Search

Rationale: Early mobilization of ECMO-supported patients is increasingly common, but it remains unknown whether there are factors predictive of achieving higher intensity mobilization among those a...

Purpose of Review Inhaled environmental exposures cause over 12 million deaths per year worldwide. Despite localized efforts to reduce environmental exposures, tobacco smoking and air pollution remain the urgent public health challenges that are contributing to the growing prevalence of respiratory diseases. The purpose of this review is to describe the mechanisms through which inhaled environmental exposures accelerate lung aging and cause overt lung disease. Recent Findings Environmental exposures related to fossil fuel and tobacco combustion and occupational exposures related to silica and coal mining generate oxidative stress and inflammation in the lungs. Sustained oxidative stress causes DNA damage, epigenetic instability, mitochondrial dysfunction, and cell cycle arrest in key progenitor cells in the lung. As a result, critical repair mechanisms are impaired, leading to premature destruction of the lung parenchyma. Summary Inhaled environmental exposures accelerate lung aging by injuring the lungs and damaging the cells responsible for wound healing. Interventions that minimize exposure to noxious antigens are critical to improve lung health, and novel research is required to expand our knowledge of therapies that may slow or prevent premature lung aging.

This article provides a history of the treatment of consumer collectives in the social sciences literature. It highlights some of the insights derived from recent work in consumer research ...

Schwer verletze Patienten benotigen nach Ende der Akutbehandlung eine qualifizierte und luckenlose Rehabilitation. Diese postakute Rehabilitation (Phase C) stellt hohe Anforderungen an die Rehabilitationseinrichtung bezuglich personeller, sachlicher, organisatorischer und raumlicher Voraussetzungen. Der Arbeitskreis Traumarehabilitation der Sektion Rehabilitation der Deutschen Gesellschaft fur Orthopadie und Unfallchirurgie (DGOU) und weitere Experten haben Anforderungen an die postakute Rehabilitation der Phase C bei Schwerverletzten konsentiert. Diese betreffen sowohl die personellen und sachlichen Voraussetzungen an eine hochspezialisierte orthopadisch-unfallchirurgische Traumarehabilitation als auch die Anspruche an Prozesse, Organisation und Qualitatssicherung. Uber eine hohe Qualifikation und entsprechende Infrastruktur uberregionaler Traumarehabilitationszentren wird ein luckenloser Ubergang in die Nach- und Weiterbehandlung von Schwerverletzten im TraumaNetzwerk DGU® sichergestellt. Dabei werden auch an die TraumaZentren DGU® neue Anforderungen gestellt. Nur wenn diese erfullt werden, kann eine Optimierung der Behandlung und Rehabilitation Schwerverletzter gelingen.

We take an institutional perspective to examine how innovation thrives under conditions of resistance. Specifically, we conceive illicit innovation as a process of successive institutionalization of a new practice in the face of contrary law. In the German federal state of Bavaria, the global movement of craft-beer brewing collides with a regional jurisdiction that prohibits precisely these brewing practices and instead protects the traditional institution of purity-brewing (Reinheitsgebot). Grounded on an embedded qualitative case study of brewers and industry representatives, we build a theory of institutional folding of new norms and practices over established ones. This way, creative brewers have succeeded in legitimizing new practices of naturalness-brewing (Natürlichkeitsgebot). Whereas the legal resistance has stimulated brewers to create an original counter-institution, the illicit innovation has also begun to change the institutional context of the beer industry in Bavaria.

The heart rate variability threshold (HRVT) is a useful and inexpensive alternative to estimate the ventilatory threshold (VT). However, its validity in women remains underexplored. We investigated...

This study investigated the effects of caffeine mouth rinse on cycling time to exhaustion (TTE) and physiological responses in trained cyclists. In a double-blinded randomized counterbalanced cross-over design, 10 recreationally trained male cyclists (mean ±SD: 32 ± 3 years, 72.8 ± 5.3 kg, 1.78 ± 0.06 m, 13.9% ± 3.3% body fat, peak power output = 289.4 ± 24.7 W) completed two TTE tests cycling at 75% of peak aerobic power following 24 hr of dietary and exercise standardization. Cyclists were administered 25-ml mouth rinses for 5 s containing either 85 mg of caffeine or control (water) every 5 min throughout the exercise tests. No significant improvement in TTE was shown with caffeine mouth rinse compared with control (33:24 ± 12:47 vs. 28:08 ± 10:18 min; Cohen’sdzeffect size: 0.51,p = .14). Caffeine mouth rinse had no significant effect on ratings of perceived exertion (p = .31) or heart rate (p = .35) throughout the cycling TTE protocol. These data indicate that a repeated dose of caffeinated mouth rinse for 5 s does not improve cycling TTE in recreationally trained male cyclists. However, these findings should be taken with caution due to the small sample size and blinding ineffectiveness, while further well-design studies with larger samples are warranted.

The overall propulsion efficiency for ion-mode electrospray thrusters has been predicted to be as high as 90%; however, experimental measurements currently fall far short of these predictions. Furt...

Background Many patients with coronary artery disease (CAD) and valvular heart disease (VHD) suffer from psychological distress. Such stress is associated with increased morbidity, reduced quality of life and delayed return to work. European guidelines emphasize recognition and intervention, but evidence-based treatment options are limited and perceived as costly. The present study will test the effect of brief, group-based cognitive therapy as an adjunct to usual cardiac rehabilitation in a randomized design. Methods A total of 148 patients with CAD and/or VHD after surgical intervention and concomitant psychological distress (defined as HADS anxiety (A) or depression (D) score ≥8) will be randomized to either usual out-patient cardiac rehabilitation (CR) comprising an 8-week multidisciplinary programme or usual care supplemented by five group-based cognitive therapy sessions performed by trained CR nurses. A structured, standardized treatment manual will be used. Patients will be randomized 1:1 at three different sites. Additionally, a non-randomized sub-group of 40 matched patients without signs of psychological distress will be followed to investigate spontaneous variation in HADS. The primary outcome is Hospital Anxiety and Depression Score (HADS). Secondary outcomes are adherence to cardiac rehabilitation (CR), health-related quality of life measured by HeartQoL, time to return to work, adherence to lifestyle interventions and cardiovascular readmissions. Patients are followed up for 12 months. Discussion To our knowledge, this is the first randomized controlled trial (RCT) on patients with cardiac disease with an intensive group-based programme of cognitive therapy performed by CR nurses, which makes it affordable and widely implementable. The outcome will elucidate the feasibility and effect of cognitive therapy as an adjunct to CR in patients with post-surgery CAD and/or VHD and psychological distress and could possibly benefit patients with other heart conditions as well. The clinical trial complies with the Declaration of Helsinki. The trial has been approved by The Regional Research Ethics Committee (file number H-16042832) and The Danish Data Protection Agency. The results will be disseminated as original research in peer-reviewed manuscripts. Trial registration www.clinicaltrials.govNCT04254315. Retrospectively registered on 30 January 2020.

Wireless communications in the low terahertz band (0.1 THz-1 THz) is a promising candidate to enable ultra-high-rate vehicular networks beyond 5G. The successful design and adoption of such systems require a deep understanding of the low THz channel specifics in complex vehicular scenarios. In this paper, a comprehensive measurement campaign is reported with the aim of analyzing the wave propagation at 300 GHz in typical vehicular deployments. Following a modular approach, the generic vehicular scenario is decomposed into basic propagation setups that are further analyzed in detail. The obtained measurement data are then applied to derive the mathematical approximations that characterize the low THz band channel properties for each scenario. Finally, the combination of measurement and modeling results is used to identify the critical propagation effects that has to be accounted for in the applied studies. The presented approach, raw and processed data, as well as the contributed analysis, serve as building blocks for future analytical and simulation tools to model prospective vehicular communication systems in the low THz band. publishedVersion

Abstract Patient-reported outcome measures obtained via E-Health tools ease the assessment burden and encourage patient participation in cancer care (PaCC Study) Background E-health based patient-reported outcome measures (PROMs) have the potential to automate early identification of both nutrition status and distress status in cancer patients while facilitating treatment and encouraging patient participation. This cross-sectional study assessed the acceptability, accuracy, and clinical utility of PROMs collected via E-Health tools among patients undergoing treatment for stomach, colorectal, and pancreatic tumors. Results Eight-nine percent mostly, or completely, agreed that PROMs via tablets should be integrated in routine clinical care. Men were significantly more likely to require help completing the questionnaires than women (inv.OR= 0.51, 95% CI=(0.27, 0.95), p = 0.035). The level of help needed increased by 3% with each 1-year increase in age (inv. OR=1.03, 95% CI=(1.01, 1.06), p = 0.013). On average, a patient tended to declare weight which was 0.84 kg inferior to their true weight (Bland and Altman 95 % CI=(-3.9, 5.6); SD: 2.41) and a height which was 0.95 cm superior to their true height (Bland and Altman 95 % CI=(−5, 3.1); SD 2.08). Patient-reported nutrition status was significantly associated with the professionally generated assessment (95% CI=(2.27, 4.15), p < 0.001). As nutrition status declined, the distress score increased (95%CI=(0.88, 1.68), p < 0.001). Of the patients, 48.8% who were both distressed and malnourished requested supportive care to address their problems. Conclusion Patient-reported assessments utilizing E-health tools are an accurate and efficient method to encourage patient participation in cancer care while simultaneously ensuring that regular assessment of psycho-social and nutritional aspects of care are efficiently integrated in the daily clinical routine.

College students make many important decisions related to sexual health, but little is known about their reproductive health knowledge. The purpose of the study was to examine health literacy and knowledge of female reproduction, contraception, and sexually transmitted infections (STIs) in college students.

This study is aimed at evaluating the readability and quality of Wikipedia articles on pelvic floor disorders (PFD) and comparing their content with International Urogynecological Association patient education leaflets. Readability was assessed using six different readability scales, including the Simple Measure of Gobbledygook (SMOG) Index, which is considered superior for scoring healthcare information. Quality was assessed by three female pelvic medicine and reconstructive surgery fellows using the modified DISCERN instrument. DISCERN is validated to evaluate the quality of written consumer health information; it was subsequently modified by health education researchers to enable the evaluation of Wikipedia articles. We evaluated 30 Wikipedia articles that correlated with 29 International Urogynecological Association leaflets. The mean SMOG score of the Wikipedia articles was 12.0 ± 2.1 (12th-grade reading level) whereas the mean SMOG score of the International Urological Association (IUGA) leaflets was 3.4 ± 0.3 (third-grade reading level, p

Potassium inward rectifier channel Kir2 is an important component of terminal cardiac repolarization and resting membrane stability. This functionality is part of balanced cardiac excitability and is a defining feature of excitable cardiac membranes. "Gain-of-function" or "loss-of-function" mutations in KCNJ2, the gene encoding Kir2.1, cause genetic sudden cardiac death syndromes, and loss of the Kir2 current IK1 is a major contributing factor to arrhythmogenesis in failing human hearts. Here we provide a contemporary review of the functional structure, physiology, and pharmacology of Kir2 channels. Beyond the structure and functional relationships, we will focus on the elements of clinically used drugs that block the channel and the implications for treatment of atrial fibrillation with IK1-blocking agents. We will also review the clinical disease entities associated with KCNJ2 mutations and the growing area of research into associated arrhythmia mechanisms. Lastly, the presence of Kir2 channels has become a tipping point for electrical maturity in induced pluripotent stem cell–derived cardiomyocytes (iPS-CMs) and highlights the significance of understanding why Kir2 in iPS-CMs is important to consider for Comprehensive In Vitro Proarrhythmia Assay and drug safety testing.

Paclitaxel injection concentrate for nano-dispersion (PICN) is a Cremophor-free, nanotechnology-driven paclitaxel formulation. This phase I study examined the safety, tolerability, pharmacokinetics and maximum tolerated dose (MTD) of PICN alone and in combination with carboplatin. Its early efficacy in unresectable biliary tract cancers (BTCs) was also evaluated. This multi-center study comprised two parts. Part A contained a dose-escalation cohort following “3 + 3” design using PICN monotherapy in advanced solid tumors (Part A1); Part A2 dose-expansion cohort was then conducted in advanced BTCs due to observed efficacy in Part A1. Part B1 and B2 evaluated escalating dose of PICN with carboplatin in advanced solid tumors. PICN was administered as a 30 min-infusion every 3 weeks without pre-medications for hypersensitivity reactions. Thirty-six patients received PICN monotherapy in Part A and 21 received PICN plus carboplatin in Part B. The MTD of PICN was determined to be 295 mg/m2 both as a monotherapy and in combination with carboplatin at AUC 5. Dose-proportional exposure in paclitaxel Cmax and AUC was observed overdose range from 175 to 325 mg/m2 for PICN monotherapy and its combination with carboplatin. Carboplatin did not alter PICN exposure. Clinically significant toxicities mainly include neutropenia and peripheral neuropathy. PICN monotherapy yielded a response rate of 20% in unresectable BTCs. This study demonstrated the safety and stable pharmacokinetics of PICN as a monotherapy and in combination with carboplatin. Single-agent PICN showed promising antitumor activity in advanced BTCs, warranting further studies to investigate its role in gastrointestinal cancers.

Guidelines vary on antibiotic prophylaxis for onabotulinumtoxinA (Botox) treatment for overactive bladder (OAB). Our primary objective was to determine whether any prophylactic regimen is more effective in preventing urinary tract infection (UTI) after Botox. The secondary objective was to identify prophylactic practice patterns among female pelvic medicine and reconstructive surgery (FPMRS) providers of different training backgrounds as well as general urologists. This was a secondary analysis of a retrospective cohort study on urinary retention after Botox injection in women with and without diabetes mellitus and OAB. Women > 18 years old who underwent Botox injection for OAB between January 2013 and September 2018 were included. Exclusion criteria were history of urinary retention and neuromuscular bladder dysfunction. A total of 565 patients were included. Two hundred eighty (49.6%) were treated by OB-GYN FPMRS, 209 (37.0%) by urology FPMRS and 76 (13.5%) by general urologists. The majority (92.9%) received antibiotic prophylaxis: 44.4% received intravenous (IV) only, 8.9% received oral (PO) only, and 39.7% received combination IV and PO prophylaxis. Urology FPMRS used antibiotic prophylaxis less frequently (p = 0.003). Within 3 months, 171 patients developed UTI (30.4%). There was no difference in post-procedural UTI for any antibiotic regimen compared to no prophylaxis. No route of antibiotic administration was superior at preventing UTI. In this cohort, no route of antibiotic administration was more effective in the prevention of UTI. Antibiotic prophylaxis did not lower the rate of post-procedural UTI compared to no antibiotics.

The coronavirus disease 2019 (COVID-19) can result in a hyperinflammatory state, leading to acute respiratory distress syndrome (ARDS), myocardial injury, and thrombotic complications, among other sequelae. Statins, which are known to have anti-inflammatory and antithrombotic properties, have been studied in the setting of other viral infections, but their benefit has not been assessed in COVID-19. This is a retrospective analysis of patients admitted with COVID-19 from February 1st through May 12th, 2020 with study period ending on June 11th, 2020. Antecedent statin use was assessed using medication information available in the electronic medical record. We constructed a multivariable logistic regression model to predict the propensity of receiving statins, adjusting for baseline sociodemographic and clinical characteristics, and outpatient medications. The primary endpoint includes in-hospital mortality within 30 days. A total of 2626 patients were admitted during the study period, of whom 951 (36.2%) were antecedent statin users. Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use is significantly associated with lower odds of the primary endpoint in the propensity-matched cohort (OR 0.47, 95% CI 0.36–0.62, p, Statins, which have anti-inflammatory and antithrombotic properties, could have effects in COVID-19 patients. Here, the authors find in a retrospective analysis of patients hospitalized with COVID-19 that antecedent statin use is associated with lower inpatient mortality.

ObjectivePain is the principal symptom in knee osteoarthritis (OA). Current non-operative treatment options have only moderate effects and often patients experience persistent pain or side-effects. Novel advances in the field of cryoneurolysis applies low temperatures to disrupt nerve signaling at the painful area, providing pain relief. The primary aim of this randomized controlled trial (RCT) is to investigate if cryoneurolysis is superior to sham at decreasing pain intensity 2 weeks after the intervention in patients with knee OA. Secondary aims are to explore effects on pain, quality of life and functional performance over 24 months.MethodsThis two-arm, parallel-group RCT, approved by the Regional Ethics Committee, will randomly allocate patients (n = 94) to a cryoneurolysis intervention group + standardized education and exercise (CRYO) or a sham group + standardized education and exercise (SHAM) (1:1 ratio). Both groups will be assessed at baseline, 2 weeks post intervention, post education and exercise and at 6, 12 and 24 months after cryoneurolysis. The primary outcome is the NRS knee pain intensity score assessed 2 weeks post the intervention. Secondary outcome measures include functional performance (chair-stand test, 40 m walk, stair test and maximum voluntary contraction of the knee), patient reported outcomes (quality of life (EQ5D), Knee and osteoarthritis outcome scores (KOOS), among others), use of analgesics, and adverse events over 24 months.Impact statementCryoneurolysis could potentially provide an effective, safe and non-pharmacological therapeutic option to treat pain in OA patients. The potential benefits include increased functional capacity and quality of life as a result of significant pain relief and improved benefits of physical exercise.Trial registrationClinicaltrials.gov,NCT03774121, registered 3 March 2018,http://www.clinicaltrials.gov

In order to realize the vision of “smart rail mobility,” a seamless high-data rate wireless connectivity with up to dozens of gigahertz bandwidth will be required. This forms a strong motivation for exploring the underutilized millimeter wave (mmWave) and sub-mmWave bands. In this article, the wireless channel in one “smart rail mobility” scenario—the intrawagon scenario—is characterized through ultrawideband (UWB) channel sounding and ray tracing (RT) at mmWave and sub-mmWave bands. To begin with, a series of horizontal directional scan-sounding measurements are performed inside a real high-speed train wagon at 60 and 300 GHz frequency bands with a bandwidth of 8 GHz. Correspondingly, the channel characteristics such as Rician $K$ -factor, root-mean-square (rms) delay spread (DS), azimuth spread of arrival, and azimuth spread of departure are extracted and analyzed. Based on the measurements, a self-developed RT simulator is validated through the reconstruction of the three-dimensional wagon model and the calibration of the electromagnetic (EM) properties of the main materials. This gives the chance to physically interpret the measurement results and characterize the intrawagon mmWave and sub-mmWave channels more comprehensively through extensive RT simulations.

Background Coinciding with other chronic comorbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote "non-microbial" inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age. Methods Alveolar bone samples were obtained from young (6 months) and old (20 to 22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS). Results Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (IL6), IL17, IGFBP4, and MMP13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of IL1α, IL1β, and IL6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190. Conclusions Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components.

Die AG „Junge DGKJ“ der Deutschen Gesellschaft fur Kinder- und Jugendmedizin (DGKJ) hat 2019 eine Weiterbildungsumfrage mit insgesamt 1694 teilnehmenden Assistenzarzt*innen aus ganz Deutschland durchgefuhrt und anhand der Antworten das vorliegende Positionspapier zu Weiterbildungs- und Arbeitsbedingungen in der Padiatrie erstellt. Es schildert die bestehenden Probleme junger arztlicher Kolleg*innen und versucht Losungsvorschlage aufzuzeigen. Dabei gliedert es sich in 6 verschiedene Themenbereiche: steigende Patientenzahlen bei hohem Okonomisierungsdruck, zunehmende Arbeitsverdichtung wegen Durchfuhrung nichtarztlicher Tatigkeiten, Bedarf an flexiblen Teilzeitmodellen, notwendige Optimierung der Weiterbildung, Herausforderungen, die der hohe Frauenanteil in der Padiatrie mit sich bringt, sowie Problematik der steigenden Zahlen seelisch/psychisch belasteter Arzte. Als Fazit bedarf es der Erarbeitung funktionierender, moderner und den gesellschaftlichen Entwicklungen gerecht werdender Arbeits(zeit)-modelle, die eine langfristige qualitativ hochwertige medizinische Versorgung von Kindern und Jugendlichen in Deutschland durch gesundes medizinisches Personal und unter Berucksichtigung der optimalen Weiterbildung von Assistenzarzt*innen ermoglichen.

aking into account the technological evolution of the last decades and the proliferation of information systems in society, today we see the vast majority of services provided by companies and institutions as digital services. Industry 4.0 is the fourth industrial revolution where technologies and automation are asserting themselves as major changes. Robotic Process Automation (RPA) has numerous advantages in terms of automating organizational and business processes. Allied to these advantages, the complementary use of Artificial Intelligence (AI) algorithms and techniques allows to improve the accuracy and execution of RPA processes in the extraction of information, in the recognition, classification, forecasting and optimization of processes. In this context, this paper aims to present a study of the RPA tools associated with AI that can contribute to the improvement of the organizational processes associated with Industry 4.0. It appears that the RPA tools enhance their functionality with the objectives of AI being extended with the use of Artificial Neural Network algorithms, Text Mining techniques and Natural Language Processing techniques for the extraction of information and consequent process of optimization and of forecasting scenarios in improving the operational and business processes of organizations. 5311-8814-F0ED | Sara Maria da Cruz Maia de Oliveira Paiva N/A

BackgroundFamily-based treatment (FBT) is an efficacious intervention for adolescents with an eating disorder. Evaluated to a lesser degree among adolescents, enhanced cognitive-behavior therapy (CBT-E) has shown promising results. This study compared the relative effectiveness of FBT and CBT-E, and as per manualized CBT-E, the sample was divided into alower weight[higher weightcohort (⩾90%mBMI).MethodParticipants (N= 97) aged 12–18 years, with a DSM-5 eating disorder diagnosis (largely restrictive, excluding Avoidant Restrictive Food Intake Disorder), and their parents, chose between FBT and CBT-E. Assessments were administered at baseline, end-of-treatment (EOT), and follow-up (6 and 12 months). Treatment comprised of 20 sessions over 6 months, except for thelower weightcohort where CBT-E comprised 40 sessions over 9–12 months. Primary outcomes were slope of weight gain and change in Eating Disorder Examination (EDE) Global Score at EOT.ResultsSlope of weight gain at EOT was significantly higher for FBT than for CBT-E (lower weight, est. = 0.597,s.e.= 0.096,p< 0.001;higher weight, est. = 0.495,s.e.= 0.83,p< 0.001), but not at follow-up. There were no differences in the EDE Global Score or most secondary outcome measures at any time-point. Several baseline variables emerged as potential treatment effect moderators at EOT. Choosing between FBT and CBT-E resulted in older and less well participants opting for CBT-E.ConclusionsResults underscore the efficiency of FBT to facilitate weight gain among underweight adolescents. FBT and CBT-E achieved similar outcomes in other domains assessed, making CBT-E a viable treatment for adolescents with an eating disorder.Clinical Trial Registration Information:Treatment Outcome in Eating Disorders;https://clinicaltrials.gov/; NCT03599921.

BACKGROUND: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies. OBJECTIVE: To assess the FVIII treatment history in patients with non-severe hemophilia A. METHODS: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR). RESULTS: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively. CONCLUSION: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:18 issue:12 pages:3203-3210 ispartof: location:England status: published

Purpose: Atezolizumab has shown antitumor activity in patients with ovarian cancer. Dual blockade of programmed death-ligand 1 (PD-L1) and VEGF enhances anticancer immunity and augments antitumor activity in several cancers. The safety and efficacy of atezolizumab plus bevacizumab were evaluated in patients with ovarian cancer. Patients and Methods: In this open-label, multicenter phase Ib study, patients with platinum-resistant ovarian cancer received intravenous atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) once every 3 weeks. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers were also evaluated. Results: Twenty patients received treatment. Treatment-related adverse events occurred in 19 patients (95%); seven (35%) had grade 3/4 events. No grade 5 events occurred. The safety profile of atezolizumab plus bevacizumab was consistent with those of the individual agents. Two patients (10%) discontinued treatment because of pneumonitis and small bowel obstruction. Three patients had partial responses of 11.3–18.9 months' duration; the ORR was 15%. Eight patients (40%) had stable disease, hence the disease control rate was 55%. The median DOR was not reached (95% confidence interval, 11.3–not reached). Median PFS was 4.9 months (range, 1.2–20.2); median OS was 10.2 months (range, 1.2–26.6). No association was seen between treatment response and PD-L1 expression, tumor histology, or number of prior therapies. Conclusions: Atezolizumab plus bevacizumab led to durable responses and/or disease stabilization in some patients with platinum-resistant ovarian cancer; the safety profiles were consistent with those of each agent.

BACKGROUND: Minimum cardiorespiratory fitness (CRF) has been recommended for firefighters due to job requirements. Thus, it is important to identify accurate and readily available methods to assess CRF in this population. Non-exercise CRF estimates (NEx-CRF) have been proposed but this approach requires validation in this population. OBJECTIVE: To evaluate the accuracy of a NEx-CRF, as compared to a field maximum exercise test, among career military firefighters of both genders using a comprehensive agreement analysis. METHODS: We evaluated the accuracy of a NEx-CRF estimate compared to the Cooper 12 min running test among 702 males and 106 female firefighters. RESULTS: Cooper and NEx-CRF tests yielded similar CRF in both genders (differences

Patients with metastatic breast cancer (MBC) refractory to standard of care therapies have a poor prognosis. The purpose of this study was to assess patient characteristics and clinical outcomes for patients with MBC treated on phase I clinical trials. We performed a retrospective review of all patients with MBC who were enrolled in phase I clinical trials at the University of Colorado Cancer Center from January 2012 to June 2018. A total of 208 patients were identified. Patients had a mean age of 57 years and received on average 2.1 (range 0‐10) prior lines of chemotherapy. The majority of patients had hormone receptor‐positive/HER2‐negative breast cancer (58.6%) and 30.3% had triple‐negative breast cancer. The median progression free survival (PFS) was 2.8 months (95% CI, 2.3‐3.9) and median overall survival (OS) was 11.5 months (95% CI, 9.6‐13.2). Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer‐selective trial or cohort (p = 0.016), age >50 years (p = 0.002), and ≤2 prior lines of chemotherapy in the metastatic setting (p = 0.025). Phase I clinical trials remain a valuable option for select patients with MBC and enrollment should be encouraged when available., We performed a retrospective review of all patients with metastatic breast cancer (MBC) who were enrolled in phase I clinical trials at the University of Colorado Cancer Center. Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer‐selective trial or cohort, age >50 years, and ≤2 prior lines of chemotherapy in the metastatic setting. Phase I clinical trials remain a valuable option for selecting patients with MBC and enrollment should be encouraged when available.

Bradycardia in athletes can range from moderate to severe, and the factors that contribute to slow heart rate are complex. Studies investigating the mechanisms associated with this condition are controversial, and may be linked to the form of exercise practiced. A systematic literature review was conducted to discuss bradycardia mechanisms in athletes who practice different forms of sport. The databases consulted were Pubmed (MEDLINE), Clinical Trials, Cochrane, Scopus, Web of Science, SciELO, Sport Discus and PEDro. The search included English language articles published up to January 2019, that evaluated athletes who practiced different forms of sport. One hundred and ninety-three articles were found, ten of which met the inclusion criteria, with 1549 male and female athletes who practiced diverse forms of sport. Resting heart rate and cardiac structure were studied in association with the form of sport practiced, through heart rate variability, electrocardiogram, echocardiogram and pharmacological blockade. The studies suggest that a slow resting heart rate cannot be explained by increased vagal modulation alone, but also includes changes in cardiac structure. According to the studies, different sports seem to produce different cardiac responses, and the bradycardia found in athletes can be explained by non-autonomic and autonomic mechanisms, depending on the type of effort or the form of sport practiced. However, the mechanism underlying the slow heart rate in each form of sport is still unclear. Level of evidence II; Prognostic studies - Investigating the effect of a patient characteristic on the outcome of disease. RESUMO A bradicardia em atletas pode variar de moderada a grave, e os fatores que contribuem para a redução da frequência cardíaca são complexos. Estudos que investigam os mecanismos associados à bradicardia são controversos e, possivelmente, ligados ao tipo de exercício. Realizou-se uma pesquisa bibliográfica sistemática para discutir os mecanismos de bradicardia em atletas de diferentes modalidades esportivas. As bases de dados consultadas foram Pubmed (MEDLINE), Clinical Trials, Cochrane, Scopus, Web of Science, SciELO, Sport Discus e PEDro. Foram incluídos artigos em inglês, que avaliaram atletas de diferentes modalidades esportivas, publicados até janeiro de 2019. Cento e noventa e três artigos foram encontrados e dez preencheram os critérios de inclusão, perfazendo 1.549 homens e mulheres atletas de diversas modalidades esportivas. A frequência cardíaca em repouso e a estrutura cardíaca foram estudadas em associação com a modalidade esportiva, por variabilidade da frequência cardíaca, eletrocardiograma, ecocardiograma e bloqueio farmacológico. Os estudos sugerem que a redução da frequência cardíaca em repouso não é explicada apenas pelo aumento da modulação vagal, mas também por alterações da estrutura cardíaca. De acordo com os estudos, diferentes esportes parecem produzir diferentes respostas cardíacas e a bradicardia encontrada em atletas pode ser explicada por mecanismos não autonômicos e autonômicos. Este achado parece depender do tipo de esforço ou modalidade esportiva praticada. No entanto, o mecanismo envolvido na redução da frequência cardíaca em cada modalidade esportiva ainda não está claro. Nível de evidência II; Estudos prognósticos – Investigação do efeito de característica de um paciente sobre o desfecho da doença. RESUMEN La bradicardia en atletas puede variar de moderada a grave, y los factores que contribuyen para la reducción de la frecuencia cardíaca son complejos. Los estudios que investigan los mecanismos asociados a la bradicardia son controvertidos y, posiblemente, vinculados al tipo de ejercicio. Se realizó una investigación bibliográfica sistemática para discutir los mecanismos de bradicardia en atletas de diferentes modalidades deportivas. Las bases de datos consultadas fueron Pubmed (MEDLINE), Clinical Trials, Cochrane, Scopus, Web of Science, SciELO, Sport Discus y PEDro. Se incluyeron artículos en inglés, que evaluaron a atletas de diferentes modalidades deportivas, publicados hasta enero de 2019. Se encontraron ciento noventa y tres artículos y diez cumplieron con los criterios de inclusión, totalizando 1549 hombres y mujeres atletas de diversas modalidades deportivas. La frecuencia cardíaca en reposo y la estructura cardíaca fueron estudiadas en asociación con la modalidad deportiva, por variabilidad de la frecuencia cardíaca, electrocardiograma, ecocardiograma y bloqueo farmacológico. Los estudios sugieren que la reducción de la frecuencia cardíaca en reposo no es explicada sólo por el aumento de la modulación vagal, sino también por alteraciones de la estructura cardíaca. De acuerdo con los estudios, los diferentes deportes parecen producir diferentes respuestas cardíacas y la bradicardia encontrada en atletas puede explicarse por mecanismos no autonómicos y autonómicos. Este hallazgo parece depender del tipo de esfuerzo o modalidad deportiva practicada. Sin embargo, el mecanismo involucrado en la reducción de la frecuencia cardíaca en cada modalidad deportiva aún no está claro. Nivel de evidencia II; Estudios pronósticos - investigación del efecto de característica de un paciente sobre el desenlace de la enfermedad.

The COVID-19 pandemic is disrupting the routine daily life of millions of people. The pandemic associated restrictive measures impose unprecedented challenges, including the need to stay physically active in a social distancing scenario that drastically reduces access to physical activity (PA) spaces and opportunities. Therefore, we aimed to discuss the need for an urgent change in the main focus of PA recommendations. The total of PA needed for health promotion has been focused on the minimum of 150min/moderate-to-vigorous PA/week. It is time for a call for action toward shifting the focus of PA recommendations. Instead of the traditional “doing at least 150min/week of PA, and less than that if you can’t reach that goal”, recommendations should emphasize the idea of “move more, sit less and, if possible, accumulate 150min/PA/week. The coronavirus pandemic, its associated social distancing and impacts on PA opportunities, impose an urgent change in PA recommendation main focus.

Christina is 35 years old and has been living with metastatic colorectal cancer for the last several years. She is bright, vivacious, and has an edgy honesty about her. Our team first met Christina...

Background Clubfoot deformity (pes equinovarus) is one of the most common birth defects, and its etiology is still unknown. Initial clubfoot treatment is based on the Ponseti method throughout most of the world. Despite the effectiveness of this therapy, clubfoot may relapse. Recent studies confirm the theory of active fibrotic remodeling processes in the extracellular matrix of the affected tissue. The aim of this study was to clarify whether relapses in clubfoot therapy are associated with altered angiogenesis and to suggest possible regulatory pathways of this pathologic process. Methods We compared microvessel density, arteriole density, and concentration of angioproliferative-related proteins found between tissues in the contracted, that is, the medial side (M-side), and noncontracted, that is, the lateral side (L-side) of the relapsed clubfeet. Tissue samples from 10 patients were analyzed. Histopathologic analysis consisted of immunohistochemistry and image analysis. Real-time polymerase chain reaction was used to study mRNA expression. Results An increase in microvessel and arteriole density was noted in contracted, relapsed clubfoot tissue. This was accompanied by a significant increase in the levels of the vascular endothelial growth factor, vascular endothelial growth factor receptor 2, β catenin and active β catenin. Vascular endothelial growth factor, vascular endothelial growth factor receptor 2, and CD31 overexpression was also seen with mRNA analysis. Conclusions Increased microvessel and arteriole density in the contracted side of the relapsed clubfoot was noted. These processes are mediated by specific proangiogenic proteins that are overexpressed in the contracted tissue. These findings contribute to the etiology and the development of relapses in the treatment of clubfoot. Level of evidence Level II-analytical and prospective.

Delayed haemolytic transfusion reaction (DHTR) is a potentially life-threatening complication of red blood cell (RBC) transfusions in sickle cell disease (SCD) and is classically induced by reactivation of previously formed antibodies. Improved antigenic matching has reduced alloimmunization and may reduce DHTR risk. We conducted a retrospective cohort study to investigate the incidence rate of DHTR in SCD patients receiving extended matched units (ABO/RhDCcEe/K/Fya /Jkb /S). Occasional transfusion episodes (OTE) between 2011 and 2020 were reviewed for occurrence of DHTR symptoms using four screening criteria: decreased Hb, increased lactate dehydrogenase (LDH), pain, and dark urine. We included 205 patients who received a cumulative number of 580 transfusion episodes of 1866 RBC units. During follow-up, 10 DHTR events were observed. The incidence rate of DHTR was 13·8/1000 OTEs [95% confidence interval (CI): 7·37-22·2], with a cumulative incidence of 15·2% (95% CI: 8·4-24·0%) after 25 patients having received RBC units. One DHTR event was fatal (10%). Symptoms were misdiagnosed in four DHTR events (40%) as other acute SCD complications. Despite a lower incidence rate compared to most other studies, the incidence rate of DHTR in SCD remains high, in spite of extended matching of donor RBCs. Increased awareness of DHTR is of utmost importance to facilitate early diagnosis and, consequently, improve outcome.

Objectives Sleep disturbances are increasingly recognized as a major part of chronic pain pathology. Obstructive sleep apnea (OSA) is a common occurrence in patients with chronic pain attending specialized pain clinics, yet its prevalence remains unclear. Using screening tools such as the Berlin and STOP-BANG questionnaires may aid in early identification of OSA and improve clinical care. This study i) examined the frequency of OSA based on objective sleep monitoring in patients with high-impact chronic pain, ii) explored potential differences in self-reported pain and sleep characteristics between patients with and without OSA, and iii) tested the agreement between OSA classification based on objective assessment and two OSA screening questionnaires. Methods A consecutive cohort of 90 patients (71 women and 19 men; mean age: 47.1 ± 11.0 years) referred for interdisciplinary pain treatment, underwent one night of sleep monitoring using portable respiratory polygraphy (RP), and suspected OSA was confirmed with polysomnography (PSG). Self-reported data on clinical pain (severity, pain drawings and health-related quality of life), sleep characteristics (sleep quality insomnia, sleepiness), and risk of OSA (Berlin and STOP-BANG questionnaires) were collected the day before RP assessment. Results Forty-six (51.1%) patients were classified with OSA according to RP and verified with PSG. Twenty-eight patients (31.1%) had moderate or severe OSA (apnea-hypopnea index [AHI] >15). Patients with OSA reported lower sleep quality compared with patients without OSA. Scores on pain severity, disability, quality of life, insomnia and sleepiness were comparable between patients with and without OSA. Sensitivity and specificity were 78.6 and 45.2% respectively for the Berlin questionnaire, and 71.4 and 58.1% respectively for the STOP-BANG questionnaire. The agreement for both questionnaires with objective assessment was poor-to-fair. Both questionnaires had acceptable negative predictive values but low positive predictive values reducing the clinical utility to identify patients with low OSA-risk in this sample. Conclusions The current study demonstrates a high prevalence of OSA in patients with high-impact chronic pain referred to specialized pain treatment, however the clinical pain profiles were similar in patients with and without OSA. The Berlin and STOP-BANG questionnaires have poor specificity and low-to-fair agreement with RP/PSG questioning their clinical utility in identifying OSA in this sample.

Objectives With the International Classification of Diseases 11th revision (classifying fibromyalgia as a primary pain disorder) soon to be implemented, the importance of pain physicians being able to identify patients with fibromyalgia is emphasized. The diagnostic criteria proposed in 2016 are based on self-reported pain distribution and symptom severity. The study aimed to evaluate the diagnostic accuracy of the 2016 diagnostic criteria for fibromyalgia applied in a population of patients with high impact chronic pain referred for pain rehabilitation. Methods The study was performed as a diagnostic accuracy study at two Danish interdisciplinary pain rehabilitation centers, including 215 participants. All participants were evaluated clinically to identify patients with fibromyalgia. The diagnosis was based on expert opinion, but the minimum requirements were: (1) pain in all four body quadrants and axially for at least three months and (2) minimum 8 of 18 positive tender points. Participants filled in the fibromyalgia survey questionnaire, the patient version of the 2016 diagnostic criteria. Sensitivity, specificity, likelihood ratios, and positive and negative post-test probabilities were calculated using a clinical diagnosis of fibromyalgia as the reference standard. Results Based on clinical diagnosis 45% of the participants were diagnosed with fibromyalgia; of these, only 19% had been diagnosed previously. The 2016 diagnostic criteria demonstrated a sensitivity of 88.5%, a specificity of 81.5%, a positive likelihood ratio of 4.79, a negative likelihood ratio of 0.14, a positive post-test probability of 79.4%, and a negative post-test probability of 10.2%. Conclusions Fibromyalgia was severely under-diagnosed among patients with high impact chronic pain referred to tertiary care in two pain rehabilitation centers in Denmark. The 2016 diagnostic criteria showed sufficient discriminatory properties suggesting that the fibromyalgia survey questionnaire can be used as a screening tool assisting the identification of fibromyalgia in this patient population.

OBJECTIVES: Delirium is a common and frequently underdiagnosed complication in acutely hospitalized patients, and its severity is associated with worse clinical outcomes. We propose a physiologically based method to quantify delirium severity as a tool that can help close this diagnostic gap: the Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S). DESIGN: Retrospective cohort study. SETTING: Single-center tertiary academic medical center. PATIENTS: Three-hundred seventy-three adult patients undergoing electroencephalography to evaluate altered mental status between August 2015 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed the E-CAM-S based on a learning-to-rank machine learning model of forehead electroencephalography signals. Clinical delirium severity was assessed using the Confusion Assessment Method Severity (CAM-S). We compared associations of E-CAM-S and CAM-S with hospital length of stay and inhospital mortality. E-CAM-S correlated with clinical CAM-S (R = 0.67; p < 0.0001). For the overall cohort, E-CAM-S and CAM-S were similar in their strength of association with hospital length of stay (correlation = 0.31 vs 0.41, respectively; p = 0.082) and inhospital mortality (area under the curve = 0.77 vs 0.81; p = 0.310). Even when restricted to noncomatose patients, E-CAM-S remained statistically similar to CAM-S in its association with length of stay (correlation = 0.37 vs 0.42, respectively; p = 0.188) and inhospital mortality (area under the curve = 0.83 vs 0.74; p = 0.112). In addition to previously appreciated spectral features, the machine learning framework identified variability in multiple measures over time as important features in electroencephalography-based prediction of delirium severity. CONCLUSIONS: The E-CAM-S is an automated, physiologic measure of delirium severity that predicts clinical outcomes with a level of performance comparable to conventional interview-based clinical assessment.

Background: The reimbursement of new technologies in inpatient care is not always linked to a requirement for evidence-based evaluation of patient benefit. In Germany, every new technology approved for market was until recently reimbursable unless explicitly excluded. It was therefore unclear whether the implementation of innovative technologies is guided by scientific evidence. This work aimed to explore the relationship between clinical evidence and utilization for 25 selected technologies in German inpatient care.Methods: Different methods were applied. A systematic search for evidence published between 2003 and 2017 was conducted in four bibliographic databases; clinical trial registries; resources for clinical guidelines; and health technology assessment - databases. Information was also collected on funding mechanisms and safety notices. Utilization was measured by hospital cases captured in claims data. The body of evidence, funding and safety notices per technology were analysed descriptively. The relationship between utilization and evidence was explored empirically using a multilevel regression analysis.Results: The number of included publications per technology ranges from two to 498. For all technologies, non-comparative studies form the bulk of the evidence. The number of randomised controlled clinical trials per technology ranges from zero to 19. Some technologies were utilized for several years without an adequate evidence base. A relationship between evidence and utilization could be shown for several but not all technologies.Conclusions: This study reveals a mixed picture regarding the evidence available for new technologies, and the relationship between the development of evidence and the use of technologies over time. Although the influence of funding and safety notices requires further investigation, these results re-emphasize the need for strengthening market approval standards and HTA pathways as well as approaches such as “coverage with evidence development”.

in press

Ocean towing in general, and non-routine tows in particular, present unique technical challenges to towing vessel owners/operators, salvors, the offshore oil/gas and wind industries, and others. When such tows “go wrong”, the harm to human life, property and/or the environment can be significant. The authors have drawn from their work on the Towing Safety Advisory Committee’s investigation of the grounding of the MODU Kulluk to present methods and considerations in analyzing ocean towing evolutions, both “routine” and “non-routine”. (TASK 14-01) The methods and considerations presented should be employed in advance of a towing evolution, but can be used in accident reconstruction and forensic analysis when an evolution has failed. The methods presented are iterative, and consider 2 x 6 degree freedom of motion (of the towing vessel(s) and towed vessel respectively) and characteristics of the towline, and facilitate determination of: Worst Case Conditions. Extreme Towline Tension (ETT) as a function of sea state and speed. Limits of the Tow (Go-No Go Criteria). Recommended Catenary Length as a function of sea state and speed. Size and Selection of the Towing Vessel and Gear, including: Required Bollard Pull. Required Strength, Characteristics and Condition of the Towline. Limits and Set Points of the Towing Winch, Automatic or Manual. Required Strength and Characteristics of the Synthetic Emergency Towline and its methods of deployment and connection. Working Load Limit (WLL) of the Shackles, Delta Plate and Attachment Points. Required Strength and Characteristics of Bridles, Pendant and Surge Gear/Shock Lines. The authors further explore the implications of single point failure modes, redundancy in gear and towing vessel(s), high cycle fatigue, and strain monitoring.

Coffee is one of the most widely consumed beverages worldwide and caffeine is known to improve performance in physical exercise. Some substances in coffee have a positive effect on glucose metabolism and are promising for post-exercise muscle glycogen recovery. We investigated the effect of a coffee beverage after exhaustive exercise on muscle glycogen resynthesis, glycogen synthase activity and glycemic and insulinemic response in a double-blind, crossover, randomized clinical trial. Fourteen endurance-trained men performed an exhaustive cycle ergometer exercise to deplete muscle glycogen. The following morning, participants completed a second cycling protocol followed by a 4-h recovery, during which they received either test beverage (coffee + milk) or control (milk) and a breakfast meal, with a simple randomization. Blood samples and muscle biopsies were collected at the beginning and by the end of recovery. Eleven participants were included in data analysis (age: 39.0 ± 6.0 years, BMI: 24.0 ± 2.3 kg/m2, VO2max: 59.9 ± 8.3 mL·kg−1·min−1, PPO: 346 ± 39 W). The consumption of coffee + milk resulted in greater muscle glycogen recovery (102.56 ± 18.75 vs. 40.54 ± 18.74 mmol·kg dw−1, p = 0.01, d = 0.94) and greater glucose (p = 0.02, d = 0.83) and insulin (p = 0.03, d = 0.76) total area under the curve compared with control. The addition of coffee to a beverage with adequate amounts of carbohydrates increased muscle glycogen resynthesis and the glycemic and insulinemic response during the 4-h recovery after exhaustive cycling exercise.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype defined by lack of hormone receptor expression and non-amplified HER2. TNBC accounts for approximately 15% of breast cancer cases, however, is associated with an increased risk of cancer recurrence, brain metastasis, and death due to metastatic breast cancer. Mutations in p53 are common in TNBC, occurring in approximately 85% of tumors. While a number of promising targeted therapies are on the horizon in TNBC including immunotherapy, there remains an unmet need for active targeted therapies where chemotherapy remains the standard treatment for metastatic disease and results in a median survival of 12-18 months. Adavosertib (AZD1775) is a potent, small molecule, ATP-competitive inhibitor of the Wee1 kinase that potentiates the activity of many DNA-damaging chemotherapeutics and is currently in clinical development for multiple indications. AZD1775 potentiates the activity of DNA-damaging and antimetabolite chemotherapeutics in preclinical models without TP53-deficiency, possibly due to baseline replicative stress or compromised DNA repair proficiency. A previous unbiased screen of CTEP compounds in TNBC PDX models demonstrated that the combination of adavosertib and capecitabine/5FU had greater anti-proliferative effects than either of the single agents. The purpose of this study was to further investigate the combination of adavosertib and capecitabine/5FU in preclinical TNBC models. Methods: HCC1937, CAL51, MDA-MB-231 and MDA-MB-468 cells were plated in 96-well plates and exposed to increasing concentrations of adavosertib, 5FU, or the combination. Cellular proliferation was assessed in real-time using IncuCyte® Live Cell Analysis. Apoptosis was assessed via the Caspase-Glo 3/7 assay system. Western blotting was used to assess changes in expression of CDC2, phospho-CDC2, H2AX, and Bcl-xL. TNBC PDX models CU_TNBC_012 and CU_TNBC_013 were treated with vehicle, adavosertib, capecitabine, or the combination and assessed for tumor growth inhibition. Results: From the initial PDX screen, two of the four TNBC PDX models demonstrated a better response in the combination treatment than either of the single agents. As confirmation, two PDX models were expanded for statistical comparison. Both PDX models demonstrated a significant growth inhibition in the combination versus either of the single agents. (TNBC012, p Citation Format: Todd M Pitts, Dennis M Simmons, Kyrie Dailey, Stacey M Bagby, Sarah J Hartman, Betelehem W Yacob, Brian Gittleman, John J Tentler, Diana Cittely, D. Ryan Ormond, Wells A Messersmith, S Gail Eckhardt, Jennifer R Diamond. Wee1 inhibition enhances the anti-tumor effects of capecitabine in preclinical models of triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-25.

BackgroundAdvanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging.MethodsWe describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine.ResultsSerum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P ConclusionsThese mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.

Immunotherapy is a rapidly evolving treatment paradigm that holds promise to provide long-lasting survival benefits for patients with cancer. This promise, however, remains unfulfilled for the majority of patients with gastrointestinal (GI) cancers, as significant limitations in efficacy exist with immune checkpoint inhibitors (ICIs) in this disease group. A plethora of novel combination treatment strategies are currently being investigated in various clinical trials to make them more efficacious as our understanding of molecular mechanisms mediating resistance to immunotherapy advances. In this article, we summarize the current status of immune checkpoint blockade in GI cancers and discuss the biological rationales that underlie the emerging treatment strategies being tested in ongoing clinical trials in combination with ICIs. We also highlight the promising early results from these strategies and provide future perspectives on enhancing response to immunotherapy for patients with GI cancers.

Autotransplantation is a treatment option with high reported survival rates to replace failing teeth in the anterior maxilla. This treatment requires a multidisciplinary approach from orthodontists, paediatric dentists, restorative dentists, and oral and maxillofacial surgeons to achieve successful outcomes. Success is dependent on many factors including stage of root development, handling of the periodontal ligament, extra-alveolar time and splinting. This case report presents the novel use of digitally designed and three-dimensional (3D) printed surgical templates to aid intraoperatively and reduce the extra-alveolar time. A preoperative cone-beam computed tomography scan allowed digital planning and construction of surgical templates that replicated the exact root dimensions of impacted maxillary canines. These templates were subsequently 3D printed in resin, sterilised and utilised intraoperatively to aid socket preparation before the surgical autotransplantation.