A close-in giant planet escapes engulfment by its star.

When main-sequence stars expand into red giants, they are expected to engulf close-in planets1-5. Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants6-8 has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars9. Here we present the discovery that the giant planet 8 Ursae Minoris b10 orbits a core-helium-burning red giant. At a distance of only 0.5 AU from its host star, the planet would have been engulfed by its host star, which is predicted by standard single-star evolution to have previously expanded to a radius of 0.7 AU. Given the brief lifetime of helium-burning giants, the nearly circular orbit of the planet is challenging to reconcile with scenarios in which the planet survives by having a distant orbit initially. Instead, the planet may have avoided engulfment through a stellar merger that either altered the evolution of the host star or produced 8 Ursae Minoris b as a second-generation planet11. This system shows that core-helium-burning red giants can harbour close planets and provides evidence for the role of non-canonical stellar evolution in the extended survival of late-stage exoplanetary systems.

Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Combination of NKG2A and PD-1 Blockade Improves Radiotherapy Response in Radioresistant Tumors.

Radiotherapy (RT) is commonly employed to treat solid tumors. Immune checkpoint blockade of programmed cell death protein 1 (PD-1) and CTLA-4 improves survival in RT patients, yet many fail to respond to combination therapy. Natural killer group 2 (NKG2) family receptors, particularly inhibitory NKG2A and activating NKG2D, have emerged as promising therapeutic targets to improve antitumor T cell responses; thus, we examined how these receptors and their ligands (Qa-1b and retinoic acid early inducible 1 [Rae-1], respectively) regulate the RT response in C57BL/6 mice bearing syngeneic B16F10 melanoma and MC38 colorectal adenocarcinoma tumors. RT (15 Gy) transiently reduced B16F10 tumor burden, whereas MC38 tumors exhibited durable response to RT. Intratumoral NK and CD8 T cells expressed NKG2A and NKG2D in both models, which was unaltered by RT. In vitro/in vivo RT increased tumor/stromal cell Qa-1b and Rae-1 expression in both models, especially B16F10 tumors, but IFN-γ stimulation induced both Qa-1b and Rae-1 only in B16F10 tumors. NKG2A/Qa-1b inhibition alone did not improve RT response in either model, but combined RT and NKG2A/PD-1 blockade improved survival in the B16F10 model. Depletion experiments indicate that the triple therapy efficacy is CD8 T cell-dependent with negligible NK cell contribution. RNA sequencing of CD8 T cells from triple therapy-treated B16F10 tumors showed increased proliferative capacity compared with RT and PD-1 blockade alone. Our work demonstrates that RT modulates NKG2A ligand expression, which inhibits RT-induced T cell responses in tumors that fail to respond to combined RT and PD-1 blockade. These results provide a rationale for combining NKG2A blockade with immune checkpoint blockade therapies and RT to improve clinical response.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Implications of Tumor Characteristics and Treatment Modality on Local Recurrence and Functional Outcomes in Children With Chest Wall Sarcoma: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: To determine the impact of tumor characteristics and treatment approach on (1) local recurrence, (2) scoliosis development, and (3) patient-reported quality of life in children with sarcoma of the chest wall. SUMMARY OF BACKGROUND DATA: Children with chest wall sarcoma require multimodal therapy including chemotherapy, surgery, and/or radiation. Despite aggressive therapy which places them at risk for functional impairment and scoliosis, these patients are also at significant risk for local recurrence. METHODS: A multi-institutional review of 175 children (median age 13 years) with chest wall sarcoma treated at seventeen Pediatric Surgical Oncology Research Collaborative institutions between 2008 and 2017 was performed. Patient-reported quality of life was assessed prospectively using PROMIS surveys. RESULTS: The most common diagnoses were Ewing sarcoma (67%) and osteosarcoma (9%). Surgical resection was performed in 85% and radiation in 55%. A median of 2 ribs were resected (interquartile range = 1-3), and number of ribs resected did not correlate with margin status ( P = 0.36). Local recurrence occurred in 23% and margin status was the only predictive factor(HR 2.24, P = 0.039). With a median follow-up of 5 years, 13% developed scoliosis (median Cobb angle 26) and 5% required corrective spine surgery. Scoliosis was associated with posteriorrib resection (HR 8.43; P= 0.003) and increased number of ribs resected (HR 1.78; P = 0.02). Overall, patient-reported quality of life is not impaired after chest wall tumor resection. CONCLUSIONS: Local recurrence occurs in one-quarter of children with chest wall sarcoma and is independent of tumor type. Scoliosis occurs in 13% of patients, but patient-reported quality of life is excellent.

Pediatric Abdominal Malignancies and Intravascular Extension: Contemporary Single-Center Experience.

INTRODUCTION: Inferior vena cava (IVC) thrombus is an uncommon and challenging complication of abdominal malignancies in the pediatric population, which significantly influences the treatment options and clinical outcomes in this population. METHODS: In this review, we present the presentation, treatments, interventions, and outcomes with this clinically and technically challenging oncological finding from a free-standing children's hospital from 2006 to 2017. RESULTS: Fourteen patients with IVC thrombus were identified as having an associated abdominal malignancy. The abdominal malignancies consisted of eight Wilms tumors (63% stage III and 37% stage IV), and one spindle cell sarcoma, neuroblastoma (stage III), kidney clear cell sarcoma (stage III), sclerosing epithelioid fibrosarcoma, hepatoblastoma-epithelial (stage IV), and hepatic embryonal sarcoma (stage IV). 50% of patients were male, 71% White, 29% Black, 7% Hispanic; mean age at diagnosis was 4.09 (SD 2.43) years. CT imaging identified IVC tumor thrombus for 79% of patients, US abdomen complete recorded 14%, and MRI lumbar 7%. 3Out of 14 patients, 13 patients were taken to the operating room with 12 patients undergoing concurrent tumor resection and IVC thrombectomy. Of the remaining patients, one had IVC thrombectomy via femoral cutdown by interventional radiology, and one was noted to have resolution of IVC thrombus with neoadjuvant chemotherapy. Of patients who underwent resection, one required IVC ligation, and one patient required IVC interposition vein graft reconstruction using a right IJ conduit. 60% of patients undergoing thrombectomy received neoadjuvant chemotherapy. Mean time from the diagnosis of IVC tumor thrombus to surgical thrombectomy was 46 (SD 44) days. No operative mortalities were reported. There were five major complications (hemothorax, pulmonary embolisms, seroma, and sepsis) and two minor complications (pneumonia and UTI). With exclusion of patient who underwent IVC ligation, no patients developed signs of IVC compression or recurrent thrombosis after thrombectomy. CONCLUSIONS: IVC tumor thrombus can significantly alter the clinical treatment, surgical options, and outcomes of malignant abdominal tumors. Treatment of IVC tumor thrombus included adjuvant chemotherapy, segmental IVC resection with or without reconstruction, thrombectomy with intimal stripping, or resection of the thrombus with part of the IVC wall. Evidence for standard treatment practices for IVC tumor thrombus in the setting of abdominal malignancy is lacking due to the rarity of this finding and the varied clinical presentations.

Hydrolyzable Poly(ß-thioether ester ketal) Thermosets via Acyclic Ketal Monomers.

Hydrolytically degradable poly(ß-thioether ester ketal) thermosets are synthesized via radical-mediated thiol-ene photopolymerization using three novel dialkene acyclic ketal monomers and a mercaptopropionate based tetrafunctional thiol. For all thermoset compositions investigated, degradation behavior is highly tunable based on the structure of the incorporated ketal and pH. Complete degradation of the thermosets is observed upon exposure to acidic and neutral pH, and under high humidity conditions. Polymer networks composed of cross-link junctions based on acyclic dimethyl ketals degrade the quickest, whereas networks containing acyclic cyclohexyl ketals undergo hydrolytic degradation on a longer timescale. Thermomechanical analysis reveals low glass transition temperatures and moduli typical of thioether-based thermosets.

Loss of MPC1 reprograms retinal metabolism to impair visual function.

Glucose metabolism in vertebrate retinas is dominated by aerobic glycolysis (the "Warburg Effect"), which allows only a small fraction of glucose-derived pyruvate to enter mitochondria. Here, we report evidence that the small fraction of pyruvate in photoreceptors that does get oxidized by their mitochondria is required for visual function, photoreceptor structure and viability, normal neuron-glial interaction, and homeostasis of retinal metabolism. The mitochondrial pyruvate carrier (MPC) links glycolysis and mitochondrial metabolism. Retina-specific deletion of MPC1 results in progressive retinal degeneration and decline of visual function in both rod and cone photoreceptors. Using targeted-metabolomics and 13C tracers, we found that MPC1 is required for cytosolic reducing power maintenance, glutamine/glutamate metabolism, and flexibility in fuel utilization.

Preoperative spinal angiography decreases risk of spinal ischemia in pediatric posterior thoracic tumor resection.

PURPOSE: Resection of pediatric posterior thoracic tumors (PTTs) can be complicated by Artery of Adamkiewicz (AKA) injury. Post-op spinal ischemia occurs in approx. 3.2% of patients, typically due to iatrogenic vascular injury. Pre-op angiography (PSA) may help to avoid this complication. Herein, we aim to evaluate outcomes after initiation of routine PSA prior to PTT resection. METHODS: A single-institution retrospective review identified 25 children (< 18 years) treated for PTTs from 2009 to 2021. PTTs included: posterior mediastinum, paraspinal thorax and posterior chest wall tumors. PSA patients were compared to those without pre-operative angiography (NA). Demographics, perioperative and long-term outcomes and event-free survival (EFS) were assessed. RESULTS: Prior to 2012, eleven patients were treated without PSA. However, the last developed post-operative paraplegia secondary to spinal ischemia. Since this event, PSA has become routine for all PTTs (n = 14) identifying six AKAs and nine accessory spinal arteries. Resection was performed in ten (90.1%) NA patients and eight (57.1%) PSA patients. Based on PSA findings, resection was not offered to six patients and planned partial resection was performed in three patients. Five PSA patients required radiation therapy for local control vs two NA patients. There were no differences in recurrence or overall EFS. CONCLUSION: PSA aids in identifying patients with high-risk thoracic vascular anatomy and may prevent risk of post-operative paraplegia associated with PTT resection.

R17C Mutation in Photoreceptor Disc-Specific Protein, PRCD, Results in Additional Lipidation Altering Protein Stability and Subcellular Localization.

Progressive rod-cone degeneration (PRCD) is a photoreceptor outer segment (OS) disc-specific protein essential for maintaining OS structures while contributing to rhodopsin packaging densities and distribution in disc membranes. Previously, we showed PRCD undergoing palmitoylation at the sole cysteine (Cys2), where a mutation linked with retinitis pigmentosa (RP) in humans and dogs demonstrates the importance of palmitoylation for protein stability and trafficking to the OS. We demonstrate a mutation, in the polybasic region (PBR) of PRCD (Arg17Cys) linked with RP where an additional lipidation is observed through acyl-RAC. Immunolocalization of transiently expressed R17C in hRPE1 cells depicts similar characteristics to wild-type PRCD; however, a double mutant lacking endogenous palmitoylation at Cys2Tyr with Arg17Cys is comparable to the C2Y protein as both aggregate, mislocalized to the subcellular compartments within the cytoplasm. Subretinal injection of PRCD mutant constructs followed by electroporation in murine retina exhibit mislocalization in the inner segment. Despite being additionally lipidated and demonstrating strong membrane association, the mutation in the PBR affects protein stability and localization to the OS. Acylation within the PBR alone neither compensates for protein stability nor trafficking, revealing defects in the PBR likely lead to dysregulation of PRCD protein associated with blinding diseases.

Shock in the cardiac intensive care unit: Changes in epidemiology and prognosis over time.

There are few studies documenting the changing epidemiology and outcomes of shock in cardiac intensive care unit (CICU) patients. We sought to describe the changes in shock epidemiology and outcomes over time in a CICU population. METHODS: We included 1859 unique patients admitted to the Mayo Clinic Rochester CICU from 2007 through 2018 with an admission diagnosis of shock. Temporal trends, including mortality, were assessed across 3-year periods. RESULTS: Shock comprised 15.1% of CICU admissions during the study period, increasing from 8.8% of CICU admissions in 2007 to 21.6% in 2018 (P < .01 for trend). Mean age was 68 ±â€¯14 years (38% females). Shock was cardiogenic in 65%, septic in 10% and mixed cardiogenic-septic in 15%. Concomitant diagnoses in patients with cardiogenic shock (CS) included acute coronary syndrome (ACS) in 17%, heart failure (HF) in 35% and both in 40%. There was no significant change in the prevalence of individual shock subtypes over time (P > .1). Among patients with CS, the prevalence of ACS decreased and the prevalence of HF increased over time (P < .01). Hospital mortality was highest among patients with mixed shock (39%; P = .05). Among patients with CS, hospital mortality was lower among those with HF compared to those without HF (31% vs. 40%, P < .01). Hospital mortality decreased over time among patients with shock (P < .01) and CS (P = .02). CONCLUSIONS: The prevalence of shock in the CICU has increased over time, with a substantial prevalence of mixed CS. The etiology of CS has changed over the last decade with HF overtaking ACS as the most common cause of CS in the CICU.

Spectroscopic Determination of Ice-Induced Interfacial Strain on Single-Layer Graphene.

Reliably determining the physical properties of ice (e.g., crystal structure, adhesion strength, interfacial state, and molecular orientation) has proven to be both challenging and highly dependent on experiment-specific conditions, including surface roughness, ice formation, water purity, and measurement method. Here, non-destructive measurements of single-layer graphene (SLG) interfaced with bulk ice are used to determine temperature-dependent, ice-induced strain and estimate ice-created strain elastic density in SLG. The use of SLG enables the precise study of interfacial strain by monitoring the 2D Raman mode. Upon ice formation, a clear, ≈2 cm-1 decrease in the 2D mode frequency is observed, which is ascribed to a 0.012% biaxial tensile shear strain at the ice-SLG interface. From this shear strain value, the ice-created SLG elastic strain energy density is estimated to be 2.4 µJ m-2 . In addition to these Raman strain measurements, intentionally ionized water is used to show that water-mediated charging of the SLG surface manifests itself in a distinctly different manner than ice-induced strain. Finally, the localized nature of the Raman probe is used to map SLG regions with and without ice, suggesting that this method cannot only determine ice-induced interfacial strain, but also correlate ice adhesion properties with surface roughness and topology.

A systematic review of the use and reporting of evaluation frameworks within evaluations of physical activity interventions.

BACKGROUND: Evaluation of physical activity interventions is vital to inform, and justify, evidence-based policy and practice to support population-wide changes in physical activity. Several evaluation frameworks and guidance documents have been developed to facilitate the evaluation and reporting of evaluation studies in public health. However, there is a lack of evidence about whether frameworks are being used to guide evaluation. There continues to be claims of poor and inconsistent reporting in evaluation studies. The aim of this review was to assess the use of evaluation frameworks and the quality of reporting of how they were applied within evaluation studies of physical activity interventions. OBJECTIVES: 1. To identify whether evaluation frameworks are reported to have been used within evaluation studies of physical activity interventions, and which frameworks have been used. 2. To appraise the quality of reporting with regards to how evaluation frameworks have been used. METHOD: We developed a checklist of indicators to enable a critical appraisal of the use and reporting of different evaluation frameworks in evaluation studies. We conducted a systematic search and review of evaluation studies published between 2015 and the date of the search to appraise the use and reporting of evaluation frameworks. A narrative synthesis is provided. RESULTS: The review identified 292 evaluation studies of physical activity interventions, only 69 (23%) of these mentioned using an evaluation framework, and only 16 different frameworks were referred to. There was variation in the quality of reporting of framework use. 51 (74%) studies were identified as being explicitly based on the stated framework, however only 26 (38%) provided detailed descriptions consistently across all the checklist indicators. Details of adaptations and limitations in how frameworks were applied were less frequently reported. The review also highlighted variability in the reporting of intervention components. More consistent and precise reporting of framework and intervention components is needed. CONCLUSION: Evaluation frameworks can facilitate a more systematic evaluation report and we argue their limited use suggests missed opportunities to apply frameworks to guide evaluation and reporting in evaluation studies. Variability in the quality of reporting of framework use limits the comparability and transferability of evidence. Where a framework has been used, the checklist of indicators can be employed to facilitate the reporting of an evaluation study and to review the quality of an evaluation report.

Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: To better characterize short-term and long-term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD). METHODS: Patients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long-term pancreatic function, recurrence, and survival) were collected. RESULTS: Sixty-five patients from 18 institutions with a median age of 13 years (4 months-22 years) and a median (IQR) follow-up of 2.8 (4.3) years were analyzed. Solid pseudopapillary tumor of the pancreas (SPN) was the most common histology. Postoperative complications included pancreatic leak in 14% (n = 9), delayed gastric emptying in 9% (n = 6), marginal ulcer in one patient, and perioperative (30-day) death due to hepatic failure in one patient. Pancreatic insufficiency was observed in 32% (n = 21) of patients, with 23%, 3%, and 6% with exocrine, or endocrine insufficiencies, or both, respectively. Children with SPN and benign neoplasms all survived. Overall, there were 14 (22%) recurrences and 11 deaths (17%). Univariate analysis revealed non-SPN malignant tumor diagnosis, preoperative vascular involvement, intraoperative transfusion requirement, pathologic vascular invasion, positive margins, and need for neoadjuvant chemotherapy as risk factors for recurrence and poor survival. Multivariate analysis only revealed pathologic vascular invasion as a risk factor for recurrence and poor survival. CONCLUSION: This is the largest series of pediatric PD patients. PD is curative for SPN and benign neoplasms. Pancreatic insufficiency is the most common postoperative complication. Outcome is primarily associated with histology.

Microspheres Encapsulating Immunotherapy Agents Target the Tumor-Draining Lymph Node in Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: The tumor-draining lymph node (TDLN) plays a role in tumor immunity. Intratumorally administered microspheres (MS) that encapsulate immunomodulatory agents have emerged as a treatment strategy capable of causing profound changes in the tumor microenvironment (TME) and eliciting potent antitumor effects. We hypothesized that local delivery of MS to the TME may also drain to and therefore target the TDLN to initiate antitumor immune responses. METHODS: Fluorescent MS were injected into orthotopically implanted murine pancreatic tumors, and tissues were examined by whole-mount microscopy and imaging flow cytometry. The role of the TDLN was investigated for mice treated with intratumoral interleukin-12 (IL-12)-encapsulated MS in combination with stereotactic body radiotherapy (SBRT) by cytokine profile and TDLN ablation. RESULTS: Fluorescent AF-594 MS delivered intratumorally were detected in the tumor, peritumoral lymphatics, and the TDLN 2 h after injection. Phagocytic cells were observed with internalized fluorescent MS. SBRT + IL-12 MS-induced upregulation of Th1 and antitumor factors IL-12, IFN-γ, CXCL10, and granzyme B in the TDLN, and excision of the TDLN partially abrogated treatment efficacy. CONCLUSIONS: Our results demonstrate that intratumorally administered MS not only target the TME, but also drain to the TDLN. Furthermore, MS encapsulated with a potent antitumor cytokine, IL-12, induce an antitumor cytokine profile in the TDLN, which is essential for treatment efficacy.

Infections due to multidrug-resistant organisms following heart transplantation: Epidemiology, microbiology, and outcomes.

BACKGROUND: Infections secondary to multidrug-resistant organisms (MDRO) have emerged as a growing problem in solid organ transplantation (SOT). Most of the published data on MDRO infections in SOT pertains to abdominal organ transplantation and data specific to heart transplantation (HT) are limited. METHODS: This is a retrospective review of HT recipients at our institution from 2011 to 2016; with the aim to investigate the epidemiology, microbiologic spectrum, and outcomes in patients with post-HT MDRO infections, classified as multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) using standardized definitions. RESULTS: Of the 149 HT recipients, 82 episodes of bacterial infection were seen in 46 patients (31%) in the year following HT. Thirty (37%) were due to MDR pathogens and 13 (16%) were XDR. The most common gram-negative MDR pathogens were extended-spectrum beta-lactamase (ESBL) Escherichia coli and Klebsiella pneumoniae; while XDR pathogens were most commonly Pseudomonas aeruginosa followed by carbapenem-resistant Klebsiella pneumoniae. Majority of infection episodes were bloodstream (54, 66%) followed by pulmonary infection (20, 24%). Within a year after transplant, HT recipients with any bacterial infection had significantly higher mortality versus those without infection; and XDR infections were associated with a 26-fold greater hazard of death on average compared to those without infection (adjusted HR, 26.1; 95% CI, 6.4-107.0; P < .001). There were no PDR infections. CONCLUSION: Bacterial infections were a significant predictor of 1-year post-HT mortality, which was highest among those with XDR infections. This study highlights the burden of MDRO infections in HT recipients and identifies an area of future research.

Archaeal Unfoldase Counteracts Protein Misfolding Retinopathy in Mice.

Deregulation of cellular proteostasis due to the failure of the ubiquitin proteasome system to dispose of misfolded aggregation-prone proteins is a hallmark of various neurodegenerative diseases in humans. Microorganisms have evolved to survive massive protein misfolding and aggregation triggered by heat shock using their protein-unfolding ATPases (unfoldases) from the Hsp100 family. Because the Hsp100 chaperones are absent in homoeothermic mammals, we hypothesized that the vulnerability of mammalian neurons to misfolded proteins could be mitigated by expressing a xenogeneic unfoldase. To test this idea, we expressed proteasome-activating nucleotidase (PAN), a protein-unfolding ATPase from thermophilic Archaea, which is homologous to the 19S eukaryotic proteasome and similar to the Hsp100 family chaperones in rod photoreceptors of mice. We found that PAN had no obvious effect in healthy rods; however, it effectively counteracted protein-misfolding retinopathy in Gγ1 knock-out mice. We conclude that archaeal PAN can rescue a protein-misfolding neurodegenerative disease, likely by recognizing misfolded mammalian proteins.SIGNIFICANCE STATEMENT This study demonstrates successful therapeutic application of an archaeal molecular chaperone in an animal model of neurodegenerative disease. Introducing the archaeal protein-unfolding ATPase proteasome-activating nucleotidase (PAN) into the retinal photoreceptors of mice protected these neurons from the cytotoxic effect of misfolded proteins. We propose that xenogeneic protein-unfolding chaperones could be equally effective against other types of neurodegenerative diseases of protein-misfolding etiology.

Changes in comorbidities, diagnoses, therapies and outcomes in a contemporary cardiac intensive care unit population.

Prior studies have demonstrated that the cardiac intensive care unit (CICU) patient population has evolved over time. We sought to describe the temporal changes in comorbidities, illness severity, diagnoses, procedures and adjusted mortality within our CICU practice in recent years. METHODS: We retrospectively reviewed unique CICU admissions at the Mayo Clinic from January 2007 to April 2018. Comorbidities, severity of illness scores, discharge diagnosis codes and CICU procedures and therapies were recorded, and temporal trends were assessed using linear regression and Cochran-Armitage trend tests. Trends in adjusted hospital mortality over time were assessed using multivariable logistic regression. RESULTS: We included 12,418 patients with a mean age of 67.6 years (including 37.7% females). Temporal trends in the prevalence of several comorbidities and discharge diagnoses were observed, reflecting an increase in the prevalence of non-coronary cardiovascular diseases, critical care diagnoses, and organ failure (all P ≪ .05). The use of several CICU therapies and procedures increased over time, including mechanical ventilation, invasive lines and vasoactive drugs (all P ≪ .05). A temporal decrease in adjusted hospital mortality was observed among the subgroup of patients with (adjusted OR per year 0.97, 95% CI 0.94-0.99, P = .023) and without (adjusted OR per year 0.91, 95% CI 0.85-0.96, P = .002) a critical care discharge diagnosis. CONCLUSIONS: We observed an increasing prevalence of critical care and organ failure diagnoses as well as increased utilization of critical care therapies in this CICU cohort, associated with a decrease in risk-adjusted hospital mortality over time.

Diagnosis of Invasive Fungal Infection Among Pediatric Oncology Patients.

INTRODUCTION: The diagnosis of pulmonary invasive fungal infection (IFI) in the pediatric oncology patient is challenging. Consensus criteria developed in 2008 state that bronchioalveolar lavage (BAL) results cannot confirm this diagnosis. A video-assisted thoracoscopic biopsy (VATS-biopsy) of lungs has been increasingly used to assist in evaluating these children for IFI. Our goal was to evaluate the impact of BAL and VATS-biopsy results on the management of IFI among pediatric oncology patients. METHODS: A retrospective review of all oncology patients evaluated for IFI with VATS-biopsy and/or BAL over 9 years was carried out at a single free-standing children's hospital. The primary outcome was management changes in the use of antifungal therapy on the basis of diagnostic procedure, fungal culture results, lung imaging, and serological markers. RESULTS: A total of 102 patients underwent 122 diagnostic evaluations for IFI. Ninety-one workups included only BAL, 17 evaluations involved only VATS-biopsy, and 14 cases involved both BAL and VATS-biopsy. The diagnostic yield of VATS-biopsy (38.7%) was superior to that of BAL (27.6%). There was poor concordance between VATS-biopsy and BAL results in the 14 cases where both were performed. Upon workup completion, IFI was proven in 12 children, probable in 29, and possible in 52. The odds of continuing antifungals increased 3-fold for patients with probable IFI and 12.7 times for those with the proven disease. DISCUSSION: On the basis of the inferior diagnostic yield of BAL, we believe that VATS-biopsy may be a more useful diagnostic adjuvant in the diagnosis of IFI in the immunocompromised pediatric oncologic patient population.

Identification of health-related behavioural clusters and their association with demographic characteristics in Irish university students.

BACKGROUND: Students engage in risky health-related behaviours that influence their current and future health status. Health-related behaviours cluster among adults and differently based on sub-populations characteristics but research is lacking for university populations. Examining the clustering of health- related behaviours can inform our initiatives and strategies, while examining cluster members' characteristics can help target those who can prosper most from health promotion efforts. This study examines the clustering of health-related behaviours in Irish university students, and investigates the relationship with students' sex, age, field of study and accommodation type. METHODS: An online survey was completed by 5672 Irish university students (51.3% male; 21.60 ± 5.65 years) during 2014. Two-step cluster analysis was used to understand how health-related behaviours (physical activity, smoking, alcohol intake, drug use and dietary habits) cluster among male and female students. Binary logistic regressions were conducted to examine the likelihood of students falling into certain clusters based on their characteristics. RESULTS: Five cluster groups were identified in males and four in females. A quarter of males were categorised as ideal healthy with older students and those from certain fields of study having a higher likelihood of being classified in a low physical activity and poor diet (OR = 1.06-2.89), alcohol consumption (OR = 1.03-3.04), or smoking and drug use (OR = 1.06-2.73) cluster. Forty-five percent of females were categorised as ideal healthy with older females more likely to be in a low active and smoking cluster (OR = 1.03), and less likely to be in a convenience food cluster (OR = 0.96). Females from certain fields of study were also more likely to be classified in these clusters (OR = 1.59-1.76). Students living away from their family home had in increased likelihood of being in a cluster related to a higher frequency of alcohol consumption (OR = 1.72-3.05). CONCLUSION: Health-related behaviours cluster among this population and need to be taken into account when designing multi-health interventions and policies. These findings can be used to target student groups at risk, leading to more efficient and successful health promotion efforts. The addition of modules providing information regarding health-related behaviours are advised in all fields of study.