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Aims: To determine the efficacy of XPro1595 to improve pathophysiological and functional outcomes in a mouse model of traumatic brain injury (TBI). Background: Symptoms associated with TBI can be debilitating, and treatment without off-target side effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. Objectives: Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation and dendritic plasticity and associated functional impairments. Methods: Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J WT and Thy1-YFPH mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. Results: We report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior, and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology’s within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus, that were prevented in mice treated with XPro1595. Conclusion: Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use in patients with TBI.

Summary Objective Dysphonia is a reduction in vocal quality that impacts communication and is often an early sign of a voice disorder. There is little information regarding the effects of auditory feedback control of loudness and pitch on voice quality. In this study, we used both loudness-shift and pitch-shift paradigms to study the relationship between auditory feedback control and vocal quality as measured by smoothed cepstral peak prominence (CPPS), which reflects the harmonicity of the voice signal. Study Design Experimental, mixed design. Methods We applied 200 ms loudness-shifts (± 0, 3, or 6 dB) and pitch-shifts (± 0, 50, and 100 cents) to auditory feedback during sustained vowel production in 25 healthy adults. We then measured CPPS before and after the loudness-shift or pitch-shift to investigate the effect of changes in auditory feedback on vocal harmonicity. Results & Conclusions Results showed that, on average, CPPS significantly decreased between the first half of the measured segment and the last half of the segment in the absence of auditory feedback shifts, suggesting that voice quality may be reduced across longer vowels over time. Upward and downward shifts in loudness auditory feedback caused a relative increase in CPPS, indicating an improvement in vocal harmonicity, even in cases when vocal intensity was reduced. Pitch alterations had inconsistent and minimal effects. We propose that there may be a control mechanism for voice quality that increases harmonicity of the voice signal to improve voice audibility (ie, ability to be heard) in the presence of unpredictable variability in voice intensity.

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear...

Introduction Enterobius vermicularis is known to be associated with appendicitis, however a causal relationship between Enterobius and appendicitis has not been established. The aim of this study was to explore the relationship between appendiceal Enterobius and histologic appendicitis. Methods A retrospective review was performed of all pediatric appendectomies between 1997 and 2019. Patients with diagnosed with Enterobius were included for analysis. Patient demographics, operative findings, and pathologic reports were queried. Data were entered into an encrypted database and subsequently analyzed. A comprehensive review of the literature was also conducted. Results Thirty-eight cases of Enterobius-associated appendicitis were identified out of 3541 (1.07%). Grossly normal appendices at operation were seen in 27% of patients. Inflammatory infiltrate was noted on histopathology in 78.3%, and Enterobius was considered to be the cause of that inflammation in 68.4%. The comprehensive literature review revealed 19 articles (1.87% incidence) that noted 35% of patients with appendiceal Enterobius had appendicitis on either histopathology or gross evaluation. Conclusion The high rate of inflammation on pathology found among our patients with pinworm appendicitis suggests an association with presentation as acute appendicitis. Our comprehensive review revealed a higher proportion of Enterobius appendicitis. Treatment with antihelminthic therapy is recommended. Level of evidence (LOE) Level IV(4)-case series and comprehensive review.

Background: The Ebola epidemics in west Africa and the Democratic Republic of the Congo highlight an urgent need for safe and effective vaccines to prevent Ebola virus disease. We aimed to assess the safety and long-term immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in Sierra Leone, a country previously affected by Ebola. Methods: The trial comprised two stages: an open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2. The study was done at three clinics in Kambia district, Sierra Leone. In stage 1, healthy adults (aged ≥18 years) residing in or near Kambia district, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) on day 1 (first dose) followed by an intramuscular injection of MVA-BN-Filo (1 × 108 infectious units) on day 57 (second dose). An Ad26.ZEBOV booster vaccination was offered at 2 years after the first dose to stage 1 participants. The eligibility criteria for adult participants in stage 2 were consistent with stage 1 eligibility criteria. Stage 2 participants were randomly assigned (3:1), by computer-generated block randomisation (block size of eight) via an interactive web-response system, to receive either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or an intramuscular injection of a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo on day 57 (second dose; control group). Study team personnel, except those with primary responsibility for study vaccine preparation, and participants were masked to study vaccine allocation. The primary outcome was the safety of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen, which was assessed in all participants who had received at least one dose of study vaccine. Safety was assessed as solicited local and systemic adverse events occurring in the first 7 days after each vaccination, unsolicited adverse events occurring in the first 28 days after each vaccination, and serious adverse events or immediate reportable events occurring up to each participant's last study visit. Secondary outcomes were to assess Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second vaccine in a per-protocol set of participants (ie, those who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response) and to assess the safety and tolerability of the Ad26.ZEBOV booster vaccination in stage 1 participants who had received the booster dose. This study is registered at ClinicalTrials.gov, NCT02509494. Findings: Between Sept 30, 2015, and Oct 19, 2016, 443 participants (43 in stage 1 and 400 in stage 2) were enrolled; 341 participants assigned to receive the Ad26.ZEBOV and MVA-BN-Filo regimen and 102 participants assigned to receive the MenACWY and placebo regimen received at least one dose of study vaccine. Both regimens were well tolerated with no safety concerns. In stage 1, solicited local adverse events (mostly mild or moderate injection-site pain) were reported in 12 (28%) of 43 participants after Ad26.ZEBOV vaccination and in six (14%) participants after MVA-BN-Filo vaccination. In stage 2, solicited local adverse events were reported in 51 (17%) of 298 participants after Ad26.ZEBOV vaccination, in 58 (24%) of 246 after MVA-BN-Filo vaccination, in 17 (17%) of 102 after MenACWY vaccination, and in eight (9%) of 86 after placebo injection. In stage 1, solicited systemic adverse events were reported in 18 (42%) of 43 participants after Ad26.ZEBOV vaccination and in 17 (40%) after MVA-BN-Filo vaccination. In stage 2, solicited systemic adverse events were reported in 161 (54%) of 298 participants after Ad26.ZEBOV vaccination, in 107 (43%) of 246 after MVA-BN-Filo vaccination, in 51 (50%) of 102 after MenACWY vaccination, and in 39 (45%) of 86 after placebo injection. Solicited systemic adverse events in both stage 1 and 2 participants included mostly mild or moderate headache, myalgia, fatigue, and arthralgia. The most frequent unsolicited adverse event after the first dose was headache in stage 1 and malaria in stage 2. Malaria was the most frequent unsolicited adverse event after the second dose in both stage 1 and 2. No serious adverse event was considered related to the study vaccine, and no immediate reportable events were observed. In stage 1, the safety profile after the booster vaccination was not notably different to that observed after the first dose. Vaccine-induced humoral immune responses were observed in 41 (98%) of 42 stage 1 participants (geometric mean binding antibody concentration 4784 ELISA units [EU]/mL [95% CI 3736–6125]) and in 176 (98%) of 179 stage 2 participants (3810 EU/mL [3312–4383]) at 21 days after the second vaccination. Interpretation: The Ad26.ZEBOV and MVA-BN-Filo vaccine regimen was well tolerated and immunogenic, with persistent humoral immune responses. These data support the use of this vaccine regimen for Ebola virus disease prophylaxis in adults. Funding: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

Summary Background Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone. Methods This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1–17 years were enrolled in three age cohorts (12–17 years, 4–11 years, and 1–3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 1010 viral particles; first dose) followed by MVA-BN-Filo (1 × 108 infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov , NCT02509494 . Findings From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1–3 years after placebo injection to 21% (30 of 144) of children aged 4–11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12–17 years and 4–11 years age cohorts after the first and second dose, and pyrexia in the 1–3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12–17 years (9929 ELISA units [EU]/mL [95% CI 8172–12 064]), in 119 (99%) of 120 aged 4–11 years (10 212 EU/mL [8419–12 388]), and in 118 (98%) of 121 aged 1–3 years (22 568 EU/mL [18 426–27 642]). Interpretation The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1–17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children. Funding Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

OBJECTIVE Prior trauma history is a reliable and robust risk predictor for PTSD development. Obtaining an accurate measurement of prior trauma history is critical in research of trauma-related outcomes. The Life Events Checklist (LEC) is a widely used self-report measure of trauma history that categorizes events by the proximity to trauma exposure; however, the field has published multiple scoring methods when assessing the LEC. Herein, we propose a novel scoring procedure in which total scores from the LEC are weighted according to the proximity of trauma exposure with "experienced" events weighted most and "learned about" events weighted least. METHOD The utility of this weighted score was assessed in two traumatically-injured civilian samples and compared against previously published scoring methods, including a nonweighted score including all events experienced, witnessed, and learned about, as well as a score consisting of only experienced events. RESULTS Results indicated the standard total score was most reliable, followed by the weighted score. The experienced events score was least reliable, but the best predictor of future PTSD symptoms. CONCLUSIONS One method to balance the predictive strength of experienced events and the excellent reliability of a total LEC score, is to adopt the newly proposed weighted score. Future use of this weighted scoring method can provide a comprehensive estimate of lifetime trauma exposure while still emphasizing the direct proximity of experienced events compared with other degrees of exposure. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive neoplasms with poor outcomes, commonly affecting older patients with comorbidities. This study aims to describe outcomes of older patients with PTCL in a large international cohort. Patients aged ≥70 years with PTCL diagnosed from 1 January 2010 to 31 December 2015 in the Swedish Lymphoma Registry (SLR) and California Cancer Registry (CCR) were identified. Data on comorbidity were retrospectively collected according to the Charlson Comorbidity Index (CCI), and clinical outcomes were extracted. A total of 891 patients were included (SLR, n = 173; CCR, n = 718). Median age was 77 (SLR) and 78 (CCR) years. Included subtypes were as follows: angioimmunoblastic T-cell lymphoma, n = 226; anaplastic large-cell lymphoma, n = 122; enteropathy-associated T-cell lymphoma (EATL), n = 31; hepatosplenic TCL, n = 7; natural killer–/T-cell lymphoma, n = 62; PTCL not otherwise specified, n = 443. CCI data were available in 775 patients (87%), and CCI scores were divided into the groups CCI = 0 (39%), CCI = 1 (22%), and CCI > 1 (39%). Median age did not differ among the CCI groups (P = .72). Patients with a CCI > 1 had a worse median overall survival (4.4 months) compared with patients with CCI = 0 (11.9 months) and CCI = 1 (8.4 months; P < .001). Comorbidity and advancing age in as little as 5-year increments are important adverse factors in this group. Most patients died of lymphoma within a year from diagnosis, underscoring the importance of developing new treatments.

Perfusion collateral index (PCI) has been recently defined as a promising measure of collateral status. We sought to compare collateral status assessed via CT-PCI in comparison to single-phase CTA and their relationship to outcome measures including final infarction volume, final recanalization status and functional outcome in ELVO patients.ELVO patients with anterior circulation large vessel occlusion who had baseline CTA and CT perfusion and underwent endovascular treatment were included. Collateral status was assessed on CTA. PCI from CT perfusion was calculated in each patient and an optimal threshold to separate good vs insufficient collaterals was identified using DSA as reference. The collateral status determined by CTA and PCI were assessed against 3 measured outcomes: 1) final infarction volume; 2) final recanalization status defined by TICI scores; 3) functional outcome measured by 90-day mRS.A total of 53 patients met inclusion criteria. Excellent recanalization defined by TICI ≥2C was achieved in 36 (68%) patients and 23 patients (43%) had good functional outcome (mRS ≤2). While having good collaterals on both CTA and CTP-PCI was associated with significantly (p0.05) smaller final infarction volume, only good collaterals status determined by CTP-PCI was associated with achieving excellent recanalization (p = 0.001) and good functional outcome (p = 0.003).CTP-based PCI outperforms CTA collateral scores in determination of excellent recanalization and good functional outcome and may be a promising imaging marker of collateral status in patients with delayed presentation of AIS.

Aim: At presentation, 15–20% of patients with rectal cancer already have synchronous liver metastases. The aim of this study was to determine the surgical and survival outcomes in patients with advanced rectal cancer who underwent combined pelvic exenteration and liver (oligometastatic) resection. Method: Data from 20 international institutions that performed simultaneous pelvic exenteration and liver resection between 2007 and 2017 were accumulated. Primarily, we examined perioperative outcomes, morbidity and mortality. We also assessed the impact that margin status had on survival. Results: Of 128 patients, 72 (56.2%) were men with a median age of 60 years [interquartile range (IQR) 15 years]. The median size of the liver oligometastatic deposits was 2 cm (IQR 1.8 cm). The median duration of surgery was 406 min (IQR 240 min), with a median blood loss of 1090 ml (IQR 2010 ml). A negative resection margin (R0 resection) was achieved in 73.5% of pelvic exenterations and 66.4% of liver resections. The 30-day mortality rate was 1.6%, and 32% of patients had a major postoperative complication. The 5-year overall survival for patients in whom an R0 resection of both primary and metastatic disease was achieved was 54.6% compared with 20% for those with an R1/R2 resection (P = 0.006). Conclusion: Simultaneous pelvic exenteration and liver resection is feasible, with acceptable morbidity and mortality. Simultaneous resection should only be performed where an R0 resection of both pelvic and hepatic disease is anticipated.

Osteopenia and osteoporosis have increasingly become a recognized morbidity in those persons with hemophilia (PwH) receiving inadequate prophylactic clotting factor replacement. Animal models can control or eliminate genetic and environmental factors and allow for invasive testing not clinically permissible. Here, we describe the skeletal phenotype of juvenile and adult male mice with a genetically engineered deficiency in coagulation factor IX (FIX KO). Although the somatic growth of FIX KO mice matched that of their wild-type (WT) littermates at 10 and 20 weeks of age, the FIX KO mice displayed reduced bone mineral density (BMD), reduced cortical and cancellous bone mass, and diminished whole bone fracture resistance. These findings coupled with parallel observations in a murine model of hemophilia A (FVIII deficiency) point to an effector downstream of the coagulation cascade that is necessary for normal skeletal development. Further study of potential mechanisms underlying the bone disease observed in rare clotting factor deficiency syndromes may lead to new diagnostic and therapeutic insights for metabolic bone diseases in general.

Key Points Severe bone marrow failure was primarily observed in early childhood in children with biallelic SBDS mutations.Absolute neutrophil counts were positively associated with age (P < .0001) in patients with biallelic SBDS mutations., Visual Abstract, Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.

High‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

Carotid plaque vulnerability features beyond the degree of stenosis may play a key role in the pathogenesis and recurrence of ischemic cerebrovascular events. This study sought to compare intraplaque hemorrhage (IPH) as a marker of plaque vulnerability in symptomatic patients with mild ( We included patients who experienced ischemic cerebrovascular events with no other identifiable sources and underwent carotid endarterectomy for mild (n=32), moderate (n=47), and severe (n=58) carotid artery stenosis. The degree of stenosis and imaging hallmarks were assessed by computed tomography angiography or magnetic resonance angiography. Plaque specimens were stained with hematoxylin and eosin and Movat pentachrome staining. Carotid plaques of patients with mild stenosis had a higher extent of IPH (%) on tissue analysis compared with patients with moderate (mild, 15.7% [interquartile range, 7.8%–26.7%]; moderate, 3.9% [0.0%–9.2%]; P P P Our major finding is the association of IPH with mild carotid artery stenosis based on histological analysis. The current study may suggest that IPH potentially plays a role in the mechanism of stroke in patients with nonobstructive carotid stenosis.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26–27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic “cure”) at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42–52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression, while 17 (46%) samples injected into 107 xenografts remained non-invasive. Among the 20 samples that showed invasive progression, nine samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained non-invasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS formalin-fixed, paraffin-embedded sections including eight DCISs that showed invasive progression, five DCISs that remained non-invasive, and three DCISs that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer-related pathogenic mutations among the groups showed no significant differences (KW: p 0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; p 0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease. © 2021 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

PURPOSE To facilitate identification of clinical trial participation candidates, we developed a machine learning tool that automates the determination of a patient's metastatic status, on the basis of unstructured electronic health record (EHR) data. METHODS This tool scans EHR documents, extracting text snippet features surrounding key words (such as metastatic, progression, and local). A regularized logistic regression model was trained and used to classify patients across five metastatic categories: highly likely and likely positive, highly likely and likely negative, and unknown. Using a real-world oncology database of patients with solid tumors with manually abstracted information as reference, we calculated sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). We validated the performance in a real-world data set, evaluating accuracy gains upon additional user review of tool's outputs after integration into clinic workflows. RESULTS In the training data set (N = 66,532), the model sensitivity and specificity (% [95% CI]) were 82.4 [81.9 to 83.0] and 95.5 [95.3 to 96.7], respectively; the PPV was 89.3 [88.8 to 90.0], and the NPV was 94.0 [93.8 to 94.2]. In the validation sample (n = 200 from five distinct care sites), after user review of model outputs, values increased to 97.1 [85.1 to 99.9] for sensitivity, 98.2 [94.8 to 99.6] for specificity, 91.9 [78.1 to 98.3] for PPV, and 99.4 [96.6 to 100.0] for NPV. The model assigned 163 of 200 patients to the highly likely categories. The error prevalence was 4% before and 2% after user review. CONCLUSION This tool infers metastatic status from unstructured EHR data with high accuracy and high confidence in more than 75% of cases, without requiring additional manual review. By enabling efficient characterization of metastatic status, this tool could mitigate a key barrier for patient ascertainment and clinical trial participation in community clinics.

This study sought to compare the brachial and carotid hemodynamic response to hot water immersion (HWI) between healthy young men and women. Ten women (W) and 11 men (M) (24 ± 4 yr) completed a 60-min HWI session immersed to the level of the sternum in 40°C water. Brachial and carotid artery hemodynamics (Doppler ultrasound) were measured at baseline (seated rest) and every 15 min throughout HWI. Within the brachial artery, total shear rate was elevated to a greater extent in women [+479 (+364, +594) s−1] than in men [+292 (+222, +361) s−1] during HWI ( P = 0.005). As shear rate is inversely proportional to blood vessel diameter and directly proportional to blood flow velocity, the sex difference in brachial shear response to HWI was the result of a smaller brachial diameter among women at baseline ( P < 0.0001) and throughout HWI (main effect of sex, P < 0.0001) and a greater increase in brachial velocity seen in women [+48 (+36, +61) cm/s] compared with men [+35 (+27, +43) cm/s] with HWI ( P = 0.047) which allowed for a similar increase in brachial blood flow between sexes [M: +369 (+287, +451) mL/min, W: +364 (+243, +486) mL/min, P = 0.943]. In contrast, no differences were seen between sexes in carotid total shear rate, flow, velocity, or diameter at baseline or throughout HWI. These data indicate the presence of an artery-specific sex difference in the hemodynamic response to a single bout of HWI.

BACKGROUND Despite tremendous efforts, the incidence of surgical site infection (SSI) following the surgical treatment of pediatric spinal deformity remains a concern. Although previous studies have reported some risk factors for SSI, these studies have been limited by not being able to investigate multiple risk factors at the same time. The aim of the present study was to evaluate a wide range of preoperative and intraoperative factors in predicting SSI and to develop and validate a prediction model that quantifies the risk of SSI for individual pediatric spinal deformity patients. METHODS Pediatric patients with spinal deformity who underwent primary, revision, or definitive spinal fusion at 1 of 7 institutions were included. Candidate predictors were known preoperatively and were not modifiable in most cases; these included 31 patient, 12 surgical, and 4 hospital factors. The Centers for Disease Control and Prevention definition of SSI within 90 days of surgery was utilized. Following multiple imputation and multicollinearity testing, predictor selection was conducted with use of logistic regression to develop multiple models. The data set was randomly split into training and testing sets, and fivefold cross-validation was performed to compare discrimination, calibration, and overfitting of each model and to determine the final model. A risk probability calculator and a mobile device application were developed from the model in order to calculate the probability of SSI in individual patients. RESULTS A total of 3,092 spinal deformity surgeries were included, in which there were 132 cases of SSI (4.3%). The final model achieved adequate discrimination (area under the receiver operating characteristic curve: 0.76), as well as calibration and no overfitting. Predictors included in the model were nonambulatory status, neuromuscular etiology, pelvic instrumentation, procedure time ≥7 hours, American Society of Anesthesiologists grade >2, revision procedure, hospital spine surgical cases

Objectives: The submental island flap is a dependable workhorse in head and neck reconstruction. However, the viability of this flap has not been established for oral cavity reconstruction when a contralateral neck dissection has already been performed in an earlier surgical setting. The aim of this study is to highlight technical considerations and outcomes of this approach with a small case series. Methods: Three cases of oral cavity reconstruction with a submental island flap elevated in the context of a prior contralateral neck dissection are presented. Results: In all cases, a doppler was used to identify the maintenance of the submental perforator in the neck opposite the previous neck dissection. In 2 cases, level IA was included within the dissection field of the previous neck dissection. Additionally, the old neck scar was included within the skin paddle of the submental island flap in 2 cases. In all cases, excellent healing of the flap was observed without partial or complete loss. Conclusions: The submental island flap appears to be a reliable reconstruction when a previous contralateral neck dissection has been performed, even when level IA was included in the prior dissection.

BACKGROUND The efficacy of preoperative oral antibiotics alone compared to mechanical bowel preparation and oral antibiotics in minimally invasive surgery is still a matter of ongoing debate. OBJECTIVE This study aimed to assess the trend of surgical site infection rates in parallel to the utilization of bowel preparation modality over time for minimally invasive surgery colorectal surgeries in the United States. DESIGN Retrospective analysis. SETTINGS The American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS Adult patients who underwent elective colorectal surgery and reported bowel preparation modality. MAIN OUTCOME MEASURES The trends and compare surgical site infection rates for mutually exclusive groups according to the underlying disease (colorectal cancer, inflammatory bowel disease, and diverticular disease) who underwent bowel preparation using oral antibiotics or combined mechanical bowel preparation and oral antibiotics. Patients who had rectal surgery were analyzed separately. RESULTS A total of 30,939 patients were included. Of them, 12,417 (40%) had rectal resections. Over the seven-year study period, mechanical bowel preparation and oral antibiotics utilization has increased from 29.3% in 2012 to 64.0% in 2018; p

Multicenter retrospective study.Recent studies have demonstrated diminishing returns in patients with early onset scoliosis (EOS) undergoing repeated lengthening of growing rods. Little is known about whether this same phenomenon occurs in patients with lax connective tissue disease (CTD). The primary purpose of this study is to investigate whether EOS patients with connective tissue laxity disorders have diminishing returns during growth friendly surgery.CTD EOS patients below 10 years old, underwent growth friendly spine surgery with distal anchors and at least 1 proximal spine anchor, and had minimum follow-up of 5 years were included in this study. Coronal T1-S1 height at preindex surgery, postindex, and every available lengthening was assessed. Mean coronal height change during early set distractions and late set distractions were calculated for the cohort. To account for varying distraction intervals, we normalized the distractions by the time interval. The outcome parameter was T1-S1 height gain, mm/year.Twenty-one CTD patients were included in this study. Total coronal height (T1-S1) was 26.7MHCcm before index, 32.2 cm at D1-D3, 34.7 cm at D4-D6, and 36.7 cm at D7-L10. There were no significant differences in coronal height gains between early and late distractions (P=0.70). Moreover, when normalized for time, there was no significant difference in net gain per year at different lengthening time points for the CTD group, P=0.59.There is no evidence of diminishing returns in coronal T1-S1 height gain in patients with EOS in the setting of CTD.Level III.

Chronic Lyme disease can manifest as a debilitating illness with symptoms that change over time. With its varied presentation, timeline variation, diagnostic difficulty, and lack of definitive treatment, clinical recognition of chronic Lyme disease remains controversial. At the same time, patients face challenges in finding a provider who is supportive and knowledgeable about diagnosing and treating Lyme. We examined the ways the medical system may have affected the lived experiences of chronic Lyme patients. In this article, we communicate the personal, health care, and community illness experiences of 14 women navigating the medical system with chronic Lyme disease through a qualitative community-based participatory research study using interviews and narrative reflection in a rural community setting. The women were interviewed by a researcher living with chronic Lyme disease and the transcripts were analyzed for themes. All participants described navigating multiple allopathic and nonallopathic care modalities to find satisfactory care. They struggled with physical and emotional burdens of chronic, nonlinear illness, as well as disbelief and discrimination by medical providers. Their lives followed patterns of illness and wellness, trust and mistrust of medical treatment, and community connection and disengagement. They learned to become their own advocates to seek affirmative care. They are aware of the controversial nature of their illness, and many have channeled their frustrations into caring for one another through their Lyme community. Women living with controversial diagnoses like chronic Lyme disease experience increased challenges navigating the medical system to find satisfactory care and thus create communities with each other for mutual aid and support. In understanding these challenges, the medical community can improve care for people living with contested chronic illnesses.

The association between familial plasma cell disorders (PCD) and prognosis in patients with MGUS, multiple myeloma (MM), and systemic light chain (AL) amyloidosis has not been well described. This study retrospectively reviewed outcomes of 25,423 patients (16,744 MGUS, 6194 MM, 2955 AL amyloidosis). Overall, 2.7% of patients reported having a family member with a PCD (defined as MGUS, MM, or AL amyloidosis). Family history was documented in 94% of MGUS, 92% of MM, and 88% of AL amyloidosis patients. The overall survival was consistently longer in patients with versus without familial PCD (crude hazard ratios: 0.52, 95% CI 0.40-0.67, p < 0.001 for MGUS patients; 0.68, 95% CI 0.57-0.79, p < 0.001 for MM patients; 0.60, 95% CI 0.43-0.84, p = 0.003 for AL patients). This association remained consistent when adjusting for baseline patient and disease characteristics. In MGUS patients, the risk of progression to MM, AL amyloidosis, or a lymphoproliferative disorder was higher in patients with familial PCD when accounting for death as a competing risk (cause-specific HR 1.9, 95% 1.3-2.7, p < 0.001). This is the first study to demonstrate that in a cohort of MGUS, MM, and systemic AL amyloidosis, patients with a PCD family history have an improved overall survival.

Objectives The majority of patients with head and neck squamous cell carcinoma (HNSCC) do not commence postoperative radiation treatment (PORT) within the recommended 6 weeks. We explore how delayed PORT affects survival outcomes, what factors are associated with delayed PORT initiation, and what interventions exist to reduce delays in PORT initiation. Methods We conducted a PubMed search to identify articles discussing timely PORT for HNSCC. We performed a narrative review to assess survival outcomes of delayed PORT as well as social determinants of health (SDOH) and clinical factors associated with delayed PORT, using the PROGRESS‐Plus health equity framework to guide our analysis. We reviewed interventions designed to reduce delays in PORT. Results Delayed PORT is associated with reduced overall survival. Delays in PORT disproportionately burden patients of racial/ethnic minority backgrounds, Medicaid or no insurance, low socioeconomic status, limited access to care, more comorbidities, presentation at advanced stages, and those who experience postoperative complications. Delays in PORT initiation tend to occur during transitions in head and neck cancer care. Delays in PORT may be reduced by interventions that identify patients who are most likely to experience delayed PORT, support patients according to their specific needs and barriers to care, and streamline care and referral processes. Conclusions Both SDOH and clinical factors are associated with delays in timely PORT. Structural change is needed to reduce health disparities and promote equitable access to care for all. When planning care, providers must consider not only biological factors but also SDOH to maximize care outcomes.

In contrast to infection and curve progression, return to OR for implant malposition is potentially within the surgeon’s control. With increasing surgeon familiarity with freehand/fluoroscopic pedicle screw placement, rates of return to OR due to malposition may have decreased over time. We sought to document the incidence and risk factors for return to OR due to screw malposition in a large cohort of patients with idiopathic scoliosis. AIS patients enrolled in a multicenter prospective registry with minimum 2-year follow-up undergoing PSF between 2003 and 2017 were included. Surgeries with the use of intraoperative CT-guided navigation were excluded. Return to OR due to screw malposition over time was tabulated. Lenke class, age at surgery, year of surgery, height, weight, surgeon and site were evaluated. 2435 patients underwent PSF with non-navigated open pedicle screw instrumentation. Mean age was 14.6 years, mean thoracic curve magnitude was 53°, and mean lumbar was 40°. Patients did not routinely undergo intraoperative or postoperative CT evaluation. There were 10 returns to OR for screw malposition at a mean of 0.83 years postoperatively (range 0.1–3.4 years), for an overall incidence of 0.4%. Of the 14 screws, 10 were thoracic, 7 were left-sided. No association was found between screw malposition and curve size, enrolling site, surgeon, BMI, Lenke class, or age. Five patients had radiculopathy which improved after screw revision. Return to OR for screw malposition changed from 2003 to 2017 (1–0.2%) but this did not reach statistical significance. Although the incidence of asymptomatic malpositioned screws is unknown, the rate of return to the OR for implant malposition overall in this registry was 1 in 250 patients. Recent data suggest the rate has decreased to 1 in 500 patients. Further work may determine whether enabling technologies can reduce the rate, ideally to a “never event”.

Black, CD, Haskins, KR, Bemben, MG, and Larson, RD. Carbohydrate mouth rinsing does not alter central or peripheral fatigue after high-intensity and low-intensity exercise in men. J Strength Cond Res 36(1): 142-148, 2022-Carbohydrate (CHO) mouth rinsing improves performance during endurance exercise. However, its ability to attenuate fatigue during strength-based exercise is less certain. This study sought to determine the effects of a CHO mouth rinse on torque production and voluntary activation (VA%) after high-intensity and low-intensity isometric exercise. Twelve male subjects (22.5 ± 2.3 years; 183.5 ± 6.5 cm; 82.2 ± 13.9 kg) completed 4 testing sessions in a double-blind crossover fashion. Knee extension maximal voluntary isometric strength (MVC) was assessed before(Pre), immediately (iPost-Ex), and 5 minutes (5-min Post Ex) after isometric exercise performed at 80% or 20% of MVC. An 8% CHO solution or placebo (PLA) was rinsed for 20 seconds after exercise. VA% was determined by twitch interpolation. A 2 condition (CHO vs. PLA) × 2 contraction intensity (20 vs. 80%) × 3 time (Pre, iPost Ex, and 5-min Post Ex) completely within subject-repeated measured analysis of variance was performed; statistical significance was set at p ≤ 0.05. Greater reductions in MVC were found at iPost-Ex after exercise at 20% compared with 80% of MVC (-25 ± 14% vs. -11 ± 8%; p0.001) as well as for VA% (-17 ± 14% vs. -8 ± 14%; p0.004). No differences were observed in the CHO vs. PLA condition (p ≥ 0.34). We were successful in eliciting differing levels of central and peripheral fatigue by exercising at a low and high intensity. Despite significantly larger declines in VA% after exercise at 20% of MVC, CHO mouth rinsing had no effects compared with placebo on any measured variable.

Pediatricians had higher rates of ordering pediatric cholesterol screening than family medicine (FM) clinicians. This study aims to compare knowledge, attitude, and practices of clinicians’ pediatric cholesterol screening practices and attitudes between these two specialties. A 14-item electronic survey using Likert scales was sent to all clinicians in the institution’s Departments of Pediatrics and FM between 2018 and 2019. Chi-square and t-tests were used to compare pediatricians and FM clinicians. 22 clinicians from Pediatrics and 111 from FM completed the survey. Compared to FM clinicians, pediatricians were more familiar with the National Heart, Lung, and Blood Institute guidelines, which are more vigorous in their recommendation of universal cholesterol screening. Pediatricians reported being more supportive of universal cholesterol screening in children (p

To determine a) if surgical skills among urology resident applicants could be reliably assessed via crowdsourcing and b) to what extent surgical skills testing impacts resident selection.Interviewees completed the following surgical skills tasks during their interview day: open knot tying (OKT), laparoscopic peg transfer (LPT), and robotic suturing (RS). Urology faculty and crowd-workers evaluated each applicant's video-recorded performance using validated scoring and were assessed for agreement using Cronbach's alpha. Applicants' USMLE scores, interview scores, and Jefferson Scale of Physician Empathy (JSPE-S) scores were assessed for correlation with skills testing scores and match rank. Additionally, a survey was distributed to interviewees assessing match outcomes.University of California Irvine Department of Urology, Surgical Skills Laboratory PARTICIPANTS: All 94 urology residency interviewees at the University of California Irvine Department of Urology from 2015-2018 were invited to complete the three surgical skills tasks on their interview day.Survey responses were received from all 94 interviewees (100%). Crowd and expert agreement was good (α=0.88), fair (α=0.67), and poor (α=0.32) for LPT, RS, and OKT scores, respectively. The skills testing scores did not correlate with match rank, USMLE score, or JSPE-S score. On multivariate analysis, only interview score (r= -0.723; p0.001) and faculty LPT score (r=-0.262; p=0.001) were significant predictors of match rank. Interviewees who reported matching into a top 3 residency choice had significantly higher faculty LPT scores than those who did not (11.9 vs. 9.7, p=0.03).Surgical skills overall did not significantly impact match rank. Expert assessment of laparoscopic peg transfer skills and interview performance among urology resident applicants correlated with match rank.

PURPOSE Cholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort. METHODS This is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020. RESULTS Our group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038). CONCLUSION FGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

Aging is associated with an increased prevalence of subclinical atherosclerosis and stiffening of the arterial walls (arteriosclerosis). These 2 coexisting conditions are mitigated by the presence of ideal cardiovascular health (optimal levels of fasting blood glucose, cholesterol, resting blood pressure, body mass index, no smoking, good dietary quality, and regular physical activity). We hypothesized that the concomitant presence of subclinical atherosclerosis (coronary artery calcification), arteriosclerosis (higher carotid-femoral pulse wave velocity), and suboptimal cardiovascular health is associated with increased risk of cardiovascular disease relative to the absence of these 3 conditions. We tested our hypothesis in the community-based Framingham Heart Study cohort (N=2580, mean age 52 years, 49% women). We classified participants based on (1) the presence versus absence of coronary artery calcium; (2) higher (>sex-specific median) carotid-femoral pulse wave velocity; (3) poor cardiovascular health (score 0–7). Thus, participants could have no abnormalities (referent group), 1, 2, or 3 suboptimal measures. We used Cox regression to relate the number of suboptimal measures (0–3) to the incidence of cardiovascular disease during follow-up (median 14 years). Cardiovascular disease incidence rates/1000 person-years in groups with 0 to 3 suboptimal measures were 1.93 (95% CI, 1.28–2.90), 4.68 (95% CI, 3.48–6.29), 8.93 (95% CI, 6.99–11.41), and 18.26 (95% CI, 14.65–22.77), respectively. Compared with the group with no abnormalities, corresponding multivariable-adjusted hazards ratios for cardiovascular disease were 1.81, 2.18, and 3.71, respectively ( P

Background Many surgical specialties have had pioneering influences from plastic surgeons. However, many of these areas of practice have evolved to include surgeons from diverse training backgrounds. This raises the question as to whether the prominence of other specialties in clinical practice translates to greater research productivity in these areas. The objective of this paper is to investigate the publication volumes of plastic surgeons in selected areas of practice compared to surgeons from other disciplines. Methods PubMed was used to examine publication trends in areas associated with plastic surgery. Searches for the following topics were performed: head and neck reconstruction, hand surgery, breast reconstruction, ventral hernia repair, abdominal component separation, brachial plexus injury, craniofacial surgery, and aesthetic surgery. Affiliation tags were used to examine contributions from nine specialties. Web of Science was used to identify the top cited articles for the last 10 years in each area. Results Articles by non-plastic surgeons comprise the majority of the literature for all areas of practice studied except for breast reconstruction and aesthetic surgery. Despite this, plastic surgeons contributed the greatest number of top cited articles over the last 10 years for five of the areas of practice. Conclusions While plastic surgeons do not contribute the greatest proportion of articles published each year in several of the selected areas of practice, they do publish a larger number of articles that are the most cited. Plastic surgeons remain the dominant academic force in terms of volume and citations for both breast and aesthetic surgery.

Introduction The purposes of this study were (1) to compare the preoperative complete blood count (with differential), c-reactive protein (cRP), erythrocyte sedimentation rate (ESR), and intraoperative pathology (frozen section) results of patients undergoing surgical treatment for shoulder PJI by C. acnes vs. non-C. acnes bacteria, and (2) to estimate sensitivity, specificity, and positive and negative predictive values of these parameters. Methods Between 2004 and 2016, 167 consecutive shoulder PJIs were treated surgically. Infected implants included hemiarthroplasty in 39, anatomic TSA in 92, and reverse TSA in 36 shoulders. Shoulders were categorized in one of 4 groups: irrigation and debridement (21), one stage reimplantation (14), two-stage reimplantation (124), and permanent resection (8). Medical records were reviewed to record microorganisms isolated, intraoperative pathology, and preoperative cell count, ESR, and c-RP. Shoulders were further grouped into those that were positive only for C. acnes (37 shoulders) and those that were positive for any other microorganism (130 shoulders). In order to calculate sensitivity, specificity, and predictive values, the same data was collected for a separate group of 700 shoulder arthroplasties that underwent revision surgery for noninfectious reasons during the same time period. Results For the whole group of 167 infected shoulder arthroplasties, values were considered abnormal for leukocyte count in 15%, neutrophil count in 17%, ESR in 42%, cRP in 56% and pathology in 55%. Abnormal values were more common in the non-C. acnes group. The following positive predictive values were obtained: Leukocytes 47% (13% C. acnes, 43% other), ESR 65% (18% C. acnes, 62% other), cRP 70% (29% C. acnes, 66% other), and pathology 73% (30% C. acnes, 63% other). The following negative predictive values were obtained: Leukocytes 79% (94% C. acnes, 93% other), ESR 68% (86% C. acnes, 76% other), cRP 70% (88% C. acnes, 78% other), and pathology 87% (96% C. acnes, 91% other). Conclusion Bacteria other than C. acnes were responsible for 75% of the shoulder PJI treated consecutively with surgery at a single institution over a 12-year period. Negative predictive values for cell count, ESR, cRP, and pathology ranged between 70% and 81%, but there were much lower for C. acnes infection. Obtaining these tests in the evaluation of a painful shoulder arthroplasty should not be discontinued, since their positive predictive value for non-C. acnes infections seem reasonable and their negative predictive value is high. Level of evidence Level III; Retrospective Comparative Study

Although therapeutic drug monitoring (TDM) is an important tool in guiding drug dosing for other areas of medicine including infectious diseases, cardiology, psychiatry and transplant medicine, it has not gained wide acceptance in oncology. For imatinib and other tyrosine kinase inhibitors, a flat dosing approach is utilised for management of oral chemotherapy. There are many published studies examining the correlation of blood concentrations with clinical effects of imatinib. The International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) determined that there was a need to examine the published literature regarding utility of TDM in imatinib therapy and to develop consensus guidelines for TDM based on the available data. This article summarises the scientific evidence regarding TDM of imatinib, as well as the consensus guidelines developed by the IATDMCT.

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Purpose To determine whether platelet-rich plasma (PRP) injection for lateral epicondylitis offers patients comparable outcomes to lateral epicondylar surgery. Methods Embase, Cochrane Library, and MEDLINE databases were searched using the terms lateral epicondylitis, lateral elbow pain, tennis elbow, lateral epicondylalgia, and elbow tendinopathy individually and combined with the terms platelet-rich plasma injections and lateral epicondylar surgery. We compared pain relief, function between the 2 treatment options, and identified whether PRP injection reduced the incidence of lateral epicondylar surgery. Studies must have compared PRP injections with lateral epicondylar surgery for the treatment of lateral epicondylitis; be of Level I, II, or III evidence; and be written in the English language. Results Three studies (1 Level II and 2 Level III) met inclusion criteria. Two of the studies suggested that PRP injections offer similar relief as surgery in the short and mid-term, one study reported that PRP injections and surgery had similar outcomes in pain improvement and return to work, whereas 1 study reported that surgery may be a better long-term solution. Conclusions In comparison with lateral epicondylar surgery, PRP injections offer similar improvements in pain and function for patients suffering from lateral epicondylitis, especially in the short- and mid-term in 2 of the 3 included investigations. Therefore, PRP injections are an appropriate alternative for the treatment of lateral epicondylitis. Level of Evidence Level III, Systematic Review of Level III or greater evidence.

The aim of this study is to identify the prevalence, predictors, and psychosocial well-being (depressive symptoms, stress) and weight-related behavior (eating behaviors, physical activity, and sedentary behavior) correlates of social distancing during COVID-19 among emerging adults. A rapid-response survey was sent to participants ( n=720; mean age=24.7 ± 2.0 years, 62% female) in a population-based cohort study in Minnesota during April–October 2020. Half of emerging adults reported fully social distancing. Emerging adults from White backgrounds were least likely to social distance while those from Asian backgrounds were most likely to social distance, in addition to those living with a parent. Females who partially/did not social distance reported less healthy eating behaviors, while males and “essential workers” reported higher levels of psychosocial distress. Public health messaging and practical supports for social distancing may need to be made more relevant to emerging adults during public health crises. Resources may need to differ depending on sex of emerging adult.

Objectives Using the American College of Cardiology/American Heart Association 2013 atherosclerotic cardiovascular disease (ASCVD) management guidelines, we conducted a retrospective cross-sectional analysis of people living with HIV in the US Military HIV Natural History Study to determine whether individuals were receiving statins when indicated. Methods Prescription data was taken from Military Health System data. Statin eligibility was defined by ASCVD guidelines. We used the 10-year ASCVD pooled cohorts' equation to evaluate risk for each participant. Results Across all categories, 31.9% (n = 390) of individuals met criteria for statin use, and when adding these subjects to the number of those already receiving statins (n = 96), 62.1% of all eligible subjects (n = 302/486) were actually receiving statin therapy. In multivariable analysis, individuals of African American race [odds ratio (OR) = 0.48, 95% confidence interval (CI): 0.31-0.73] or Hispanic ethnicity (OR = 0.42, 95% CI: 0.19-0.94) were less likely to receive statin prescriptions than white individuals. Individuals with a higher CD4 count (OR = 1.12, 95% CI: 1.05-1.20 per 100 cells/μL]) were significantly more likely to receive a statin prescription. Conclusions These data highlight discrepancies between ASCVD guidelines and primary care management of people living with HIV (PLWH) in the military health system, along with important racial differences. Targeted interventions are critical to identify and treat appropriate candidates for statin therapy among PLWH in the military and other settings.

Scholars in disability studies have recently sought to account for fatness, claiming an inseparable link between disability and fat scholarship. Interrogating the stigmas of fatness as a sign of ba...

INTRODUCTION Although vitamin D is intimately involved in bone metabolism, the relationship between vitamin D status, as measured by serum total 25-hydroxyvitamin D [25(OH)D] concentration, and bone mineral density (BMD) is weak, particularly in non-White populations. Measurement of bioavailable 25(OH)D has been suggested as a better indicator of vitamin D status than total 25(OH)D concentration. To date, the bioavailable 25(OH)D biomarker has been explored minimally in athletic populations. The purpose of this study was to investigate the relationship between total and bioavailable 25(OH)D concentrations and BMD in collegiate athletes. METHODS NCAA Division 1 basketball and swimming athletes served as study participants (n = 53; 28 females, 25 males; 28 basketball players, 25 swimmers). All participants completed dual energy x-ray absorptiometry (DXA) scans for analysis of BMD, blood draws for vitamin D measures, and diet/lifestyle questionnaires. RESULTS Overall, total 25(OH)D was 80.0 + 13.9 nmol/L and bioavailable 25(OH)D was 6.0 ± 1.9 nmol/L. There was strong disagreement between total 25(OH)D and bioavailable 25(OH)D concentrations (κ = -0.299; r = -0.129) (p = 0.100); 53% of total participants and 77% of Black participants were classified differently (low vs. normal vitamin D status) based on total and bioavailable 25(OH)D criteria. Black participants had significantly lower total 25(OH)D and higher bioavailable 25(OH)D concentrations than White participants (59.5 vs. 102.5 nmol/L and 7.9 vs. 5.4 nmol/L, respectively) (p < 0.001). Total 25(OH)D and total BMD were not correlated, but bioavailable 25(OH)D and total BMD demonstrated a positive correlation (r = 0.618, p < 0.01). CONCLUSIONS These results suggest that bioavailable 25(OH)D concentration may be a better clinical measure of vitamin D status than total 25(OH)D in collegiate athletes as related to BMD, particularly in Black athletes. Further research on the utility of the bioavailable 25(OH)D biomarker in athletes is needed.

Background and ObjectivesTo report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson disease (PD) and motor fluctuations.MethodsPD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic l-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5 × 1011 vector genomes (vg); cohort 2, ≤1.5 × 1012 vg; cohort 3, ≤4.7 × 1012 vg.ResultsNo serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector–related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21%–30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, Unified Parkinson's Disease Rating Scale III “off”-medication and “on”-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and quality of life (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.DiscussionsVY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years.Trial Registration InformationNCT01973543.Classification of EvidenceThis study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Introduction Suicide is a leading cause of death among adolescents. Oregon ranks 17th nationally for youth suicide rates, and ingestion of medications as a means of suicide is common. Despite the high prevalence of intentional poisoning among youth in Oregon, information about medications used by children and adolescents for attempted suicide, in particular the sources of medications, is not readily available. Methods The objective of this study is to describe types and sources of medications used for intentional ingestion among patients seen by the Doernbecher Children's Hospital Child and Adolescent Psychiatry Consultation-Liaison Service. This was a retrospective analysis of patients seen by the Child and Adolescent Psychiatry Consultation-Liaison Service for intentional ingestion from 2015 to 2017. Data on 434 total intentional ingestions were collected, including demographic information, types of medications ingested, and sources of both over-the-counter (OTC) and prescription (Rx) medications. Ingestions without intent of suicide were excluded. Descriptive analysis of ingestion data was performed. Results Intentional ingestions included Rx and OTC medications in similar frequencies. For Rx medications, 68% of ingestions included patients' own Rxs. Eighty-eight percent of ingestions that were not the patients' own Rx belonged to someone else living in their home. For OTC medications, 66% of medications were available at home. Conclusions Intentional ingestions among adolescents most frequently involve medications that are readily available in their homes, and these include both OTC and Rx medications. This study highlights the importance of securing medications at home as a preventative measure and the importance of anticipatory guidance for primary care providers.

INTRODUCTION Quinidine is an effective therapy for a subset of polymorphic ventricular tachycardia and ventricular fibrillation (VF) syndromes; however, the efficacy of quinidine in scar-related monomorphic ventricular tachycardia (MMVT) is unclear. METHODS AND RESULTS Between 2009 and 2020 a single VT referral center, a total of 23 patients with MMVT and structural heart disease (age 66.7 ± 10.9, 20 males, 15 with ischemic cardiomyopathy, mean LVEF 22.2 ± 12.3%, 9 with left ventricular assist device [LVAD]) were treated with quinidine (14 quinidine gluconate; 996 ± 321 mg, 8 quinidine sulfate; 1062 ± 588 mg). Quinidine was used in combination with other antiarrhythmics (AAD) in 19 (13 also on amiodarone). All patients previously failed >1 AAD (amiodarone 100%, mexiletine 73%, sotalol 32%, other 32%) and eight had prior ablations (median of 1.5). Quinidine was initiated in the setting of VT storm despite AADs (6), inability to tolerate other AADs (4), or recurrent VT(12). Ventricular arrhythmias recurred despite quinidine in 13 (59%) patients at a median of 26 (4-240) days after quinidine initiation. In patients with recurrent MMVT, VT cycle length increased from 359 to 434 ms (p = .02). Six (27.3%) patients remained on quinidine at 1 year with recurrence of ventricular arrhythmias in all. The following adverse effects were seen: gastrointestinal side effects (6), QT prolongation (2), rash (1), thrombocytopenia (1), neurologic side effects (1). One patient discontinued due to cost. CONCLUSION Quinidine therapy has limited tolerability and long-term efficacy when used in the management of amiodarone-refractory scar-related MMVT.

Introduction Viral suppression prevents HIV transmission and disease progression, but socio-economic and clinical factors can hinder the goal of suppression. We evaluated factors associated with viral non suppression (VNS) and persistent viremia (PV) in people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in Guatemala. Methods We conducted a cross sectional analysis using data from an ongoing cohort of PLHIV attending the largest HIV clinic in Guatemala. Univariable and multivariable analyses were conducted between PLHIV with viral suppression and detectable viremia. VNS was defined as most recent HIV RNA ≥ 200 copies/ml and PV as two consecutive HIV RNA ≥ 200 copies/ml. Results Of 664 participants, 13.3% had VNS and 7.1% had PV. In univariable analysis disaggregated by gender, low income, poor education, perceived difficulty attending healthcare, and alcohol use were associated with VNS in men while low CD4 at diagnosis, multiple prior ART regimens and treatment interruptions were significant in both genders. Multiple prior ART regimens (adjusted Odds Ratio (aOR) 2.82, [95% confidence interval (CI) 1.59, 4.99], p p p p p Conclusions We conclude that socio-economic and clinical factors influence viral suppression in our cohort and vary between men and women. Gender specific approaches are necessary to achieve the 90% suppression goal.

Background Implementation of quality improvement (QI) practices varies considerably among public health units (PHUs) in Ontario. With the emphasis on continuous quality improvement (CQI) in the revised Ontario Public Health Standards (OPHS), there is a need to understand the level of QI maturity in Ontario’s PHUs. The objective of this research was to establish a baseline understanding of QI maturity in Ontario’s PHUs. Methods The QI Maturity Tool - Modified Ontario Version was used to assess the state of QI maturity in 34 PHUs across Ontario. QI maturity was assessed through 23 questions across three dimensions: QI Organizational Culture; QI Capacity and Competency; and QI Perceived Value. QI maturity scores were classified into five stages: Beginning; Emerging; Progressing; Achieving; and Excelling. QI maturity scores were calculated for each of the 34 participating PHUs to determine their stage of QI maturity. Each PHU’s score was then used to determine the provincial average for QI maturity. Participants were also asked to answer three questions related to core CQI organizational structures. Results Across the 34 PHUs, 3503 staff participated in the survey. A review of individual PHU scores indicates that Ontario’s PHUs are at varying stages of QI maturity. The average QI maturity score of 4.94 for the 34 participating PHUs places the provincial average in the “Emerging” stage of QI maturity. By QI dimensions, the participating PHUs scored in the “Emerging” stage for QI Organizational Culture (5.09), the “Beginning” stage for QI Competency and Capacity (4.58), and the “Achieving” stage for QI Perceived Value (6.00). Conclusion There is an urgent need for Ontario’s PHUs to progress to higher stages of QI maturity. Participants place a high value on QI, but collectively are at less “mature” stages of QI in relation to QI organizational culture and the competency and capacity to engage in QI activities. PHUs should leverage the value that staff place on QI to foster the development of a culture of QI and provide staff with relevant knowledge and skills to engage in QI activities.

Most orthopedic studies involve survival analysis examining the time to an event of interest, such as a specific complication or revision surgery. Competing risks commonly arise in such studies when patients are at risk of more than one mutually exclusive event, such as death, or when the rate of an event depends on the rates of other competing events. In this article, we briefly describe the survival analysis censoring methodology, common fatal and nonfatal competing events, and define circumstances where standard survival analysis can fail in the setting of competing risks with real-world examples from orthopedics. Please visit the following https://youtu.be/ifj_Mm3eGu8 for a video that explains the highlights of the paper in practical terms.

Objective To examine associations of cumulative exposure to proton pump inhibitors (PPIs) with total cardiovascular disease (CVD; composed of stroke, coronary heart disease, and heart failure [HF]) and HF alone in a cohort study of White and African American participants of the Atherosclerosis Risk in Communities (ARIC) study. Methods Use of PPIs was assessed by pill bottle inspection at visit 1 (January 1, 1987 to 1989) and up to 10 additional times before baseline (visit 5; 2011 to 2013). We calculated cumulative exposure to PPIs as days of use from visit 1 to baseline. Participants (n=4346 free of total CVD at visit 5; mean age, 75 years) were observed for incident total CVD and HF events through December 31, 2016. We used Cox regression to measure associations of PPIs with total CVD and HF. Results After adjustment for potential confounding variables, participants with a cumulative exposure to PPIs of more than 5.1 years had a 2.02-fold higher risk of total CVD (95% CI, 1.50 to 2.72) and a 2.21-fold higher risk of HF (95% CI, 1.51 to 3.23) than nonusers. Conclusion Long-term PPI use was associated with twice the risk of total CVD and HF compared with nonusers. Our findings are in concordance with other research and suggest another reason to be cautious of PPI overuse.

Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov