Health Care Resource Utilization and Total Costs of Care for Adult Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia in the United States: A Retrospective Claims Analysis.

PURPOSE: Although immunotherapies such as blinatumomab and inotuzumab have led to improved outcomes, financial burden and health resource utilization (HRU) have increased for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). This study assessed real-world HRU and costs of care among adult patients with R/R B-ALL by line of therapy (LoT) in the United States. METHODS: We selected patients from the MarketScanⓇ Database (January 1, 2016 through December 31, 2020) as follows: ≥1 claims of ALL-indicated first-line (1L) therapies, ≥1 diagnosis of ALL before the index date (1L initiation date), 6-month continuous enrollment before the index date, second-line (2L) therapy initiation, ≥18 years old at 2L, no clinical trial enrollment, no diagnosis of other forms of non-Hodgkin's lymphoma, and no claim for daratumumab or nelarabine during the study period. Outcome measures included claim-based time to next treatment (TTNT), all-cause and adverse event (AE)-related HRU, and all-cause and AE-related costs. FINDINGS: The R/R B-ALL cohort (N = 203) was 60% male, median age of 41 years, and median Charlson Comorbidity Index score of 3.0. Mean (SD) follow-up was 17.8 (11.8) months. Of those who received 2L, 55.7% (113/203) required 3L, and 15% (30/203) initiated 4L+. Patients relapsed quickly, with a median TTNT of 170 days, 169 days, and 205 days for 2L, 3L, and 4L+, respectively. Hospitalization rates were high across each LoT (2L, 88%; 3L, 73%; 4L+, 73%), and the mean (SD) inpatient length of stay increased by LoT as follows: 8.6 (6.8) days for 2L, 10.6 (13.3) for 3L, and 11.6 (13.6) for 4L+. Mean (SD) overall costs were substantial within each LoT at $513,279 ($599,209), $340,419 ($333,555), and $390,327 ($332,068) for 2L, 3L, and 4L+, respectively. The mean (SD) overall/per-patient-per-month AE-related costs were $358,676 ($497,998) for 2L, $202,621 ($272,788) for 3L, and $210,539 ($267,814) for 4L+. Among those receiving blinatumomab or inotuzumab within each LoT, the mean (SD) total costs were $566,373 ($621,179), $498,070 ($376,260), and $512,908 ($159,525) for 2L, 3L, and 4L+, respectively. IMPLICATIONS: These findings suggest that adult patients with R/R B-ALL relapse frequently with standard of care and incur a substantial HRU and cost burden with each LoT. Those treated with blinatumomab or inotuzumab incurred higher total costs within each LoT compared with the overall R/R B-ALL cohort. Alternative therapies with longer duration of remission are urgently needed, and HRU should be considered for future studies examining the optimal sequencing of therapy.

Towards the definition of progressive disease in brain metastasis treated with laser ablation: an evidence-based study.

PURPOSE: The postoperative period after laser interstitial thermal therapy (LITT) is marked by a temporary increase in volume, which can impact the accuracy of radiographic assessment. The current criteria for progressive disease (PD) suggest that a 20% increase in size of brain metastasis (BM) assessed in 6-12 weeks intervals should be considered as local progression (LP). However, there is no agreement on how LP should be defined in this context. In this study, we aimed to statistically analyze which tumor volume variations were associated with LP. METHODS: We analyzed 40 BM that underwent LITT between 2013 and 2022. For this study, LP was defined following radiographic features. A ROC curve was generated to evaluate volume change as a predictor of LP and find the optimal cutoff point. A logistic regression analysis and Kaplan Meier curves were performed to assess the impact of various clinical variables on LP. RESULTS: Out of 40 lesions, 12 (30%) had LP. An increase in volume of 25.6% from baseline within 120-180 days after LITT presented a 70% sensitivity and 88.9% specificity for predicting LP (AUC: 0.78, p = 0.041). The multivariate analysis showed a 25% increase in volume between 120 and 180 days as a negative predictive factor (p = 0.02). Volumetric changes within 60-90 days after LITT did not predict LP (AUC: 0.57; p = 0.61). CONCLUSION: Volume changes within the first 120 days after the procedure are not independent indicators of LP of metastatic brain lesions treated with LITT.

Thalamic responsive neurostimulation for the treatment of refractory epilepsy: an individual patient data meta-analysis.

OBJECTIVE: In recent years, the treatment of drug-resistant epilepsy (DRE) has made greater use of surgery and expanded options for neurostimulation or neuromodulation. Up to this point, responsive neurostimulation (RNS) has been very promising but has mainly used only the cortex as a target. In this individual patient data meta-analysis (IPDMA), the authors sought to establish if a novel RNS target, the thalamus, can be used to treat DRE. METHODS: The literature regarding the management of DRE by targeting the thalamus with RNS was reviewed per IPDMA guidelines. Five databases were searched with keywords [((Responsive neurostimulation) OR (RNS)) AND ((thalamus) OR (thalamic) OR (Deep-seated) OR (Diencephalon) OR (limbic))] in March 2022. RESULTS: The median (interquartile range) age at implantation was 17 (13.5-27.5) years (n = 42) with an epilepsy duration of 12.1 (5.8-15.3) years. In total, 52.4% of patients had previously undergone epilepsy surgery, 28.6% had prior vagus nerve stimulation, and 2.4% had prior RNS. The median preimplant seizure frequency was 12 per week. The median seizure reduction at last follow-up was 73%. No study in this IPDMA reported complications, although 7 cases (16.3%) did require reoperation. Behavioral improvements and reduced antiepileptic drug dose or quantity were reported for 80% and 28.6% of patients, respectively. CONCLUSIONS: This review indicates that thalamic RNS may be safe and effective for treating DRE. Long-term and controlled studies on thalamic RNS for DRE would further elucidate this technique's potential benefits and complications and help guide clinical judgment in the management of DRE.

Plant-hummingbird pollination networks exhibit limited rewiring after experimental removal of a locally abundant plant species.

Mutualistic relationships, such as those between plants and pollinators, may be vulnerable to the local extinctions predicted under global environmental change. However, network theory predicts that plant-pollinator networks can withstand species loss if pollinators switch to alternative floral resources (rewiring). Whether rewiring occurs following species loss in natural communities is poorly known because replicated species exclusions are difficult to implement at appropriate spatial scales. We experimentally removed a hummingbird-pollinated plant, Heliconia tortuosa, from within tropical forest fragments to investigate how hummingbirds respond to temporary loss of an abundant resource. Under the rewiring hypothesis, we expected that behavioural flexibility would allow hummingbirds to use alternative resources, leading to decreased ecological specialization and reorganization of the network structure (i.e. pairwise interactions). Alternatively, morphological or behavioural constraints-such as trait-matching or interspecific competition-might limit the extent to which hummingbirds alter their foraging behaviour. We employed a replicated Before-After-Control-Impact experimental design and quantified plant-hummingbird interactions using two parallel sampling methods: pollen collected from individual hummingbirds ('pollen networks', created from >300 pollen samples) and observations of hummingbirds visiting focal plants ('camera networks', created from >19,000 observation hours). To assess the extent of rewiring, we quantified ecological specialization at the individual, species and network levels and examined interaction turnover (i.e. gain/loss of pairwise interactions). H. tortuosa removal caused some reorganization of pairwise interactions but did not prompt large changes in specialization, despite the large magnitude of our manipulation (on average, >100 inflorescences removed in exclusion areas of >1 ha). Although some individual hummingbirds sampled through time showed modest increases in niche breadth following Heliconia removal (relative to birds that did not experience resource loss), these changes were not reflected in species- and network-level specialization metrics. Our results suggest that, at least over short time-scales, animals may not necessarily shift to alternative resources after losing an abundant food resource-even in species thought to be highly opportunistic foragers, such as hummingbirds. Given that rewiring contributes to theoretical predictions of network stability, future studies should investigate why pollinators might not expand their diets after a local resource extinction.

Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity.

Importance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main Outcomes and Measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Neuroimaging evidence for the direct role of auditory scene analysis in object perception.

Auditory Scene Analysis (ASA) refers to the grouping of acoustic signals into auditory objects. Previously, we have shown that perceived musicality of auditory sequences varies with high-level organizational features. Here, we explore the neural mechanisms mediating ASA and auditory object perception. Participants performed musicality judgments on randomly generated pure-tone sequences and manipulated versions of each sequence containing low-level changes (amplitude; timbre). Low-level manipulations affected auditory object perception as evidenced by changes in musicality ratings. fMRI was used to measure neural activation to sequences rated most and least musical, and the altered versions of each sequence. Next, we generated two partially overlapping networks: (i) a music processing network (music localizer) and (ii) an ASA network (base sequences vs. ASA manipulated sequences). Using Representational Similarity Analysis, we correlated the functional profiles of each ROI to a model generated from behavioral musicality ratings as well as models corresponding to low-level feature processing and music perception. Within overlapping regions, areas near primary auditory cortex correlated with low-level ASA models, whereas right IPS was correlated with musicality ratings. Shared neural mechanisms that correlate with behavior and underlie both ASA and music perception suggests that low-level features of auditory stimuli play a role in auditory object perception.

Surgical Approaches to Thalamic Gliomas: A Systematic Review.

BACKGROUND: Adult thalamic gliomas (ATGs) present a surgical challenge given their depth and proximity to eloquent brain regions. Choosing a surgical approach relies on different clinical variables such as anatomical location and size of the tumor. However, conclusive data regarding how these variables influence the balance between extent of resection and complications are lacking. We aim to systematically review the literature to describe the current surgical outcomes of ATG and to provide tools that may improve the decision-making process. METHODS: Literature regarding the surgical management of ATG patients was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four databases were queried and a description of clinical characteristics and survival analysis were performed. An individual patient data analysis was conducted when feasible. RESULTS: A total of 462 patients were included from 13 studies. The mean age was 39.8 years with a median preoperative Karnofsky performance scale of 70. The lateral approaches were most frequently used (74.9%), followed by the interhemispheric (24.2%). Gross total and subtotal/partial resections were achieved in 81%, and 19% of all cases, respectively. New permanent neurological deficits were observed in 51/433 patients (11.8%). individual patient data was pooled from 5 studies (n = 71). In the multivariate analysis, tumors located within the posterior thalamus had worse median overall survival compared to anterior gliomas (14.5 vs. 27 months, P = 0.003). CONCLUSIONS: Surgical resection of ATGs can increase survival but at the risk of operative morbidity. Knowing which factors impact survival may allow neurosurgeons to propose a more evidence-based treatment to their patients.

Early-life dietary exposures mediate persistent shifts in the gut microbiome and visceral fat metabolism.

In utero dietary exposures are linked to the development of metabolic syndrome in adult offspring. These dietary exposures can potentially impact gut microbial composition and offspring metabolic health. Female BALB/c mice were administered a lard, lard + flaxseed oil, high sugar, or control diet 4 wk before mating, throughout mating, pregnancy, and lactation. Female offspring were offered low-fat control diet at weaning. Fecal 16S sequencing was performed. Untargeted metabolomics was performed on visceral adipose tissue (VAT) of adult female offspring. Immunohistochemistry was used to determine adipocyte size, VAT collagen deposition, and macrophage content. Hippurate was administered via weekly intraperitoneal injections to low-fat and high-fat diet-fed female mice and VAT fibrosis and collagen 1A (COL1A) were assessed by immunohistochemistry. Lard diet exposure was associated with elevated body and VAT weight and dysregulated glucose metabolism. Lard + flaxseed oil attenuated these effects. Lard diet exposures were associated with increased adipocyte diameter and VAT macrophage count. Lard + flaxseed oil reduced adipocyte diameter and fibrosis compared with the lard diet. Hippurate-associated bacteria were influenced by lard versus lard + flax exposures that persisted to adulthood. VAT hippurate was increased in lard + flaxseed oil compared with lard diet. Hippurate supplementation mitigated VAT fibrosis pathology. Maternal high-fat lard diet consumption resulted in long-term metabolic and gut microbiome programming in offspring, impacting VAT inflammation and fibrosis, and was associated with reduced VAT hippurate content. These traits were not observed in maternal high-fat lard + flaxseed oil diet-exposed offspring. Hippurate supplementation reduced VAT fibrosis. These data suggest that detrimental effects of early-life high-fat lard diet exposure can be attenuated by dietary omega-3 polyunsaturated fatty acid supplementation.

Bright light therapy for mental and behavioral illness: A systematic umbrella review.

Bright light therapy (BLT) is a promising non-pharmacological treatment for a range of psychiatric conditions. The goal of this review was to provide a comprehensive overview of the efficacy of BLT across mental and behavioral illnesses. Using systematic umbrella review methodology, we searched Ovid MEDLINE, Embase, PsycInfo, Web of Science, and Google Scholar for systematic reviews of randomized controlled trials (RCTs) evaluating BLT for any mental or behavioral illness from the date of inception until March 2021. Review quality was assessed using the AMSTAR 2 tool and summary efficacy data were extracted from recent reviews. Of 792 unique records, 67 systematic reviews were included which targeted a range of disorders related to mood, neurocognition, sleep, and eating. Recent meta-analyses targeting seasonal or non-seasonal depression found that BLT outperformed light-related control conditions. Reviews of other disorders identified few RCTs and generally did not support the efficacy of BLT for various outcomes. Overall, the extant literature supports the efficacy of BLT for seasonal and non-seasonal depression, although higher quality systematic reviews are needed to increase confidence in these findings. There was no specific funding for this review, and it was preregistered on Prospero (ID: CRD42021240751).

Pollinator foraging tactics have divergent consequences for the mating system of a tropical plant.

Resolving the consequences of pollinator foraging behaviour for plant mating systems is a fundamental challenge in evolutionary ecology. Pollinators may adopt particular foraging tactics: complete trapline foraging (repeated movements along a fixed route), sample-and-shift trapline foraging (a variable route that incorporates information from previous experiences) and territorial foraging (stochastic movements within a restricted area). Studies that integrate these pollinator foraging tactics with plant mating systems are generally lacking. We investigate the consequences of particular pollinator foraging tactics for Heliconia tortuosa. We combine parentage and sibship inference analysis with simulation modelling to: estimate mating system parameters; infer the foraging tactic adopted by the pollinators; and quantify the impact of pollinator foraging tactics on mating system parameters. We found high outcrossing rates, ubiquitous multiple paternity and a pronounced departure from near-neighbour mating. We also found that plants repeatedly receive pollen from a series of particular donors. We infer that the pollinators primarily adopt complete trapline foraging and occasionally engage in sample-and-shift trapline foraging. This enhances multiple paternity without a substantial increase in near-neighbour mating. The particular pollinator foraging tactics have divergent consequences for multiple paternity and near-neighbour mating. Thus, pollinator foraging behaviour is an important driver of the ecology and evolution of plant mating systems.

Targeting the CD47/thrombospondin-1 signaling axis regulates immune cell bioenergetics in the tumor microenvironment to potentiate antitumor immune response.

BACKGROUND: CD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the CD47/TSP1 signaling axis on melanoma patient response to anti-PD-1 therapy due to alterations in T cell activation, proliferation, effector function, and bioenergetics. METHODS: A syngeneic B16 mouse melanoma model was performed to determine if targeting CD47 as monotherapy or in combination with anti-PD-1 impacted tumor burden. Cytotoxic (CD8+) T cells from Pmel-1 transgenic mice were used for T cell activation, cytotoxic T lymphocyte, and cellular bioenergetic assays. Single-cell RNA-sequencing, ELISA, and flow cytometry was performed on peripheral blood mononuclear cells and plasma of melanoma patients receiving anti-PD-1 therapy to examine CD47/TSP1 expression. RESULTS: Human malignant melanoma tissue had increased CD47 and TSP1 expression within the tumor microenvironment compared with benign tissue. Due to the negative implications CD47/TSP1 can have on antitumor immune responses, we targeted CD47 in a melanoma model and observed a decrease in tumor burden due to increased tumor oxygen saturation and granzyme B secreting CD8+ T cells compared with wild-type tumors. Additionally, Pmel-1 CD8+ T cells exposed to TSP1 had reduced activation, proliferation, and effector function against B16 melanoma cells. Targeting CD47 allowed CD8+ T cells to overcome this TSP1 interaction to sustain these functions. TSP1 exposed CD8+ T cells have a decreased rate of glycolysis; however, targeting CD47 restored glycolysis when CD8+ T cells were exposed to TSP1, suggesting CD47 mediated metabolic reprogramming of T cells. Additionally, non-responding patients to anti-PD-1 therapy had increased T cells expressing CD47 and circulating levels of TSP1 compared with responding patients. Since CD47/TSP1 signaling axis negatively impacts CD8+ T cells and non-responding patients to anti-PD-1 therapy have increased CD47/TSP1 expression, we targeted CD47 in combination with anti-PD-1 in a melanoma model. Targeting CD47 in combination with anti-PD-1 treatment further decreased tumor burden compared with monotherapy and control. CONCLUSION: CD47/TSP1 expression could serve as a marker to predict patient response to immune checkpoint blockade treatment, and targeting this pathway may preserve T cell activation, proliferation, effector function, and bioenergetics to reduce tumor burden as a monotherapy or in combination with anti-PD-1.

American Thyroid Association Guidelines and National Trends in Management of Papillary Thyroid Carcinoma.

Importance: Over time, the American Thyroid Association (ATA) guidelines have increasingly promoted more limited treatments for well-differentiated thyroid cancers. Objective: To determine whether the 2009 and 2015 ATA guidelines were associated with changes in the management of low-risk papillary thyroid carcinomas on a national scale. Design, Setting, and Participants: This historical cohort study used the National Cancer Database. All papillary thyroid carcinomas diagnosed from 2004 to 2019 in the National Cancer Database were selected. Patients with tumors of greater than 4 cm, metastases, or clinical evidence of nodal disease were excluded. Data were analyzed from August 1, 2021, to September 1, 2022. Main Outcomes and Measures: The primary aim was to tabulate changes in the rates of thyroid lobectomy (TL), total thyroidectomy (TT), and TT plus radioactive iodine (RAI) therapy after the 2009 and 2015 ATA guidelines. The secondary aim was to determine in which settings (eg, academic vs community) the practice patterns changed the most. Results: A total of 194 254 patients (155 796 [80.2%] female patients; median [range] age at diagnosis, 51 [18-90] years) who underwent treatment during the study period were identified. Among patients who underwent surgery, rates of TL decreased from 15.1% to 13.7% after the 2009 guidelines but subsequently increased to 22.9% after the 2015 changes. Among patients undergoing TT, rates of adjuvant RAI decreased from 48.7% to 37.1% after 2009 and to 19.3% after the 2015 guidelines. Trends were similar for subgroups based on sex and race and ethnicity. However, academic institutions saw larger increases in TL rates (14.9% to 25.7%) than community hospitals (16.3% to 19.5%). Additionally, greater increases in TL rates were observed for tumors 1 to 2 cm (6.8% to 18.9%) and 2 to 4 cm (6.6% to 16.0%) than tumors less than 1 cm (22.8% to 29.2%). Conclusions and Relevance: In this cohort study among patients with papillary thyroid carcinomas up to 4 cm, ATA guideline changes corresponded with increased TL and reduced adjuvant RAI. These changes were primarily seen in academic institutions, suggesting an opportunity to expand guideline-based care in the community setting.

Understanding Hospital-Level Patterns of Nonoperative Management for Low-risk Thyroid and Kidney Cancer.

Importance: There is a growing trend toward conservative management for certain low-risk cancers. Hospital and health-system factors may play a role in determining how these patients are managed. Objective: To explore the contribution of hospitals on patients' odds of nonoperative management for low-risk cancer. Design, Setting, and Participants: In this cross-sectional study, individuals with low-risk papillary thyroid cancer and solitary kidney masses were identified, and those receiving nonoperative management vs surgery were compared. Patients with low-risk thyroid cancer and kidney cancer from 2015 to 2017 eligible for nonoperative management according to National Comprehensive Cancer Network guidelines within the National Cancer Database were included. Data were analyzed from October 2021 to March 2022. Main Outcomes and Measures: For each facility, the proportion of these patients who received operative and nonoperative management was calculated. A mixed-effects logistic regression model with a hospital-level random effects term was used to calculate factors associated with nonoperative management. Between-hospital variability was assessed using ranked caterpillar plots. Results: There were 19 570 individuals with low-risk thyroid cancer (15 344 women [78.4%]; mean [SD] age, 51.74 [95% CI, 51.39-52.08] years) and 41 403 with kidney cancer (25 253 men [61.0%]; mean [SD] age, 61.93 [95% CI, 61.70-62.17] years). In the group with low-risk thyroid cancer, 2.1% (419 patients) received nonoperative management, and in the group with kidney cancer, 9.5% (3928 patients) received nonoperative management. This varied between hospitals from 1.1% (95% CI, 1.0%-1.1%) in the bottom decile to 10.3% (95% CI, 8.0%-12.4%) in the top decile for low-risk thyroid cancer, and from 4.3% (95% CI, 4.1%-4.4%) in the bottom decile to 24.6% (95% CI, 22.7%-26.5%) in the top decile for small kidney masses. For both cancers, age was associated with increased odds of nonoperative treatment. The hospital-level odds of nonoperative management of thyroid and kidney cancer using unadjusted probabilities (observed proportions) were minimally correlated (Spearman ρ = .33; P < .001). Conclusions and Relevance: The findings of this study suggest that although health systems factors may be associated with the tendency to pursue nonoperative management, hospital-level factors may differ when comparing unrelated cancers.

Radiologists' Contribution to Variation in Detecting Clinically Significant Prostate Cancer in Men With Prostate MRI.

OBJECTIVE: Assess radiologists' contribution to variation in clinically significant prostate cancer (csPCa) detection in patients with elevated prostate-specific antigen (PSA) and multiparametric MRI (mpMRI). METHODS: This institutional review board-approved, retrospective cohort study was performed at a tertiary, academic, National Cancer Institute-designated Comprehensive Cancer Center with a multidisciplinary prostate cancer program. Men undergoing mpMRI examinations from January 1, 2015, to December 31, 2019, with elevated PSA (≥4 ng/mL) and biopsy within 6 months pre- or post-MRI or prostatectomy within 6 months post-mpMRI were included. Univariate and multivariable hierarchical logistic regression assessed impact of patient, provider, mpMRI examination, mpMRI report, and pathology factors on the diagnosis of Grade Group ≥ 2 csPCa. RESULTS: Study cohort included 960 MRIs in 928 men, mean age 64.0 years (SD ± 7.4), and 59.8% (555 of 928) had csPCa. Interpreting radiologist was not significant individually (P > .999) or combined with mpMRI ordering physician and physician performing biopsy or prostatectomy (P = .41). Prostate Imaging Reporting and Data System (PI-RADS) category 2 (odds ratio [OR] 0.18, P = .04), PI-RADS category 4 (OR 2.52, P < .001), and PI-RADS category 5 (OR 4.99, P < .001) assessment compared with no focal lesion; PSA density of 0.1 to 0.15 ng/mL/cc (OR 2.46, P < .001), 0.15 to 0.2 ng/mL/cc (OR 2.77, P < .001), or ≥0.2 ng/mL/cc (OR 4.52, P < .001); private insurance (reference = Medicare, OR 0.52, P = .001), and unambiguous extraprostatic extension on mpMRI (OR 2.94, P = .01) were independently associated with csPCa. PI-RADS 3 assessment (OR 1.18, P = .56), age (OR 0.99, P = .39), and African American race (OR 0.90, P = .75) were not. DISCUSSION: Although there is known in-practice variation in radiologists' interpretation of mpMRI, in our multidisciplinary prostate cancer program we found no significant radiologist-attributable variation in csPCa detection.

Templated encapsulation of platinum-based catalysts promotes high-temperature stability to 1,100 °C.

Stable catalysts are essential to address energy and environmental challenges, especially for applications in harsh environments (for example, high temperature, oxidizing atmosphere and steam). In such conditions, supported metal catalysts deactivate due to sintering-a process where initially small nanoparticles grow into larger ones with reduced active surface area-but strategies to stabilize them can lead to decreased performance. Here we report stable catalysts prepared through the encapsulation of platinum nanoparticles inside an alumina framework, which was formed by depositing an alumina precursor within a separately prepared porous organic framework impregnated with platinum nanoparticles. These catalysts do not sinter at 800 °C in the presence of oxygen and steam, conditions in which conventional catalysts sinter to a large extent, while showing similar reaction rates. Extending this approach to Pd-Pt bimetallic catalysts led to the small particle size being maintained at temperatures as high as 1,100 °C in air and 10% steam. This strategy can be broadly applied to other metal and metal oxides for applications where sintering is a major cause of material deactivation.

Randomised clinical non-inferiority trial of breathing-based meditation and cognitive processing therapy for symptoms of post-traumatic stress disorder in military veterans.

OBJECTIVE: Test whether Sudarshan Kriya Yoga (SKY) was non-inferior to cognitive processing therapy (CPT) for treating symptoms of post-traumatic stress disorder (PTSD) among veterans via a parallel randomised controlled non-inferiority trial. SETTING: Outpatient Veterans Affairs healthcare centre. PARTICIPANTS: 85 veterans (75 men, 61% white, mean age 56.9) with symptoms of PTSD participated between October 2015 and March 2020: 59 participants completed the study. INTERVENTIONS: SKY emphasises breathing routines and was delivered in group format in a 15-hour workshop followed by two 1-hour sessions per week for 5 weeks. CPT is an individual psychotherapy which emphasises shifting cognitive appraisals and was delivered in two 1-hour sessions per week for 6 weeks. MEASURES: The primary outcome measure was the PTSD Checklist-Civilian Version (PCL-C). The secondary measures were the Beck Depression Inventory-II (BDI-II) and Positive and Negative Affect Scale (PANAS). RESULTS: Mean PCL-C at baseline was 56.5 (±12.6). Intent-to-treat analyses showed that PCL-C scores were reduced at 6 weeks (end of treatment) relative to baseline (SKY, -5.6, d=0.41, n=41: CPT, -6.8, d=0.58, n=44). The between-treatment difference in change scores was within the non-inferiority margin of 10 points (-1.2, 95% CI -5.7 to 3.3), suggesting SKY was not inferior to CPT. SKY was also non-inferior at 1-month (CPT-SKY: -2.1, 95% CI -6.9 to 2.8) and 1-year (CPT-SKY: -1.8, 95% CI -6.6 to 2.9) assessments. SKY was also non-inferior to CPT on the BDI-II and PANAS at end of treatment and 1 month, but SKY was inferior to CPT on both BDI-II and PANAS at 1 year. Dropout rates were similar (SKY, 27%, CPT, 34%: OR=1.36, 95% CI 0.51 to 3.62, p=0.54). CONCLUSIONS: SKY may be non-inferior to CPT for treating symptoms of PTSD and merits further consideration as a treatment for PTSD. TRIAL REGISTRATION NUMBER: NCT02366403.

Endoscopic Balloon Dilation Is Cost-Effective for Crohn's Disease Strictures.

BACKGROUND: Endoscopic balloon dilation (EBD) has emerged as an alternative intervention to manage Crohn's disease (CD) strictures. We determined the cost-effectiveness of EBD versus resection surgery for patients with short (< 4-5 cm) primary or secondary/anastomotic small or large bowel strictures. METHODS: A microsimulation state-transition model analyzed the benefits and risks of EBD and resection surgery for patients with primary or anastomotic CD strictures. Our primary outcome was quality-adjusted life years (QALYs) over ten years, and strategies were compared using a willingness to pay of $100,000/QALY from a societal perspective. Costs (2021 $US) and incremental cost-effectiveness ratios (ICER) were calculated. Deterministic 1-way and probabilistic analyses assessed model uncertainty. RESULTS: The EBD strategy cost $19,822 and resulted in 6.18 QALYs while the surgery strategy cost $41,358 and resulted in 6.37 QALYs. Surgery had an ICER of $113,332 per QALY, making EBD a cost-effective strategy. The median number of EBDs was 5 in the EBD strategy and 0 in the surgery strategy. The median number of surgeries was 2 in the surgery strategy and 1 in the EBD strategy. Of individuals who initially received EBD, 50.4% underwent subsequent surgery. One-way sensitivity analyses showed that the probabilities of requiring repeated interventions, surgery mortality (< 0.7%), and quality of life after interventions were the most influential model parameters. Probabilistic sensitivity analyses favored EBD in 50.9% of iterations. CONCLUSIONS: EBD is a cost-effective strategy for managing CD strictures. Differences in patient risk and quality of life after intervention impact cost-effectiveness. Intervention decisions should consider cost-effectiveness, patient risks, and quality of life.

Visible blue light inactivates SARS-CoV-2 variants and inhibits Delta replication in differentiated human airway epithelia.

The emergence of SARS-CoV-2 variants that evade host immune responses has prolonged the COVID-19 pandemic. Thus, the development of an efficacious, variant-agnostic therapeutic for the treatment of early SARS-CoV-2 infection would help reduce global health and economic burdens. Visible light therapy has the potential to fill these gaps. In this study, visible blue light centered around 425 nm efficiently inactivated SARS-CoV-2 variants in cell-free suspensions and in a translationally relevant well-differentiated tissue model of the human large airway. Specifically, 425 nm light inactivated cell-free SARS-CoV-2 variants Alpha, Beta, Delta, Gamma, Lambda, and Omicron by up to 99.99% in a dose-dependent manner, while the monoclonal antibody bamlanivimab did not neutralize the Beta, Delta, and Gamma variants. Further, we observed that 425 nm light reduced virus binding to host ACE-2 receptor and limited viral entry to host cells in vitro . Further, the twice daily administration of 32 J/cm 2 of 425 nm light for three days reduced infectious SARS-CoV-2 Beta and Delta variants by >99.99% in human airway models when dosing began during the early stages of infection. In more established infections, logarithmic reductions of infectious Beta and Delta titers were observed using the same dosing regimen. Finally, we demonstrated that the 425 nm dosing regimen was well-tolerated by the large airway tissue model. Our results indicate that blue light therapy has the potential to lead to a well-tolerated and variant-agnostic countermeasure against COVID-19.

Computed Tomography Hounsfield Units as a Predictor of Reoperation and Graft Subsidence After Standalone and Multilevel Lateral Lumbar Interbody Fusion.

BACKGROUND: Standalone single and multilevel lateral lumbar interbody fusion (LLIF) have been increasingly applied to treat degenerative spinal conditions in a less invasive fashion. Graft subsidence following LLIF is a known complication and has been associated with poor bone mineral density (BMD). Previous research has demonstrated the utility of computed tomography (CT) Hounsfield units (HUs) as a surrogate for BMD. In the present study, we investigated the relationship between the CT HUs and subsidence and reoperation after standalone and multilevel LLIF. METHODS: A prospectively maintained single-institution database was retrospectively reviewed for LLIF patients from 2017 to 2020, including single and multilevel standalone cases with and without supplemental posterior fixation. Data on demographics, graft parameters, BMD determined by dual-energy x-ray absorptiometry, preoperative mean segmental CT HUs, and postoperative subsidence and reoperation were collected. We used 36-in. standing radiographs to measure the preoperative global sagittal alignment and disc height and subsidence at last follow-up. Subsidence was classified using the Marchi grading system corresponding to disc height loss: grade 0, 0%-24%; grade I, 25%-49%; grade II, 50%-74%; and grade III, 75%-100%. RESULTS: A total of 89 LLIF patients had met the study criteria, with a mean follow-up of 19.9 ± 13.9 months. Of the 54 patients who had undergone single-level LLIF, the mean segmental HUs were 152.0 ± 8.7 for 39 patients with grade 0 subsidence, 136.7 ± 10.4 for 9 with grade I subsidence, 133.9 ± 23.1 for 3 with grade II subsidence, and 119.9 ± 30.9 for 3 with grade III subsidence (P = 0.032). Of the 96 instrumented levels in the 35 patients who had undergone multilevel LLIF, 85, 9, 1, and 1 level had had grade 0, grade I, grade II, and grade III subsidence, with no differences in the HU levels. On multivariate logistic regression, increased CT HU levels were independently associated with a decreased risk of reoperation after both single-level and multilevel LLIF (odds ratio, 0.98; 95% confidence interval, 0.97-0.99; P = 0.044; and odds ratio, 0.97; 95% confidence interval, 0.94-0.99; P = 0.017, respectively). Overall, the BMD determined using dual-energy x-ray absorptiometry was not associated with graft subsidence or reoperation. Using a receiver operating characteristic curve to separate the patients who had and had not required reoperation, the threshold HU level determined for single-level and multilevel LLIF was 131.4 (sensitivity, 0.62; specificity 0.65) and 131.0 (sensitivity, 0.67; specificity, 0.63), respectively. CONCLUSIONS: Lower CT HUs were independently associated with an increased risk of graft subsidence after single-level LLIF. In addition, lower CT HUs significantly increased the risk of reoperation after both single and multilevel LLIF with a critical threshold of 131 HUs. The determination of the preoperative CT HUs might provide a more robust gauge of local bone quality and the likelihood of graft subsidence requiring reoperation following LLIF than overall BMD.

Dietary Supplement Intake and Factors Associated with Increased Use in Preadolescent Endurance Runners.

BACKGROUND: The prevalence of dietary supplement intake among preadolescent endurance runners is currently unknown. OBJECTIVE: Our aim was to describe use of dietary supplements, higher-risk supplements, and sport foods among preadolescent endurance athletes and identify associated characteristics of dietary supplement users in this population. DESIGN: This was a retrospective, cross-sectional study. PARTICIPANTS/SETTING: Participants were 2,113 preadolescent endurance runners (male: n = 1,255, female: n = 858; mean age ± standard deviation = 13.2 ± 0.9 years). MAIN OUTCOME MEASURES: Use of dietary supplements, higher-risk dietary supplements, and sport foods on 2 or more days per week during the past year. STATISTICAL ANALYSES PERFORMED: Mann-Whitney U tests, χ2 tests, univariate and multivariate analyses. RESULTS: Twenty-six percent (n = 551) of preadolescent runners used dietary supplements on 2 or more days per week during the past year; 1.3% (n = 27) reported taking higher-risk supplements. Compared with male runners, female runners reported higher use of 1 or more supplements (32.5% vs 21.7%; P < .001) and 4 or more supplements (4.0% vs 1.9%; P = 0.005), multivitamin/minerals (24.2% vs 14.4%; P < .001), vitamin D (12.4% vs 5.6%; P < .001), calcium (8.9% vs 4.8%; P < .001), iron (3.1 vs 1.1%; P < .001), probiotic supplements (8.2% vs 1.3%; P < .001), and diet pills (0.5% vs 0.0%; P = .02). Male runners reported higher use of creatine (1.3% vs 0.0%; P < .001) and sport foods, including protein bars and drinks (19.5% vs 8.4%; P < .001), energy bars (23.5% vs 9.7%; P < .001), and carbohydrate-electrolyte drinks (27.9% vs 13.3%; P < .001) than female runners. Factors independently associated with a higher likelihood for dietary supplement use included weight loss in the past year, female (vs male) gender, following a vegetarian diet, skipping meals, attempting to gain weight, and history of a running-related bone stress injury. CONCLUSIONS: More than one-quarter of preadolescent runners regularly consumed dietary supplements. Behaviors consistent with dietary restriction and history of bone stress injury were associated with higher likelihood for supplement use. Further work to understand supplement use patterns and potential value for nutrition education is advised to optimize health of preadolescent runners.