much broader scales than North Carolina.

Characterization of Rotator Cuff Tears: Ultrasound Versus Magnetic Resonance Imaging.

Ultrasound and magnetic resonance imaging (MRI) are both capable of diagnosing full-thickness rotator cuff tears. However, it is unknown which imaging modality is more accurate and precise in evaluating the characteristics of full-thickness rotator cuff tears in a surgical population. This study reviewed 114 patients who underwent arthroscopic repair of a full-thickness rotator cuff tear over a 1-year period. Of these patients, 61 had both preoperative MRI and ultrasound for review. Three musculoskeletal radiologists evaluated each ultrasound and MRI in a randomized and blinded fashion on 2 separate occasions. Tear size, retraction status, muscle atrophy, and fatty infiltration were analyzed and compared between the 2 modalities. Ultrasound measurements were statistically smaller in both tear size (P=.001) and retraction status (P=.001) compared with MRI. The 2 image modalities showed comparable intraobserver reliability in assessment of tear size and retraction status. However, MRI showed greater interobserver reliability in assessment of tear size, retraction status, and atrophy. Independent observers are more likely to agree on measurements of the characteristics of rotator cuff tears when using MRI compared with ultrasound. As tear size increases, the 2 image modalities show greater differences in measurement of tear size and retraction status. Additionally, compared with MRI, ultrasound shows consistently low reliability in detecting subtle, but clinically important, degeneration of the soft tissue envelope. Although it is inexpensive and convenient, ultrasound may be best used to identify a tear, and MRI is superior for use in surgical planning for larger tears. [Orthopedics. 2017; 40(1):e124-e130.].

Do Lumbar Decompression and Fusion Patients Recall Their Preoperative Status?: A Cohort Study of Recall Bias in Patient-Reported Outcomes.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To characterize the accuracy of patient recollection of preoperative symptoms after lumbar spine surgery. SUMMARY OF BACKGROUND DATA: Although patient-reported outcomes have become important in the evaluation of spine surgery patients, the accuracy of patient recall remains unknown. METHODS: Patients undergoing lumbar decompression with or without fusion were enrolled. Back and leg Numeric Pain Scores and Oswestry Disability Indices were recorded preoperatively. Patients were asked to recall their preoperative status at a minimum of 1 year after surgery. Actual and recalled scores were compared using paired t tests and relations were quantified using Pearson correlation coefficients. Multivariable linear regression was used to identify factors that affected recollection. RESULTS: Sixty-two patients with a mean age of 66.1 years were included. Compared to their preoperative scores, patients showed significant improvement in back pain (mean difference [MD] = -3.2, 95% CI -4.0 to -2.4), leg pain (MD -3.3, 95% CI -4.3 to -2.2), and disability (MD -25.0%, 95% CI -28.7 to -19.6). Patient recollection of preoperative status was significantly more severe than actual for back pain (MD +2.3, 95% CI 1.5-3.2), leg pain (MD +1.8, 95% CI 0.9-2.7), and disability (MD +9.6%, 95% CI 5.6-14.0). No significant correlation between actual and recalled scores with regards to back (r = 0.18) or leg (r = 0.24) pain and only moderate correlation with disability (r = 0.44) were seen. This was maintained across age, sex, and time between date of surgery and recollection. More than 40% of patients switched their predominant symptom from back pain to leg pain or leg pain to back pain on recall. CONCLUSION: Relying on patient recollection does not provide an accurate measure of preoperative status after lumbar spine surgery. Recall bias indicates the importance of obtaining true baseline scores and patient-reported outcomes prospectively and not retrospectively. LEVEL OF EVIDENCE: 2.

Scar-improving efficacy of avotermin administered into the wound margins of skin incisions as evaluated by a randomized, double-blind, placebo-controlled, phase II clinical trial.

BACKGROUND: The authors report on a prospective, randomized, placebo-controlled phase II trial to investigate avotermin (transforming growth factor beta-3) for reducing scarring resulting from acute incised skin wounds. METHODS: Seventy-one healthy male subjects (18 to 45 years) received avotermin at 50 or 200 ng/100 µl/linear centimeter of wound margin. Subjects received three standardized 1-cm incisional wounds on the inner aspect of each upper arm. Wounds were randomized to receive (into each margin): no injection (standard wound care only), one intradermal injection of avotermin or placebo (immediately before surgery), or two injections of avotermin or placebo (immediately before surgery and 24 hours later). The primary efficacy variable was a 10-cm visual analog scale score, which assessed how closely scars resembled normal skin, administered at month 12 by an independent external scar assessment panel (a panel of lay public individuals). RESULTS: Avotermin at 200 ng/100 µl/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (p<0.02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (p=0.043). Treatment was well tolerated. CONCLUSION: These results confirm that avotermin is the first of a new class of regenerative medicines that reduce scarring when administered once or twice to the approximated margins of acute skin incisions.

Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies.

BACKGROUND: Research into mechanisms of skin scarring identified transforming growth factor beta3 (TGFbeta3) as a potential antiscarring therapy. We assessed scar improvement with avotermin (recombinant, active, human TGFbeta3). METHODS: In three double-blind, placebo-controlled studies, intradermal avotermin (concentrations ranging from 0.25 to 500 ng/100 microL per linear cm wound margin) was administered to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 h later, in healthy men and women. Treatments (avotermin and placebo or standard wound care) were randomly allocated to wound sites by a computer generated randomisation scheme, and within-participant controls compared avotermin versus placebo or standard wound care alone. Primary endpoints were visual assessment of scar formation at 6 months and 12 months after wounding in two studies, and from week 6 to month 7 after wounding in the third. Investigators, participants, and scar assessors were blinded to treatment. Efficacy analyses were intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00847925, NCT00847795, and NCT00629811. RESULTS: In two studies, avotermin 50 ng/100 microL per linear cm significantly improved median score on a 100 mm visual analogue scale (VAS) by 5 mm (range -2 to 14; p=0.001) at month 6 and 8 mm (-29 to 18; p=0.0230) at month 12. In the third, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14.84 mm [95 % CI 5.5-24.2] at 5 ng/100 microL per linear cm to 64.25 mm [49.4-79.1] at 500 ng/100 microL per linear cm). Nine [60%] scars treated with avotermin 50 ng/100 microL per linear cm showed 25% or less abnormal orientation of collagen fibres in the reticular dermis versus five [33%] placebo scars. After only 6 weeks from wounding, avotermin 500 ng/100 microL per linear cm improved VAS score by 16.12 mm (95% CI 10.61-21.63). Adverse events at wound sites were similar for avotermin and controls. Erythema and oedema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing. INTERPRETATION: Avotermin has potential to provide an accelerated and permanent improvement in scarring.

Maturation of the human scar: an observational study.

BACKGROUND: The natural history of scar maturation in humans has never been formally described from either a clinical or a histologic standpoint. METHODS: The maturation of incisional scars was observed in 58 healthy male volunteers who each had 2 x 1-cm incisional wounds created on the inner aspect of both upper arms. The resulting scars were photographed digitally at monthly intervals for 12 months and excised for histologic analysis at specific time points. All histologic specimens were stained using Masson's trichrome and reviewed together with the corresponding digital clinical scar images to produce macroscopic and microscopic descriptions of the maturation process. RESULTS: Three distinct groups, each displaying a different rate of longitudinal progression of scar maturation, were identified from within the study group. The majority of volunteers belonged to a "representative" subset but distinct "poor" and "excellent" subsets were also identified. The poor subset invariably contained volunteers younger than 30 years of age, whereas the majority of the excellent subset comprised subjects older than 55 years of age. CONCLUSIONS: Scar maturation occurs as a series of defined macroscopic and microscopic stages over the course of 1 year. The rate of scar maturation varied within the study group, with older subjects (>55 years) displaying accelerated maturation, whereas a prolonged high turnover state and a retarded rate of maturation were observed in younger subjects (<30 years).

Scar redness in humans: how long does it persist after incisional and excisional wounding?

BACKGROUND: The natural history of scar redness in humans has never been formally described, and the point at which normal scar redness fades is unknown. METHODS: As part of a randomized, placebo-controlled, clinical trial investigating the effects of various doses of transforming growth factor-beta3 on scar quality, the authors observed the process of scar redness and maturation in non-drug-treated incisional and excisional wounds made on the upper inner arms of 103 volunteers. Scar photographic images were assessed by a review panel to ascertain the month during which redness faded for a particular scar. Scar histology documented the level of inflammation and angiogenesis. RESULTS: Scar redness faded at an average of 7 months. Scar redness for incisions faded significantly faster than excisions (p = 0.0001, Kruskal-Wallis test), and significant differences were also seen between anteriorly and posteriorly placed scars for incisions (p = 0.0008) and excisions (p = 0.0035), respectively. Month 12 histologic examination revealed the absence of any ongoing inflammatory processes in all scars. CONCLUSIONS: Scar redness fades on average at 7 months. This is influenced by the wound type and position. The authors advocate the use of the term "rubor perseverans" to describe the physiologic redness of a normal scar as it matures beyond the first month, a process that does not involve inflammation.