Citations

Abstract Objectives Urine drug testing (UDT) is a critical tool used in medical, forensic, and occupational settings, but interpreting results can be challenging. We performed a study to assess the ability of health care professionals to interpret UDT results accurately. Methods In total, 911 clinical and laboratory professionals in the United States and Canada responded to a survey with questions gauging expertise in UDT interpretation. Responses were analyzed to identify knowledge gaps. Results Toxicologists and laboratory PhD scientists performed well, with means of 4.82 and 4.63 questions answered correctly (out of 6 possible), respectively. Physicians specializing in pathology, emergency medicine, primary care, and internal medicine, however, displayed concerning knowledge gaps, as did laboratorians with nondoctoral degrees. Experience and training correlated with interpretation accuracy. Identification of simulated compliance as well as understanding opioid exposure, metabolism, and immunoassay cross-reactivity were among the most clinically significant knowledge gaps. More than 30% of survey respondents indicated that they would seek UDT information from the internet or peers rather than clinical or laboratory experts. Conclusions The study highlighted the need for targeted education and better collaboration between clinical and laboratory experts and other health care professionals to ensure that when physicians order UDT, they can accurately interpret results and reduce harm.

AbstractThe present study investigated the impact of central α2‐adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2‐adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg−1; maintenance infusion of 0.1–0.5 µg kg h−1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats−1, P = 0.003) most strongly for medium‐sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats−1; P < 0.001). Dexmedetomidine progressively de‐recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de‐recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats−1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ –0.09 ± 0.07 to Δ –0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium‐sized APs (normalized cluster 2: –6.0 ± 5 to –1.6 ± 2 % mmHg−1; P = 0.008). These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. imageKey points Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2‐adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

Abstract Aims The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. Methods and results We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular–pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660–0.737, p &lt; 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656–0.734, p &lt; 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference −0.072, 95% CI −0.123 to −0.020, p = 0.006, and −0.043, 95% CI −0.067 to −0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p &gt; 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p &lt; 0.05 for all). Conclusions Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

[ 18 F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer’s disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-β. It is also unclear whether flortaucipir can detect tau in definite primary age–related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [ 18 F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-β PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-β phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-β phase. Flortaucipir uptake linearly increased with the amyloid-β phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer’s disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-β phase, and were useful for distinguishing different ADNC scores and PART.

The CD40-CD40L co-stimulatory dyad has been identified as critical player in atherosclerosis. Our previous work has shown that CD40 and CD40L have cell divergent effects on atherosclerosis. Deficiency of the CD40-CD40L dendritic cell-T cell axis decreased atherosclerosis via reducing T helper 1 responses, whereas deficiency of macrophages CD40 reduced atherosclerosis by enhancing efferocytosis and reducing necrotic core content. CD40 is highly expressed on B cells and interacts with CD40L on T cells to induce antibody production and T follicular helper cell responses. We therefore hypothesize that deletion of CD40 will reduce atherosclerosis. We aim to unravel the role of B cell CD40 in atherosclerosis. CD40 expression on B cell subsets was determined on peripheral blood mononuclear cells of patients and correlated with severity of coronary artery disease (CAD). Atherosclerosis was analyzed in CD19 Cre CD40 flfl ApoE -/- mice that were fed an atherogenic diet for 14 weeks. Patients with CAD showed a decrease in CD40 on their putative B1 cells, which was associated with increased plaque burden and decreased plaque fibrosis as detected by coronary intravascular ultrasound. Depletion of CD40 on B cells in ApoE -/- mice resulted in a decreased germinal center formation and inadequate IgM production as expected. However, in line with our patient data, absence of B cell-CD40 increased atherosclerosis. This was caused by a reduction in B1 cells and consequently a reduction in atheroprotective anti-oxidation specific epitope (OSE) IgMs. Transfer of CD40-competent B1b cells in B cell-CD40-deficient mice restored anti-OSE IgM levels and prevented the increase in atherosclerosis. CD40-deficient B1b cells have an altered mTOR signaling pathway, impaired mitochondrial function, excessive uptake of lipids, increased cellular stress and accelerated cell death. Data indicate that CD40-deficiency promotes phosphorylation of RAPTOR and protein kinase B (AKT). We have identified a novel function of CD40 on B1b cells. B1b cell-CD40 exerts an anti-atherogenic role by regulating B1b cell metabolic homeostasis via mTOR pathway. Further mechanistic insights into how CD40 mounts adequate atheroprotective anti-OSE IgM production are currently being investigated.

Abstract Objective To describe and illustrate septal perforation shape through the documentation and analysis of length and height measurements. A secondary objective is to correlate perforation size to surgical and nonsurgical etiologies. Stuy Design Retrospective case series. Setting Tertiary academic medical center. Methods Length and height of consecutively treated perforations over a 3‐year period were measured directly or through computed tomography. Mean differences in length and height measurements were compared and regression analysis used to determine perforation shape and the effect of etiology on perforation size. Perforations were classified by length into small (1‐5 mm), medium (6‐15 mm), and large (>15 mm) and correlated to shape and etiology. Results One hundred twenty‐four patients (mean age 50.4 years, 60.5% female) met study inclusion criteria. Height was less than length in 93% of perforations 5 mm or greater in length. Mean perforation height was significantly less than length for medium and large perforations ( P < .001). Mean length and height measurements of nonsurgical perforations were greater than those for surgical perforations ( P < .001). Conclusion Height is less than length in over 90% of septal perforations. Most perforations assume an elliptical shape as they enlarge. Accurate measurement and presentation of length and height is relevant information to perforation management decisions and for the evaluation of treatment outcomes.

Breast cancer imposes a significant burden globally. While the survival rate is steadily improving, much remains to be elucidated. This observational, single time point, multiomic study utilizing genomics, proteomics, targeted and untargeted metabolomics, and metagenomics in a breast cancer survivor (BCS) and age-matched healthy control cohort (N = 100) provides deep molecular phenotyping of breast cancer survivors. In this study, the BCS cohort had significantly higher polygenic risk scores for breast cancer than the control group. Carnitine and hexanoyl carnitine were significantly different. Several bile acid and fatty acid metabolites were significantly dissimilar, most notably the Omega-3 Index (O3I) (significantly lower in BCS). Proteomic and metagenomic analyses identified group and pathway differences, which warrant further investigation. The database built from this study contributes a wealth of data on breast cancer survivorship where there has been a paucity, affording the ability to identify patterns and novel insights that can drive new hypotheses and inform future research. Expansion of this database in the treatment-naïve, newly diagnosed, controlling for treatment confounders, and through the disease progression, can be leveraged to profile and contextualize breast cancer and breast cancer survivorship, potentially leading to the development of new strategies to combat this disease and improve the quality of life for its victims.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P &amp;lt; .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P &amp;lt; .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

Abstract Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (&lt;5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with &lt;5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (&lt;5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.