Circulating tumor DNA analysis guiding adjuvant treatment in resected stage III cholangiocarcinoma: a case report.

Background: Cholangiocarcinoma (CCA) is a rare and aggressive gastrointestinal cancer. Unfortunately, 60% to 70% of early-stage CCA patients experience disease recurrence after curative resection and standard adjuvant therapy. Currently, there is no reliable tool to identify CCA recurrence before radiographic detection. Longitudinal monitoring of circulating tumor DNA (ctDNA) has shown promising value in molecular identification of relapse prior to conventional surveillance in other solid tumors. However, there is a scarcity of data on ctDNA in CCA after curative surgery. Case Description: An 81-year-old male with stage 3A intrahepatic CCA achieved radiographic remission after curative resection and was started on standard adjuvant capecitabine on post-operative day (POD) 50. Tumor-informed ctDNA tested positive on two consecutive occasions, with the titer increasing from 0.16 mean tumor molecule (MTM)/mL on POD 92 to 0.80 MTM/mL on POD 183, despite being on capecitabine. carbohydrate antigen 19-9 (CA19-9) also continued to increase from 175.6 U/mL on POD 92 to 7,594.9 U/mL on POD 217. Notably, surveillance computed tomography (CT) scans showed no evidence of disease (NED) on POD 126, 186, and 211. Molecular profiling and next-generation sequencing (NGS) panels from CCA tissue revealed microsatellite instability-high (MSI-H). After extensive discussions with the patient regarding the rising ctDNA titer despite being on capecitabine for nearly 6 months, we initiated pembrolizumab on POD 224 prior to radiographic recurrence. Given the tumor is MSI-H, and the preferred toxicity profile compared to the front-line chemotherapy option for CCA, we started pembrolizumab. ctDNA became undetectable, and CA19-9 returned to the reference range with pembrolizumab. As of the last follow-up on POD 876, the patient has continued pembrolizumab without noticeable side effects, and imaging continues to show NED, with persistent negative ctDNA and normal CA19-9 levels. Conclusions: This case demonstrates the potential utility of tumor-informed ctDNA in CCA as (I) an early detection tool before radiographic recurrence; (II) a response monitoring tool as a surrogate biomarker that can guide therapy optimization; and (III) shows that early intervention with immunotherapy or potentially targeted agents based on ctDNA may lead to improved survival outcomes.

The Association of the Lactate-Albumin Ratio With Mortality and Multiple Organ Dysfunction in PICU Patients.

OBJECTIVES: To compare the relative associations of lactate, albumin, and the lactate-albumin ratio (LAR) measured early in disease course against mortality and prevalence of multiple organ dysfunction syndrome (MODS) in a general sample of critically ill pediatric patients. DESIGN: Retrospective analysis of the Health Facts (Cerner Corporation, Kansas City, MO) national database. SETTING: U.S. hospitals with PICUs. PATIENTS: Children admitted to the ICU ( n = 648) from 2009 to 2018 who had lactate and albumin measured within 6 hours of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 648 admissions were included, with an overall mortality rate of 10.8% ( n = 70) and a MODS prevalence of 29.3% ( n = 190). Compared with survivors, deaths had higher initial lactates (7.3 mmol/L [2.6-11.7 mmol/L] vs 1.9 mmol/L [1.2-3.1 mmol/L]; p < 0.01), lower initial albumins (3.3 g/dL [2.7-3.8 g/dL] vs 4.2 g/dL [3.7-4.7 g/dL]; p < 0.01), and higher LARs (2.2 [1.0-4.2] vs 0.5 [0.3-0.8]; p < 0.01), with similar trends in patients with MODS versus those without MODS. LAR demonstrated a higher odds ratio (OR) for death than initial lactate alone (2.34 [1.93-2.85] vs 1.29 [1.22-1.38]) and a higher OR for MODS than initial lactate alone (2.10 [1.73-2.56] vs 1.22 [1.16-1.29]). Area under the receiver operating characteristic (AUROC) curve of LAR for mortality was greater than initial lactate (0.86 vs 0.82; p < 0.01). The LAR AUROC for MODS was greater than the lactate AUROC (0.71 vs 0.66; p < 0.01). Trends of lactate, albumin, and LAR for mortality were consistent across several diagnostic subgroups (trauma, primary respiratory failure, toxicology), but not all. CONCLUSIONS: LAR measured early in the course of critical illness is significantly associated with mortality and development of MODS when compared with initial lactate or initial albumin alone in critically ill pediatric patients.

Probable Cerebral Amyloid Angiopathy-Related Inflammation Associated With Sitravatinib: A Case Report.

Background and Objectives: We present the case of a 67-year-old man who developed encephalopathy, headaches, and seizure activity after initiating treatment with the novel tyrosine kinase inhibitor, sitravatinib. Methods: The patient was identified in routine clinical practice. Results: Brain MRI revealed lobar microhemorrhages and bihemispheric vasogenic edema. The patient met the criteria for probable cerebral amyloid angiopathy-related inflammation (CAA-ri) and responded favorably to high-dose methylprednisolone. Discussion: This report of neurologic autoimmunity in a patient receiving sitravatinib opens new lines of inquiry into the pathophysiology of CAA-ri. We emphasize the importance of early recognition and treatment of CAA-ri among patients receiving immunomodulatory chemotherapy.

Is Dose Volume a Better Predictor of Osteoradionecrosis Risk Than Total Dose for Patients Who Have Received Head and Neck Radiation?

PURPOSE: Oral and maxillofacial surgeons frequently encounter patients who require extractions following exposure to head and neck radiation, and they must assess the risk of extraction and consider alternatives such as deliberate root retention. The purpose of this study was to determine whether dose volume would be a better predictor for osteoradionecrosis (ORN) than total dose. METHODS: This is a retrospective cohort study of patients diagnosed with ORN following head and neck radiation (administered between January 2006 and December 2018) and a comparison group selected based on site and dosage who did not develop ORN. The predictor variables were total radiation dose and mandibular dose volume, and the outcome variable was ORN occurrence. Covariates included age, sex, cancer stage and site, radiation therapy type, smoking status, alcohol use, adjuvant chemotherapy use, medical comorbidities, and concomitant tumor surgery. Logistic regression models were employed and area under receiver operating characteristic curve (AUROC) and model accuracy (Acc) were used to determine the better predictor. RESULTS: A total of 56 patients were included in the study: 27 ORN positive (ORN+) and 29 matched controls who did not develop ORN (ORN-). Most patients were male (76.8%), considered smokers (78.6%), used alcohol (80.4%), were in stage IV (66.1%), received chemotherapy (75.0%), and received intensity modulated radiation therapy radiation (55.4%). The statistical models with V50 Gy (cc) and V65 Gy (cc) dosage variables exhibited greater predictability of ORN occurrence than total dose (AUROC: 0.90 vs 0.76 and model accuracy: 0.82 vs 0.75, respectively). CONCLUSIONS: The results suggest that following head and neck radiation, dose volume may be a better predictor of ORN risk than total dose. This finding is significant, both for the oral and maxillofacial surgeon who is preoperatively assessing ORN risk following radiation exposure, and for the radiation oncologist striving to minimize the risk associated with their treatment.

The evolution of hydrochemical and isotopic signatures from precipitation, surface water to groundwater in a typical karst watershed, Central Texas, USA.

The Upper Cibolo Creek (UCC) karst watershed in Central Texas, USA, represents a portion of the drainage area that supplies water to the recharge zone for the Edwards Aquifer. However, the surface water-groundwater interactions along the UCC are not well quantified, and the hydraulic interactions are important for water budget and water quality of the aquifer. In this study, we investigated the evolution of hydrochemical and isotopic signatures (δ18O, δ2H and d-excess) from precipitation, surface water to groundwater in the UCC watershed from 2017 to 2019, and investigated surface water-groundwater interactions using samples from 14 creeks/spring sites. Factor analysis for the observed parameters demonstrates that changes in water hydrochemistry are primarily controlled by human activity, precipitation input, and water-rock interaction. Hierarchical clustering analysis of temporal isotope variations confirms that significant surface water-groundwater interactions occur in the UCC watershed. We identified relationships between nitrate concentrations at creek/spring sites and land-use conditions, and nitrate input sources were determined utilizing the dual-isotope analyses (δ15N and δ18O) of nitrate. This study provides capacity for a more precise assessment of water resources and water quality in Central Texas.

Appendiceal adenocarcinoma with breast metastases.

Malignant lesions of the vermiform appendix make up a rare subset of colorectal cancer. While colorectal cancer frequently metastasises to the liver, lung, regional lymph nodes and peritoneum, metastasis to the breast is extremely rare. Here, we describe the case of an 84-year-old woman who had the incidental finding of appendiceal adenocarcinoma following emergency laparoscopic appendectomy. She declined further operative or adjuvant treatment for her disease. She represented 1 year later with metastatic appendiceal adenocarcinoma disease to her left breast. A simple mastectomy for symptomatic treatment was performed. In this report, we describe the first case of appendiceal adenocarcinoma metastases to the breast. Due to its rarity, there is a paucity of evidence related to the management of this condition. The limited evidence is reviewed and discussed.

Effects of Procedural Discomfort and Expectation of Benefit on Therapy Continuation in Chronic Migraine Patients Treated With OnabotulinumtoxinA.

BACKGROUND: OnabotulinumtoxinA (BTX) has become a mainstream treatment for chronic migraine (CM). Patients often have varied expectations for treatment success but little is known about how these initial impressions influence continuation of therapy. OBJECTIVE: To record expectations of benefit and procedural discomfort (PD) from initial BTX treatment and to investigate their association with treatment success, defined as continuation of treatment for >3 sessions within a 2-year period. METHODS: A retrospective chart review of CM patients receiving initial treatment with BTX was performed. Patients were questioned about their expectations of benefit and PD as rated on a 0-10 scale. Responses were then compared with continuation of therapy beyond 3 sessions to identify the presence of significant association. RESULTS: Responses from patients (N = 297) were analyzed. About 173 subjects continued with BTX therapy for more than 3 sessions (173/297, 58.3%). Unadjusted odds ratios (OR) for expectation of benefit (EOB) (OR 1.11, 95% CI 0.99-1.24, P = .087) and PD (OR 1.02, 95% CI 0.90-1.16, P = .780) were not significantly predictive of continuing treatment. After considering sex, age, year of treatment, and previous headache preventative trials, only female sex (OR 2.02, 95% CI 1.09-3.74, P = .025) was found to be significantly associated with treatment continuation. CONCLUSIONS: In the usual care setting, PD and EOB are not significantly associated with therapy continuation in patients receiving initial treatment with BTX for the prevention of CM. However, after considering sex, age, year of treatment, and number of previous headache preventives attempted, we found that female patients had twice the likelihood of continuing with BTX therapy compared to male patients with CM.

Implications of Temperature Abuse on Unpasteurized Beer Quality Using Organoleptic and Chemical Analyses.

Beer flavor and sensory quality are affected by storage time and temperature due to chemical breakdown and aging. This study aimed to investigate the organoleptic properties of temperature-abused, unpasteurized craft beer and analyze the chemical breakdown associated with the process. Sensory tests were performed using a triangle test to determine consumer identification of temperature-abused beer. The chemical tests were conducted to determine the chemical breakdown of the two beer groups: control beer (COB) and temperature-abused beer (TAB). The chemical analysis of the two beer groups showed significant changes in multiple chemical compounds such as ethyl esters, linear aldehydes, and sulphur-compounds; however, the sensory analysis results were not significant even though 39% of participants were able to detect differences. in this study, two factors identified that caused chemical reactions in the TABs were oxidation and live yeast cells. In conclusion, these results can be used by beer producers to ensure a quality product throughout the distribution chain by controlling time and temperature.

Aspergillus niger production of pectinase and α-galactosidase for enzymatic soy processing.

Soybean is a most promising sustainable protein source for feed and food to help meet the protein demand of the rapidly rising global population. To enrich soy protein, the environment-friendly enzymatic processing requires multiple carbohydrases including cellulase, xylanase, pectinase, α-galactosidase and sucrase. Besides enriched protein, the processing adds value by generating monosaccharides that are ready feedstock for biofuel/bioproducts. Aspergillus could produce the required carbohydrases, but with deficient pectinase and α-galactosidase. Here we address this critical technological gap by focused evaluation of the suboptimal productivity of pectinase and α-galactosidase. A carbohydrases-productive strain A. niger (NRRL 322) was used with soybean hull as inducing substrate. Temperatures at 20 °C, 25 °C and 30 °C were found to affect cell growth on sucrose with an Arrhenius-law activation energy of 28.7 kcal/mol. The 30 °C promoted the fastest cell growth (doubling time = 2.1 h) and earliest enzyme production, but it gave lower final enzyme yield due to earlier carbon-source exhaustion. The 25 °C gave the highest enzyme yield. pH conditions also strongly affected enzyme production. Fermentations made with initial pH of 6 or 7 were most productive, e.g., giving 1.9- to 2.3-fold higher pectinase and 2.2- to 2.3-fold higher α-galactosidase after 72 h, compared to the fermentation with a constant pH 4. Further, pH must be kept above 2.6 to avoid limitation in pectinase production and, in the later substrate-limiting stage, kept below 5.5 to avoid pectinase degradation. α-Galactosidase production always followed the pectinase production with a 16-24 h lag; presumably, the former relied on pectin hydrolysis for inducers generation. Optimal enzyme production requires controlling the transient availability of inducers.

Decreasing deceased donor transplant rates among children (≤6 years) under the new kidney allocation system.

The Kidney Allocation System (KAS) was implemented in December 2014 with unknown impact on the pediatric waitlist. To understand the effect of KAS on pediatric registrants, deceased donor kidney transplant (DDKT) rate was assessed using interrupted time series analysis and time-to-event analysis. Two allocation eras were defined with an intermediary washout period: Era 1 (01/01/2013-09/01/2014), Era 2 (09/01/2014-03/01/2015), and Era 3(03/01/2015-03/01/2017). When using Cox proportional hazards, there was no significant association between allocation era and DDKT likelihood as compared to Era 1 (Era 3: aHR: 1.07, 95% CI: 0.97-1.18, P = .17). However, this was not consistent across all subgroups. Specifically, while highly sensitized pediatric registrants were consistently less likely to be transplanted than their less sensitized counterparts, this disparity was attenuated in Era 3 (Era 1 aHR: 0.04, 95%CI: 0.01-0.14, P < .001; Era 3 aHR: 0.33, 95% CI: 0.21-0.53, P < .001) whereas the youngest registrants aged 0-6 experienced a 21% decrease in DDKT likelihood in Era 3 as compared to Era 1 (aHR: 0.79, 95% CI: 0.64-0.98, P = .03). Thus, while overall DDKT likelihood remained stable with the introduction of KAS, registrants ≤ 6 years of age were disadvantaged, warranting further study to ensure equitable access to transplantation.

Killing of Serratia marcescens biofilms with chloramphenicol.

Serratia marcescens is a Gram-negative bacterium with proven resistance to multiple antibiotics and causative of catheter-associated infections. Bacterial colonization of catheters mainly involves the formation of biofilm. The objectives of this study were to explore the susceptibility of S. marcescens biofilms to high doses of common antibiotics and non-antimicrobial agents. Biofilms formed by a clinical isolate of S. marcescens were treated with ceftriaxone, kanamycin, gentamicin, and chloramphenicol at doses corresponding to 10, 100 and 1000 times their planktonic minimum inhibitory concentration. In addition, biofilms were also treated with chemical compounds such as polysorbate-80 and ursolic acid. S. marcescens demonstrated susceptibility to ceftriaxone, kanamycin, gentamicin, and chloramphenicol in its planktonic form, however, only chloramphenicol reduced both biofilm biomass and biofilm viability. Polysorbate-80 and ursolic acid had minimal to no effect on either planktonic and biofilm grown S. marcescens. Our results suggest that supratherapeutic doses of chloramphenicol can be used effectively against established S. marcescens biofilms.

Biopsychosocial Characteristics, Using a New Functional Measure of Balance, of an Elderly Population with CLBP.

This study examined the biopsychosocial characteristics of chronic low back pain (CLBP) in an understudied but increasingly larger part of the population: the elderly (i.e., 65 years and older). A new innovative physical functioning measure (postural control, which is a proxy for the common problem of slips and falls in the elderly) was part of this biopsychosocial evaluation. Also, the National Institutes of Health (NIH)-developed Patient-Reported Outcome Measurement Information System (PROMIS) was also part of this comprehensive evaluation. Two demographically-matched groups of elderly participants were evaluated: one with CLBP (n = 24); and the other without (NCLBP, n = 24). Results revealed significant differences in most of these measures between the two groups, further confirming the importance of using a biopsychosocial approach for future studies of pain and postural control in the elderly.

Fear-Avoidance Beliefs and Chronic Pain.

Fear-avoidance (FA) beliefs are significantly associated with the experience of pain, especially when the pain becomes chronic in nature. The anticipated threat of intense pain will often result in the constant vigilance and monitoring of pain sensations, which, in turn, can cause even low-intensity sensations of pain to become unbearable for the person. Just the anticipation of increased pain or reinjury can further stimulate avoidance behaviors. A vicious cycle may develop, in which fears of increased pain or reinjury contribute to the avoidance of many activities, leading to inactivity and, ultimately, to greater disability. Anyone who assesses and treats pain-related disability should also be prepared to assess and treat pain-related FA.

Nutrient control for stationary phase cellulase production in Trichoderma reesei Rut C-30.

This work describes the use of nutrient limitations with Trichoderma reesei Rut C-30 to obtain a prolonged stationary phase cellulase production. This period of non-growth may allow for dependable cellulase production, extended fermentation periods, and the possibility to use pellet morphology for easy product separation. Phosphorus limitation was successful in halting growth and had a corresponding specific cellulase production of 5±2 FPU/g-h. Combined with the addition of Triton X-100 for fungal pellet formation and low shear conditions, a stationary phase cellulase production period in excess of 300 h was achieved, with a constant enzyme production rate of 7±1 FPU/g-h. While nitrogen limitation was also effective as a growth limiter, it, however, also prevented cellulase production.

The Nanolithography Toolbox.

This article introduces in archival form the Nanolithography Toolbox, a platform-independent software package for scripted lithography pattern layout generation. The Center for Nanoscale Science and Technology (CNST) at the National Institute of Standards and Technology (NIST) developed the Nanolithography Toolbox to help users of the CNST NanoFab design devices with complex curves and aggressive critical dimensions. Using parameterized shapes as building blocks, the Nanolithography Toolbox allows users to rapidly design and layout nanoscale devices of arbitrary complexity through scripting and programming. The Toolbox offers many parameterized shapes, including structure libraries for micro- and nanoelectromechanical systems (MEMS and NEMS) and nanophotonic devices. Furthermore, the Toolbox allows users to precisely define the number of vertices for each shape or create vectorized shapes using Bezier curves. Parameterized control allows users to design smooth curves with complex shapes. The Toolbox is applicable to a broad range of design tasks in the fabrication of microscale and nanoscale devices.

Easy-to-use, general, and accurate multi-Kinect calibration and its application to gait monitoring for fall prediction.

Falls are the most-common causes of unintentional injury and death in older adults. Many clinics, hospitals, and health-care providers are urgently seeking accurate, low-cost, and easy-to-use technology to predict falls before they happen, e.g., by monitoring the human walking pattern (or "gait"). Despite the wide popularity of Microsoft's Kinect and the plethora of solutions for gait monitoring, no strategy has been proposed to date to allow non-expert users to calibrate the cameras, which is essential to accurately fuse the body motion observed by each camera in a single frame of reference. In this paper, we present a novel multi-Kinect calibration algorithm that has advanced features when compared to existing methods: 1) is easy to use, 2) it can be used in any generic Kinect arrangement, and 3) it provides accurate calibration. Extensive real-world experiments have been conducted to validate our algorithm and to compare its performance against other multi-Kinect calibration approaches, especially to show the improved estimate of gait parameters. Finally, a MATLAB Toolbox has been made publicly available for the entire research community.