Search

Inspired by the success of the Students @ Work project [1] run at Hamburg University, Curtin University (Perth, Western Australia) has recently concluded the running of a pilot course in Second Life with their Information Systems Project (ISP) students. The need for a change was evident as student motivation and engagement in the Final Year ISP course was strikingly low. Left with such a tall order for improvement, the ISP teaching staff looked to find suitable options for change. Staff combined new and interesting tools in an effort to boost and maintain student interest, specifically the Second Life virtual environment and a screen capturing technique known as Machinima. [ABSTRACT FROM AUTHOR]

Background: In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [ 68 Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters., Methods: We identified 41 metastasized ACC patients imaged with [ 68 Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUV mean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded., Results: After [ 68 Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07)., Conclusions: In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [ 68 Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information., (© 2024. The Author(s).)

C-X-C motif chemokine receptor 4 (CXCR4)-directed molecular imaging provides excellent read-out capabilities in patients with marginal zone lymphoma (MZL). We aimed to determine the interobserver agreement rate of CXCR4-targeted PET/CT among readers with different levels of experience., Methods: 50 subjects with MZL underwent CXCR4-targeted PET/CT, which were reviewed by four readers (including two experienced and two less experienced observers). The following 8 parameters were investigated: overall scan result, CXCR4 density in lymphoma tissue, extranodal organ involvement, No. of affected extranodal organs and extranodal organ metastases, lymph node (LN) involvement and No. of affected LN areas and LN metastases. We applied intraclass correlation coefficients (ICC; < 0.4, poor; 0.4-0.59, fair; 0.6-0.74, good and > 0.74 excellent agreement rates)., Results: Among all readers, fair agreement was recorded for No. of affected extranodal organs (ICC, 0.40; 95% confidence interval [CI], 0.25-0.68), overall scan result (ICC, 0.42; 95%CI, 0.28-0.57), CXCR4 density in lymphoma tissue (ICC, 0.52; 95%CI, 0.38-0.66), and No. of extranodal organ metastases (ICC, 0.55; 95%CI, 0.41-0.61) and LN involvement (ICC, 0.59; 95%CI, 0.46-0.71). Good agreement rates were observed for No. of LN metastases (ICC, 0.71; 95%CI, 0.60-0.81) and No. of LN areas (ICC, 0.73; 95%CI, 0.63-0.82), while extranodal organ involvement (ICC, 0.35; 95%CI, 0.21-0.51) achieved poor concordance. On a reader-by-reader comparison, the experienced readers achieved significantly higher agreement rates in 4/8 (50%) investigated scan items (ICC, range, 0.21-0.90, P < / = 0.04). In the remaining 4/8 (50%), a similar trend with higher ICCs for the experienced readers was recorded (n.s.)., Conclusion: CXCR4-directed PET/CT mainly provided fair to good agreement rates for scan assessment, while a relevant level of experience seems to be required for an accurate imaging read-out., (© 2024. The Author(s).)

Background: Reduction of surgical site infections (SSIs) is important in improving cervical spine surgery outcomes. Plastic surgery involvement and an enhanced modified prophylaxis protocol may reduce infection rates. Methods: A total of 962 cervical spine operations were conducted by a single surgeon (TFC). An enhanced modified prophylaxis protocol and plastic surgery were used in some operations. Differences in infection rates, surgical approach, previous operations, prophylaxis use, and plastic surgery involvement were compared using Fisher's exact tests and multivariate linear regression. Results: Four patients (0.42%) experienced SSIs. All 4 infections involved the standard protocol, posterior approach, and did not involve plastic surgery. The infection rate was lower in the enhanced protocol group when compared to the standard protocol (β -0.78, 95% CI -1.23 to -0.33, P  = .0008). The enhanced protocol group had an increased percentage of operations with plastic surgery (β 0.19, 95% CI 0.10 to 0.28, P  < .0001). The infection rate among the plastics group was 0.00% compared to 0.60% for the non-plastics group ( P  = .32). The plastics group had a lower rate of anterior approach when compared to the non-plastics group (β -0.20, 95% CI -0.24 to -0.15, P  = .049). Among the posterior approach group, procedures with plastic surgery had an infection rate of 0.00% compared to 2.53% without plastic surgery ( P  = .13). Conclusion: The enhanced protocol was associated with a lower SSI rate and increased plastic surgery involvement. Posterior approaches were associated with increased infection rates and the likelihood of utilizing plastic surgery. Both the enhanced protocol and plastic surgery may decrease infection., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2022 The Author(s).)

Background: C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings., Methods: A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [ 68  Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUV max ) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUV max (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUV max above 10)., Results: One hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05-24.98), thereby indicating high image contrast. The highest SUV max was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUV max was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUV max was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUV max above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort., Conclusions: In a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [ 68  Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [ 68  Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy., (© 2023. The Author(s).)

Background: After C-X-C motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT), lymphoma patients are scheduled for conditioning therapy (CON) followed by hematopoietic stem cell transplantation (HSCT). We aimed to determine whether CXCR4-RLT can achieve bone marrow ablation and direct antilymphoma activity independent from CON/HSCT and also evaluated the safety profile of this theranostic approach in an acute setting., Patients and Methods: After CXCR4-directed 68 Ga-pentixafor PET/CT, 21 heavily pretreated patients with hematological malignancies underwent CXCR4-directed RLT using 90 Y-pentixather. The extent of myeloablative efficacy was determined by investigating hematologic laboratory parameters before RLT (day -1), at the day of RLT (day 0), 2 days after RLT (day 2), and before CON (median day 10). Serving as surrogate marker of antilymphoma activity, lactate dehydrogenase (LDH) levels were also assessed until CON. We also screened for laboratory-defined tumor lysis syndrome after the Cairo-Bishop definition and recorded acute laboratory adverse events using the Common Terminology Criteria for Adverse Events version 5.0., Results: After RLT, we observed a significant decline of leukocyte levels by 79.4% ± 18.7% till CON (granulocytes, drop by 70.3% ± 21%; platelets, reduction by 43.1% ± 36%; P ≤ 0.0005 vs day 0, respectively). After RLT, LDH levels already reached a peak at day 2, which was followed by a rapid decline thereafter (peak vs day of CON, P = 0.0006), indicating that 90 Y-pentixather exhibits direct antilymphoma activity. At day of CON, LDH levels were also significantly lower when compared with day -1 ( P = 0.04), suggestive for durable response mediated by RLT. No patient fulfilled the criteria of tumor lysis syndrome, whereas 25 laboratory adverse events attributable to CXCR4-directed treatment were identified (≥grade 3 in 2/25 [8%]). During further treatment course, all patients (100%) received HSCT., Conclusions: CXCR4-directed RLT causes effective myeloablation, which allows for HSCT. In addition, it also exerts direct antilymphoma activity independent of subsequent therapeutic steps, whereas safety profile was acceptable., Competing Interests: Conflicts of interest and sources of funding: This project is partially supported by the German Research Foundation (453989101, R.A.W. and T.H.; 507803309, R.A.W.). This work was sponsored in part by Okayama University “RECTOR” Program, KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science (T.H.). R.A.W. has received speaker honoraria from Novartis/AAA and PentixaPharm, reports advisory board work for Novartis/AAA and Bayer, and is involved in 68 Ga-pentixafor PET imaging in marginal zone lymphoma (LYMFOR). A.K.B. has received speaker’s honoraria from PentixaPharm and is a member of the advisory board of PentixaPharm. All authors declare that there is no conflict of interest as well as consent for scientific analysis and publication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Because of gastral and extranodal manifestations, guideline-compatible diagnostic work-up of marginal zone lymphoma is challenging. We aimed to determine the diagnostic performance of C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT compared with routine diagnostics, along with PET/CT-based retrospective changes in therapeutic management. The predictive potential of the PET signal was also investigated, and the number of patients eligible for CXCR4-directed radioligand therapy in a theranostic setting was determined. Methods: For this study, 100 marginal zone lymphoma patients underwent CXCR4-directed PET/CT. We compared staging results and treatment decisions from molecular imaging with respective results from guideline-compatible work-up (CT, esophagogastroduodenoscopy, and bone marrow-derived biopsy). Prognostic performance of the in vivo CXCR4 PET signal for progression-free survival (PFS) was evaluated (using log-rank test and Kaplan-Meier curves). Results: Relative to CT, CXCR4-directed imaging led to Ann Arbor (AA) staging changes for 27 of 100 patients (27.0%). Among those, clinically relevant upstaging from AA I or AA II to AA III or AA IV was observed for 23 patients (85.2%), along with respective changes in therapeutic management (escalation, 6/23 [26.1%]; deescalation, 17/23 [73.9%]). CXCR4 PET/CT yielded diagnostic accuracy of 94.0% relative to esophagogastroduodenoscopy and 76.8% relative to bone marrow-derived biopsy. An increased CXCR4 PET signal was linked to shorter PFS (707 d vs. median PFS not reached; hazard ratio, 3.18; 95% CI, 1.37-7.35; P = 0.01). CXCR4-directed radioligand therapy would have been feasible for 18 of 100 patients (18.0%). Conclusion: Relative to CT, CXCR4-directed PET/CT led to AA changes for 27 of 100 patients. Chemokine receptor PET/CT may improve current diagnostic algorithms and influence management relative to CT alone, potentially obviating some biopsies., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Recent studies investigating a tumor-sink effect in solid tumors reported on decreasing uptake in normal organs in patients with higher tumor burden. This phenomenon, however, has not been evaluated yet for theranostic radiotracers applied to hematological neoplasms. As such, we aimed to determine a potential "lymphoma-sink effect" in patients with marginal zone lymphoma (MZL) imaged with C-X-C motif chemokine receptor (CXCR) 4-directed PET/CTs., Procedures: We retrospectively analyzed 73 patients with MZL who underwent CXCR4-directed [ 68 Ga]Ga-PentixaFor PET/CT. Normal unaffected organ uptake (heart, liver, spleen, bone marrow, kidneys) was quantified using volumes of interests (VOIs) and mean standardized uptake values (SUV mean ) were derived. MZL manifestations were also segmented to determine the maximum and peak standardized uptake values SUV (SUV max/peak ) and volumetric parameters, including lymphoma volume (LV), and fractional lymphoma activity (FLA, defined as LV*SUV mean of lymphoma burden). This approach resulted in 666 VOIs to capture the entire MZL manifestation load. We used Spearman's rank correlations to determine associations between organ uptake and CXCR4-expressing lymphoma lesions., Results: We recorded the following median SUV mean in normal organs: heart, 1.82 (range, 0.78-4.11); liver, 1.35 (range, 0.72-2.99); bone marrow, 2.36 (range, 1.12-4.83); kidneys, 3.04 (range, 2.01-6.37); spleen, 5.79 (range, 2.07-10.5). No relevant associations between organ radiotracer uptake and MZL manifestation were observed, neither for SUV max (ρ ≤ 0.21, P ≥ 0.07), SUV peak (ρ ≤ 0.20, P ≥ 0.09), LV (ρ ≤ 0.13, P ≥ 0.27), nor FLA (ρ ≤ 0.15, P ≥ 0.33)., Conclusions: Investigating a lymphoma-sink effect in patients with hematological neoplasms, we observed no relevant associations between lymphoma burden and uptake in normal organs. Those observations may have therapeutic implications, e.g., for "cold" SDF1-pathway disrupting or "hot," CXCR4-directed radiolabeled drugs, as with higher lymphoma load, normal organ uptake seems to remain stable., (© 2023. The Author(s).)

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90 Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131 I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131 I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective/ Background: Chronic headaches and sports-related concussions are among the most common neurological morbidities in adolescents and young adults. Given that the two can overlap in presentation, studying the effects of one on another has proven difficult. In this longitudinal study, we sought to assess the relationship between chronic headaches and concussions, analyzing the role of historic concussions on chronic headaches, as well as that of premorbid headaches on future concussion incidence, severity, and recovery., Methods: This multi-center, longitudinal cohort study followed 7,453 youth athletes who were administered demographic and clinical surveys as well as a total of 25,815 Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) assessments between 2009 and 2019. ImPACT was administered at baseline. Throughout the season concussions were examined by physicians and athletic trainers, followed by re-administration of ImPACT post-injury (PI), and at follow-up (FU), a median of 7 days post-concussion. Concussion incidence was calculated as the total number of concussions per patient years. Concussion severity and recovery were calculated as standardized deviations from baseline to PI and then FU in Symptom Score and the four neurocognitive composite ImPACT scores: Verbal Memory, Visual Memory, Processing Speed, and Reaction Time. Data were collected prospectively in a well-organized electronic format supervised by a national research-oriented organization with rigorous quality assurance. Analysis was preformed retrospectively., Results: Of the eligible athletes, 1,147 reported chronic headaches (CH) at the start of the season and 6,306 reported no such history (NH). Median age of the cohort was 15.4 ± 1.6 years, and students were followed for an average of 1.3 ± 0.6 years. A history of concussions (OR 2.31, P < 0.0001) was associated with CH. Specifically, a greater number of past concussions (r 2  = 0.95) as well as concussions characterized by a loss of consciousness (P < 0.0001) were associated with more severe headache burden. The CH cohort had a greater future incidence of concussion than the NH cohort (55.6 vs. 43.0 per 100 patient-years, P < 0.0001). However, multivariate analysis controlling for demographic, clinical, academic, and sports-related variables yielded no such effect (OR 0.99, P = 0.85). On multivariable analysis the CH cohort did have greater deviations from baseline to PI and FU in Symptom Score (PI OR per point 1.05, P = 0.01, FU OR per point 1.11, P = 0.04) and Processing Speed (OR per point 1.08, P = 0.04), suggesting greater concussion severity and impaired symptomatic recovery as compared to the NH cohort., Conclusion: A history of concussions was a significant contributor to headache burden among American adolescents and young adults. However, those with chronic headaches were not more likely to be diagnosed with a concussion, despite presenting with more severe concussions that had protracted recovery. Our findings not only suggest the need for conservative management among youth athletes with chronic headaches, they also indicate a potential health care gap in this population, in that those with chronic headaches may be referred for concussion diagnosis and management at lower rates than those with no such comorbidity., (© 2023. The Author(s).)

C-X-C motif chemokine receptor 4 (CXCR4)-targeted radioligand therapy (RLT) has already been applied to advanced blood cancers, such as multiple myeloma or diffuse large B-cell lymphoma. We present a series of patients with advanced T-cell lymphoma (TCL) who were scheduled for CXCR4-directed therapy as a conditioning regimen, followed by hematopoietic stem cell transplantation (HSCT). Methods: Four patients with advanced, heavily pretreated, and relapsed TCL (2 men, 2 women; median age, 50 y) without suitable alternative therapeutic options underwent CXCR4-directed PET and pretherapeutic dosimetry. We then conducted CXCR4-targeted RLT in combination with allogeneic (3/4, 75%) or autologous (1/4, 25%) HSCT. One patient also underwent radioimmunotherapy targeting CD66 to enhance therapeutic efficacy. We investigated safety, best response, progression-free survival, and overall survival. Results: Pretherapeutic dosimetry indicated lymphoma-absorbed doses of up to 33.2 Gy from CXCR4-targeted RLT. Except for 1 patient who developed tumor lysis syndrome along with transient grade 3 kidney failure, no acute toxicity, allergic reactions, or other adverse events were recorded during therapy. One patient developed septicemia and subsequently died 16 d after RLT, whereas engraftment was achieved in the remaining 3 patients (75%). During follow-up, a partial response was recorded in 1 of 3 patients (33.3%) and a complete metabolic response in the other two (66.7%, with 1 patient also receiving additional radioimmunotherapy). Median progression-free survival was 7 mo (range, 4-25 mo). After a median follow-up of 54 mo (range, 4-56 mo), 3 patients were still alive at the date of censoring. Conclusion: For advanced, heavily pretreated TCL, CXCR4-directed RLT may serve as an effective conditioning therapy before HSCT and can cause substantial antilymphoma activity, leading to a remarkable response in selected cases., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

In recent years, molecular imaging addressing the C-X-C motif chemokine receptor 4 (CXCR4) has increasingly been used in various clinical settings. Here, we aimed to assess radiopharmaceutical uptake and image contrast to determine the most relevant clinical applications for CXCR4-directed imaging. We also investigated the impact of specific activity on scan contrast. Methods: Patients ( n = 690) with a variety of neoplasms underwent a total of 777 PET/CT scans with 68 Ga-Pentixafor, serving as the CXCR4-specific radioligand. A semiquantitative target lesion analysis was conducted (providing SUV max and target-to-blood pool ratio [TBR], defined as SUV max [from target lesion] divided by SUV mean [from blood pool]). The applied specific activity (in MBq/μg) was compared with semiquantitative assessments. Results: Of the 777 scans, 242 did not show discernible uptake in disease sites, leaving 535 PET scans (68.9%) for further analysis. Very high tracer uptake (SUV max > 12) was found in multiple myeloma ( n = 113), followed by adrenocortical carcinoma ( n = 30), mantle cell lymphoma ( n = 20), adrenocortical adenoma ( n = 6), and small cell lung cancer ( n = 12). Providing information on image contrast, comparable results for TBR were recorded, with TBR (>8) in multiple myeloma, mantle cell lymphoma, and acute lymphoblastoid leukemia ( n = 6). When comparing specific activity with semiquantitative parameters, no significant correlation was found for SUV max or TBR ( P ≥ 0.612). Conclusion: In this large cohort, 68 Ga-Pentixafor demonstrated high image contrast in a variety of neoplasms, particularly for hematologic malignancies, small cell lung cancer, and adrenocortical neoplasms. The present analysis may provide a roadmap for detecting patients who may benefit from CXCR4-targeted therapies., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs., Methods: Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [ 68 Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV mean ) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV max ), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV mean x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden., Results: Median SUV mean in unaffected organs was 5.2 for the spleen (range, 2.44 - 10.55), 3.27 for the kidneys (range, 1.52 - 17.4), followed by bone marrow (1.76, range, 0.84 - 3.98), heart (1.66, range, 0.88 - 2.89), and liver (1.28, range, 0.73 - 2.45). No significant correlation between SUV max in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found., Conclusions: In patients with solid tumors imaged with [ 68 Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged., (© 2022. The Author(s).)

(1) Background: We aimed to quantitatively investigate [ 68 Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [ 68 Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV mean ) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV max ), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV mean ). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV mean values were 2.15 in the pancreas (range, 1.05-9.91), 1.42 in the right (range, 0.57-3.06) and 1.41 in the left kidney (range, 0.73-2.97), 1.2 in the heart (range, 0.46-2.59), 0.86 in the spleen (range, 0.55-1.58), 0.65 in the liver (range, 0.31-2.11), and 0.57 in the bone marrow (range, 0.26-0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV max (ρ = 0.29, p = 0.07) and TV (ρ = -0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV max (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV max (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [ 68 Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs.

Background: High altitude may affect concussion, but prior studies are limited . We tested whether high altitude affects sport-related concussion (SRC) incidence, severity, and recovery., Methods: Twenty-five thousand eight hundred fifteen baseline and post-injury Immediate Post-Concussion Assessment and Cognitive Testing results were compiled from Florida and Colorado, low (27 m or 62 m) and high (1,640 m or 1,991 m) altitude locations, respectively. Incidence, severity, and recovery of injury were compared between altitudes., Results: High altitude was associated with increased suspected concussion incidence (adjusted OR, 2.04 [95% CI, 1.86 to 2.24]; P < .0001). However, high altitude was associated with lower concussion severity measured by Severity Index (SI) (adjusted OR, 0.42 [95% CI, 0.37 to 0.49]; P < .0001). High altitude was associated with decreased recovery from post-concussive symptoms in the migraine (β, -2.72 [95% CI, -3.31 to -2.13]; P < .0001), cognitive (β, -1.88 [95% CI, -2.40 to -1.36]; P < .0001), and sleep symptom clusters (β, -0.30 [95% CI, -0.52 to -0.08]; P = .007). Athletes with initial SI≥8 showed prolonged neurocognitive dysfunction at high altitude (HR, 1.38 [95% CI, 1.06 to 1.81]; P = .02)., Conclusions: High altitude was associated with increased suspected concussions and prolonged recovery but less severe initial injury.

Background: Studies investigating seasonality as a risk factor for surgical site infections (SSIs) after spine surgery show mixed results. This study used national data to analyze seasonal effects on spine surgery SSIs., Methods: National Surgical Quality Improvement Program data (2011-2018) were queried for posterior cervical fusions (PCFs), cervical laminoplasties, posterior lumbar fusions (PLFs), lumbar laminectomies, and deformity surgeries. Patients aged >89 and procedures for tumors, fractures, infections, and nonelective indications were excluded. Patients were divided into warm (admitted April-September) and cold (admitted October-March) seasonal groups. End points were SSIs and reoperations for wound débridement/drainage. Stratified analyses were performed by surgery type and pre-versus postdischarge infections., Results: Overall (N = 208,291), SSIs were more likely in the warm season (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.08-1.23, P < 0.0001) and for PCFs (OR 1.40, 95% CI 1.08-1.80, P = 0.011), PLFs (OR 1.15, 95% CI 1.04-1.28, P = 0.006), and lumbar laminectomies (OR 1.13, 95% CI 1.03-1.25, P = 0.014). Postdischarge infections were also more likely in the warm season overall (OR 1.15, 95% CI 1.07-1.23, P < 0.0001) and for PCFs (OR 1.32, 95% CI 1.01-1.73, P = 0.041), PLFs (OR 1.14, 95% CI 1.03-1.27, P = 0.014), and lumbar laminectomies (OR 1.15, CI 1.04-1.27, P = 0.007). In-hospital infections were more likely during the warm season only for PCFs (OR 2.54, 95% CI 1.06-6.10, P = 0.037). Reoperations for infection were more likely during the warm season for PLFs (OR 1.29, 95% CI 1.08-1.54, P = 0.005)., Conclusions: PCF, PLF, and lumbar laminectomy performed during the warm season had significantly higher odds of SSI, especially postdischarge SSIs. Reoperation rates for wound management were significantly increased during the warm season for PLFs. Identifying seasonal causes merits further investigation and may influence surgeon scheduling and expectations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Neurocognitive tests are an integral component of sport-related concussion (SRC) workup. A history of psychiatric illness (HPI) is common among young athletes. Investigations of factors that influence athletes' baseline neurocognitive function are crucial for an accurate assessment of SRC., Objective: In this study, we aim to elucidate the effect of HPI and selective-serotonin reuptake inhibitor (SSRI) medication use on baseline neurocognitive performance in young athletes., Methods: We conducted a retrospective cross-sectional study of Immediate Post-Concussion Assessment and Cognitive Testing assessments. A total of 268 athletes with HPI and a control group of 6,364 athletes were included. The outcomes were total symptom score based on post-concussion symptom scale, verbal memory, visual memory, visual motor, reaction time, and impulse control scores with self-reported HPI status and SSRI use., Results: Athletes with HPI had an elevated symptom score in both univariate analysis (p < .0001) and multivariate analysis (p < .0001). HPI influence on visual memory score was not robust to multivariate analysis (p = .24). Athletes with HPI who reported SSRI medication use had the same baseline neurocognitive performance as other athletes with HPI. HPI influences athletes' baseline neurocognitive performance by elevating symptom scores. HPI does not alter any of the objective neurocognitive composite scores in contrast to previous work., Conclusions: Clinicians should consider the impact of HPI on baseline neurocognitive performance during the assessment of a suspected SRC. Additional research is required to bolster our findings on SSRI use and ascertain the effects of other drug classes on baseline neurocognitive performance., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Introduction: Gender differences in neurocognitive function have been reported over the past few decades. However, multiple studies that report gender differences in Immediate Post-Concussion Assessment and Cognitive Tests composite scores ignore potential confounders which may lead to inaccurate results., Methods: A total of 4829 male and 2477 female baseline Immediate Post-Concussion Assessment and Cognitive Tests from 2009 to 2019 of subjects ages 12-18 years were used to evaluate gender differences in baseline neurocognitive scores and symptom severity ratings. Regression analyses were used to assess the effects of gender on neurocognitive performance at baseline while controlling for a number of potential confounders including symptom burden at the time of testing., Results: Differences in 3 of 5 composite scores as well as severity rating scores were maintained in multivariate analysis. Females had increased Post-Concussion Symptom Scale (β = 3.54, 95% confidence interval, 2.91 to 4.16, P < .0001) along with higher verbal memory (β = 1.82, 95% confidence interval, 1.15 to 2.50, P < .0001) and visual motor (β = 1.29, 95% confidence interval, 0.85-1.72, P < .0001) scores., Conclusions: Statistically significant gender differences were found in baseline neurocognitive function. This study clarifies for the first time that gender differences in these neurocognitive domains are not simply an artifact of differences in symptom burden. However, the small effect sizes call into question the clinical relevance of these differences.

Purpose: The Breast Cancer Surveillance Consortium (BCSC) model is a widely used risk model that predicts 5- and 10-year risk of developing invasive breast cancer for healthy women aged 35-74 years. Women with high BCSC risk may also be at elevated risk to develop interval cancers, which present symptomatically in the year following a normal screening mammogram. We examined the association between high BCSC risk (defined as the top 2.5% by age) and breast cancers presenting as interval cancers., Methods: We conducted a case-case analysis among women with breast cancer in which we compared the mode of detection and tumor characteristics of patients in the top 2.5% BCSC risk by age with age-matched (1:2) patients in the lower 97.5% risk. We constructed logistic regression models to estimate the odds ratio (OR) of presenting with interval cancers, and poor prognosis tumor features, between women from the top 2.5% and bottom 97.5% of BCSC risk., Results: Our analysis included 113 breast cancer patients in the top 2.5% of risk for their age and 226 breast cancer patients in the lower 97.5% of risk. High-risk patients were more likely to have presented with an interval cancer within one year of a normal screening, OR 6.62 (95% CI 3.28-13.4, p < 0.001). These interval cancers were also more likely to be larger, node positive, and higher stage than the screen-detected cancers., Conclusion: Breast cancer patients in the top 2.5% of BCSC risk for their age were more likely to present with interval cancers. The BCSC model could be used to identify healthy women who may benefit from intensified screening., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Contact level affects the incidence of sports-related concussion. However, the effects of contact level on injury severity and recovery are less clear and are the focus of this study., Method: Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) for athletes aged 12-22 was performed at baseline (n = 10,907 for 7,058 athletes), after suspected concussion determined by physicians or athletic trainers (n = 5,062 for 4,419 athletes), and during follow-up visits (n = 3,264 for 2,098 athletes). Athletes played contact/collision (CC), limited contact (LC), and noncontact (NC) sports. Injury incidence, severity, and recovery were measured using raw and change from baseline neurocognitive test scores. Comparisons between groups used univariate analysis and multivariable regression controlling for demographic variables., Results: Compared to CC athletes, LC and NC athletes showed decreased suspected concussion incidence. At initial post-injury testing, all neurocognitive test scores were similar between groups except changes from baseline for processing speed were improved for LC compared to CC athletes. Upon follow-up testing, raw neurocognitive scores were better for NC compared to the contact collision athletes in verbal memory, processing speed, total symptom score, migraine cluster, cognitive cluster, and neuropsychiatric cluster scores. For change from baseline scores, LC athletes exhibited better performance on verbal memory, processing speed, and reaction time but also showed higher neuropsychiatric scores than CC athletes., Conclusion: Neurocognitive scores between contact levels were similar at the first post-injury test. However, follow up showed many improved scores and symptoms for limited and NC sports compared to CC sports, which may indicate faster recovery., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Attention deficit hyperactivity disorder (ADHD) may affect concussion risk and recovery in youth athletes., Purpose: To evaluate the association between incidence of concussion and postinjury recovery of symptoms and neurocognitive dysfunction among youth athletes with ADHD and differential stimulant use., Study Design: Cohort study; Level of evidence, 3., Methods: From 2009 to 2019, the authors administered the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) to youth athletes at the beginning of each season. Throughout the season, athletes with concussions were examined and readministered the ImPACT both postinjury and again 7 days after the postinjury administration. These athletes (N = 7453) were divided into those with ADHD on stimulant-based therapy (ADHD+meds; n = 167), those with ADHD not on stimulant-based therapy (ADHD-only; n = 354), and those with no ADHD (non-ADHD; n = 6932). Recovery of neurocognitive dysfunction at postinjury and follow-up was calculated using the ImPACT symptom score, verbal memory, visual memory, visual motor skills, and reaction time (calculated as standardized deviations from baseline). Univariate results were confirmed with multivariate analysis., Results: The ADHD+meds cohort had a lower incidence of concussion (37.3 concussions per 100 patient-years) compared with the ADHD-only group (57.0 concussions per 100 patient-years) (odds ratio [OR], 0.51 [95% CI, 0.37-0.71]; P < .0001) and non-ADHD group (52.8 concussions per 100 patient-years) (OR, 0.50 [95% CI, 0.37-0.67]; P < .0001). At postinjury, ImPACT scores were elevated from baseline to a similar extent in the ADHD+meds cohort compared with the other 2 groups. By follow-up, however, deviations from baseline were lower among the ADHD+meds group compared with the non-ADHD group in verbal memory (OR, 0.46 [95% CI, 0.28-0.76]; P = .002), visual memory (OR, 0.27 [95% CI, 0.10-0.66]; P = .005), and visual motor skills (OR, 0.58 [95% CI, 0.33-0.99]; P = .048). The deviation at follow-up was also lower among the ADHD+meds group compared with the ADHD-only group in visual memory (OR, 0.56 [95% CI, 0.33-0.96]; P = .04) and visual motor skills (OR, 0.42 [95% CI, 0.22-0.81]; P = .01)., Conclusion: Stimulant use among youth athletes with ADHD was independently associated with reduced incidence for concussion and lower deviation from baseline in verbal memory, visual memory, and visual motor skills at 7 days postconcussion, suggesting lower neurocognitive impairment at follow-up in this group versus their peers., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Objective: Given concerns about the potential long-term effects of concussion in young athletes, concussion prevention has become a major focus for amateur sports leagues. Athletes have been known to frequently use anti-inflammatory medications to manage injuries, expedite return to play, and treat concussion symptoms. However, the effects of baseline nonsteroidal anti-inflammatory drug (NSAID) use on the susceptibility to head injury and concussion remain unclear. This study aims to assess the effects of preinjury NSAID use on concussion incidence, severity, and recovery in young athletes., Methods: Data from 25,815 ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) tests were obtained through a research agreement with ImPACT Applications Inc. Subjects ranged in age from 12 to 22 years old. Those who reported NSAID use at baseline were assigned to one (anti-inflammatory [AI]) cohort, whereas all others were assigned to the control (CT) cohort. Differences in head trauma and concussion incidence, severity, and recovery were assessed using chi-square tests, unpaired t-tests, and Kaplan-Meier plots., Results: The CT cohort comprised a higher percentage (p < 0.0001) of males (66.30%) than the AI cohort (44.16%) and had a significantly greater portion of athletes who played football (p = 0.004). However, no statistically significant differences were found between the two cohorts in terms of the incidence of head trauma (CT = 0.489, AI = 0.500, p = 0.9219), concussion incidence (CT = 0.175, AI = 0.169, p = 0.7201), injury severity, or median concussion recovery time (CT = 8, AI = 8, p = 0.6416). In a multivariable analysis controlling for baseline differences between the cohorts, no association was found between NSAID use and concussion incidence or severity., Conclusions: In this analysis, the authors found no evidence that preinjury use of NSAIDs affects concussion risk in adolescent athletes. They also found no indication that preinjury NSAID use affects the severity of initial injury presentation or concussion recovery.

Objective: To examine the effects of recurrent concussions on the incidence, severity, and recovery of significant neurocognitive dysfunction (SND) in young athletes., Setting: Various US youth sports organizations that utilize Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) for baseline and postinjury concussion testing., Participants: Data from 11 563 ImPACT baseline evaluations of US student-athletes aged 12 to 22 years were separated into 2 cohorts: subjects reporting 2 or more previous concussions (PC; n = 976 baseline evaluations) at baseline and a control group reporting zero previous concussions (CT; n = 7743 baseline evaluations). Subjects reporting 1 prior concussion were excluded., Design: Retrospective cohort., Main Measures: Differences in SND incidence, severity, and recovery between the 2 cohorts were assessed using chi-squared tests, t tests, survival analyses, and multivariate regressions., Results: The PC cohort had a higher incidence of head injury leading to ImPACT (436.7 per 1000 person-years vs 194.4 per 1000 person-years, P < .0001) and a higher incidence of SND (140.4 vs 71.8, P < .0001) than controls. However, the Severity Index (SI) demonstrated that SND severity was lower in the PC group (7.55 vs 8.59, P = .04). Adjusted analyses similarly demonstrated that the PC cohort had increased SND incidence (odds ratio = 1.93; 95% CI, 1.61 to 2.31; P < .0001), decreased SI (β = -1.37; 95% CI, -2.40 to -0.34; P = .009), and equivalent recovery (hazard ratio = 0.98; 95% CI, 0.76 to 1.72; P = .90)., Conclusion: Participants with a history of concussion have a higher incidence of SND but present with lower severity SND, which may be a result of increased concussion education or symptom awareness. Recurrent concussion has no significant impact on acute neurocognitive recovery. Together, these results provide evidence against the supposition that a history of concussion increases the severity of future SND., Competing Interests: Dr Lovell is the founder of ImPACT Applications, Inc. The other authors declare no conflict of interest. The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Symptom burden and reduced quality of life (QOL) are considerable hurdles in oncology. The authors used the Patient-Reported Outcomes Measurement Information System (PROMIS), which assesses physical and psychosocial health, to establish a mean symptom burden, examine potential drivers, and characterize severe symptom burden in breast cancer patient subgroups with the goal of characterizing stage IV patient QOL and triaging patients to individualized supportive care services., Methods: New patients at the University of California San Francisco Breast Care Center received questionnaires with 8 PROMIS domains: depression, anxiety, fatigue, sleep-related impairment, sleep disturbance, cognitive function, cognitive abilities, and physical function. PROMIS values were scored with the HealthMeasures service and were compared by age, cancer stage, and educational status., Results: Stage IV patients with breast cancer (n = 169) reported higher depression and fatigue and worse cognitive function, cognitive abilities, and physical function than patients with stage 0 to III disease (n = 2577). As age increased, cognitive function impairment, depression, anxiety, and sleep-related symptoms decreased. More educated patients showed better physical function and less severe sleep disturbance and fatigue. Across all subgroups, patients with high anxiety had the greatest probability of worse symptom burden and function in other domains., Conclusions: This study provides an additional set of PROMIS population estimates across breast cancer demographic groups. The analysis of a large stage IV population reinforces that metastatic patients have impaired QOL across multiple domains. Because anxiety emerged as a potential driver of impaired QOL in other domains, earlier interventions to reduce anxiety could improve QOL overall. These analyses will help to determine appropriate thresholds of intervention., Lay Summary: Patients receiving treatment for breast cancer can experience decreased quality of life. This study characterized differences in self-reported quality of life among patients of different ages, with different stages of cancer, and with different educational backgrounds. This study also examined the effect of decreased quality of life in one area (eg, anxiety) on another area (eg, difficulty in sleeping). Patients who were younger, had not attended college or technical school, or had stage IV cancer tended to have worse quality of life. Patients who had high levels of anxiety also tended to have high levels of impairment in other areas., (© 2021 American Cancer Society.)

Background: The sex of an athlete is thought to modulate concussion incidence; however, the effects of sex on concussion severity and recovery are less clear., Purpose: To evaluate sex differences in concussion severity and recovery using a large, heterogeneous sample of young student-athletes with the goal of understanding how sex affects concussion outcomes in young athletes., Study Design: Cohort study; Level of evidence, 3., Methods: The Immediate Post-Concussion Assessment and Cognitive Testing results of 11,563 baseline and 5216 postinjury tests were used to calculate the incidence of concussion of adolescent male and female student-athletes ages 12 to 22 years (median, 15 years). The postinjury tests of 3465 male and 1751 female student-athletes evaluated for concussion or head trauma were used to assess differences in the Severity Index (SI) and recovery. Chi-square tests and t tests were used to compare differences in demographic characteristics, incidence, and SI between the 2 cohorts. Multivariable linear, logistic, and Cox proportional hazards regressions were used to control for differences between cohorts in analyses of incidence, SI, and recovery., Results: When we controlled for demographic differences, female participants had higher odds of concussion (odds ratio, 1.62; 95% CI, 1.40-1.86; P < .0001) and higher SI after concussion (β = 0.67; 95% CI, 0.02-1.32; P = .04). This discrepancy in SI was a result of differences in Symptom (2.40 vs 2.94; P < .0001) and Processing Speed (0.91 vs 1.06; P = .01) composite scores between male and female participants, respectively. We found no effect of sex on time to recovery when controlling for initial concussion SI (hazard ratio, 0.94; 95% CI, 0.78-1.12; P = .48)., Conclusion: Using large, multisport cohorts, this study provides evidence that female athletes are at higher risk for more concussions and these concussions are more severe, but male and female athletes have similar recovery times when the analysis controls for initial concussion SI.

Objective: Concussions in youth sports comprise an estimated 1.6-3.8 million annual injuries in the US. Sex, age, and attention-deficit hyperactivity disorder (ADHD) have been identified as salient risk factors for concussion. This study seeks to evaluate the role of premorbid depression or anxiety (DA), with or without antidepressant use, on the incidence of concussion and the recovery of symptoms and neurocognitive dysfunction after concussion., Methods: Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) was administered to 7453 youth athletes at baseline. Throughout the season, concussions were examined by physicians and athletic trainers, followed by readministration of ImPACT postinjury (PI) and again at follow-up, a median of 7 days PI. Individuals were divided into three categories: 1) unmedicated athletes with DA (DA-only, n = 315), athletes taking antidepressants (DA-meds, n = 81), and those without DA or antidepressant use (non-DA, n = 7039). Concussion incidence was calculated as the total number of concussions per total number of patient-years. The recovery of neurocognitive measures PI was calculated as standardized deviations from baseline to PI and then follow-up in the 5 composite ImPACT scores: symptom score, verbal memory, visual memory, visual motor skills, and reaction time. Univariate results were confirmed with multivariate analysis., Results: There was no difference in concussion incidence between the DA-only cohort and the non-DA group. However, the DA-meds group had a significantly greater incidence of concussion than both the DA-only group (OR 2.67, 95% CI 1.88-7.18, p = 0.0001) and the non-DA group (OR 2.19, 95% CI 1.16-4.12, p = 0.02). Deviation from baseline in PI symptom scores was greater among the DA-meds group as compared to the non-DA group (OR 1.14, 95% CI 1.01-1.28, p = 0.03). At follow-up, the deviation from baseline in symptom scores remained elevated among the DA-meds group as compared to the non-DA group (OR 1.62, 95% CI 1.20-2.20, p = 0.002) and the DA-only group (OR 1.87, 95% CI 1.12-3.10, p = 0.02). Deviation from baseline in follow-up verbal memory was also greater among the DA-meds group as compared to both the non-DA group (OR 1.57, 95% CI 1.08-2.27, p = 0.02) and the DA-only group (OR 1.66, 95% CI 1.03-2.69, p = 0.04)., Conclusions: Premorbid DA itself does not seem to affect the incidence of concussion or the recovery of symptoms and neurocognitive dysfunction PI. However, antidepressant use for DA is associated with 1) increased concussion incidence and 2) elevated symptom scores and verbal memory scores up to 7 days after concussion, suggesting impaired symptomatic and neurocognitive recovery on ImPACT.

Background: Various non-pharmaceutical interventions (NPIs) such as stay-at-home orders and school closures have been employed to limit the spread of Coronavirus disease (COVID-19). This study measures the impact of social distancing policies on COVID-19 transmission in US states during the early outbreak phase to assess which policies were most effective., Methods: To measure transmissibility, we analyze the average effective reproductive number (R t ) in each state the week following its 500th case and doubling time from 500 to 1000 cases. Linear and logistic regressions were performed to assess the impact of various NPIs while controlling for population density, GDP, and certain health metrics. This analysis was repeated for deaths with doubling time to 100 deaths with several healthcare infrastructure control variables., Results: States with stay-at-home orders in place at the time of their 500th case were associated with lower average R t the following week compared to states without them (p<0.001) and significantly less likely to have an R t >1 (OR 0.07, 95% CI 0.01-0.37, p = 0.004). These states also experienced longer doubling time from 500 to 1000 cases (HR 0.35, 95% CI 0.17-0.72, p = 0.004). States in the highest quartile of average time spent at home were also slower to reach 1000 cases than those in the lowest quartile (HR 0.18, 95% CI 0.06-0.53, p = 0.002)., Conclusions: Stay-at-home orders had the largest effect of any policy analyzed. Multivariate analyses with cellphone tracking data suggest social distancing adherence drives these effects. States that plan to scale back such measures should carefully monitor transmission metrics., Competing Interests: Declaration of Competing Interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: There has been much interest in environmental temperature and race as modulators of Coronavirus disease-19 (COVID-19) infection and mortality. However, in the United States race and temperature correlate with various other social determinants of health, comorbidities, and environmental influences that could be responsible for noted effects. This study investigates the independent effects of race and environmental temperature on COVID-19 incidence and mortality in United States counties., Methods: Data on COVID-19 and risk factors in all United States counties was collected. 661 counties with at least 50 COVID-19 cases and 217 with at least 10 deaths were included in analyses. Upper and lower quartiles for cases/100,000 people and halves for deaths/100,000 people were compared with t-tests. Adjusted linear and logistic regression analyses were performed to evaluate the independent effects of race and environmental temperature., Results: Multivariate regression analyses demonstrated Black race is a risk factor for increased COVID-19 cases (OR=1.22, 95% CI: 1.09-1.40, P=0.001) and deaths independent of comorbidities, poverty, access to health care, and other risk factors. Higher environmental temperature independently reduced caseload (OR=0.81, 95% CI: 0.71-0.91, P=0.0009), but not deaths., Conclusions: Higher environmental temperatures correlated with reduced COVID-19 cases, but this benefit does not yet appear in mortality models. Black race was an independent risk factor for increased COVID-19 cases and deaths. Thus, many proposed mechanisms through which Black race might increase risk for COVID-19, such as socioeconomic and healthcare-related predispositions, are inadequate in explaining the full magnitude of this health disparity., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objective: Concussions are a major public health concern, especially for high school and college student athletes. However, there are few prognostic metrics that can accurately quantify concussion severity in order to anticipate recovery time and symptom regression. The Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) is a widely used neurocognitive assessment that can diagnose and track recovery from concussions. This study assesses whether initial ImPACT scores, collected within 48 hours of the injury, can predict persistence of concussion at follow-up., Methods: Results from 6912 ImPACT tests were compiled in 2161 unique student athletes, ages 12-22 years. The authors defined a novel metric, the Severity Index (SI), which is a summation of the number of standard deviations from baseline at the 80% CI for each of the 5 composite scores reported by ImPACT. Patients were binned into groups based on SI (0-3.99, 4-7.99, 8-11.99, 12+) and the relationships between SI groups, composite scores, symptom profiles, and recovery time were characterized using 1-way and 2-way ANOVAs and Kaplan-Meier plots. A logistic regression assessed the value of SI for predicting concussion at follow-up., Results: Patients with a higher SI at diagnosis were more likely to still be concussed at their first follow-up (F3,2300 = 93.06; p < 0.0001). Groups with a higher SI also displayed consistently slower recovery over a 42-day period and were more likely to report symptoms in all 4 symptom clusters (Migraine, Cognition, Sleep, and Neuropsychiatric). When controlling for sex, age, number of previous concussions, days between assessments, and location, SI significantly increased the odds of being concussed at follow-up (OR 1.122, 95% CI 1.088-1.142; p < 0.001). This model showed good discrimination with an area under the curve of 0.74., Conclusions: SI is a useful prognostic tool for assessing head injury severity. Concussions with higher initial SI tend to last longer and have broader symptomatic profiles. These findings can help patients and providers estimate recovery based on similar ImPACT score profiles.

Background: Many patients' activity levels decrease during chemotherapy. Wearable devices, such as Fitbits, track activity patterns and may encourage behavior change. This study aimed to determine the utility of using Fitbits to measure physical activity and sleep throughout chemotherapy., Patients and Methods: Patients with early stage breast cancer were enrolled prior to starting chemotherapy. Patients received a Fitbit Charge HR and were instructed to wear it and sync at least weekly throughout chemotherapy and up to 6 months post therapy. Patients completed baseline surveys, and treatment information was collected from their medical records. Fitbit data was downloaded from the Fitabase data management platform. To assess utility, we evaluated how many days patients wore their Fitbit for at least 10 hours., Results: Adherence to wearing the Fitbit was low, with 16.9% of patients never syncing their device. For those who did sync, the mean number of valid days (> 10 hours of use) across the 9-month study period was 44.5% (SD, 36.9%), and the median was 39.6%, with a range of 0% to 100% of the total study days. Adherence was higher among participants receiving adjuvant chemotherapy versus neoadjuvant chemotherapy (51.9% vs. 29.6% valid days, respectively [P = .037]). Baseline questions indicating positive attitudes toward technology were significantly correlated with higher adherence., Conclusions: Fitbit use during breast cancer chemotherapy was poor in the absence of prompts to encourage wear. Interventions including phone calls, texts, or other reminders to maintain adherence are likely necessary to increase wear in active treatment settings., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction Concussion incidence in the National Football League (NFL) has been shown to generally increase as the season progresses. Yet, there is evidence that suggests that the incidence stagnates or decreases in the final quarter of the season in comparison to the third quarter. This anomaly cannot be explained by any of the known modulators of concussion incidence. However, the fact that the teams start getting eliminated from playoff contention in the fourth quarter of the season may explain this pattern in concussion incidence. This study tests whether there is a difference in concussion incidence in games between teams who are still in the playoff hunt [in the hunt (IH) games] versus games where both teams have had their playoff fate already determined (non-IH games). Methods We obtained details of 166 documented concussions from weeks 13-16 of each of the four NFL seasons from 2012 to 2015 from Public Broadcasting Service's (PBS) Frontline Concussion Watch and matched them to the games in which they occurred. Each game was categorized based on the playoff status [clinched (CL), eliminated (EL), or IH] of the teams playing in the game. Concussion incidence of the game types was compared to each other using a one-way analysis of variance (ANOVA) test and student t-tests. Additionally, concussion incidences at six different player positions in important games were compared to the corresponding incidences in unimportant games. An ordinary least squares regression was used to examine the effects of game importance and plays per game on concussion incidence. Results Concussion incidence in important games (mean = 0.651 ±0.055) did not differ significantly (p: 0.890) from the incidence in unimportant games (mean = 0.623 ±0.143). Instead, plays per game was found to be the primary driver of concussion in the regression analysis (β = 0.01605; p: 0.025). At the position-specific level, running backs (RB) were the only position to demonstrate a significant increase in concussion incidence (p: 0.004) in important games (mean = 0.049 ±0.017) compared to unimportant games (mean = 0.00 ±0.00). Conclusions The results suggest that, in general, players are not more likely to suffer concussions in IH games than in non-IH games. However, RBs may have an increased risk of concussion in games with playoff implications than in games without., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2019, Hannah et al.)

Purpose: This study evaluated the use of an electronic Health Questionnaire System (HQS) within the University of California San Francisco Breast Care Center as a screening and triage tool to proactively recognize patients' supportive care needs during new patient consultations and identify demographic characteristics associated with referrals to three supportive care services., Patients and Methods: A total of 428 patients with and without breast cancer between the ages of 18 and 84 years completed HQS intake forms before appointments at the University of California San Francisco Breast Care Center between November 2014 and May 2015 and agreed to participate in this study. Patient HQS responses triggered referrals to supportive care services, and a review of electronic health records was conducted to determine the outcomes of these referrals., Results: A total of 242 patients (56.5%) met criteria for at least one supportive care referral. Women with invasive breast cancer or ductal carcinoma in situ met criteria for supportive services more frequently than women without breast cancer diagnoses (76.9% v 23.8%; P < .001) and were most likely to receive referrals for genetic counseling (67.0%), psychological services (32.2%), and social services (12.1%). Multivariable logistic regression analysis showed that being married was associated with fewer referrals to social work (OR, 0.42; 95% CI, 0.21 to 0.81) and that those between 45 and 54 years of age were less likely to receive referrals to genetic counseling than those ≥ 55 years of age (OR, 0.41; 95% CI, 0.23 to 0.73). Among all referrals (n = 369), 26.8% resulted in completed appointments., Conclusion: Using an automated intake form is an efficient way to identify and triage individuals in need of supportive care services and can provide insight into the populations with supportive care needs for targeted outreach.

Purpose: Hirschsprung's associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in Hirschsprung's disease (HSCR). Nitric oxide (NO) mediates intestinal homoeostasis and is inhibited by NOSIP, a modulator of NO production. We designed this study to investigate the expression of NOSIP in the colon of patients with HSCR., Methods: We investigated NOSIP, endothelial NO synthase, and neuronal NO synthase expression in both the aganglionic and ganglionic regions of HSCR patients (n=10) versus normal control colon (n=10). Protein distribution was assessed by using immunofluorescence and confocal microscopy. Gene and protein expression were quantified using quantitative real-time polymerase chain reaction (qPCR), Western blot analysis, and densitometry., Main Results: qPCR and Western blot analysis demonstrate that NOSIP was significantly increased in the aganglionic and ganglionic colon compared to controls (p<0.05). Confocal microscopy revealed a markedly increased expression of NOSIP in the colon epithelium of patients with HSCR compared to controls., Conclusion: To our knowledge, we demonstrate for the first time the expression of NOSIP in the human colon. While NOSIP expression was increased in HSCR vs. non-HSCR patients, no significant difference was observed in patients with HAEC. The increased expression of NOSIP in the aganglionic and ganglionic bowel of HSCR may contribute to the development of enterocolitis by inhibiting local NO production in patients with Hirschsprung's disease., Level of Evidence: II., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The pathophysiology of Hirschsprung's disease (HSCR) is not fully understood. A significant proportion of patients have persisting bowel symptoms such as constipation, soiling, and enterocolitis despite correctly performed operations. Animal data suggest that stretch-activated 2-pore domain K + channels play a critical role in the maintenance of intestinal barrier integrity., Methods: We investigated TREK-1 protein expression in ganglionic and aganglionic regions of HSCR patients (n = 10) vs. normal control colon (n = 10). Protein distribution was assessed by using immunofluorescence and confocal microscopy. Gene and protein expression were quantified using quantitative real-time polymerase chain reaction, western blot analysis, and densitometry., Results: Confocal microscopy of the normal colon revealed strong TREK-1 channel expression in the epithelium. TREK-1-positive cells were decreased in aganglionic and ganglionic bowel compared to controls. TREK-1 gene expression levels were significantly decreased in aganglionic and ganglionic bowel compared to controls (P < 0.05). Western blotting revealed decreased TREK-1 protein expression in aganglionic and ganglionic bowel compared to controls., Conclusion: We demonstrate, for the first time, the expression and distribution of TREK-1 channels in the human colon. The decreased TREK-1 expression in the aganglionic and ganglionic bowel observed in HSCR may alter intestinal epithelial barrier function leading to the development of enterocolitis.

Purpose: Hirschsprung's disease-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in Hirschsprung's disease (HSCR). Altered intestinal epithelial barrier function has been suggested to play a role in the causation of HAEC. In rodent experimental models of colitis, a decreased expression of K(ATP) channels (Subunits: Kir6.1/6.2 and SUR1/2) is reported. We designed this study to determine if K(ATP) channels exist within the human colon and to investigate the expression of different subunits in Hirschsprung's disease., Methods: We investigated Kir6.1, Kir6.2, SUR1, and SUR2 expression in ganglionic and aganglionic bowel of HD patients (n=5) and controls (n=5). Western blotting and confocal immunofluorescence were performed., Main Results: Western blot analysis revealed that Kir6.1, Kir6.2, SUR1, and SUR2 are strongly expressed in the normal human colon. Kir6.1, Kir6.2, SUR1, and SUR2 expression was significantly decreased in the aganglionic bowel compared to ganglionic bowel and controls. Kir6.1 and SUR1 expression were also significantly decreased in the ganglionic bowel of HSCR patients compared to controls., Conclusion: We demonstrate for the first time the existence of K(ATP) channels in the human colon. The decreased K(ATP) channel expression in HSCR specimens suggests that an altered K(ATP) expression may interfere with intestinal epithelium barrier function and predispose to HAEC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This report demonstrates the utilization of a new serum factor, Toxicity Preventing Activity (TxPA) in the diagnosis of coronary disease prone individuals. Our laboratory has recently identified TxPA, which offsets the toxicity of very low density lipoproteins (VLDL) upon arterial cells in vitro. In the present study, we measured TxPA activity and serum lipoprotein levels in 73 individuals undergoing coronary angiography. Serum from control subjects demonstrated 270% more TxPA than aged matched individuals with angiographically demonstrable coronary disease (CHD). When TxPA was combined with serum lipoprotein values, a new atherogenic index was generated which further distinguished these individuals with CHD from non-angiographed controls. These results demonstrate that TxPA is a new protective factor in coronary artery disease, and that the new atherogenic index provides for the first time an accurate classification of individuals with coronary artery disease.