The Mammalian Ribo-interactome Reveals Ribosome Functional Diversity and Heterogeneity.

During eukaryotic evolution, ribosomes have considerably increased in size, forming a surface-exposed ribosomal RNA (rRNA) shell of unknown function, which may create an interface for yet uncharacterized interacting proteins. To investigate such protein interactions, we establish a ribosome affinity purification method that unexpectedly identifies hundreds of ribosome-associated proteins (RAPs) from categories including metabolism and cell cycle, as well as RNA- and protein-modifying enzymes that functionally diversify mammalian ribosomes. By further characterizing RAPs, we discover the presence of ufmylation, a metazoan-specific post-translational modification (PTM), on ribosomes and define its direct substrates. Moreover, we show that the metabolic enzyme, pyruvate kinase muscle (PKM), interacts with sub-pools of endoplasmic reticulum (ER)-associated ribosomes, exerting a non-canonical function as an RNA-binding protein in the translation of ER-destined mRNAs. Therefore, RAPs interconnect one of life's most ancient molecular machines with diverse cellular processes, providing an additional layer of regulatory potential to protein expression.

Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer.

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.

Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases.

To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-ß/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.

Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.

Oncogenic Kras drives invasion and maintains metastases in colorectal cancer.

Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Krasmut ) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Krasmut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-ß pathway as a key mediator of Krasmut -driven invasiveness. Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases.

Global reductions in manual agricultural work capacity due to climate change.

Manual outdoor work is essential in many agricultural systems. Climate change will make such work more stressful in many regions due to heat exposure. The physical work capacity metric (PWC) is a physiologically based approach that estimates an individual's work capacity relative to an environment without any heat stress. We computed PWC under recent past and potential future climate conditions. Daily values were computed from five earth system models for three emission scenarios (SSP1-2.6, SSP3-7.0, and SSP5-8.5) and three time periods: 1991-2010 (recent past), 2041-2060 (mid-century) and 2081-2100 (end-century). Average daily PWC values were aggregated for the entire year, the growing season, and the warmest 90-day period of the year. Under recent past climate conditions, the growing season PWC was below 0.86 (86% of full work capacity) on half the current global cropland. With end-century/SSP5-8.5 thermal conditions this value was reduced to 0.7, with most affected crop-growing regions in Southeast and South Asia, West and Central Africa, and northern South America. Average growing season PWC could falls below 0.4 in some important food production regions such as the Indo-Gangetic plains in Pakistan and India. End-century PWC reductions were substantially greater than mid-century reductions. This paper assesses two potential adaptions-reducing direct solar radiation impacts with shade or working at night and reducing the need for hard physical labor with increased mechanization. Removing the effect of direct solar radiation impacts improved PWC values by 0.05 to 0.10 in the hottest periods and regions. Adding mechanization to increase horsepower (HP) per hectare to levels similar to those in some higher income countries would require a 22% increase in global HP availability with Sub-Saharan Africa needing the most. There may be scope for shifting to less labor-intensive crops or those with labor peaks in cooler periods or shift work to early morning.

Unexpected thermal stability of two enveloped megaviruses, Emiliania huxleyi virus and African swine fever virus, as measured by viability PCR.

BACKGROUND: The particle structure of Emiliania huxleyi virus (EhV), an algal infecting member of nucleocytoplasmic large DNA viruses (NCLDVs), contains an outer lipid membrane envelope similar to that found in animal viruses such as African swine fever virus (ASFV). Despite both being enveloped NCLDVs, EhV and ASFV are known for their stability outside their host environment. METHOD: Here we report for the first time, the application of a viability qPCR (V-qPCR) method to describe the unprecedented and similar virion thermal stability of both EhV and ASFV. This result contradicts the cell culture-based assay method that suggests that virus "infectivity" is lost in a matter of seconds (for EhV) and minutes (for ASFV) at temperature greater than 50 °C. Confocal microscopy and analytical flow cytometry methods was used to validate the V-qPCR data for EhV. RESULTS: We observed that both EhV and ASFV particles has unprecedented thermal tolerances. These two NCLDVs are exceptions to the rule that having an enveloped virion anatomy is a predicted weakness, as is often observed in enveloped RNA viruses (i.e., the viruses causing Porcine Reproductive and Respiratory Syndrome (PRRS), COVID-19, Ebola, or seasonal influenza). Using the V-qPCR method, we confirm that no PRRSV particles were detectable after 20 min of exposure to temperatures up to 100 °C. We also show that the EhV particles that remain after 50 °C 20 min exposure was in fact still infectious only after the three blind passages in bioassay experiments. CONCLUSIONS: This study raises the possibility that ASFV is not always eliminated or contained after applying time and temperature inactivation treatments in current decontamination or biosecurity protocols. This observation has practical implications for industries involved in animal health and food security. Finally, we propose that EhV could be used as a surrogate for ASFV under certain circumstances.

Pharmacokinetics of vancomycin in sputum of intubated patients: Optimized intravenous delivery vs. inhaled therapy.

AIMS: Intubated patients with methicillin-resistant Staphylococcus aureus pneumonia, fail optimized treatment with intravenous (IV) vancomycin (serum trough 15-20 µg/mL) in 38-79% of cases. Airway blood flow is diminished compared to alveoli and we hypothesized that vancomycin concentrations achieved in airway secretions are suboptimal and nonbactericidal. Targeted therapy by inhalation may overcome this deficit. METHODS: Airway pharmacokinetics of optimized IV and inhaled vancomycin in infected clinically stable prolonged mechanically ventilated patients were measured. First, IV vancomycin was given until optimized concentrations were achieved (15-20 µg/mL), and, at the same time point, sputum vancomycin concentrations were measured. Then, sputum concentrations were re-assessed after 4 treatments of inhaled vancomycin (120 mg/2 mL) via a previously characterized nebulizing system that deposited 18 ± 2 mg in the lungs. Vancomycin post-distribution phase serum peak and trough concentrations were also obtained. Serum albumin was measured to assess binding to vancomycin. RESULTS: Mean serum trough concentration was 18.4 ± 6.5 µg/mL. Sputum concentrations were affected by serum albumin. Only patients with severe hypoalbuminaemia had penetration of drug leading to therapeutic (15.7-17 µg/mL) sputum concentrations. Following inhaled vancomycin, sputum concentrations increased significantly to 199 ± 37.0 µg/mL (P = .002) exceeding minimum inhibitory concentration by 2 orders of magnitude. CONCLUSION: Despite optimized serum concentrations, patients with albumin near normal had suboptimal concentrations of vancomycin in their sputum. Inhaled therapy may be clinically important for successful treatment of ventilator-associated methicillin-resistant Staphylococcus aureus infection. Further studies of inhaled therapy are needed to define their role as adjunctive therapy in ventilator-associated pneumonia and as single therapy in tracheobronchitis.

History and Iatrogenic Effects of Conversion Therapy.

Research indicates that sexual orientation change efforts (SOCEs) are not effective and furthermore commonly lead to iatrogenic effects such as depression, anxiety, and even suicide. Negative attitudes toward homosexuality derive from most formal religions and are incarnated in medical and psychological theories that support and encourage SOCEs. Oppression of sexual minorities makes it unlikely that change requests by patients are voluntary. Recently there has been a dramatic change as the field moves from reparative to affirmative approaches. Here, we review the history of SOCEs, their consequences, current affirmative treatments, and future directions in the field as they pertain to the well-being of the queer community. From an institutional community psychology perspective, we argue that even if true conversion were possible, such efforts are unethical and should not be pursued even if requested. As is the case with all psychological/psychiatric interventions, the issue is not "can" but "ought."

The mast cell stimulator compound 48/80 causes urothelium-dependent increases in murine urinary bladder contractility.

Mast cells and degranulation of preformed inflammatory mediators contribute to lower urinary tract symptoms. This study investigated pathways by which the mast cell stimulator compound 48/80 alters urinary bladder smooth muscle contractility via mast cell activation. We hypothesized that 1) mast cell degranulation causes spontaneous urinary bladder smooth muscle contractions and 2) these contractions are caused by urothelium-derived PGE2. Urothelium-intact and -denuded urinary bladder strips were collected from mast cell-sufficient (C57Bl/6) and mast cell-deficient (B6.Cg-Kitw-sh) mice to determine if compound 48/80 altered urinary bladder smooth muscle (UBSM) contractility. Electrical field stimulation was used to assess the effects of compound 48/80 on nerve-evoked contractions. Antagonists/inhibitors were used to identify prostanoid signaling pathways activated or if direct activation of nerves was involved. Compound 48/80 caused slow-developing contractions, increased phasic activity, and augmented nerve-evoked responses in both mast cell-sufficient and -deficient mice. Nerve blockade had no effect on these responses; however, they were eliminated by removing the urothelium. Blockade of P2 purinoreceptors, cyclooxygenases, or G protein signaling abolished compound 48/80 responses. However, only combined blockade of PGE2 (EP1), PGF2α (FP), and thromboxane A2 (TP) receptors inhibited compound 48/80-induced responses. Thus, the effects of compound 48/80 are urothelium dependent but independent of mast cells. Furthermore, these effects are mediated by druggable inflammatory pathways that may be used to manage inflammatory nonneurogenic bladder hyperactivity. Finally, these data strongly suggest that great care must be taken when using compound 48/80 to determine mast cell-dependent responses in the urinary bladder.NEW & NOTEWORTHY Urothelial cells are first responders to noxious contents of the urine. Our study demonstrates that the urothelium is not only a barrier but also a modulator of urinary bladder smooth muscle phasic activity and contractility independent of immune cell recruitment in response to an inflammatory insult.

Modeling National Embedded Phosphorus Flows of Corn Ethanol Distillers' Grains to Elucidate Nutrient Reduction Opportunities.

Freshwater quality and ecosystem impairment associated with excess phosphorus (P) loadings have led to federally mandated P reduction for certain organic waste streams. Phosphorus reduction from livestock and poultry feeds such as corn ethanol distillers' grains (DGs) presents a centralized strategy for reducing P loss from animal manurein agriculturally intensive states, but little is known about the actual distribution and geospatial P contributions of DGs as animal feed. Here, a county-level flow network for corn ethanol DGs was simulated in the United States to elucidate opportunities for P reduction and the potential for nutrient trading between centralized sources. Overall, the estimated P in DGs that was transferred to US animal feeding operations was nearly twice that present in all human waste prior to treatment. Simulation results suggest that Midwestern states account for an estimated 63% of domestic DG usage, with 72% utilized within the state of production. County-level data were also used to highlight the potential of using nutrient trading markets to incentivize P recovery from DGs at biorefineries within an agriculturally intensive watershed region in Iowa. In summary, corn ethanol biorefineries represent a key leverage point for sustainable P management at the national and local scales.

Histamine receptors rapidly desensitize without altering nerve-evoked contractions in murine urinary bladder smooth muscle.

Histamine has been implicated in urinary bladder dysfunction as an inflammatory mediator driving sensory nerve hypersensitivity. However, the direct influence of histamine on smooth muscle has not been thoroughly investigated. We hypothesized that histamine directly contracts urinary bladder smooth muscle (UBSM) independent of effects on nerves. Single cell quantitative RT-PCR determined that only histamine H1 and H2 receptors were expressed on UBSM cells. In isolated tissue bath experiments, histamine (200 µM) caused a highly variable and rapidly desensitizing contraction that was completely abolished by the H1 receptor antagonist fexofenadine (5 µM) and the Gq/11 inhibitor YM254890 (1 µM). Neither the muscarinic receptor antagonist atropine (1 µM), the Na+ channel blocker tetrodotoxin (1 µM), nor the transient receptor potential vanilloid type 1 antagonist capsazepine (10 µM) altered responses to histamine, suggesting that nerve activation was not involved. UBSM desensitization to histamine was not due to receptor internalization, as neither the cholesterol-depleting agent methyl-ß-cyclodextrin (10 mM), the dynamin-mediated endocytosis inhibitor dynasore (100 µM), nor the clathrin-mediated endocytosis inhibitor pitstop2 (15 µM) augmented or prolonged histamine contractions. Buffer from desensitized tissues still contracted histamine-naïve tissues, revealing that histamine was not metabolized. Prolonged exposure to histamine also had no effect on contractions due to electrical field stimulation, suggesting that both efferent nerve and UBSM excitability were unchanged. Together, these data suggest that histamine, although able to transiently contract UBSM, does not have a lasting effect on UBSM excitability or responses to efferent nerve input. Thus, any acute effects of histamine directly on UBSM contractility are unlikely to alter urinary bladder function.NEW & NOTEWORTHY Histamine is commonly associated with inflammatory bladder pathologies. We sought to investigate the role of histamine on urinary bladder contractility. Histamine contracts the bladder, but this response is highly variable and desensitizes completely in minutes. This desensitization is not due to internalization of the receptor or metabolism of histamine. Because nerve-evoked contractions are also not increased in the presence of histamine, our findings suggest that histamine is not directly acting to change contractility.

Decreased nutrient digestibility due to viscosity is independent of the amount of dietary fibre fed to growing pigs.

Fibre content and its effect on chyme viscosity are associated with changes in the digestive system of humans and pigs. It is unclear if fibre content and viscosity affect digestive function independently or interactively. We evaluated apparent ileal digestibility (AID) of nutrients and intestinal function in thirty-six ileal-cannulated barrows fed for 29 d either maize-soyabean meal (MSBM) or high-fibre MSBM + 30 % distillers dried grains with solubles (MSBM + DDGS) modified to three levels of viscosity by adding 5 % non-viscous cellulose (CEL), 6·5 % medium-viscous carboxymethylcellulose (MCMC) or 6·5 % high-viscous CMC (HCMC). Digesta were collected on days 27 and 28 and intestinal samples on day 29. Feeding CMC, regardless of fibre content, increased viscosity of whole digesta (P = 0·003) and digesta supernatant (P < 0·0001) compared with CEL. Feeding MSBM + DDGS or CMC decreased AID of DM (P = 0·003; P < 0·0001) and crude protein (P = 0·02; P < 0·0001) compared with MSBM or CEL. Feeding CMC regardless of fibre content increased jejunal crypt depth (P = 0·02) and ileal goblet cell area (P = 0·004) compared with CEL. Adding DDGS or CMC did not affect villus height and gene expression of jejunal monosaccharide and amino acid transporters. Feeding HCMC, regardless of fibre content, elevated amylase activity by 46 and 50 % in jejunal (P = 0·03) and ileal digesta (P = 0·01) compared with CEL. In summary, diets with increased viscosity decreased nutrient digestibility and induced intestinal changes that were independent of the amount of fibre fed.

Rapid and longer-term effects of selective breeding for voluntary exercise behavior on skeletal morphology in house mice.

Selection experiments can elucidate the varying course of adaptive changes across generations. We examined the appendicular skeleton of house mice from four replicate High Runner (HR) lines bred for physical activity on wheels and four non-selected Control (C) lines. HR mice reached apparent selection limits between generations 17 and 27, running ~3-fold more than C. Studies at generations 11, 16, and 21 found that HR mice had evolved thicker hindlimb bones, heavier feet, and larger articular surface areas of the knee and hip joint. Based on biomechanical theory, any or all of these evolved differences may be beneficial for endurance running. Here, we studied mice from generation 68, plus a limited sample from generation 58, to test whether the skeleton continued to evolve after selection limits were reached. Contrary to our expectations, we found few differences between HR and C mice for these later generations, and some of the differences in bone dimensions identified in earlier generations were no longer statistically significant. We hypothesize that the loss of apparently coadapted lower-level traits reflects (1) deterioration related to a gradual increase in inbreeding and/or (2) additional adaptive changes that replace the functional benefits of some skeletal changes.

Precision Therapy for Brain Tumors in Hereditary Syndromes.

OPINION STATEMENT: Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.

Control de la fuente respiratoria mediante el uso de una mascarilla quirúrgica: un estudio in vitro.

RESUMENLa etiqueta para la tos y la higiene respiratoria son formas de control de la fuente de emisión cuyo uso se alienta para evitar la propagación de infecciones respiratorias. El uso de mascarillas quirúrgicas como medio de control de la fuente en términos de reducción de la exposición de terceros no se ha investigado. En este estudio diseñamos un modelo in vitro utilizando varias mascarillas faciales con el fin de evaluar su aporte a la reducción de la exposición cuando son utilizadas en la fuente infecciosa (Fuente) en comparación con la reducción proporcionada por las mascarillas usadas para la protección primaria (Receptor), así como los factores que contribuyen a cada una. En una cámara con diversos flujos de aire se exhalaron aerosoles radiomarcados desde una cabeza de maniquí de cara blanda ventilada, utilizando respiración periódica y tos (Fuente). En otro maniquí, al que se le colocó un filtro, se cuantificó la exposición del Receptor. Se probaron una mascarilla quirúrgica de ajuste natural, una mascarilla quirúrgica de ajuste seguro (SecureFit) y una mascarilla respiratoria autofiltrante de clase N95 (comúnmente conocida como "mascarilla autofiltrante N95") con y sin sello de vaselina. Con la tos, el control de la fuente (mascarilla quirúrgica/autofiltrante colocada en la Fuente) fue estadísticamente superior a la protección brindada por la mascarilla quirúrgica/mascarilla autofiltrante sin sellar en el Receptor (protección del Receptor) en todos los entornos. Para igualar el control de la fuente durante la tos, la mascarilla autofiltrante N95 debe estar sellada con vaselina. Durante la respiración periódica, el control de la fuente fue comparable o superior a la protección brindada por la mascarilla quirúrgica/autofiltrante en el Receptor. El control de la fuente mediante mascarillas quirúrgicas puede ser una importante defensa adicional contra la propagación de infecciones respiratorias. El ajuste de la mascarilla quirúrgica/autofiltrante combinado con los patrones de flujo de aire en un entorno determinado contribuye de manera significativa a la eficacia del control de la fuente. Los futuros ensayos clínicos deberían incluir un brazo de control de la fuente con mascarilla quirúrgica a fin de evaluar el aporte realizado por el control de la fuente a la protección general contra infecciones de transmisión aérea.

Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270.

Financial difficulties are associated with greater total pain and suffering among patients with advanced cancer: results from the COMPASS study.

BACKGROUND: The Universal Health Coverage goals call for access to affordable palliative care to reduce inequities in "total pain" and suffering. To achieve this, a patient-centred understanding of these inequities is required. AIM: To assess association of total pain and suffering (i.e. physical, psychological, social, and spiritual health outcomes) and perceived health care quality with financial difficulties among stage IV solid malignancy patients. DESIGN: Using baseline data from the COMPASS cohort study, we assessed total pain and suffering including physical (physical and functional well-being, pain, symptom burden), psychological (anxiety, depression, emotional well-being), social (social well-being), and spiritual (spiritual well-being, hope) outcomes and perceived health care quality (physician communication, nursing care, and coordination/responsiveness). Financial difficulties were scored by assessing patient perception of the extent to which their resources were meeting expenses for their treatments, daily living, and other obligations. We used multivariable linear/logistic regression to test association between financial difficulties and each patient-reported outcome. SETTING/PARTICIPANTS: Six hundred stage IV solid malignancy patients in Singapore. RESULTS: Thirty-five percent reported difficulty in meeting expenses. A higher financial difficulties score was associated with worse physical, psychological, social, spiritual outcomes, and lower perceived quality of health care coordination and responsiveness (i.e. greater total pain and suffering) (all p < 0.05). These associations persisted after adjustment for socio-economic indicators. CONCLUSION: Results identify advanced cancer patients with financial difficulties to be a vulnerable group with greater reported total pain and suffering. A holistic patient-centred approach to care at end-of-life may help meet goals for Universal Health Coverage.

Transition in Care from EMS Providers to Emergency Department Nurses: A Systematic Review.

Background: Transitions in care between emergency medical services (EMS) providers and emergency department (ED) nurses are critical to patient care and safety. However, interactions between EMS providers and ED nurses can be problematic with communication gaps and have not been extensively studied. The aim of this review was to examine (1) factors that influence transitions in care from EMS providers to ED nurses and (2) the effectiveness of interventional strategies to improve these transitions. Methods: We conducted a mixed-methods systematic review that included searches of electronic databases (DARE, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Joanna Briggs Institute EBP), gray literature databases, organization websites, querying experts in emergency medicine, and the reference lists cited in included studies. All English-language studies of any design were eligible for inclusion. Two reviewers independently screened titles/abstracts and full-texts for inclusion and methodological quality, as well as extracted data from included studies. We used narrative and thematic synthesis to integrate and explore relationships within the data. Results: In total, 8,348 studies were screened and 130 selected for full text review. The final synthesis included 20 studies. Across 15 studies of moderate-to-high methodological quality, 6 factors influenced transitions: different professional lenses, operational constraints, professional relationships, information shared between the professions, components of the transition process, and patient presentation and involvement. Three interventions were identified in 6 methodologically weak studies: (1) transition guideline (DeMIST, Identification, Mechanism/Medical complaint, Injuries/Information related to the complaint, Signs, Treatment and Trends - Allergies, Medication, Background history, Other information [IMIST-AMBO]) with training, (2) mobile web-based technology (EMS smartphone and geographic information system location data), and (3) a new clinical role (ED ambulance off-load nurse dedicated to triaging and assessing EMS patients). There were mixed findings for the effectiveness of transition guidelines and the new clinical role. Mobile technology was seen positively by both EMS providers and ED nurses as helpful for better describing the pre-hospital context and for planning flow in the ED. Conclusion: While multimedia applications may potentially improve the handoff process, future intervention studies need to be rigorously designed. We recommend interdisciplinary training of EMS and ED staff in the use of flexible structured protocols, especially given review findings that interdisciplinary communication and relationships can be challenging.