Microvascular free flap coverage of complex soft tissue defects after revision total knee arthroplasty: a cross-sectional observation study.

BACKGROUND AND PURPOSE: Soft tissue defects after total knee arthroplasties (TKA) represent a major orthopedic challenge with amputation as a feared outcome. Microvascular free flap coverage (FFC) can increase limb salvage rates, but complications related to the procedure are yet to be explored further. We aimed to review a single-center experience with FFC for soft tissue defects related to revision total knee arthroplasty. METHODS: Through a retrospective chart review from 2006 to 2021, we identified all patients who had FFC of a knee with an existing TKA. Typically, patients underwent 2-stage revision arthroplasty. To identify areas of intervention, we divided the entire regimen into 2 phases divided by the free flap surgery (pre- and post-free flap). RESULTS: We identified 18 patients with a median age at free flap surgery of 69 years (range 39-85), who were followed for a median of 5.1 years (range 2 months to 10.6 years). The median duration from primary TKA to their final operation was 17.5 months (range 19 days to 7 years). Patients underwent a mean of 7.6 surgical procedures on their knee with 3.6 orthopedic revisions prior to the FFC and 0.6 after. Soft tissue coverage was achieved in all patients and no patients underwent amputation. One-third of patients experienced early complications at recipient site after free flap surgery. There were no donor site complications. CONCLUSION: Microvascular FFC of complex soft tissue defects after revision total knee arthroplasty proved achievable in all patients with successful limb salvage in all patients.

PHARMACOKINETICS OF TRAMADOL AND O-DESMETHYLTRAMADOL IN GIANT TORTOISES (CHELONOIDIS VANDENBURGHI, CHELONOIDIS VICINA).

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (1 mg/kg and 5 mg/kg) and its metabolite, O-desmethyltramadol (M1) in giant tortoises (Chelonoidis vandenburghi, Chelonoidis vicina). Eleven giant tortoises (C. vandenburghi, C. vicina) received two randomly assigned, oral doses of tramadol (either 1 mg/kg or 5 mg/kg), with a washout period of 3 wk between each dose. The half-life (t½) of orally administered tramadol at 1 mg/kg and 5 mg/kg was 11.9 ± 4.6 h and 13.2 ± 6.1 h, respectively. After oral administration of tramadol at 1 mg/kg and 5 mg/kg, the maximum concentration (Cmax) was 125 ± 69 ng/ml and 518 ± 411 ng/ml, respectively. There were not enough data points to determine pharmacokinetic (PK) parameters for the M1 metabolite from either dose. Tramadol administered orally to giant tortoises at both doses provided measurable plasma concentrations of tramadol for approximately 48 h with occasional transient sedation. Oral tramadol at 5 mg/kg, on average, achieves concentrations of >100 ng/ml, the reported human therapeutic threshold, for 24 h. Based on the low levels of M1 seen in this study, M1 may not be a major metabolite in this taxon.

Lidocaine constant rate infusion improves the probability of survival in rabbits with gastrointestinal obstructions: 64 cases (2012-2021).

OBJECTIVE: To determine the survival to discharge rate of rabbits with gastrointestinal obstructions treated with lidocaine constant rate infusion (CRI) and other factors associated with survival. ANIMALS: Cases of gastrointestinal obstruction in rabbits (n = 56, including 64 events) that had presented to a veterinary teaching hospital from 2012 to 2021. METHODS: This was a retrospective study in which data on rabbits with evidence of gastrointestinal obstruction were extracted from veterinary teaching hospital medical records over a 9-year period. Systemic lidocaine treatment, breed, sex, age, temperature at presentation, blood glucose at presentation, and time to discharge or death were evaluated with univariate and multivariate logistic regression to identify factors significantly associated with survival to hospital discharge in rabbits with gastrointestinal obstruction. RESULTS: Comparatively, 89.7% of rabbits treated with lidocaine CRI (n = 39) survived to hospital discharge, while only 56% of rabbits that were not treated with lidocaine CRI (25) survived. In the final multivariate analysis, 2 factors were associated with survival to discharge: rabbits treated with systemic lidocaine and male rabbits had increased odds of survival compared to those not treated with systemic lidocaine and female rabbits, respectively. CLINICAL RELEVANCE: Results demonstrated that rabbits with gastrointestinal obstruction and treated with a lidocaine CRI were more likely to survive compared to rabbits not treated with lidocaine CRI.

Treatment of Pain in Fish.

This chapter provides an overview of our current understanding of clinical analgesic use in fish. Recently, the efficacy and pharmacokinetics of several analgesic drugs for use in fish have been investigated, and the most important data indicates that µ-opioid agonist drugs (e.g, morphine) are consistently effective as analgesics across fish species. In addition, bath application of some analgesic drugs may be useful, which affords multiple methods for delivering analgesics to fish. Although few published studies of non-steroidal anti-inflammatory drugs administered to fish show promise, we have much to learn about the analgesic efficacy of most drugs in this class.

Treatment of Pain in Reptiles.

This chapter provides an overview of our current understanding of clinical analgesic use in reptiles. Currently, µ-opioid agonist drugs are the standard of care for analgesia in reptiles. Reptile pain is no longer considered a necessary part of recovery to keep the reptile from becoming active too early. Rather, treating pain allows for the reptile to begin normalizing their behavior. This recognition of pain and analgesia certainly benefits our reptile patients and greatly improves reptile welfare, but it also benefits our students and house officers, who will carry the torch and continue to demand excellence in reptile medicine.

Application of Machine Learning to Ranking Predictors of Anti-VEGF Response.

Age-related macular degeneration (AMD) is a heterogeneous disease affecting the macula of individuals and is a cause of irreversible vision loss. Patients with neovascular AMD (nAMD) are candidates for the anti-vascular endothelial growth factor (anti-VEGF) treatment, designed to regress the growth of abnormal blood vessels in the eye. Some patients fail to maintain vision despite treatment. This study aimed to develop a prediction model based on features weighted in order of importance with respect to their impact on visual acuity (VA). Evaluations included an assessment of clinical, lifestyle, and demographic factors from patients that were treated over a period of two years. The methods included mixed-effects and relative importance modelling, and models were tested against model selection criteria, diagnostic and assumption checks, and forecasting errors. The most important predictors of an anti-VEGF response were the baseline VA of the treated eye, the time (in weeks), treatment quantity, and the treated eye. The model also ranked the impact of other variables, such as intra-retinal fluid, haemorrhage, pigment epithelium detachment, treatment drug, baseline VA of the untreated eye, and various lifestyle and demographic factors. The results identified variables that could be targeted for further investigation in support of personalised treatments based on patient data.

Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

Incorporating a Trauma-Informed Care Protocol Into Pediatric Trauma Evaluation: The Pediatric PAUSE Does Not Delay Imaging or Disposition.

OBJECTIVES: Trauma evaluation in the emergency department (ED) can be a stressful event for children. With the goal of minimizing pain, anxiety, and unneeded interventions in stable patients, we implemented the Pediatric PAUSE at our level 1 adult/level 2 pediatric trauma center. The Pediatric PAUSE is a brief protocol performed after the primary survey, which addresses Pain/Privacy, Anxiety/IV Access, Urinary Catheter/Rectal exam/Genital exam, Support from family or staff, and Explain to patient/Engage with PICU team. The aim was to assess whether performing the PAUSE interfered with timeliness of emergent imaging in pediatric patients and their disposition. METHODS: We identified all patients aged 0 to 18 years evaluated as trauma activations at our institution after the Pediatric PAUSE was implemented (October 1, 2016-March 31, 2017) as well as 2 analogous 6-month pre-PAUSE periods. Patient demographics, time to imaging studies, and time to ED disposition were analyzed. RESULTS: One hundred seventy-two patients met the study criteria, with a mean age of 10.9 years and mean injury severity score of 10.6. One hundred fifteen participants (68.5%) were transferred from other hospitals, and 101 (87.8%) had ≥1 imaging study performed before arrival. The Pediatric PAUSE was performed for 41 (25%) of 163 study participants. There was no difference in time to first imaging study in participants for whom the PAUSE was performed (18.4 vs 15.0 minutes, P = 0.09). CONCLUSIONS: The PAUSE is a practice intervention designed to address the psychosocial needs of pediatric trauma patients and their families to help prevent posttraumatic stress symptoms. Implementation did not interfere with the timeliness of first imaging in pediatric trauma patients.

Analgesic Efficacy of Tramadol and Morphine in White's Tree Frogs (Litoria caerulea).

Published data are sparse regarding the recognition of clinically relevant pain and appropriate analgesia in amphibians. The amphibian analgesia literature has primarily focused on nociceptive pathways in a single species, the northern leopard frog (Rana pipiens). The objective of the current study was to assess the analgesic efficacy and safety of oral tramadol and subcutaneous morphine in a commonly maintained zoo and pet species, White's tree frog (Litoria caerulea). We hypothesized that tramadol and morphine would provide dose-dependent antinociception, as measured by significant increases in hindlimb withdrawal latency after exposure to a noxious thermal stimulus. Two randomized, placebo-controlled, complete crossover studies were performed, with tramadol (n = 12) administered at 15, 25, and 40 mg/kg PO and morphine (n = 12) administered at 5 and 10 mg/kg SC. Hindlimb withdrawal latency was measured for a maximum of 72 h. No adverse side effects or signs of sedation were observed with any dose or drug evaluated. No significant difference in withdrawal latency was detected between the control and either tramadol or morphine. These negative results were surprising, suggesting that the thermal nociceptive model may not be biologically relevant in amphibian species.

Progression of Geographic Atrophy: Epistemic Uncertainties Affecting Mathematical Models and Machine Learning.

Purpose: The purpose of this study was to identify a taxonomy of epistemic uncertainties that affect results for geographic atrophy (GA) assessment and progression. Methods: An important source of variability is called "epistemic uncertainty," which is due to incomplete system knowledge (i.e. limitations in measurement devices, artifacts, and human subjective evaluation, including annotation errors). In this study, different epistemic uncertainties affecting the analysis of GA were identified and organized into a taxonomy. The uncertainties were discussed and analyzed, and an example was provided in the case of model structure uncertainty by characterizing progression of GA by mathematical modelling and machine learning. It was hypothesized that GA growth follows a logistic (sigmoidal) function. Using case studies, the GA growth data were used to test the sigmoidal hypothesis. Results: Epistemic uncertainties were identified, including measurement error (imperfect outcomes from measuring tools), subjective judgment (grading affected by grader's vision and experience), model input uncertainties (data corruption or entry errors), and model structure uncertainties (elucidating the right progression pattern). Using GA growth data from case studies, it was demonstrated that GA growth can be represented by a sigmoidal function, where growth eventually approaches an upper limit. Conclusion: Epistemic uncertainties contribute to errors in study results and are reducible if identified and addressed. By prior identification of epistemic uncertainties, it is possible to (a) quantify uncertainty not accounted for by natural statistical variability, and (b) reduce the presence of these uncertainties in future studies. Translational Relevance: Lowering epistemic uncertainty will reduce experimental error, improve consistency and reproducibility, and increase confidence in diagnostics.

Comparison of Thermal and Mechanical Noxious Stimuli for Testing Analgesics in White's Tree Frogs (Litoria caerulea) and Northern Leopard Frogs (Lithobates pipiens).

Determining the clinical efficacy of analgesic drugs in amphibians can be particularly challenging. The current study investigated whether a thermal nociceptive stimulus is useful for the evaluation of analgesic drugs in 2 amphibian species. The objectives of this study were 2-fold: 1) compare 2 models of nociception (thermal and mechanical) using 2 frog species; White's Tree Frogs (Litoria caerulea; WTF) and Northern Leopard Frogs (Lithobates pipiens; NLF) after administration of saline or morphine sulfate; and 2) evaluate antinociceptive efficacy of morphine sulfate at 2 doses in a common amphibian research species, the NLF, using a mechanical stimulus. Neither WTF nor NLF displayed consistent drug-dependent changes in withdrawal responses to a noxious thermal stimulus applied using the Hargreaves apparatus, but NLF exposed to the noxious mechanical stimulus demonstrated a significant dose-dependent antinociceptive response to morphine sulfate. These results indicate that morphine is not antinociceptive in WTF, supporting previously reported results, and demonstrate the importance of using an appropriate experimental antinociceptive test in amphibians. Our data suggest that nociception in amphibian species may be best evaluated by using mechanical nociceptive models, although species differences must also be considered.

Deep Learning Applied to Automated Segmentation of Geographic Atrophy in Fundus Autofluorescence Images.

Purpose: This study describes the development of a deep learning algorithm based on the U-Net architecture for automated segmentation of geographic atrophy (GA) lesions in fundus autofluorescence (FAF) images. Methods: Image preprocessing and normalization by modified adaptive histogram equalization were used for image standardization to improve effectiveness of deep learning. A U-Net-based deep learning algorithm was developed and trained and tested by fivefold cross-validation using FAF images from clinical datasets. The following metrics were used for evaluating the performance for lesion segmentation in GA: dice similarity coefficient (DSC), DSC loss, sensitivity, specificity, mean absolute error (MAE), accuracy, recall, and precision. Results: In total, 702 FAF images from 51 patients were analyzed. After fivefold cross-validation for lesion segmentation, the average training and validation scores were found for the most important metric, DSC (0.9874 and 0.9779), for accuracy (0.9912 and 0.9815), for sensitivity (0.9955 and 0.9928), and for specificity (0.8686 and 0.7261). Scores for testing were all similar to the validation scores. The algorithm segmented GA lesions six times more quickly than human performance. Conclusions: The deep learning algorithm can be implemented using clinical data with a very high level of performance for lesion segmentation. Automation of diagnostics for GA assessment has the potential to provide savings with respect to patient visit duration, operational cost and measurement reliability in routine GA assessments. Translational Relevance: A deep learning algorithm based on the U-Net architecture and image preprocessing appears to be suitable for automated segmentation of GA lesions on clinical data, producing fast and accurate results.

Pharmacokinetics of ceftazidime in Northern leopard frogs (Lithobates pipiens) at two different doses and administration routes.

OBJECTIVE: To determine an optimal ceftazidime dosing strategy in Northern leopard frogs (Lithobates pipiens) by evaluation of 2 different doses administered SC and 1 dose administered transcutaneously. ANIMALS: 44 Northern leopard frogs (including 10 that were replaced). PROCEDURES: Ceftazidime was administered to frogs SC in a forelimb at 20 mg/kg (n = 10; SC20 group) and 40 mg/kg (10; SC40 group) or transcutaneously on the cranial dorsum at 20 mg/kg (10; TC20 group). Two frogs in each ceftazidime group were euthanized 12, 24, 48, 72, and 96 hours after drug administration. Plasma, renal, and skin concentrations of ceftazidime were measured by means of reversed-phase high-performance liquid chromatography. Four control frogs were used for assay validation. RESULTS: Mean plasma half-life of ceftazidime in the SC20, SC40, and TC20 groups was 9.01 hours, 14.49 hours, and too low to determine, respectively. Mean maximum plasma ceftazidime concentration was 92.9, 96.0, and 1.3 µg/mL, respectively. For 24 hours after drug administration in the SC20 and SC40 groups, plasma ceftazidime concentration exceeded 8 µg/mL. Renal and skin concentrations were detectable at both doses and routes of administration; however, skin concentrations were significantly lower than renal and plasma concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Findings indicated that ceftazidime administration to Northern leopard frogs at 20 mg/kg, SC, every 24 hours would achieve a plasma concentration exceeding the value considered effective against common amphibian pathogens. Transcutaneous administration of the injectable ceftazidime formulation at 20 mg/kg warrants further investigation but is not currently recommended because of a potential lack of efficacy.

Model Structure Uncertainty in the Characterization and Growth of Geographic Atrophy.

Purpose: To identify the most suitable model for assessing the rate of growth of total geographic atrophy (GA) by analysis of model structure uncertainty. Methods: Model structure uncertainty refers to unexplained variability arising from the choice of mathematical model and represents an example of epistemic uncertainty. In this study, we quantified this uncertainty to help identify a model most representative of GA progression. Fundus autofluorescence (FAF) images and GA progression data (i.e., total GA area estimation at each presentation) were acquired using Spectralis HRA+OCT instrumentation and RegionFinder software. Six regression models were evaluated. Models were compared using various statistical tests, [i.e., coefficient of determination (r2), uncertainty metric (U), and test of significance for the correlation coefficient, r], as well as adherence to expected physical and clinical assumptions of GA growth. Results: Analysis was carried out for 81 GA-affected eyes, 531 FAF images (range: 3-17 images per eye), over median of 57 months (IQR: 42, 74), with a mean baseline lesion size of 2.62 ± 4.49 mm2 (range: 0.11-20.69 mm2). The linear model proved to be the most representative of total GA growth, with lowest average uncertainty (original scale: U = 0.025, square root scale: U = 0.014), high average r2 (original scale: 0.92, square root scale: 0.93), and applicability of the model was supported by a high correlation coefficient, r, with statistical significance (P = 0.01). Conclusions: Statistical analysis of uncertainty suggests that the linear model provides an effective and practical representation of the rate and progression of total GA growth based on data from patient presentations in clinical settings. Translational Relevance: Identification of correct model structure to characterize rate of growth of total GA in the retina using FAF images provides an objective metric for comparing interventions and charting GA progression in clinical presentations.

Migratory movements of Atlantic puffins Fratercula arctica naumanni from high Arctic Greenland.

Although the Atlantic puffin Fratercula arctica is well studied throughout its temperate and low Arctic breeding range, few have studied the species in its far northern distribution. This study is the first to present data on the migratory movements of the "large-billed" subspecies, F. a. naumanni, that breeds in the high Arctic and which has significantly larger body size than those farther south. During 2013-2015, migration tracks were collected from nine adult puffins (6 males and 3 females) tagged with geolocators in northwest Greenland. Overall, female puffins traveled farther than males on their annual migration, with one female puffin traveling over 13,600 km, which was nearly a third farther than any tagged male in our study. Differential migration was observed in migratory phenology and route, with males using a form of chain migration with acute synchrony between individuals while females appeared to largely use leap-frog migration and showed little synchrony between individuals. Extreme sexual segregation in wintering areas was evidenced by two females that migrated to the southern limit of the species' range while the six males remained at the northern limit, and wintered along the sea ice edge during portions of the non-breeding season. Male puffins thus wintered in regions with sea surface temperatures up to 10° C cooler than female puffins, and in areas with generally colder sea surface temperatures when compared to previously known wintering areas of temperate and low Arctic puffin breeding populations. The degree to which body size enables male F. a. naumanni to remain in colder waters likely reflects differing life history constraints between sexes and populations (i.e., subspecies). Further study is warranted to investigate how recent changes in climate have further exacerbated the observed differences between sexes in high Arctic puffins and possibly other marine avian species.

Artificial Intelligence and Telehealth may Provide Early Warning of Epidemics.

The COVID-19 pandemic produced a very sudden and serious impact on public health around the world, greatly adding to the burden of overloaded professionals and national medical systems. Recent medical research has demonstrated the value of using online systems to predict emerging spatial distributions of transmittable diseases. Concerned internet users often resort to online sources in an effort to explain their medical symptoms. This raises the prospect that incidence of COVID-19 may be tracked online by search queries and social media posts analyzed by advanced methods in data science, such as Artificial Intelligence. Online queries can provide early warning of an impending epidemic, which is valuable information needed to support planning timely interventions. Identification of the location of clusters geographically helps to support containment measures by providing information for decision-making and modeling.

Respiratory and antinociceptive effects of dexmedetomidine and doxapram in ball pythons (Python regius).

OBJECTIVE: To determine the effects of dexmedetomidine, doxapram, and dexmedetomidine plus doxapram on ventilation ([Formula: see text]e), breath frequency, and tidal volume (Vt) in ball pythons (Python regius) and of doxapram on the thermal antinociceptive efficacy of dexmedetomidine. ANIMALS: 14 ball pythons. PROCEDURES: Respiratory effects of dexmedetomidine and doxapram were assessed with whole-body, closed-chamber plethysmography, which allowed for estimates of [Formula: see text]e and Vt. In the first experiment of this study with a complete crossover design, snakes were injected, SC, with saline (0.9% NaCl) solution, dexmedetomidine (0.1 mg/kg), doxapram (10 mg/kg), or dexmedetomidine and doxapram, and breath frequency, [Formula: see text]e, and Vt were measured before and every 30 minutes thereafter, through 240 minutes. In the second experiment, antinociceptive efficacy of saline solution, dexmedetomidine, and dexmedetomidine plus doxapram was assessed by measuring thermal withdrawal latencies before and 60 minutes after SC injection. RESULTS: Dexmedetomidine significantly decreased breath frequency and increased Vt but did not affect [Formula: see text]e at all time points, compared with baseline. Doxapram significantly increased [Formula: see text]e, breath frequency, and Vt at 60 minutes after injection, compared with saline solution. The combination of dexmedetomidine and doxapram, compared with dexmedetomidine alone, significantly increased [Formula: see text]e at 30 and 60 minutes after injection and did not affect breath frequency and Vt at all time points. Thermal withdrawal latencies significantly increased when snakes received dexmedetomidine or dexmedetomidine plus doxapram, versus saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Concurrent administration of doxapram may mitigate the dexmedetomidine-induced reduction of breathing frequency without disrupting thermal antinociceptive efficacy in ball pythons.

Radiofrequency electromagnetic field exposure assessment: a pilot study on mobile phone signal strength and transmitted power levels.

In many epidemiological studies mobile phone use has been used as an exposure proxy for radiofrequency electromagnetic field (RF-EMF) exposure. However, RF-EMF exposure assessment from mobile phone use is prone to measurement errors limiting epidemiological research. An often-overlooked aspect is received signal strength levels from base stations and its correlation with mobile phone transmit (Tx) power. The Qualipoc android phone is a tool that provides information on both signal strength and Tx power. The phone produces simultaneous measurements of Received Signal Strength Indicator (RSSI), Reference Signal Received Power (RSRP), Received Signal Code Power (RSCP), and Tx power on the 3G and 4G networks. Measurements taken in the greater Melbourne area found a wide range of signal strength levels. The correlations between multiple signal strength indicators and Tx power were assessed with strong negative correlations found for 3G and 4G data technologies (3G RSSI -0.93, RSCP -0.93; 4G RSSI -0.85, RSRP -0.87). Variations in Tx power over categorical levels of signal strength were quantified and showed large increases in Tx power as signal level decreased. Future epidemiological studies should control for signal strength or factors influencing signal strength to reduce RF-EMF exposure measurement error.