One-year follow-up of conservative management of appendicitis: results from a single centre during extended lockdown in the COVID-19 pandemic.

INTRODUCTION: Conservative management with antibiotics was recommended by the UK Surgical Royal Colleges early in the COVID-19 pandemic as the first-line treatment for acute uncomplicated appendicitis. METHODS: This is a prospective single-centre cohort study of patients aged 16 years or over, diagnosed clinically and confirmed radiologically with acute appendicitis in a secondary care setting who were initially treated conservatively with antibiotics. The primary outcome was the response to conservative management with antibiotics. Secondary outcomes were: antibiotic duration; operative rates; surgical approach (open, laparoscopic or conversion to open); complication rates; COVID-19 positive rate; rates of readmission within 12 months; and length of hospital stay. RESULTS: A total of 109 patients were included in the study, 67 of whom were male. Median age was 37 (range 17-93) years. A further 28 patients were excluded because of a decision to manage operatively on the index admission or because of other diagnoses. Thirty-three patients (30.3%) had surgery on the index admission after failed conservative management and 15 (13.8%) had surgery on readmission. On histology, 32/48 patients (66.7%) had a diagnosis of complicated appendicitis and 18/48 (37.5%) had a confirmed appendicolith. CONCLUSIONS: There was a high readmission rate (47/109; 43.1%) for surgery, a radiological drain or conservative management within the first year following initial conservative management. There is a significant risk of recurrence of symptoms, particularly in the presence of an appendicolith. Laparoscopic appendicectomy should be the first-line treatment, with conservative management reserved for patients with acute uncomplicated appendicitis who are COVID-19 positive or have comorbidities.

The smartphone as a tool to screen for scoliosis, applicable by everyone.

PURPOSE (MAIN PURPOSES AND RESEARCH QUESTION): The purpose of this study is to assess the accuracy and precision of the smartphone with application and casing (Scolioscreen) compared to the Scoliometer. METHODS: The Axial Trunk Rotation (ATR) was measured in adolescent scoliosis patients visiting the outpatient clinic while performing the Adam Forward Bending Test. The Scolioscreen measurements were performed by the orthopedic surgeon and a parent. They were compared to the measurement with the Scoliometer by the orthopedic surgeon, the gold standard. The accuracy was determined with the Pearson's correlation coefficient, and precision was determined by assessing the intra- and inter-variability with the intra-class correlation coefficient (ICC). RESULTS: Fifty patients with adolescent idiopathic scoliosis (44 girls) were included with a mean age of 14.1 years and a mean Cobb angle of 38.5°. The accuracy of both the parents and orthopedic surgeon was excellent with a Pearson correlation coefficient of 0.92 and 0.97, respectively. All the ICC's, both intra- and inter-observer, were over 0.92 demonstrating excellent precision. CONCLUSION: This study confirms the accuracy and precision of the Scolioscreen when measuring the ATR on patients with AIS. Therefore, the Scoliometer can be replaced by the more easily available Scolioscreen which can be used by both physician and parents.

Proteome and secretome profiling of zinc availability in Cryptococcus neoformans identifies Wos2 as a subtle influencer of fungal virulence determinants.

BACKGROUND: Fungal infections impact over 25% of the global population. For the opportunistic fungal pathogen, Cryptococcus neoformans, infection leads to cryptococcosis. In the presence of the host, disease is enabled by elaboration of sophisticated virulence determinants, including polysaccharide capsule, melanin, thermotolerance, and extracellular enzymes. Conversely, the host protects itself from fungal invasion by regulating and sequestering transition metals (e.g., iron, zinc, copper) important for microbial growth and survival. RESULTS: Here, we explore the intricate relationship between zinc availability and fungal virulence via mass spectrometry-based quantitative proteomics. We observe a core proteome along with a distinct zinc-regulated protein-level signature demonstrating a shift away from transport and ion binding under zinc-replete conditions towards transcription and metal acquisition under zinc-limited conditions. In addition, we revealed a novel connection among zinc availability, thermotolerance, as well as capsule and melanin production through the detection of a Wos2 ortholog in the secretome under replete conditions. CONCLUSIONS: Overall, we provide new biological insight into cellular remodeling at the protein level of C. neoformans under regulated zinc conditions and uncover a novel connection between zinc homeostasis and fungal virulence determinants.

STRAWB2 (Stress and Wellbeing After Childbirth): a randomised controlled trial of targeted self-help materials to prevent post-traumatic stress disorder following childbirth.

OBJECTIVES: To test whether providing psychological self-help materials would significantly lower the incidence of post-traumatic stress disorder (PTSD) at 6-12 weeks postnatally. DESIGN: Open-label randomised controlled trial, with blinded outcome assessment. SETTING: Community midwifery services in two National Health Service (NHS) trusts in the North West. SAMPLE: A cohort of 2419 women receiving normal NHS postnatal care. METHODS: Midwives screened women for traumatic birth experience; 678 women who screened positively (28.1%) were randomly allocated to self-help with usual care (n = 336) or to usual care alone (n = 342). The self-help materials were a leaflet and online film designed to prevent the development of PTSD after trauma exposure through explaining how to manage early psychological responses. MAIN OUTCOME MEASURE: The primary outcome was a composite of diagnostic and subdiagnostic PTSD at 6-12 weeks postnatally using the gold-standard Clinician-Administered PTSD Scale (CAPS-5) interview. RESULTS: Of the 678 women correctly randomised plus the nine women randomised in error, 478 (70.5%) were followed up. Diagnostic or subdiagnostic PTSD rates at follow-up did not differ between groups who received self-help (26.7%, 65/243) or usual care alone (26.2%, 64/244) (intention-to-treat analysis: RR 1.02, 95% CI 0.68-1.53). Findings remained consistent in the per-protocol analysis (RR 1.04, 95% CI 0.85-1.27). Women viewed the materials very positively. There were no adverse effects. Health economic micro-costing indicated implementation would be very low cost. CONCLUSIONS: Many women experience a traumatic birth and risk developing PTSD, but self-help strategies without professional support are insufficient and should not be routinely introduced. TWEETABLE ABSTRACT: Self-help information alone does not reduce the number of women developing PTSD after a traumatic childbirth.

Quantitative Synthetic MRI in Children: Normative Intracranial Tissue Segmentation Values during Development.

BACKGROUND AND PURPOSE: Synthetic MR imaging is a new technique to create absolute R1 relaxivity (1/T1), R2 relaxivity (1/T2), and proton-density maps using a single multiple-spin-echo saturation recovery sequence. These relaxivity maps allow rapid automated intracranial segmentation of tissue types. To assess its utility in children, we created a normative data base of intracranial volume and brain parenchymal, GM, WM, CSF, and myelin volumes in a pediatric population with normal brain MRI findings using synthetic MR imaging. MATERIALS AND METHODS: All multiple-spin-echo saturation recovery sequences containing brain MR imaging examinations performed during 34 months were retrospectively reviewed. Abnormal examination findings were excluded following a detailed radiographic and clinical chart review. The remaining normal examination findings were then quantitatively analyzed with synthetic MR imaging. Intracranial, brain parenchymal, GM, WM, CSF, and myelin volumes were plotted versus age. Qualitative assessment of segmentation accuracy was performed. Selected abnormal examination findings were compared with these normative curves. RESULTS: One hundred twenty-two MRI examinations with normal findings were included of individuals ranging from 0.1 to 21.5 years of age (median, 11.8 years). Resulting normative data plots compared favorably with previously published data obtained using more onerous techniques. Differentiation from pathologic states was possible using quantitative values in select cases. CONCLUSIONS: A pediatric data base of normal intracranial tissue volumes using a single sequence and rapid software analysis has been compiled and correlates with previously published data. This provides a framework for clinical interpretation of quantitative synthetic MR images during development. Improved age-based segmentation algorithms in young children are needed.

Use of antibiotic prophylaxis in elective inguinal hernia repair in adults in London and south-east England: a cross-sectional survey.

PURPOSE: Evidence regarding whether or not antibiotic prophylaxis is beneficial in preventing post-operative surgical site infection in adult inguinal hernia repair is conflicting. A recent Cochrane review based on 17 randomised trials did not reach a conclusion on this subject. This study aimed to describe the current practice and determine whether clinical equipoise is prevalent. METHODS: Surgeons in training were recruited to administer the Survey of Hernia Antibiotic Prophylaxis usE survey to consultant-level general surgeons in London and the south-east of England on their practices and beliefs regarding antibiotic prophylaxis in adult elective inguinal hernia repair. Local prophylaxis guidelines for the participating hospital sites were also determined. RESULTS: The study was conducted at 34 different sites and received completed surveys from 229 out of a possible 245 surgeons, a 93 % response rate. Overall, a large majority of hospital guidelines (22/28) and surgeons' personal beliefs (192/229, 84 %) supported the use of single-dose pre-operative intravenous antibiotic prophylaxis in inguinal hernia repair, although there was considerable variation in the regimens in use. The most widely used regimen was intravenous co-amoxiclav (1.2 g). Less than half of surgeons were adherent to their own hospital antibiotic guidelines for this procedure, although many incorrectly believed that they were following these. CONCLUSION: In the south-east of England, there is a strong majority of surgical opinion in favour of the use of antibiotic prophylaxis in this procedure. It is therefore likely to be extremely difficult to conduct further randomised studies in the UK to support or refute the effectiveness of prophylaxis in this commonly performed procedure.

Cardiovascular safety assessments in the conscious telemetered dog: utilisation of super-intervals to enhance statistical power.

INTRODUCTION: ICH S7A and S7B guidelines recommend the use of conscious animals for assessment of non-clinical cardiovascular safety of new chemical entities prior to testing in humans. Protocol design and data analysis techniques can affect the quality of the data produced and can therefore ultimately influence the clinical management of cardiovascular risk. It is therefore essential to have an understanding of the magnitude of changes detectable and the clinical relevance of these changes. This paper describes the utilisation of "super-intervals" to analyse and interpret data obtained from our conscious telemetered dog cardiovascular safety protocol and reports the statistical power achieved to detect changes in various cardiovascular parameters. METHODS: Cardiovascular data from 18 dog telemetry studies were used to calculate the statistical power to detect changes in cardiovascular parameters. Each study followed a test compound versus vehicle cross-over experimental design with 24h monitoring (n=4). 1 min mean raw data from each individual animal was compressed into 15 min mean data for each dose group for visualisation. Larger summary periods, or "super-intervals", were then selected to best represent any observed cardiovascular effects whilst taking into account the pharmacokinetic profile of the drug e.g. intervals of 1 to 6, 7 to 14 and 14 to 22h post-dose. RESULTS: With this methodology and study design we predict, using the median percentile that our studies have 80% power to detect the following changes: HR (+/-10bpm), LV +dP/dt max (+/-375mmHg/s), MBP (+/-5mmHg) and QTc (+/-4ms). DISCUSSION: Super-intervals are a simple way to handle the high degree of natural variability seen with any ambulatory cardiovascular assessment and, in our hands, result in highly statistically powered studies. The ability of this model to detect cardiovascular changes of small, but biologically relevant, magnitude enables confident decision making around the cardiovascular safety of new chemical entities.

Creative potential: mental well-being impact assessment of the Liverpool 2008 European capital of culture programme.

OBJECTIVES: Culture has a number of potential impacts upon health and well-being. This project was undertaken to assess the potential impacts of the Liverpool 2008 European Capital of Culture programme upon mental well-being, so that positive effects can be maximized and negative impacts reduced, in order that health and well-being are promoted and inequalities are reduced. STUDY DESIGN: A mental well-being impact assessment (MWIA) toolkit has been developed, and was piloted in this study. MWIA uses a sequence of procedures designed to systematically assess the effect of projects, programmes and policies upon people's mental well-being and health. METHODS: The MWIA toolkit was used to explore the potential positive and negative impacts on mental well-being of a sample of projects and policies from the European Capital of Culture programme. This was achieved by asking stakeholders to answer a series of questions, holding participative workshops, constructing a community profile and reviewing the research literature. Recommendations were developed which aim to enhance the impact of the programme on people's mental well-being. RESULTS: As expected, both positive and negative impacts of the European Capital of Culture programme on mental well-being were identified. Fourteen themes were identified as emerging from the workshops, screening and reviewing the research evidence. Based on these data, 33 recommendations were developed by the project steering group and have been presented to the Liverpool Culture Company. CONCLUSIONS: The process of conducting the assessment, particularly its participatory nature and its awareness-raising role, had impacts upon mental well-being. The findings demonstrate the potential for the Culture Company programme to have a profound impact upon mental well-being, and highlight areas which could be addressed to optimize the impact of the programme.

QA interval as an indirect measure of cardiac contractility in the conscious telemeterised rat: model optimisation and evaluation.

INTRODUCTION: Conscious telemeterised rats are used for early assessment of cardiovascular drug safety. This paper details the surgery required to allow key cardiovascular parameters to be determined and describes how QA interval (QAI), a surrogate measure of cardiac contractility, is related to a more direct measure of cardiac contractility, dP/dt(max) (LVdP/dt(max)). Experimental studies examining the effect of both positive and negative inotropes are described. METHODS: Eight rats were surgically implanted with telemetry probes for measuring blood pressure, heart rate, activity, body temperature and ECG parameters. Initial studies focussed on evaluating surgical procedures aimed at improving the ECG signal to allow QAI quantification. Once achieved, experimental studies were undertaken with verapamil, salmeterol, milrinone or vehicle. Following treatment, data was collected for approximately 20 h from pair-housed animals to establish effects on QAI or LVdP/dt(max), which was measured directly from the left ventricle in a separate group of rats. RESULTS: The modified ECG lead placement produced both a qualitative and quantitative improvement in ECGs. Increases in cardiac contractility (measured directly) were paralleled by a decrease in QAI (measured indirectly). Salmeterol and milrinone increased (all p<0.05) LVdP/dt(max) (1942+/-452 and 2333+/-506 mmHg/s, respectively) and decreased QAI (3.5+/-0.54 and 2.9+/-0.43 ms, respectively). In contrast, the negative inotrope verapamil decreased LVdP/dtmax (-2119+/-300 mmHg/s) and increased QAI (4.9+/-0.46 ms). A statistically significant (p<0.001) linear relationship was identified between log(10)(QAI) and log(10)(LVdP/dt(max)). DISCUSSION: Improvements in ECG signal quality, resulting from refinements in surgical techniques allowed for the reliable quantification of ECG parameters. The linear relationship demonstrated between log(10)(QAI) and log(10)(LVdP/dt(max)) indicates that QAI may be a useful index of cardiac contractility in routine rat cardiovascular safety studies. These limited studies support the use of QAI as an indirect measure of cardiac contractility in the rat.

Gemcitabine and pemetrexed administered in rapid sequence as front-line chemotherapy for advanced non-small-cell lung cancer: a phase II clinical trial.

BACKGROUND: Previous studies of the gemcitabine-pemetrexed combination in patients with late-stage non-small-cell lung cancer (NSCLC) utilized a 90-min delay between gemcitabine and pemetrexed administration. This phase II study evaluated activity when these agents were administered in rapid succession. MATERIALS AND METHODS: Chemonaive patients with late-stage NSCLC received gemcitabine 1250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) immediately following day 8 gemcitabine every 21 days for six cycles, folic acid, B(12), and steroid prophylaxis. RESULTS: Fifty-four enrolled patients (53 treated) completed a median of four cycles. Median dose intensity was 84% (gemcitabine) and 83% (pemetrexed); 68% of patients required dose adjustments. Response was as follows: complete response, 0; partial response, 7 (13%); stable disease, 29 (54%); progressive disease, 9 (17%); and unknown/unavailable, 9 (17%). Median progression-free and overall survival was 4.6 and 12.4 months, respectively. Common grade 3 or 4 toxic effects were as follows: neutropenia (40%); fatigue and dyspnea (21% each); pneumonia (17%); febrile neutropenia and thrombocytopenia (11% each); and anemia (6%). CONCLUSIONS: The gemcitabine-pemetrexed combination is minimally active in late-stage NSCLC, with a high incidence of grade 3 or 4 toxic effects requiring frequent dose adjustments. A gemcitabine dose <1250 mg/m(2) warrants consideration for future trials exploring this doublet. Administering day 8 pemetrexed immediately after gemcitabine does not appear to negatively impact therapeutic index.

Mitochondrial genomes of the sheep blowfly, Lucilia sericata, and the secondary blowfly, Chrysomya megacephala.

This paper presents complete mitochondrial genomes for the sheep blowfly, Lucilia sericata (Meigen), and the secondary blowfly, Chrysomya megacephala (Fabricius). Both L. sericata and C. megacephala had standard dipteran-type mitochondrial genome architectures and lengths of 15 945 bp and 15 831 bp, respectively. Additionally, C. megacephala possessed a tRNA duplication either side of the D-loop, as previously reported in another Chrysomya species, C. putoria; this duplication appears to be synapomorphic for the genus Chrysomya. As in other insect mitochondrial genomes, base compositions had a high AT content, with both genomes more than 76% AT-rich.

Phytoextraction of cadmium and zinc from arable soils amended with sewage sludge using Thlaspi caerulescens: development of a predictive model.

The objectives of this study were to assess the potential for using Thlaspi caerulescens as a phytoextraction plant and develop a user-advice model, which can predict the frequency of phytoextraction operation required under prescribed conditions. Pot and field trials were conducted using soil collected from a dedicated sewage sludge disposal facility. Soil amendments (sulphuric acid, potassium chloride and EDTA) intended to increase Cd solubility were also tested. Predictive models of Cd and Zn uptake were developed which were able to reproduce the observed pH-dependence of Cd uptake with an apparent maximum around pH 6. Chemical treatments did not significantly increase the uptake of Cd. The periodic use of phytoextraction with T. caerulescens to maintain soils below statutory metal concentration limits, when modern sewage sludges are repeatedly applied, seems very attractive given the non-intrusive and cost-effective nature of the process. The major limitations lie with the large-scale husbandry of T. caerulescens.

Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib.

BACKGROUND: Biological markers for optimal selection of patient to epidermal growth factor receptor (EGFR)-targeted therapies are not established in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: EGFR/HER2 gene copy number by FISH, EGFR protein and pAKT expression by immunohistochemistry (IHC) and EGFR and KRAS mutations were tested in 204 gefitinib-treated NSCLC patients. RESULTS: Increased EGFR and HER2 gene copy number (FISH+), EGFR protein overexpression (IHC+), EGFR mutations and pAKT overexpression were all associated with significantly higher response rates (33%, 29%, 22%, 39% and 20% respectively). EGFR FISH+ (32%) and IHC+ (61%) correlated with improved survival, while EGFR mutations (27%), KRAS mutations (26%) and pAKT expression (69%) did not. In multivariate survival analysis EGFR FISH and IHC were independent predictive markers. EGFR FISH+/IHC+ patients (23%) had a median survival of 21 months versus 6 months for double-negative patients (30%). CONCLUSION: Combination of EGFR FISH and IHC is effective predictor for benefit from gefitinib. Patients with double-negative results are unlikely to benefit in western NSCLC populations.

Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study.

BACKGROUND: There are no published prospective trials of chemotherapy for advanced bronchioloalveolar carcinoma (BAC), a subtype of non-small-cell lung cancer for which there is no current standard therapy. This phase II study assesses the efficacy and toxicity of 96-h paclitaxel in chemotherapy-naive patients with advanced BAC. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with pleural effusion) or stage IV BAC were eligible. Treatment consisted of paclitaxel 35 mg/m2/24 h continuously infused over 96 h (days 1-4) every 21 days for up to six courses. RESULTS: A total of 58 eligible patients were enrolled. The objective response rate was 14% (all partial responses, 9% confirmed); 40% of patients demonstrated stable disease. The median progression-free and overall survivals were 5 and 12 months, respectively. Grade 3 or greater toxicities included neutropenia/granulocytopenia (43%), febrile neutropenia (12%), infection (22%), and stomatitis/pharyngitis (10%); there were five treatment-related deaths. CONCLUSIONS: S9714 represents the first prospective multi-institutional cooperative group trial focusing on treatment outcomes in BAC. Studies targeting this population are feasible, and while first-line paclitaxel administered as a prolonged infusion is active in this setting, toxicities limits the utility of this regimen. S9714 serves as a historical control for BAC patients against which future therapeutic approaches can be compared.

Use of failure rate databases and process safety performance measurements to improve process safety.

Employing equipment reliability databases can generate a process of continual improvement. This paper suggests a methodology that uses equipment reliability databases, and a process of benchmarking to establish a continual improvement procedure by learning "how others are doing it". A simple decision-making procedure is suggested too, to assist in prioritizing the processes/equipment that are considered to be improved as well as a methodology to measure the improvement.

Basic infant life support: retention of knowledge and skill.

Successful resuscitation depends upon several factors including the underlying cause for the cardiac arrest and the availability of advanced life support. Another key factor is the ability of those first on the scene to administer basic life support. Knowledge and skills in basic life support were tested in six registered children's nurses, who were randomly chosen to take part in a small exploratory study. Knowledge was tested by means of a questionnaire and skill was tested with a practical test using an infant manikin. The Resuscitation Council (RC) (1997) guidelines were used as a guide. The results demonstrated that the knowledge and skills of those assessed were unsatisfactory, so a resuscitation update was arranged. The sample group was re-tested using the same questionnaire and practical test immediately following the resuscitation update and again six weeks later. Knowledge and skills improved in five of the six participants, although the order in which they were performing aspects of basic infant life support was beginning to alter by the six-week retest.

Cancer vaccines for the treatment and prevention of non small-cell lung cancer.

Cancer vaccines targeting non small-cell lung cancer (NSCLC) have been studied for decades; clinical trials, for the most part, have focused on the use of autologous and allogeneic whole-tumor cell vaccines. Recent advances in molecular biology and immunology, however, have allowed the identification of many tumor antigens involved in the generation of immunity to NSCLC. Although small-cell lung cancer (SCLC) is commonly thought of as an immunogenic tumor, it is now clear that NSCLC is also capable of eliciting an endogenous immune response in patients with the disease and, in fact, has a natural history that may make NSCLC more amenable to vaccine therapy as an adjuvant treatment strategy. This review will high-light the major components of the immune system that may potentially interact with tumor-associated proteins as well as outline the immunologic similarities and differences between SCLC and NSCLC. Tumor antigens that elicit immune responses in patients with NSCLC will be discussed. Finally, clinical trials of whole-tumor cell vaccines, both autologous and allogeneic, and tumor antigen-specific vaccines will also be discussed.