Pulmonary Metastasectomy in Colorectal Cancer: updated analysis of 93 randomized patients - control survival is much better than previously assumed.

AIM: Lung metastases from colorectal cancer are resected in selected patients in the belief that this confers a significant survival advantage. It is generally assumed that the 5-year survival of these patients would be near zero without metastasectomy. We tested the clinical effectiveness of this practice in Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC), a randomized, controlled noninferiority trial. METHOD: Multidisciplinary teams in 14 hospitals recruited patients with resectable lung metastases into a two-arm trial. Randomization was remote and stratified according to site, with minimization for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, number of metastases and carcinoembryonic antigen level. The trial management group was blind to patient allocation until after intention-to-treat analysis. RESULTS: From 2010 to 2016, 93 participants were randomized. These patients were 35-86 years of age and had between one and six lung metastases at a median of 2.7 years after colorectal cancer resection; 29% had prior liver metastasectomy. The patient groups were well matched and the characteristics of these groups were similar to those of observational studies. The median survival after metastasectomy was 3.5 (95% CI: 3.1-6.6) years compared with 3.8 (95% CI: 3.1-4.6) years for controls. The estimated unadjusted hazard ratio for death within 5 years, comparing the metastasectomy group with the control group, was 0.93 (95% CI: 0.56-1.56). Use of chemotherapy or local ablation was infrequent and similar in each group. CONCLUSION: Patients in the control group (who did not undergo lung metastasectomy) have better survival than is assumed. Survival in the metastasectomy group is comparable with the many single-arm follow-up studies. The groups were well matched with features similar to those reported in case series.

Six-year experience of detection and investigation of possible Middle East Respiratory Syndrome coronavirus cases, England, 2012-2018.

OBJECTIVES: Surveillance for Middle East Respiratory Syndrome (MERS) has been undertaken in the UK since September 2012. This study describes the surveillance outcomes in England from 2012 to 2018. STUDY DESIGN: This was a descriptive study using surveillance data. METHODS: Local health protection teams in England report possible MERS cases to the National Infection Service with clinical and laboratory data. RESULTS: A total of 1301 possible MERS cases were identified in the study period. Five cases were laboratory-confirmed MERS. The majority of cases had travelled to Saudi Arabia (56.7%) and United Arab Emirates (25.9%). Fifty-four percent of cases were men and 43.7% were women. The majority of cases (65.1%) were aged 45 years or older. The number of tests increased in the period after Hajj each year. Laboratory-confirmed alternative diagnoses were available for 513 (39.4%) cases; influenza was the most common virus detected (n = 255, 52.4%). CONCLUSIONS: Our study highlights the importance of differential diagnosis of influenza and other respiratory pathogens and early influenza antiviral treatment.

Aortic arch replacement with a beating heart: a simple method using continuous 3-way perfusion.

We describe a simplified 3-way perfusion strategy that could be used in complex aortic procedures, which ensures continuous end-organ perfusion and minimizes the potential risks of cardiac, cerebral and peripheral ischaemic complications.

A comparison of persistence of SARS-CoV-2 variants on stainless steel.

The survival of newer variants of SARS-CoV-2 on a representative surface has been compared to the established UK circulating isolate to determine whether enhanced environmental stability could play a part in their increased transmissibility. Stainless steel coupons were inoculated with liquid cultures of the three variants, with coupons recovered over seven days and processed for recoverable viable virus using plaque assay. After drying, there was no significant difference in inactivation rates between variants, indicating that there is no increased environmental persistence from the new variants.

Detection of SARS-CoV-2 within the healthcare environment: a multi-centre study conducted during the first wave of the COVID-19 outbreak in England.

BACKGROUND: Understanding how severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spread within the hospital setting is essential in order to protect staff, implement effective infection control measures, and prevent nosocomial transmission. METHODS: The presence of SARS-CoV-2 in the air and on environmental surfaces around hospitalized patients, with and without respiratory symptoms, was investigated. Environmental sampling was undertaken within eight hospitals in England during the first wave of the coronavirus disease 2019 outbreak. Samples were analysed using reverse transcription polymerase chain reaction (PCR) and virus isolation assays. FINDINGS: SARS-CoV-2 RNA was detected on 30 (8.9%) of 336 environmental surfaces. Cycle threshold values ranged from 28.8 to 39.1, equating to 2.2 x 105 to 59 genomic copies/swab. Concomitant bacterial counts were low, suggesting that the cleaning performed by nursing and domestic staff across all eight hospitals was effective. SARS-CoV-2 RNA was detected in four of 55 air samples taken <1 m from four different patients. In all cases, the concentration of viral RNA was low and ranged from <10 to 460 genomic copies/m3 air. Infectious virus was not recovered from any of the PCR-positive samples analysed. CONCLUSIONS: Effective cleaning can reduce the risk of fomite (contact) transmission, but some surface types may facilitate the survival, persistence and/or dispersal of SARS-CoV-2. The presence of low or undetectable concentrations of viral RNA in the air supports current guidance on the use of specific personal protective equipment for aerosol-generating and non-aerosol-generating procedures.

Ozone: nonlinear relation of dose and injury in plants.

Ozone produces a sigmoidal dose-injury response in sensitive tobacco and pinto bean. A definite threshold concentration and presentation time are required before injury is initiated.

China's forest policy for the 21st century.

A half-century policy of forest exploitation and monoculture in China has led to disastrous consequences, including degradation of forests and landscapes, loss of biodiversity, unacceptable levels of soil erosion, and catastrophic flooding. A new forest policy had been adopted in China called the Natural Forest conservation Program (NFCP), which emphasizes expansion of natural forests and increasing the productivity of forest plantations. Through locally focused management strategies, biodiversity and forest resources will be sustained, and downstream regions will be better protected from flooding. This new policy is being implemented with a new combination of policy tools, including technical training and education, land management planning, mandatory conversion of marginal farmlands to forest, resettlement and retaining of forest dwellers, share in private ownership, and expanded research. These policy tools may have wider relevance for other countries, particularly developing countries.

An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy.

The brain is generally considered immunoprivileged, although increasing examples of immunological responses to brain antigens, neuronal expression of major histocompatibility class I genes, and neurological autoimmunity have been recognized. An adeno-associated virus (AAV) vaccine generated autoantibodies that targeted a specific brain protein, the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor. After peroral administration of the AAV vaccine, transgene expression persisted for at least 5 months and was associated with a robust humoral response in the absence of a significant cell-mediated response. This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination. Thus, a vaccination strategy targeting brain proteins is feasible and may have therapeutic potential for neurological disorders.

Treatment options and strategies for acute severe pulmonary embolism.

Pulmonary thromboembolism (PE) is the third most frequent cause of cardiovascular death after ischaemic heart disease and stroke. In fatal PE, 2/3 of patients die within first hour of presentation. There is a clinical impetus to rapidly recognize, risk-stratify and appropriately treat patients with acute severe PE. Current recommendations present conflicting classification systems, and there is often some confusion in the clinical evaluation and management of patients with acute severe PE. This review presents a series of real clinical cases, which illustrate the available treatment options, ranging from conservative therapy to thrombolysis through to percutaneous catheter fragmentation and open surgical embolectomy. We evaluate the evidence for the various strategies and propose an algorithm for clinicians with a focus on early risk stratification and timely referral. This is particularly relevant to regional and remote centres, as well as secondary and tertiary institutions.

Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease.

There are limited data on the efficacy of T cell-based assays to detect tuberculosis (TB) antigen-specific responses in immune-deficient human immunodeficiency virus (HIV) patients. The aim of this study is to determine whether TB antigen-specific immune responses can be detected in patients with HIV-1 infection, especially in those with advanced disease (CD4 T cell count < 300 cells/microl). An enzyme-linked immunospot (ELISPOT) assay, which detects interferon (IFN)-gamma secreted by T cells exposed to TB antigens, was used to assess specific immune responses in a prospective study of 201 HIV-1-infected patients with risk factors for TB infection, attending a single HIV unit. The performance of the ELISPOT assay to detect TB antigen-specific immune responses is independent of CD4 T cell counts in HIV-1 patients. The sensitivity and specificity of this assay for the diagnosis of active tuberculosis does not differ significantly from values obtained in immunocompetent subjects. The negative predictive value of the TB ELISPOT test is 98.2%. A positive predictive value of 86% for the diagnosis of active tuberculosis was found when the combined number of early secretory antigen target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) IFN-gamma spots to CD4 T cell count ratio was > 1.5. TB antigen-specific immune responses can be detected in HIV patients with low CD4 T cell counts using ELISPOT technology in a routine diagnostic laboratory and is a useful test to exclude TB infection in immune-deficient HIV-1 patients. A combination of TB antigen-specific IFN-gamma responses and CD4 T cell counts has the potential to distinguish active tuberculosis from latent infection.

Diagnosis of pulmonary embolism with CT pulmonary angiography: a systematic review.

OBJECTIVE: To appraise the evidence on the diagnostic accuracy of CT pulmonary angiography and the prognostic value of a negative CT pulmonary angiogram in the diagnosis of pulmonary embolism. METHODS: Medline, EMBASE, and grey literature were systematically searched by two researchers. Any study which compared CT pulmonary angiography to an acceptable reference standard or prospectively followed up a cohort of patients with a normal CT pulmonary angiogram was included. Study methods were appraised independently by two researchers, and data were extracted independently by three researchers. RESULTS: Thirteen diagnostic and 11 follow up studies were identified. Studies varied in prevalence of pulmonary embolism (19-79%), patient groups, and method quality. Few studies recruited unselected emergency department patients. There was heterogeneity in the analysis of sensitivity (53 to 100%), specificity (79 to 100%), and false negative rate (1.0 to 10.7%). The pooled false negative rate of combined negative CT pulmonary angiography and negative deep vein thrombosis testing was 1.5% (95% CI 1.0 to 1.9%). CONCLUSION: Diagnostic studies give conflicting results for the diagnostic accuracy of CT pulmonary angiography. Follow up studies show that CT pulmonary angiography can be used in combination with investigation for deep vein thrombosis to exclude pulmonary embolism.

Could Sentinel Skin Transplants Have Some Utility in Solid Organ Transplantation?

Accurate diagnosis of allograft rejection can be hazardous and challenging. A strategy that has emerged from experience with vascularized composite allografts (VCAs) is the use of sentinel skin transplants (SSTs)-portions of donor skin transplanted synchronously to an allograft. Work in nonhuman animal models and experience with VCAs suggest concordance between rejection occurring in the primary allograft and the SST, and that appearance of rejection in the SST may precede rejection in the primary allograft, permitting early therapeutic intervention that may improve outcomes with lower rates of chronic rejection. The encouraging findings reported in VCA transplantation raise the possibility that SST may also be useful in solid organ transplantation. Some evidence is provided by experience with abdominal wall transplantation in some intestinal and multivisceral transplant recipients. Results from those reports raise the possibility that rejection may manifest in the skin component before emergence in the intestinal allograft, providing a "lead time" during which treatment of rejection of the abdominal wall could prevent the emergence of intestinal rejection. It is plausible that these findings may be extrapolated to other solid organ allografts, especially those for which obtaining an accurate diagnosis of acute rejection can be hazardous and challenging, such as the lung or pancreas. However, more data are required to support widespread adoption of this technique.

A maximally sensitive clinical decision rule to reduce the need for radiography in mandibular trauma.

INTRODUCTION: To identify clinical symptoms and signs that exclude the presence of mandibular fracture in patients presenting with mandibular trauma and thus devise a clinical decision rule that will rule out the need for radiography in some patients. PATIENTS AND METHODS: A prospective study was conducted of consecutive patients with a possible diagnosis of mandibular fracture who attended a city-centre emergency department between July 2000 and December 2001. Clinical symptoms and signs were recorded for each patient using a predesigned proforma. Radiographic evaluation of a suspected mandibular fracture consisted of lateral-oblique and postero-anterior mandibular views. The presence of a fracture was based on the interpretation of the X-rays by a radiologist who was blinded to the clinical probability of a fracture. Data were initially analysed using the chi-square test. Recursive partitioning was then performed to create a maximally sensitive decision tree. RESULTS: 280 patients were included in the study, 65 of whom had a mandibular fracture. A maximally sensitive decision rule was found that identified 5 parameters (malocclusion, trismus, broken teeth, pain with mouth closed, step deformity) whose absence excluded mandibular fracture. This rule has a sensitivity of 100% and specificity of 39% in identifying patients with mandibular fracture. If applied to our patient cohort, this rule would have saved 83 radiographs without missing any fractures. CONCLUSIONS: A simple decision rule is presented that can be used to exclude the need for radiography in a subset of patients with mandibular trauma.

Development of an integrated surface stimulation device for systematic evaluation of wound electrotherapy.

Ideally, all chronic wounds would be prevented as they can become life threatening complications. The concept that a wound produces a 'current of injury' due to the discontinuity in the electrical field of intact skin provides the basis for the concept that electrical stimulation (ES) may provide an effective treatment for chronic wounds. The optimal stimulation waveform parameters are unknown, limiting the reliability of achieving a successful clinical therapeutic outcome. In order to gain a more thorough understanding of ES for chronic wound therapy, systematic evaluation using a valid in vivo model is required. The focus of the current paper is development of the flexible modular surface stimulation (MSS) device by our group. This device can be programed to deliver a variety of clinically relevant stimulation paradigms and is essential to facilitate systematic in vivo studies. The MSS version 2.0 for small animal use provides all components of a single-channel, programmable current-controlled ES system within a lightweight, flexible, independently-powered portable device. Benchtop testing and validation indicates that custom electronics and control algorithms support the generation of high-voltage, low duty-cycle current pulses in a power-efficient manner, extending battery life and allowing ES therapy to be delivered for up to 7 days without needing to replace or disturb the wound dressing.

Calorie restriction, stress and the ubiquitin-dependent pathway in mouse livers.

Calorie restriction (R) is the only known method to delay the aging process and extend mean and maximal lifespan in rodents. R has been shown to delay the age-related accumulation of damaged proteins and to protect organisms from various stresses which can produce damaged proteins. Such stresses include irradiation, heat shock, and oxidative stress. The ubiquitin- and ATP-dependent proteolytic pathway (UPP) has been associated with the degradation of abnormal and/or damaged proteins. We examined the effect of diet and oxidative stress on activities of the UPP in supernatants from livers taken from 23-month-old Emory mice which had been exposed to an in-vivo injection of paraquat. Paraquat induces oxidative stress by generating superoxide radicals. In livers from non-stressed animals, steady-state levels of endogenous ubiquitin conjugates, de novo conjugate formation, and E1 and E2 activities were significantly lower in R animals than in control (C) animals. However, after exposure to paraquat, levels of endogenous ubiquitin conjugates were significantly higher in R versus C animals, and de novo conjugate formation and E1 and E2 activities in R animals rose to levels which were indistinguishable from levels of these activities noted in C animals. R was associated with an increased ability to degrade beta-lactoglobulin by the UPP after an oxidative stress was imposed. Ability to degrade beta-lactoglobulin by the C or R livers in non-stressed animals was not significantly different. Taken together, these data indicate that oxidative stress in R animals is associated with enhanced levels of ubiquitin conjugates and that this enhancement may be due to an increase in UPP activity. These data also indicate that the ability to form ubiquitin conjugates and the UPP system does not change with oxidative stress in C animals. The latter is consistent with prior reports that suggests that older C animals may already be in a state of enhanced oxidative stress and that activities of the UPP provide a sensitive indicator of levels of cellular redox status.

Aging, calorie restriction and ubiquitin-dependent proteolysis in the livers of Emory mice.

Calorie restriction (R), the only known method to delay the aging process and extend mean and maximal lifespan, has been shown to delay the age-related decline in protein degradation. There are several proteolytic pathways. The ubiquitin- and ATP-dependent proteolytic pathway (UPP) is frequently associated with degradation of damaged abnormal and/or regulatory proteins. We examined the effect of aging and R on supernatants of livers taken from young (4.5 months) and old (23 months) Emory mice. Aging was associated with increased levels of endogenous ubiquitin conjugates, enhanced ability to form high molecular weight conjugates and ubiquitin activating (E1) and ubiquitin conjugating (E2) activity in the control (C) liver supernatants. The age-related increase in levels of endogenous ubiquitin conjugates in liver appears to be primarily due to increased E1 and E2 activities. R prevented the age-related increase in E1 and E2 activity, and thus prevented the age-related increase in levels of ubiquitin conjugates. In spite of the age-related increase in ubiquitin conjugates, no age-related changes in ubiquitin-dependent proteolytic pathway were observed in the C animals. R was associated with an enhanced ability (130%) to degrade beta-lactoglobulin by the ubiquitin-dependent proteolytic pathway in livers from 4.5-month-old animals relative to age-matched C livers. However, rates of the ubiquitin-dependent degradation of beta-lactoglobulin in the 23-month-old C and R animals were indistinguishable. There were no age- or diet-related differences in the ability to degrade another substrate, oxidized ribonuclease (RNase).