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Cancer Biomarkers are the key to unlocking the promise of precision oncology, selecting which patients will respond to a more personalised treatment while sparing non-responders the therapy-related toxicity. In this paper, we highlight the primacy of cancer biomarkers, but focus on their importance to patients and to health systems. We also highlight how cancer biomarkers represent value for money. We emphasise the need for cancer biomarkers infrastructure to be embedded into European health systems. We also highlight the need to deploy multiple biomarker testing to deliver the optimal benefit for patients and health systems and consider cancer biomarkers from the perspective of cost, value and regulation. Cancer biomarkers must also be situated in the context of the upcoming In Vitro Diagnostics Regulation, which may pose certain challenges (e.g. non-compliance of laboratory developed tests, leading to cancer biomarker shortages and increased costs) that need to be overcome. Cancer biomarkers must be embedded in the real world of oncology delivery and testing must be implemented across Europe, with the intended aim of narrowing, not widening the inequity gap for patients. Cancer patients must be placed firmly at the centre of a cancer biomarker informed precision oncology care agenda.

Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits

The authors examined whether there were positive spillovers in opioid use disorder medication prescribing to Medicare Part D beneficiaries in Medicaid expansion states. Although prior studies have shown several positive benefits of Medicaid expansion for Americans with opioid use disorder, research has not examined potential spillovers to Medicare beneficiaries who have been hit hard by the opioid crisis.Prescribing data were taken from the Medicare Part D Prescription Public Use File (2010-2017). A difference-in-differences linear regression framework was used to identify spillovers in prescribing of buprenorphine and injectable naltrexone to Medicare Part D beneficiaries in Medicaid expansion states. Three sets of dependent variables measured medication prescribing at the county-year level (N=24,850). All models included county and year fixed effects, with standard errors clustered at the state level to address within-state serial correlation.Medicaid expansion was associated with an increase in the probability of a county having an injectable naltrexone provider (p0.01). After expansion, the number of buprenorphine providers in expansion states increased by 5.6% (p0.05), and the number of injectable naltrexone providers increased by 3.3% (p0.01), relative to nonexpansion states. Expansion was associated with a 23.1% (p0.01) increase in the number of daily doses of injectable naltrexone, relative to nonexpansion states.Medicaid expansion states may be better equipped to address the opioid crisis because of direct benefits to Medicaid beneficiaries and availability of opioid use disorder medications for Medicare Part D beneficiaries. However, additional efforts are likely needed to close the opioid use disorder treatment gap for Medicare beneficiaries.

The percentage of individuals who are functionally bilingual in the United States has grown substantially in the last 3 to 4 decades. Nevertheless, bilingual mental health providers remain relatively scarce and bilingualism in psychosis or schizophreniaspectrum disorders remains relatively unexplored. Here, we present a clinical case study of a man with schizophrenia who presented his psychotic symptoms differently in his primary and secondary languages. We also consider this case in the context of other published cases with similar themes. Based on our review, we hypothesize that the presentation of psychotic symptoms may be influenced by the language a person uses, and more specifically, by their cognitive abilities to speak that language and/or their emotional attachment to that language. We outline the importance of obtaining a thorough language background of each patient with psychosis and investigate the ways in which a second language could serve as a protective factor against functional decline in psychotic and healthy populations. We suggest that attempts to engage bilingual patients with psychosis clinically in each language could lead to a more holistic evaluation of psychotic and disorganized symptoms and thus lead to more multidimensional intervention strategies.

Objectives Tumor vasculature is structurally abnormal, with anatomical deformities, reduced pericyte coverage and low tissue perfusion. As a result of this vascular dysfunction, tumors are often hypoxic, which is associated with an aggressive tumor phenotype, and reduced delivery of therapeutic compounds to the tumor. We have previously shown that a peptide containing the thrombospondin-1 type I repeats (3TSR) specifically targets tumor vessels and induces vascular normalization in a mouse model of epithelial ovarian cancer (EOC). However, due to its small size, 3TSR is rapidly cleared from circulation. We now introduce a novel construct with the 3TSR peptide fused to the C-terminus of each of the two heavy chains of the Fc region of human IgG1 (Fc3TSR). We hypothesize that Fc3TSR will have greater anti-tumor activity in vitro and in vivo compared to the native compound. Methods Fc3TSR was evaluated in vitro using proliferation and apoptosis assays to investigate differences in efficacy compared to native 3TSR. In light of the multivalency of Fc3TSR, we also investigate whether it induces greater clustering of its functional receptor, CD36. We also compare the compounds in vivo using an orthotopic, syngeneic mouse model of advanced stage EOC. The impact of the two compounds on changes to tumor vasculature morphology was also investigated. Results Fc3TSR significantly decreased the viability and proliferative potential of EOC cells and endothelial cells in vitro compared to native 3TSR. High-resolution imaging followed by image correlation spectroscopy demonstrated enhanced clustering of the CD36 receptor in cells treated with Fc3TSR. This was associated with enhanced downstream signaling and greater in vitro and in vivo cellular responses. Fc3TSR induced greater vascular normalization and disease regression compared to native 3TSR in an orthotopic, syngeneic mouse model of advanced stage ovarian cancer. Conclusion The development of Fc3TSR which is greater in size, stable in circulation and enhances receptor activation compared to 3TSR, facilitates its translational potential as a therapy in the treatment of metastatic advanced stage ovarian cancer.

The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multi-platform metabolic phenotyping with Nuclear Magnetic Resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Quantitative measurements of lipoprotein sub-fractions, alpha-1-acid glycoprotein, glucose and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested positive for the SARS-CoV-2 virus (n = 17) and from age and gender-matched controls (n = 25). Data were analyzed using an orthogonal-projections to latent structures (O-PLS) method and used to construct an exceptionally strong (AUROC=1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochemical relationships. Key discriminant metabolites included markers of inflammation including elevated alpha-1 acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides). Plus, multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer’s ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from additional SARS-CoV-2 positive patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidaemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study reference: MTBLS2014.

Background The risk of severe COVID-19 varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). Objective To examine whether deficits in IR that antedate or are induced by SARS-CoV-2 infection independently predict COVID-19 mortality. Methods IR levels were quantified with two novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n=522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n=13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to clinical outcomes. Results IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection associated with underrepresentation of IHG-I (21%) vs. overrepresentation (77%) of IHG-II or IHG-IV, especially in males vs. females (P Conclusion Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19. Clinical implications Biomarkers tracking immunologic resilience may have broad prognostic utility, as they associated with longevity, as well as resistance to a progressive disease course during SARS-CoV-2, influenza, or HIV infection.

BACKGROUND Warfarin is the only oral anticoagulant approved for use following mechanical valve surgery (MeVS). Patients may experience prolonged hospital length of stay (LOS) following MeVS awaiting an appropriate warfarin effect. We aimed to determine whether an association exists between time to achieve the first therapeutic international normalized ratio (INR) and LOS following MeVS. MATERIALS AND METHODS Retrospective single center cohort study. We included consecutive adult patients undergoing elective MeVS from 2013 to 2018. Landmark analyses and multivariable regression with time-updated INR were used to estimate the association between time to therapeutic INR (TTI) and LOS. RESULTS Among 384 patients (median age: 51 years, interquartile range [IQR]: 41-57; 58.3% male), the median TTI was 4 days (IQR: 2-5). Thirty seven percent of patients were discharged with a subtherapeutic INR, many on bridging anticoagulation or with an INR close to target. Those achieving therapeutic INR had an increased rate of hospital discharge (adjusted hazard ratio: 2.17; 95% confidence interval: 1.71-2.76; p

Dramatic fluctuations of west coast (USA) California sea lion (CSL) population sizes are well-known historical events. More recently, the episodes have involved extensive losses from pup starvation. However, beyond dams’ lactation failure that results from loss of preferred prey, proximate causes of malnutrition-related death among youngest CSL remain somewhat speculative. We hypothesized that age-related differences in presentation status and postmortem pathology would clarify elements of death trajectories. Records of 494 California sea lions included young pups to late adolescents, all present in the same environment and ecology. We identified differential starvation-related im-pacts among young CSL populations. Rapid and extreme loss of muscle and fat body mass, and resulting emaciation, were the primary overall features of morbidity. More specifically, the death trajectory among young pups was associated more proximately with contributing fluid deficit, hypovolemia, hypoglycemia, and loss of respiratory capacity. The death trajectory among non-pups was associated more proximately with negative effects of forced diet change that resulted in severe-to-overwhelming chronic parasitism. The vast majority of death trajectories appeared to be non-reversible, either in short term or over longer term. The sentinel status of marine mammals such as CSL forewarns of potential threats to local or regional ecology. It is especially concerning if recurring similar events appear to differ causally from historical patterns. We suggest that starvation events occurring in seemingly new patterns can signal new influences on a marine ecology.

Precision diagnostic testing (PDT) employs appropriate biomarkers to identify cancer patients that may optimally respond to precision medicine (PM) approaches, such as treatments with targeted agents and immuno‐oncology drugs. To date, there are no published systematic appraisals evaluating the cost‐effectiveness of PDT in non‐small‐cell lung cancer (NSCLC). To address this gap, we conducted Preferred Reporting Items for Systematic Reviews and Meta‐Analyses searches for the years 2009–2019. Consolidated Health Economic Evaluation Reporting Standards were employed to screen, assess and extract data. Employing base costs, life years gained or quality‐adjusted life years, as well as willingness‐to‐pay (WTP) threshold for each country, net monetary benefit was calculated to determine cost‐effectiveness of each intervention. Thirty‐seven studies (50%) were included for analysis; a further 37 (50%) were excluded, having failed population‐, intervention‐, comparator‐, outcomes‐ and study‐design criteria. Within the 37 studies included, we defined 64 scenarios. Eleven scenarios compared PDT‐guided PM with non‐guided therapy [epidermal growth factor receptor (EGFR), n = 5; programmed death‐ligand 1 (PD‐L1), n = 6]. Twenty‐eight scenarios compared PDT‐guided PM with chemotherapy alone (anaplastic lymphoma kinase, n = 3; EGFR, n = 17; PD‐L1, n = 8). Twenty‐five scenarios compared PDT‐guided PM with chemotherapy alone, while varying the PDT approach. Thirty‐four scenarios (53%) were cost‐effective, 28 (44%) were not cost‐effective, and two were marginal, dependent on their country’s WTP threshold. When PDT‐guided therapy was compared with a therapy‐for‐all patients approach, all scenarios (100%) proved cost‐effective. Seven of 37 studies had been structured appropriately to assess PDT‐PM cost‐effectiveness. Within these seven studies, all evaluated scenarios were cost‐effective. However, 81% of studies had been poorly designed. Our systematic analysis implies that more robust health economic evaluation could help identify additional approaches towards PDT cost‐effectiveness, underpinning value‐based care and enhanced outcomes for patients with NSCLC., Precision diagnostic testing guides therapy to non‐small‐cell lung carcinoma (NSCLC) patients who will best respond, increasing both quantity and quality of life. Our analysis demonstrates the inherent value of precision medicines for NSCLC patients in over half of cases. However, to build the health economic evidence base further, cost‐effectiveness analyses should be appropriately designed to maximise the potential of precision diagnostic testing.

Objectives To determine if three short daily sessions of physiotherapy for rehabilitation inpatients after hip fracture is more effective than providing one long daily session in improving mobility. Design A single-blinded randomised controlled trial. Setting Two inpatient rehabilitation wards at a hospital in Melbourne, Australia. Participants Seventy-six rehabilitation inpatients after hip fracture. The key exclusion criterion was not being allowed to weight bear. Interventions All participants received multidisciplinary rehabilitation. Experimental participants received three 15-minute sessions of physiotherapy 5 days per week until discharge. Control participants received one 45-minute session of physiotherapy 5 days per week until discharge. Main outcome measures The primary outcome, mobility, was assessed with the de Morton Mobility Index 2 weeks after admission and at discharge. Secondary outcomes were Functional Independence Measure mobility (transfers, ambulation, steps), physical activity measured with an accelerometer, length of stay, discharge destination, readmissions within 30 days of discharge, and patient and physiotherapist satisfaction. Results Sixty-seven (88%) participants completed mobility assessment at discharge and 34 (45%) at 2 weeks. There were a greater proportion of missed sessions in the experimental group (84% adherence vs 95%). There was no between-group difference in mobility at discharge (MD −1.9 points, 95%CI−6.9 to 3.2) or at 2 weeks (MD −3.5 points, 95%CI−15.4 to 8.4). There were no between-group differences in any secondary outcomes. Conclusions: Providing inpatient physiotherapy rehabilitation in three shorter sessions resulted in more missed sessions and likely did not improve mobility outcomes compared with providing one longer session for patients recovering from hip fracture. Clinical trial registration number ACTRN 12617000863336.

We aimed to determine the association between sepsis and long-term cardiovascular events. We conducted a systematic review of observational studies evaluating post-sepsis cardiovascular outcomes in adult sepsis survivors. MEDLINE, Embase, and the Cochrane Controlled Trials Register and Database of Systematic Reviews were searched from inception until April 21st, 2021. Two reviewers independently extracted individual study data and evaluated risk of bias. Random-effects models estimated the pooled crude cumulative incidence and adjusted hazard ratios (aHRs) of cardiovascular events compared to either non-septic hospital survivors or population controls. Primary outcomes included myocardial infarction, stroke, and congestive heart failure; outcomes were analysed at maximum reported follow-up (from 30 days to beyond 5 years post-discharge). Of 12,649 screened citations, 27 studies (25 cohort studies, 2 case-crossover studies) were included with a median of 4,289 (IQR 502–68,125) sepsis survivors and 18,399 (IQR 4,028–83,506) controls per study. The pooled cumulative incidence of myocardial infarction, stroke, and heart failure in sepsis survivors ranged from 3 to 9% at longest reported follow-up. Sepsis was associated with a higher long-term risk of myocardial infarction (aHR 1.77 [95% CI 1.26 to 2.48]; low certainty), stroke (aHR 1.67 [95% CI 1.37 to 2.05]; low certainty), and congestive heart failure (aHR 1.65 [95% CI 1.46 to 1.86]; very low certainty) compared to non-sepsis controls. Surviving sepsis may be associated with a long-term, excess hazard of late cardiovascular events which may persist for at least 5 years following hospital discharge.

Aims While myocardial ischaemia plays a major role in the pathogenesis of heart failure (HF), the indications for coronary angiography during acute HF are not established. We determined the association of early coronary angiography during acute HF hospitalization with 2-year mortality, cardiovascular death, HF readmissions, and coronary revascularization. Methods and results In a two-stage sampling process, we identified acute HF patients who presented to 70 emergency departments in Ontario (April 2010 to March 2013) and determined whether they underwent early coronary angiography within 14 days after presentation using administrative databases. After clinical record review, we defined a cohort with acute ischaemic HF as patients with at least one factor suggesting underlying ischaemic heart disease, including previous myocardial infarction, troponin elevation, or angina on presentation. We oversampled patients undergoing angiography. We used inverse-probability-of-treatment weighting (IPTW) to adjust for baseline differences. Of 7239 patients with acute HF, 2994 met inclusion criteria [median age 75 (interquartile range 65–83) years; 40.9% women]. Early angiography was performed in 1567 patients (52.3%) and was associated with lower all-cause mortality [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.61–0.90, P = 0.002], cardiovascular death (HR 0.72, 95% CI 0.56–0.93, P = 0.012), and HF readmissions (HR 0.84, 95% CI 0.71–0.99, P = 0.042) after IPTW. Those undergoing early angiography experienced higher rates of percutaneous coronary intervention (HR 2.58, 95% CI 1.73–3.86, P Conclusions Early coronary angiography was associated with lower all-cause mortality, cardiovascular death, HF readmissions, and higher rates of coronary revascularization in acute HF patients with possible ischaemia.

Emerging infectious disease epidemics require a rapid response from health systems; however, evidence-based consensus guidelines are generally absent early in the course of events. Formed in 2017 by 5 high-level isolation units spanning 3 continents, the experience of the Global Infectious Disease Preparedness Network (GIDPN) early in the course of coronavirus disease 2019 (COVID-19) provides a model for accelerating best practice development and improving decision-making in health emergencies. The network served as a platform for real-time, open and transparent information-sharing during unknowns of an active outbreak by clinicians caring for patients, by researchers conducting clinical trials and transmission and infection prevention studies, and by teams advising local and national policy makers. Shared knowledge led to earlier adoption of some treatment modalities as compared to most peer institutions and to implementation of protocols prior to incorporation into national guidelines. GIDPN and similar networks are integral in enhancing preparedness for and response to future epidemics/pandemics.

AIM To examine the impact of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on plasma and urine metabolites in participants with type 1 diabetes. MATERIAL AND METHODS Participants (n = 40, 50% male, mean age 24.3 years) with type 1 diabetes and without overt evidence of diabetic kidney disease had baseline assessments performed under clamped euglycaemia and hyperglycaemia, on two consecutive days. Participants then proceeded to an 8-week, open-label treatment period with empagliflozin 25 mg/day, followed by repeat assessments under clamped euglycaemia and hyperglycaemia. Plasma and urine metabolites were first grouped into metabolic pathways using MetaboAnalyst software. Principal component analysis was performed to create a representative value for each sufficiently represented metabolic group (false discovery rate ≤ 0.1) for further analysis. RESULTS Of the plasma metabolite groups, tricarboxylic acid (TCA) cycle (P

SIGIRR has been described as a negative regulator of several IL-1R/TLR family members and has been implicated in several inflammatory disease conditions. However, it is unknown whether it can suppress IL-36 family cytokines, which are members of the broader IL-1 superfamily that have emerged as critical orchestrators of psoriatic inflammation in both humans and mice. In this study, we demonstrate that SIGIRR is downregulated in psoriatic lesions in humans and mice, and this correlates with increased expression of IL-36 family cytokines. Using Sigirr−/− mice, we identify, for the first time (to our knowledge), SIGIRR as a negative regulator of IL-36 responses in the skin. Mechanistically, we identify dendritic cells and keratinocytes as the primary cell subsets in which IL-36 proinflammatory responses are regulated by SIGIRR. Both cell types displayed elevated IL-36 responsiveness in absence of SIGIRR activity, characterized by enhanced expression of neutrophil chemoattractants, leading to increased neutrophil infiltration to the inflamed skin. Blockade of IL-36R signaling ameliorated exacerbated psoriasiform inflammation in Sigirr−/− mice and inhibited neutrophil infiltration. These data identify SIGIRR activity as an important regulatory node in suppressing IL-36–dependent psoriatic inflammation in humans and mice.

BACKGROUND The objective of this study was to describe bladder cancer outcomes as a function of race among patients with high-risk non-muscle-invasive bladder cancer (NMIBC) in an equal-access setting. METHODS A total of 412 patients with high-risk NMIBC who received bacille Calmette-Guerin (BCG) from January 1, 2010, to December 31, 2015, were assessed. The authors used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, disease-specific, and overall survival outcomes. RESULTS A total of 372 patients who had complete data were included in the analysis; 48 (13%) and 324 (87%) were Black and White, respectively. There was no difference in age, sex, smoking status, or Charlson Comorbidity Index by race. White patients had a higher socioeconomic status with a greater percentage of patients living above the poverty level in comparison with Black patients (median, 85% vs 77%; P < .001). A total of 360 patients (97%) received adequate induction BCG, and 145 patients (39%) received adequate maintenance BCG therapy. There was no significant difference in rates of adequate induction or maintenance BCG therapy according to race. There was no significant difference in recurrence (hazard ratio [HR], 1.53; 95% confidence interval [CI], 0.64-3.63), progression (HR, 0.77; 95% CI, 0.33-1.82), bladder cancer-specific survival (HR, 1.01; 95% CI, 0.30-3.46), or overall survival (HR, 0.97; 95% CI, 0.56-1.66) according to Black race versus White race. CONCLUSIONS In this small study from an equal-access setting, there was no difference in the receipt of BCG or any differences in bladder cancer outcomes according to race.

EXECUTIVE SUMMARY: This article describes the use and findings of the Hospital Medical Surge Preparedness Index (HMSPI) tool to improve the understanding of hospitals' ability to respond to mass casualty events such as the COVID-19 pandemic. For this investigation, data from the U.S. Census Bureau, the Dartmouth Atlas Project, and the 2005 to 2014 annual surveys of the American Hospital Association (AHA) were analyzed. The HMSPI tool uses variables from the AHA survey and the other two sources to allow facility, county, and referral area index calculations. Using the three data sets, the HMSPI also allows for an index calculation for per capita ratios and by political (state or county) boundaries. In this use case, the results demonstrated increases in county and state HMSPI scores through the period of analysis; however, no statistically significant difference was found in HMSPI scores between 2013 and 2014. The HMSPI builds on the limited scientific foundation of medical surge preparedness and could serve as an objective and standardized measure to assess the nation's medical readiness for crises such as the COVID-19 pandemic and other large-scale emergencies such as mass shootings. Future studies are encouraged to refine the score, assess the validity of the HMSPI, and evaluate its relevance in response to future legislative and executive policies that affect preparedness measures.

This exploratory pilot study examined perspectives of family members of young adults with a diagnosis of Autism Spectrum Disorder regarding the experiences, and level of support their child or sibl...

We have reached a watershed moment in Europe in our efforts to ensure increased survival and better outcomes for cancer patients. The EU Cancer Mission and the European Beating Cancer Plan together provide an unrivalled opportunity to make significant inroads into a disease that kills over 1.7 million European citizens annually. Harnessing these twin pillars of cancer research and cancer control can be transformative for the European cancer community and in particular for the European cancer patient. However, from a research perspective, in order to fully realise these benefits, we need to ensure that all aspects of the cancer continuum are addressed. Previous research efforts have focussed more on the diagnosis and treatment of cancer, whereas cancer survivorship, to date, has been overlooked. Here, we aim to redress this balance, by identifying the key challenges in cancer survivorship research that need to be addressed and proposing a series of recommended solutions, which, if acted upon, would deliver significant benefits for the nearly 20 million cancer survivors in Europe. To achieve this, we propose the development of a clearly articulated and sustainably funded European Cancer Survivorship Research and Innovation Plan. Embedding this plan within the framework of the EU Cancer Mission would be transformative for cancer survivors and society., Previous research efforts have focussed more on the diagnosis and treatment of cancer, and less so on cancer survivorship. Here, we identify the key challenges in cancer survivorship research and propose the development of a clearly articulated and sustainably funded European Cancer Survivorship Research and Innovation Plan to deliver significant benefits for the nearly 20 million cancer survivors in Europe.

Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD). Methods Participants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks. Results Ertugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed. Conclusion In conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function., Graphical abstract

Background Since 1995, 14 states have passed laws encouraging or mandating influenza vaccination for hospital workers. Although the Centers for Disease Control and Prevention recommends vaccinating health care workers to reduce disease transmission and patient risk, the effect of these laws on pneumonia and influenza mortality is unknown. Objective To measure the effect of state-level hospital worker influenza vaccination laws on pneumonia and influenza mortality. Design Quasi-experimental observational study. Setting United States. Participants Population of all states from 1995 to 2017. Intervention State adoption of a law promoting influenza vaccination for hospital workers. Measurements Pneumonia and influenza mortality per 100 000 persons by state and by month, both population-wide and separately by age group, obtained from restricted-access National Vital Statistics System files. Linear and log-linear models were used to compare changes in mortality rates for adopting versus nonadopting states. Results Implementation of state laws requiring hospitals to offer influenza vaccination to their employees was associated with a 2.5% reduction in the monthly pneumonia and influenza mortality rate (-0.16 deaths per 100 000 persons [95% CI, -0.29 to -0.02]; P = 0.022) during the years when the vaccine was well matched to the circulating strains. The largest effects occurred among elderly persons and during peak influenza months. Limitation Utilization of large-scale national data precluded analysis of more specific outcomes, such as laboratory-confirmed or hospital-acquired influenza. Conclusion State laws promoting hospital worker vaccination against influenza may be effective in preventing pneumonia- and influenza-related deaths, particularly among elderly persons. Vaccinating hospital workers may substantially reduce the spread of influenza and protect the most vulnerable populations. Primary funding source None.

Cardiogenic shock (CS) portends high morbidity and mortality in the contemporary era. Despite advances in temporary mechanical circulatory supports (MCS), their routine use in CS to improve outcomes has not been established. Delays in diagnosis and timely delivery of care, disparities in accessing adjunct therapies such revascularization or MCS, and lack of a systematic approach to care of CS contribute to the poor outcomes observed in CS patients. There is growing interest for developing a standardized multidisciplinary team‐based approach in the management of CS. Recent prospective studies have shown feasibility of CS teams in improving survival across a spectrum of CS presentations. Herein, we will review the rationale for CS teams focusing on evidence supporting its use in streamlining care, optimizing revascularization strategies, and patient identification and MCS selection. The proposed structure and flow of CS teams will be outlined. An in‐depth analysis of four recent studies demonstrating improved outcomes with CS teams is presented. Finally, we will explore potential implementation hurdles and future directions in refining and widespread implementation of dedicated cross‐specialty CS teams.

Systemic vascular inflammation plays multiple maladaptive roles which contribute to the progression and destabilization of atherosclerotic cardiovascular disease (ASCVD). These roles include: (i) driving atheroprogression in the clinically stable phase of disease; (ii) inciting atheroma destabilization and precipitating acute coronary syndromes (ACS); and (iii) responding to cardiomyocyte necrosis in myocardial infarction (MI). Despite an evolving understanding of these biologic processes, successful clinical translation into effective therapies has proven challenging. Realizing the promise of targeting inflammation in the prevention and treatment of ASCVD will likely require more individualized approaches, as the degree of inflammation differs among cardiovascular patients. A large body of evidence has accumulated supporting the use of high-sensitivity C-reactive protein (hsCRP) as a clinical measure of inflammation. Appreciating the mechanistic diversity of ACS triggers and the kinetics of hsCRP in MI may resolve purported inconsistencies from prior observational studies. Future clinical trial designs incorporating hsCRP may hold promise to enable individualized approaches. The aim of this Clinical Review is to summarize the current understanding of how inflammation contributes to ASCVD progression, destabilization, and adverse clinical outcomes. We offer forward-looking perspective on what next steps may enable successful clinical translation into effective therapeutic approaches—enabling targeting the right patients with the right therapy at the right time—on the road to more individualized ASCVD care.

Modern methods of acquiring molecular data have improved rapidly in recent years, making it easier for researchers to collect large volumes of information. However, this has increased the challenge of recognizing interesting patterns within the data. Atlas Correlation Explorer (ACE) is a user-friendly workbench for seeking associations between attributes in The Cancer Genome Atlas (TCGA) database. It allows any combination of clinical and genomic data streams to be searched using an evolutionary algorithm approach. To showcase ACE, we assessed which RNA sequencing transcripts were associated with estrogen receptor (ESR1) in the TCGA breast cancer cohort. The analysis revealed already well-established associations with XBP1 and FOXA1, but also identified a strong association with CT62, a potential immunotherapeutic target with few previous associations with breast cancer. In conclusion, ACE can produce results for very large searches in a short time and will serve as an increasingly useful tool for biomarker discovery in the big data era. Significance: ACE uses an evolutionary algorithm approach to perform large searches for associations between any combinations of data in the TCGA database.

Introduction: Out-of-hospital cardiac arrest (OHCA) is a major cause of death and disability in the United States. Cardiac arrest centers (CAC) are necessary for the management of these critically ill and complex post arrest patients due to their specialized services and provider expertise. We report the case of a patient with OHCA and the systems of care involved in his resuscitation and recovery. Case Report: Emergency medical services attended a 39-year-old male with ongoing bystander cardiopulmonary resuscitation (CPR) after a witnessed collapse. Despite receiving appropriate advanced cardiac life support, including three defibrillations, he remained in refractory ventricular fibrillation. A prehospital physician identified him as an extracorporeal cardiopulmonary resuscitation (ECPR) candidate due to his age, witnessed arrest, refractory rhythm, and functional status. He was expedited to a CAC but no longer qualified for ECPR due to the time limit. He was resuscitated by the multiple teams activated prior to his arrival. He eventually had sustained return of circulation, was taken to the catheterization lab for emergent percutaneous coronary intervention, and recovered with a good neurologic outcome. Conclusion: Cardiac arrest centers may be capable of advanced interventions including ECPR. However, the systems of care offered by these centers is itself a lifesaving intervention. As this case highlights, despite not receiving the specified intervention (ECPR) the systems of care required to offer such a resource led to this favorable outcome.

Background: Globally, reverse shoulder arthroplasty (RSA) has moved away from the Grammont design to modern prosthesis designs. The purpose of this study was to provide a focused, updated systematic review for each of the most common complications of RSA by limiting each search to publications after 2010. In this part II, the following were examined: (1) instability, (2) humerus/glenoid fracture, (3) acromial/scapular spine fractures (AF/SSF), and (4) problems/miscellaneous. Methods: Four separate PubMed database searches were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Overall, 137 studies for instability, 94 for humerus/glenoid fracture, 120 for AF/SSF, and 74 for problems/miscellaneous were included in each review, respectively. Univariate analysis was performed with chi-square and Fisher exact tests. Results: The Grammont design had a higher instability rate vs. all other designs combined (4.0%, 1.3%; P < .001), and the onlay humerus design had a lower rate than the lateralized glenoid design (0.9%, 2.0%; P = .02). The rate for intraoperative humerus fracture was 1.8%; intraoperative glenoid fracture, 0.3%; postoperative humerus fracture, 1.2%; and postoperative glenoid fracture, 0.1%. The rate of AF/SSF was 2.6% (371/14235). The rate for complex regional pain syndrome was 0.4%; deltoid injury, 0.1%; hematoma, 0.3%; and heterotopic ossification, 0.8%. Conclusions: Focused systematic reviews of recent literature with a large volume of shoulders demonstrate that using non-Grammont modern prosthesis designs, complications including instability, intraoperative humerus and glenoid fractures, and hematoma are significantly reduced compared with previous studies. As the indications continue to expand for RSA, it is imperative to accurately track the rate and types of complications in order to justify its cost and increased indications.

Objective To evaluate the dementia knowledge of allied health professionals and identify their specific learning needs. Methods An online survey was conducted with allied health professionals enrolled in the Understanding Dementia Massive Open Online Course, a free course open to anyone, worldwide. The primary outcome measure was the Dementia Knowledge Assessment Scale, assessed prior to course commencement. Results The survey was completed by 1591 participants. The mean dementia knowledge score was 35.0 (SD 8.4), with 13% (n = 207) achieving a target score of 45/50 or above, indicating comprehensive dementia knowledge. Key knowledge gaps were in the areas of dementia onset and non‐pharmacological management of behavioural and psychological symptoms of dementia. Conclusions Allied health professionals surveyed had significant gaps in dementia knowledge. Educators planning dementia curriculum for allied health professionals could consider addressing areas of knowledge related to the identified items, with view to providing a foundation for excellence in dementia care.

Objective Describe pathological features on internal and external aspects of the skull of an ancient grey wolf. Materials Wolf remains that were found at the southwestern settlement Area A of Gravettian site Pavlov I. Methods Visual observation and description; microcomputed tomography; porosity and fragmentation indices for internal and external skull features; histological section of the fourth upper premolar tooth. Results Dorsally, the sagittal crest revealed bone healing and remodeling. The sagittal lesion differential diagnosis was blunt trauma with or without fracture. Ventrally, otic region pathology included severe proliferation and lysis (osteomyelitis). The pathology was not resolvable among differential (microbial) causes of osteomyelitis, although other potential etiologies were ruled out. Conclusions Probable first report of otic region osteomyelitis in an ancient grey wolf. Significance The proximity of the wolf remains to human-related findings, and presence of red ochre and shells, suggest human involvement in the burial. Limitations This is a single specimen with differential diagnoses that were not resolvable to a single definitive diagnosis. Suggestions for Further Research Further investigation of the possible anthropological significance of the burial circumstances.

Background Vasoplegia has been reported in patients receiving angiotensin receptor-neprilysin inhibitors (ARNI) with heart failure with reduced ejection fraction (HFrEF). We present a case of vasoplegic shock after initiation of ARNI in a hospitalized 65-year-old man recovering from cardiogenic shock (CS) and acute kidney injury (AKI). Case summary A 65-year-old man with HFrEF presented to a community hospital with CS with evidence of poor perfusion with a lactate of 5.6 mmol/L and creatinine (Cr) 125 µmol/L. He was treated with intravenous furosemide infusion. Subsequently, his lactate normalized but he developed an AKI with a Cr of 176 µmol/L. He was then started on ARNI and beta blockers. Over the next 24 h, he developed a vasoplegic shock necessitating multiple vasopressors and a transfer to a tertiary academic centre. With supportive therapy, his vasoplegic shock improved and he was discharged home. Discussion PARADIGM-HF found that the introduction of an ARNI in patients with ambulatory symptomatic HFrEF reduces the risk of death and heart failure hospitalization. Most recently, PIONEER-HF showed that ARNI reduced N-terminal pro-B-type natriuretic peptide levels at 4 and 8 weeks, without significantly different rates of medication-related adverse effects. However, thus far, no clinical trials have examined the role of ARNI in CS. Our case report highlights the risk of vasoplegic shock caused by initiation of ARNI in patients hospitalized with CS especially in whom renal and hepatic impairment is present.

Ninety-six people died following a crowd crush at the Hillsborough Football Stadium, Sheffield, UK in 1989. The cause of death in nearly all cases was compression asphyxia. The clinical and pathological features of deaths encountered in crowds are discussed with a particular focus on the Hillsborough disaster.

Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. Clinical Trial Registration NCT01921335.

The use of continuous subcutaneous insulin infusion (CSII) in the management of paediatric patients with type 1 diabetes mellitus (T1DM) has increased substantially in the last decade. The aim of this study was to evaluate and compare glycaemic control in a population of paediatric patients with T1DM before commencing CSII compared with 2 years after commencing CSII. This is a retrospective study with data collection from diabetes clinic records. Complete data were obtained on 34/45 eligible patients. Glycosylated haemoglobin (HbA1c) and body mass index (BMI) were compared 6 months pre- and 2 years post CSII commencement. Data were stratified in 6-month blocks. Mean HbA1c improved over 2 years post CSII with the lowest value in the first 6 months post-commencement. When gender, age, time since diagnosis and time on pump were added as covariates, results became non-significant, with only age exhibiting a statistically significant influence on glycaemic control (p = 0.03). This improved glycaemic control is associated with some increment in BMI which showed no statistical significance in the first year post-CSII. CSII commencement is associated with significantly improved glycaemic control most notably in the first 6 months after CSII commencement. There is association between CSII commencement and increased BMI noted to be statistically significant in the second year.

Background Cancer outcomes are complex, involving prevention, early detection and optimal multidisciplinary care. Postoperative infection and surgical site‐infection (SSI) are not only uncomfortable for patients and costly, but may also be associated with poor oncological outcomes. A meta‐analysis was undertaken to assess the oncological effects of SSI in patients with colorectal cancer. Methods An ethically approved PROSPERO‐registered meta‐analysis was conducted following PRISMA guidelines. PubMed and Scopus databases were searched for studies published between 2007 and 2017 reporting the effects of postoperative infective complications on oncological survival in colorectal cancer. Results were separated into those for SSI and those concerning anastomotic leakage. Articles with a Methodological Index for Non‐Randomized Studies score of at least 18 were included. Hazard ratios (HRs) with 95 per cent confidence intervals were computed for risk factors using an observed to expected and variance fixed‐effect model. Results Of 5027 articles were reviewed, 43 met the inclusion criteria, with a total of 154 981 patients. Infective complications had significant negative effects on overall survival (HR 1·37, 95 per cent c.i. 1·28 to 1·46) and cancer‐specific survival (HR 2·58, 2·15 to 3·10). Anastomotic leakage occurred in 7·4 per cent and had a significant negative impact on disease‐free survival (HR 1·14, 1·09 to 1·20), overall survival (HR 1·34, 1·28 to 1·39), cancer‐specific survival (HR 1·43, 1·31 to 1·55), local recurrence (HR 1·18, 1·06 to 1·32) and overall recurrence (HR 1·46, 1·27 to 1·68). Conclusion This meta‐analysis identified a significant negative impact of postoperative infective complications on overall and cancer‐specific survival in patients undergoing colorectal surgery., Postoperative infective complications have significant negative effects on oncological outcomes in colorectal cancer. Anastomotic leakage has a negative effect on every measured outcome. New registries should include oncological outcomes and complications to facilitate future research and optimize outcomes. Colorectal cancer surgery infectious complications affect overall and cancer‐specific survival

Context While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. Objective The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. Design Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. Results Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. Conclusion Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin’s effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.

The optimal time to initiate research on emergencies is before they occur. However, timely initiation of high-quality research may launch during an emergency under the right conditions. These include an appropriate context, clarity in scientific aims, preexisting resources, strong operational and research structures that are facile, and good governance. Here, Nebraskan rapid research efforts early during the 2020 coronavirus disease pandemic, while participating in the first use of U.S. federal quarantine in 50 years, are described from these aspects, as the global experience with this severe emerging infection grew apace. The experience has lessons in purpose, structure, function, and performance of research in any emergency, when facing any threat.

Objective Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)-approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. Methods This single-center, phase 2, randomized, double-blind, placebo-controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. Results Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well-tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (-27%) at 12 months and phospho-tau-181 was reduced at 6 months and 12 months in the nilotinib group. Interpretation Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183-194.

AIM: In 1999, a cooperative tripartite cancer research and training agreement was signed between Ireland (IE), Northern Ireland (NI) and the United States (US) National Cancer Institute, giving rise to the All-Ireland Cancer Consortium (AICC). We wished to consider if AICC increased the amount/impact of cancer research on the island of Ireland and what effect this enhanced research activity had on cancer services and cancer outcomes.METHODS: As comparator, we chose the city regions of Copenhagen and Lund & Malmö, whose physical connection was greatly improved following construction of bridges between Denmark and Sweden around the time AICC was established. We analysed cancer research outputs from all four geographical regions in the Web of Science (1988-2017), with a particular focus on citations and journal impact factors. We evaluated disability-adjusted life years (DALYs) as an indicator of change in health status.RESULTS: Research outputs increased in all four regions, but more in IE/NI than in the Scandinavian cities, while collaboration between IE and NI and both the US and the Rest of Europe increased even more substantially. Citation scores also showed a greater improvement for IE and NI. Journal citation impact factors indicated that IE/NI papers were increasingly being published in more highly cited journals. Research-enabled cancer service provision improved on the island of Ireland, with concomitant increases in cancer survival.CONCLUSION: The AICC collaborative agreement delivered significant additionality on the island of Ireland, promoting transnational cooperation, enhancing cancer research activity, and underpinning improved cancer services and better cancer outcomes.

BACKGROUNDThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODSIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTSThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.CONCLUSIONSIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589. opens in new tab, NCT04505774. opens in new tab, NCT02735707. opens in new tab, and NCT04359277. opens in new tab.)

Background: Machine learning (ML) methods are increasingly used in addition to conventional statistical modelling (CSM) for predicting readmission and mortality in patients with myocardial infarction (MI). However, the two approaches have not been systematically compared across studies of prognosis in patients with MI. Methods: Following PRISMA guidelines, we systematically reviewed the literature via Medline, EPub, Cochrane Central, Embase, Inspec, ACM Digital Library, and Web of Science. Eligible studies included primary research articles published from January 2000 to March 2020, comparing ML and CSM for prognostication after MI. Results: Of 7,348 articles, 112 underwent full-text review, with the final set composed of 24 articles representing 374,365 patients. ML methods included artificial neural networks (n = 12 studies), random forests (n = 11), decision trees (n = 8), support vector machines (n = 8), and Bayesian techniques (n = 7). CSM included logistic regression (n = 19 studies), existing CSM-derived risk scores (n = 12), and Cox regression (n = 2). Thirteen of 19 studies examining mortality reported higher C-indexes with the use of ML compared with CSM. One study examined readmissions at 2 different time points, with C-indexes that were higher for ML than CSM. Across all studies, a total of 29 comparisons were performed, but the majority (n = 26, 90%) found small (< 0.05) absolute differences in the C-index between ML and CSM. With the use of a modified CHARMS checklist, sources of bias were identifiable in the majority of studies, and only 2 were externally validated. Conclusion: Although ML algorithms tended to have higher C-indexes than CSM for predicting death or readmission after MI, these studies exhibited threats to internal validity and were often unvalidated. Further comparisons are needed, with adherence to clinical quality standards for prognosis research. (Trial registration: PROSPERO CRD42019134896)

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.

Allogeneic natural killer (aNK) cell adoptive therapy has the potential to dramatically impact clinical outcomes of glioblastoma multiforme (GBM). However, in order to exert therapeutic activity, NK cells require tumor expression of ligands for activating receptors, such as MHC Class I peptide A/B (MICA/B) and ULBPs. Here, we describe the use of a blood–brain barrier (BBB) permissive supramolecular cationic drug vehicle comprising an inhibitor of the chaperone heat shock protein 90 (Hsp90), which sustains a cytotoxic effect on GBM cells, boosts the expression of MICA/B and ULBPs on the residual population, and augments the activity of clinical-grade aNK cells (GTA002). First, we identify Hsp90 mRNA transcription and gain of function as significantly upregulated in GBM compared to other central nervous system tumors. Through a rational chemical design, we optimize a radicicol supramolecular prodrug containing cationic excipients, SCI-101, which displays >2-fold increase in relative BBB penetration compared to less cationic formulations in organoids, in vitro. Using 2D and 3D biological models, we confirm SCI-101 sustains GBM cytotoxicity 72 h after drug removal and induces cell surface MICA/B protein and ULBP mRNA up to 200% in residual tumor cells compared to the naked drug alone without augmenting the shedding of MICA/B, in vitro. Finally, we generate and test the sequential administration of SCI-101 with a clinical aNK cell therapy, GTA002, differentiated and expanded from healthy umbilical cord blood CD34+ hematopoietic stem cells. Using a longitudinal in vitro model, we demonstrate >350% relative cell killing is achieved in SCI-101–treated cell lines compared to vehicle controls. In summary, these data provide a first-of-its-kind BBB-penetrating, long-acting inhibitor of Hsp90 with monotherapy efficacy, which improves response to aNK cells and thus may rapidly alter the treatment paradigm for patients with GBM.

We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine glioblastoma models (Williams et al. Cancer Research 2011). However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Mechanistically, BiA is thought to act as a broadly selective serine-threonine protein kinase inhibitor, with activity against Src family kinases, GSK-3 and JAK2. Our preliminary data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p < 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further preliminary mechanistic studies have shown that PPRX-1701/BiA blocks the expression multiple immunosuppressive molecules in GBM downstream of interferon-g (IFNg) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models. This data supports further development of PPRX-1701 is a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies.

Despite the positive association between tourism and quality of life among the general population, a range of challenges has been found to prevent people with disabilities from participating in tourism. Participation in tourism is lower among families with a child diagnosed with Autism Spectrum Disorder than among comparable families. Although travelling by airplane has been identified as a particular challenge for these families, few studies investigating air travel experiences have been published. The present study surveyed 97 parents of autistic young people about their experiences of air travel. Participants identified stressors and enablers relevant to these experiences. In particular periods of waiting, crowds, and sensory stimuli emerged as significant stressors across every stage of the air travel process. These factors are discussed in the context of developing effective interventions to improve air travel experiences among autistic young people and their families. Building on these findings will allow researchers to better understand these experiences, better support families, and better address accessibility issues in tourism. Enhancing air travel experiences could allow a cohort of autistic people and their families to enjoy the improved quality of life outcomes that have been reported by tourists in the general population and increase family participation more broadly. A focus on improving customer experience could also entice new customers to air travel and encourage higher frequency of trips for returning customers.

Limited evidence exists on the effects of weight loss on chronic disease risk and patient-reported outcomes in breast cancer survivors. Breast cancer survivors (stage I-III, body mass index 25–45 kg/m2) were randomized to a 12-month, remotely delivered (22 telephone calls, mailed material, optional text messages) weight loss (diet and physical activity) intervention (n = 79) or usual care (n = 80). Weight loss (primary outcome), body composition, metabolic syndrome risk score and components, quality of life, fatigue, musculoskeletal pain, menopausal symptoms, fear of recurrence, and body image were assessed at baseline, 6 months, 12 months (primary endpoint), and 18 months. Participants were 55 ± 9 years and 10.7 ± 5.0 months post-diagnosis, retention was 81.8% (12 months) and 80.5% (18 months). At 12-months, intervention participants had significantly greater improvements in weight (−4.5% [95%CI: −6.5,−2.5], p &lt, 0.001), fat mass (−3.3 kg [−4.8,−1.9], 0.001), metabolic syndrome risk score (−0.19 [−0.32,−0.05], p = 0.006), waist circumference (−3.2 cm [−5.5,−0.9], p = 0.007), fasting plasma glucose (−0.23 mmol/L [−0.44,−0.02], p = 0.032), physical quality of life (2.7 [0.7,4.6], p = 0.007, Cohen’s effect size (d) = 0.40), musculoskeletal pain (−0.5 [−0.8,−0.2], p = 0.003, d = 0.49), and body image (−0.2 [−0.4,−0.0], p = 0.030, d = 0.31) than usual care. At 18 months, effects on weight, adiposity, and metabolic syndrome risk scores were sustained, however, significant reductions in lean mass were observed (−1.1 kg [−1.7,−0.4], 0.001). This intervention led to sustained improvements in adiposity and metabolic syndrome risk.

CONTEXT: Few studies have examined the clinical characteristics that predict durable, long-term diabetes remission after bariatric surgery. OBJECTIVE: To compare diabetes prevalence and remission rates during 7-year follow-up after Roux-en-Y gastric bypass (RYGB) and laparoscopic gastric banding (LAGB). DESIGN: An observational cohort of adults with severe obesity recruited between 2006 and 2009 who completed annual research assessments for up to 7 years after RYGB or LAGB. SETTING: Ten US hospitals. PARTICIPANTS: A total sample of 2256 participants, 827 with known diabetes status at both baseline and at least 1 follow-up visit. INTERVENTIONS: Roux-en-Y gastric bypass or LAGB. MAIN OUTCOME MEASURES: Diabetes rates and associations of patient characteristics with remission status. RESULTS: Diabetes remission occurred in 57% (46% complete, 11% partial) after RYGB and 22.5% (16.9% complete, 5.6% partial) after LAGB. Following both procedures, remission was greater in younger participants and those with shorter diabetes duration, higher C-peptide levels, higher homeostatic model assessment of β-cell function (HOMA %B), and lower insulin usage at baseline, and with greater postsurgical weight loss. After LAGB, reduced HOMA insulin resistance (IR) was associated with a greater likelihood of diabetes remission, whereas increased HOMA-%B predicted remission after RYGB. Controlling for weight lost, diabetes remission remained nearly 4-fold higher compared with LAGB. CONCLUSIONS: Durable, long-term diabetes remission following bariatric surgery is more likely when performed soon after diagnosis when diabetes medication burden is low and beta-cell function is preserved. A greater weight-independent likelihood of diabetes remission after RYGB than LAGB suggests mechanisms beyond weight loss contribute to improved beta-cell function after RYGB. Trial Registration clinicaltrials.gov Identifier: NCT00465829.

Patients with type 2 diabetes are at high risk of developing renal and cardiovascular complications. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have garnered interest due to their glucose-independent cardiorenal protective effects, as reported in trials including participants with and without diabetes, such as Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) (1,2). These trials have demonstrated that SGLT2 inhibitors reduce cardiovascular disease (CVD) risk, especially hospitalization for heart failure (1,2). Despite these clinical benefits, the underlying physiological mechanisms of SGLT2 inhibitors are incompletely understood, particularly in patients with chronic kidney disease (CKD). Accordingly, this analysis examined the impact of treatment with an SGLT2 inhibitor, ertugliflozin, on markers of plasma volume contraction and myocardial strain in participants with type 2 diabetes and moderate CKD. We performed a post hoc exploratory analysis in a subset of 231 participants from the eValuation of ERTugliflozin efficacy and Safety (VERTIS) RENAL trial (clinical trial reg. no. NCT01986855, ClinicalTrials.gov) with type 2 diabetes and stage 3 CKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) who were randomized to SGLT2 inhibitor therapy with ertugliflozin (5 mg or 15 mg daily; pooled herein) or placebo (3). Clinical and biomarker measurements were obtained at baseline and 26 weeks and 52 weeks postrandomization. Biomarkers were quantified with Luminex xMAP (cardiac troponin, renin, and N-terminal pro B-type natriuretic peptide [NT-proBNP]) or ELISA (atrial natriuretic peptide [ANP], human erythropoietin [EPO], ACE, and ACE2). Aldosterone was quantified by DiaSorin LIAISON XL Analyzer based on competitive chemiluminescent immunoassay. Differences in longitudinal changes in biomarkers among participants receiving either …

This study provides the first quasi-experimental evidence on the effects of nonbinding vaccine recommendations targeted at high school–aged adolescents. Using data from the National Immuniz...

To generate a Hospital Medical Surge Preparedness Index that can be used to evaluate hospitals across the United States in regard to their capacity to handle patient surges during mass casualty events. Data from the American Hospital Association's annual survey, conducted from 2005 to 2014. Our sample comprised 6239 hospitals across all 50 states, with an annual average of 5769 admissions. An extensive review of the American Hospital Association survey was conducted and relevant variables applicable to hospital inpatient services were extracted. Subject matter experts then categorized these items according to the following subdomains of the "Science of Surge" construct: staff, supplies, space, and system. The variables within these categories were then analyzed through exploratory and confirmatory factor analyses, concluding with the evaluation of internal reliability. Based on the combined results, we generated individual (by hospital) scores for each of the four metrics and an overall score. The exploratory factor analysis indicated a clustering of variables consistent with the "Science of Surge" subdomains, and this finding was in agreement with the statistics generated through the confirmatory factor analysis. We also found high internal reliability coefficients, with Cronbach's alpha values for all constructs exceeding 0.9. A novel Hospital Medical Surge Preparedness Index linked to hospital metrics has been developed to assess a health care facility's capacity to manage patients from mass casualty events. This index could be used by hospitals and emergency management planners to assess a facility's readiness to provide care during disasters.