Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Molecular Pathogenesis of Cholangiocarcinoma

Abstract Background Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development. Risk Factors for cholangiocarcinogenesis Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders. Molecular pathogenesis of cholangiocarcinoma Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis. Conclusion Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease

Flow of slag through coke channels at 1500C

The ironmaking blast furnace forms part of the dominant process route for steelmaking worldwide. In the lower zone of this shaft reactor, liquid iron and slag descend countercurrent to reducing gases through a packed bed of coke. The fundamental characteristics of these liquid flows are not fully understood, but influence the product quality, production rate, fuel use and asset life of the process, and hence the greenhouse gas emissions and competitiveness of the integrated steel industry. The present study aimed to establish the criteria for the passage of slag through the narrow pore necks that form between coke particles. To simulate the flow of slag through the pore necks, a new experimental technique was developed. This involved melting a slag pellet in a coke funnel with a channel of known diameter cut out of synthetic coke. Synthetic coke was used to minimise experimental uncertainty associated with the use of variable industrial coke and allow control of the coke mineralogy. Coke and slag were heated to 1500°C under argon and held at temperature for 30 minutes. After cooling, the penetration of slag into, or passage of slag through the channel was determined and the interactions of the slag with coke were characterized. Variables assessed included slag composition in the CaO-SiO2- MgO-Al2O3 system, coke mineralogy and channel diameter. For the slags and cokes studied, the minimum channel diameter that allowed slag to flow was between 4.4 and 5.0 mm. The results were in good agreement with a simple gravity and capillary force balance

A review of existing trauma and musculoskeletal impairment (TMSI) care capacity in East, Central, and Southern Africa

Background: We conducted an assessment of orthopaedic surgical capacity in the following countries in East, Central, and Southern Africa: Burundi, Ethiopia, Kenya, Malawi, Mozambique, Rwanda, Tanzania, Uganda, Zambia, and Zimbabwe. Methods: We adapted the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care with questions specific to trauma and orthopaedic care. In May 2013–May 2014, surgeons from the College of Surgeons of East, Central and Southern Africa (COSECSA) based at district (secondary) and referral (tertiary) hospitals in the region completed a web-based survey. COSECSA members contacted other eligible hospitals in their country to collect further data. Findings: Data were collected from 267 out of 992 (27%) hospitals, including 185 district hospitals and 82 referral hospitals. Formal accident and emergency departments were present in 31% of hospitals. Most hospitals had no general or orthopaedic surgeons or medically-qualified anaesthetists on staff. Functioning mobile C-arm X-ray machines were available in only 4% of district and 27% of referral hospitals; CT scanning was available in only 3% and 26%, respectively. Closed fracture treatment was offered in 72% of the hospitals. While 20% of district and 49% of referral hospitals reported adequate instruments for the surgical treatment of fractures, only 4% and 10%, respectively, had a sustainable supply of fracture implants. Elective orthopaedic surgery was offered in 29% and Ponseti treatment of clubfoot was available at 42% of the hospitals. Interpretation: The current capacity of hospitals in sub-Saharan Africa to manage traumatic injuries and orthopaedic conditions is significantly limited. In light of the growing burden of trauma and musculoskeletal impairment within this region, concerted efforts should be made to improve hospital capacity with equipment, trained personnel, and specialist clinical services

Influence of (S)-ketamine on human motor cortex excitability

Background: We conducted an assessment of orthopaedic surgical capacity in the following countries in East, Central, and Southern Africa: Burundi, Ethiopia, Kenya, Malawi, Mozambique, Rwanda, Tanzania, Uganda, Zambia, and Zimbabwe. Methods: We adapted the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care with questions specific to trauma and orthopaedic care. In May 2013–May 2014, surgeons from the College of Surgeons of East, Central and Southern Africa (COSECSA) based at district (secondary) and referral (tertiary) hospitals in the region completed a web-based survey. COSECSA members contacted other eligible hospitals in their country to collect further data. Findings: Data were collected from 267 out of 992 (27%) hospitals, including 185 district hospitals and 82 referral hospitals. Formal accident and emergency departments were present in 31% of hospitals. Most hospitals had no general or orthopaedic surgeons or medically-qualified anaesthetists on staff. Functioning mobile C-arm X-ray machines were available in only 4% of district and 27% of referral hospitals; CT scanning was available in only 3% and 26%, respectively. Closed fracture treatment was offered in 72% of the hospitals. While 20% of district and 49% of referral hospitals reported adequate instruments for the surgical treatment of fractures, only 4% and 10%, respectively, had a sustainable supply of fracture implants. Elective orthopaedic surgery was offered in 29% and Ponseti treatment of clubfoot was available at 42% of the hospitals. Interpretation: The current capacity of hospitals in sub-Saharan Africa to manage traumatic injuries and orthopaedic conditions is significantly limited. In light of the growing burden of trauma and musculoskeletal impairment within this region, concerted efforts should be made to improve hospital capacity with equipment, trained personnel, and specialist clinical services

The endoscopic endonasal eustachian tube anterolateral mobilization strategy: minimizing the cost of the extreme-medial approach.

OBJECTIVE: The ventral jugular foramen and the infrapetrous region are difficult to access through conventional lateral and posterolateral approaches. Endoscopic endonasal approaches to this region are obstructed by the eustachian tube (ET). This study presents a novel strategy for mobilizing the ET while preserving its integrity. Qualitative and quantitative comparisons with previous ET management paradigms are also presented. METHODS: Ten dry skulls were analyzed. Four ET management strategies were sequentially performed on a total of 6 sides of cadaveric head specimens. Four measurement groups were generated: in group A, the ET was intact and not mobilized; in group B, the ET was mobilized inferolaterally; in group C, the ET underwent anterolateral mobilization; and in group D, the ET was resected. ET range of mobilization, surgical exposure area, and surgical freedom were measured and compared among the groups. RESULTS: Wide exposure of the infrapetrous region and jugular foramen was achieved by removing the pterygoid process, unroofing the cartilaginous ET up to the level of the posterior aspect of the foramen ovale, and detaching the ET from the skull base and soft palate. Anterolateral mobilization of the ET facilitated significantly more retraction (a 126% increase) of the ET than inferolateral mobilization (mean ± SD: 20.8 ± 11.2 mm vs 9.2 ± 3.6 mm [p = 0.02]). Compared with group A, groups C and D had enhanced surgical exposure (142.5% [1176.9 ± 935.7 mm2] and 155.9% [1242.0 ± 1096.2 mm2], respectively, vs 485.4 ± 377.6 mm2 for group A [both p = 0.02]). Furthermore, group C had a significantly larger surgical exposure area than group B (p = 0.02). No statistically significant difference was found between the area of exposure obtained by ET removal and anterolateral mobilization. Anterolateral mobilization of the ET resulted in a 39.5% increase in surgical freedom toward the exocranial jugular foramen compared with that obtained through inferolateral mobilization of the ET (67.2° ± 20.5° vs 48.1° ± 6.7° [p = 0.047]) and a 65.4% increase compared with that afforded by an intact ET position (67.2° ± 20.5° vs 40.6° ± 14.3° [p = 0.03]). CONCLUSIONS: Anterolateral mobilization of the ET provides excellent access to the ventral jugular foramen and infrapetrous region. The surgical exposure obtained is superior to that achieved with other ET management strategies and is comparable to that obtained by ET resection

Essential role of MCM proteins in premeiotic DNA replication.

A critical event in eukaryotic DNA replication involves association of minichromosome maintenance (MCM2-7) proteins with origins, to form prereplicative complexes (pre-RCs) that are competent for initiation. The ability of mutants defective in MCM2-7 function to complete meiosis had suggested that pre-RC components could be irrelevant to premeiotic S phase. We show here that MCM2-7 proteins bind to chromatin in fission yeast cells preparing for meiosis and during premeiotic S phase in a manner suggesting they in fact are required for DNA replication in the meiotic cycle. This is confirmed by analysis of a degron mcm4 mutant, which cannot carry out premeiotic DNA replication. Later in meiosis, Mcm4 chromatin association is blocked between meiotic nuclear divisions, presumably accounting for the absence of a second round of DNA replication. Together, these results emphasize similarity between replication mechanisms in mitotic and meiotic cell cycles

Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture