"They paged me what?": A transplant infectious disease guide to donor calls.

Donor-derived infections in solid organ transplantation can be prevented by risk stratification of donors based on available information, and inquiries surrounding possible or diagnosed infection are common questions posed to transplant infectious disease subspecialists. This article outlines the five key steps in addressing a donor call from a transplant team in a systematic approach, focusing on donor and recipient-specific factors, transmissibility and treatment of possible infections, and the likelihood of a patient's future organ offers and mortality remaining on the waitlist. These principles are then applied to five donor call cases, in which we review the key takeaway points and supporting literature. These cases can be used as a resource for teaching with trainees.

Impact of surgeon volume on 18-month unclosed ileostomy rate after restorative rectal cancer resection.

AIM: The impact of surgeon volume on 18-month unclosed ileostomy rates after rectal cancer surgery has not been fully explored. The aim of this study was to describe the effect of surgeon volume and evaluate factors predictive of an unclosed ileostomy. METHOD: Patients undergoing anterior resection with a diverting ileostomy for rectal cancer from March 2004 to October 2018 were identified from a prospectively maintained database. The unclosed ileostomy rate was determined by those with an unclosed ileostomy at 18 months. High- and low-volume surgeons (HVS and LVS, respectively) were classed as those performing five or more or fewer than five rectal cancer resections per year, respectively. Data on sex, age, American Society of Anesthesiologists grade, neoadjuvant chemoradiotherapy (CRT), tumour height, T-stage, anastomotic leak, surgical approach and adjuvant chemotherapy were also collected. Factors predictive of an unclosed ileostomy at 18 months were explored using a multivariate binary logistic regression analysis. RESULTS: A total of 415 patients (62.4% male) with a median age of 67 were eligible for analysis. Of these, 115 (27.7%) had an unclosed ileostomy at 18 months. HVS had an unclosed ileostomy rate of 24.6% (72/292) compared with 34.9% (43/123) for LVS. Volume was associated with an unclosed ileostomy in univariable analysis (p = 0.032) but not in multivariate analysis (OR 1.75, 95% CI 0.92-3.32, p = 0.08). Independent factors predictive of an unclosed ileostomy were anastomotic leak (OR 10.41, 3.95-27.0, p < 0.01), adjuvant chemotherapy (OR 2.23, 1.24-3.96, p < 0.01) and neoadjuvant CRT (OR 2.16, 1.15-5.75, p = 0.01). CONCLUSION: LVS were associated with a higher unclosed ileostomy at 18 months compared with HVS. This study adds further weight to the call for adoption of a minimum annual case threshold in rectal cancer surgery.

Creatine Kinase Equilibration and ΔGATP over an Extended Range of Physiological Conditions: Implications for Cellular Energetics, Signaling, and Muscle Performance.

In this report, we establish a straightforward method for estimating the equilibrium constant for the creatine kinase reaction (CK Keq″) over wide but physiologically and experimentally relevant ranges of pH, Mg2+ and temperature. Our empirical formula for CK Keq″ is based on experimental measurements. It can be used to estimate [ADP] when [ADP] is below the resolution of experimental measurements, a typical situation because [ADP] is on the order of micromolar concentrations in living cells and may be much lower in many in vitro experiments. Accurate prediction of [ADP] is essential for in vivo studies of cellular energetics and metabolism and for in vitro studies of ATP-dependent enzyme function under near-physiological conditions. With [ADP], we were able to obtain improved estimates of ΔGATP, necessitating the reinvestigation of previously reported ADP- and ΔGATP-dependent processes. Application to actomyosin force generation in muscle provides support for the hypothesis that, when [Pi] varies and pH is not altered, the maximum Ca2+-activated isometric force depends on ΔGATP in both living and permeabilized muscle preparations. Further analysis of the pH studies introduces a novel hypothesis around the role of submicromolar ADP in force generation.

The molecular landscape of well differentiated retroperitoneal liposarcoma.

Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Tumor necrosis is significantly associated with reduced recurrence-free survival after curative resection of gastrointestinal stromal tumors.

BACKGROUND OBJECTIVES: The impact of tumor necrosis as a prognostic factor in gastrointestinal stromal tumor (GISTs) is still debated. The objective was to determine whether tumor necrosis is an independent risk factor for survival in patients with GISTs. METHODS: Patients undergoing surgery for primary GIST from March 2003 to October 2018 at two sarcoma referral centers were retrospectively identified. Patients who received neoadjuvant imatinib were excluded. Multivariable Cox regression models were produced, to assess whether tumor necrosis was an independent predictor of either overall or recurrence-free survival. RESULTS: Forty-one out of 195 (21.0%) patients had tumor necrosis. Tumor necrosis was associated with a significantly higher modified National Institute of Health risk score, with 29 out of 41 (70.7%) patients with necrosis classified as high risk, compared to 52 out of 153 (34.0%) without (p < .001). Tumor necrosis was found to be independently predictive of recurrence-free survival (hazard ratio: 5.26, 95% CI: 2.62-10.56, p < .001) on multivariable analysis. At 5 years, 44.3% of patients with necrosis had either died or developed recurrence, compared to 9.9% of those without. CONCLUSION: Tumor necrosis is an independent predictor of recurrence-free survival in patients with operable GISTs. It should be routinely reported by pathologists, and used by clinicians when counseling patients and deciding on adjuvant therapy.

Simulation in shoulder arthroplasty education using three-dimensional planning software: the role of guidelines and predicted range of motion.

AIM: To demonstrate how reverse shoulder arthroplasty (RSA) planning software could be used to improve how the trainees position glenoid and humeral implants and obtain optimal simulated range of motion (ROM). METHODS: We selected four groups of five various level participants: medical student (MS), junior resident (JR), senior resident (SR), and shoulder expert (SE). Thereafter, the 20 participants planned five cases of arthritic shoulders for a RSA on a validated planning software following three phases: (1) no guidelines and no ROM feedback, (2) guidelines but no ROM feedback, and (3) guidelines and ROM feedback. We evaluated the final simulated impingement-free ROM, the choice of the implant (baseplate size, graft, glenosphere), and the glenoid implant positioning. RESULTS: MS planning were significantly improved by the ROM feedback only. JR took the best advantage of both guidelines and ROM in final results. SR planning were less performant than SE into phase 1 regarding flexion, external rotation, and adduction (respectively - 10°, p = 0.03; - 11°, p = 0.003; and - 3°, p = 0,03), but reached similar results into phase 3 (respectively - 2°, p = 0.329; - 4°, p = 0.44; - 2°, p = 0.319). For MS, JR, and SR, we observed a systematic improvement in the agreement over the study course. The glenoid diameter remained highly variable even for SE. Comparing glenoid implant position to SE, the distance error decreased with advancing phases. CONCLUSION: Planning software can be used as a simulation training tool to improve implant positioning in shoulder arthroplasty procedures.

Innovations Through Virtual Reality Simulation.

The need to augment standardized learner outcomes related to performance and clinical competency led to creating curricular elements that would provide instruction and assessment from multiple perspectives. The COVID-19 pandemic brought about needs for re-imagination of standardized simulated clinical experiences given the need for increased distance-learning and asynchronous formats. Our goal was to identify activities that would engage pre-clinical simulation through asynchronous virtual reality (VR) case scenarios. The intent was to provide additional resources whereby competencies could be more defined through performance metrics and standardized assessments additive to our established simulation-based curriculum throughout all curricular phases. Student reflection and metacognition identified gaps to guide future performance improvement through the VR activities. Learner outcomes encompassing history-taking, physical assessment, evidence-based clinical reasoning, and medical decision-making guided the instructional objectives. The composite data showed progressive improvements over five scenarios delivered in our second-year clinical medicine curriculum.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

Electrical conductivity of the global ocean.

The electrical conductivity of the ocean is a fundamental parameter in the electrodynamics of the Earth System. This parameter is involved in a number of applications ranging from the calibration of in situ ocean flow meters, through extensions of traditional induction studies, and into quite new opportunities involving the remote sensing of ocean flow and properties from space-borne magnetometers such as carried aboard the three satellites of the Swarm mission launched in 2013. Here, the first ocean conductivity data set calculated directly from observed temperature and salinity measurements is provided. These data describe the globally gridded, three-dimensional mean conductivity as well as seasonal variations, and the statistics of spatial and seasonal variations are shown. This "climatology" data set of ocean conductivity is offered as a standard reference similar to the ocean temperature and salinity climatologies that have long been available.

Examination of Glycosaminoglycan Binding Sites on the XCL1 Dimer.

Known for its distinct metamorphic behavior, XCL1 interconverts between a canonical chemokine folded monomer (XCL1mon) that interacts with the receptor, XCR1, and a unique dimer (XCL1dim) that interacts with glycosaminoglycans and inhibits HIV-1 activity. This study presents the first detailed analysis of the GAG binding properties of XCL1dim. Basic residues within a conformationally selective dimeric variant of XCL1 (W55D) were mutated and analyzed for their effects on heparin binding. Mutation of Arg23 and Arg43 greatly diminished the level of heparin binding in both heparin Sepharose chromatography and surface plasmon resonance assays. To assess the contributions of different GAG structures to XCL1 binding, we developed a solution fluorescence polarization assay and correlated affinity with the length and level of sulfation of heparan sulfate oligosaccharides. It was recently demonstrated that the XCL1 GAG binding form, XCL1dim, is responsible for preventing HIV-1 infection through interactions with gp120. This study defines a GAG binding surface on XCL1dim that includes residues that are important for HIV-1 inhibition.

A Requirement for Metamorphic Interconversion in the Antimicrobial Activity of Chemokine XCL1.

Chemokines make up a superfamily of ∼50 small secreted proteins (8-12 kDa) involved in a host of physiological processes and disease states, with several previously shown to have direct antimicrobial activity comparable to that of defensins in efficacy. XCL1 is a unique metamorphic protein that interconverts between the canonical chemokine fold and a novel all-ß-sheet dimer. Phylogenetic analysis suggests that, within the chemokine family, XCL1 is most closely related to CCL20, which exhibits antibacterial activity. The in vitro antimicrobial activity of WT-XCL1 and structural variants was quantified using a radial diffusion assay (RDA) and in solution bactericidal assays against Gram-positive and Gram-negative species of bacteria. Comparisons of WT-XCL1 with variants that limit metamorphic interconversion showed a loss of antimicrobial activity when restricted to the conserved chemokine fold. These results suggest that metamorphic folding of XCL1 is required for potent antimicrobial activity.

Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily.

Known for its unusual metamorphic native state structure, XCL1 has been the focus of most efforts to elucidate the structural, functional, and physiological properties of chemokines in the C subfamily. By comparison, its closely related paralog XCL2 remains virtually uncharacterized. Based on the importance of the chemokine N-terminus in receptor activation, it was hypothesized that two amino acid differences in XCL2 would alter its agonist activity relative to XCL1 for their shared receptor XCR1. This present study reveals several properties of XCL2 that were unexamined until now. Structurally, XCL1 and XCL2 are very similar, exchanging between the monomeric chemokine fold and an unrelated dimeric state under physiological NaCl and temperature conditions. Ca(2+) flux, chemotaxis, and heparin binding assays showed that the monomer form of XCL2 is responsible for G protein-coupled receptor activation while the dimeric form is important for GAG binding. Despite their high structural similarity, XCL2 displays a slightly higher affinity for heparin than XCL1. Because their in vitro functional profiles are virtually identical, distinct physiological roles for XCL1 and XCL2 are probably encoded at the level of expression.

Electron capture dissociation and drift tube ion mobility-mass spectrometry coupled with site directed mutations provide insights into the conformational diversity of a metamorphic protein.

Ion mobility mass spectrometry can be combined with data from top-down sequencing to discern adopted conformations of proteins in the absence of solvent. This multi-technique approach has particular applicability for conformationally dynamic systems. Previously, we demonstrated the use of drift tube ion mobility-mass spectrometry (DT IM-MS) and electron capture dissociation (ECD) to study the metamorphic protein lymphotactin (Ltn). Ltn exists in equilibrium between distinct monomeric (Ltn10) and dimeric (Ltn40) folds, both of which can be preserved and probed in the gas-phase. Here, we further test this mass spectrometric framework, by examining two site directed mutants of Ltn, designed to stabilise either distinct fold in solution, in addition to a truncated form consisting of a minimum model of structure for Ltn10. The truncated mutant has similar collision cross sections to the wild type (WT), for low charge states, and is resistant to ECD fragmentation. The monomer mutant (CC3) presents in similar conformational families as observed previously for the WT Ltn monomer. As with the WT, the CC3 mutant is resistant to ECD fragmentation at low charge states. The dimer mutant W55D is found here to exist as both a monomer and dimer. As a monomer W55D exhibits similar behaviour to the WT, but as a dimer presents a much larger charge state and collision cross section range than the WT dimer, suggesting a smaller interaction interface. In addition, ECD on the W55D mutant yields greater fragmentation than for the WT, suggesting a less stable ß-sheet core. The results highlight the power of MS to provide insight into dynamic proteins, providing further information on each distinct fold of Ltn. In addition we observe differences in the fold stability following single or double point mutations. This approach, therefore, has potential to be a useful tool to screen for the structural effects of mutagenesis, even when sample is limited.

Strong ocean tidal flow and heating on moons of the outer planets.

Data from recent space missions have added strong support for the idea that there are liquid oceans on several moons of the outer planets, with Jupiter's moon Europa having received the most attention. But given the extremely cold surface temperatures and meagre radiogenic heat sources of these moons, it is still unclear how these oceans remain liquid. The prevailing conjecture is that these oceans are heated by tidal forces that flex the solid moon (rock plus ice) during its eccentric orbit, and that this heat entering the ocean does not rapidly escape because of the insulating layer of ice over the ocean surface. Here, however, I describe strong tidal dissipation (and heating) in the liquid oceans; I show that a subdominant and previously unconsidered tidal force due to obliquity (axial tilt of the moon with respect to its orbital plane) has the right form and frequency to resonantly excite large-amplitude Rossby waves in these oceans. In the specific case of Europa, the minimum kinetic energy of the flow associated with this resonance (7.3 x 10(18) J) is two thousand times larger than that of the flow excited by the dominant tidal forces, and dissipation of this energy seems large enough to be a primary ocean heat source.

Gastrointestinal Tolerance to Daily Canned Chickpea Intake.

PURPOSE: Consumption of pulses is recommended to improve diet quality and decrease the risk of chronic disease. However, their constituent α-galactosides, including raffinose, are commonly thought to contribute to unpleasant gastrointestinal symptoms. METHODS: Using a random crossover design, healthy adults (n = 12) received control foods, control foods with 5 g raffinose, and foods with 200 g of canned chickpea (11 g fibre per day), each for three weeks following a 3-day diet rotation. Gastrointestinal symptoms (rating 0 = none to 3 = severe), compliance, and stool frequency were recorded daily. RESULTS: No change in daily stool frequency (mean ± SD) was found with chickpea (1.7 ± 0.3) or raffinose (1.7 ± 0.4) compared with control (1.5 ± 0.3). Reported flatulence (mean ± SD) was rated higher with chickpea (1.0 ± 0.2, P < 0.001) and raffinose (0.7 ± 0.2, P < 0.001) compared with control (0.4 ± 0.1). Although bloating was infrequent, ratings were higher with chickpea (0.2 ± 0.1, P < 0.001) and raffinose (0.3 ± 0.1, P < 0.001) compared with control (0.0). No differences were found for diarrhea or abdominal pain. CONCLUSIONS: As gastrointestinal symptoms were mild for most participants, canned chickpea may be a feasible way of increasing pulse intake and improving overall diet quality.

Glomus tumor of the scapular neck with axillary nerve compression at the shoulder. A case report.

Background: Glomus tumors, also known as benign acral tumors are extremely rare. Previous glomus tumors from other regions of the body have been linked to neurological compression symptoms, however axillary compression at the scapular neck has never been described. Case presentation: Here, we report a case of axillary nerve compression in a 47-year-old man, secondary to a glomus tumor of the neck of the right scapula, initially misdiagnosed with biceps tenodesis performed and no pain improvement. The magnetic resonance imaging demonstrated a well-contoured, 12 mm tumefaction at the inferior pole of the scapular neck T2-hyperintense and T1-isointense and interpreted as a neuroma. An axillary approach allowed the dissection of the axillary nerve, and the tumor was completely removed. The pathological anatomical analysis resulted in a nodular red lesion measuring 14 × 10 mm, delimited and encapsulated with a definitive diagnostic of glomus tumor. The neurologic symptoms and pain disappeared 3 weeks after surgery and the patient reported satisfaction with the surgical procedure. After 3 months, the results remain stable with a complete resolution of the symptoms. Conclusions: In cases of unexplained and atypical pain in the axillary area, and to avoid potential misdiagnoses and inappropriate treatments, an in-depth exploration for a compressive tumor should be performed as a differential diagnosis.

Electrostatic optimization of the conformational energy landscape in a metamorphic protein.

The equilibrium unfolding reaction of Ltn, a metamorphic C-class chemokine, was monitored by tryptophan fluorescence to determine unfolding free energies. Measurements revealed that addition of 150 mM NaCl stabilized the Ltn chemokine fold by approximately 1 kcal/mol. Specific mutations involving Arg23 and Arg43 also increased the stability by 1 kcal/mol, suggesting their involvement in chloride ion coordination. This interaction was confirmed by nuclear magnetic resonance (NMR) salt titration studies that revealed chemical shift perturbations localized to these residues and backbone amides within the proximal 40s loop. The effects of NaCl on the free energy landscape were further verified by ZZ-exchange NMR spectroscopy. Our results suggest that changes in the electrostatic environment modulate the Gibbs free energy of folding and alter the forward and reverse rates of interconversion. These results demonstrate how solution ions can promote metamorphic folding by adjusting the relative stabilities of two unrelated Ltn native-state structures.

Review of the health benefits of peas (Pisum sativum L.).

Pulses, including peas, have long been important components of the human diet due to their content of starch, protein and other nutrients. More recently, the health benefits other than nutrition associated with pulse consumption have attracted much interest. The focus of the present review paper is the demonstrated and potential health benefits associated with the consumption of peas, Pisum sativum L., specifically green and yellow cotyledon dry peas, also known as smooth peas or field peas. These health benefits derive mainly from the concentration and properties of starch, protein, fibre, vitamins, minerals and phytochemicals in peas. Fibre from the seed coat and the cell walls of the cotyledon contributes to gastrointestinal function and health, and reduces the digestibility of starch in peas. The intermediate amylose content of pea starch also contributes to its lower glycaemic index and reduced starch digestibility. Pea protein, when hydrolysed, may yield peptides with bioactivities, including angiotensin I-converting enzyme inhibitor activity and antioxidant activity. The vitamin and mineral contents of peas may play important roles in the prevention of deficiency-related diseases, specifically those related to deficiencies of Se or folate. Peas contain a variety of phytochemicals once thought of only as antinutritive factors. These include polyphenolics, in coloured seed coat types in particular, which may have antioxidant and anticarcinogenic activity, saponins which may exhibit hypocholesterolaemic and anticarcinogenic activity, and galactose oligosaccharides which may exert beneficial prebiotic effects in the large intestine.

Effect of genotype and environment on the concentrations of starch and protein in, and the physicochemical properties of starch from, field pea and fababean.

BACKGROUND: The effects of genotype and environment and their interaction on the concentrations of starch and protein in, and the amylose content and thermal and pasting properties of starch from, pea and fababean are not well known. RESULTS: Differences due to genotype were observed in the concentrations of starch and protein in pea and fababean, in the onset temperature (To) and peak temperature (Tp) of gelatinization of fababean starch, and in the pasting, trough, cooling and final viscosities of pea starch and fababean starch. Significant two-way interactions (location × genotype) were observed for the concentration of starch in fababean and the amylose content, To, endothermic enthalpy of gelatinization (ΔH) and trough viscosity of fababean starch. Significant three-way interactions (location × year × genotype) were observed for the concentration of starch in pea and the pasting, trough, cooling and final viscosities of pea starch. CONCLUSION: Differences observed in the concentrations of starch and protein in pea and fababean were sufficient to be of practical significance to end-users, but the relatively small differences in amylose content and physicochemical properties of starch from pea and fababean were not.