Parameter ESTimation With the Gauss-Levenberg-Marquardt Algorithm: An Intuitive Guide.

In this paper, we review the derivation of the Gauss-Levenberg-Marquardt (GLM) algorithm and its extension to ensemble parameter estimation. We explore the use of graphical methods to provide insights into how the algorithm works in practice and discuss the implications of both algorithm tuning parameters and objective function construction in performance. Some insights include understanding the control of both parameter trajectory and step size for GLM as a function of tuning parameters. Furthermore, for the iterative Ensemble Smoother (iES), we discuss the importance of noise on observations and show how iES can cope with non-unique outcomes based on objective function construction. These insights are valuable for modelers using PEST, PEST++, or similar parameter estimation tools.

Towards Improved Remedial Outcomes in Categorical Aquifers with an Iterative Ensemble Smoother.

Categorical parameter distributions consisting of geologic facies with distinct properties, for example, high-permeability channels embedded in a low-permeability matrix, are common at contaminated sites. At these sites, low-permeability facies store solute mass, acting as secondary sources to higher-permeability facies, sustaining concentrations for decades while increasing risk and cleanup costs. Parameter estimation is difficult in such systems because the discontinuities in the parameter space hinder the inverse problem. This paper presents a novel approach based on Traveling Pilot Points (TRIPS) and an iterative ensemble smoother (IES) to solve the categorical inverse problem. Groundwater flow and solute transport in a hypothetical aquifer with a categorical parameter distribution are simulated using MODFLOW 6. Heads and concentrations are recorded at multiple monitoring locations. IES is used to generate posterior ensembles assuming a TRIPS prior and an approximate multi-Gaussian prior. The ensembles are used to predict solute concentrations and mass into the future. The evaluation also includes an assessment of how the number of measurements and the choice of the geological prior determine the characteristics of the posterior ensemble and the resulting predictions. The results indicate that IES was able to efficiently sample the posterior distribution and showed that even with an approximate geological prior, a high degree of parameterization and history matching could lead to parameter ensembles that can be useful for making certain types of predictions (heads, concentrations). However, the approximate geological prior was insufficient for predicting mass. The analysis demonstrates how decision-makers can quantify uncertainty and make informed decisions with an ensemble-based approach.

Bilateral Lower Extremity Calcific Myonecrosis: A Case Report.

Introduction: Calcific myonecrosis is a rare soft-tissue disease where a single muscle or muscle compartment is replaced with central liquefaction and peripheral calcification. This disease usually occurs in a single limb after trauma. Until now, bilateral muscle involvement has not been previously reported. Case Report: A 73-year-old woman presented with symptomatic masses in the soft tissues of bilateral anterior thighs. She had no known history of trauma but recalled a specific tearing sensation episode in both her legs while squatting when weightlifting in the distant past. The patient had calcified masses that had replaced the rectus femoris muscle bilaterally with associated effects on hip and knee range of motion. The patient underwent excision of a portion of calcific myonecrosis and two locations of rectus femoris tenotomies in one leg and only a simple rectus femoris tenotomy on the contralateral leg. The patient subsequently experienced a significant improvement in hip and knee motion and a reduction in associated pain on both sides. Conclusion: Historical and radiographic information are key in making the diagnosis of calcific myonecrosis. Treatment decisions should be based on the patient's symptoms balanced with the morbidity of the expected procedures. Symptomatic patients should be considered for excision of the symptomatic involved areas. A tenotomy may be a viable option if a limitation in motion is the primary complaint. Asymptomatic patients with a stable lesion and imaging should undergo conservative management due to the high risk of infection and wound healing problems.

A Generic Closed-Loop Contaminant Treatment System Package for MODFLOW 6.

We present a contaminant treatment system (CTS) package for MODFLOW 6 that facilitates the simulation of pump-and-treat systems for groundwater remediation. Using the "nonintrusive" MODFLOW 6 application programming interface (API) capability, the CTS package can balance flows between extraction and injection wells within the outer flow solution loop and applies blended concentration/mass treatment efficiency within the outer transport solution loop. The former can be important when the requested extraction rate cannot be satisfied by the current simulated groundwater system conditions, while the latter can be important for simulating incomplete/imperfect treatment schemes. Furthermore, the CTS package allows users to temporally vary all aspects of a simulated CTS system, including the configuration and location of injection and extraction wells, and the CTS efficiency. This flexibility combined with the API-based implementation provide a generic and general CTS package that can be applied across the wide range of MODFLOW 6 simulation options and that evolves in step with MODFLOW 6 code modifications and advancements without needing to update the CTS package itself.

Transcutaneous Oximetry Does Not Reliably Predict Wound-healing Complications in Preoperatively Radiated Soft Tissue Sarcoma.

BACKGROUND: Surgical wound-healing complications after tumor resections in tissue that has been preoperatively radiated are a major clinical problem. Most studies have reported that complications occur in more than 30% of patients undergoing such resections in the lower extremity. There is currently no available method to predict which patients are likely to have a complication. Transcutaneous oximetry has been identified in preliminary studies as potentially useful, but the available evidence on its efficacy for this application thus far is inconclusive. QUESTIONS/PURPOSES: (1) Does transcutaneous oximetry measurement below 25 mmHg at any location in the surgical wound bed predict a wound-healing complication? (2) Does recovery (increase) in transcutaneous oxygen measurement during the rest period between the end of radiation and the time of surgery protect against wound-healing complications? METHODS: A prospective, multi-institution study was coordinated to measure skin oxygenation at three timepoints in patients undergoing surgery for a lower extremity soft tissue sarcoma after preoperative radiation. Between 2016 and 2020, the five participating centers treated 476 patients for lower extremity soft tissue sarcoma. Of those, we considered those with a first-time sarcoma treated with radiation before limb salvage surgery as potentially eligible. Based on that, 21% (98 of 476) were eligible; a further 12% (56 of 476) were excluded because they refused to participate or ultimately, they were treated with a flap, amputation, or skin graft. Another 1% (3 of 476) of patients were lost because of incomplete datasets or follow-up less than 6 months, leaving 8% (39 of 476) for analysis here. The mean patient age was 62 ± 14 years, 62% (24 of 39) of the group were men, and 18% (7 of 39) of patients smoked cigarettes; 87% (34 of 39) of tumors were intermediate/high grade, and the most common histologic subtype was undifferentiated pleomorphic sarcoma. In investigating complications, a cutoff of 25 mmHg was chosen based on a pilot investigation that identified this value. All patients were assessed for surgical wound-healing complications, which were defined as: those resulting in a return to the operating room, initiation of oral or IV antibiotics, intervention for seroma, or prolonged wound packing or dressing changes. To answer the first research question, we compared the proportion of patients who developed a wound-healing complication between those patients who had any reading below 25 mmHg (7 of 39) and those who did not (32 of 39). To answer the second question, we compared the group with stable or decreased skin oxygenation (22 of 37 patient measurements [two patients missed the immediate postoperative measurement]) to the group that had increased skin oxygen measurement (15 of 37 measurements) during the period between the end of radiation and the surgical procedure; again, the endpoint was the development of a wound-healing complication. This study was powered a priori to detect an unadjusted odds ratio for wound-healing complications as small as 0.71 for a five-unit (5 mmHg) increase in TcO 2 between the groups, with α set to 0.05, ß set to 0.2, and a sample size of 40 patients. RESULTS: We found no difference in the odds of a wound-healing complication between patients whose transcutaneous oxygen measurements were greater than or equal to 25 mmHg at all timepoints compared with those who had one or more readings below that threshold (odds ratio 0.27 [95% confidence interval (CI) 0.05 to 1.63]; p = 0.15). There was no difference in the odds of a wound-healing complication between patients who had recovery of skin oxygenation between radiation and surgery and those who did not (OR 0.63 [95% CI 0.37 to 5.12]; p = 0.64). CONCLUSION: Transcutaneous oximetry cannot be considered a reliable test in isolation to predict wound-healing complications. This may be a function of the fact that transcutaneous oximetry samples a relatively small portion of the landscape in which a wound-healing complication could potentially arise. In the absence of a reliable diagnostic test, clinicians must still use their best judgment regarding surgical timing and work to address modifiable risk factors to avoid complications. The unanswered question that remains is whether there is a skin perfusion or oxygenation issue at the root of these complications, which seems likely. Alternative approaches that can assess the wound more broadly and in real time, such as fluorescent probes, may be deserving of further investigation. LEVEL OF EVIDENCE: Level II, diagnostic study.

Incomplete recovery of seeds from scatterhoards by granivorous rodents: Implications for plant establishment.

Granivorous rodents are important components of ecosystems not only because they consume seeds but also because some aid in seed dispersal through seed-caching behaviors. Some rodents bury seeds in shallow pits throughout territories, called scatterhoards, that individuals recover, pilfer, or transfer to other caches. We suspect some single-seed caches in environments represent missed seeds from reclaiming or pilfering caches. We documented the sloppiness of seed removal from scatterhoards of soapweed yucca (Yucca glauca) seeds by Ord's kangaroo rats (Dipodomys ordii). We quantified the frequency and location of seeds remaining. In an experiment with artificial caches of three sizes, kangaroo rats harvested 51% of caches after one night, and 53% had incomplete recovery with at least one seed remaining. The greater the number of seeds in caches, the greater frequency of incomplete recovery. In another experiment with natural and artificial caches, 75% of caches were excavated after 8 days, with at least 70% having at least one seed remaining. Regardless of original cache size, a single seed represented the mode for seeds remaining. Incomplete recovery of seeds likely benefits plant establishment, potentially significantly in some systems. Remaining seeds, especially those buried at bottoms of caches, likely will stay undetected in landscapes, yielding propagules for subsequent plant generations. Soapweed yucca has large but light, flat wind-dispersed seeds, and removal of caches with smaller seeds might have greater frequency of missed seeds during recovery and pilfering by rodents. Our results suggest that scatter-hoarding granivores also contribute to plant establishment by leaving limited numbers of seeds behind when removing caches, at least in some systems.

Risk-Based Wellhead Protection Decision Support: A Repeatable Workflow Approach.

Environmental water management often benefits from a risk-based approach where information on the area of interest is characterized, assembled, and incorporated into a decision model considering uncertainty. This includes prior information from literature, field measurements, professional interpretation, and data assimilation resulting in a decision tool with a posterior uncertainty assessment accounting for prior understanding and what is learned through model development and data assimilation. Model construction and data assimilation are time consuming and prone to errors, which motivates a repeatable workflow where revisions resulting from new interpretations or discovery of errors can be addressed and the analyses repeated efficiently and rigorously. In this work, motivated by the real world application of delineating risk-based (probabilistic) sources of water to supply wells in a humid temperate climate, a scripted workflow was generated for groundwater model construction, data assimilation, particle-tracking and post-processing. The workflow leverages existing datasets describing hydrogeology, hydrography, water use, recharge, and lateral boundaries. These specific data are available in the United States but the tools can be applied to similar datasets worldwide. The workflow builds the model, performs ensemble-based history matching, and uses a posterior Monte Carlo approach to provide probabilistic capture zones describing source water to wells in a risk-based framework. The water managers can then select areas of varying levels of protection based on their tolerance for risk of potential wrongness of the underlying models. All the tools in this workflow are open-source and free, which facilitates testing of this repeatable and transparent approach to other environmental problems.

Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity.

Obesity affects nearly one billion globally and can lead to life-threatening sequelae. Consequently, there is an urgent need for novel therapeutics. We have previously shown that laminin, alpha 4 (Lama4) knockout in mice leads to resistance to adipose tissue accumulation; however, the relationship between LAMA4 and obesity in humans has not been established. In this study we measured laminin-α chain and collagen mRNA expression in the subcutaneous white adipose tissue (sWAT) of mice placed on chow (RCD) or 45% high fat diet (HFD) for 8 weeks, and also in HFD mice then placed on a "weight loss" regimen (8 weeks HFD followed by 6 weeks RCD). To assess extracellular matrix (ECM) components in humans with obesity, laminin subunit alpha mRNA and protein expression was measured in sWAT biopsies of female control subjects (BMI<30) or subjects with obesity undergoing bariatric surgery at the University of Chicago Medical Center (BMI>35) both before and three months after surgery. Lama4 was significantly higher in sWAT of HFD compared to RCD mice at both the RNA and protein level (p<0.001, p<0.05 respectively). sWAT from human subjects with obesity also showed significantly higher LAMA4 mRNA (p<0.01) and LAMA4 protein expression (p<0.05) than controls. Interestingly, even though LAMA4 expression was increased in both humans and murine models of obesity, no significant difference in Lama4 or LAMA4 expression was detected following short-term weight loss in either mouse or human samples, respectively. From these results we propose a significant association between obesity and elevated LAMA4 expression in humans, as well as in mouse models of obesity. Further studies should clarify the mechanisms underlying this association to target LAMA4 effectively as a potential therapy for obesity.

Evaluating Lower Computational Burden Approaches for Calibration of Large Environmental Models.

Realistic environmental models used for decision making typically require a highly parameterized approach. Calibration of such models is computationally intensive because widely used parameter estimation approaches require individual forward runs for each parameter adjusted. These runs construct a parameter-to-observation sensitivity, or Jacobian, matrix used to develop candidate parameter upgrades. Parameter estimation algorithms are also commonly adversely affected by numerical noise in the calculated sensitivities within the Jacobian matrix, which can result in unnecessary parameter estimation iterations and less model-to-measurement fit. Ideally, approaches to reduce the computational burden of parameter estimation will also increase the signal-to-noise ratio related to observations influential to the parameter estimation even as the number of forward runs decrease. In this work a simultaneous increments, an iterative ensemble smoother (IES), and a randomized Jacobian approach were compared to a traditional approach that uses a full Jacobian matrix. All approaches were applied to the same model developed for decision making in the Mississippi Alluvial Plain, USA. Both the IES and randomized Jacobian approach achieved a desirable fit and similar parameter fields in many fewer forward runs than the traditional approach; in both cases the fit was obtained in fewer runs than the number of adjustable parameters. The simultaneous increments approach did not perform as well as the other methods due to inability to overcome suboptimal dropping of parameter sensitivities. This work indicates that use of highly efficient algorithms can greatly speed parameter estimation, which in turn increases calibration vetting and utility of realistic models used for decision making.

Risk-Based Decision-Support Groundwater Modeling for the Lower San Antonio River Basin, Texas, USA.

A numerical surface-water/groundwater model was developed for the lower San Antonio River Basin to evaluate the responses of low base flows and groundwater levels within the basin under conditions of reduced recharge and increased groundwater withdrawals. Batch data assimilation through history matching used a simulation of historical conditions (2006-2013); this process included history-matching to groundwater levels and base-flow estimates at several gages, and was completed in a high-dimensional (highly parameterized) framework. The model was developed in an uncertainty framework such that parameters, observations, and scenarios of interest are envisioned stochastically as distributions of potential values. Results indicate that groundwater contributions to surface water during periods of low flow may be reduced from 6% to 25% with a corresponding 25% reduction in recharge and a 25% increase in groundwater pumping over an 8-year planning period. Furthermore, results indicate groundwater-level reductions in some hydrostratigraphic units are more likely than in other hydrostratigraphic units over an 8-year period under drought conditions with the higher groundwater withdrawal scenario.

Extending the Capture Map Concept to Estimate Discrete and Risk-Based Streamflow Depletion Potential.

A popular and contemporary use of numerical groundwater models is to estimate the discrete relation between groundwater extraction and surface-water/groundwater exchange. Previously, the concept of a "capture map" has been put forward as a means to effectively summarize this relation for decision-making consumption. While capture maps have enjoyed success in the environmental simulation industry, they are deterministic, ignoring uncertainty in the underlying model. Furthermore, capture maps are not typically calculated in a manner that facilitates analysis of varying combinations of extraction locations and/or reaches. That is, they are typically constructed with focus on a single reach or group of reaches. The former of these limitations is important for conveying risk to decision makers and stakeholders, while the latter is important for decision-making support related to surface-water management, where future foci may include reaches that were not the focus of the original capture analysis. Herein, we use the concept of a response matrix to generalize the theory of the capture-map approach to estimate spatially discrete streamflow depletion potential. We also use first-order, second-moment uncertainty estimation techniques with the concept of "risk shifting" to place capture maps and streamflow depletion potential in a stochastic, risk-based framework. Our approach is demonstrated for an integrated groundwater/surface-water model of the lower San Antonio River, Texas, USA.

Mitogenome of northern long-eared bat.

The complete mitogenome of the northern long-eared bat (Myotis septentrionalis) was determined to be 17,362 bp and contained 22 tRNA genes, 2 rRNA genes and one control region. The whole genome base composition was 33.8% GC. Phylogenetic analysis suggests that M. septentrionalis be positioned next to M. auriculus in the Nearctic subclade of the Myotis genus. This complete mitochondrial genome provides essential molecular markers for resolving phylogeny and future conservation efforts.

Reduction of IL-6 gene expression in human adipose tissue after sleeve gastrectomy surgery.

OBJECTIVE: There is increasing evidence that immune cell interactions in adipose tissue contribute to the development of metabolic dysfunction. Pro-inflammatory cytokines have been shown to mediate insulin resistance, and the presence of macrophages is a salient feature in the development of obesity. The present study aimed to evaluate adipocyte size and macrophage activation in women before and 3 months after laparoscopic vertical sleeve gastrectomy (VSG). METHODS: Subcutaneous abdominal adipose tissue biopsies were obtained from women scheduled to undergo VSG. Histological evaluation of adipocytes and macrophages was performed as well as cytokine expression quantification before and after VSG-induced weight loss. RESULTS: Weight loss following VSG resulted in a reduction in adipocyte size as well as a decrease in interleukin (IL)-6 cytokine mRNA expression in subcutaneous adipose tissue. There was no change in the presence of crownlike structures after weight loss. CONCLUSIONS: Early weight loss after VSG is associated with a reduction in adipocyte size and a decline in IL-6 gene expression in local adipose tissue. Macrophage infiltration and crownlike density structures persist in adipose tissue from tissues impacted by excess body weight 3 months after VSG-induced weight loss.

Consequences of Groundwater-Model Vertical Discretization in Risk-Based Decision-Making.

One of the first and most important decisions facing practitioners when constructing a numerical groundwater model is vertical discretization. Several factors will influence this decision, such as the conceptual model of the system and hydrostratigraphy, data availability, resulting computational burden, and the purpose of the modeling analysis. Using a coarse vertical discretization is an attractive option for practitioners because it reduces data requirements and model construction efforts, can increase model stability, and can reduce computational demand. However, using a coarse vertical discretization as a form of model simplification is not without consequence; this may give rise to unwanted side-effects such as biases in decision-relevant simulated outputs. Given its foundational role in the modeled representation of the aquifer system, herein we investigate how vertical discretization may affect decision-relevant simulated outputs using a paired complex-simple model analysis. A Bayesian framework and decision analysis approach are adopted. Two case studies are considered, one of a synthetic, linked unsaturated-zone/surface-water/groundwater hydrologic model and one of a real-world linked surface-water/groundwater hydrologic-nitrate transport model. With these models, we analyze decisions related to abstraction-induced changes in ecologically important streamflow characteristics and differences in groundwater and surface-water nitrate concentrations and mass loads following potential land-use change. We show that for some decision-relevant simulated outputs, coarse vertical discretization induces bias in important simulated outputs, and can lead to incorrect resource management action. For others, a coarse vertical discretization has little or no consequence for resource management decision-making.

Reference Gene Optimization for Circadian Gene Expression Analysis in Human Adipose Tissue.

A hallmark of biology is the cyclical nature of organismal physiology driven by networks of biological, including circadian, rhythms. Unsurprisingly, disruptions of the circadian rhythms through sleep curtailment or shift work have been connected through numerous studies to positive associations with obesity, insulin resistance, and diabetes. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) measures oscillation in messenger RNA expression, an essential foundation for the study of the physiological circadian regulatory network. Primarily, measured oscillations have involved the use of reference gene normalization. However, the validation and identification of suitable reference genes is a significant challenge across different biological systems. This study focuses on adipose tissue of premenopausal, otherwise healthy, morbidly obese women voluntarily enrolled after being scheduled for laparoscopic sleeve gastrectomy surgery. Acquisition of tissue was accomplished by aspiratory needle biopsies of subcutaneous adipose tissue 1 to 2 weeks prior to surgery and 12 to 13 weeks following surgery and an in-surgery scalpel-assisted excision of mesenteric adipose tissue. Each biopsy was sterile cultured ex vivo and serially collected every 4 h over approximately 36 h. The candidate reference genes that were tested were 18S rRNA, GAPDH, HPRT1, RPII, RPL13α, and YWHAZ. Three analytic tools were used to test suitability, and the candidate reference genes were used to measure oscillation in expression of a known circadian clock element (Dbp). No gene was deemed suitable as an individual reference gene control, which indicated that the optimal reference gene set was the geometrically averaged 3-gene panel composed of YWHAZ, RPL13α, and GAPDH. These methods can be employed to identify optimal reference genes in other systems.

Revisiting "An Exercise in Groundwater Model Calibration and Prediction" After 30 Years: Insights and New Directions.

In 1988, an important publication moved model calibration and forecasting beyond case studies and theoretical analysis. It reported on a somewhat idyllic graduate student modeling exercise where many of the system properties were known; the primary forecasts of interest were heads in pumping wells after a river was modified. The model was calibrated using manual trial-and-error approaches where a model's forecast quality was not related to how well it was calibrated. Here, we investigate whether tools widely available today obviate the shortcomings identified 30 years ago. A reconstructed version of the 1988 true model was tested using increasing parameter estimation sophistication. The parameter estimation demonstrated the inverse problem was non-unique because only head data were available for calibration. When a flux observation was included, current parameter estimation approaches were able to overcome all calibration and forecast issues noted in 1988. The best forecasts were obtained from a highly parameterized model that used pilot points for hydraulic conductivity and was constrained with soft knowledge. Like the 1988 results, however, the best calibrated model did not produce the best forecasts due to parameter overfitting. Finally, a computationally frugal linear uncertainty analysis demonstrated that the single-zone model was oversimplified, with only half of the forecasts falling within the calculated uncertainty bounds. Uncertainties from the highly parameterized models had all six forecasts within the calculated uncertainty. The current results outperformed those of the 1988 effort, demonstrating the value of quantitative parameter estimation and uncertainty analysis methods.

Creating a dual articulating antibiotic spacer for management of an infected total femur prosthesis hemiarthroplasty.

The gold standard for management of chronic periprosthetic joint infections is a 2-stage revision arthroplasty with the first stage being explantation, debridement, and placement of a spacer. While there are implants designed to manage periprosthetic infections in hip and knee arthroplasty, there are not any commercially available implants designed to specifically manage an infected total femur megaprosthesis. This creates a unique surgical challenge and requires custom construction of a spacer to be performed by the surgeon intraoperatively. Here, we present our surgical technique for manufacturing a dual articulating total femur spacer. This technique facilitates range of motion at both the hip and knee joints, provides stability for axial loading in the extremity, and preserves the acetabulum while the patient undergoes antibiotic therapy to eradicate the infection.