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Abstract Background The legality and use of marijuana is a controversial topic. With increased prevalence of usage, cannabis detection for legal, medical, and workforce drug testing is on the rise. LC-MS/MS quantification of delta 9-carboxy tetrahydrocannabinol (delta 9-THC-COOH) in urine is accepted as the standard to detect marijuana use. One challenge faced by testing laboratories has been identifying adulterated samples. Many products/reagents can be used to manipulate the urine to avoid positive drug testing results. In this study, we developed a dilute-and-shoot strategy to separate and quantify both the delta 8- and 9-THC-COOH in urine samples and tested the effects of adulteration using a combination of nitrite and/or acids which can be used to mask cannabinoid use. Methods Five authentic delta 8- and 9-THC-COOH positive specimens, and one spiked sample were treated with strong acids (1N HCL or 10% TCA), 500 µg/mL nitrite, or a combination. After hydrolysis with sodium hydroxide, the analytes were quantified using a 6495 Mass Spectrometer coupled to a StreamSelect LC system (Agilent). LC separation was performed with a CORTECS T3 column utilizing a shallow gradient. In addition, twelve urine specimens with varying concentrations of delta 8- and 9-THC-COOH were treated with nitrite and screened using a delta 9-THC-COOH immunoassay on the Roche Cobas C501 and analyzed by LC-MS/MS. Results Nitrite did not change the physical appearance or the pH of the urine samples. Strong acid treatment also did not alter the appearance but did drop the urine pH ≤2. Pre-treated specimens with 1N HCL, 10% TCA, or 500 µg/mL of nitrite did not affect the delta 8- and 9-THC-COOH concentrations up to 6 days (refrigerated); however, specimens treated with strong acid combined with 500 µg/mL of nitrite for 30 min made both analytes undetectable. Additional experiments confirmed that 0.5 and 1 mol/L of nitrite lowered the concentration of all analytes, including internal standard, to undetectable levels in 48 h. Twelve additional specimens were collected, 3 with delta 8-THC-COOH, 3 with delta 9-THC-COOH, and 6 with both. All 12 samples screened positive using the Roche immunoassay and were quantified using the LC-MS/MS method. After treatment with 0.5 mol/L of nitrite, 10 of the 12 samples were negative using the immunoassay, but 2 samples remained positive. However, all nitrite treated specimens were negative (<LLOQ) using the LC-MS/MS method and the internal standard was eliminated. Later experiments confirmed that the delta 8- and 9-THC-COOH could be eliminated with as little as 0.1 mol/L nitrite for 30 min. Conclusion The unique dilute-and-shoot method can separate and quantify delta 8- and 9-THC-COOH. In addition, high concentrations of nitrite were shown to degrade both analytes along with the isotopically labeled internal standard. As a result, labs can distinguish true negative delta 8- and 9-THC-COOH (no analyte peaks) from nitrite adulterated specimens since the adulterated samples have no peaks for both the analytes and internal standard. A limitation of the study is that only sodium nitrite was tested. Other adulterants, such as potassium nitrite, pyridinium chlorochromate, peroxide etc. require further investigation.

Abstract Background Warfarin monitoring may be done at the point-of-care (POC) at home, in a clinic environment, or be performed using plasma specimens in a central laboratory. With a goal of standardizing International Normalization Ratio (INR) measurements and improving data integrity by enabling electronic transmission of results from any location, we evaluated two POC INR devices against an internal plasma INR reference method. Methods We conducted a multicenter study to test the accuracy of two commercially available point of care devices: Coag-Sense PT2 Meter (Coagusense, Inc., Fremont, CA) and CoaguChek XS Pro or XS Plus (Roche Diagnostics, Indianapolis, IN) compared with plasma INR values among warfarin treated patients. Bias and linear regression analysis were assessed for device-plasma INR comparisons. Warfarin dosing decisions were assessed for each device compared to an internal plasma INR reference method (Instrumentation Laboratories ACLTOP 500, 550, 750 analyzers (Werfen Diagnostics, Bedford MA) in one of three CLIA-certified laboratories. The thromboplastin used at our institution for INR measures is HemosIL RecombiPlasTin 2G (R2G) reagent (Werfen Diagnostics, Bedford MA) which has an International Sensitivity Index (ISI) of 1.0. Results Two hundred ninety-nine warfarin patients treated across three Mayo Clinic sites agreed to participate in the study. Common anticoagulant indications were atrial fibrillation (63.9%), venous thromboembolism (21.7%) and heart valve prosthesis (15.4%) with a 2.0–3.0 INR target range for 93.6% of patients. For the CoaguChek devices, 81.3% of values fell within 0.2 INR units of plasma INR referent and 95.3% within 0.4 units. The correlation between CoaguChek whole blood and plasma INR was excellent (R2 = 0.93). For the Coag-Sense device, 34.1% of values fell within 0.2 INR units and 60.2% within 0.4 INR units of plasma INR values, with a slightly weaker correlation between Coag-Sense whole blood and plasma INR (R2 = 0.83; P < 0.0001). Mean (± standard deviation) deviation from plasma INR was 0.04 ± 0.2 for CoaguChek compared to 0.4 ± 0.3 for Coag-Sense (P < 0.0001). The difference between POC devices was largely attributed to systematic negative bias between Coag-Sense and ACL TOP plasma INR values. Using the plasma INR as the reference method for dosing decision making, appropriate dosing recommendations would have occurred for 97.7% of CoaguChek and 81.6% of Coag-Sense results. Conclusion Compared to our institution's plasma reference method, INR values obtained from the CoaguChek devices (XS Pro and XS Plus) exhibited less systematic bias compared to the Coag-Sense values. This translates to greater percentage of concordant management decisions between POC and laboratory plasma INR methods when the CoaguChek device is used.

PURPOSE To evaluate the efficacy and safety of tucatinib and trastuzumab in patients with previously treated human epidermal growth factor receptor 2–positive (HER2+) metastatic biliary tract cancer (mBTC). METHODS SGNTUC-019 (ClinicalTrials.gov identifier: NCT04579380 ) is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors. In the biliary tract cancer cohort, patients had previously treated HER2 overexpressing or amplified (HER2+) tumors (identified with local testing) with no prior HER2-directed therapy. The primary end point was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks). RESULTS Thirty patients were enrolled. As of data cutoff (January 30, 2023), the median duration of follow-up was 10.8 months. The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively. At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8). The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs. CONCLUSION Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC.

Triceps spasticity can occur in patients with upper motor neuron syndrome. It is often undetected when there is predominant elbow flexion spasticity and/or contracture. This condition can become apparent after surgery for elbow flexor spasticity, leading to impaired active elbow. Although triceps muscle-tendon lengthening procedures can be performed, these techniques do not directly address the issue of spasticity which is neurally mediated. This article presents a surgical technique for addressing triceps spasticity with a combined approach of hyperselective neurectomy of the medial head of the triceps and muscle-tendon lengthening of the long and lateral heads.

In the last decade there has been incredible interest and advancement in the surgical care of adult patients with upper motor neuron (UMN) injuries. Spasticity represents a prevalent and debilitating feature of UMN syndrome, which can result from cerebral palsy, spinal cord injury, cerebrovascular accident and traumatic or anoxic brain injury. While several diagnostic tools and management strategies have been described for upper limb spasticity, evidence-based practice guidelines do not currently exist due to low patient volume and a paucity of surgeons routinely performing surgeries in UMN syndrome patients. As such, expert consensus may help provide guidance for patients, therapists and clinicians alike. In this article an expert panel was assembled, and the Delphi method was utilized to present diagnostic considerations, define operative indications, discuss surgical treatment modalities and encourage a standard set of outcome measures for patients with upper extremity spasticity.

Abstract Objectives To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. Methods Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron’s papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). Results In total 1054 patients were included (DM, n = 405; ASyS, n = 649). In the ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic’s hands, Raynaud’s phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P < 0.001), whereas higher frequency of any of four DM-type rashes—heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V-sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%)—differentiated DM from ASyS-DMskin (all P < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both P < 0.001). Conclusion DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Traumatic brain injury (TBI) remains a major cause of morbidity and death among the pediatric population. Timely diagnosis, however, remains a complex task because of the lack of standardized methods that permit its accurate identification. The aim of this study was to determine whether serum levels of brain injury biomarkers can be used as a diagnostic and prognostic tool in this pathology. This prospective, observational study collected and analyzed the serum concentration of neuronal injury biomarkers at enrollment, 24h and 48h post-injury, in 34 children ages 0–18 with pTBI and 19 healthy controls (HC). Biomarkers included glial fibrillary acidic protein (GFAP), neurofilament protein L (NfL), ubiquitin-C-terminal hydrolase (UCH-L1), S-100B, tau and tau phosphorylated at threonine 181 (p-tau181). Subjects were stratified by admission Glasgow Coma Scale score into two categories: a combined mild/moderate (GCS 9–15) and severe (GCS 3–8). Glasgow Outcome Scale-Extended (GOS-E) Peds was dichotomized into favorable (≤4) and unfavorable (≥5) and outcomes. Data were analyzed utilizing Prism 9 and R statistical software. The findings were as follows: 15 patients were stratified as severe TBI and 19 as mild/moderate per GCS. All biomarkers measured at enrollment were elevated compared with HC. Serum levels for all biomarkers were significantly higher in the severe TBI group compared with HC at 0, 24, and 48h. The GFAP, tau S100B, and p-tau181 had the ability to differentiate TBI severity in the mild/moderate group when measured at 0h post-injury. Tau serum levels were increased in the mild/moderate group at 24h. In addition, NfL and p-tau181 showed increased serum levels at 48h in the aforementioned GCS category. Individual biomarker performance on predicting unfavorable outcomes was measured at 0, 24, and 48h across different GOS-E Peds time points, which was significant for p-tau181 at 0h at all time points, UCH-L1 at 0h at 6–9 months and 12 months, GFAP at 48h at 12 months, NfL at 0h at 12 months, tau at 0h at 12 months and S100B at 0h at 12 months. We concluded that TBI leads to increased serum neuronal injury biomarkers during the first 0–48h post-injury. A biomarker panel measuring these proteins could aid in the early diagnosis of mild to moderate pTBI and may predict neurological outcomes across the injury spectrum.

Abstract Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector‐based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well‐described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.