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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.

BACKGROUND: Neoadjuvant chemoradiotherapy can provide downstaging and improve margin negativity for borderline resectable and resectable pancreatic adenocarcinoma [(B)RPC]. Little is known about the relative efficacy of capecitabine (CAPE)-based vs. gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. METHODS: A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009–12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. RESULTS: Thirty-one patients were included in the analysis. Twenty-two (71%) patients were treated with CAPE, while 9 (29%) were treated with GEM. All patients in the GEM group were borderline resectable, vs. 18 (82%) patients in the CAPE group, P=0.30. Nineteen (86%) patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, vs. 4 (44%) patients in the GEM group, P=0.03. The CAPE group had higher odds of achieving surgical resection [OR =9.33; 95% confidence interval (CI): 1.50–58.20]. Adjusting for covariates, the odds of achieving surgical resection were still statistically higher in the CAPE group vs. the GEM group (OR =25.34; 95% CI: 1.14–563.72). The CAPE group had superior mTTP compared to the GEM group (15.4 months, 95% CI: 4.9–71.1 vs. 4.0 months, 95% CI: 0.4–14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14–0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08–0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04–0.40) and adjusted models (HR =0.13, 95% CI: 0.03–0.52). CONCLUSIONS: For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.

Purpose: PARP inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers. This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI versus FOLFIRI (control) for metastatic pancreatic cancer. Patients and Methods: This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1–27). BRCA1/2 and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1–7 with mFOLFIRI days 3–5, or FOLFIRI in 14-day cycles. Results: After 123 of planned 143 patients were accrued, an interim futility analysis indicated that the veliparib arm was unlikely to be superior to control, and the study was halted. Median overall survival (OS) was 5.4 versus 6.5 months (HR, 1.23; P = 0.28), and median progression-free survival (PFS) was 2.1 versus 2.9 months (HR, 1.39; P = 0.09) with veliparib versus control. Grade 3/4 toxicities were more common with veliparib (69% vs. 58%, P = 0.23). For cancers with HR-DDR defects versus wild-type, median PFS and OS were 7.3 versus 2.5 months (P = 0.05) and 10.1 versus 5.9 months (P = 0.17), respectively, with FOLFIRI, and 2.0 versus 2.1 months (P = 0.62) and 7.4 versus 5.1 months (P = 0.10), respectively, with veliparib plus mFOLFIRI. Conclusions: Veliparib plus mFOLFIRI did not improve survival for metastatic pancreatic cancer. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.

Background: Despite the widespread use of combination antiretroviral therapy (cART), HIV-associated neurocognitive impairment (NCI) persists in people living with HIV (PLWH). Studies have generated inconsistent results regarding etiological factors for NCI in PLWH. Furthermore, a user-friendly and readily available predictive tool is desirable in clinical practice to screen PLWH for NCI. Objective: This study aimed to identify factors associated with NCI using a large and diverse sample of PLWH and build a nomogram based on demographic, clinical, and behavioral variables. Methods: We performed Bayesian network analysis using a supervised learning technique with the Markov Blanket (MB) algorithm. Logistic regression was also conducted to obtain the adjusted regression coefficients to construct the nomogram. Results: Among 1,307 participants, 21.6% were neurocognitively impaired. During the MB analysis, age provided the highest amount of mutual information (0.0333). Logistic regression also showed that old age (>50 vs. ≤50 years) had the strongest association (OR=2.77, 95% CI=1.99-3.85) with NCI. The highest possible points on the nomogram were 626, translated to a nomogram-predicted probability of NCI to be approximately 0.95. The receiver operating characteristic (ROC) curve's concordance index was 0.75, and the nomogram's calibration plot exhibited an excellent agreement between observed and predicted probabilities. Conclusion: The nomogram used variables that can be easily measured in clinical settings and, thus, easy to implement within a clinic or web-interface platform. The nomogram may help clinicians screen for patients with a high probability of having NCI and thus needing a comprehensive neurocognitive assessment for early diagnosis and appropriate management.

Despite the widespread use of combination antiretroviral therapy (cART), HIV-associated neurocognitive impairment (NCI) remains a health concern. However, limited research has been done to identify factors associated with neurocognitive decline. We assessed risk factors associated with neurocognitive decline in people living with HIV using a definition of decline that is statistically easy to adopt, is based on a commonly used neuropsychological cut-off and may be clinically relevant. Cox proportional hazards modeling was performed using the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study database. 581 participants were followed for up to 12 years. Neurocognitive decline was defined as the first observed drop in global T-scores of at least 2.67. Lifetime methamphetamine use had the strongest association with neurocognitive decline (adjusted Hazard Ratio; aHR = 1.48; 95% CI = 0.92–2.39) followed by no current antiretroviral medication use (aHR = 1.32; 95% CI = 0.91–1.92). Other risk factors included Hispanic ethnicity, lifetime history of major depressive disorder, lifetime cannabis use, hepatitis-C infection, and difficulty eating, dressing, bathing, or using the toilet. Results indicate that consistent use of ART may be of high significance to preserving neurocognition. Furthermore, Hispanic patients, those with a history of depression and substance use, and those having difficulty in essential activities of daily living may require vigilant follow-up.

Background Stability following multilevel decompressive laminectomy without fusion has been debated using in vitro biomechanical and radiographic models. However, there is a lack of information regarding clinical outcomes for these patients. The aim of the present study was to determine the association between clinical outcomes and number of levels decompressed via laminectomy for treatment of lumbar spinal stenosis. Methods We performed a retrospective cohort analysis of patients who underwent a primary lumbar laminectomy between 2009 and 2015 by senior orthopedic spine surgeons for lumbar spinal stenosis. Patients were divided into 2 groups based on the number of decompression levels: single level or 3 or more levels. Patient-reported outcomes were obtained in the form of Oswestry Disability Index (ODI) scores, visual analog scale (VAS) scores for the back and leg, 12-Item Short Form Mental and Physical Survey scores, and Veterans Rand 12-Item Health Mental and Physical Survey scores. Results Overall, 138 consecutive patients were assessed, of which 106 underwent a single-level and 32 underwent a 3-or-more-level laminectomy. Average follow-up was 24.2 months. There were no significant differences in the preoperative VAS back, VAS leg, or ODI scores between the single-level laminectomy and 3-or-more-level laminectomy groups. Both groups of patients experienced significant improvements in these clinical outcomes postoperatively with no clinically significant difference in the degree of improvement. Reoperation rates were low and similar between the 2 groups. Conclusions Patients undergoing decompression of 3 or more levels present with similar postoperative outcomes to those who undergo a single-level decompression for lumbar spinal stenosis. Under specific clinical and radiographic criteria, a multilevel decompression of 3 or more levels may be a safe and effective procedure with acceptable outcomes at 2 years after surgery. Level of Evidence 3.

Aim: Cytokine release syndrome (CRS) is an infrequently described immune-related adverse event of checkpoint inhibitors (CPI). CPI-induced CRS typically presents with fevers, hemodynamic instability and organ dysfunction within 2 weeks of the last treatment cycle. Case study: We report an unusual case of delayed and severe CRS occurring postoperatively in a patient with hepatic-limited metastatic colorectal cancer who received neoadjuvant immunotherapy. After a negative workup for alternative causes, he received prolonged corticosteroid treatment with symptom resolution. Conclusion: CPI-induced CRS can mimic sepsis and clinicians should maintain a high-index of suspicion to diagnose this immune-related adverse event early and initiate appropriate treatment. As use of perioperative immunotherapy increases, the potential role of surgery to trigger CRS in this case warrants further investigation.

It is well recognized that not all individuals age equivalently, with functional dependence attributable, at least in part, to stress accumulated across the lifespan. Amongst these dependencies are age-related declines in cognitive function, which may be the result of impaired inhibitory processing (e.g., sensory gating). Herein, we examined the unique roles of life and biological stress on somatosensory gating dynamics in 74 adults (22-72 years old). Participants completed a sensory gating paired-pulse electrical stimulation paradigm of the right median nerve during magnetoencephalography (MEG) and data were subjected to advanced oscillatory and time-domain analysis methods. We observed separable mechanisms by which increasing levels of life and biological stress predicted higher oscillatory gating ratios, indicative of age-related impairments in inhibitory function. Specifically, elevations in life stress significantly modulated the neural response to the first stimulation in the pair, while elevations in biological stress significantly modulated the neural response to the second stimulation in the pair. In contrast, neither elevations in life nor biological stress significantly predicted the gating of time-domain neural activity in the somatosensory cortex. Finally, our study is the first to link stress-induced decline in sensory gating to cognitive dysfunction, suggesting that gating paradigms may hold promise for detecting discrepant functional trajectories in age-related pathologies in the future.

To compare clinical features and outcomes in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) treated in the early experience with Impella percutaneous ventricular assist device and patients treated recently.Since pre-market approval (PMA) of Impella device as treatment for AMICS, use of the device has grown considerably.We retrospectively analyzed 649 AMICS patients treated with perioperative Impella, with 291 patients treated from 2008 to 2014 comprising the early experience cohort and 358 patients treated from 2017 to 2019 comprising the recent experience cohort. The primary end point was risk adjusted in-hospital mortality.Mean age and gender distribution of patients was similar in the two cohorts. The recent cohort had more invasive hemodynamic monitoring (64% vs 46%; P.001) and less use of an intra-aortic balloon pump prior to Impella (15% vs 41%; P.001). Recently treated patients were significantly more likely to receive Impella support prior to PCI (58% vs 44%; P = .005). In-hospital mortality was lower in the recent cohort (48% vs 56%; P = .043). This difference was however no longer significant after risk adjustment (adjusted OR 0.89, 95% CI 0.59-1.34, P = .59). Rates of acute kidney injury, major bleeding, and vascular complications requiring surgery were also significantly lower in the recent cohort.Use of Impella for AMICS during recent years is associated with lower unadjusted in-hospital mortality, which may reflect better patient selection, earlier device implantation, and improved management algorithms. In-depth understanding of these factors may inform the development of future treatment protocols.

Surgical treatment of herniated lumbar intervertebral disks is a common procedure worldwide. However, recurrent herniated nucleus pulposus (re-HNP) may develop, complicating outcomes and patient management. The purpose of this study was to utilize machine-learning (ML) analytics to predict lumbar re-HNP, whereby a personalized risk prediction can be developed as a clinical tool. A retrospective, single center study was conducted of 2630 consecutive patients that underwent lumbar microdiscectomy (mean follow-up: 22-months). Various preoperative patient pain/disability/functional profiles, imaging parameters, and anthropomorphic/demographic metrics were noted. An Extreme Gradient Boost (XGBoost) classifier was implemented to develop a predictive model identifying patients at risk for re-HNP. The model was exported to a web application software for clinical utility. There were 1608 males and 1022 females, 114 of whom experienced re-HNP. Primary herniations were central (65.8%), paracentral (17.6%), and far lateral (17.1%). The XGBoost algorithm identified multiple re-HNP predictors and was incorporated into an open-access web application software, identifying patients at low or high risk for re-HNP. Preoperative VAS leg, disability, alignment parameters, elevated body mass index, symptom duration, and age were the strongest predictors. Our predictive modeling via an ML approach of our large-scale cohort is the first study, to our knowledge, that has identified significant risk factors for the development of re-HNP after initial lumbar decompression. We developed the re-herniation after decompression (RAD) profile index that has been translated into an online screening tool to identify low–high risk patients for re-HNP. Additional validation is needed for potential global implementation.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin 70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.

Summary The 2030 Sustainable Development Goals agenda calls for health data to be disaggregated by age. However, age groupings used to record and report health data vary greatly, hindering the harmonisation, comparability, and usefulness of these data, within and across countries. This variability has become especially evident during the COVID-19 pandemic, when there was an urgent need for rapid cross-country analyses of epidemiological patterns by age to direct public health action, but such analyses were limited by the lack of standard age categories. In this Personal View, we propose a recommended set of age groupings to address this issue. These groupings are informed by age-specific patterns of morbidity, mortality, and health risks, and by opportunities for prevention and disease intervention. We recommend age groupings of 5 years for all health data, except for those younger than 5 years, during which time there are rapid biological and physiological changes that justify a finer disaggregation. Although the focus of this Personal View is on the standardisation of the analysis and display of age groups, we also outline the challenges faced in collecting data on exact age, especially for health facilities and surveillance data. The proposed age disaggregation should facilitate targeted, age-specific policies and actions for health care and disease management.

Objective Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures. Methods We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation. Results Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation. Significance Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.

Responding to a major pandemic and planning for allocation of scarce resources (ASR) under crisis standards of care requires coordination and cooperation across federal, state and local governments in tandem with the larger societal infrastructure. Maryland remains one of the few states with no state-endorsed ASR plan, despite having a plan published in 2017 that was informed by public forums across the state. In this article, we review strengths and weaknesses of Maryland’s response to COVID-19 and the role of the Maryland Healthcare Ethics Committee Network (MHECN) in bridging gaps in the state’s response to prepare health care facilities for potential implementation of ASR plans. Identified “lessons learned” include: Deliberative Democracy Provided a Strong Foundation for Maryland’s ASR Framework; Community Consensus is Informative, Not Normative; Hearing Community Voices Has Inherent Value; Lack of Transparency & Political Leadership Gaps Generate a Fragmented Response; Pandemic Politics Requires Diplomacy & Persistence; Strong Leadership is Needed to Avoid Implementing ASR … And to Plan for ASR; An Effective Pandemic Response Requires Coordination and Information-Sharing Beyond the Acute Care Hospital; and The Ability to Correct Course is Crucial: Reconsidering No-visitor Policies.

BackgroundIntracerebral hemorrhage (ICH) occurs in ~20%–30% of stroke patients undergoing endovascular therapy (EVT). However, there is conflicting evidence regarding the effect of asymptomatic ICH (aICH) on post-EVT outcomes. We sought to evaluate the effect of aICH on immediate and 90-day post-EVT neurological outcomes.MethodsIn this post-hoc analysis of the multicenter, prospective Blood Pressure after Endovascular Therapy (BEST) study we identified subjects with ICH following EVT. This population was divided into no ICH, aICH, and symptomatic ICH (sICH). Associations with 90-day modified Rankin Scale (mRS) dichotomized by functional independence (0–2 vs 3–6) and early neurological recovery (ENR) were determined using univariate/multivariate logistic regression models.ResultsOf 485 patients enrolled in BEST, 446 had 90-day follow-up data available. 92 (20.6%) developed aICH, and 18 (4%) developed sICH. Compared with those without ICH, aICH was not associated with worse 90-day outcome or lower ENR (OR 0.84 [0.53–1.35], P=0.55, aOR 0.84 [0.48–1.44], P=0.53 for 90-day mRS 0–2; OR 0.77 [0.48–1.23], P=0.34, aOR 0.72 [0.43–1.22] for ENR). aICH was not associated with 90-day outcome or ENR in patients with mTICI ≥2 b (OR 0.78 [0.48–1.26], P=0.33 for 90-day mRS 0–2; OR 0.89 [0.69–1.12], P=0.15 for ENR). A higher proportion of patients with aICH had mTICI ≥2 b than those without ICH (97%vs 87%, P=0.01).ConclusionsaICH was not associated with worse outcomes in patients with large-vessel stroke treated with EVT. aICH was more frequent in patients with successful recanalization. Further validation of our findings in large cohort studies of EVT-treated patients is warranted.

Objectives Patient knowledge deficits related to opioid risks, including lack of knowledge regarding addiction, are well documented. Our objective was to characterize patients' perceptions of signs of addiction. Methods This study utilized data obtained as part of a larger interventional trial. Consecutively discharged English-speaking patients, age >17 years, at an urban academic emergency department, with a new opioid prescription were enrolled from July 2015 to August 2017. During a follow-up phone interview 7 to 14 days after discharge, participants were asked a single question, "What are the signs of addiction to pain medicine?" Verbatim transcribed answers were analyzed using a directed content analysis approach and double coding. These codes were then grouped into themes. Results There were 325 respondents, 57% female, mean age 43.8 years, 70.1% privately insured. Ten de novo codes were added to the 11 DSM-V criteria codes. Six themes were identified: (1) effort spent acquiring opioids, (2) emotional and physical changes related to opioid use, (3) opioid use that is "not needed, (4) increasing opioid use, (5) an emotional relationship with opioids, and (6) the inability to stop opioid use. Conclusions Signs of addiction identified by opioid naive patients were similar to concepts identified in medical definitions. However, participants' understanding also included misconceptions, omissions, and conflated misuse behaviors with signs of addiction. Identifying these differences will help inform patient-provider risk communication, providing an opportunity for counseling and prevention.

PURPOSE BRAF V600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAF V600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS One hundred six patients with BRAF V600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% ( P = .05), with a disease control rate of 65% versus 21% ( P < .001). A decline in circulating tumor DNA BRAF V600E variant allele frequency was seen in 87% versus 0% of patients ( P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF V600E-mutated CRC.

This study analyzes trends in hospital emergency room visits and admissions for patients with opioid diagnoses seen at 214 hospitals in Illinois over 42 months. Visits were coded hierarchically for opioid overdose, dependence, abuse, or use. Visit rates per 100,000 were stratified by zip code level of poverty. Regression estimates of the likelihood of inpatient admission and death are presented. There were 239,069 visits accounting for almost $5 billion in total charges and over 710,000 inpatient hospital days with less than a 1% death rate. The Illinois opioid epidemic is concentrated in the poorest areas of the Chicago metropolitan area. There was a sharp gradient in visits rates and deaths rates by poverty level area and more than a fivefold difference in hospital deaths. Effective state policy responses should expand to include decriminalization and proven harm reduction strategies such as medically assisted treatment, access to safe syringes, take home naloxone, and supervised safe consumption facilities.

Background TAS-102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. Methods This investigator-initiated, open-label, single-arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Results Forty-one patients were treated with TAS-OX. No dose-limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS-102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. In the intention-to-treat population, the ORR was 2.4% (95% CI, 0%-12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival was 2.7 months (95% CI, 2.4-4.8 months) and median overall survival was 6.8 months (95% CI, 5.7-10 months). Conclusions TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression-free survival and overall survival were encouraging in this heavily pretreated population. Lay summary For metastatic colorectal cancer, the treatment combination of TAS-102 and oxaliplatin was found to be well-tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.

BackgroundThe workup for idiopathic normal pressure hydrocephalus (INPH) can be difficult to coordinate, and determining appropriate patients for ventriculoperitoneal shunting can be challenging. Therefore, we hypothesized that implementing a formalized protocol can improve patient selection for a shunt. In conjunction with neurology and neurosurgery, we instituted a standardized means of assessing patients whose presentation is concerning for INPH and compared their workup with similar patients seen without the Protocol (i.e., preprotocol [PP]) regarding baseline characteristics, assessment, and outcomes.MethodsTwenty-six PP patients were compared with 40 Protocol patients on measures, including baseline deficits, workup, neurosurgical evaluation, and response to shunt.ResultsAverage age was similar between groups, and the percentage of patients who had a decline in gait, cognition, and/or incontinence was not statistically different (p > 0.05). Significantly more Protocol patients underwent high-volume lumbar puncture (HVLP; 97.5%; PP, 61.5%; p < 0.001) and received formalized gait assessment with the Gait Scale (90%; PP, 0%, p < 0.001) and standardized cognitive testing (95%; PP, 38.5%; p < 0.001). Significantly more Protocol patients had no improvement after HVLP (33.3%; PP, 6.25%; p < 0.045); subsequently, fewer got shunted (57.5%; PP, 84.6%; p < 0.030). More Protocol patients who were shunted reported gait improvement (100%; PP, 72.7%; p = 0.009), although there was no difference in cognition (59.2%; PP, 82.6%; p = 0.108) or incontinence (18.2%; PP, 39.1%; p = 0.189).ConclusionsImplementing an INPH Protocol leads to standardized and more extensive assessment and better patient selection for and subsequent outcomes from shunting, specifically regarding gait.

BACKGROUND CONTEXT Targeting chemokines or chemokine receptors is a promising treatment strategy for diseases with chronic inflammation such as rheumatoid arthritis and discogenic pain. Identifying specific molecules and determining their effectiveness in animal models are the first steps in developing these treatments. Macrophage markers have been detected in the intervertebral disc tissues of patients with disc degenerative disease and discogenic pain and in different animal models. Macrophage recruitment into the disc may play a role in initiation of inflammation and if unresolved may lead to chronic inflammation and subsequent back pain. PURPOSE The objectives of these studies are to (1) identify chemokine receptor antagonists that can block macrophage migration induced by disc cells in vitro and (2) determine if intradiscal treatment with these antagonists can reduce disc inflammation and degeneration in vivo. STUDY DESIGN In vitro migration assays were used to test effectiveness of chemokine receptor antagonists to block macrophage migration induced by disc cells. The rabbit annular puncture model was used to test for anti-inflammatory and regenerative effects of chemokine receptor antagonist treatment in vivo. METHODS In vitro – THP-1 human monocytic cell line and freshly isolated rabbit primary splenocytes were assayed for migration using 3 µm Corning Transwell inserts with conditioned media of interleukin (IL)-1β treated human or rabbit disc cells. Inhibition of macrophage migration was evaluated using different concentrations of small molecule antagonists of C-C chemokine receptor (CCR)1 and CCR2. In vivo – New Zealand White rabbits (n=40) underwent disc puncture and intradiscal treatment with saline, CCR1 or CCR2 antagonists within the same procedure. X-ray and magnetic resonance (MR) images and serum samples were taken for disc height, MRI grade and IL-8 serum level analyses. Intervertebral discs were isolated for RNA analysis of inflammatory and disc phenotypic markers and for immunohistochemical analysis of macrophage marker, RAM11. The outcome measures were compared between the three treatment groups. These studies were funded by a research grant from AO Foundation, Switzerland (Project no S-14-86A; 120000 CHF). CCR1 and CCR2 antagonists were kindly provided by ChemoCentryx (Mountain View, CA). RESULTS In vitro migration assays showed that THP-1 migration induced by disc cells was blocked by CCR2 antagonist more effectively than CCR1 antagonist, while rabbit splenocyte migration was inhibited by CCR1 antagonist and not the other. In the rabbit annular puncture model, rabbit discs treated with CCR1 antagonist had significantly better MRI grades than those treated with CCR2 antagonist at 6 weeks post-treatment. Gene expression studies demonstrate that discs treated with CCR1 or CCR2 antagonists expressed less inflammatory markers than saline-treated discs at 3 weeks post-treatment. Although CCR2 antagonist treatment did not reduce inflammatory marker expression at 6 weeks, discs treated with CCR1 antagonist expressed less inflammatory markers and also a higher ratio of collagen type 2 to collagen type 1 genes indicating favorable disc matrix production. There were no significant differences between all three treatment groups in regards to disc height indexes, IL-8 serum levels or macrophage marker detection. CONCLUSIONS These studies have identified that small molecule antagonists against CCR2 and CCR1 were respectively effective in blocking THP-1 and rabbit splenocyte migration induced by disc cells in vitro. Further, both CCR2 and CCR1 antagonist intradiscal treatments were effective in reducing disc inflammation at an early time point of 3 weeks. Lastly, only CCR1 antagonist demonstrated anti-inflammatory effects and better MRI grades at 6 weeks. CLINICAL SIGNIFICANCE Our preclinical studies demonstrate that CCR1 and CCR2 antagonist delivery through intradiscal injection is sufficient to reduce disc inflammation at early time points, whereas CCR1 antagonists had longer term anti-inflammatory effects. Clinical studies have found that CCR1 antagonist was safe, tolerable and clinically active in reducing inflammation in rheumatoid arthritis patients. These studies suggest that CCR1 antagonist may be a promising biological treatment to reduce disc inflammation that translates to back pain relief.

Author(s): Mallow, G Michael; Siyaji, Zakariah K; Galbusera, Fabio; Espinoza-Orias, Alejandro A; Giers, Morgan; Lundberg, Hannah; Ames, Christopher; Karppinen, Jaro; Louie, Philip K; Phillips, Frank M; Pourzal, Robin; Schwab, Joseph; Sciubba, Daniel M; Wang, Jeffrey C; Wilke, Hans-Joachim; Williams, Frances MK; Mohiuddin, Shoeb A; Makhni, Melvin C; Shepard, Nicholas A; An, Howard S; Samartzis, Dino

Study Design: Retrospective cohort study. Objectives: This study aimed to address the prevalence, distribution, and clinical significance of cervical high-intensity zones (HIZs) on magnetic resonance imaging (MRI) with respect to pain and other patient-reported outcomes in the setting of patients that will undergo an anterior cervical discectomy and fusion (ACDF) procedure. Methods: A retrospective cohort study of ACDF patients surgically treated at a single center from 2008 to 2015. Based on preoperative MRI, HIZ subtypes were identified as either traditional T2-hyperintense, T1-hypointense (“single-HIZs”), or combined T1- and T2-hyperintense (“dual-HIZs”), and their level-specific prevalence was assessed. Preoperative symptoms, patient-reported outcomes, and disc degeneration pathology were assessed in relation to HIZs and HIZ subtypes. Results: Of 861 patients, 58 demonstrated evidence of HIZs in the cervical spine (6.7%). Single-HIZs and dual-HIZs comprised 63.8% and 36.2% of the overall HIZs, respectively. HIZs found outside of the planned fusion segment reported better preoperative Neck Disability Index (NDI; P = .049) and Visual Analogue Scale (VAS) Arm ( P = .014) scores relative to patients without HIZs. Furthermore, patients with single-HIZs found inside the planned fusion segment had worse VAS Neck ( P = .045) and VAS Arm ( P = .010) scores. In general, dual-HIZ patients showed no significant differences across all clinical outcomes. Conclusions: This is the first study to evaluate the clinical significance of HIZs in the cervical spine, noting level-specific and clinical outcome–specific variations. Single-HIZs were associated with significantly more pain when located inside the fusion segment, while dual-HIZs showed no associations with patient-reported outcomes. The presence of single-HIZs may correlate with concurrent spinal pathologies and should be more closely evaluated.

Discharge to acute/intermediate care facilities is a common occurrence after posterior lumbar fusion and can be associated with increased costs and complications after these procedures. This is particularly relevant with the growing popularity of bundled payment plans, creating a need to identify patients at greatest risk.To develop and validate a risk-stratification tool to identify patients at greatest risk for facility discharge after open posterior lumbar fusion.Retrospective cohort study.Patients were queried using separate databases from the institution of study and the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) for all patients undergoing open lumbar fusion between 2011 and 2018.Discharge to intermediate care and/or rehabilitation facilities.Using an 80:20 training and testing NSQIP data split, collected preoperative demographic and operative variables were used in a multivariate logistic regression to identify potential risk factors for postoperative facility discharge, retaining those with a p value.05. A nomogram was generated to develop a scoring system from this model, with probability cutoffs determined for facility discharge. This model was subsequently validated within the NSQIP database, in addition to external validation at the institution of study. Overall model performance and calibration was assessed using the Brier score and calibration plots, respectively.A total of 11,486 patients (10,453 NSQIP, 1,033 local cohort) were deemed eligible for study, of which 16.1% were discharged to facilities (16.7% NSQIP, 9.6% local cohort). Utilizing training data, age (p.001), body mass index (p.001), female sex (p.001), diabetes (p=.043), peripheral vascular disease (p=.001), cancer (p=.010), revision surgery (p.001), number of levels fused (p.001), and spondylolisthesis (p=.049) were identified as significant risk factors for facility discharge. The area under the receiver operating characteristic curve (AUC) indicated a strong predictive model (AUC=0.750), with similar predictive ability in the testing (AUC=0.757) and local data sets (AUC=0.773). Using this tool, patients identified as low- and high-risk had a 7.94% and 33.28% incidence of facility discharge in the testing data set, while rates of 4.44% and 16.33% were observed at the institution of study.Using preoperative variables as predictors, this scoring system demonstrated high efficiency in risk-stratifying patients with an approximate four to fivefold difference in rates of facility discharge after posterior lumbar fusion. This tool may help inform medical decision-making and guide reimbursement under bundled-care repayment plans.

Purpose: Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. Patients and Methods: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. Results: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25–7.20 months)/9.9 (6.74–12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06–23.49 months)]. Overall response rate (95% CI) was 18% (8.6%–31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 Conclusions: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Study Design: Cross-sectional observational cohort study. Objective: To investigate preparation, response, and economic impact of COVID-19 on private, public, academic, and privademic spine surgeons. Methods: AO Spine COVID-19 and Spine Surgeon Global Impact Survey includes domains on surgeon demographics, location of practice, type of practice, COVID-19 perceptions, institutional preparedness and response, personal and practice impact, and future perceptions. The survey was distributed by AO Spine via email to members (n = 3805). Univariate and multivariate analyses were performed to identify differences between practice settings. Results: A total of 902 surgeons completed the survey. In all, 45.4% of respondents worked in an academic setting, 22.9% in privademics, 16.1% in private practice, and 15.6% in public hospitals. Academic practice setting was independently associated with performing elective and emergent spine surgeries at the time of survey distribution. A majority of surgeons reported a >75% decrease in case volume. Private practice and privademic surgeons reported losing income at a higher rate compared with academic or public surgeons. Practice setting was associated with personal protective equipment availability and economic issues as a source of stress. Conclusions: The current study indicates that practice setting affected both preparedness and response to COVID-19. Surgeons in private and privademic practices reported increased worry about the economic implications of the current crisis compared with surgeons in academic and public hospitals. COVID-19 decreased overall clinical productivity, revenue, and income. Government response to the current pandemic and preparation for future pandemics needs to be adaptable to surgeons in all practice settings.

BACKGROUND: Anticoagulation increases the risk of intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA), so the management of stroke-risk in patients with both atrial fibrillation (AF) and CAA is controversial. Advances in left atrial appendage closure (LAAC) techniques provide a stroke-risk-reduction option which avoids long-term oral anticoagulation (OAC). We aimed to evaluate the safety of this intervention in patients with CAA. METHODS: This is an observational cohort study of patients with severe CAA (with or without ICH) and AF who were treated with LAA closure. The Watchman™ and Amulet® LAAC devices, Lariat procedure or open surgical closure of the LAA were all considered acceptable means of closure. Patients with symptomatic ICH and those naive to anticoagulation were placed on clopidogrel and/or aspirin for 6 weeks after the procedure; patients who previously tolerated anticoagulation remained on warfarin or a DOAC for 6 weeks post-procedure. All antiplatelet and anticoagulation therapy was discontinued after confirmation of LAAC. All patients had aggressively optimized blood pressure and fall precautions in addition to surgical intervention. Safety, tolerability, stroke and hemorrhage rates were documented. OUTCOME: Twenty-six patients with a mean CHA(2)DS(2)-VASc score of 4.6 were treated, 13 with a history of symptomatic lobar hemorrhage and 13 without. All patients who completed LAAC tolerated device implantation. There were no documented ischemic strokes or symptomatic ICH during the 30 days after device implantation. Patients were followed for an average of 25 months. One patient who underwent LARIAT LAAC had an ischemic stroke in follow-up, but recovered well; there were no other thromboemboli in this cohort. CONCLUSIONS: This cohort study provides evidence that LAAC appears to be a safe and tolerable treatment to reduce stroke risk in patients with CAA. Because of the small size of the cohort and relatively short follow-up, the efficacy for stroke and ICH prevention is not conclusive, but the preliminary results are encouraging. LAA closure may be a good alternative to anticoagulation in patients with CAA and atrial fibrillation.

Summary Background Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. Methods CP-MGAH22–05 was a single-arm, open-label, phase 1b–2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov , NCT02689284 . Recruitment for the trial has completed and follow-up is ongoing. Findings Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7–23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3–4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15–27·93) of 92 evaluable patients. Interpretation These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). Funding MacroGenics.

Remote consultations likely will grow in importance if the COVID-19 pandemic continues. This review analyzes which methods of teledermatology patients prefer by categorizing how recent studies have defined satisfaction, conducted surveys and concluded patients respond to the different modalities of teledermatology. Using PubMed and Cochrane databases, we reviewed studies from April 5th, 2010 to April 5th, 2020 that included the search terms patient satisfaction and teledermatology. All studies that included patient satisfaction as an outcome were included, but studies not published in English were excluded. We examined domains of satisfaction, survey method, study characteristics (including patient population, country, age, study design and evidence score), findings and statistical comparisons. We thoroughly reviewed 23 studies. Definitions of satisfaction varied, but all concluded patients were satisfied with the live-interactive and store-and-forward modalities. The studies reveal that store-and-forward is appropriate for clinicians with established patients who require regular follow-up. Verified areas of care include treatment of chronic conditions, topical skin cancer therapy, wound monitoring, and post-procedural follow-up. Only four studies conducted statistical analyses. One of those studies compared patient preference for each modality of teledermatology with face-to-face dermatology. While this study reported high satisfaction with each mode of teledermatology, patients still preferred face-to-face. Favorable responses to remote diagnostic capabilities suggest that these offerings improve preference for teledermatology. With only one study evaluating preference between each modality and face-to-face dermatology, more studies should address the discrepancy. Surveys that cover all domains of satisfaction may improve assessments and identify where gaps in preference exist.

Objective The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear. Methods S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity. Results Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA. Conclusions We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.

A 27-year-old man admitted with tricuspid valve endocarditis with a large vegetation, persistent bacteremia, and pulmonary and systemic septic embolization was deemed not a suitable surgical candidate. He underwent percutaneous vegetation debulking using the AngioVac system. The patient defervesced post-operatively with clinical improvement but with abruptly worsened tricuspid regurgitation. (Level of Difficulty: Beginner.), Central Illustration, A 27-year-old man admitted with tricuspid valve endocarditis with a large vegetation, persistent bacteremia, and pulmonary and systemic septic…

Objective: To determine if personal health of spine surgeons worldwide influences percep-tions, healthcare delivery, and decision-making during the coronavirus disease 2019 (CO-VID-19) pandemic. Methods: A cross-sectional study was performed by distributing a multidimensional survey to spine surgeons worldwide. Questions addressed demographics, impacts and perceptions of COVID-19, and the presence of surgeon comorbidities, which included cancer, cardiac disease, diabetes, obesity, hypertension, respiratory illness, renal disease, and current tobacco use. Multivariate analysis was performed to identify specific comorbidities that influenced various impact measures. Results: Across 7 global regions, 36.8% out of 902 respondents reported a comorbidity, of which hypertension (21.9%) and obesity (15.6%) were the most common. Multivariate analysis noted tobacco users were more likely to continue performing elective surgery during the pandemic (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.46–4.72; p = 0.001) and were less likely to utilize telecommunication (OR, 0.51; 95% CI, 0.31–0.86; p = 0.011), whereas those with hypertension were less likely to warn their patients should the surgeon become infected with COVID-19 (OR, 0.57; 95% CI, 0.37–0.91; p = 0.017). Clinicians with multiple comorbidities were more likely to cite personal health as a current stressor (OR, 1.32; 95% CI, 1.07–1.63; p = 0.009) and perceived their hospital’s management un-favorably (OR, 0.74; 95% CI, 0.60–0.91; p = 0.005). Conclusion: This is the first study to have mapped global variations of personal health of spine surgeons, key in the development for future wellness and patient management initia-tives. This study underscored that spine surgeons worldwide are not immune to comorbidi-ties, and their personal health influences various perceptions, healthcare delivery, and de-cision-making during the COVID-19 pandemic.

Objectives The aim of this study was to describe the performance and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in Michigan. Background CTO PCI has been associated with reduction in angina, but previous registry analyses showed a higher rate of major adverse cardiac events with this procedure. Methods To study uptake and outcomes of CTO PCI in Michigan, patients enrolled in the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry (2010 to 2017) were evaluated. CTO PCI was defined as intervention in a 100% occluded coronary artery ≥3 months old. Results Among 210,172 patients enrolled in the registry, 7,389 CTO PCIs (3.5%) were attempted, with 4,614 (58.3%) achieving post-procedural TIMI (Thrombolysis In Myocardial Infarction) flow grade 3. The proportion of PCIs performed on CTOs increased over the study period (from 2.67% in 2010 to 4.48% in 2017). Thirty of 47 hospitals performed >50 CTO interventions in 2017. Pre-procedural angina class ≤2 was present in one-quarter, and functional assessment for ischemia was performed in 46.6% of patients. Major complications occurred in 245 patients (3.3%) and included death (1.4%), post-procedural stroke (0.4%), cardiac tamponade (0.5%), and urgent coronary artery bypass graft surgery (1.3%). Procedural success improved modestly from 44.5% in 2010 to 54.9% in 2017 (p for trend Conclusions The rate of CTO PCI in Michigan increased over the study period. Although the success rate of CTO PCI has increased modestly in contemporary practice, it remained far below the >80% reported by select high-volume CTO operators. The rate of periprocedural major adverse cardiac events or death remained unchanged over time. These data suggest room for improvement in the selection and functional assessment of CTO lesions before subjecting patients to the increased procedural risk associated with CTO PCI.

The petrous apex is a difficult to reach surgical area due to its deep position in the skull base and many vital surrounding structures. Petrous apex pathology ranges from extradural cholesterol granulomas, cholesteatomas, asymmetric pneumatization, and osteomyelitis to intradural meningiomas and schwannomas. Certain lesions, such as cholesterol granulomas, can be managed with drainage while neoplastic lesions must be completely resected. Surgical options use open, endoscopic, and combined techniques and are categorized into anterior, lateral, and posterior approaches. The choice of approach is determined by the nature of the pathology and location relative to vital structures and extension into surrounding structures and requires thorough preoperative evaluation and discussion of surgical goals with the patient. The purpose of this state-of-the-art review is to discuss the most commonly used surgical approaches to the petrous apex, and the anatomy on which these approaches are based.

Study Design: Cross-sectional, international survey. Objectives: The current study addressed the multi-dimensional impact of COVID-19 upon healthcare professionals, particularly spine surgeons, worldwide. Secondly, it aimed to identify geographical variations and similarities. Methods: A multi-dimensional survey was distributed to surgeons worldwide. Questions were categorized into domains: demographics, COVID-19 observations, preparedness, personal impact, patient care, and future perceptions. Results: 902 spine surgeons representing 7 global regions completed the survey. 36.8% reported co-morbidities. Of those that underwent viral testing, 15.8% tested positive for COVID-19, and testing likelihood was region-dependent; however, 7.2% would not disclose their infection to their patients. Family health concerns were greatest stressor globally (76.0%), with anxiety levels moderately high. Loss of income, clinical practice and current surgical management were region-dependent, whereby 50.4% indicated personal-protective-equipment were not adequate. 82.3% envisioned a change in their clinical practice as a result of COVID-19. More than 33% of clinical practice was via telemedicine. Research output and teaching/training impact was similar globally. 96.9% were interested in online medical education. 94.7% expressed a need for formal, international guidelines to manage COVID-19 patients. Conclusions: In this first, international study to assess the impact of COVID-19 on surgeons worldwide, we identified overall/regional variations and infection rate. The study raises awareness of the needs and challenges of surgeons that will serve as the foundation to establish interventions and guidelines to face future public health crises.

Background The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. Methods Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. Results The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%–19%) in arm 1 versus 10% (95% CI 0%–23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. Conclusions This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

Squamous cell carcinoma of the anorectal canal (SCCA) is a rare HPV-related malignancy that is steadily increasing in incidence. A high unmet need exists for patients with persistent loco-regional and metastatic disease. Axalimogene filolisbac (ADXS11-001) is an investigational immunotherapy that stimulates tumor-specific responses against HPV-associated cancers, and has demonstrated benefit in metastatic cervical cancer. We conducted this single-arm, multicenter, phase 2 trial in patients with persistent/recurrent, loco-regional or metastatic SCCA. Patients received ADXS11-001, 1 × 109 colony-forming units intravenously every 3 weeks. A Simon 2-stage design was used to test primary co-endpoints of overall response rate (ORR) and 6-month progression-free survival (PFS) rate. Study would proceed to full enrollment if ORR ≥ 10% or 6-month PFS rate ≥ 20%. Thirty-six patients were treated; 29 patients were evaluable for response. One patient had a prolonged partial response (3.4% ORR). The 6-month PFS rate was 15.5%. Grade 3 adverse event were noted in 10 patients, with the majority being cytokine-release symptoms; one grade 4 adverse event was noted. No grade 5 adverse events occurred. ADXS11-001 was safe and well-tolerated in patients with SCCA. However, this study did not meet either primary endpoint. ADXS11-001 may be more beneficial when administered in combination with other cytotoxic or targeted agents.

Despite the growing senior population within the United States, there is a lack of consensus regarding the safety and efficacy of performing lumbar spinal fusion for this population.To evaluate the clinical and radiographic outcomes in different age cohorts following lumbar spinal fusion.Retrospective cohort analysis.Analysis of 1,184 patients who underwent posterolateral lumbar fusion from 2011 to 2018. Surgery was indicated after failure of conservative treatment to address radiculopathy and/or neurogenic claudication. Patients were excluded if they were under 18 years of age at the time of surgery, had a lumbar fracture, tumor, or infection, or had fusions involving the thoracic spine, high-grade spondylolisthesis, or concomitant deformity. Of the 1,184 patients, 850 patients were included. Patients were divided into three roughly equal groups for analysis: young (18-54 years), middle-aged (55-69 years), and senior (≥70 years).Visual Analog Scale Back/Leg pain, and Oswestry Disability Index (ODI) were collected, and achievement of minimal clinically important difference was evaluated. Lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), and PI-LL difference were measured on radiographs. Rates of postoperative complications were analyzed.Several radiographic parameters were measured using plain radiographs obtained at preoperative, immediately postoperative (standing radiographs performed on postoperative day 1), and most recent follow-up visits. Preoperative and final patient-reported outcomes, along with demographic information, were obtained all patients. Binary outcome variables were compared between groups with multivariate logistic regression, and continuous outcome variables were compared using multivariate linear regression, with age 18 to 54 years used as the reference. Multivariate regressions were used to compare outcomes between cohorts while controlling baseline characteristics.A total of 850 patients were included; 330 young (38.80%), 317 middle-aged (37.30%), and 203 senior (23.90%). Seniors had higher postoperative length of stay compared to younger patients (p.001). Younger patients had worse final ODI scores compared to middle-aged patients (p=.002). Seniors had higher rates of proximal ASD (p=.002) compared to young patients. There was no difference in achievement of minimal clinically important differences (MCID) between all three groups.Senior patients have significant improvement in patient-reported clinical outcomes, despite having greater comorbidities, and longer length of stay. However, given a general lack of achievement of MCID across all cohorts, these findings suggest the need for a critical re-evaluation of the role of lumbar spinal fusion in the management of patients with refractory radiculopathic and/or neurogenic claudication symptoms.

Highlights •ICH, although less common than ischemic stroke, is the major cause of stroke mortality and there is not yet a definitive therapy beyond supportive care. •Early stabilization of acute ICH involves identifying and treating the cause(s) of decreased alertness, aggressively correcting blood pressure, and reversing any coagulopathy. •Long-term management of ICH requires correctly identifying the underlying etiology and, when possible, correcting it. •Initial clinical trials of minimally invasive hemorrhage evacuation were promising and ongoing trials are evaluating new hemorrhage evacuation technologies.

Objective To assess the impact of Modic changes (MC) on preoperative symptoms, and postoperative outcomes in anterior cervical discectomy and fusion (ACDF) patients. Methods We performed a retrospective study of prospectively collected data of ACDF patients at a single institution. Preoperative magnetic resonance imagings were used to assess the presence of MC. MC were stratified by type and location, and compared to patients without MC. Associations with symptoms, patient-reported measures, and surgical outcomes were assessed. Results A total of 861 patients were included, with 356 patients with MC (41.3%). MC more frequently occurred at C5–6 (15.1%), and type II was the most common type (61.2%). MC were associated with advanced age (p < 0.001), more levels fused (p < 0.001), a longer duration of symptoms, but not with specific symptoms. MC at C7–T1 resulted in higher postoperative disability (p < 0.001), but did not increase risk of adjacent segment degeneration or reoperation. Conclusion This study is the first to systematically examine the impact of cervical MC, stratified by type and location, on outcomes in ACDF patients. Patients with MC were generally older, required larger fusions, and had longer duration of preoperative symptoms. While MC may not affect specific outcomes following ACDF, they may indicate a more debilitating preoperative state for patients.

Degenerative spine imaging findings have been extensively studied in the lumbar region and are associated with pain and adverse clinical outcomes after surgery. However, few studies have investigated the significance of these imaging "phenotypes" in the cervical spine. Patients with degenerative cervical spine pathology undergoing anterior cervical discectomy and fusion (ACDF) from 2008 to 2015 were retrospectively and prospectively assessed using preoperative MRI for disc degeneration, narrowing, and displacement, high-intensity zones, endplate abnormalities, Modic changes, and osteophyte formation from C2-T1. Points were assigned for these phenotypes to generate a novel Cervical Phenotype Index (CPI). Demographics were evaluated for association with phenotypes and the CPI using forward stepwise regression. Bootstrap sampling and multiple imputations assessed phenotypes and the CPI in association with patient-reported outcomes (Neck Disability Index [NDI], Visual Analog Scale [VAS]-neck, VAS-arm) and adjacent segment degeneration (ASDeg) and disease (ASDz). Of 861 patients, disc displacement was the most common (99.7%), followed by osteophytes (92.0%) and endplate abnormalities (57.3%). Most findings were associated with age and were identified at similar cervical vertebral levels; at C5-C7. Imaging phenotypes demonstrated both increased and decreased associations with adverse patient-reported outcomes and ASDeg/Dz. However, the CPI consistently predicted worse NDI (P = .012), VAS-neck (P = .007), and VAS-arm (P = .013) scores, in addition to higher odds of ASDeg (P = .002) and ASDz (P = .004). The CPI was significantly predictive of postoperative symptoms of pain/disability and ASDeg/Dz after ACDF, suggesting that the totality of degenerative findings may be more clinically relevant than individual phenotypes and that this tool may help prognosticate outcomes after surgery.

Objectives Recent guidelines advise limiting opioid prescriptions for acute pain to a three-day supply; however, scant literature quantifies opioid use patterns after an emergency department (ED) visit. We sought to describe opioid consumption patterns after an ED visit for acute pain. Design Descriptive study with data derived from a larger interventional study promoting safe opioid use after ED discharge. Setting Urban academic emergency department (>88,000 annual visits). Subjects Patients were eligible if age >17 years, not chronically using opioids, and newly prescribed hydrocodone-acetaminophen and were included in the analysis if they returned the completed 10-day medication diary. Methods Patient demographics and opioid consumption are reported. Opioid use is described in daily number of pills and daily morphine milligram equivalents (MME) both for the sample overall and by diagnosis. Results Two hundred sixty patients returned completed medication diaries (45 [17%] back pain, 52 [20%] renal colic, 54 [21%] fracture/dislocation, 40 [15%] musculoskeletal injury [nonfracture], and 69 [27%] “other”). The mean age (SD) was 45 (15) years, and 59% of the sample was female. A median of 12 pills were prescribed. Patients with renal colic used the least opioids (total pills: median [interquartile range {IQR}] = 3 [1–7]; total MME: median [IQR] = 20 [10–50]); patients with back pain used the most (total pills: median [IQR] = 12 [7–16]; total MME: median [IQR] = 65 [47.5–100]); 92.5% of patients had leftover pills. Conclusions In this sample, pill consumption varied by illness category; however, overall, patients were consuming low quantities of pills, and the majority had unused pills 10 days after their ED visit.

Objective To determine the risk factors associated with radiographic changes and clinical outcomes following 3-level anterior cervical discectomy and fusion (ACDF) using rigidplate constructs and cortico-cancellous allograft. ACDF has demonstrated efficacy for treatment of multilevel degenerative cervical conditions, but current data exists in small heterogeneous forms. Methods A retrospective review included 98 patients with primary 3-level ACDF surgery at one institution from 2008 to 2013 with minimum 1-year follow-up. Cervical sagittal vertical axis (SVA), segmental height, fusion, and lordosis radiographs were measured preoperatively and at 2 postoperative periods. Results Rates of asymptomatic pseudarthroses and total reoperations were 18% and 4%, respectively. Results demonstrated immediate improvements in cervical lordosis (5.5°, p < 0.01) and segmental height (5.0-mm increase, p < 0.01) with little changes in the cervical SVA (3.2-mm increase, p < 0.01). The segmental height decreased from immediate postoperative period to final follow-up (1.7-mm decrease, p < 0.01). Older age was protective against radiolucent lines (p < 0.05). Patient-reported outcomes significantly improved following surgery (p < 0.01). Current smoking status and diagnosis of diabetes mellitus had no impact on radiographic or clinical outcomes. Risk factors were not identified for the 5 reoperations (4%). Conclusion Three-level ACDF with rigid-plating and cortico-cancellous allograft is an effective procedure for degenerative diseases of the cervical spine without the application of additional adjuncts or combined anteriorposterior cervical surgeries. Significant improvements in cervical lordosis, segmental height, and segmental alignment can be achieved with little change in cervical SVA and a low rate of reoperations over short-term follow-up. Similarly, patient-reported outcomes show significant improvements.

OBJECTIVE To identify possible radiographic predictors markers of dynamic instability including disc height (DH), disc degeneration, and spondylosis in the setting of degenerative spondylolisthesis (DS). METHODS A retrospective review with prospectively collected data was performed on 125 patients with L4-5 DS who underwent decompression and fusion. Patients were divided into groups with dynamic instability and those without. Radiographs of the lumbar spine in neutral, flexion, and extension were used to determine degree of slip, DH, translational motion, angular motion, spondylotic changes, and lumbar lordosis. Magnetic resonance imaging (MRI) scans were reviewed to assess disc degeneration. RESULTS Thirty-one percent of the patients met criteria for dynamic instability. Significant correlations (p < 0.05) were found between preserved DH and dynamic instability; increased spondylotic changes and decreased translational motion; as well as advanced MRI-based disc degeneration scores with decreased angular motion, respectively. Six radiographic parameters were utilized to create a predictive model for dynamic instability, and a receiver operating characteristic curve was able to validate the predictive model (area = 0.891, standard error = 0.034, p < 0.001). CONCLUSION In DS patients, preserved DH was significantly related to dynamic instability. This finding may represent a greater potential for slip progression over time in these patients. In contrast, disc degeneration on MRI, and spondylotic changes were inversely related to dynamic instability and may represent restabilization mechanisms that decrease the chance of future slip progression in DS.

Magnetic resonance imaging (MRI) is a critical tool for evaluating the normal and pathologic states of the spine and associated tissues. Advancements in MRI technology have greatly improved visualization of vertebral anatomy and identification of pathologic abnormalities, including spinal stenosis, degenerative disc disease, tumors, ligamentous abnormalities, and more. In addition to eliminating exposure to harmful radiation, MRI offers superior depiction of soft tissues relative to plain radiography and computed tomography. However, its potential to highlight clinically insignificant abnormalities requires correlation with patient history and clinical exam findings when determining diagnosis and guiding surgical decision-making. This chapter focuses on the efficacy of various MRI imaging sequences in evaluating vertebral anatomy and identifying various pathologic presentations within the cervical spine.

Imaging methods of the spine have greatly expanded since 1895, providing anatomical clarity for diagnosis and treatment of the cervical, thoracic, lumbar, and sacral vertebrae. The complex anatomy of the vertebrae and irregular contours and geometry of the spinal elements have influenced the rapid development of more precise imaging modalities. Various advancements to two- and three-dimensional imaging through plain radiographs, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and EOS imaging along with multiple dimensional views of the spine are continuously optimized. Future developments in imaging may improve the assessment of pedicle screw placement and image definition, reduce radiation, and provide autonomous spinal mapping using artificial intelligence.