Association between anaemia and hospital readmissions in patients undergoing major surgery requiring postoperative intensive care.

Anaemia is a common sequela of surgery, although its relationship with patient recovery is unclear. The goal of this investigation was to assess the associations between haemoglobin concentrations at the time of hospital discharge following major surgery and early post-hospitalisation outcomes, with a primary outcome of 30 day unanticipated hospital readmissions. This investigation includes data from two independent population-based observational cohorts of adult surgical patients (aged ≥ 18 years) requiring postoperative intensive care unit admission between 1 January 2010 and 31 December 2019 in hospitals in Olmsted County, Minnesota, and between 1 July 2010 and 30 June 2017 in the Kaiser Permanente Northern California integrated healthcare system, California. Cox proportional hazards models assessed the associations between discharge haemoglobin concentrations (per 10 g.l-1 ) and outcomes, with prespecified multivariable adjustment. A total of 3260 patients were included from Olmsted County hospitals and 29,452 from Kaiser Permanente Northern California. In adjusted analyses, each 10 g.l-1 decrease in haemoglobin at hospital discharge was associated with a 9% (hazard ratio 1.09, 95%CI 1.02-1.18; p = 0.014) and 8% increase (hazard ratio 1.08, 95%CI 1.06-1.11; p < 0.001) in the hazard for readmission within 30 days in Olmsted County and Kaiser Permanente Northern California, respectively. In a sensitivity analysis exploring relationships across varying levels of pre-operative anaemia severity, these associations remained consistent, with lower discharge haemoglobin concentrations associated with higher readmissions irrespective of pre-operative anaemia severity. Anaemia at hospital discharge in surgical patients requiring postoperative intensive care is associated with increased rates of hospital readmission in two large independent cohorts. Future studies are necessary to evaluate strategies to prevent and/or treat anaemia in these patients for the improvement of post-hospitalisation outcomes.

Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Marginal warming associated with a COVID-19 quarantine and the implications for disease transmission.

During January-February 2020, parts of China faced restricted mobility under COVID-19 quarantines, which have been associated with improved air quality. Because particulate pollutants scatter, diffuse, and absorb incoming solar radiation, a net negative radiative forcing, decreased air pollution can yield surface warming. As such, this study (1) documents the evolution of China's January-February 2020 air temperature and concurrent particulate changes; (2) determines the temperature response related to reduced particulates during the COVID-19 quarantine (C19Q); and (3) discusses the conceptual implications for temperature-dependent disease transmission. C19Q particulate evolution is monitored using satellite analyses, and concurrent temperature anomalies are diagnosed using surface stations and Aqua AIRS imagery. Meanwhile, two WRF-Chem simulations are forced by normal emissions and the satellite-based urban aerosol changes, respectively. Urban aerosols decreased from 27.1% of pre-C19Q aerosols to only 17.5% during C19Q. WRF-Chem resolved ~0.2 °C warming across east-central China, that represented a minor, though statistically significant contribution to C19Q temperature anomalies. The largest area of warming is concentrated south of Chengdu and Wuhan where temperatures increased between +0.2-0.3 °C. The results of this study are important for understanding the anthropogenic forcing on regional meteorology. Epidemiologically, the marginal, yet persistent, warming during C19Q may retard temperature-dependent disease transmission, possibly including SARS-CoV-2.

FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma.

Background: Immune checkpoint inhibitor therapy has resulted in impressive and durable clinical activity for many cancers including melanoma; however, there remain few reliable predictors for long-term response. This study investigated whether [18F]2-fluoro-2-deoxy-D-glucose (FDG-PET) imaging may better predict long-term outcomes compared with standard computed tomography (CT) response criteria. Patients and methods: Retrospective analysis of metastatic melanoma patients treated with anti-PD-1-based immunotherapy with baseline and 1-year FDG-PET and CT imaging at Melanoma Institute Australia. One-year response was determined using RECIST for CT and EORTC criteria for PET, coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD). Progression-free survival (PFS) was determined from the 1-year landmark. Results: Patients (n = 104) were evaluated with median follow-up 30.1 months and 98% remain alive. Most received anti-PD-1 as monotherapy (67%) or combined with ipilimumab (31%). At 1 year, 28% had CR, 66% had PR and 6% had SD on CT, while 75% had CMR, 16% PMR and 9% SMD/PMD on PET. CMR was observed in 68% of patients with PR on CT. RECIST PFS post 1-year landmark was similar in patients with CR versus PR/SD, but improved in patients with CMR versus non-CMR {median not reached [NR] versus 12.8 month; hazard ratio [HR] 0.06 [95% confidence interval (CI) 0.02-0.23]; P < 0.01}. In patients with PR on CT, PFS was improved in patients with PR + CMR versus PR + non-CMR (median NR versus 12.8 months; HR 0.07 [95% CI 0.02-0.27]; P < 0.01). In the 78 CMR patients, 78% had discontinued treatment and 96% had ongoing response. Conclusions: Whilst only a small proportion of patients have a CR at 1 year, most patients with a PR have CMR on PET. Almost all patients with CMR at 1 year have ongoing response to therapy thereafter. PET may have utility in predicting long-term benefit and help guide discontinuation of therapy.

Miniaturized, biopsy-implantable chemical sensor with wireless, magnetic resonance readout.

Biopsy is an important diagnostic tool for a broad range of conditions. Cancer diagnoses, for example, are confirmed using tissue explanted with biopsy. Here we demonstrate a miniaturized wireless sensor that can be implanted during a biopsy procedure and return chemical information from within the body. Power and readout are wireless via weak magnetic resonant coupling to an external reader. The sensor is filled with responsive nuclear magnetic resonance (NMR) contrast agents for chemical sensitivity, and on-board circuitry constrains the NMR measurement to the contents. This sensor enables longitudinal monitoring of the same location, and its simple readout mechanism is ideal for applications not requiring the spatial information available through imaging techniques. We demonstrated the operation of this sensor by measuring two metabolic markers, both in vitro and in vivo: pH in flowing fluid for over 25 days and in a xenograft tumor model in mice, and oxygen in flowing gas and in a rat hind-limb constriction experiment. The results suggest that this in vivo sensing platform is generalizable to other available NMR contrast agents. These sensors have potential for use in biomedicine, environmental monitoring and quality control applications.

The Accuracy of an Electronic Pulmonary Embolism Severity Index Auto-Populated from the Electronic Health Record: Setting the stage for computerized clinical decision support.

BACKGROUND: The Pulmonary Embolism (PE) Severity Index identifies emergency department (ED) patients with acute PE that can be safely managed without hospitalization. However, the Index comprises 11 weighted variables, complexity that can impede its integration into contextual workflow. OBJECTIVE: We designed a computerized version of the PE Severity Index (e-Index) to automatically extract the required variables from discrete fields in the electronic health record (EHR). We tested the e-Index on the study population to determine its accuracy compared with a gold standard generated by physician abstraction of the EHR on manual chart review. METHODS: This retrospective cohort study included adults with objectively-confirmed acute PE in four community EDs from 2010-2012. Outcomes included performance characteristics of the e-Index for individual values, the number of cases requiring physician editing, and the accuracy of the e-Index risk category (low vs. higher). RESULTS: For the 593 eligible patients, there were 6,523 values automatically extracted. Fifty one of these needed physician editing, yielding an accuracy at the value-level of 99.2% (95% confidence interval [CI], 99.0%-99.4%). Sensitivity was 96.9% (95% CI, 96.0%-97.9%) and specificity was 99.8% (95% CI, 99.7%-99.9%). The 51 corrected values were distributed among 47 cases: 43 cases required the correction of one variable and four cases required the correction of two. At the risk-category level, the e-Index had an accuracy of 96.8% (95% CI, 95.0%-98.0%), under-classifying 16 higher-risk cases (2.7%) and over-classifying 3 low-risk cases (0.5%). CONCLUSION: Our automated extraction of variables from the EHR for the e-Index demonstrates substantial accuracy, requiring a minimum of physician editing. This should increase user acceptability and implementation success of a computerized clinical decision support system built around the e-Index, and may serve as a model to automate other complex risk stratification instruments.

Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.

Islet transplantation for type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in non-obese diabetic (NOD) diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus carrying neurogenin3 (Ngn3), an islet lineage-defining transcription factor, and betacellulin (Btc), an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these 'neo-islets' from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with Ngn3 and Btc. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing 'neo-islets' in treated mouse livers. Despite evidence of persistent 'insulitis' with activated T cells, these 'neo-islets' persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice.

Lower limb complications of diabetes mellitus: a comprehensive review with clinicopathological insights from a dedicated high-risk diabetic foot multidisciplinary team.

Diabetic complications in the lower extremity are associated with significant morbidity and mortality, and impact heavily upon the public health system. Early and accurate recognition of these abnormalities is crucial, enabling the early initiation of treatments and thus avoiding or minimizing deformity, dysfunction and amputation. Following careful clinical assessment, radiological imaging is central to the diagnostic and follow-up process. We aim to provide a comprehensive review of diabetic lower limb complications designed to assist radiologists and to contribute to better outcomes for these patients.

Antibacterial efficacy of casein-derived peptides against Enterococcus faecalis.

BACKGROUND: The aim of this study was to test a casein peptide in its glycosylated form (kappa-casein glycopeptide, KCGP) and its non-glycosylated form (kappa-casein peptide, KCP) for antibacterial efficacy against Enterococcus faecalis in planktonic and biofilm cultures. METHODS: E. faecalis strain JKD 15036 was exposed to different concentrations of KCGP and KCP in a 96-well culture plate. The effect of the peptides on the growth of E. faecalis in planktonic culture was monitored by measuring optical density over 7 hours. Biofilm formation was measured after 24 hours using a crystal violet assay. All experiments were performed in triplicate. RESULTS: KCGP and KCP inhibited growth of E. faecalis in planktonic culture with no significant difference in activity between the peptides. KCGP at 0.16% w/v was significantly better at inhibiting E. faecalis biofilm formation than KCP at the same concentration and significantly better than NaOCl at 1.0% w/v. CONCLUSIONS: KCGP effectively inhibited E. faecalis biofilm formation and may have potential to augment the efficacy of traditional antiseptic agents.

Increasing lung allocation scores predict worsened survival among lung transplant recipients.

Implemented in 2005, the lung allocation score (LAS) aims to distribute donor organs based on overall survival benefits for all potential recipients, rather than on waiting list time accrued. While prior work has shown that patients with scores greater than 46 are at increased risk of death, it is not known whether that risk is equivalent among such patients when stratified by LAS score and diagnosis. We retrospectively evaluated 5331 adult lung transplant recipients from May 2005 to February 2009 to determine the association of LAS (groups based on scores of < or =46, 47-59, 60-79 and > or =80) and posttransplant survival. When compared with patients with LAS < or = 46, only those with LAS > or = 60 had an increased risk of death (LAS 60-79: hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.21-1.90; LAS > or = 80: HR, 2.03; CI, 1.61-2.55; p < 0.001) despite shorter median waiting list times. This risk persisted after adjusting for age, diagnosis, transplant center volume and donor characteristics. By specific diagnosis, an increased hazard was observed in patients with COPD with LAS > or = 80, as well as those with IPF with LAS > or = 60.

A multi-drug regimen for respiratory syncytial virus and parainfluenza virus infections in adult lung and heart-lung transplant recipients.

BACKGROUND: Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can cause significant morbidity and mortality in lung and heart-lung transplant recipients. We evaluated the utility of a multi-drug protocol for the treatment of RSV- and PIV-related infections. PATIENTS AND METHODS: RSV or PIV was identified in 25 patients with a total of 29 infectious episodes between January 2006 and December 2007. The study included 20 women and 5 men, mean age 42 +/- 13 years. Fifteen patients had received bilateral lung transplant and the remainder either received single lung or heart-lung transplant. Mean time from transplant to infection was 1192 days. RSV was identified in 23 cases, PIV in 7 cases. Patients underwent treatment with inhaled ribavirin, methylprednisolone, and intravenous immunoglobulin (IVIG). RSV-positive patients were also treated with palivizumab. We retrospectively evaluated their clinical status and pulmonary function for a 1-year interval before and after the date of infection. RESULTS: Average baseline forced expiratory volume in 1 s (FEV(1)) before infection was 2.14 +/- 0.68 L/min. Average decline in FEV(1) was 5.7% at the time of infection. Average FEV(1) during post-treatment follow-up was not significantly different than baseline (2.16 +/- 0.80 L/min). Among patients with bronchiolitis obliterans syndrome (BOS) stages 1, 2, or 3 at the time of infection, average FEV(1) declined by 14.8% and remained lower at 9.1% during follow-up when compared with patients with BOS stages 0 or 0p. No complications resulted from treatment. One patient died during follow-up as a result of pre-existing liver failure. CONCLUSIONS: This study of lung and heart-lung transplant recipients infected with RSV and PIV shows that a multi-drug regimen including inhaled ribavirin, corticosteroids, and IVIG (with or without palivizumab) is safe and effective. Prompt diagnosis and therapy for patients with RSV or PIV infections are critical for maintaining lung function.

[Four cases of photopheresis treatment for cutaneous lupus erythematosus refractory to standard therapy]. / Traitement par photochimiothérapie extracorporelle de quatre cas de lupus érythémateux cutané réfractaires aux traitements conventionnels.

BACKGROUND: Photopheresis is a leucopheresis procedure in which cells are photoactivated by psoralen and then irradiated by ultraviolet A. We report four cases of women with refractory cutaneous lupus erythematosus (LE) who responded to this treatment. PATIENTS AND METHODS: We treated one patient with subacute LE having a contraindication to antimalarials and to thalidomide and three patients with chronic LE (lupus panniculitis, lupus tumidus and disseminated discoid LE) refractory to treatment with hydroxychloroquine, chloroquine, thalidomide and dapsone, and also, in some cases, to oral and intravenous corticosteroids, methotrexate, colchicine, acitretine, sulfasalazine, mycophenolate mofetil and intravenous immunoglobulin. Treatment consisted of two 4-hour sessions fortnightly. Only antimalarials were continued during photopheresis. RESULTS: Photopheresis had a positive effect on all four patients. We noticed complete remission in two patients and interruption of progression followed by partial remission in the other two after a mean delay of two to three months of treatment. All treatments other than antimalarials were stopped. DISCUSSION: Photopheresis appears to be an effective treatment option in patients with cutaneous LE. Due to its high cost, it should nevertheless remain an exceptional therapeutic option restricted to patients with cutaneous LE resistant to standard therapy.

Overexpression of FOXG1 contributes to TGF-beta resistance through inhibition of p21WAF1/CIP1 expression in ovarian cancer.

BACKGROUND: Loss of growth inhibitory response to transforming growth factor-beta (TGF-beta) is a common feature of epithelial cancers. Recent studies have reported that genetic lesions and overexpression of oncoproteins in TGF-beta/Smads signalling cascade contribute to the TGF-beta resistance. Here, we showed that the overexpressed FOXG1 was involved in attenuating the anti-proliferative control of TGF-beta/Smads signalling in ovarian cancer. METHODS: FOXG1 and p21(WAF1/CIP1) expressions were evaluated by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR), western blot and immunohistochemical analyses. The effect of FOXG1 on p21(WAF1/CIP1) transcriptional activity was examined by luciferase reporter assays. Cell lines stably expressing or short hairpin RNA interference-mediated knockdown FOXG1 were established for studying the gain-or-loss functional effects of FOXG1. XTT cell proliferation assay was used to measure cell growth of ovarian cancer cells. RESULTS: Quantitative RT-PCR and western blot analyses showed that FOXG1 was upregulated and inversely associated with the expression levels of p21(WAF1/CIP1) in ovarian cancer. The overexpression of FOXG1 was significantly correlated with high-grade ovarian cancer (P=0.025). Immunohistochemical analysis on ovarian cancer tissue array was further evidenced that FOXG1 was highly expressed and significantly correlated with high-grade ovarian cancer (P=0.048). Functionally, enforced expression of FOXG1 selectively blocked the TGF-beta-induced p21(WAF1/CIP1) expressions and increased cell proliferation in ovarian cancer cells. Conversely, FOXG1 knockdown resulted in a 20-26% decrease in cell proliferation together with 16-33% increase in p21(WAF1/CIP1) expression. Notably, FOXG1 was able to inhibit the p21(WAF1/CIP1) promoter activity in a p53-independent manner by transient reporter assays. CONCLUSION: Our results suggest that FOXG1 acts as an oncoprotein inhibiting TGF-beta-mediated anti-proliferative responses in ovarian cancer cells through suppressing p21(WAF1/CIP1) transcription.

Two phase II trials of temozolomide with interferon-alpha2b (pegylated and non-pegylated) in patients with recurrent glioblastoma multiforme.

BACKGROUND: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls. METHODS: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks. RESULTS: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study. CONCLUSION: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.