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Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

GOAL: To develop a low-cost magnetic resonance imaging (MRI)-free transcranial focused ultrasound (FUS) system for microbubble-mediated therapy. METHODS: A 128-element 11 MHz array for skull localization was integrated within a 256-module multi-frequency (306/612/1224 kHz) dual-mode phased array. The system’s transcranial transmit and receive performance was evaluated with ex-vivo human skullcaps using phase aberration corrections calculated from computed tomography (CT)-based simulations via ultrasound-based (USCT) and landmark-based (LMCT) registrations, and a gold-standard fixed source emitter (FSE)-based method. RESULTS: Displacement and rotation registration errors of 1.4 ± 0.4 mm and 2.1 ± 0.2° were obtained using USCT, resulting in sub-millimeter transmit targeting errors driven at 306 kHz (0.9 ± 0.2 mm) and 612 kHz (0.9 ± 0.3 mm), and source localization errors of 1.0 ± 0.3 mm and 0.6 ± 0.2 mm at receive frequencies of 306 kHz and 612 kHz, respectively (mean ± SD). Similar errors were obtained using LMCT and no significant differences between these two approaches were found on either transmit (p = 0.64/0.99) or receive (p = 0.45/0.36) at 306 kHz/612kHz. During volumetric multi-point exposures, approximately 70% and 60% of the transmit frames in which microbubble activity was detected via FSE were recovered using USCT when imaging at the second-harmonic and half-harmonic, respectively, compared to 60% and 69% using LMCT. CONCLUSION: This low-cost ultrasound-guided transcranial FUS system affords USCT skull registration with accuracy comparable to LMCT methods. SIGNIFICANCE: Such systems have great potential to advance the adoption of microbubble-mediated FUS brain therapy by improving access to the technology.

Patients with advanced lung disease can develop pulmonary hypertension and succumb to right ventricular failure/cor pulmonale. Patients with pulmonary hypertension owing to chronic lung disease, or World Health Organization group 3 pulmonary hypertension, are more limited and carry a high risk of mortality. Adjunctive therapies remain the cornerstones of treatment. Recent evidence suggests that inhaled pulmonary vasodilator therapy can be helpful in patients with pulmonary hypertension owing to interstitial lung disease. Lung transplantation may be the only life-saving option in select patients, whereas palliative care and hospice should be sought for those who are not candidates as the disease progresses.

OBJECTIVE To convene a multi-disciplinary panel to develop a pathway for Emergency Department (ED) patients with suspected nephrolithiasis and then prospectively evaluate its effect on patient care. MATERIALS AND METHODS The STONE Pathway was developed and linked to order sets within our Electronic Health Record in April 2019. Records were prospectively reviewed for ED patients who underwent ultrasound or Computerized Tomography (CT) to evaluate suspected nephrolithiasis between January 2019 and August 2019 within our institution. The primary outcome measure was the proportion of patients whose ED CT was low dose (

Background Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILAs are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. Research Question Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? Study Design and Methods Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. Results Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System “S-modifier” [which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of FVC and diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. Interpretation Guidance for identifying clinically relevant ILA, with subsequent referral and follow-up, was established. These results lay the foundation for developing practical guidance on managing patients with ILA.

BACKGROUND CONTEXT Excessive use of postoperative imaging after lumbar surgery has been documented, becoming a target for cutting costs. This must be balanced with the patient's need for information and allay their postoperative concerns. PURPOSE To determine the incidence and associated costs of patient interactions with the healthcare system, outside the standard follow up routine, in the first postoperative year. STUDY DESIGN Retrospective longitudinal cohort. PATIENT SAMPLE Consecutive series of 200 patients who underwent lumbar fusions from 2018 to 2019 from a multi-surgeon single tertiary spine center. OUTCOME MEASURES All healthcare encounters: phone calls, office and emergency department visits, and additional testing METHODS A consecutive series of 200 patients who underwent lumbar fusions from 2018 to 2019 were identified. All non-routine healthcare encounters: phone calls, office and emergency department visits, and additional testing were collected. Direct costs for all healthcare services were determined using the Medicare Allowable rates. Indirect costs were determined using local, median income, length of office visits, and distance from the clinic to the patient's home. RESULTS Of 200 patients, 14 with thoracic fusion were excluded. The mean age of the 186 included patients was 58.26 years and 85 (46%) were male. Forty-seven percent (87/186) had only routine postoperative visits and 24 had revision surgery. Seventy-five patients made a total of 102 phone calls, 55 office visits, leading to 38 diagnostic studies none of which led to an additional intervention. Using Medicare Allowable rates, the mean direct cost was $776 per patient and the using a median income of $16/h the mean indirect cost was $124 per patient. There were no differences in the baseline characteristics among the patients who only had routine post-op encounters, had non-routine encounters or had a repeat surgery. CONCLUSIONS Forty percent of the patients undergoing lumbar surgery had a healthcare encounter outside their routine follow up that did not result in additional intervention after their index operation. These potentially unnecessary encounters create additional cost and inconvenience to both the patient and healthcare system. Providing patient reassurance is important and providers should identify ways to reduce associated costs through patient education, virtual visits, or new technologies to monitor patient's postoperative progress.

Background Riociguat is effective in delaying the time to clinical worsening (TCW) in patients with groups 1 and 4 pulmonary hypertension. Research Question Is riociguat more effective than placebo in prolonging TCW in sarcoidosis-associated pulmonary hypertension (SAPH)? Study Design and Methods This was a double-blind placebo-controlled trial. Patients with SAPH confirmed by right heart catheterization were randomized 1:1 to riociguat or placebo. Patients underwent 6-min walk distance (6MWD) and spirometry testing every 8 weeks. The primary end point was TCW, which was defined by the time to the first of the following: (1) all-cause mortality, (2) need for hospitalization because of worsening cardiopulmonary status attributable to progression of disease, (3) > 50 m decrease in the 6MWD test, or (4) worsening of World Health Organization functional class. Results A total of 16 patients were randomized to riociguat (n = 8) or placebo (n = 8). No difference was found in pulmonary artery mean, pulmonary vascular resistance, initial 6MWD, or FVC between the two groups. Five of eight patients who received placebo met TCW criteria, whereas none of the patients who received riociguat experienced a qualifying event. By log-rank analysis, patients who received riociguat were in the study for a significantly longer period (χ 2 = 6.259; P = .0124). The 6MWD decreased in the placebo group (median, –55.9 m; range, –176.8 to 60 m), but rose in the riociguat group (median, +42.7 m; range, –7.5 to +91.4 m; P = .0149), with a placebo-corrected difference of 94 m (P 30-m improvement in 6MWD (P > .05). No significant adverse events associated with riociguat occurred. Interpretation Over the 1 year of the study, riociguat was effective in preventing clinical worsening and improving exercise capacity in patients with SAPH. Trial Registry ClinicalTrials.gov ; No.: NCT02625558 ; URL: www.clinicaltrials.gov

Background Transcarotid arterial revascularization (TCAR) offers a novel technique for carotid artery stenting (CAS) that provides flow reversal in the carotid artery and avoids aortic arch manipulation, thus, potentially lowering ipsilateral and contralateral periprocedural stroke rates. As a new technology, adoption may be limited by concern for learning a new technique. This study seeks to examine the number of cases needed for a surgeon to reach technical proficiency. Methods Retrospective analysis was performed using a prospectively collected database of all TCAR procedures performed in a tertiary health care system between 2016 and 2020. Patient demographics and anatomic characteristics were collected. Intraoperative variables and perioperative outcomes were examined. These variables were collated into groups for the first 4 procedures, procedures 5–8, and after 8. Independent Samples t test, 1-way ANOVA, and logarithmic regression were used to statistically analyze the data. Results One-hundred and eighty-seven TCARs were performed by 14 surgeons. One hundred and twenty-two (65%) were male, 59 (32%) were older than 75 years, and 83 (44%) were symptomatic. The most common indications were high-lesions in 87 patients (47%) and recurrent stenosis after CEA in 37 patients (20%). Significant differences were found between the first and second groups of 4 cases when comparing mean operative time (71 vs. 58 min; P = 0.001) and flow reversal time (10.8 vs. 7.9 min; P= 0.004). similar significant differences were found between the first and third groups of 4 cases but not between the second and third groups. There was a reduction in contrast usage and fluoroscopy time after the first 4 cases, however, this did not reach statistical significance. There was no ipsilateral perioperative strokes. One patient had a contralateral stroke on postoperative day 2 due to intracranial atherosclerosis, and there was one perioperative mortality that occurred on postoperative day 3 after discharge. Conclusions Procedural and flow reversal times significantly shorten after 4 TCAR procedures are performed. Other metrics, such as fluoroscopy time and contrast usage, are also decreased. Complications, in general, are minimal. Proficiency in TCAR, as measured by these metrics, is met after performing only 4 procedures.

Patients with advanced pyogenic spondylodiscitis can present with neurologic deficits. However, the prevalence, severity, and outcome of the neurologic deficits are not well known. A systematic review was performed to improve the knowledge of this commonly encountered clinical scenario. The considerable number of severe neurologic deficits in addition to their poor recovery, even after surgical intervention, demonstrates that the early diagnosis of pyogenic spondylodiscitis is crucial. Prompt surgical intervention is likely associated with a greater chance of improvement of neurologic status than nonsurgical treatment.

Symptomatic postoperative epidural hematomas are rare, with an incidence of 0.10% to 0.69%. Risk factors have varied in the literature, but multiple studies have reported advanced age, preoperative or postoperative coagulopathy, and multilevel laminectomy as risk factors for hematoma. The role of pharmacologic anticoagulation after spine surgery remains unclear, but multiple studies suggest it can be done safely with a low risk of epidural hematoma. Prophylactic suction drains have not been found to lower hematoma incidence. Most symptomatic postoperative epidural hematomas present within the first 24 to 48 hours after surgery but can present later. Diagnosis of a symptomatic hematoma requires correlation of clinical signs and symptoms with a compressive hematoma on MRI. Patients will usually first complain of a marked increase in axial pain, followed by radicular symptoms in the extremities, followed by motor weakness and sphincter dysfunction. An MRI should be obtained emergently, and if it confirms a compressive hematoma, surgical evacuation should be carried out as quickly as possible. The prognosis for neurologic improvement after evacuation depends on the time delay and the degree of neurologic impairment before evacuation.

Objective Venous insufficiency is often not readily recognized as a contributing etiology to nonhealing wounds by nonvascular surgery specialists, potentially delaying appropriate treatment to achieve wound healing and increasing healthcare costs. The objective of the present study was to understand the time and resources used before the definitive treatment of venous ulcers. Methods A single-institution retrospective medical record review of C6 patients undergoing radiofrequency saphenous and perforator vein ablation from May 2016 to January 2018 identified 56 patients with 67 diseased limbs. The numbers of inpatient, emergency department, and wound care visits and the intervals to vein ablation from the initial evaluation of the ulceration by a healthcare provider were collected. The demographics, comorbidities, previous venous interventions, wound characteristics, duplex ultrasound imaging, and available wound healing follow-up through July 2018 were assessed for all patients. Results For the 67 limbs examined, 588 total healthcare visits were performed for wound assessment before a referral to a vascular surgeon, with 413 visits at a wound care center (70% of all visits). Other specialty visits included emergency medicine (17.9% of limbs) and rheumatology (22.4% of limbs). Six patients (nine limbs) were admitted to inpatient services for treatment of their ulceration. Overall, the patients were seen an average of 8.6 ± 9.7 times for their ulcer with the wound center before determination of a contributing venous etiology and subsequent treatment. These visits translated to a median of 230 days (interquartile range, 86.5-1088 days) between the first identification of the ulcer by healthcare providers and subsequent accurate diagnosis and definitive treatment of their venous disease with radiofrequency saphenous and perforator vein ablation. After intervention, 18.64% of the limbs had healed at 1 month, 33.92% had healed at 3 months, 50% had healed at 6 months, and 82.92% had healed by 12 months. Conclusions An earlier and accurate diagnosis of the venous contribution to ulcers and subsequent appropriate treatment of venous etiologies in wound formation by a vascular venous specialist could significantly improve healing and minimize resource usage.

OBJECTIVE Microsurgical resection of arteriovenous malformations (AVMs) can be aided by staged treatment consisting of stereotactic radiosurgery followed by resection in a delayed fashion. This approach is particularly useful for high Spetzler-Martin (SM) grade lesions because radiosurgery can reduce flow through the AVM, downgrade the SM rating, and induce histopathological changes that additively render the AVM more manageable for resection. The authors present their 28-year experience in managing AVMs with adjunctive radiosurgery followed by resection. METHODS The authors retrospectively reviewed records of patients treated for cerebral AVMs at their institution between January 1990 and August 2019. All patients who underwent stereotactic radiosurgery (with or without embolization), followed by resection, were included in the study. Of 1245 patients, 95 met the eligibility criteria. Univariate and multivariate regression analyses were performed to assess relationships between key variables and clinical outcomes. RESULTS The majority of lesions treated (53.9%) were high grade (SM grade IV–V), 31.5% were intermediate (SM grade III), and 16.6% were low grade (SM grade I–II). Hemorrhage was the initial presenting sign in half of all patients (49.5%). Complete resection was achieved among 84% of patients, whereas 16% had partial resection, the majority of whom received additional radiosurgery. Modified Rankin Scale (mRS) scores of 0–2 were achieved in 79.8% of patients, and 20.2% had poor (mRS scores 3–6) outcomes. Improved (44.8%) or stable (19%) mRS scores were observed among 63.8% of patients, whereas 36.2% had a decline in mRS scores. This includes 22 patients (23.4%) with AVM hemorrhage and 6 deaths (6.7%) outside the perioperative period but prior to AVM obliteration. CONCLUSIONS Stereotactic radiosurgery is a useful adjunct in the presurgical management of cerebral AVMs. Multimodal therapy allowed for high rates of AVM obliteration and acceptable morbidity rates, despite the predominance of high-grade lesions in this series of patients.