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Purpose Hematopoietic stem cell transplant (HSCT) is an intensive treatment associated with distressing treatment and disease-related symptoms that affect patient outcomes such as functional status and quality of life. Self-efficacy for symptom management (SESM) is a person's belief in their ability to perform behaviors to prevent and relieve symptoms. Presence of SESM can impact symptom distress and functional status. This study describes the changes over time and relationships among SESM, symptom distress, and physical functional status in adults during the acute phase of HSCT. Methods Patients (n = 40) completed measures of symptom distress, SESM, and physical function at time points prior to and at days 7, 15 and 30 post-transplant. Clinical outcomes were length of stay and number of readmissions. Results Symptom distress, physical function, and SESM changed significantly over time. There was a significant negative relationship between symptom distress and physical function and between symptom distress and SESM at all points. The lowest levels of SESM and physical function were at day 7 when symptom distress was highest. Symptom distress was a moderator for the relationship between physical function and SESM at day 15. Conclusion This was the first study to examine SESM in the acute phase of HSCT. Higher SESM was associated with fewer symptoms and increased physical function. Less symptom distress was associated with higher physical function and confidence to manage symptoms. These findings provide the basis for development of patient-centered interventions to enhance SESM when symptoms are at their highest immediately after HSCT.

Management strategy evaluation (MSE) is a simulation-based approach to examine the efficacy of management options in achieving fishery-, ecosystem-, and socioeconomic-related objectives while integrating over system uncertainties. As a form of structured decision analysis, MSE is amenable to stakeholder involvement, which can reduce implementation barriers associated with nontransparent decision-making procedures. Based on analysis of three MSE processes (Atlantic tunas (Thunnus spp.), Atlantic herring (Clupea harengus), and eastern oysters (Crassostrea virginica)), we provide suggestions for improving stakeholder engagement in MSE. By assembling a workgroup and modeling team with diverse backgrounds, including professional facilitators, communication liaisons, and social scientists, dialogue can be improved and an atmosphere of mutual learning fostered. Communication further benefits from clearly defining roles, responsibilities, and terms of engagement for all involved; explicitly and transparently identifying goals and objectives of the MSE before modeling has begun; and, when appropriate, revisiting goals and objectives throughout the MSE process. Although MSEs are not without limitations, the participatory modeling framework, wherein stakeholders are actively engaged at each stage of MSE development, provides a useful mechanism to support fisheries management.

Management strategy evaluation (MSE) is an increasingly popular tool for developing, testing, and implementing fisheries management regimes, oftentimes utilizing participatory modeling. This special issue, “Under pressure: addressing fisheries challenges with Management Strategy Evaluation”, includes eleven articles highlighting cutting edge MSE approaches and perspectives on improving stakeholder engagement. The special issue is the culmination of a two-session MSE symposium held during the 147th American Fisheries Society Annual Meeting in Tampa, Florida. We summarize the themes from the symposium and special issue articles. Contributions demonstrated that important strides have been made in quantifying and exploring risk (by including more sophisticated multispecies and socioeconomic components), developing and testing data-limited harvest control rules, acknowledging and diagnosing limitations of MSE (e.g., identifying exceptional circumstances), and dealing with issues of stakeholder engagement and dimensionality (e.g., determining appropriate representation, communication techniques, and participation levels). Although MSE is a not a panacea for marine policy and resource utilization issues, it is a useful tool for implementing co-management regimes that should become increasingly robust as the multidisciplinary nature of MSE processes continues to expand.

Zusammenfassung Notfallmedikamente kommen an nahezu allen Orten dieser Erde zum Einsatz. Damit werden sie unterschiedlichsten Umweltbedingungen (Kälte, Hitze, direkte Sonneneinstrahlung) ausgesetzt. Sämtliche Daten zur Pharmakokinetik, Pharmakodynamik, Medikamentensicherheit und -haltbarkeit werden jedoch unter standardisierten Bedingungen erhoben, die sich von den Anwendungsbedingungen in der Notfallmedizin erheblich unterscheiden können. Durch die Kälte bei Wintereinsätzen im Gebirge können ebenso wie bei Einsätzen in großer Hitze und bei direkter Sonnenexposition chemische Reaktionen entstehen, welche die Eigenschaften der Medikamente bis hin zur kompletten Wirkungslosigkeit verändern können. Zusätzlich können Unterkühlung oder Überhitzung des Patienten zu einer Zentralisation bzw. Vasodilatation führen und damit das pharmakologische Verteilungsvolumen erheblich verändern, woraus Unter- bzw. Überdosierungen resultieren können. Gleichzeitig kann durch einen temperaturbedingt veränderten Metabolismus die Konjugation und Elimination von Medikamenten beeinflusst sein und zu einer unvorhersehbaren Verlängerung der Medikamentenwirkung führen. Trotz der erheblichen klinischen Relevanz dieser Thematik existieren bisher kaum Daten zu den konkreten Effekten extremer Umweltbedingungen auf die pharmakologischen Eigenschaften von Notfallmedikamenten. Diese Übersicht soll dazu dienen, den aktuellen Kenntnisstand der notfallmedizinischen Pharmakotherapie unter Extrembedingungen darzustellen.

Herein we report the synthesis of new N-4-piperazinyl thiadiazole and oxadiazole ciprofloxacin derivatives and their antibacterial and antimycobacterial activities. Although thiadiazole ciprofloxacin derivatives compound showed broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative organisms, the oxadiazole derivatives exhibited weaker antibacterial and antimycobacterial activities than thiadiazole derivatives against most of the tested strains compared with the reference ciprofloxacin. Moreover, the antimycobacterial screening revealed that compounds which containing thiadiazole scaffold potently inhibited Mycobacterium smegmatis at MIC of 1.56 and 3.13, respectively, and modestly inhibited the drug-resistant strains. DNA cleavage assay revealed that thiadiazole ciprofloxacin derivatives inhibited supercoil relaxation, albeit to a lesser extent than ciprofloxacin, and it also increased the amount of nicked substrate produced.

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABAB receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.

Reference points identify benchmarks, thresholds, or decision points for fisheries management, and are commonly defined by stock status indicators that presume equilibrium population conditions in the absence of fishing (e.g., equilibrium biomass, B0). However, equilibrium population biomass may be an inappropriate reference level when stock productivity is influenced by environmental change, predator-prey dynamics, ecosystem thresholds, and myriad other factors. Simulations were conducted to compare equilibrium-based (static B0) and non-equilibrium based (dynamic B0) indicators of stock status under alternative states of nature driven by time-varying recruitment dynamics (productivity regime), fishing dynamics (mortality regime), and species life history. Using dynamic B0 often implied a different state of the stock under directional productivity regime shifts, but was more similar to static B0 reference points under cyclic or white noise productivity scenarios. Uncertainty in stock status arising from incorrectly identifying changes in system productivity generally outweighed the uncertainty associated with initial equilibrium conditions. Empirical results across 18 U.S. West Coast groundfish stock assessments indicated predominantly small differences (

Complement plays important roles in both ischemia-reperfusion injury (IRI) and antibody-mediated rejection (AMR) of solid organ allografts. One approach to possibly improve outcomes after transplantation is the use of C1 inhibitor (C1-INH), which blocks the first step in both the classical and lectin pathways of complement activation and also inhibits the contact, coagulation, and kinin systems. C1-INH can also directly block leukocyte-endothelial cell adhesion. C1-INH contrasts with eculizumab and other distal inhibitors, which do not affect C4b or C3b deposition or noncomplement pathways. Authors of reports on trials in kidney transplant recipients have suggested that C1-INH treatment may reduce IRI and delayed graft function, based on decreased requirements for dialysis in the first month after transplantation. This effect was particularly marked with grafts with Kidney Disease Profile Index ≥ 85. Other clinical studies and models suggest that C1-INH may decrease sensitization and donor-specific antibody production and might improve outcomes in AMR, including in patients who are refractory to other modalities. However, the studies have been small and often only single-center. This article reviews clinical data and ongoing trials with C1-INH in transplant recipients, compares the results with those of other complement inhibitors, and summarizes potentially productive directions for future research.

Objective Neuroimaging studies of hematologic cancer patients report altered activity in dorsal attention and central executive networks. To determine the consequences of these altered brain networks, we evaluated neurophysiological correlates of attention and working memory in hematologic cancer patients prior to initiating treatment. Methods Hematologic cancer patients (19–80 years) were excluded for premorbid cognitive impairment, prior non-hematologic cancer diagnosis, and prior chemotherapy. Attention was manipulated by presenting an irrelevant spatial cue prior to visual search displays. Working memory was manipulated by presenting irrelevant distractors within memory displays. Electroencephalogram was recorded during task performance. Results Patients (n = 28) and controls (n = 15) were balanced on age, gender, and education. Spatial cues evoked larger N2pc amplitudes, a correlate of spatial attention, in patients than controls (p 0.7). Memory distractors evoked larger contralateral delay activity amplitudes, a correlate of working memory load, in patients (p = .028; Cohen’s d = 1.1) but not controls (p = .64). Conclusions Prior to initiating treatment, hematologic cancer patients demonstrated poor control over spatial attention and working memory, consistent with altered dorsal attention and central executive network activity. Significance Hematologic cancer patients may be at a higher risk for selecting, processing, and storing distracting information that would compete with more immediate goal-related behaviors.

BackgroundWith an ageing population, the demand for joint arthroplasties and the burden of postoperative delirium is likely to increase. Given the lack of large-scale data, we investigated associations between perioperative risk factors and postoperative delirium in arthroplasty surgery.MethodsThis retrospective population-based cohort study, utilized national claims data from the all-payer Premier Healthcare database containing detailed billing information from >25% nationwide hospitalizations. Patients undergoing elective total hip/knee arthroplasty surgery (2006–2016) were included.The primary outcome was postoperative delirium, while potential risk factors included age, gender, race, insurance type, and modifiable exposures including anesthesia type, opioid prescription dose (low/medium/high), benzodiazepines, meperidine, non-benzodiazepine hypnotics, ketamine, corticosteroids, and gabapentinoids.ResultsAmong 1 694 795 patients’ postoperative delirium was seen in 2.6% (14 785/564 226) of hip and 2.9% (32 384/1 130 569) of knee arthroplasties. Multivariable models revealed that the utilization of long acting (OR 2.10 CI 1.82 to 2.42), combined long/short acting benzodiazepines (OR 1.74 CI 1.56 to 1.94), and gabapentinoids (OR 1.26 CI 1.16 to 1.36) was associated with increased odds of postoperative delirium. Lower odds of postoperative delirium were seen for neuraxial versus general anesthesia (OR 0.81 CI 0.70 to 0.93) and with the utilization of non-steroidal anti-inflammatory drugs (OR 0.85 CI 0.79 to 0.91) as well as cyclooxygenase-2 inhibitors (OR 0.82 CI 0.77 to 0.89). Age-stratified analysis revealed lower odds with high versus low opioid dose (OR 0.86 CI 0.76 to 0.98) in patients >65 years. Findings were consistent between hip and knee arthroplasties.ConclusionsIn this large national cohort, we identified various modifiable risk factors (including anesthesia type and pharmaceutical agents) for postoperative delirium, demonstrating possible prevention pathways.

Згідно з новими стандартними операційними процедурами ESPEN були оновлені попередні рекомендації щодо забезпечення найкращого медичного нутритивного забезпечення для критично хворих пацієнтів. Дані рекомендації визначають, хто є пацієнтами в групі ризику, як оцінити нутритивний статус пацієнта ВІТ, як визначити кількість енергії, яку необхідно забезпечити, який обрати шлях для нутритивного забезпечення та як адаптувати пацієнта у відповідності до різних клінічних умов. Також описано, коли слід розпочати і як просуватися в управлінні процесом адекватного забезпечення поживними речовинами. Запропоновано найкраще визначення кількості та походження вуглеводів, жирів і білків. Особлива увага приділяється глутаміну і омега-3 жирним кислотам. Обговорюються конкретні стани, що часто спостерігаються в інтенсивній терапії, такі як пацієнти з дисфагією, виснажені пацієнти, пацієнти з множинними травмами, абдомінальна хірургія, сепсис і ожиріння, з метою ознайомлення практикуючого лікаря з найкращою доказовою терапією. Моніторинг цієї нутритивної терапії обговорюється в окремому документі.

New nitric oxide (NO) donating fluoroquinolones/nitrate ester hybrids were prepared and their structures were characterized by various spectroscopic and analytical tools. The release of NO from the prepared nitrate esters was measured using the modified Griess colorimetric method. Evaluation of antitubercular activity showed that most of tested compounds exhibited comparable or higher activity than the parent fluoroquinolones. Compounds 2b, 3a, 4a, 5a, and 2d showed better activity than ciprofloxacin. Nevertheless, none of the new compounds were superior to the parent fluoroquinolones in terms of DNA cleavage stimulation in mycobacteria. The additional growth inhibition effect that is distinct from gyrase poisoning may be due to release of NO or enhancement of lipophilicity. These data are augmented by docking results where the docked compounds did not exert additional significant bindings over the parent fluoroquinolones.

Little research exists on the contributions that noncustodial fathers make to children they have had in different families. We use baseline survey data from an intervention for noncustodial...

After several centuries of cultural continuity, the Late Woodland transition (AD 600-1000) in the Southeastern Woodlands involved a significant intensification of existing lifeways. This study examines the biocultural consequences of the Late Woodland transition at Forbush Creek (AD 800-1200), a Yadkin River Valley site from the Piedmont region of North Carolina. Twelve percent of individuals recovered from the site sustained violence-related trauma, including five individuals with healed blunt force trauma, two individuals with perimortem cranial trauma, and a single projectile point injury. Secondary burial individuals exhibited significantly more trauma (n = 10, 42%) and nutrient deficiencies (n = 12, 50%) than primary burial individuals (n = 1, 4%; and n = 5, 19%, respectively). The Forbush Creek remains provide new evidence of the biological impacts of cultural transitions and suggest that uncertainty, scarcity, and conflict arising from changing lifeways contributed to inequality in the Forbush Creek community. Secondary bundle burial inclusion may represent marginalization and an increased vulnerability to morbidity and mortality risks. The emergence of social inequality in the Late Woodland period likely shaped long-term cultural dynamics that preceded the complex sociopolitical hierarchies of the later Mississippian period.

Based on writing produced by second language learners at different proficiency levels (CEFR A1 to C1), we adopted a usage-based approach (Ellis, Römer, & O’Donnell, 2016; Tyler & Ortega, 2018) to investigate how German and Spanish learner knowledge of 19 English verb-argument constructions (VACs; e.g., “Vwithn,” illustrated byhe always agrees with her) develops. We extracted VACs from subsets of the Education First-Cambridge Open Language Database, altogether comprising more than 68,000 texts and 6 million words. For each VAC, L1 learner group, and proficiency level, we determined type and token frequencies, as well as the most dominant verb-VAC associations. To study effects of proficiency and L1 on VAC production, we carried out correlation analyses to compare verb-VAC associations of learners at different levels and different L1 backgrounds. We also correlated each learner dataset with comparable data from a large reference corpus of native English usage. Results indicate that with increasing proficiency, learners expand their VAC repertoire and productivity, and verb-VAC associations move closer to native usage.

There is a dearth of research on racially and ethnically diverse bisexual women. Samples routinely over-represent White women, and studies often combine women of Color into a single analytic catego...

Throughout the cancer continuum, patients are faced with the cancer- and treatment-related side effects that can have a negative impact on their overall quality of life. Cancer-related fatigue (CRF) and sleep deficiency are among the symptoms that patients and their caregivers most often experience. An increasing body of literature suggests that a strong correlation between CRF and sleep deficiency exists, indicating that they may be reciprocally related and that they may have similar underlying etiology. This paper aims at bringing together the opinions of leading cancer control (i.e., CRF and sleep) and oncology experts in order to increase the understanding of CRF and sleep deficiency's assessment, associated symptom clustering, symptom burden shared by caregivers, and CRF and sleep deficiency management in the cancer care context.

Background and objectivesThe significance of intravenous over oral acetaminophen (APAP) as part of multimodal analgesic protocols is contested, particularly when considering its relatively high price and use in a surgical cohort such as total hip or knee arthroplasty (THA/TKA), which generally tolerates oral medications. This study aims to elucidate APAP’s effectiveness in a large, population-based patient sample.Methods1 039 647 THA/TKA procedures were sampled from the Premier Healthcare claims database 2011–2016. APAP use was categorized by intravenous/oral and use on the day of surgery, postoperative day 1 and thereafter. Outcomes were opioid utilization (in oral morphine equivalents), length and cost of hospitalization, and opioid-related adverse effects (respiratory, gastrointestinal, and naloxone use as a proxy). Mixed-effects models measured the associations between intravenous/oral APAP use and outcomes. Percent (%) change and 95% CIs are reported.ResultsOverall, 23.6% (n=245 454) of patients received intravenous APAP; of these, 56.3% (n=138 180) received just one dose on the day of surgery. After adjustment for relevant covariates, particularly use of >1 dose of intravenous APAP (compared with no use) on postoperative day 1 was associated with −6.0% (CI −7.2% to −4.7%) reduced opioid utilization; this was −10.7% (CI −11.4% to -9.9%) for use of > 1 dose oral APAP on postoperative day 1. Further comparisons regarding other outcomes also favored oral (over intravenous) APAP.ConclusionsThese results do not support the routine use of intravenous APAP in patients undergoing lower joint arthroplasty, especially since oral APAP shows more beneficial outcome patterns.

Die chirurgische Therapie analer und rektaler Fistelrezidive mit starren rigiden Narbenhohlen und Exkavationen, entsprechend der Typen 1–4 b und c nach Parks, ist schwierig. Die Idee des korpereigenen perfundierten Gewebes zur Defektfullung ist eine haufig genutzte Therapieoption bei verschiedenen Entitaten und wurde auf die Anwendbarkeit bei der obigen Indikation uberpruft. Geeignet ist der M. gracilis auf Grund seiner raumlichen Verfugbarkeit, und es wird kein funktionelles Defizit hinterlassen. Unter Stomaschutz kann mit einer hohen Erfolgswahrscheinlichkeit ein kompliziertes Analfistelrezidiv versorgt werden.

The bacterial hexameric helicase known as Rho is an archetypal sequence-specific transcription terminator that typically halts the synthesis of a defined set of transcripts, particularly those bearing cytosine-rich 3’ untranslated regions. However, under conditions of translational stress, Rho can also terminate transcription at cytosine-poor sites when assisted by the transcription factor NusG. Recent structural, biochemical, and computational studies of the Rho•NusG interaction in Escherichia coli have helped establish how NusG reprograms Rho activity. NusG is found to be an allosteric activator of Rho that directly binds to the ATPase motor domain of the helicase and facilitates closure of the Rho ring around non-ideal (purine-rich) target RNAs. The manner in which NusG acts on Rho helps to explain how the transcription terminator is excluded from acting on RNA polymerase by exogenous factors, such as the antitermination protein NusE, the NusG paralog RfaH, and RNA polymerase-coupled ribosomes. Collectively, an understanding of the link between NusG and Rho provides new insights into how transcriptional and translational fidelity are maintained during gene expression in bacteria.

Following the new ESPEN Standard Operating Procedures, the previous guidelines to provide best medical nutritional therapy to critically ill patients have been updated. These guidelines define who are the patients at risk, how to assess nutritional status of an ICU patient, how to define the amount of energy to provide, the route to choose and how to adapt according to various clinical conditions. When to start and how to progress in the administration of adequate provision of nutrients is also described. The best determination of amount and nature of carbohydrates, fat and protein are suggested. Special attention is given to glutamine and omega-3 fatty acids. Particular conditions frequently observed in intensive care such as patients with dysphagia, frail patients, multiple trauma patients, abdominal surgery, sepsis, and obesity are discussed to guide the practitioner toward the best evidence based therapy. Monitoring of this nutritional therapy is discussed in a separate document.

BACKGROUND The School Breakfast Program (SBP) has grown and evolved substantially since its inception, yet relatively little is known about its impact on school engagement and academic outcomes. OBJECTIVES The purpose of this study is to estimate the impact of the SBP on school attendance and standardized test scores, as well as how impacts differ among student subpopulations and between traditional and nontraditional program models. METHODS The study uses administrative data from ∼1000 Wisconsin elementary schools during 2009-2014, including almost all public elementary schools in the state except those in Milwaukee Public School District. Over the 5-y period, 168 schools in our sample introduced a new SBP and/or changed the location of breakfast (classroom or cafeteria) or the payment structure. The impact of breakfast availability and type was evaluated using multivariable regression models with school fixed effects and extensive demographic controls, leveraging within-school changes in SBP availability and type. RESULTS Implementing the SBP was associated with a 3.5-percentage-point reduction in the percentage of students with low attendance and an increase of 0.08 SD in normalized reading scores among likely-participant boys (P = 0.015), with no impact among girls. When breakfast was offered free to all students, the probability of low attendance was 3.5 percentage points lower than with traditional SBP for a broad cross-section of students (P

The catalytic influence of iron oxide on the oxidation of synthetic chars as a function of the phase composition was investigated by temperature-programmed measurements in a thermobalance and isothermal oxidation experiments in a fixed-bed reactor. The synthetic solid fuels originated from hydrothermal carbonization of cellulose and subsequent pyrolysis of the obtained hydrochars. Incorporation of iron oxide was either achieved by in situ doping during the hydrothermal carbonization or by tight contact mixing of the chars with iron oxide particles. Temperature-programmed oxidation of the synthetic char doped by tight contact resulted only in a slight decrease of the oxidation temperature. Pyrolysis of the in situ doped chars at 800 °C led to the carbothermal reduction of iron oxide to catalytically inactive iron carbide, and it was not possible to re-oxidize iron carbide by means of an additional pretreatment in 20 % O2 at 350 °C. When pyrolysis of the in situ doped hydrochar was performed at 500 °C, iron oxide was not reduced, and the oxidation of the corresponding char occurred much faster due to the catalytic effect of the iron oxide particles, which had a high degree of contact with the embedding carbon matrix.

The applied pyrolysis temperature was found to strongly affect composition, structure, and oxidation behavior of pure and iron oxide nanoparticle (NP)-loaded carbon materials originating from hydrothermal carbonization (HTC) of cellulose. A strong loss of functional groups during pyrolysis at temperatures beyond 300 degrees C of the HTC-derived hydrochars was observed, resulting in an increase of the carbon content up to 95 wt% for the carbon materials pyrolyzed at 800 degrees C and an increase of the specific surface area with a maximum of 520 m(2) g(-1) at a pyrolysis temperature of 600 degrees C. Devolatilization mainly took place in the range from 300 to 500 degrees C, releasing light pyrolysis gases such as CO, CO2, H2O and larger oxygen-containing molecules up to C-11. The presence of iron oxide NPs lowered the specific surface areas by about 200 m(2) g(-1) and resulted in the formation of mesopores. For the iron oxide-containing composites pyrolyzed up to 500 degrees C, the oxidation temperature was decreased by about 100 degrees C, indicating tight contact between the iron oxide NPs and the carbon matrix. For higher pyrolysis temperatures, this catalytic effect of iron oxide on carbon oxidation vanished due to carbothermal reduction to iron and iron carbide, which, however, catalyzed the graphitization of the carbon matrix. Thus, the well-controlled two-step synthesis based on a biomass-derived precursor yielded stably embedded iron NPs in a corrosion-resistant graphitic carbon matrix.

Summary Background & aims Major burn patients are characterized by large exudative losses of Cu, Se and Zn. Trace element (TE) repletion has been shown to improve clinical outcome. Having increased the TE doses over time, the study aimed at analysing if our repletion protocol corrected TE plasma concentrations and if the necessity for continuous renal replacement therapy (CRRT) might increase the TE needs. Methods Retrospective analysis of prospectively collected data in burn patients requiring intensive care (ICU) between 1999 and 2015. Inclusion criteria: Admission on day 1, full treatment, burned surface area (TBSA) ≥20% and ≥1 TE plasma determination during the stay. Four groups were constituted according to protocol changes. Period 1 (P1): 1999–2000, P2: 2001–2005, P3: 2006–2010, P4: 2011–2015. Changes consisted in increasing TE repletion doses and duration. Demographic data, daily TE intakes and weekly plasma concentrations were retrieved for the first 21 ICU-days. Data as median (IQR). Results 139 patients completed the criteria, aged 37 (28) years, burned on 35 (25) % TBSA. As a result of prescription, Cu, Se and Zn intakes increased significantly between P1 and P4, resulting in normalization of plasma Cu (16 μmol/l) since P3 and Zn (13.5 μmol/l) since P2. Median plasma Se were above reference range (1400 nmol/l) during P3 and P4. CRRT patients required higher doses of Cu for maintenance within normal ranges. Conclusion This dose finding study shows that the latest repletion protocol is safe and normalizes Cu and Zn concentrations. Se doses result in supra-normal Se concentrations, suggesting prescription reduction. CRRT patients are at high risk of Cu depletion and require specific monitoring.

Cardiologic assessment was conducted on a 78-year-old male patient scheduled for elective aortic valve surgery who complained of angina and dyspnea that had arisen over the previous few months. Evaluation showed stable coronary artery disease and iron deficiency anemia (hemoglobin, 7.7 g/dL). Colonoscopy revealed a non-stenosing carcinoma of the right colonic flexure that was causing chronic blood loss. The interdisciplinary tumor board of the hospital decided that his need for an extended right hemicolectomy followed by resection of two pulmonary nodules that were suspicious of metastatic lesions had priority over his cardiac surgery. Prior to abdominal surgery, the patient received 4 × 500 mg intravenous iron (Ferric-Carboxymaltose) over 2 weeks, for correction of iron deficiency and optimization of hemoglobin concentration. This treatment led to rapid improvement of his angina and exertion-induced dyspnea. His hemoglobin concentration continued to rise even after completion of the iron supplementation, and reached normal levels before thoracoscopic removal of the lung nodules, which took place 1 month after resection of the colon tumor. The patient remained in good clinical condition without any need for blood transfusions. As follow-up visits showed persistent abatement of angina and dyspnea, aortic valve surgery and other cardiac interventions were no longer deemed necessary.

In hamburger manufacturing, meat is subjected to four main processing steps (pre-grinding, mixing, grinding, and forming), whereby muscle fibers are disintegrated. In this study, the influence of these process steps was characterized by structural (amount of non-intact cells (ANIC), CLS-Microscopy), functional (drip loss) and qualitative (soluble protein content, lactate dehydrogenase (LDH) activity, myoglobin content (Mb)) parameters of the meat. Therefore, meat samples were analyzed after each process step. Histological analyses revealed an increased ANIC with progressive processing. Thereby, the first and second grinding steps caused the strongest increases (factors 2.43 and 2.69). Comparable results were found in the relative LDH activity (factor 2.20 and 1.62) and the Mb concentration (factor 2.24 and 1.33) of the extracted meat solution. The findings suggest that the disintegration of the meat structure increases with progressive processing, causing more vulnerable structures which result in increased leakage of intramuscular substances. Further, the type of stress acting on the meat determines the extent of the changes. The presented findings enable manufacturers to precisely adjust their process towards more gentle production parameters and thus, to meet the legal regulations.

Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.

Background: Sensory ganglionopathy (SG) is a rare form of neuropathy affecting the dorsal root ganglia and leading to non-length-dependent sensory abnormalities. Although balance problems are frequently reported by patients, a comprehensive balance assessment in SG has not been conducted. This study quantifies balance deficits in SG and examines their relation to patient-reported outcome measures (PROMs). Methods: Prospective data was collected from five participants with SG. Balance assessments included Fullerton Advanced Balance scale, Berg Balance scale, and 360 degree turn. Participants completed PROMs assessing balance confidence (ABC scale), pain, fatigue, quality of life (QoL), and daily activity and participation. Assessment also included neurological exam, nerve conduction studies (NCS) and posturography. Results: All participants had severe SG on NCS with normal strength and significant sensory abnormalities. Balance scores indicated severe balance deficits in all participants and aligned with posturography and truncal sway measures. PROMs revealed low confidence in balance, high levels of pain and fatigue, difficulties with daily activities, and reduced QoL. Conclusions: Although balance testing is not part of routine clinical practice, PROMs and targeted assessment may help monitor patients with SG and their response to treatment. Larger sample sizes are needed to understand the impact of balance on PROMs and optimize bedside balance testing.

Problem identification Self-efficacy for symptom management plays a key role in outcomes, such as quality of life (QOL), functional status, and symptom distress, for adults with cancer. This integrative review identified and assessed evidence regarding self-efficacy for management of symptoms and symptom distress in adults with cancer. Literature search The authors performed a search of literature published from 2006-2018, and articles that examined the relationship among self-reported self-efficacy, symptom management, symptom distress or frequency, and severity in adults with cancer were selected for inclusion. Data evaluation 22 articles met the inclusion criteria. All articles were critically appraised and met standards for methodologic quality. Synthesis Evidence from this review showed that high self-efficacy was associated with low symptom occurrence and symptom distress and higher general health and QOL. High self-efficacy predicted physical and emotional well-being. Low self-efficacy was associated with higher symptom severity, poorer outcomes, and better overall functioning. Implications for research Self-efficacy can be assessed using developed instruments. Presence of a theoretical model and validated instruments to measure self-efficacy for symptom management have set the groundwork for ongoing research.

Early childbearing is associated with a host of educational and economic disruptions for teenage girls and increased risk of adverse outcomes for their children. Low-income, maltreated, and foster youth have a higher risk of teen motherhood than the general population of youth. In this study, we assessed differences in the risk of early motherhood among these groups and investigated whether differences likely reflect selection factors versus effects of involvement with Child Protective Services (CPS) or foster care. Using a statewide linked administrative data system for Wisconsin, we employed survival analysis to estimate the hazard of early birth (child conceived prior to age 18) among females. We found that both the youth involved in CPS and youth in foster care were at significantly higher risk of early motherhood than low-income youth, and these differences were not explained by a range of sociodemographic and family composition characteristics. Moreover, our findings indicate that CPS and foster care are unlikely to be causal agents in the risk of early motherhood: among foster youth, risk was lower during foster care compared with before; among CPS-involved girls, risk was the same or lower after CPS investigation compared with before. Subsequent analysis showed that after girls exited foster care, those who were reunified with their birth families were at higher risk than those placed in adoption or guardianship. Overall, our findings suggest that whereas CPS and foster youth are high-risk populations for early motherhood, CPS involvement and foster care placement do not exacerbate, and may instead reduce, risk.

Background Human immunoglobulins (H-Ig) are widely used in solid organ transplantation for immunoglobulin G (IgG) replacement and for desensitization and treatment of antibody-mediated rejection. They are obtained from plasma pools and may contain HLA antibodies that can be detrimental to transplant recipients. The goal of this study was to evaluate HLA antibodies in multiple lots of 2 commercial H-Ig preparations by Luminex single-antigen bead (SAB) and cell-based crossmatch assays. Methods Thirty lots of 2 commercial H-Ig products (CSL Behring, King of Prussia, PA) were evaluated: 6 Hizentra and 24 Privigen. All were adsorbed and diluted 1:10 before testing. HLA IgG antibodies were determined by 2 Luminex SAB kits and C1q screen for complement-binding capability. Lots were tested for the presence of antibody to denatured vs. intact class I HLA alleles using acid-treated SAB. Surrogate T and B-cell flow cytometry crossmatches (FCXM) were performed with peripheral blood lymphocytes from 2 healthy donors. Results Twenty-two (73%) lots at 1:10 showed SAB reactivity with mean fluorescent intensity of 2000 or greater for HLA class I, 67% (20/30 lots) for class II. The reactivity pattern was similar using both SAB kits. Acid treatment revealed antibodies to denatured class I: the majority of HLA-C, half of HLA-B and few HLA-A alleles. No C1q reactivity was observed. Surrogate flow cytometry crossmatch results were positive (>150 median channel shift), but were fourfold to eightfold lower than expected. Conclusions The H-Ig products tested consisted of low titer, non-complement-binding HLA class I and class II antibodies; most of the observed class I HLA reactivity was toward denatured HLA antigens.

Muscle wasting deteriorates life quality after critical illness and increases mortality. Wasting starts upon admission to intensive care unit (ICU). We aimed to determine whether β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine, can attenuate this process.Prospective randomized, placebo-controlled double blind trial.ICU patients depending on mechanical ventilation on day 3 having a functional gastrointestinal tract. They were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on for 30 days.magnitude of loss of skeletal muscle area (SMA) of the quadriceps femoris measured by ultrasound at days 4 and 15.body composition, change in protein metabolism assessed by amino acids tracer pulse, and global health at 60 days. Data are mean [95% CI]. Statistics by ANCOVA with correction for confounders sex, age and/or BMI.Thirty patients completed the trial, aged 65 [59, 71] years, SAPS2 score 48 [43, 52] and SOFA 8.5 [7.4, 9.7]. The loss of total SMA was 11% between days 4 and 15 (p 0.001), but not different between the groups (p = 0.86). In the HMB group, net protein breakdown (Δ Estimate HMB-Placebo: -153 [-242, -63]; p = 0.0021) and production of several amino acid was significantly reduced, while phase angle increased more (0.66 [0.09, 1.24]; p = 0.0247), and SF-12 global health improved more (Δ Estimate HMB-Placebo: 27.39 [1.594, 53.19], p = 0.04).HMB treatment did not significantly reduce muscle wasting over 10 days of observation (primary endpoint), but resulted in significantly improved amino acid metabolism, reduced net protein breakdown, a higher phase angle and better global health. CLINICALTRIALS.NCT03628365.

Nurses are on the frontline of palliative care, and in some countries, are the only contact for patients and families facing life-threatening illness. The Oman Cancer Association in the Sultanate of Oman, in collaboration with the Middle Eastern Cancer Consortium and the Oncology Nursing Society, led a palliative care initiative over the past decade to better integrate palliative care into the health care system. Components of this initiative include integrating palliative care into the health care curricula and providing palliative care education to over 400 nurses and other health care professionals within Oman. The four-part education series includes the following courses: (1) Foundations of Palliative Care, (2) Advanced Concepts in Palliative Care, (3) Palliative Care Leadership, and (4) Palliative Care Research. Additional participants from 17 different countries in the Middle East and northern Africa also attended the training. Twenty of the trainees who were considered palliative care leaders in their countries then participated in a Train the Trainer course. This group trained the last cohort of health care professionals in Oman and then took learned concepts and strategies back to their respective countries in order to provide country-wide education and build palliative care capacity in the region. Outcomes include the development of palliative care units, quality improvement projects that improved care, and advocacy projects to increase opioid availability within some countries. The collaborative continues its work and connections through social medial, email, and virtual collaboration. Other countries can use this model to permeate palliative care within their regions.

In many bacteria and eukaryotes, replication fork establishment requires the controlled loading of hexameric, ring-shaped helicases around DNA by AAA+(ATPases Associated with various cellular Activities) ATPases. How loading factors use ATP to control helicase deposition is poorly understood. Here, we dissect how specific ATPase elements ofEscherichia coliDnaC, an archetypal loader for the bacterial DnaB helicase, play distinct roles in helicase loading and the activation of DNA unwinding. We have identified a new element, the arginine-coupler, which regulates the switch-like behavior of DnaC to prevent futile ATPase cycling and maintains loader responsiveness to replication restart systems. Our data help explain how the ATPase cycle of a AAA+-family helicase loader is channeled into productive action on its target; comparative studies indicate that elements analogous to the Arg-coupler are present in related, switch-like AAA+ proteins that control replicative helicase loading in eukaryotes, as well as in polymerase clamp loading and certain classes of DNA transposases.

Supplemental Digital Content is available in the text., Background. The ability of transplant (Tx) patients to generate a protective antiviral response under immunosuppression is pivotal in COVID-19 infection. However, analysis of immunity against SARS-CoV-2 is currently lacking. Methods. Here, we analyzed T cell immunity directed against SARS-CoV-2 spike-, membrane-, and nucleocapsid-protein by flow cytometry and spike-specific neutralizing antibodies in 10 Tx in comparison to 26 nonimmunosuppressed (non-Tx) COVID-19 patients. Results. Tx patients (7 renal, 1 lung, and 2 combined pancreas-kidney Txs) were recruited in this study during the acute phase of COVID-19 with a median time after SARS-CoV-2-positivity of 3 and 4 d for non-Tx and Tx patients, respectively. Despite immunosuppression, we detected antiviral CD4+ T cell-response in 90% of Tx patients. SARS-CoV-2–reactive CD4+ T cells produced multiple proinflammatory cytokines, indicating their potential protective capacity. Neutralizing antibody titers did not differ between groups. SARS-CoV-2–reactive CD8+ T cells targeting membrane- and spike-protein were lower in Tx patients, albeit without statistical significance. However, frequencies of anti-nucleocapsid–protein-reactive, and anti-SARS-CoV-2 polyfunctional CD8+ T cells, were similar between patient cohorts. Tx patients showed features of a prematurely aged adaptive immune system, but equal frequencies of SARS-CoV-2–reactive memory T cells. Conclusions. In conclusion, a polyfunctional T cell immunity directed against SARS-CoV-2 proteins as well as neutralizing antibodies can be generated in Tx patients despite immunosuppression. In comparison to nonimmunosuppressed patients, no differences in humoral and cellular antiviral-immunity were found. Our data presenting the ability to generate SARS-CoV-2–specific immunity in immunosuppressed patients have implications for the handling of SARS-CoV-2–infected Tx patients and raise hopes for effective vaccination in this cohort.

The $E2/M1$ multipole mixing ratio of the ${1}_{\text{sc}}^{+}\ensuremath{\rightarrow}{2}_{1}^{+}\phantom{\rule{4pt}{0ex}}\ensuremath{\gamma}$-ray transition and therefore the $F$-vector $E2$ decay of the scissors mode of the shape-phase transitional nucleus $^{152}\mathrm{Sm}$ have been measured with the nuclear resonance fluorescence method at the High-Intensity $\ensuremath{\gamma}$-ray Source ($\mathrm{HI}\ensuremath{\gamma}\mathrm{S}$). Furthermore, parity quantum numbers of several dipole-excited states have been remeasured, making use of the polarized $\ensuremath{\gamma}$-ray beam at $\mathrm{HI}\ensuremath{\gamma}\mathrm{S}$, and partially reassigned. The new data enable an unambiguous determination of the proton and neutron effective boson quadrupole charges within the proton-neutron interacting boson model. With the well-constrained parameter set, a new mixed-symmetry state is predicted.

Background The treatment and management of massive burns, defined as burns affecting≥ 50% of total body surface area (TBSA) has considerably changed since the 90s. This study aimed at analyzing if the length of intensive care unit (ICU) stay, the success of skin grafting operations and the mortality changed in the last 18 years. Methods Between 2000 and 2018, 77 patients were admitted for massive burns to the ICU of a university hospital. Transfers and early care withdrawal precluded inclusion for 38 patients, leaving 39 for analysis. Study variables were year of admission, demographics, burn characteristics, critical care treatment (fluid resuscitation, ventilation and nutrition) and surgical therapy. Association between outcomes and year of admission were assessed through correlation and logistic regression analysis. Potential confounders were assessed through stepwise linear regression. Results Patients' characteristics were stable over time with a median age of 36[25.0, 48.0] years, burns 65% [55.0, 83.0] TBSA and deep burns 55% [50.0, 68.0] TBSA . Length of ICU stay remained stable at 0.97 [0.6, 1.5] days/%TBSA. Mortality was stable as well. Energy and carbohydrate delivery decreased in parallel with the number of infectious episodes per patient. Number of operations was stable but the take rate of skin grafts increased significantly. The multivariate analysis retained year of admission, weight, total number of infections, daily lipid intakes and fluid resuscitation as independent predicting variables. Conclusion Length of ICU stay and mortality did not change over time but skin grafts take rates improved significantly.

Histone H3K4 methylation serves as post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat containing protein 5 (WDR5) that has also been associated with controlling long non-coding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic function. This study presents the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

Liquid-liquid phase separation (LLPS) of intrinsically disordered regions (IDRs) in proteins can drive the formation of membraneless compartments in cells. Phase-separated structures enrich for specific partner proteins and exclude others. We have shown that the IDRs of metazoan DNA replication initiators drive DNA-dependent phase separationin vitroand chromosome bindingin vivo, and that initiator condensates selectively recruit specific partner proteins. How initiator IDRs facilitate LLPS and maintain compositional specificity is unknown. UsingD. melanogaster (Dm)Cdt1 as a model initiation factor, we show that phase separation results from a synergy between electrostatic DNA-bridging interactions and hydrophobic inter-IDR contacts. Both sets of interactions depend on sequence composition (but not sequence order), are resistant to 1,6- hexanediol, and do not depend on aromaticity. These findings demonstrate that distinct sets of interactions drive self-assembly and condensate specificity across different phase-separating systems and advance efforts to predict IDR LLPS propensity and specificitya priori.

Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.

Chronic inflammation-related diseases are characterized by persistent leukocyte infiltration into the underlying tissue. The vascular endothelium plays a major role in this pathophysiological condition. Only few therapeutic strategies focus on the vascular endothelium as a major target for an anti-inflammatory approach. In this study, we present the natural compound-derived carbazole derivative C81 as chemical modulator interfering with leukocyte-endothelial cell interactions. An in vivo assay employing intravital microscopy to monitor leukocyte trafficking after C81 treatment in postcapillary venules of a murine cremaster muscle was performed. Moreover, in vitro assays using HUVECs and monocytes were implemented. The impact of C81 on cell adhesion molecules and the NFκB signaling cascade was analyzed in vitro in endothelial cells. Effects of C81 on protein translation were determined by incorporation of a puromycin analog-based approach and polysome profiling. We found that C81 significantly reduced TNF-activated leukocyte trafficking in postcapillary venules. Similar results were obtained in vitro when C81 reduced leukocyte-endothelial cell interactions by down-regulating cell adhesion molecules. Focusing on the NFκB signaling cascade, we found that C81 reduced the activation on multiple levels of the cascade through promoted IκBα recovery by attenuation of IκBα ubiquitination and through reduced protein levels of TNFR1 caused by protein translation inhibition. We suggest that C81 might represent a promising lead compound for interfering with inflammation-related processes in endothelial cells by down-regulation of IκBα ubiquitination on the one hand and inhibition of translation on the other hand without exerting cytotoxic effects.

SummaryBackgroundDuring the second wave of the coronavirus disease 2019 (COVID-19) pandemic Austria suffered one of the highest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rates worldwide. We report performance parameters of a SARS-CoV‑2 screening program established for cancer outpatients at our center.MethodsInstitutional policy recommended routine biweekly SARS-CoV‑2 testing. Adherence to the testing recommendation during the second wave of the COVID-19 pandemic between 1 October and 30 November 2020 was analyzed. The SARS-CoV‑2 infection rate during first wave period (21 March to 4 May 2020) was compared to the one during second wave.ResultsA total of 1577 cancer patients were seen at our outpatient clinic during the second wave. In 1079/1577 (68.4%) patients, at least 1 SARS-CoV2 test was performed. Overall 2833 tests were performed, 23/1577 (1.5%, 95% confidence interval, CI 1.0–2.2%) patients were tested positive for SARS-CoV‑2, which indicates a significant increase compared to the first wave (4/1016; 0.4%, 95% CI 0.1–1.0%) with an odds ratio of 3.9 (95% CI 1.5–10.1;p p p ConclusionWe identified clinical patient parameters influencing SARS-CoV‑2 testing coverage in cancer outpatients. Our data can provide information on generation of standard operating procedures and resource allocation during subsequent infection waves.

A direct measurement of the decay width of the excited ${0}_{1}^{+}$ state of $^{6}\mathrm{Li}$ using the relative self-absorption technique is reported. Our value of ${\mathrm{\ensuremath{\Gamma}}}_{\ensuremath{\gamma},{0}_{1}^{+}\ensuremath{\rightarrow}{1}_{1}^{+}}=8.17(14{)}_{\mathrm{stat}.}(11{)}_{\mathrm{syst}.}\text{ }\text{ }\mathrm{eV}$ provides sufficiently low experimental uncertainties to test modern theories of nuclear forces. The corresponding transition rate is compared to the results of ab initio calculations based on chiral effective field theory that take into account contributions to the magnetic dipole operator beyond leading order. This enables a precision test of the impact of two-body currents that enter at next-to-leading order.