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Telehealth use has increased in the setting of the COVID-19 pandemic. However, there are disparities in telehealth use based on age, income, race/ethnicity, low health, digital literacy, and limited English proficiency. There are multilevel barriers to telehealth use at the patient, health systems, telehealth portal, and policy levels. To ensure equity in telehealth services and to leverage these services to maximize the reach of health care services, concerted efforts are needed to design telehealth tools and workflows. It should include reimbursement for staff training, patient education, and technical support needed for telehealth use. Furthermore, ongoing monitoring and responsive modifications in the use of telehealth services are needed to promote telehealth equity.

Ramanna (Unreliable accounts: How regulators fabricate conceptual narratives to diffuse criticism. Accounting, Economics and Law: A Convivium, this issue) argues that the FASB’s new Conceptual Framework deemphasizes reliability, and especially verifiability, in favor of representational faithfulness to facilitate the FASB’s promotion of an “asset-liability” approach measured at fair values. More importantly, he argues that this change is likely to generate costly unintended consequences by undermining reporting quality. We agree and consider more broadly whether FASB creates social value through better accounting knowledge, and whether it is time to sunset the FASB monopoly in establishing accounting standards.

Rationale: Indoor particulate matter is associated with worse COPD outcomes. It remains unknown whether reductions of indoor pollutants improve respiratory morbidity. Methods: Eligible former smoke...

Rationale Environmental exposures have been associated with adverse outcomes in COPD. Approximately one third of individuals with COPD have allergic sensitization, but it is unknown whether exposure to allergens in the home are associated with outcomes. Objectives To determine the prevalence and associations of allergen sensitization with exposure to common indoor allergens with symptoms and exacerbation risk in COPD. Methods Allergen sensitization to five common indoor allergens was assessed in former smokers with COPD. Home settled dust was assessed for presence of corresponding allergens. Sensitization and exposure status were determined and associations evaluated in adjusted models with longitudinal outcomes including symptoms, lung function and exacerbations. Interactions were assessed between sensitization/exposure status and lung function. Measurements and Main Results One hundred eighty-three individuals studied were on average 67.3 years old (SD 8.22) with average FEV1 of 53.2 % (SD 17.6%). Seventy-seven percent of participants were exposed to at least one tested allergen, and 17% had sensitization with corresponding allergen exposure. After adjustment, sensitization with exposure was associated with lower lung function (β -8.29, 95% CI -14.80 to -1.77), higher SGRQ (β 6.71, 95% CI 0.17 to 13.25) and higher exacerbation risk (OR 2.31, 95% CI 1.11 to 4.79). Associations appeared to be more pronounced among individuals with lower lung function. Conclusions Allergen exposures are common in COPD and associated with adverse outcomes among those with concomitant allergen sensitization. This study establishes allergens as an important home exposure that potentially could be addressed with comprehensive home environmental modification strategies to improve COPD outcomes.

Background and Aims Closure of endoscopic resection defects can be achieved with through-the-scope clips, over-the-scope clips or endoscopic suturing. However, these devices are often limited by their inability to close large, irregular, and difficult to reach defects. Thus, we aimed to assess the feasibility and safety of the novel through-the-scope suture-based closure system that was developed to overcome these limitations. Methods This is a retrospective multicenter study involving 8 centers in the United States. Primary outcomes included feasibility and safety of early use of the device. Secondary outcomes included assessment of need for additional closure devices, prolonged procedure time, and technical feasibility of performing the procedure with an alternative device(s). Results A total of 93 patients (48.4% female) with mean age 63.6 ± 13.1 years were included. Technical success was achieved in 83 patients (89.2%) and supplemental closure was required in 24.7% (n=23) of patients with a mean defect size of 41.6 ± 19.4 mm. Closure with an alternative device was determined to be impossible in 24.7% of patients due to location, size, or shape of the defect. The use of the tack and suture device prolonged the procedure in 8.6% of the cases but was considered acceptable. Adverse events occurred in 2 patients (2.2%) over a duration of follow-up of 34 days (interquartile range: 13-93.5 days) and were mild and moderate in severity. No serious adverse events or procedure-related deaths occurred. Conclusions The novel endoscopic through-the-scope tack and suture system is safe, efficient, and permits closure of large, and irregularly shaped defects that were not possible with predicate devices.

Decreased posterior tibial slope has been associated with increased risk of graft failure and knee instability after posterior cruciate ligament (PCL) reconstruction. Premature physeal arrest at the tibial tubercle is a common cause of osseous genu recurvatum. Surgical management is recommended to correct the tibial slope and prolong the integrity of the PCL graft. This article discusses our preferred treatment using a proximal tibial opening wedge osteotomy for surgical management of posterior knee instability and genu recurvatum secondary to significant anterior tibial slope., Technique Video Video 1 The patient is examined under anesthesia and is found to have a right heel height of 15 cm and a positive right posterior drawer test. An incision is made from the midportion of the patella down distally to the tibial tubercle, raising full-thickness subcutaneous flaps. A proximal tibial opening wedge osteotomy is performed with 2 guide pins, a small saw blade, and osteotomes. The osteotomy is then widened using a spreader device until the desired tibial slope is achieved. Measurements are taken intraoperatively, confirming preoperative planning for appropriate size of the posteriorly sloped Puddu plate. The osteotomy is completed by placing the plate just medial to the patellar tendon anteriorly. A large Richards staple is placed on the anterolateral aspect of the osteotomy, and the incision is then closed.

BACKGROUND Academic conferences such as the annual Pediatric Orthopaedic Society of North America (POSNA) meeting provide opportunities to present up-to-date scientific work that can influence clinical decision making. This study reviewed 4 years of abstracts presented at POSNA to assess trends in poster and podium presentation publication rates and associated metrics and the impact of academic presentations on the pediatric orthopaedic literature. METHODS All abstracts presented at POSNA annual meetings from 2013 to 2016 were analyzed for presentation type, subspeciality, level of evidence, study design, peer-reviewed publication within 4 years of presentation, 1-year publication rates, journal impact factors, number of authors, and citations of the final publication. χ2, analysis of variance, and t tests were conducted to measure independence of variables. Statistical significance was indicated at P

Editorial

Multiple knee ligament injuries are defined as a disruption of any combination of the four main ligament complexes; the cruciate ligaments, posterolateral corner, and posteromedial corner. Evaluation requires consideration of the entire clinical picture, including injury to associated structures, directions and degree of instability, neurovascular compromise and appropriate imaging, and physical examination. Reconstruction is favored over repair and anatomic- based reconstruction techniques have been validated to restore the native biomechanics of the knee and lead to successful patient-reported and objective outcomes. Anatomic-based reconstruction of many knee ligaments simultaneously requires precise knowledge of the relevant anatomical landmarks, careful planning of reconstruction tunnel positions, and orientations to avoid tunnel convergence, and employment of immediate early motion in the post-operative rehabilitation regimen to provide the patient the best chance for relatively normal use of the affected limb.

Background Most research and health education efforts to address the opioid crisis have focused on white populations. However, opioid use, opioid use disorder, and opioid overdose deaths also have increased among Hispanics. Methods This study conducted four focus groups in a Hispanic community in Southern California ( N = 45) to assess opioid-related knowledge, perceptions, and preventive behaviors among Hispanic residents. Focus group questions assessed medication storage, disposal, and sharing; opioid-related knowledge; how to recognize a drug problem; perceptions of the extent of the opioid use problem in the community; and sources of help for drug problems. Results Qualitative analysis revealed that most participants were aware of the potential dangers of opioids and the importance of keeping them out of the reach of children. However, participants reported stockpiling, sharing, and borrowing prescription medications for financial reasons. They perceived marijuana use as a larger problem in the community than opioids. They were familiar with the behavioral indicators of opioid addiction, but they were unaware of the availability of naloxone to reverse overdoses. They were ambivalent about searching for information about opioids and treatment options because they lacked self-efficacy to find accurate information on the internet. Conclusions Findings identify some knowledge gaps about opioids among Hispanics and suggest opportunities for culturally accessible health education to provide Hispanics with information about opioid use disorder, overdose reversal, and treatment options.

Despite years of study, controversy remains regarding the optimal graft for anterior cruciate ligament reconstruction (ACLR), suggesting that a single graft type is not ideal for all patients. A large community based ACLR Registry that collects prospective data is a powerful tool that captures information and can be analyzed to optimize surgery for individual patients. The studies highlighted in this paper were designed to optimize and individualize ACLR surgery and have led to changes in surgeon behavior and improvements in patient outcomes. Kaiser Permanente (KP) is an integrated health care system with 10.6 million members and more than 50 hospitals. Every KP member who undergoes an ACLR is entered into the Registry, and prospectively monitored. The Registry uses a variety of feedback mechanisms to disseminate Registry findings to the ACLRR surgeons and appropriately influence clinical practices and enhance quality of care. Allografts were found to have a 3.0 times higher risk of revision than bone-patellar tendon-bone (BPTB) autografts. Allograft irradiation >1.8 Mrad, chemical graft processing, younger patients, BPTB allograft, and male patients were all associated with a higher risk of revision surgery. By providing feedback to surgeons, overall allograft use has decreased by 27% and allograft use in high-risk patients ≤21 years of age decreased 68%. We have identified factors that influence the outcomes of ACLR. Statement of Clinical Significance: We found that information derived from an ACLR Registry and shared with the participating surgeons directly decreased the use of specific procedures and implants associated with poor outcomes.

Anterior cruciate ligament reconstruction (ACLR) failure is multifactorial, but it is known that increased posterior tibial slope (PTS) leads to a greater likelihood of ACLR failure. This technical note describes the senior author’s technique for performing an anterior closing wedge proximal tibial osteotomy, in which the osteotomy is made proximal to the tibial tubercle. This procedure is the first part of a staged surgery for patients with multiple failed ACLRs and increased sagittal plane PTS. Debridement of osteolytic reconstruction tunnels with bone grafting is also undertaken in preparation for a second-stage revision ACLR., Technique Video Video 1 Proximal tibial closing wedge osteotomy with tibial tubercle sparing and bone grafting. In a patient with multiple failed anterior cruciate ligament (ACL) reconstructions and increased posterior tibial slope (PTS) in the right knee, a proximal tibial closing wedge osteotomy is performed with bone grafting as a first stage to maximize the chances of success of a subsequent second stage ACL reconstruction. Examination under anesthesia reveals 3+ positive pivot-shift and Lachman tests. An anterior midline incision is made, and subcutaneous skin flaps develop medially and laterally. A scalpel and Cobb elevator are used to develop subperiosteal flaps laterally to the proximal tibiofibular joint and medially to the posteromedial aspect of the tibia. The patellar tendon is carefully outlined and protected, as the tibial tubercle will be preserved. Arthroscopy is then performed to address any intraarticular pathology and debride osteolytic bone tunnels from previous ACL reconstructions. Two guide pins are then placed parallel to the joint line at the inferior extent of the desired osteotomy. After confirming their position extending to the posterior tibial cortex fluoroscopically, two additional pins are drilled, parallel to the joint line, at the anterior extent of the planned osteotomy. These are angled such that they will meet the first two pins at the posterior tibial cortex, and fluoroscopy is used for verification of position. An ACL saw is then used to cut the anterior tibial cortex colinear with the inferior and superior guide pins, the desired wedge of bone is removed with curettes and rongeurs, and the guide pins are removed. To verify enough bone has been removed, a curette is inserted into the posterior extent of the wedge, and a lateral fluoroscopic image is taken. The wedge is then gently closed and a bump placed under the heel. The closed osteotomy is secured with several large staples, and anteroposterior and lateral radiographs confirm position of hardware. Bone grafting of the tibial and femoral tunnels is accomplished with autologous bones from the osteotomy and allograft bone matrix.

OBJECTIVES/HYPOTHESIS Few studies address the demographics/epidemiology/socioeconomic status of patients presenting to a laryngologist at a tertiary care center for treatment. To identify any possible disparities in voice, airway, and swallowing care, we sought to analyze the aforementioned data for new patients presenting to the voice center at an academic medical center. METHODS This is a retrospective cohort study of prospectively collected data from an institutional database of 4,623 new adult patients presenting for laryngological care at a tertiary care, academic medical center from 2015 to 2020. Demographic data were analyzed. RESULTS Of 4,623 patients, 62.8% were female and 37.2% were male with ages ranging from 19 to 99 years (Avg 59.51, standard deviation 15.83). Patients were 81.8% white, 13% black, and 5.2% other, compared with 56.3% white, 34.8% black, 20% other in the local municipality from US Census Data. Payer mix included 46.98% Medicare, 42.59% commercial insurance, 3.22% Medicaid, 5.19% other, and 2.01% uninsured/self-insured. Patient demographics based on primary diagnosis codes were also examined. A majority of patients presented with voice-related complaints. CONCLUSIONS Understanding the demographics of those with laryngological disorders will help to develop targeted interventions and effective outreach programs for underrepresented patient populations. Future multicenter studies could provide further insight into the distribution of healthcare disparities in laryngology. LEVEL OF EVIDENCE 3 Laryngoscope, 2021.

MEK inhibition (MEKi) is proposed to enhance antitumor immunity but has demonstrated mixed results as an immunomodulatory strategy in human clinical trials. MEKi exerts direct immunomodulatory effects on tumor cells and tumor-infiltrating lymphocytes (TIL), but these effects have not been independently investigated. Here we modeled tumor-specific MEKi through CRISPR/Cas-mediated genome editing of tumor cells [MEK1 knockout (KO)] and pharmacologic MEKi with cobimetinib in a RAS-driven model of colorectal cancer. This approach allowed us to distinguish tumor-mediated and tumor-independent mechanisms of MEKi immunomodulation. MEK1 KO tumors demonstrated upregulation of JAK/STAT signaling, enhanced MHCI expression, CD8+ T-cell infiltration and T-cell activation, and impaired tumor growth that is immune dependent. Pharmacologic MEKi recapitulated tumor-intrinsic effects but simultaneously impaired T-cell activation in the tumor microenvironment. We confirmed a reduction in human peripheral-lymphocyte activation from a clinical trial of anti–PD-L1 (atezolizumab) with or without cobimetinib in biliary tract cancers. Impaired activation of TILs treated with pharmacologic MEKi was reversible and was rescued with the addition of a 4-1BB agonist. Collectively, these data underscore the ability of MEKi to induce context-dependent immunomodulatory effects and suggest that T cell–agonist therapy maximizes the beneficial effects of MEKi on the antitumor immune response.

Introduction In the management of postoperative acute moderate-to-severe pain, opioids remain an important component. However, conventional opioids have a narrow therapeutic index and are associated with dose-limiting opioid-related adverse events (ORAEs) that can result in worse patient outcomes. Oliceridine, a new intravenous µ-opioid receptor agonist, is shown in nonclinical studies to be biased for G protein signaling (achieving analgesia) with limited recruitment of β-arrestin (associated with ORAEs). In two phase 3 randomized controlled studies of patients with moderate-to-severe acute pain following hard or soft tissue surgery, in which analgesia was measured using Sum of Pain Intensity Differences (SPID) from baseline over 48 and 24 h (SPID-48 and -24 respectively, oliceridine at demand doses of 0.1, 0.35, or 0.5 mg was highly effective compared to placebo, with a favorable safety profile compared to morphine. This exploratory analysis was conducted to determine whether the safety benefits seen with oliceridine persisted when adjusted for equal levels of analgesia compared to morphine. Methods Presence of at least one treatment-emergent ORAE (based on Medical Dictionary for Regulatory Activities [MedDRA]-coded events: hypoxemia, nausea, vomiting, sedation, pruritus, or dizziness) was used as the composite safety endpoint. A logistic regression model was utilized to compare oliceridine (pooled regimens) versus morphine, after controlling for analgesia (using SPID-48 or SPID-24 with pre-rescue scores carried forward 6 h). This analysis excluded patients receiving placebo and was repeated for each study and for pooled data. Results At a given level of SPID-48 or SPID-24, patients receiving oliceridine were less likely to experience the composite safety endpoint. Although not statistically significant at the 0.05 level in the soft tissue model, the odds ratio (OR) showed a consistent numerical trend for oliceridine, being approximately half that observed with morphine in both the hard (OR 0.499; 95% confidence interval [CI] 0.255, 0.976; p = 0.042) and soft (OR 0.542; 95% CI 0.250, 1.175; p = 0.121) tissue studies. Results from the pooled data were consistent with those observed in the individual studies (OR 0.507; 95% CI 0.304, 0.844; p = 0.009). Conclusion Findings from this exploratory analysis suggest that at comparable levels of analgesia, patients receiving oliceridine were less likely to experience the composite safety endpoint consisting of ORAEs compared to patients treated with morphine. Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials- A Video (MP4 99188 kb) Supplementary Information The online version contains supplementary material available at 10.1007/s40122-021-00299-0.

Introduction Helping Opioid Prescription Elimination (HOPE) is a project designed to provide surgeons with practical, real-world solutions to effectively manage postoperative pain and eliminate the need for opioids using HTX-011 (extended-release bupivacaine/low-dose meloxicam). In phase 3 herniorrhaphy and bunionectomy studies, HTX-011 without multimodal analgesia (MMA) was superior to bupivacaine hydrochloride in reducing pain and opioid consumption. Here, we examine the HOPE Hernia-1 study, which was designed to compare alternating ibuprofen/acetaminophen with concurrent use as part of an HTX-011-based non-opioid MMA regimen in patients undergoing herniorrhaphy and to evaluate the effectiveness of a personalized opioid prescription algorithm. Methods Patients undergoing outpatient open inguinal herniorrhaphy with intraoperative administration of HTX-011 (300 mg bupivacaine/9 mg meloxicam) were randomly assigned to receive a scheduled oral regimen of ibuprofen plus acetaminophen, either taken together every 6 hours or alternating every 3 hours, for 5 days following surgery, while awake. Based on the opioid prescription algorithm evaluated here, patients could receive an oxycodone prescription upon discharge only if they had a numeric rating scale pain score of ≥ 6 at discharge and/or had received a postoperative rescue opioid. Results The majority of patients did not require an opioid prescription through 2 weeks following surgery, and this was similar between cohorts (alternating MMA, 89.1%; concurrent MMA, 93.6%). Patient satisfaction was high for both regimens, and 95% of patients had an opioid-free recovery. No patient discharged without a prescription called back to request one. Treatment was well tolerated, without evidence of nonsteroidal anti-inflammatory drug-related toxicity. Conclusions HTX-011, used with over-the-counter products ibuprofen/acetaminophen and personalized opioid prescription algorithm in a real-world environment, has the potential to reduce opioid use and opioid prescriptions after herniorrhaphy without compromising patient satisfaction. Trial Registration ClinicalTrials.gov, NCT03237481.

Objective. To develop methods for a rapid distance computer diagnosis of COVID-19 based on the analysis of breath sounds. It is known that changes in breath sounds can be the indicators of respiratory organs diseases. Computer analysis of these sounds can indicate their typical changes caused by COVID-19, and can be used for a rapid preliminary diagnosis of this disease. Materials and methods. The method of fast Fourier transform (FFT) was used for computer analysis of breath sounds, recorded near the mouth of 14 COVID-19 patients (aged 1880 years) and 17 healthy volunteers (aged 548 years). The frequency of breath sound records ranged from 44 to 96 kHz. Unlike the conventional methods of computer analysis for diagnosis of diseases based on respiratory sound studying, we offer to test a high-frequency part of FFT (20006000 kHz). Results. While comparing the breath sound FFT in patients and healthy volunteers, we developed the methods for COVID-19 computer diagnosis and determined the numerical criteria in patients and healthy persons. These criteria do not depend on sex and age of the examined persons. Conclusions. The offered computer methods based on the analysis of breath sound FFT in patients and volunteers permit to diagnose COVID -19 with relatively high diagnostic parameters. These methods can be used in development of noninvasive means for preliminary self-express diagnosis of COVID-19.

BackgroundHigh-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models.MethodsTo leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells. To enhance the effects of PAC-1, combinations with either hydroxyurea or temozolomide were explored in cell culture. Both combinations were further investigated in small groups of canine meningioma patients and assessed by MRI, and the novel apoptosis tracer, [18F]C-SNAT4, was evaluated in patients treated with PAC-1 + HU.ResultsIn meningioma cell lines in culture, PAC-1 + HU are synergistic while PAC-1 + TMZ show additive-to-synergistic effects. In canine meningioma patients, PAC-1 + HU led to stabilization of disease and no change in apoptosis within the tumor, whereas PAC-1 + TMZ reduced tumor burden in all three canine patients treated.ConclusionsOur results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor.

Introduction The transaxillary approach to resection of the first rib is one of several operative techniques for treating thoracic outlet syndrome. Unfortunately, moderate to severe postoperative pain is anticipated for patients undergoing this particular operation. While opioids can be used for analgesia, they have well described side effects, which has led investigators to search for clinically relevant alternative analgesic modalities. We hypothesized that a regional analgesic procedure, commonly called a pectoral nerve (PECS II) block, which anesthetizes the second through sixth intercostal nerves as well as the long thoracic nerve and the medial and lateral pectoral nerves, would improve postoperative analgesia for patients undergoing a transaxillary first rib resection. Methods We performed a retrospective study by reviewing the charts of all patients that had undergone a transaxillary first rib resection for thoracic outlet syndrome during the defined study period. Patients that received a PECS II block were compared to those that did not. The primary outcome was a comparison of numeric rating scale pain scores during the first 24-hours following the operation. Secondary outcomes included cumulative opioid consumption during the same time period. Results Pain scores during the first 24-hours following the operation were not statistically different between groups (Block Group: 3.9 [2.1-5.3] [median (IQR 25-75%)] vs. Non-block Group: 3.6 [2.4-4.1]; P = 0.40. In addition, opioid use through the first 24-hours after the operation was not significantly different (43.5 [22.0-81.0] [median morphine equivalents in mg's] vs. 42.0 [12.5-75.0]; P = 0.53). Conclusion An ultrasound-guided PECS II nerve block did not reduce postoperative pain scores or opioid consumption for patients undergoing a transaxillary first rib resection. However, a prospective, randomized, study with improved power would be beneficial to further explore the potential utility of a PECS II block for patients presenting for this surgical procedure.

Background Clinical and/or neuroimaging changes after whole-brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for metastatic brain tumor(s) present the clinical dilemma of differentiating tumor recurrence from radiation necrosis. Several imaging modalities attempt to answer this clinical question, including magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) computed tomography (CT). We evaluated our experience regarding the ability of MRS and PET CT to differentiate tumor recurrence from radiation necrosis in patients who have received WBRT or SRS. Methods We retrospectively reviewed records of 242 patients with previous WBRT or SRS to identify those who had MRS and/or PET CT to differentiate tumor recurrence from radiation necrosis. Patients were sorted into true-positive, false-positive, false-negative, and true-negative groups on the basis of imaging interpretation and clinical course combined with surgical pathology results or reaction to nonsurgical treatments including SRS, dexamethasone, or observation. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were then calculated. Results Of 25 patients presenting such diagnostic questions, 19 were evaluated with MRS and 13 with PET CT. MRS sensitivity was 100%, specificity was 50%, and accuracy was 81.8%, whereas PET CT sensitivity was 36.4%, specificity was 66.7%, and accuracy was 42.9%. Conclusions MRS has better accuracy than PET CT and a high negative predictive value, therefore making it more useful in distinguishing recurrent tumor from radiation necrosis. We encourage correlation with symptoms at imaging to aid in clinical decision making.

In this review, we examine the current understanding of posterolateral corner (PLC) injuries and treatment methods. We discuss the anatomy of the major structures of the PLC and the biomechanics of how these structures function together as a unit. The diagnosis using physical examination, radiographs, and magnetic resonance imaging is discussed. The development of an anatomic reconstruction technique is then described, along with the surgical technique and rehabilitation protocols. Anatomic-based reconstruction methods and a regimented rehabilitation protocol better restore the native biomechanics of the knee, and improve subjective and objective outcomes at follow-up.

Objectives To evaluate concentrations of procalcitonin (PCT) in transplant recipients receiving immunosuppressive therapy compared with nonimmunosuppressed patients. Methods We analyzed a data set of 9,500 inpatient encounters to compare levels of PCT and other biomarkers of infection (C-reactive protein [CRP], WBC count, and absolute neutrophil count [ANC]) between immunosuppressed and nonimmunosuppressed cohorts. We also assessed the correlation between PCT and clinical variables in immunosuppressed patients. Results Patients receiving immunosuppressive drugs had significantly higher levels of maximal and minimal PCT compared with the nonimmunosuppressed patients (P Conclusions Our results from real-world data demonstrated that PCT dynamics remain intact despite immunosuppressive therapy, in contrast to other biomarkers such as CRP, WBC, and ANC. In addition, higher PCT levels are associated with systemic infections and reflect disease severity.

BACKGROUND AND OBJECTIVES This study analyzed persistent opioid use in opioid-naive and nonopioid-naive patients undergoing hepatectomy for neoplastic disease. METHODS A retrospective review was performed of a prospective database using inclusion criteria of hepatectomy for neoplastic disease from October 2013 to December 2017. Prescription data were collected from the North Carolina Controlled Substance Reporting System. Persistent opioid use was defined as patients who continued filling opioid prescriptions 90 days to 1 year after surgery. Patients who did not receive opioid prescriptions between 12 months and 31 days before surgery were defined as naive. RESULTS The analysis included 75 surgeries on naive and 58 surgeries on nonnaive patients. 56% of naive patients and 79% of nonnaive patients developed persistent opioid use, respectively (p = .0056). Naive patients received 2.24 ± 4.30 MMEs/day, while nonnaive patients received 5.50 ± 5.98 MMEs/day during Postoperative days 90-360 (95% CI, 1.41-5.10; p

Background The efficacy of just-in-time teaching (JiTT) screencasts for graduate medical education on an inpatient adult hematology-oncology service (HOS) setting is not known. Our preceding pilot data identified six high-yield topics for this setting. The study objective was to evaluate screencast educational efficacy. Methods Internal medicine residents scheduled to start a rotation on the primary HOS of an academic medical center were eligible for this parallel, unblinded, randomized controlled trial with concealed allocation. Participants underwent block randomization to the usual educational curriculum either with or without access to a series of novel screencasts; all participants received an anonymous online end-of-rotation survey and a $20 gift certificate upon completion. The primary outcome was the change in attitude among learners, measured as their self-reported confidence for managing the clinical topics. Results From 12/9/2019 through 6/15/2020, accrual was completed with 67 of 78 eligible residents (86%) enrolled and randomized. Analysis was by intention-to-treat and participant response rate was 91%. Sixty-four percent of residents in the treatment arm rated their clinical management comfort level as “comfortable” or “very comfortable” versus 21% of residents in the usual education arm (p = 0.001), estimated difference = 43% (95% CI: 21–66%), using a prespecified cumulative cutoff score. Treatment arm participants reported that the screencasts improved medical oncology knowledge base (100%), would improve their care for cancer patients (92%), and had an enjoyable format (96%). Conclusion Residents on a busy inpatient HOS found that a JiTT screencast increased clinical comfort level in the management of HOS-specific patient problems. Supplementary Information The online version contains supplementary material available at 10.1007/s13187-021-02016-z.

BACKGROUND AND AIM Recently, the BLI Adenoma Serrated International Classification (BASIC) system was developed by European experts to differentiate colorectal polyps. Our aim was to validate the BASIC classification system among the US-based endoscopy experts. METHODS Participants utilized a web-based interactive learning system where the group was asked to characterize polyps using the BASIC criteria: polyp surface (presence of mucus, regular/irregular and [pseudo]depressed), pit appearance (featureless, round/non-round with/without dark spots; homogeneous/heterogeneous distribution with/without focal loss), and vessels (present/absent, lacy, peri-cryptal, irregular). The final testing consisted of reviewing BLI images/videos to determine whether the criteria accurately predicted the histology results. Confidence in adenoma identification (rated "1" to "5") and agreement in polyp (adenoma vs non-adenoma) identification and characterization per BASIC criteria were derived. Strength of interobserver agreement with kappa (k) value was reported for adenoma identification. RESULTS Ten endoscopy experts from the United States identified conventional adenoma (vs non-adenoma) with 94.4% accuracy, 95.0% sensitivity, 93.8% specificity, 93.8% positive predictive value, and 94.9% negative predictive value using BASIC criteria. Overall strength of interobserver agreement was high: kappa 0.89 (0.82-0.96). Agreement for the individual criteria was as follows: surface mucus (93.8%), regularity (65.6%), type of pit (40.6%), pit visibility (66.9%), pit distribution (57%), vessel visibility (73%), and being lacy (46%) and peri-cryptal (61%). The confidence in diagnosis was rated at high ≥4 in 67% of the cases. CONCLUSIONS A group of US-based endoscopy experts have validated a simple and easily reproducible BLI classification system to characterize colorectal polyps with >90% accuracy and a high level of interobserver agreement.

Recurrent patellar dislocations have been correlated with an elevated risk of further patellar dislocations, often requiring surgical treatment. Risk factors include medial patellofemoral ligament (MPFL) tears, patella alta, trochlear dysplasia, and an increased tibial tubercle–trochlear groove distance. Surgical management must be based on a patient’s unique joint pathoanatomy and may require MPFL reconstruction with tibial tubercle osteotomy or trochleoplasty either alone or in combination. This article discusses our preferred technique for surgical treatment of recurrent patellar instability with MPFL reconstruction using a quadriceps tendon autograft, an open trochleoplasty, and a tibial tubercle osteotomy for patients with patella alta, trochlear dysplasia, and an increased tibial tubercle–trochlear groove distance., Technique Video Video 1 The patient is examined under anesthesia and found to have a positive J-sign, dislocating laterally and remaining so until 60° of flexion, consistent with severe trochlear dysplasia. An anterior arthrotomy is made, and partial-thickness quadriceps tendon graft is harvested. Q-Fix anchors are placed at the adductor tubercle. A tibial tubercle osteotomy is performed with a drill, osteotomes, and a small anterior cruciate ligament saw, and the tibia, 12 mm distally, is prepared for reattachment. A medial parapatellar arthrotomy is next incised, and the trochlear groove is outlined. The periosteum is elevated with a scalpel, and a burr and osteotomes are used to create the new trochlear shape, with an arthroscope passed beneath the osteochondral flap to help clear the undersurface. Four guide pins are placed and screws are used to keep the cartilage flap reduced. The tibial tubercle osteotomy is completed by reattaching the tubercle to its new distal position with cannulated screws and washers. The arthrotomy is closed, and medial patellofemoral ligament reconstruction is completed by passing the folded quadriceps graft, attached at the superior pole of the patella with a Q-Fix anchor, through the retinacular channel and affixing it to the adductor tubercle with 2 Q-Fix anchors. Once patellar stability is ensured through range of motion, the incision is closed.

In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units., Visual Abstract. COVID-19–Related Critical Illness In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units. Visual Abstract. COVID-19–Related Critical Illness In a large health system in the United States, investigators examined whether mortality, receipt of mechanical ventilation, and patient acuity changed over time among adult patients with COVID-19–related critical illness admitted to intensive care units., Background: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally. Objective: To describe the epidemiology of COVID-19–related critical illness, including trends in outcomes and care delivery. Design: Single–health system, multihospital retrospective cohort study. Setting: 5 hospitals within the University of Pennsylvania Health System. Patients: Adults with COVID-19–related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic. Measurements: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions. Results: Among 468 patients with COVID-19–related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change. Limitation: Single–health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications. Conclusion: Among patients with COVID-19–related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms. Primary Funding Source: Agency for Healthcare Research and Quality.

Background Current international consensus is that ‘early’ referral to palliative care services improves cancer patient and family carer outcomes. In practice, however, these referrals are not routine. An approach which directly addresses identified barriers to early integration of palliative care is required. This protocol details a trial of a standardized model of early palliative care (Care Plus) introduced at key defined, disease-specific times or transition points in the illness for people with cancer. Introduced as a ‘whole of system’ practice change for identified advanced cancers, the key outcomes of interest are population health service use change. The aims of the study are to examine the effect of Care Plus implementation on (1) acute hospitalisation days in the last 3 months of life; (2) timeliness of access to palliative care; (3) quality and (4) costs of end of life care; and (5) the acceptability of services for people with advanced cancer. Methods Multi-site stepped wedge implementation trial testing usual care (control) versus Care Plus (practice change). The design stipulates ‘control’ periods when usual care is observed, and the process of implementing Care Plus which includes phases of planning, engagement, practice change and evaluation. During the practice change phase, all patients with targeted advanced cancers reaching the transition point will, by default, receive Care Plus. Health service utilization and unit costs before and after implementation will be collated from hospital records, and state and national health service administrative datasets. Qualitative data from patients, consumers and clinicians before and after practice change will be gathered through interviews and focus groups. Discussion The study outcomes will detail the impact and acceptability of the standardized integration of palliative care as a practice change, including recommendations for ongoing sustainability and broader implementation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN 12619001703190. Registered 04 December 2019.

Introduction Patients on extracorporeal membrane oxygenator (ECMO) therapy are critically ill and often develop acute kidney injury (AKI) during hospitalisation. Little is known about the association of exposure to and the effect of the type of ECMO and extent of renal recovery after AKI development. Aim of the study In patients who developed AKI, renal recovery was characterised as complete, partial or dialysis-dependent at the time of hospital discharge in both the Veno-Arterial (VA) and Veno-Venous (VV) ECMO treatment groups. Material and methods The study consisted of a single-centre retrospective cohort that includes all adult patients (n=125) who received ECMO treatment at a tertiary academic medical centre between 2015 to 2019. Data on demographics, type of ECMO circuit, comorbidities, exposure to nephrotoxic factors and receipt of renal replacement therapy (RRT) were collected as a part of the analysis. Acute Kidney Injury Network (AKIN) criteria were used for the diagnosis and classification of AKI. Group differences were assessed using Fisher’s exact tests for categorical data and independent t-tests for continuous outcomes. Results Sixty-four patients received VA ECMO, and 58 received VV ECMO. AKI developed in 58(91%) in the VA ECMO group and 51 (88%) in the VV ECMO group (p=0.77). RRT was prescribed in significantly higher numbers in the VV group 38 (75%) compared to the VA group 27 (47%) (p=0.0035). At the time of discharge, AKI recovery rate in the VA group consisted of 15 (26%) complete recovery and 5 (9%) partial recovery; 1 (2%) remained dialysis-dependent. In the VV group, 22 (43%) had complete recovery (p=0.07), 3(6%) had partial recovery (p=0.72), and 1 (2%) was dialysis-dependent (p>0.99). In-hospital mortality was 64% in the VA group and 49% in the VV group (p=0.13). Conclusions Renal outcomes in critically ill patients who develop AKI are not associated with the type of ECMO used. This serves as preliminary data for future studies in the area.

The posterior cruciate ligament (PCL) is the largest intra-articular ligament in the knee and is the primary stabilizer to posterior tibial translation. Historically, the PCL’s functional dynamics and appropriate management after injury have been controversial. However, recent biomechanical and anatomic studies have elucidated a better understanding of PCL function, which has led to development of more anatomic reconstruction techniques. The larger anterolateral bundle and the smaller posteromedial bundle of the PCL exhibit a codominant relationship and have a wide femoral attachment footprint. For these reasons, the native kinematics of the knee is better restored with a double-bundle PCL reconstruction (DB-PCLR) technique than with a single-bundle PCL reconstruction (SB-PCLR). Likewise, clinical studies have demonstrated excellent outcomes for DB-PCLR compared to SB-PCLR, with decreased posterior knee laxity on stress radiography and improved International Knee Documentation Committee scores. This review will provide a detailed overview of the clinically relevant anatomy, biomechanics, injury evaluation, and treatment options, with an emphasis on arthroscopic DB-PCLR.

Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Because successful self-dealing cannot be observed in naturally occurring data, we conduct an experiment where self-dealing emerges endogenously along with concealment strategies. We show that subjects can profitably self-deal while fashioning complex strategies that include opacity-preserving resource divisions and misleading direct communication that can build false trust in partners that can be later exploited. These strategies also entail profit skimming that has the paradoxical effect of reducing private gains from self-dealing. Ultimately, self-dealing occurs frequently in economies that generate larger social gains from exchange than economies where hard information provision leads to fully transparent resource allocation.

KEY POINTS People with type 2 diabetes (T2D) have impaired skeletal muscle oxidative flux due to limited oxygen delivery. In the current study, this impairment in oxidative flux in people with T2D was abrogated with a single-leg exercise training protocol. Additionally, single-leg exercise training increased skeletal muscle CD31 content, calf blood flow and state 4 mitochondrial respiration in all participants. ABSTRACT Cardiorespiratory fitness is impaired in type 2 diabetes (T2D), conferring significant cardiovascular risk in this population; interventions are needed. Previously, we reported that a T2D-associated decrement in skeletal muscle oxidative flux is ameliorated with acute use of supplemental oxygen, suggesting that skeletal muscle oxygenation is rate-limiting to in vivo mitochondrial oxidative flux during exercise in T2D. We hypothesized that single-leg exercise training (SLET) would improve the T2D-specific impairment in in vivo mitochondrial oxidative flux during exercise. Adults with (n = 19) and without T2D (n = 22) with similar body mass indexes and levels of physical activity participated in two weeks of SLET. Following SLET, in vivo oxidative flux measured by 31 P-MRS increased in participants with T2D, but not people without T2D, measured by the increase in initial phosphocreatine synthesis (P = 0.0455 for the group × exercise interaction) and maximum rate of oxidative ATP synthesis (P = 0.0286 for the interaction). Additionally, oxidative phosphorylation increased in all participants with SLET (P = 0.0209). After SLET, there was no effect of supplemental oxygen on any of the in vivo oxidative flux measurements in either group (P > 0.02), consistent with resolution of the T2D-associated oxygen limitation previously observed at baseline in subjects with T2D. State 4 mitochondrial respiration also improved in muscle fibres ex vivo. Skeletal muscle vasculature content and calf blood flow increased in all participants with SLET (P

Many soft tissue masses have an indeterminate appearance on MRI, often displaying varying degrees and extent of T2 hyperintensity. However, a subset of neoplasms and tumor-like lesions may exhibit prominent areas of T2 hypointensity relative to skeletal muscle. The hypointensity observed on T2-weighted MRI can be caused by a variety of substances, including evolving blood products, calcifications or other inorganic crystals, or fibrous tissue. Carefully evaluating the presence and pattern of T2 hypointensity in soft tissue masses and considering potential causes in their associated clinical contexts can help to narrow the differential diagnosis among neoplastic and non-neoplastic possibilities. These include endometriosis, aneurysmal bone cysts, tenosynovial giant cell tumor, arteriovenous malformation and pseudoaneurysm, calcium pyrophosphate and hydroxyapatite deposition diseases, tumoral calcinosis, gout, amyloidosis, hemangiomas with phleboliths, low-grade fibromyxoid sarcoma, ossifying fibromyxoid tumor, collagenous fibroma, desmoid-type fibromatosis, myxofibrosarcoma, peripheral nerve sheath tumors, dedifferentiated liposarcoma, and treated sarcoma.

The presence of detrusor muscle is essential for accurate staging of T1 cancers. Detrusor muscle presence can be a quality indicator of transurethral resection of bladder tumor for nonmuscle invasive bladder cancer. We hypothesized that increasing surgeon awareness of personal and institutional detrusor muscle sampling rates could improve resection quality and long-term oncologic outcomes.A retrospective review of transurethral resections of bladder tumor from 1/2006 to 2/2018 was performed. The presence of detrusor muscle in the pathology report and transurethral resection specimen were extracted from records. Individual surgeon scorecards were created and distributed. Rates of detrusor muscle sampling were compared prior to and 12 months after distribution. Chart review was done to compare 3-year recurrence and progression outcomes before and after distribution of scorecards.The rate of detrusor muscle sampling increased from 36% (1,250/3,488) to 54% (202/373) (p=0.001) in the 12 months after scorecard distribution, ie from 30% (448/1,500) to 55% (91/165) (p0.001) in Ta tumors and from 47% (183/390) to 72% (42/58) (p0.001) in T1 tumors. Pathological reporting of muscle also improved for all samples (73%, 2,530/3,488 to 90%, 334/373, p0.001), Ta (75%, 1,127/1,500 to 94%, 155/165, p0.001) and T1 (93%, 362/390 to 100%, 58/58, p=0.04). On multivariate Cox regression analysis, the surgeon scorecard was associated with decreased 3-year risk of recurrence (HR 0.63, 95% CI 0.40-0.99).Creation and distribution of individual surgeon scorecards improved detrusor muscle sampling on transurethral resection and was associated with decreased risk of disease recurrence. Quality evaluation of transurethral resection of bladder tumor may contribute to improved outcomes of patients with nonmuscle invasive bladder cancer.

Background To evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center. Methods Progression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion. Results Five women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47–68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4–370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16–83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and 18Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab). Conclusions The clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1β was suggested in this small observational cohort study. The hypothesis that HNF-1β is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of “Big Data” may improve OCCC care standards in the future.

In this review article, the authors describe the most current knowledge surrounding meniscal root tears with a primary focus on diagnosis, management, and implications for the health of the knee joint. Historically overlooked or treated with meniscectomy, meniscal root tears are now known to disrupt the biomechanical role of the meniscus in the joint, leading to the rapid development of knee osteoarthritis. Tears of the medial and lateral posterior meniscal roots are associated with differing etiologies and sequelae, especially in regard to their action as secondary stabilizers of the knee, making root tears an important consideration in ligament reconstruction surgery. We will discuss diagnostic challenges and well-established hallmarks of meniscus tears on imaging, and will conclude by explaining the preferred method for surgical repair of the meniscal roots and appropriate rehabilitation.

This paper presents closed-loop intervention simulations for an identified, data-validated model of Social Cognitive Theory (SCT). A reduced-complexity SCT model structure consisting of dynamic operant conditioning and self-efficacy loops is considered for the prediction of physical activity behavior. Consistent with real-world requirements, including the need for hybrid decision rules policies, the proposed closed-loop intervention design follows a Hybrid Model Predictive Control formulation. The prime goal of this paper is to reinforce the viability of the system identification and control engineering frameworks in the design of optimized and perpetually adaptive behavioral health interventions.

Ayman Eissa,1 Eva Tarau,2 Christoph Beuter,3 Tatjana Radic,3 Estelle Watson,3 Melanie Sohns,3 Claudia Lefeber,3 Gregory B Hammer4 1Anaesthetic Department, Sheffield Children’s Hospital, Western Bank, Sheffield, UK; 2Grünenthal USA Inc., Overland Park, KS, USA; 3Grünenthal GmbH, Aachen, Germany; 4Department of Pediatrics and Anesthesiology, Perioperative and Pain Management, Stanford University School of Medicine, Stanford, CA, USACorrespondence: Christoph BeuterGrünenthal GmbH, Zieglerstraße 6, 52078 Aachen, GermanyTel +49 241 569 0Email Christoph.Beuter@grunenthal.comBackground: Pharmacokinetics (PK), efficacy, and safety of the opioid analgesic tapentadol in the treatment of moderate-to-severe acute pain have so far not been investigated in pediatric patients < 2 years of age.Patients and Methods: Two multicenter, open-label trials assessed the pharmacokinetic profile, safety, tolerability, and efficacy of single doses of tapentadol oral solution (OS; NCT02221674; n=19) or intravenous infusion (IV, EudraCT 2014-002259-24; n=38) in children from birth to < 2 years of age. Of these, 8 preterm neonates were included in the IV trial. A third randomized, double-blind, placebo-controlled trial (NCT02081391) investigated the efficacy and safety of multiple tapentadol OS doses in patients from birth to < 2 years (placebo n=4, tapentadol n=11) using an immediate rescue trial design. Patients in all three trials underwent surgery that, in the investigator’s opinion, reliably produced moderate-to-severe pain requiring opioid treatment.Results: Administration of single tapentadol doses resulted in tapentadol serum concentrations within the targeted range known to be safe and efficacious in adults and compared well to the range observed for children aged 2 to < 18 years. Pain intensity already improved 15 min after administration. In the multiple dose trial, amounts of supplemental opioid analgesic medication within the first 24 h after start of trial medication were low (placebo 0.02 mg/kg, tapentadol 0.05 mg/kg). All patients stopped treatment with the trial medication because opioid analgesics were no longer required. Treatment-emergent adverse events occurred in 42.1% (tapentadol OS single dose), 28.9% (tapentadol IV), and 75% of placebo and 54.5% of tapentadol patients (tapentadol OS multiple doses), none of them serious.Conclusion: Tapentadol showed a favorable PK and safety profile in children < 2 years of age. Multiple tapentadol OS dosing is efficacious and generally well tolerated in children ≥ 2 years and might also be a useful treatment option for children < 2 years in need of strong analgesics.Keywords: infants, intravenous formulation, neonates, oral formulation, pain management, tapentadol

One-third of epilepsy patients suffer from medication-resistant seizures. While surgery to remove epileptogenic tissue helps some patients, 30–70% of patients continue to experience seizures following resection. Surgical outcomes may be improved with more accurate localization of epileptogenic tissue. We have previously developed novel thin-film, subdural electrode arrays with hundreds of microelectrodes over a 100–1,000 mm2 area to enable high-resolution mapping of neural activity. Here we used these high-density arrays to study microscale properties of human epileptiform activity. We performed intraoperative micro-electrocorticographic recordings within epileptic cortex (the site of seizure onset and early spread) in nine patients with epilepsy. In two of these patients, we obtained recordings from cortical areas distal to the epileptic cortex. Additionally, we recorded from two non-epileptic patients with movement disorders undergoing deep brain stimulator implantation as non-epileptic tissue controls. A board-certified epileptologist identified microseizures, which resembled electrographic seizures normally observed with clinical macroelectrodes. Epileptic cortex exhibited a significantly higher microseizure rate (2.01 events/min) than non-epileptic cortex (0.01 events/min; permutation test, P=0.0068). Using spatial averaging to simulate recordings from larger electrode contacts, we found that the number of detected microseizures decreased rapidly with increasing contact diameter and decreasing contact density. In cases in which microseizures were spatially distributed across multiple channels, the approximate onset region was identified. Our results suggest that micro-electrocorticographic electrode arrays with a high density of contacts and large coverage are essential for capturing microseizures in epilepsy patients and may be beneficial for localizing epileptogenic tissue to plan surgery or target brain stimulation.