Demographic and clinical characteristics associated with advanced stage colorectal cancer: a registry-based cohort study in Saudi Arabia

Background In Saudi Arabia, approximately one-third of colorectal cancer (CRC) patients are diagnosed at an advanced stage. Late diagnosis is often associated with a worse prognosis. Understanding the risk factors for late-stage presentation of CRC is crucial for developing targeted interventions enabling earlier detection and improved patient outcomes. Methods We conducted a retrospective cohort study on 17,541 CRC patients from the Saudi Cancer Registry (1997–2017). We defined distant CRCs as late-stage and localized and regional CRCs as early-stage. To assess risk factors for late-stage CRC, we first used multivariable logistic regression, then developed a decision tree to segment regions by late-stage CRC risk, and finally used stratified logistic regression models to examine geographical and sex variations in risk factors. Results Of all cases, 29% had a late-stage diagnosis, and 71% had early-stage CRC. Young (< 50 years) and unmarried women had an increased risk of late-stage CRC, overall and in some regions. Regional risk variations by sex were observed. Sex-related differences in late-stage rectosigmoid cancer risk were observed in specific regions but not in the overall population. Patients diagnosed after 2001 had increased risks of late-stage presentation. Conclusion Our study identified risk factors for late-stage CRC that can guide targeted early detection efforts. Further research is warranted to fully understand these relationships and develop and evaluate effective prevention strategies

A systematic review of methods to estimate colorectal cancer incidence using population-based cancer registries

Background Epidemiological studies of incidence play an essential role in quantifying disease burden, resource planning, and informing public health policies. A variety of measures for estimating cancer incidence have been used. Appropriate reporting of incidence calculations is essential to enable clear interpretation. This review uses colorectal cancer (CRC) as an exemplar to summarize and describe variation in commonly employed incidence measures and evaluate the quality of reporting incidence methods. Methods We searched four databases for CRC incidence studies published between January 2010 and May 2020. Two independent reviewers screened all titles and abstracts. Eligible studies were population-based cancer registry studies evaluating CRC incidence. We extracted data on study characteristics and author-defined criteria for assessing the quality of reporting incidence. We used descriptive statistics to summarize the information. Results This review retrieved 165 relevant articles. The age-standardized incidence rate (ASR) (80%) was the most commonly reported incidence measure, and the 2000 U.S. standard population the most commonly used reference population (39%). Slightly more than half (54%) of the studies reported CRC incidence stratified by anatomical site. The quality of reporting incidence methods was suboptimal. Of all included studies: 45 (27%) failed to report the classification system used to define CRC; 63 (38%) did not report CRC codes; and only 20 (12%) documented excluding certain CRC cases from the numerator. Concerning the denominator estimation: 61% of studies failed to state the source of population data; 24 (15%) indicated census years; 10 (6%) reported the method used to estimate yearly population counts; and only 5 (3%) explicitly explained the population size estimation procedure to calculate the overall average incidence rate. Thirty-three (20%) studies reported the confidence interval for incidence, and only 7 (4%) documented methods for dealing with missing data. Conclusion This review identified variations in incidence calculation and inadequate reporting of methods. We outlined recommendations to optimize incidence estimation and reporting practices. There is a need to establish clear guidelines for incidence reporting to facilitate assessment of the validity and interpretation of reported incidence

Direct and indirect contacts between cattle farms in north-west England

Little is known regarding the types and frequencies of contact that exist between farms and which of these may act as pathogen transmission routes; however it is likely that farms demonstrate considerable heterogeneity in such contacts. In this cross-sectional study, we explored the direct and indirect contact types and frequencies that exist between cattle farms within a region, focusing on potential routes of pathogen transmission. The owners/managers of 56 farms located in a 10 km by 10 km study area in north-west England were administered an interview-based questionnaire between June and September 2005. Information was obtained relating to contact types and frequencies, including those involving animal movements, equipment sharing between farms and any contractors or companies visiting the farms. The data was explored using hierarchical cluster analysis and network analysis. There was considerable variation between farms arising from different contact types. Some networks exhibited great connectivity, incorporating approximately 90% of the farms interviewed in a single component, whilst other networks were more fragmented, with multiple small components (sets of connected farms not linked with other farms). A range of factors influencing contact between farms were identified. For example, contiguous farms were more likely to be linked via other contacts, such as sharing of equipment and direct farm-to-farm animal movements (p < 0.001 and p = 0.02, respectively). The frequency of contacts was also investigated; it is likely that the amount of contact a farm receives from a company or contractor and whether or not biosecurity is performed after contact would impact on disease transmission potential. We found considerable heterogeneity in contact frequency and that many company and contractor personnel undertook little biosecurity. These findings lead to greater understanding of inter-farm contact and may aid development of appropriate biosecurity practices and control procedures, and inform mathematical modelling of infectious diseases

Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization

Background: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s Methods: Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. Results: Excitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury. Conclusions: Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.Grants to RDA from the Canadian Heart & Stroke Foundation, National Science Engineering and Research Council and the New Frontiers in Research Fund, to E.F from the National Research, Development and Innovation Office of Hungary, grant no. K134377; and the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, and to JPD from the DFG (German research Council) (DFG DR323/5-1,DFG DR 323/10-1) BMBF Bundesministerium fuer Bildung und Forschung (Era-Net Neuron EBio2, with funds from BMBF 01EW2004)

Substantial reductions in the number of diabetic ketoacidosis and severe hypoglycaemia episodes requiring emergency treatment lead to reduced costs after structured education in adults with Type 1 diabetes

Aims To determine the impact of structured education promoting flexible intensive insulin therapy on rates of diabetic ketoacidosis, and the costs associated with emergency treatment for severe hypoglycaemia and ketoacidosis in adults with Type 1 diabetes. Methods Using the Dose Adjustment For Normal Eating research database we compared the rates of ketoacidosis and severe hypoglycaemia during the 12 months preceding Dose Adjustment For Normal Eating training with the rates during the 12-month follow-up after this training. Emergency treatment costs were calculated for associated paramedic assistance, Accident and Emergency department attendance and hospital admissions. Results Complete baseline and 1-year data were available for 939/1651 participants (57%). The risk of ketoacidosis in the 12 months after Dose Adjustment For Normal Eating training, compared with that before training, was 0.39 (95% CI: 0.23 to 0.65, P < 0.001), reduced from 0.07 to 0.03 episodes/patient/year. For every 1 mmol/mol unit increase in HbA1c concentration, the risk of a ketoacidosis episode increased by 6% (95% CI: 5 to 7%; 88% for a 1% increase), and for each 5-year increase in diabetes duration, the relative risk reduced by 20% (95% CI: 19 to 22%). The number of emergency treatments decreased for ketoacidosis (P < 0.001), and also for severe hypoglycaemia, including paramedic assistance (P < 0.001), Accident and Emergency department attendance (P = 0.029) and hospital admission (P = 0.001). In the study cohort, the combined cost of emergency treatment for ketoacidosis and severe hypoglycaemia fell by 64%, from £119,470 to £42,948. Conclusions Structured training in flexible intensive insulin therapy is associated with a 61% reduction in the risk of ketoacidosis and with 64% lower emergency treatment costs for ketoacidosis and severe hypoglycaemia

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention

Background: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. Methods: In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na/K pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. Results: We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na/K ATPase elicits SD. Elevated K or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. Conclusions: Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory.This work was supported by grants from the Heart and Stroke Foundation of Canada and the National Science and Engineering Research Council of Canada to RDA, an NIH grant (NS106901) to CWS, a National Research, Development and Innovation Office of Hungary grant (K1343777) and EU Horizon 2020 research and innovation program (739953) to EF and from DFG Deutsche Forschungsgemeinschaft (German Research Council) (DFG DR 323/5-1), DFG DR 323/10-1, and BMBF Bundesministerium fuer Bildung und Forschung (EraNet Neuron EBio2, with funds from BMBF 01EW2004) to JPD

Cherenkov radiation emitted by ultrafast laser pulses and the generation of coherent polaritons

We report on the generation of coherent phonon polaritons in ZnTe, GaP and LiTaO$_{3}$ using ultrafast optical pulses. These polaritons are coupled modes consisting of mostly far-infrared radiation and a small phonon component, which are excited through nonlinear optical processes involving the Raman and the second-order susceptibilities (difference frequency generation). We probe their associated hybrid vibrational-electric field, in the THz range, by electro-optic sampling methods. The measured field patterns agree very well with calculations for the field due to a distribution of dipoles that follows the shape and moves with the group velocity of the optical pulses. For a tightly focused pulse, the pattern is identical to that of classical Cherenkov radiation by a moving dipole. Results for other shapes and, in particular, for the planar and transient-grating geometries, are accounted for by a convolution of the Cherenkov field due to a point dipole with the function describing the slowly-varying intensity of the pulse. Hence, polariton fields resulting from pulses of arbitrary shape can be described quantitatively in terms of expressions for the Cherenkov radiation emitted by an extended source. Using the Cherenkov approach, we recover the phase-matching conditions that lead to the selection of specific polariton wavevectors in the planar and transient grating geometry as well as the Cherenkov angle itself. The formalism can be easily extended to media exhibiting dispersion in the THz range. Calculations and experimental data for point-like and planar sources reveal significant differences between the so-called superluminal and subluminal cases where the group velocity of the optical pulses is, respectively, above and below the highest phase velocity in the infrared.Comment: 13 pages, 11 figure

Isospin dependence of electromagnetic transition strengths among an isobaric triplet

Electric quadrupole matrix elements, M, for the J=2→0, ΔT=0, T=1 transitions across the A=46 isobaric multiplet Cr-V-Ti have been measured at GSI with the FRS-LYCCA-AGATA setup. This allows direct insight into the isospin purity of the states of interest by testing the linearity of M with respect to T. Pairs of nuclei in the T=1 triplet were studied using identical reaction mechanisms in order to control systematic errors. The M values were obtained with two different methodologies: (i) a relativistic Coulomb excitation experiment was performed for Cr and Ti; (ii) a “stretched target” technique was adopted here, for the first time, for lifetime measurements in V and Ti. A constant value of M across the triplet has been observed. Shell-model calculations performed within the fp shell fail to reproduce this unexpected trend, pointing towards the need of a wider valence space. This result is confirmed by the good agreement with experimental data achieved with an interaction which allows excitations from the underlying sd shell. A test of the linearity rule for all published data on complete T=1 isospin triplets is presented.Peer Reviewe

Malignant islet-cell tumors of the pancreas

Although malignant islet-cell tumors are uncommon, they are an important group of pancreatic neoplasms because appropriate treatment can often result in effective palliation even though cure is infrequent. In general, these tumors are relatively slow growing so that a combination of surgical and chemotherapeutic measures may prove very beneficial. In some patients with tumors hypersecreting insulin, gastrin, glucagon, or vasoactive intestinal polypeptide (VIP), the hormonal effects of the neoplasm can be life-threatening. Surgical treatment must, therefore, consider both the functional and malignant characteristics of the individual tumor. In many patients with functional tumors, surgical debulking of the primary tumor may be indicated even when a curative resection cannot be accomplished. Some malignancies may be cured by an appropriate pancreatic resection even when peripancreatic lymph nodes are already involved. Although a Whipple procedure is not indicated when hepatic metastases are present, this procedure may cure tumors localized to the pancreatic head and/or peripancreatic lymph nodes. Because hepatic metastases are usually multiple and involve both lobes, liver resections, other than wedge excisions of peripherally located functional metastases, are not indicated. Malignant nonfunctioning islet-cell tumors are probably best treated with systemic or regional chemotherapy when metastatic. Surgical resections or bypass procedures may be infrequently useful in those cases in which the primary tumor causes either duodenal or bile duct obstruction. The most effective methods used to control hepatic metastases are systemic and hepatic arterial chemotherapy. An alternative is selective hepatic artery embolization. Recently, an implantable hepatic arterial infusion pump has been used with encouraging results in this group of patients. The chemotherapeutic agents that have been most effective in the treatment of hepatic metastases include streptozotocin, DTIC, and fluorouracil . Les tumeurs insulaires malignes sont rares mais elles présentent un grand intérêt car si le traitement entraîne exceptionnellement leur guérison il assure une survie des malades qui en sont porteurs. Ce sont en effet des tumeurs malignes à développement lent, sensibles à l'action de l'association de la chimiothérapie et de la chirurgie. Chez certains sujets les tumeurs secrétant de l'insuline, de la gastrine, du glucagon, du V.I.P. peuvent mettre en jeu la vie du malade sous l'effet de l'hypersecrétion hormonale. Le traitement chirurgical dépend de ce fait, des caractères fonctionnels et du degré de malignité de chaque type de tumeur. En présence de lésions hypersecrétantes l'exérèse de la tumeur primitive doit être envisagée alors même que la possibilité d'obtenir une guérison définitive ne peut être escomptée. Il est aussi à noter que certaines lésions malignes ont été traitées avec succès alors que les ganglions lymphatiques correspondants étaient déjà envahis. Si l'opération est contre-indiquée en présence de métastases hépatiques la duodénopancréatectomie céphalique s'applique aux tumeurs insulaires céphaliques qu'elles s'accompagnent ou non d'un envahissement des ganglions juxta-pancréatiques. Du fait que les métastases hépatiques sont souvent multiples et qu'elles intéressent les deux lobes l'action sur le foie se limite à l'éxérèse des métastases accessibles à la résection hépatique segmentaire. Les tumeurs insulaires malignes qui ne sont pas hypersecrétantes relèvent de la chimiothérapie par voie générale ou de la chimiothérapie régionale dès lors qu'elles s'accompagnent de métastases. C'est seulement lorsque ces lésions entraînent une obstruction de la voie biliaire principale ou du duodénum que la résection ou les anastomoses de dérivation sont indiquées. La chimiothérapie par voie générale ou par la voie de l'artère hépatique ou encore l'embolisation de cette dernière représentent les meilleures méthodes de traitement des métastases hépatiques. L'emploi récent de pompes à infusion de l'artère hépatique a donné des résultats intéressants chez ces malades. Les agents chimiques les plus efficaces sont la streptozotocine, le DTIC et le Fluorouracil. Aunque los tumores malignos de células insulares del páncreas son raros, éstos constituyen un grupo importante entre las neoplasias pancreáticas por cuanto el tratamiento apropiado con frecuencia resulta en una paliación efectiva a pesar de que la curación sea poco frecuente. En general estos tumores son de crecimiento lento y la combinación de la cirugía con quimioterapia puede llegar a ser beneficiosa. En algunos pacientes con tumores que hipersecretan insulina, gastrina, glucagón o VIP (polipéptido vasoactivo intestinal), los efectos hormonales del neoplasma pueden poner en peligro la vida. Por ello el tratamiento quirúrgico debe considerar tanto las caracteristicas funcionales como las de malignidad de cada tumor en particular. En muchos pacientes con neoplasmas funcionantes, el debultamiento quirúrgico del tumor primario puede estar indicado cuando la resección curativa no es realizable. Algunas neoplasias malignas pueden ser curadas mediante una resección pancreática adecuada a pesar de que los ganglios linfáticos peripancreáticos ya se hallen afectados. Aún cuando el procedimiento de Whipple no esta indicado en presencia de metástasis hepáticas, esta operación puede curar tumores localizados en la cabeza del páncreas y/o en los ganglios linfáticos peripancreáticos. Debido a que las metástasis hepáticas generalmente son múlitples y afectan a ambos lóbulos, las resecciones hepáticas, diferentes de las resecciones en cuña para lesiones funcionantes localizadas en la periferie del higado no están indicadas. Los tumores malignos no funcionantes de células insulares probablemente deben ser tratadas con quimioterapia sistémica o regional cuando se encuentren en fase metastásica. Las resecciones quirúrgicas o los procedimientos derivativos infrecuentemente son de utilidad en aquellos casos en los cuales el tumor primario causa obstrucción duodenal o del conducto biliar. Los métodos de mayor efectividad en el control de las metéstasis hepáticas son los de quimioterapia sistémica y arterial hepática. Una alternativa es la embolización selectiva de la arteria hepática. Recientemente ha venido a ser utilizada una bomba implantable de infusión arterial heptica con resultados halagadores en este grupo de pacientes. Los agentes quimioterapéuticos que han probado ser de mayor efectividad en el tratamiento de las metástasis hepáticas incluyen la estreptozotocina, la dimetiltrizenoimidazol carboxamida (DTIC) y el Fluorouracilo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41316/1/268_2005_Article_BF01656036.pd