Search

Purpose Femoroacetabular impingement (FAI) is a known risk factor for hip osteoarthritis. The gold standard for diagnostics is X-ray and MRI. The accuracy of hip joint alpha angle measurements obtained using sonography is equal to measurements in MRI for patients with cam impingement of the hip joint. Materials and Methods Patients with hip pain and MRI and sonography were evaluated between January 2015 and December 2019 in a single center. Musculoskeletal sonography was performed according to the DEGUM guidelines by ultrasound-certified specialists. Measurements were repeated three times by two independent investigators. Results 285 patients were screened, and 110 patients (49 females, 61 males) met the inclusion criteria. The mean age at time of investigation of 54 left and 56 right hip joints was 54.2 years. 1320 measurements were performed. The mean alpha angle was 50.7° in MRI and 50.4° in sonography with a mean difference of 0.28° (p>0.05). Conclusion Determining hip alpha angle using sonography is a safe and reproducible method. No statistically significant differences between results in MRI and sonography could be seen. Although this is a retrospective, single-center study including only Caucasian mid-Europeans and with the known limitations of ultrasound imaging, it nevertheless shows that sonography can be used as a simple, cheap, and fast technique to assess the hip alpha angle without losing diagnostic quality.

Purpose This study explored the clinicopathologic outcomes of rectal tumor morphological descriptors used in a synoptic rectal MRI reporting template and determined that prognostic differences were observed. Methods This retrospective study was conducted at a comprehensive cancer center. Fifty patients with rectal tumors for whom the synoptic descriptor “polypoid” was chosen by three experienced radiologists were compared with ninety comparator patients with “partially circumferential” and “circumferential” rectal tumors. Two radiologists re-evaluated all cases. The outcome measures were agreement among two re-interpreting radiologists, clinical T staging with MRI (mrT) and descriptive nodal features, and degrees of wall attachment of tumors (on MRI) compared with pathological (p) T and N stage when available. Results Re-evaluation by two radiologists showed moderate to excellent agreement in tumor morphology, presence of a pedicle, and degree of wall attachment (k = 0.41–0.76) and excellent agreement on lymph node presence and size (ICC = 0.83–0.91). Statistically significant lower mrT stage was noted for polypoid morphology, wherein 98% were mrT1/2, while only 7% and 2% of partially circumferential and circumferential tumors respectively were mrT1/2. Pathologic T and N stages among the three morphologies also differed significantly, with only 14% of polypoid cases higher than stage pT2 compared to 48% of partially circumferential cases and 60% of circumferential cases. Conclusion Using a “polypoid” morphology in rectal cancer MRI synoptic reports revealed a seemingly distinct phenotype with lower clinical and pathologic T and N stages when compared with alternative available descriptors. Precis “Polypoid” morphology in rectal cancer confers a lower clinical and pathologic T and N stage and may be useful in determining whether to proceed with surgery versus neoadjuvant treatment.

Objective: To describe quantitative EEG (electroencephalography) suppression ratio in children with increased intracranial pressure comparing acute suppression ratio changes to imaging and/or examination findings. Methods: We retrospectively reviewed the suppression ratio from patients with neuroimaging and /or examination findings of increased intracranial pressure while on continuous EEG. The time of the first change in the suppression ratio was compared to the time of the first image and/or examination change confirming increased intracranial pressure. Results: Thirteen patients with a median age of 3.1 years(interquartile range 1.8-6.3) had a rise in the suppression ratio with median time from identification to acute neuroimaging or examination of increased intracranial pressure of 3.12 hours (interquartile range 2.2-33.5) after the first increase in the suppression ratio. Conclusions: Acute suppression ratio increase is seen prior to imaging and/or examination findings of increased intracranial pressure. With further study, the suppression ratio can be targeted with intracranial pressure–lowering agents to prevent morbidity and mortality associated with increased intracranial pressure.

PURPOSE NTHL1 and MSH3 have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic NTHL1 and MSH3 pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize NTHL1 and MSH3 from a large pan-cancer patient population. MATERIALS AND METHODS Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database). RESULTS NTHL1-PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. NTHL1-associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any NTHL1 patient. MSH3-PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic MSH3 variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 MSH3 carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type MSH3 allele. Ancestry-specific burden tests demonstrated that NTHL1 and MSH3 prevalence was not significantly different in this pan-cancer population versus controls. CONCLUSION NTHL1 and MSH3 germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.

BACKGROUND AND AIMS: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with an increased lifetime risk of gastric and duodenal cancers of 8–16% and 7% respectively, therefore, we aim to describe an esophagogastroduodenoscopy (EGD) surveillance program for upper gastrointestinal (GI) precursor lesions and cancer in LS patients. METHODS: Patients who either had positive genetic testing or met clinical criteria for LS who had a surveillance EGD at our institution from 1996 to 2017 were identified. Patients were included if they had at least two EGDs or an upper GI cancer detected on the first surveillance EGD. EGD and pathology reports were extracted manually. RESULTS: Our cohort included 247 patients with a mean age of 47.1 years (SD 12.6) at first EGD. Patients had a mean of 3.5 EGDs (range 1–16). Mean duration of follow-up was 5.7 years. Average interval between EGDs was 2.3 years. Surveillance EGD detected precursor lesions in 8 (3.2%) patients, two (0.8%) gastric cancers and two (0.8%) duodenal cancers. Two interval cancers were diagnosed: a duodenal adenocarcinoma was detected 2 years, 8 months after prior EGD and a jejunal adenocarcinoma was detected 1 year, 9 months after prior EGD. CONCLUSIONS: Our data suggest that surveillance EGD is a useful tool to help detect precancerous and cancerous upper GI lesions in LS patients. To our knowledge, this is the first study to examine a program of surveillance EGDs in LS patients. More data are needed to determine the appropriate surveillance interval.

Background After activation of the Hospital Readmission Reduction Program (HRRP) in 2012, hospitals nationwide experimented broadly with the implementation of Transitional Care (TC) strategies to reduce hospital readmissions. Although numerous evidence-based TC models exist, they are often adapted to local contexts, rendering large-scale evaluation difficult. Little systematic evidence exists about prevailing implementation patterns of TC strategies among hospitals, nor which strategies in which combinations are most effective at improving patient outcomes. We aimed to identify and define combinations of TC strategies, or groups of transitional care activities, implemented among a large and diverse cohort of U.S. hospitals, with the ultimate goal of evaluating their comparative effectiveness. Methods We collected implementation data for 13 TC strategies through a nationwide, web-based survey of representatives from short-term acute-care and critical access hospitals (N = 370) and obtained Medicare claims data for patients discharged from participating hospitals. TC strategies were grouped separately through factor analysis and latent class analysis. Results We observed 348 variations in how hospitals implemented 13 TC strategies, highlighting the diversity of hospitals’ TC strategy implementation. Factor analysis resulted in five overlapping groups of TC strategies, including those characterized by 1) medication reconciliation, 2) shared decision making, 3) identifying high risk patients, 4) care plan, and 5) cross-setting information exchange. We determined that the groups suggested by factor analysis results provided a more logical grouping. Further, groups of TC strategies based on factor analysis performed better than the ones based on latent class analysis in detecting differences in 30-day readmission trends. Conclusions U.S. hospitals uniquely combine TC strategies in ways that require further evaluation. Factor analysis provides a logical method for grouping such strategies for comparative effectiveness analysis when the groups are dependent. Our findings provide hospitals and health systems 1) information about what groups of TC strategies are commonly being implemented by hospitals, 2) strengths associated with the factor analysis approach for classifying these groups, and ultimately, 3) information upon which comparative effectiveness trials can be designed. Our results further reveal promising targets for comparative effectiveness analyses, including groups incorporating cross-setting information exchange.

Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI-1, especially in the aged (murine endotoxemia), that circulating PAI-1 protein levels match the trajectory of PAI-1 transcript levels in VAT (clinical sepsis), and that PAI-1 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI-1 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI-1 induction in VAT, were identified. In aged mice with sepsis, PAI-1 gene expression was significantly higher in VAT than in other major organs. VAT PAI-1 gene expression correlated with PAI-1 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI-1 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI-1 is secreted robustly in response to recombinant transforming growth factor β (TGFβ) and tumor necrosis factor α (TNFα) treatment; however, neutralization was effective only for TNFα indicating that TGFβ is not an endogenous modulator of PAI-1. Within VAT, TNFα was localized to neutrophils and macrophages. PAI-1 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI-1 in a similar fashion. PAI-1 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI-1 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI-1 contributes to AKI in sepsis, understanding PAI-1 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI-1 overproduction.

Purpose Emergency trauma room treatment follows established algorithms such as ATLS®. Nevertheless, there are injuries that are not immediately recognized here. The aim of this study was to evaluate the residual risk for manifesting life-threatening injuries despite strict adherence to trauma room guidelines, which is different to missed injuries that describe recognizable injuries. Methods In a retrospective study, we included 2694 consecutive patients admitted to the emergency trauma room of one single level I trauma center between 2016 and 2019. In accordance with the trauma room algorithm, primary and secondary survey, trauma whole-body CT scan, eFAST, and tertiary survey were performed. Patients who needed emergency surgery during their hospital stay for additional injury found after guidelines-oriented emergency trauma room treatment were analyzed. Results In seven patients (0.26%; mean age 50.4 years, range 18–90; mean ISS 39.7, range 34–50), a life-threatening injury occurred in the further course: one epidural bleeding (13 h after tertiary survey) and six abdominal hollow organ injuries (range 5.5 h–4 days after tertiary survey). Two patients (0.07% overall) with abdominal injury died. The “number needed to fail” was 385 (95%–CI 0.0010–0.0053). Conclusion Our study reveals a remaining risk for delayed diagnosis of potentially lethal injuries despite accurate emergency trauma room algorithms. In other words, there were missed injuries that could have been identified using this algorithm but were missed due to other reasons. Continuous clinical and instrument-based examinations should, therefore, not be neglected after completion of the tertiary survey. Level of evidence Level II: Development of diagnostic criteria on the basis of consecutive patients (with universally applied reference “gold” standard).

Photophobia (fear of light) occurs in a wide range of ophthalmic, neurological and behavioural conditions, the most common of which is migraine. The visual discomfort associated with migraine can occur not only in response to bright light but also flicker, spatial pattern and colour. The principles that underlie the discomfort are explored and methods to reduce it are proposed.

PURPOSE: We evaluated interictal discharges (IEDs) as a biomarker for the time to development of electrographic seizures (ES). METHODS: Prospective observational study of 254 critically ill children who underwent continuous electroencephalography (cEEG) monitoring. We excluded neonates and patients with known epilepsy or the sole cEEG indication to characterize events. Interictal discharges included sporadic epileptiform discharges and periodic and rhythmic patterns. Sporadic epileptiform discharges were categorized as low frequency (rare [

Purpose Stability of the dorsal pelvic ring is important for patient mobilisation and can be restored using several surgical procedures after fracture. Placement of percutaneous iliosacral screws is a reliable and minimal-invasive technique to achieve stabilisation of the dorsal pelvic ring by placement of two screws in the first sacral vertebra. Aim of this study was to evaluate 3D CT scans regarding the anatomical possibility to place two 7.3 mm iliosacral screws for fixation of the dorsal pelvic ring. Methods 3D CT datasets of 500 consecutive trauma patients with 1000 hemipelves of a mid-european level I trauma centre with or without pelvic injury were evaluated and measured bilaterally in this retrospective study. Results One thousand hemipelvic datasets of 500 patients (157 females, 343 males) with a mean age of 49.7 years (18 to 95) were included in this study. Only 16 hemipelves (1.6%, 11 in females, 5 in males) in 14 patients (2.8%, 9 females = 5.73%, 5 males = 1.5%) showed too narrow corridors so that 7.3 mm screw placement would not be possible (p = 0.001). In women, too narrow corridors occurred 3.9 times as often as in men. Only two females showed this bilaterally. Conclusion The evaluation of 3D CT scans of the pelvis showed the importance of planning iliosacral screw placement, especially if two 7.3 mm screws are intended to be placed in the first sacral vertebra.

The use of immune checkpoint inhibitors (ICI) to activate adaptive immune responses against some tumor types has clearly been a major advance in cancer therapeutics1 . Despite the significant impact of ICI implementation on the outcomes of cancers, treatments with ICI currently fail to eradicate the majority of tumors as a result of inadequate priming of an autologous tumor-specific immune response. Three collaborative studies published by the groups of B. Vogelstein, S. B. Gabelli and S. Zhou indicate that specially-designed bispecific antibodies may help overcome limitations of ICI.

Arthrodesis of the knee joint is still a salvage procedure after recurrent prosthetic joint infections (PJI) of total knee arthroplasties (TKA) with substantial bone loss and seems to be a good solution to avoid amputation. Until now, intramedullary arthrodesis has increasingly been performed; no study has yet been published to compare these techniques after septic removal of TKA in terms of functional assessment and quality of daily life. In a single-centre retrospective setting, clinical and radiographic evaluation of consecutive patients after knee arthrodesis using intramedullary and external fixation for infected knee joints was performed. All patients were evaluated clinically, with x-ray and questionnaire including analysis regarding any complications at latest follow-up of a minimum 12 months postoperatively. We included 152 patients (75 females, 77 males) in this study. The mean age of the patients at surgery was 63.6 years (range 12 to 90 years). The minimum follow-up was 12 months (mean 3.1 years, range 12 to 49 months). Arthrodesis with external fixator (83 patients, 52.2%) showed less blood loss and less peri-operative complications (1.6%) but a high rate of post-operative, pin-track infections (35.5%); loose pins (12.7%); and pin fractures (4.8%), and therefore risk factors for instability and nonunion (30.9%). Revision rate was 22.6% for arthrodesis with external fixator, and the primary union rate was 65.6%. Intramedullary arthrodesis (69 patients, 43.4%) showed a similar re-infection rate to external fixation (16.1% and 15.9%, respectively) but a significantly lower revision rate (5.4%, p

Aim The Prevention of Arrhythmia Device Infection Trial (PADIT) infection risk score, developed based on a large prospectively collected data set, identified five independent predictors of cardiac implantable electronic device (CIED) infection. We performed an independent validation of the risk score in a data set extracted from U.S. healthcare claims. Methods and results Retrospective identification of index CIED procedures among patients aged ≥18 years with at least one record of a CIED procedure between January 2011 and September 2014 in a U.S health claims database. PADIT risk factors and major CIED infections (with system removal, invasive procedure without system removal, or infection-attributable death) were identified through diagnosis and procedure codes. The data set was randomized by PADIT score into Data Set A (60%) and Data Set B (40%). A frailty model allowing multiple procedures per patient was fit using Data Set A, with PADIT score as the only predictor, excluding patients with prior CIED infection. A data set of 54 042 index procedures among 51 623 patients with 574 infections was extracted. Among patients with no history of prior CIED infection, a 1 unit increase in the PADIT score was associated with a relative 28% increase in infection risk. Prior CIED infection was associated with significant incremental predictive value (HR 5.66, P, Graphical Abstract

Purpose: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. Experimental Design: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. Results: Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). Conclusions: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Objectives This study characterized the microbiology of major cardiac implantable electronic device (CIED) infections that occurred during the WRAP-IT (Worldwide Randomized Antibiotic Enve...

Background As health systems transition to value-based care, improving transitional care (TC) remains a priority. Hospitals implementing evidence-based TC models often adapt them to local contexts. However, limited research has evaluated which groups of TC strategies, or transitional care activities, commonly implemented by hospitals correspond with improved patient outcomes. In order to identify TC strategy groups for evaluation, we applied a data-driven approach informed by literature review and expert opinion. Methods Based on a review of evidence-based TC models and the literature, focus groups with patients and family caregivers identifying what matters most to them during care transitions, and expert review, the Project ACHIEVE team identified 22 TC strategies to evaluate. Patient exposure to TC strategies was measured through a hospital survey (N = 42) and prospective survey of patients discharged from those hospitals (N = 8080). To define groups of TC strategies for evaluation, we performed a multistep process including: using ACHIEVE’S prior retrospective analysis; performing exploratory factor analysis, latent class analysis, and finite mixture model analysis on hospital and patient survey data; and confirming results through expert review. Machine learning (e.g., random forest) was performed using patient claims data to explore the predictive influence of individual strategies, strategy groups, and key covariates on 30-day hospital readmissions. Results The methodological approach identified five groups of TC strategies that were commonly delivered as a bundle by hospitals: 1) Patient Communication and Care Management, 2) Hospital-Based Trust, Plain Language, and Coordination, 3) Home-Based Trust, Plain language, and Coordination, 4) Patient/Family Caregiver Assessment and Information Exchange Among Providers, and 5) Assessment and Teach Back. Each TC strategy group comprises three to six, non-mutually exclusive TC strategies (i.e., some strategies are in multiple TC strategy groups). Results from random forest analyses revealed that TC strategies patients reported receiving were more important in predicting readmissions than TC strategies that hospitals reported delivering, and that other key co-variates, such as patient comorbidities, were the most important variables. Conclusion Sophisticated statistical tools can help identify underlying patterns of hospitals’ TC efforts. Using such tools, this study identified five groups of TC strategies that have potential to improve patient outcomes.

OBJECTIVENeonatal intraventricular hemorrhage (IVH) leads to posthemorrhagic hydrocephalus (PHH), brain injury, and long-term disability. Current therapy for IVH is based on treating PHH but does not address the underlying brain injury. In order to develop pharmacological treatment for IVH, there must be a better understanding of the underlying pathology of this disease. This study was designed to determine the time course of the acute inflammation and oxidative stress that may underlie the progressive pathology of IVH. The authors sought to understand the temporal relationships among inflammation, oxidative stress, and white matter pathology in a rat model of IVH.METHODSA rat model of IVH consisting of hemoglobin injection into the lateral ventricle was used. Tissue was analyzed via biochemical and histological methods to map the spatiotemporal distribution of innate immune activation and oxidative stress. White matter was quantified using both immunohistochemistry and Western blot for myelin basic protein (MBP) in the corpus callosum.RESULTSIVH led to acute induction of inflammatory cytokines, followed by oxidative stress. Oxidative stress was concentrated in white matter, adjacent to the lateral ventricles. Animals with IVH initially gained weight at a lower rate than control animals and had larger ventricles and less MBP than control animals.CONCLUSIONSExperimental IVH induces global inflammation throughout the brain and oxidative stress concentrated in the white matter. Both of these phenomena occur early after IVH. This has implications for human neonates with immature white matter that is exquisitely sensitive to inflammation and oxidative stress. Antiinflammatory or antioxidant therapy for IVH may need to be initiated early in order to protect developing white matter.

Zusammenfassung Hintergrund Krankenhäuser in Deutschland betreiben ein Risikomanagement, welches die Prävention und systematische Aufarbeitung unerwünschter Ereignisse unterstützen kann. Ein wichtiger Aspekt davon ist die Etablierung einer Sicherheitskultur. Die Erhebung der Sicherheitskultur findet im deutschsprachigen Raum bisher selten und fast ausschließlich durch quantitative Instrumente statt. Im Fachbereich Orthopädie und Unfallchirurgie ist in Deutschland eine hohe Zahl an bestätigten Behandlungsfehlern und Risikoaufklärungsmängeln verzeichnet. Deshalb untersucht die vorliegende Studie die Sicherheitskultur in diesem Fachbereich. Fragestellung (I) Wie nehmen Ärzte der Orthopädie und Unfallchirurgie den Umgang mit unerwünschten Ereignissen im klinischen Alltag wahr, und (II) was sind die relevanten Bestandteile einer Sicherheitskultur aus ärztlicher Perspektive? Material und Methoden Es wurden 14 Einzelinterviews mit Ärzten der Orthopädie und Unfallchirurgie geführt. Die Interviews wurden audioaufgezeichnet, transkribiert und anhand der Thematic Analysis nach Braun und Clarke und des Yorkshire Contributory Factors Framework analysiert. Zur Organisation der Daten wurde die Software MAXQDA verwendet. Ergebnisse Es konnte ein starker Einfluss der Führungskräfte auf den Umgang mit unerwünschten Ereignissen im ärztlichen Team festgestellt werden. Von Chefärzten wurde erwartet, eine gute Sicherheitskultur vorbildhaft vorzuleben, da sie durch ihr Verhalten die Handlungsweisen des Teams in sicherheitsrelevanten Situationen beeinflussen. Diskussion Der Einbezug von Chefärzten in die Entwicklung von Maßnahmen zur Verbesserung der Sicherheitskultur in der Orthopädie und Unfallchirurgie sollte aufgrund der Bedeutsamkeit hierarchischer Strukturen in Betracht gezogen werden.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel’s recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

Objective This study evaluated the risk of subclinical atrial fibrillation (AF) in patients with central retinal artery occlusion (CRAO) compared to those with cryptogenic stroke using implantable loop recorders (ILR). Methods We conducted a retrospective analysis of 273 consecutive patients who had ILRs inserted at our institution for either cryptogenic stroke (n = 227) or CRAO (n = 46). Our primary endpoint was a time to event analysis for the new diagnosis of AF by ILR. Univariable and multivariable Cox proportional hazard models were used to determine the predictors of time-to-AF. Results A total of 64 patients were found to have newly diagnosed AF by remote monitoring of the ILR. AF was detected in 57 of 227 (25%) cryptogenic stroke patients by the end of a maximum 5.1 years follow-up and in 7 of 46 (15%) CRAO patients by the end of a maximum 3.6year follow-up (p = .215, log-rank test). The Kaplan-Meier estimates for freedom from AF was 59.4% for CRAO and 66.6% for cryptogenic stroke (p = NS, log-rank test). Baseline variables predicting AF included older patients, higher CHADS2 VASC score, longer PR interval on initial EKG evaluation and mitral annular calcification (MAC) on transthoracic echocardiogram. Conclusions Patients with CRAO are at risk for subclinical AF, similar to those with cryptogenic stroke. Long term monitoring to detect AF may lead to changes in pharmacotherapy to reduce the risk for subsequent stroke. This article is protected by copyright. All rights reserved.

Visual Abstract, Highlights • Contractile assays were performed using multicellular preparations isolated from the left and right ventricles of organ donors and patients with heart failure. • Heart failure reduced maximum force and power by approximately 30% in the myocardium from both ventricles. • Heart failure increased the Ca2+ sensitivity of contraction, but the effect was bigger in right ventricular tissue than in left ventricular samples. • The changes in Ca2+ sensitivity may reflect ventricle-specific post-translational modifications to sarcomeric proteins., Summary This study measured how heart failure affects the contractile properties of the human myocardium from the left and right ventricles. The data showed that maximum force and maximum power were reduced by approximately 30% in multicellular preparations from both ventricles, possibly because of ventricular remodeling (e.g., cellular disarray and/or excess fibrosis). Heart failure increased the calcium (Ca2+) sensitivity of contraction in both ventricles, but the effect was bigger in right ventricular samples. The changes in Ca2+ sensitivity were associated with ventricle-specific changes in the phosphorylation of troponin I, which indicated that adrenergic stimulation might induce different effects in the left and right ventricles.

ObjectiveTo examine EEG features of major pathophysiology in children undergoing extracorporeal membrane oxygenation (ECMO).MethodsThis was a single-center, retrospective study of 201 pediatric patients on ECMO, using the first 24 hours of continuous EEG (cEEG) monitoring, collating background activity and electrographic seizures (ES) with imaging, ECMO type, and outcome.ResultsSeverely abnormal cEEG background occurred in 12% (25/201), and was associated with death (sensitivity 0.23, specificity 0.97). ES occurred in 16% (33/201) within 3.2 (0.6–20.3) hours (median [interquartile range]) of cEEG commencement, and higher ES burden was associated with death. ES was always associated with ipsilateral injury (p= 0.006), but occurred in only one-third of cases with abnormal imaging. In 28 patients with isolated hemisphere lesion, type of arterial ECMO cannulation was associated with side of injury: right carotid cannulation was associated with right hemisphere lesions, and ascending aorta cannulation with left hemisphere lesions (odds ratio, 0.29 [95% confidence interval, 0.08–0.98],p= 0.03).ConclusionsAfter starting ECMO, cEEG background activity has the potential to inform prognosis. Type of arterial (carotid vs aortic) ECMO correlates with side of focal cerebral injury, which in ≈33% is associated with presence of ES. We hypothesize that the differential distribution reflects abnormal flow dynamics or embolic injury.

Current bacterial RNA switches suffer from lack of versatile inputs and are difficult to engineer. We present versatile and modular RNA switches that are trans‐encoded and based on tRNA‐mimicking structures (TMSs). These switches provide a high degree of freedom for reengineering and can thus be designed to accept a wide range of inputs, including RNA, small molecules, and proteins. This powerful approach enables control of the translation of protein expression from plasmid and genome DNA., Switch‐hitter: A bacterial genetic switch that accepts RNAs, small molecules, and proteins as inputs was developed based on a tRNA‐mimicking structure. The switch is trans‐encoded, which makes manipulation of the target mRNA redundant. It is stable to RNase, shows a strong dynamic response, and exhibits a high level of orthogonality.

Bevacizumab is a humanized anti-vascular endothelial growth factor monoclonal antibody used in the treatment of cervical cancer, ovarian cancer, colorectal cancer, lung cancer, renal cell cancer, and recurrent glioblastomas. Its approval by US FDA was issued with a black box warning that its use has been associated with a risk of gastrointestinal (GI) tract perforation and that it should be discontinued in patients who have experienced such. The reported incidence of GI perforation in those receiving bevacizumab is as high as 3%. However, the incidence of GI perforation in those receiving bevacizumab undergoing GI endoscopic procedures has not been well studied. A retrospective, single-center observational study was conducted at Memorial Sloan Kettering Cancer Center (MSKCC) between 2011 and 2018. All patients who underwent upper GI endoscopy with percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) tube placement and received bevacizumab within 6 months of their endoscopic procedure were included. We identified 176 patients who underwent PEG or PEJ tube placement and received bevacizumab within 6 months. Eighty-one percent of patients were female (n = 144) and the median age was 61 years. Prior to endoscopic procedures, patients received a median of seven doses of bevacizumab. Patients received bevacizumab from 170 days before to 170 days after their endoscopic procedures (median 44 days). No GI perforations were observed during or after the time of the endoscopic procedures. Our study demonstrated that receiving bevacizumab within 6 months prior to their endoscopic procedure was not associated with an increased risk of GI tract perforation and thus not an absolute contraindication to proceeding with PEG and PEJ tube placement in these patients.

The Mdm2 oncoprotein and its association with p53 were discovered 30 years ago, and a cornucopia of activities and regulatory pathways have been associated with it. In this review, we will raise questions about Mdm2 and its cousin Mdm4 that we consider worth pursuing in future research, reaching from molecular structures and intracellular activities all the way to development, evolution, and cancer therapy. We anticipate that such research will not only close a few gaps in our knowledge but could add new dimensions to our current view. This compilation of questions contributes to the preparation for the 10th Mdm2 Workshop in Tokyo.

Introduction In women with T1-2 breast cancer and one to two positive axillary lymph nodes (LN) at low risk for recurrence, postmastectomy radiation therapy (PMRT) may provide insufficient benefit to justify its toxicity. This study evaluated the interaction of factors associated with overall survival (OS) after PMRT in these patients. Methods The National Cancer Database was queried for women with T1-2 breast cancer undergoing mastectomy with one to two positive LN identified on lymphadenectomy. Patients were grouped according to number of positive LN and then stratified by PMRT use. Differences in OS were evaluated. Results Multivariable modeling demonstrated an interaction effect of age on the efficacy of PMRT. In patients more than or equal to 60 years old, PMRT was associated with improved survival when adjusting for age and tumor grade in patients with 1 to 2 positive LN (risk ratio = 0.62, 95% confidence interval = 0.40-0.93, P = .018). In patients less than 60 years old, tumor size and grade, but not PMRT, were associated with improved OS. Conclusion For women with T1-2 breast cancer and one to two positive LN, PMRT's association with OS is influenced by age, tumor grade, and number of positive LN. PMRT appears to be associated with improvements in OS in older patients, but not younger patients, regardless of tumor size or nodal status.

Background: While major complications associated with CIED lead extractions are uncommon, they carry a significant risk of morbidity and mortality in the absence of surgical intervention. However, there is limited data on the differences in outcomes of these procedures between centers with and without on-site CS support. The present study examined outcomes of transvenous cardiac implantable electronic device (CIED) lead extractions according to admitting hospitals’ cardiac surgery (CS) facilities.\ud \ud Methods: We analyzed the National Inpatient Sample for CIED lead extraction procedures, stratified by hospitals’ CS facilities into two groups; on-site and off-site CS. Logistic regression analyses were performed to estimate the adjusted odds (aOR) of procedure-related complications in off-site CS centers. \ud \ud Results: In 221,606 procedures over an 11-year-period, CIED lead extractions were increasingly undertaken in on-site as opposed to off-site CS centers (Onsite CS 2004 vs. 2014: 78.2% vs. 90.4%, p

Filamentous fungi are highly productive cell factories, often used in industry for the production of enzymes and small bioactive compounds. Recent years have seen an increasing number of synthetic-biology-based applications in fungi, emphasizing the need for a synthetic biology toolkit for these organisms. Here we present a collection of 96 genetic parts, characterized in Penicillium or Aspergillus species, that are compatible and interchangeable with the Modular Cloning system. The toolkit contains natural and synthetic promoters (constitutive and inducible), terminators, fluorescent reporters, and selection markers. Furthermore, there are regulatory and DNA-binding domains of transcriptional regulators and components for implementing different CRISPR-based technologies. Genetic parts can be assembled into complex multipartite assemblies and delivered through genomic integration or expressed from an AMA1-sequence-based, fungal-replicating shuttle vector. With this toolkit, synthetic transcription units with established promoters, fusion proteins, or synthetic transcriptional regulation devices can be more rapidly assembled in a standardized and modular manner for novel fungal cell factories.

PurposeNetwork analysis methods can potentially quantify cancer disturbances in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. The method is applied to high grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs), and to rank key genes associated with prognosis.MethodsCopy number alterations (CNAs) from targeted and whole exome sequencing data were extracted for HGSOC patients (n= 45) treated with ICIs. CNAs at a gene level were represented on a protein-protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier-Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan-Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups.ResultsThe network curvature analysis stratified patients at high risk of mortality with p=0.00047 in Kaplan-Meier analysis. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer.ConclusionNetwork curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.

Vancomycin is a first-line agent used in the treatment of methicillin-resistant Staphylococcus aureus; however, vancomycin is associated with acute kidney injury (AKI). Previous literature demonstrates decreased incidence of AKI using 24-h area under the concentration-time curve (AUC(24)) monitoring, but its safety is unknown in obese populations. Patients ≥18 years, with body mass indices (BMI) ≥30 kg/m(2), admitted between August 2015 and July 2017 or October 2017 and September 2019, who received vancomycin for ≥72 h and had level(s) drawn within 96 h of initiation were included. The primary outcome was incidence of AKI. Secondary outcomes included inpatient mortality rate, median inpatient length of stay, median vancomycin trough concentration, and median vancomycin AUC(24). AKI was identified using the highest serum creatinine value compared with the value immediately prior to vancomycin initiation based on Kidney Disease Improving Global Outcomes (KDIGO) criteria. Overall, 1,024 patients met inclusion criteria, with 142 out of 626 patients in the trough group and 65 out of 398 patients in the AUC(24) group meeting criteria for AKI (22.7% versus 16.3%, P = 0.008). Logistic regression of the data to account for confounding factors maintained significance for the reduction in incidence of AKI with AUC(24) monitoring compared to trough monitoring (P = 0.010). Monitoring of vancomycin with AUC(24) was associated with a decreased risk of AKI when compared with trough monitoring in obese patients.

Manufacturers of cardiac implantable electronic devices have incorporated automatic features to allow for remote monitoring, improve device longevity, and additional safety. Algorithms to automatically measure capture threshold and adjust output to preserve battery life are one such feature. Automatic features may occasionally result in unexpected or undesirable clinical outcomes. We report on a patient who developed ventricular tachycardia inadvertently induced by the AutoCapture. feature of an Abbott/St. Jude Medical (SJM) pacemaker.

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

Background:Esophageal atresia (EA) is often accompanied by tracheomalacia (TM). TM can lead to severe respiratory complaints requiring invasive treatment. This study aims to evaluate if thoracoscopic primary posterior tracheopexy (PPT) can prevent the potential sequelae of TM in patients with EA.Methods:A cohort study including all consecutive EA patients treated between 2014 and July 2019 at the Wilhelmina Children's Hospital was conducted. Two groups were distinguished: (group 1) all EA patients born between January 2014 and December 2016 and (group 2) all EA patients born between January 2017 and July 2019, after introduction of PPT. In the latter group, PPT was performed in EA patients with moderate (33–66%) or severe (67–100%) tracheomalacia, seen during preoperative bronchoscopy. Group differences were assessed using the Fisher's exact test for bivariate variables and the Mann–WhitneyU-test for continuous variables.Results:A total of 64 patients were included in this study (28 patients in group 1; 36 patients in group 2). In group 2, PPT was performed in 14 patients. Respiratory tract infections (RTIs) requiring antibiotics within the first year of life occurred significantly less in group 2 (61 vs. 25%,p= 0.004). Brief resolved unexplained events (BRUEs) seemed to diminish in group 2 compared to group 1 (39 vs. 19%,p= 0.09).Conclusion:Thoracoscopic primary posterior tracheopexy decreases the number of respiratory tract infections in EA patients. The clinical impact of reducing RTIs combined with the minimal additional operating time and safety of PPT outweighs the risk of overtreatment.

Despite the known deleterious effects of obesity, clinical data indicate that overweight or obese patients experience higher rates of sepsis survival compared to normal and underweight patients; a phenomenon called the obesity paradox. Results from preclinical sepsis studies have not been able to replicate these findings. The objective of this study was to test the existence of the obesity paradox in a murine model of cecal slurry (CS)-induced sepsis with insulin-resistant diet-induced obese mice. Male C57BL/6 mice were provided high-fat (HFD) or low-fat (LFD) diets for 20 weeks. HFD-fed mice experienced higher rates of survival compared to LFD-fed mice after septic challenge induced by CS injection (66% vs. 25%, p = 0.01, survival assessed for 14 days). Despite the survival advantage, HFD-fed mice had higher rates of positive bacterial cultures and increased markers of kidney injury. Circulating levels of IL-6, IL-1β, TNFα, and IL-23 were equivalent 24 h after CS-injection; however, IL-17A was uniquely increased in HFD-fed mice. While LFD-fed mice maintained euglycemia, HFD-fed mice were hyperglycemic 6 and 12 h after CS-injection. Stable isotope resolved metabolomics analysis of liver tissue showed diverging pathways of glucose utilization during sepsis, with LFD-fed mice significantly upregulating glycolytic activity and HFD-fed mice decreasing glucose entry into the TCA cycle. This murine study corroborates clinical data that obesity confers a survival benefit in sepsis, albeit at the expense of more significant organ injury. The mechanisms promoting survival in the obese remain unknown; however, this model appears to be well-poised to begin answering this question. Differences in glucose utilization are a novel target to investigate this paradox.

Background: Compare arterial stiffness among law enforcement officers (LEOs) versus general population normative values and identify predictors of arterial stiffness in LEOs. Methods: Seventy male LEOs (age: 24–54 years) completed body composition, blood pressures, physical activity level, and carotid-femoral pulse wave velocity (cfPWV) measurements. T-tests and regression analyses were utilized to compare LEO data to normative data and predict cfPWV, respectively. Results: Compared to similar age strata within the general population, cfPWV was lower among LEO’s under 30-years (mean difference = −0.6 m·s−1), but higher among LEOs 50–55-years (mean difference = 1.1 m·s−1). Utilizing regression, age, relative body fat, and diastolic blood pressure explained the greatest variance in LEO’s cfPWV (adj. R2 = 0.56, p &lt, 0.001). Conclusion: This investigation demonstrated that arterial stiffness may progress more rapidly in LEOs and LEOs’ relative body fat and blood pressure may primarily affect arterial stiffness and risk of CVD.

Background: Esophageal atresia (EA) is a rare congenital malformation of the esophagus. Surgical treatment is required to restore the continuity of the esophagus. This can be performed through thoracotomy. However, an increasing number of hospitals is performing minimal invasive surgery (MIS). In this article, we describe the technique of thoracoscopic repair of EA in neonates in more detail and show the outcome of a patient cohort operated by young pediatric surgeons in training. Methods: Between 2014 and 2019 correction was performed in 64 EA type C patients at the UMC Utrecht, Wilhelmina Children's Hospital, mainly by young pediatric surgeons in training. Results: All patients were corrected through MIS, 3 days after birth. The median operation duration was 181 (127-334) minutes. Nasogastric tube feeding was started on the first postoperative day, and oral feeding 6 days postop. Postoperative complications included leakage (14.1%), stenosis (51.1%), and recurrent tracheoesophageal fistula (7.8%). Conclusion: Thoracoscopic repair of EA can be performed safely, with good outcome and all the benefits of MIS. However, it remains a challenging procedure and should be performed only in pediatric centers with a vast experience in MIS, especially when training young pediatric surgeons. These centers must have access to a multidisciplinary team of neonatologists, pediatric anesthesiologists, surgeons, and ENT specialists to ensure the best possible care in hemodynamic, respiratory, and cerebral monitoring and gastrointestinal and developmental outcome.

Background The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). Methods Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. Results In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P Conclusions EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

Lesniak, AY, Bergstrom, HC, Clasey, JL, Stromberg, AJ, and Abel, MG. The effect of personal protective equipment on firefighter occupational performance. J Strength Cond Res 34(8): 2165-2172, 2020-The purpose of this study was to evaluate the effects of load carriage (LC) and LC plus respirator use (LC + self-contained breathing apparatus [SCBA]) on firefighters' work capacity to enhance our understanding of occupational demands. Twenty-one male structural firefighter recruits (age: 28.6 ± 4.3 years; height: 178.6 ± 7.2 cm; body mass: 94.1 ± 15.4 kg; body fat: 22.9 ± 6.1%) participated. Occupational performance was assessed by time to complete a simulated fire ground test (SFGT). After 2 familiarization trials, recruits performed the following SFGT conditions in a randomized order: PT (physical training clothes), LC only, and LC + SCBA. To describe within-group differences between SFGT conditions, relative difference scores were calculated as follows: % difference = ([experimental trial outcome - PT trial outcome]/PT trial outcome) × 100. Statistical differences between conditions were assessed with repeated-measures analysis of variance. The level of significance was set p < 0.01. Time to complete the LC + SCBA trial (345.9 ± 43.7 seconds; p < 0.001) and LC-only trial (331.2 ± 39.3 seconds; p < 0.001) were significantly greater than the PT trial (241.0 ± 33.3 seconds). Post-SFGT rating of perceived exertion was higher in the LC + SCBA trial (6.7 ± 1.7) and LC trial (6.4 ± 1.5) compared with the PT trial (4.7 ± 1.8; p < 0.001). Heart rate and lactate measures were similar across conditions (p = 0.488; p = 0.287). Personal protective equipment (PPE) significantly decreases the work capacity and increases the perceived effort of occupational tasks. Thus, these findings describe the additional physical demands produced by PPE and indicate that performance of firefighting tasks in an unloaded condition does not reflect work capacity in a bona fide condition.

Double somatic mismatch-repair-gene mutation/alteration is a recently recognized molecular mechanism that underlies microsatellite instability-high in some colorectal carcinomas. It remains to be determined whether and how microsatellite instability-high tumors with this molecular defect differ from their counterparts caused by other mechanisms, specifically, Lynch syndrome-associated and MLH1-promoter hypermethylated. In this study, we evaluated the clinical and pathological characteristics of a series of 15 double somatic mutation/alteration-associated microsatellite instability-high colorectal carcinomas identified from our genetics service and 68 such cases reported in the literature. We observed that these cases presented at an age similar to MLH1-promoter hypermethylated (n = 20) and microsatellite-stable (n = 39) cases but older than Lynch syndrome-associated cases (n = 20, p 0.05). While these tumors simulated other microsatellite instability-high tumors in their prevalent right-sided location, they appeared to differ in TNM stages at presentation (73% stage III/IV versus 25% stage III/IV in other microsatellite instability-high tumors, p = 0.04). Histologically, 40% of them had a dominant solid growth pattern. Inter-tumoral heterogeneity was a striking feature, spanning the spectrum from medullary type (with a tumor-infiltrating-lymphocyte/high-power-field count as high as 59) to conventional-type with only few tumor-infiltrating-lymphocytes (1/high-power-filed). As a group, these tumors seemed less likely to show robustly high lymphocytic infiltration than other microsatellite instability-high tumors (only 20% had ≥10 tumor-infiltrating-lymphocytes/high-power-filed, whereas this rate in Lynch syndrome-associated and MLH1-promoter hypermethylated tumors was 60% and 75%, respectively). Three double somatic mutation/alteration-associated tumors were treated with a PD1/PD-L1 checkpoint inhibitor. While all three had an elevated tumor-mutation-burden (47 mut/megabase), only one had tumor-infiltrating-lymphocytes10/high-power-field, yet all three exhibited measurable response. In summary, microsatellite instability-high colorectal carcinomas caused by double somatic mismatch-repair-gene mutation/alteration may have varied clinical and pathological characteristics, and some may have relatively low tumor-infiltrating-lymphocytes; response to immune checkpoint inhibitors can be achieved in this group even when the lymphocytic infiltration is not abundant.

Light-emitting diode-based lighting systems are now applied in both general lighting and automotive lighting. Time-modulated control methods such as pulse width modulation are frequently applied as a dimming method. This paper presents the characteristics of the visibility of the phantom array effect according to luminance, chromaticity and angular field of view. The threshold frequency of the visibility of the phantom array increases in proportion to the logarithm of the luminance of the light source. As the angular field of view of the light source increases, the threshold frequency of the visibility of the array decreases exponentially over a range from 0.125° to 4° in our experimental conditions. The threshold frequency at which the array is visible depends on chromaticity at high light source modulation frequencies. When designing time-modulated light sources, our findings can be applied so as to minimize the phantom array effect.

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

We aimed to determine whether clinical EEG reports obtained from children in the intensive care unit with refractory status epilepticus could provide data for comparative effectiveness research studies.We conducted a retrospective descriptive study to assess the documentation of key variables within clinical continuous EEG monitoring reports based on the American Clinical Neurophysiology Society's standardized EEG terminology for children with refractory status epilepticus from 10 academic centers. Two pediatric electroencephalographers reviewed the EEG reports. We compared reports generated using free text or templates.We reviewed 191 EEG reports. Agreement between the electroencephalographers regarding whether a variable was described in the report ranged from fair to very good. The presence of electrographic seizures (ES) was documented in 46% (87/191) of reports, and these reports documented the time of first ES in 64% (56/87), ES duration in 72% (63/85), and ES frequency in 68% (59/87). Reactivity was documented in 16% (31/191) of reports, and it was more often documented in template than in free-text reports (40% vs. 14%, P = 0.006). Other variables were not differentially reported in template versus free-text reports.Many key EEG features are not documented consistently in clinical continuous EEG monitoring reports, including ES characteristics and reactivity assessment. Standardization may be needed for clinical EEG reports to provide informative data for large multicenter observational studies.

To evaluate factors affecting incidence of complications after secondary alveolar bone grafting with premaxillary osteotomy (SABG + PO) in children with complete bilateral cleft of lip and palate (BCLP). Data were collected from children with BCLP treated with SABG + PO from 2004 to 2014 at our institute. Preoperative parameters included age, donor site, race, gingival health, bone quality around cleft-related teeth, premaxilla position, graft timing, presence of canines in the cleft, and presence of deciduous teeth around the cleft area. Logistic regression and the chi-squared test were used to assess correlations and the incidence of complications. In the 64 patients, a significant correlation was found between complication rate and timing of bone grafting with respect to early versus late SABG + PO (p = 0.041), age > 12 years (p = 0.011; odds ratio (OR) 5.9; 95% confidence interval (CI) 1.49–23.93), malposition of the premaxilla (p = 0.042; OR 3.3; 95% CI 1.04–10.13), and preoperative bone quality around cleft-related teeth (p = 0.005; OR 5.3; 95% CI 1.6–17.2). The timing of SABG + PO is essential, as early SABG + PO is associated with fewer complications. A malpositioned premaxilla and poor bone quality around cleft-related teeth are associated with more complications. Therefore, preoperative orthodontic repositioning of the malpositioned premaxilla before SABG + PO should be considered. Analysis of treatment protocols and complications for BCLP patients underscores that proper timing of SABG + PO and correct premaxilla repositioning help reduce complications.

A flickering light can be seen during a saccadic eye movement as a pattern of contours known as a phantom array. On repeated pairs of trials, observers made saccades across a narrow (1 arc minutes), bright (10−4 cd/m2) source of flickering light and were required to detect the phantom array. On one of each pair of trials, chosen at random, the light flickered at 60 kHz and on the other at a frequency chosen in the range 1–11 kHz. In two such studies, a few observers were reliably able to discriminate 11 kHz from 60 kHz on the basis of the visibility of the phantom array. The average threshold at which the array was visible was about 6 kHz and therefore double that previously obtained with larger targets. Those observers who were able to see the phantom array tended reliably to report more symptoms of visual discomfort in everyday life.