Walid Al-Wali MBChB FRCPath

• Professor of microbiology, Consultant
• medical microbiologist, Lead infection
• control doctor, Director for infection
• prevention and control, Medical director
• Department of Medical Microbiology,
• Rotherham NHS Foundation Trust,
• Rotherham, UK

Example box: Examples of node parcellations On the primer website you will find a few different parcellations that were obtained with different data-driven methods sleep aid headphones buy provigil once a day. The examples include some hard and soft parcellations insomnia 80s song order provigil in united states online, and some parcellations that are contiguous and some that are not contiguous sleep aid pregnant cheap 200 mg provigil with visa. The aim of this is to familiarize yourself with the similarities and differences between different parcellations sleep aid hangover generic provigil 100mg free shipping. It is important that the timecourse represents the temporal dynamics of the functional region well sleep aid home remedies purchase provigil 200 mg line, as it forms the basis for calculating the edges (connectivity) between nodes insomnia early pregnancy purchase provigil australia. The mean timeseries approach is easy to implement and is, therefore, commonly used. However, one disadvantage of the mean timeseries is that it is sensitive to potential noisy voxels in the node. The second approach to timecourse extraction is to use dual regression (specifically, the output of the first stage; please see Chapter 4 for a more detailed explanation of dual regression). Dual regression can be understood in part as a weighted average (where voxels that contribute less to the nodes are down-weighted). Therefore, dual regression deals with spatial overlap between nodes by partitioning the variance between the timecourses of the components depending on their degree of correlation. In a perfect dataset that contains no noise and has perfectly defined, non-overlapping node boundaries, these two methods will result in very similar node timeseries. It is useful to realize that all methods essentially generate a timecourse based on some form of averaging of the voxel timecourses within the node. As a result, larger nodes that contain more voxels will undergo more averaging and, therefore, should be expected to result in smoother timecourses with less high-frequency power than smaller nodes. The type of information reflected by the edge can take on three different forms, namely: (i) the existence of a connection, (ii) the strength of a connection, or (iii) the direction of information flow of the connection. Edges that reflect the existence of a connection are simply binary (0 or 1) and represent whether a functional connection between the pair of regions exists (1) or does not exist (0). Finally, it is possible to have two edges that reflect the causal flow of information from region A to region B and inversely from region B to region A. Some causal connectivity measures are briefly mentioned at the end of this section, and causality is discussed in more detail in Chapter 6. Once the edges between all pairs of nodes have been estimated (whether they reflect binary, strength, or directional edges), the resulting network matrix. Remember that functional connectivity is typically defined as the observed temporal correlation (or other statistical dependencies) between two measurements from different parts of the brain (as explained in Chapter 1). This approach is also often called "full correlation" to differentiate it from partial correlation (which is described below). The advantage of full correlation is that it is easy and fast to compute and intuitive to interpret. However, the main disadvantage of full correlation is that it is sensitive to both direct and indirect functional connections in the brain. In this case, there are direct connections between A and B, and between B and C, and hence, there is only an indirect connection between A and C (via B). In this example, full correlation will show a positive connection between all combinations of regions A, B, and C without being able to distinguish between the direct and indirect connections. Another disadvantage of full correlation (compared with partial correlation), is that it is more sensitive to any noise confounds that are shared between multiple node timeseries and that have not been removed during preprocessing. This is achieved by regressing the timeseries from region B out of the timeseries of both regions A and C before calculating the correlation between A and C. If regions A and C are only indirectly connected via B, this will remove the parts of the data in the timecourses of regions A and C that are similar, and will therefore result in a correlation that is close to zero. However, if there is still a correlation between A and C after regressing out B, then a direct connection between A and C is likely to exist. When considering a larger network, it is necessary to regress out all other node timeseries in order to calculate the partial correlation. Therefore, in this 4-node example, the indirect connection between nodes 1 and 2 can be explained by their joined connection with node 3, and disappears when looking at partial correlation. Regularization can be used in partial correlation to reduce noisy edge estimates (compare, for example, the edge between regions 3 and 4, between partial and regularized partial correlation in the bottom part of the figure). The advantage of partial correlation compared with full correlation is clearly that it is primarily sensitive to direct connections. The first is that regressing out all other nodes before calculating an edge results in a reduction in the temporal degrees of freedom. As a result, there is a limit to the number of nodes that are possible to include in a partial correlation analysis, particularly when the resting state scan contains relatively few volumes. So, while full correlation analysis can suffer from detecting too many connections. This is a reason why having collinear nodes (or, in the extreme case, using individual voxel as nodes) is problematic. Mathematically, partial correlation edges for a set of nodes can be estimated via calculating the inverse covariance matrix, rather than regressing out all other nodes before estimating each edge. To address this noise problem, a common approach is to apply some regularization when calculating the partial correlation matrix. One regularization approach is to assume that the final partial correlation matrix should be sparse, meaning that we expect that not all of the nodes are connected to all of the other nodes and that a large number of the edges should be zero. Here, regularized partial correlations can be calculated, in which edges that are estimated as being close to zero are penalized and forced to become zero. More regularization is required for shorter timeseries and/or when including more nodes, and less regularization for longer timeseries and/or when including fewer nodes (because of the degrees of freedom issue discussed previously). Briefly, coherence is the equivalent of correlation in the spectral (frequency) domain, meaning that the strength of coherence is not reduced if one timeseries lags behind the other, unlike with correlation. The other three methods aim at inferring the direction of functional connectivity. It does not suffer from the confounds that make Granger unsuitable, but is a quite noisy measure and not very accurate on many datasets. Finally, Bayes nets test the likelihood of different network configurations by making use of the concept of conditional independence. Multiple different methods for edge definition have previously been compared in a study using simulated data. The results of these simulations suggest that full and (regularized) partial correlation are among the most reliable methods for edge definition. Hence, it uses the network matrix to ask the research questions, such as: i) which edges differ in strength between the patient and healthy control groups In the case of defining edges in terms of full or partial correlation this is done by discarding one half of the network matrix (which contains the same information as the other half, because the matrix is symmetric, i. Multiple subjects can then be stacked onto subsequent rows to form a large subjects-by-edges matrix. Subjects can then be stacked below each other to form a matrix ready for group-level analysis. The first is to use a mass univariate method, which treats each edge separately and performs Subjects Example box: Calculating subject and group network matrices In this example you will calculate and visualize network matrices from individual subjects, and perform a simple group analysis to estimate the group-level network matrix. On the primer website you will find a set of subject timeseries that are ready for further network modeling analysis. You will estimate the network matrix using both full and partial correlation in order to look at the similarities and differences between these edge definition approaches. The aim of this example is to familiarize yourself with the types of results obtained from a network modeling analysis. Permutation testing ("General Statistics Box: Multiple Comparisons Correction" in Chapter 4) is often used to obtain p-values of the group comparison for each edge. Classification algorithms use a set of features (in our case the edges) to find patterns of edges that best predict whether a given subject is part of group 1 or group 2 (or to predict one or more continuous variables). First, feature selection is often performed to reduce the number of edges that are included in the classification analysis (as a very large number of noisy edges can reduce the classifier performance). This can be achieved by thresholding the network matrix, for example only including the top 10% of edges that are either strongest overall, or that show the biggest group difference as features. Secondly, the subjects need to be split up into a training and test set of subjects. Thirdly, the training dataset (which includes information about which group the subjects belong to) is used to train the classifier. Here, the classification algorithm learns a function that maps a pattern of edges onto the subject labels. Fourthly, the classifier now has to label the test subjects based on the function it estimated from the training subjects. The main result of the analysis is the classification accuracy, which is the percentage of test subjects that were accurately labeled. It is also possible (for linear multivariate methods) to look at which edges contributed to the multivariate pattern that was used for the classification (also called the classification weights). For example, some edges may have a weight that is close to zero in the classifier pattern even though it is, in fact, different between groups 1 and 2. This can happen because multiple edges contain the same information and in this case only one of the edges shows up in the pattern. On the other hand, it is possible that an edge receives a high predictive weight in the pattern, even though it does not contain any direct information about the difference between groups 1 and 2. For example, edges that cancel out noise that is correlated with the two subject groups would increase the accuracy of the overall pattern and, therefore, receive a high weight. Hence, the classification weights are not always helpful in order to interpret the most important edges for the classifier. However, the univariate method is rarely sensitive to small changes in edge strength as these would not survive the relatively harsh correction for multiple comparisons that would be required to control for the risk of finding a result by chance given the number of tests that are performed (see "General Statistics Box" at the end of Chapter 4). Multivariate techniques, on the other hand, are potentially sensitive to small changes in edge strengths (across multiple edges) because they search for a multivariate pattern. However, as a result it is more challenging to interpret the weights produced by a classification, because the resulting pattern has to be inferred as a whole (although the classification/prediction accuracy is more straightforward to interpret). Specifically, network modeling analysis enables us to look at changes in connection strength between specific regions of interest in a relatively hypothesis-driven approach compared with voxel-based methods (see Section 5. Additionally, node-based methods play an important role in mapping the functional connectome of the human brain. Mapping the connectome involves identifying the (functional) connectivity between all functional regions in the brain. Therefore, a network modeling analysis that builds a network matrix of edges between a comprehensive set of regions covering the whole brain is an important method for connectomics. However, it is important to be aware of the disadvantages of network modeling analysis. The most important drawback of performing a network modeling analysis is that the nodes must be spatially defined at the start and cannot change shape or size as part of the analysis. However, instead of directly comparing the network matrix across (groups of) subjects, graph theoretic approaches use it to extract higher level summary measures that describe aspects of network functioning. Typically, graph theory analysis uses correlation to calculate the network matrix edges, and subsequently thresholds the network matrix into a binary matrix (meaning that the edges are either 1 or 0, i. This binarized (also called "unweighted") network matrix can be used to extract local and global measures of network characteristics. Node-wise summary measures: the minimum path length between two nodes is defined as the smallest number of edges that are needed to travel from node A to node B. The clustering coefficient of a node measures the number of other nodes that it has edges with, which also have edges with each other. Hence, a high clustering coefficient means that if nodes A and B are both connected to node C, they are also likely to be connected to each other. Calculating the clustering coefficient takes into account the number of connected triangles of nodes. Nodes with a degree that is larger than the averaged degree in the graph are called hubs. Hubs are often densely connected to other hubs (usually via long-distance connections) forming a so-called "rich club" of nodes. Global summary measures: the local measures for minimum path length and clustering coefficient can be averaged to calculate the mean path length and clustering coefficient of the whole graph. These measures relate to the organization and efficiency of the network and describe things like the minimum path length, clustering coefficient, degree, and small worldness. Global efficiency is inversely proportional to the average minimum path length. Small worldness is a characteristic of networks that is found in many complex systems such as social networks, the internet, and also the brain. Small world network organization means that nodes are densely connected locally, with a few longdistance connections between hubs. Using hubs in this way is beneficial in terms of network efficiency because it means that nodes are well connected without the need for a large number of random connections. Hence, small world networks are characterized by a low minimum path length and high clustering coefficient. The small worldness of a network can be calculated by comparing the average minimum path length and average clustering coefficient of the network against a randomly connected network. These graph theoretic summary measures can be calculated for each subject and compared between groups to inform us about differences in network organization between, for example, patients and healthy controls. Regular statistics such as a t-test can be used to compare the summary measures, because graph theory measures typically summarize the functional connectivity into a single value per subject.

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Subsequent bicarbonate secretion by the pancreatic and biliary ducts neutralizes gastric acid insomnia first trimester order provigil in united states online. This is an essential step insomnia by dana gioia order provigil 200 mg without prescription, as both Pancreatitis: Medical and Surgical Management insomnia reviews cheap provigil online master card, First Edition sleep aid while pregnant order 200mg provigil free shipping. Appropriate control of luminal pH insomnia 1997 full movie discount provigil 200 mg visa, coupled with the presence of sufficient concentrations of both digestive enzymes and bile acids insomnia cookies nutrition order provigil 100 mg on-line, is necessary for fat digestion. The human pancreas has a substantial reserve capacity for secretion, and pancreatic exocrine insufficiency does not appear until lipase secretion is reduced by 90% or more [5]. This would suggest that delivering approximately 10% of normal pancreatic enzyme output of enzyme replacement therapy with each meal would be sufficient to eliminate maldigestion and exocrine insufficiency. A number of disorders may result in disruption of the normal process of pancreatic enzyme secretion. Chronic pancreatitis is associated with slowly progressive fibrosis and destruction of the gland. In addition to destruction of parenchyma, a number of ductal changes including strictures and stones may result in duct blockage, which augments exocrine insufficiency. Steatorrhea and other signs of maldigestion generally do not occur until late in the course of chronic pancreatitis [6], often years or even decades after disease onset. Exocrine insufficiency is seen most commonly in those with chronic pancreatitis due to alcohol or smoking, and in certain genetic causes. In addition, these patients often undergo pancreatic surgery, which may further reduce enzyme secretory capacity. A majority of patients continue to require pancreatic enzyme supplementation after surgical treatment [7]. Patients with severe acute pancreatitis with complications such as pancreatic necrosis are at a high risk of developing pancreatic insufficiency. The risk of pancreatic exocrine (and endocrine) insufficiency is highest in patients who have undergone necrosectomy due to the resulting loss of pancreatic parenchyma, but exocrine insufficiency may occur after less severe episodes of acute pancreatitis [8]. Pancreatic cancer patients are also at risk of pancreatic insufficiency depending on the location and degree of pancreatic ductal obstruction. These can include patients with ductal adenocarcinoma of the pancreatic head, which prevents enzyme access to the duodenum. Most patients with tumors in the pancreas requiring pancreatic resection either had exocrine insufficiency at diagnosis or became exocrine insufficient soon after surgical resection [9]. Patients who undergo upper gastrointestinal surgery are at risk of asynchrony of pancreatic secretions in response to nutrient entry into the lumen, thereby causing inadequate mixing of enzymes with food resulting in malabsorption [10]. In these patients, the enzymes have to travel through the Roux limb before entering the efferent limb where nutrients are entering the digestive tract. Malabsorption can ensue, as simultaneous mixing following nutrient intake does not happen [11]. This contributes to the maldigestion and malabsorption associated with Roux-en-Y gastric bypass. Low intraluminal pH in the duodenum results in inactivation of lipase and bile acids, which can result in maldigestion. The duodenal bicarbonate concentration may be insufficient to neutralize the acid, thereby resulting in malabsorption [12]. Another mechanism for low duodenal pH is dumping of gastric contents too quickly into the duodenum, thereby giving inadequate time for bicarbonate action. It is noteworthy that patients with chronic pancreatitis often have a lower duodenal pH than normal controls, and this may also contribute to the maldigestion seen in these patients. Diagnosis of pancreatic exocrine insufficiency Two diagnostic challenges exist in these patients. The first is establishing accurately the diagnosis of chronic pancreatitis or alternative diagnosis that may cause exocrine insufficiency. Patients with pancreatic exocrine insufficiency do not present clinically until the majority of glandular production of enzymes has been compromised. In careful analyses, fat maldigestion does not occur until pancreatic lipase falls below 10% of normal secretion [5]. However, patients who have pancreatic cancer may present with maldigestion after removal of as little as 30% of the parenchyma. This is probably the result of diminished functional capacity of the remnant parenchyma, coupled with asynchrony after surgery. Patients may present with oily clay colored stools, abdominal bloating and gas, loose stools or diarrhea, and an inability to maintain weight despite adequate oral intake. Many patients can have dramatic steatorrhea, despite having only one formed bowel movement a day. The lack of diarrhea is often attributed to better preserved carbohydrate and protein digestion, compared with diseases of the small bowel producing malabsorption of all dietary components. Measuring unabsorbed carbohydrates or protein is also possible, but more complex than fat. The 72-hour fecal fat test was designed to quantify fat malabsorption, which remains the gold standard for quantification of steatorrhea. Patients are required to go off of pancreatic enzymes for at least a week and should be consuming at least 100 g/day of fat for 3 days preceding the test as well as the 3 days during the test. It is noteworthy that unlike when the test was originally developed, an intake of 100 g/day of fat is significant but is still less than the average daily fat intake in the United States (>160 g daily per capita) and many other developed countries. The need to know rather precisely the fat content of the diet during the test makes it difficult to perform accurately in an outpatient setting and often requires the services of a dietician or a metabolic kitchen. The levels of steatorrhea are often much higher (>20 g/day) in patients with confirmed pancreatic disease [15]. The test is not widely used in clinical practice, due to the number of practical and logistical issues mentioned earlier. The test is simpler than a 72-hour fecal fat analysis but must also be performed on a high-fat diet. This is a relatively insensitive test with positive results mainly in patients who have greater than 25 g of fecal fat per day [16]. A similar test, which is not available, is the acid steatocrit in which stool is acidified and centrifuged, with the height of the fat layer compared with the total height of the sample being used to quantify fat in stool (>31% fat layer of total sample height in a test tube is abnormal). Several noninvasive tests have also been developed over time to diagnose pancreatic insufficiency in the outpatient and inpatient setting. Chymotrypsin avoids degradation in the small bowel by binding to insoluble debris in the stool and remains detectable for several days. Fecal chymotrypsin below 3 U/g of stool is suggestive of pancreatic insufficiency [17]. Pancreas elastase -1 is a pancreas-specific elastase that evades digestion and degradation in the small bowel and can be reliably detected in stool. Similar to fecal chymotrypsin, the levels correlate well with the functionality of the pancreas. Typically, values less than 100 mcg/g of stool is diagnostic of pancreatic insufficiency [18]. The accuracy of fecal elastase exceeds that of fecal chymotrypsin, and it is preferred as it is more stable during intestinal passage [19, 20]. A number of conditions other than exocrine insufficiency can produce a falsely low fecal elastase. Fecal elastase (human) may be measured while the patient is taking exogenous porcine enzymes as the assay is not affected. Serum trypsin is abnormally low in patients with advanced chronic pancreatitis and steatorrhea, but may be normal in other conditions associated with pancreatic exocrine 198 Pancreatitis insufficiency and in those with less-advanced chronic pancreatitis. A number of breath tests have also been developed to identify exocrine insufficiency, using triglycerides radiolabeled with 13 C or 14 C. These tests are available at a few research centers but are not available for patients in the United States [20]. The tube is introduced fluoroscopically with the weighted tip positioned close to the ligament of Treitz and the tapered radiopaque portion of the tube is kept close to the pylorus [22]. Basal duodenal and gastric pH along with the volume secreted is then measured over 15 minutes. This is followed by the injection of a supraphysiologic dose of synthetic human secretin at a dose of 0. It does appear to be reasonably sensitive and specific as a diagnostic tool, with sensitivities of over 90% for late stages of chronic pancreatitis, and about 75% in early-stage chronic pancreatitis [25]. After secretin infusion, the duodenal fluid is then collected every 15 minutes for 60 minutes, and this fluid is measured for volume, pH, and bicarbonate concentration in mEq/L. The secretin test measures maximal stimulated secretory capacity of ductal cells and is not a direct measurement of enzyme secretion. Maximum stimulated secretory capacity drops prior to the later development of exocrine insufficiency, but there is not a specific bicarbonate concentration cutoff below which exocrine insufficiency invariably occurs. The fluid is analyzed for lipase secretion, which has shown to be sensitive for diagnosis of early- and late-stage chronic pancreatitis [27]. Even the secretin test is rarely performed except at a few research centers, and even there it was not possible for several years due to an unavailability of secretin. Both tests require unsedated placement of a relatively large caliber oroduodenal tube, which also limits their acceptability by patients. One alternative to conventional pancreatic function testing is to utilize endoscopy to collect fluid in the duodenum after secretin injection. This test is likely better tolerated than the Dreiling tube insertion under fluoroscopy as the patient is well sedated for the procedure. There are, however, cost and time constraints in using an endoscopy room for 60 minutes for the procedure. In addition to testing of pancreatic function to determine the presence of pancreatic exocrine insufficiency, the presence of exocrine insufficiency may be suspected based on imaging tests of the pancreas documenting features consistent with advanced chronic pancreatitis. In the case of chronic pancreatitis, the development of a dilated pancreatic duct, pancreatic gland atrophy, or diffuse pancreatic calcification often signal disease, which is advanced enough to be likely associated with exocrine insufficiency. One of the main drawbacks with this system is that it measures volume rather than bicarbonate concentration. In addition, obstructive lesions of the ampulla can also give false-positive results [29]. Pancreatic function tests, whether invasive or noninvasive, do very well in detecting advanced disease, the setting in which exocrine insufficiency is most commonly encountered. However, the diagnosis of early chronic pancreatitis or even the diagnosis of pancreatic exocrine insufficiency is more challenging. In many patients, the diagnosis of exocrine insufficiency is empiric, considered in the right clinical setting and with the right constellation of symptoms and supported by tests such as fecal elastase or serum trypsin. For many years, these products were marketed in the United States as unapproved products. The drug companies were instructed to demonstrate that they were able to manufacture their products with sufficient consistency and quality to ensure that patients did not experience dose variation. Approval was based on these criteria in at least 200 patients studied over 6 months (or 100 patients over 1 year). Approval was granted for both cystic fibrosis and chronic pancreatitis, even if the supporting clinical studies only analyzed those with cystic fibrosis. Five of these products are capsules containing enteric-coated microspheres, including one (Pertzye) that includes bicarbonate. Pancreatic Consequences of pancreatic exocrine insufficiency In addition to diagnosis, additional testing of nutritional status is often useful to gauge the degree and severity of nutritional complications of exocrine insufficiency as enzyme therapy is begun. Those with exocrine insufficiency may develop frank malnutrition, although this is unusual unless p. In those without malnutrition, deficiencies of fat-soluble vitamins may develop even in the presence of rather mild steatorrhea. Deficiency of vitamin D is particularly important, and numerous studies have documented high rates of osteopenia and osteoporosis in patients with chronic pancreatitis. Thus, it is important to not only measure vitamin D levels at the onset of therapy but to monitor this over time and to also assess bone density. Product Zenpep Creon Pancreaze Viokace Ultresa Pertzye Formulation Enteric-coated porcine Enteric-coated porcine Enteric-coated porcine Tablet non-enteric-coated porcine Enteric-coated porcine Enteric-coated porcine with bicarbonate Manufacturer Aptalis AbbVie Janssen Aptalis Aptalis Digestive care Lipase content/capsule or pill 3,000; 5,000; 10,000; 15,000; 20,000; 25,000 3,000; 6,000; 12,000; 24,000; 36,000 4,200; 10,500; 16,800; 21,000 10,440; 20,880 13,800; 20,700; 23,000 8,000; 16,000 enzymes (particularly lipase) become irreversibly denatured in the acidic gastric environment, hence the fact that most preparations are available in an enteric-coated formulation. The microspheres in these enteric-coated agents have a polyacrylic acid layer that dissolves only in an environment with pH >5. This prevents the granules from being released in the stomach where the pH is normally less than 4. Once in the intestinal lumen, the contents are released for digestion, but this may occur significantly downstream in the small bowel. In the normal state, these enzymes are most active in the duodenum, whereas in patients on pancreatic enzyme replacement therapy the release may be in the distal jejunum or even the ileum. These capsules are designed to be taken orally as whole capsules without being chewed [31]. In addition to enzyme secretion, the pancreas secretes a significant quantity of bicarbonate, which is responsible for maintaining an alkaline milieu in the small intestine. Studies have demonstrated that bicarbonate secretion may not drop proportionately to the degree of enzyme secretion drop in pancreatic insufficiency.

Some infections may be asymptomatic: in a wool processing factory in Belgium insomnia 9 months pregnant cheap 200mg provigil amex, where live anthrax spores were identi ed but no clinical cases occurred insomnia xbox one buy generic provigil 200mg online, eight out of 66 employees had relevant antibodies sleep aid mouthpiece purchase provigil canada, and workers who sorted or processed raw goat hair were more likely to be seropositive (Kissling et al sleep aid on morning joe purchase provigil toronto. Anthrax as a Bioweapon the bioweapon potential of Bacillus anthracis was rst explored early in the twentieth century insomnia with zoloft order discount provigil line. The organism is easily grown sleep aid breathing techniques order generic provigil pills, has an inhalable and dispersible form that can persist in the environment for long periods, causes a fatal disease in humans and animals and is not directly transmissible from person to person. Most cases occurred in people handling or processing the contaminated mail in transit (four mail workers, two of whom died, and two mail processors) or receiving the contaminated mail (a media company mailroom worker, a government of ce mail processor and a media company employee, who died), but a hospital supply worker and a retired elderly woman, both thought to have become infected after exposure to cross-contaminated mail, also died. Post-exposure antibiotic prophylaxis (a 60-day course of oral cipro oxacin or doxycycline) was recommended for approximately 10,000 people assessed as being at risk of spore exposure; most of these individuals probably did not complete the course, but no cases of anthrax occurred. A laboratory worker dealing with outbreak-related samples acquired cutaneous anthrax (Jernigan et al, 2002). In consequence, there has been an explosion of work on anthrax in research and diagnostic laboratories; several incidents have occurred in which live anthrax has been transferred between laboratories as a result of lapses in laboratory procedure (Centers for Disease Control and Prevention, 2014; Weiss et al. Some national health authorities recommend preexposure vaccination of laboratory workers who are at high risk of exposure to anthrax spores (Public Health England, 2014). These cause cell death and disruption of cell signalling systems, and also hypotension via direct effects on the myocardium and peripheral vasculature. Pathologically, infection is characterised by oedema and haemorrhagic necrosis; typical autopsy ndings report haemorrhagic mediastinitis with oedema, large serosanguinous pleural effusions, pericardial effusion, ascites, splenic involvement, cerebral oedema and haemorrhagic meningitis (Albrink et al. Pulmonary anthrax may present as a non-speci c febrile illness; diagnosis may be delayed unless other cases have recently been reported. In severe cases, a short prodromal phase is followed by a fulminant phase with rapid progression to hypotension, refractory shock and death. In the 2001 outbreak, cases treated with antibiotics in the prodromal phase survived; those treated later did not. Modern intensive care, with haemodynamic monitoring, treatment of coagulopathy or thrombocytopenia and early and aggressive drainage of effusions (which may reduce toxin load as well as improve ventilation), may increase survival. There is no speci c treatment, but early diagnosis and intensive care support may reduce mortality. HenipaViRus infeCtions these highly pathogenic paramyxoviruses have a natural reservoir in fruit bats (ying foxes, Pteropus spp. There is evidence of Nipah virus (NiV) infection in fruit bats in South and South East Asia. Infected bats are asymptomatic, but shed virus in urine, faeces, saliva and other body uids. HeV (formerly equine morbillivirus) was discovered after an outbreak of fatal respiratory and neurological disease in horses in a training stable near Brisbane in 1994 (Murray et al. The trainer died of a fulminant pneumonia; the stable foreman survived an in uenza-like illness. Horse-to-horse transmission occurs, but bat-to-human and human-to-human transmission has not been reported. Other preventative measures include preventing access of horses to bat habitats, segregation of sick horses and use of personal protective equipment (Biosecurity Queensland, 2011). There is published guidance on exposure assessment and the management of cases and their contacts (Australian Government Department of Health, 2012). NiV was rst isolated from a patient in Malaysia in 1999 during an outbreak of severe neurological illness, initially thought to be Japanese encephalitis, among pig farmers and others in contact with pigs in intensive farming units in Malaysia, and abattoir workers in Singapore in contact with imported pigs (Centers for Disease Control and Prevention, 1999; Chua et al. Almost half of the affected individuals died; some survivors had long-term neurological sequelae or late relapses. The dense pig farm populations and transport of infected pigs between farms ampli ed the porcine epidemic. Each hantavirus has a speci c rodent host; humans are infected by inhaling the virus in dust contaminated with rodent excreta or by direct contact with rodents. Occupational groups that are at risk include forestry workers and farmers (Schmaljohn and Hjelle, 1997; Riquelme et al. Human-to-human transmission has been reported only for Andes virus, which often occurs in household clusters (Wells et al. Although NiV has been found since 1999 in fruit bats in Malaysia, no further human cases have been reported. Two-thirds of NiV cases in Bangladesh have had cough and breathlessness, with diffuse bilateral pulmonary opacities on the chest radiograph. Infection may be through drinking fresh date palm sap contaminated with infected bat secretions (Rahman et al. Person-to-person transmission has occurred frequently (to family caregivers, healthcare workers and a rickshaw driver who transported a case) and NiV has been isolated from human saliva. In an outbreak of 24 cases of henipavirus infection associated with the slaughter and consumption of meat from sick horses in the Philippines (Ching et al. Two healthcare workers who had cared for the patients using gloves and masks but without eye protection were infected. When henipavirus infection is suspected, public health authorities should be alerted. There is no speci c treatment, although both ribavirin and virusspeci c monoclonal antibody have been used. Most human in uenza A (H5N1) and avian in uenza A (H7N9) cases have reported exposure either to birds or to markets in which live birds are sold. Sustained humanto-human transmission has not occurred, but both viruses may have pandemic potential, and both have caused more aggressive human disease than seasonal in uenza virus. There is evidence that healthcare workers exposed to patients with in uenza A (H5N1) are at risk of contracting the infection (Bridges et al. Cases present with fever, cough and a rapidly progressive pneumonia that does not respond to antibiotic therapy. There may be lymphopenia, thrombocytopenia, impaired liver and renal function and rapid progression to acute respiratory distress syndrome. If the diagnosis is suspected, empiric antiviral treatment with a neuraminidase inhibitor (oseltamivir, zanamivir or peramivir) is recommended, as it is for close contacts of either birds or humans with known infection who develop fever or respiratory symptoms in the 7 days after exposure. It occurs worldwide, but especially in the tropics; over half a million cases occur each year. Infected animal hosts (rodents, dogs and many wild and domestic mammals) shed leptospirae in their urine. Many infections are asymptomatic or produce an acute, non-speci c febrile illness. Leptospirosis may be mistaken for in uenza A, dengue, malaria, viral Human aVian influenza infeCtion Avian in uenza A viruses cause infection in poultry and many wild birds. Most are not serious avian pathogens, but some (highly pathogenic avian in uenza A virus) are highly transmissible and cause lethal disease in poultry ocks. In 1997, the rst cases of human infection occurred during a poultry outbreak of in uenza A (H5N1) in Hong Kong. In uenza A (H5N1) remerged in 2003, and has since become endemic in birds in China and much of South East Asia, and is found widely elsewhere. Avian in uenza virus A (H7N9) rst infected humans in China in 2013 (Cowling et al. These farmers work all day with their feet in water without any footwear, and this puts them at risk of contracting leptospirosis. There is debate regarding the role of antibiotics given after the initial phase, doubt regarding whether mild disease should be treated and few trials to guide recommendations. High-dose intravenous benzyl penicillin is usually recommended for severe disease, although ceftriaxone has become widely used, with doxycycline, azithromycin or amoxicillin for mild disease (Phimda et al. Human-to-human transmission occurs through exposure to large respiratory droplets. In an outbreak of 16 cases in India in 2002, the index case was a hunter who had killed and skinned a wild cat (Gupta and Sharma, 2007). Mild respiratory symptoms, including a dry cough, are common in the leptospiraemic phase. Laboratory con rmation of leptospirosis is dif cult outside of specialist centres. This 59 year old man contracted plague after exposure to an infected cat and a dead mouse. Two days after the exposure, he developed fever and myalgia, and by the following day, he had developed a left axillary bubo. Seven days after the initial exposure, he became critically ill with multiple organ failure. He was treated with gentamicin and survived, but necrosis of the hands and feet developed and he required amputation of the hands and feet. In Madagascar, cases continue to occur in highland villages (Andrianaivoarimanana et al. In Yunnan, China, cases (including a truck driver) were exposed in a truck taking the index case to hospital (Luo et al. A wildlife biologist in Arizona, who had performed an autopsy on a mountain lion, died of pneumonic plague in 2007; his occupational exposure was missed when he presented with fever and haemoptysis (Wong et al. Initial symptoms of high fever, headache, chills, malaise and dry cough progress very rapidly to an increasingly bloody productive cough, with breathlessness and chest pain. Effective antibiotics include aminoglycosides (gentamicin and streptomycin), doxycycline, chloramphenicol and uoroquinolones (Inglesby et al. Molecular techniques may allow isolates from human cases to be linked to their zoonotic source (Lowell et al. Contacts who have been within 6 feet of a coughing patient with suspected or con rmed pneumonic plague in the preceding 7 days should be given post-exposure prophylaxis, usually doxycycline. Standard and respiratory/droplet (disposable face mask) precautions should be used for suspected cases during the rst 48 hours of antibiotic treatment. It infects a wide range of birds; occupationally acquired infection is usually through exposure to psittacine birds (parrots, parakeets, macaws and budgerigars), to poultry or to the organism in the laboratory. Infected birds may be asymptomatic but shed the organism in nasal discharge and faeces, where it can survive in the environment for months. Human infection follows inhalation of the organism during activities such as handling of carcasses, cage cleaning or pet handling (Smith et al. Systemic generalised infection, which may be fulminant, has been described, as have myocarditis, endocarditis, encephalitis and hepatitis. There is some evidence from animal models that the severity of infection may be dose related (Knittler et al. Transmission from a severely ill patient to ten people, including seven hospital caregivers, has been described, highlighting the need for respiratory infection control precautions in all cases of febrile respiratory disease (Wallensten et al. Diagnosis is made by serology on paired sera (although early antibiotic treatment may blunt the antibody response). Recommended management of severe community-acquired pneumonia includes treatment with a macrolide (erythromycin, clarithromycin and azithromycin), which will usually treat C. If a de nitive diagnosis is made early, doxycycline is a preferred treatment for adult men and for women in whom pregnancy has been excluded. Dog deworming programmes, improved abattoir and carcass disposal practices and education decrease transmission to humans, and have largely prevented it in high-income countries. In adults, the liver is affected more often than the lungs, although pulmonary disease tends to present earlier; in children, pulmonary disease is more common than hepatic disease (Santivanez and Garcia, 2010). It may present with pressure symptoms from an enlarging cyst, including cough, chest pain and breathlessness, or a cyst may rupture into the bronchial tree or pleural space. Diagnosis and management require specialist advice and assessment (Tamarozzi et al. Q feVeR this highly infectious zoonosis caused by Coxiella burnetii was rst described after an outbreak of febrile respiratory illness in abattoir workers in Queensland, Australia, in 1935 (Derrick, 1937) and is now known to occur worldwide. Infected animals shed the organism in blood, amniotic uid and other birth products (concentrations may reach 109 organisms/g), as well as in milk, urine and faeces; it may survive for years in the environment in a sporelike form. Humans are usually infected by inhalation of the organism, in aerosols created at animal birthing or in the laboratory or in dusts contaminated with dried blood and excreta. Windborne spread has caused outbreaks miles from the originating site (Tissot-Dupont et al. Rarely, infection is acquired by eating or drinking unpasteurised milk or milk products, or by tick bite. Person-to-person transmission is rare; cases have been reported in pathologists conducting autopsies, obstetricians caring for infected pregnant women and in recipients of blood or bone marrow from infected donors (Porter, 2011). Adult tapeworms live in the intestine of dogs and wild carnivores; these animals excrete gravid tapeworm segments and eggs in their faeces. Sheep, cattle, goats and other herbivore intermediate hosts eat these; the oncospheres released in the gastrointestinal tract then migrate, usually to the liver or lungs, where they mature into a hydatid (metacestode) cyst. Humans are infected by hand-to-mouth transfer of eggs after handling an infected dog or its faeces or, less often, by eating contaminated food.

Recommended HealthBased Limits in Occupational Exposure to Selected Mineral Dusts (Silica - insomnia best buy provigil, Coal) insomnia sucks buy provigil cheap online. Inorganic dusts may be inhaled in their pure form or in association with other brogenic dusts insomnia treatment guidelines discount provigil 100mg visa, notably free silica in the form of quartz or cristobalite insomnia movie review provigil 100 mg with amex. This chapter rst considers metals sleep aid bracelet quality provigil 200 mg, metalloids and their oxides in order of their atomic number sleep aid zazen order provigil 200mg free shipping, grouping together those with similar chemical properties. Aluminium is used in non-ferrous alloys and has had a multitude of applications throughout industry. Commercially available aluminium powders are coated with sodium or potassium stearate, which protects against oxidation and hydrolysis. Reports of aluminium causing pulmonary brosis are relatively rare compared to the frequency with which the metal is used. Pathology Aluminium powder as a cause of pulmonary brosis is described in workers exposed to nely divided aluminium powders, in the reworks industry (Mitchell et al. Whether aluminium oxide (as opposed to pure aluminium) is a cause of pulmonary brosis has been a subject of debate. An early description of interstitial lung disease in corundum (aluminium oxide) abrasive workers (Shaver and Riddell, 1947) was more probably acute silicosis. In contrast, cross-sectional studies of Swedish aluminium welders failed to show an excess of pulmonary brosis (Sjogren and Ulfvarson, 1985). Thus, aluminium oxide and silicates appear to be less brogenic (Lindenschmidt et al. Aluminium lung disease is characterised by pulmonary nodules or ground-glass changes and, in some reports, generalised pulmonary brosis with more marked changes in the upper lobes (Mitchell et al. Lung tissue macroscopically has a metallic Pneumoconiosis and Interstitial Lung Diseases Caused by Other Inorganic Dusts 227 sheen on the cut surfaces and within brotic nodules. Microscopically, diffuse and focal brosis with localised in ltrates by lymphocytes are found with dense accumulations of macrophages containing metallic material. Case reports have described granulomatous reactions in people exposed to high concentrations of aluminium oxide dust, but the incidence appears to be very low (Chen et al. Symptoms, Radiology and Lung function Typically, symptoms include dyspnoea (Vallyathan et al. Prognosis Progressive respiratory impairment and death are reported both in early and more recent case reports (Mitchell et al. TiO2 is a white powder that is used extensively in household products including paints, cosmetics and paper, and most studies of the pulmonary toxicity of titanium are based on TiO2 or, more rarely, titanium tetrachloride (TiCl4). Pathology Animal and epidemiological studies of TiO2 have produced con icting ndings. The differences might be explained by titanium manufacturing and re ning processes that often involve other brogenic elements, including silica dust and asbestos. Other factors may include the use of synthetic rutiles in some animal studies (Nolan et al. Most animal studies conclude that TiO2 is not brogenic (Ferin and Oberdorster, 1985), although this is not a universal nding (Lee et al. Chen and Fayerweather (1988) found no increase in chronic lung disease in a population of 1576 workers exposed to TiO2 over a 30-year period; smaller studies, however, have described pulmonary brosis (Yamadori et al. Again, the possibility of previous or co-exposure to other minerals, including silica, cannot be excluded as a potential alternative cause. Particles of TiO2 are birefringent and show up brightly under Polaroid lters on lung biopsy. Most descriptions of titanium deposited in tissue report a macrophage response and some associated brosis of varying severity. Variations in pathology may be a result of differential particle sizes altering inhalational toxicity (Ferin et al. Animal studies indicate that TiO2 nanoparticles are genotoxic to mice (Trouiller et al. TiCl4 is a caustic liquid and has been associated with endobronchial polyposis and pneumonitis (Park et al. Symptoms, Radiology and Lung Function Small, discrete opacities similar to those in siderosis have been recorded where TiO2 is used in the manufacture of titanium (ti): atomiC numbeR 22 Titanium is a silver transition metal with high strength and corrosion resistance. There are no speci c symptoms associated with TiO2 exposure, which most texts describe as harmless, and consequently there are no speci c lung function changes reported unless other minerals are present that are associated with pulmonary brosis. Lung deposition, however, and its consequences may be different when newer technologies employ particles of smaller sizes than have previously been studied. Vanadium (V): atomiC numbeR 23 Vanadium is a hard, silver transition metal that is used in alloys, steel and brass. Cross-sectional studies in vanadium pentoxide workers found no increase in pneumoconiosis or interstitial pulmonary disorders (Kiviluoto, 1980). The macroscopic appearance of the pulmonary pleura in siderosis is described as marbled and rustbrown in colour due to iron oxide deposited in lymphatics; where haematite exposure has occurred, the colour is a deep brick-red. Microscopic appearances include peri-vascular and peri-bronchiolar aggregates of darkpigmented iron oxide in macrophages and alveolar spaces and walls. Symptoms, Radiology and Lung Function There are no symptoms or physical signs caused by siderosis, which is essentially a radiological disorder. Most changes develop after many years of exposure, but can be observed over periods as short as 3 years if exposures are high (Kleinfeld et al. Functional impairment is not usually described with pure siderosis unless (as is not uncommon) there is concomitant exposure to other elements such as quartz, asbestos or cristobalite, causing a mixed-dust brosis. Prognosis After removal from exposure, iron dust is slowly eliminated from the lungs with a gradual improvement in radiographic opacities. Iron Oxide and Lung Cancer Numerous studies of iron workers and miners have found an increased risk of bronchial carcinoma, but this appears to be attributable to smoking habits and exposure to known carcinogens (Duggan et al. It occurs naturally as an oxide and is used in batteries, paint, ink, matches, reworks and fertilisers. Acute inhalation of manganese dust and fumes may cause chemical pneumonitis and fume fever (Nemery, 1990), but its main toxicity is a Parkinsonian-like syndrome (Roels et al. Exposure to iron and iron oxide fumes occurs when producing steel and cast iron, iron mining, crushing of iron ore and the re ning, welding, cutting, grinding and nishing of iron products. While exposures to iron are very common, the reporting of siderosis itself is rare. Pneumoconiosis and Interstitial Lung Diseases Caused by Other Inorganic Dusts (a) 229 (b) alloys, batteries, coins and in the steel industry. Nickel is extracted from its ores by roasting and reduction and causes skin allergy, asthma and lung cancer. Animal studies report non-speci c dust pneumoconiosis with nickel oxide inhalation (Wehner et al. Nickel carbonyl inhalation may cause acute pulmonary oedema and acute interstitial pneumonitis (Shi, 1986). Zirconium dioxide (ZrO2) is known commercially as Zirconia and is used for polishing lenses and in thermal and electric installation, abrasives, enamels and glazes. In zircon, zirconium and hafnium are geochemically associated in a ratio of 50:1; the two are only separated for use in nuclear applications. Zirconium is used in niobium tantalum alloys, which are used in atomic reactors and to line reaction vessels. Hafnium is used mainly for control rods in naval and, to a lesser extent, commercial nuclear reactors. Zircon dust may be produced when it is processed from sand or rock; quartz dust may be a hazard during milling of the raw material and in separation processes, but is otherwise absent after processing. Pathology Zirconium-containing compounds are associated with non-caseating granulomata in the skin when repeatedly applied in deodorants (Neuhauser et al. There are subtle, ill-de ned, widespread, centrilobular nodules of ground-glass density (a) that correspond with very limited peri-bronchiolar brosis (b), which may not be functionally signi cant. Chest radiography may be normal or subtly abnormal with ill-de ned, small, mid and lower zone nodules. FeO) is the mineral ore of chromium and consists of chromium and iron oxides (FeCrO4). Chest radiographs of chromite miners exposed for over 8 years showed a pneumoconiosis described as very ne nodulation on chest radiograph, with nodules smaller than 1 mm in diameter. When the changes are advanced, the whole of the lung elds are involved, with a degree of sparing of the extreme apices, but no enlargement of hilar shadows (Sluis-Cremer and Du Toit, 1968). The categories did not correlate well with duration of exposure (McCallum and Leathart, 1975). Symptoms, Radiology and Lung Function Cough, breathlessness and sputum production are the most common symptoms (Homma et al. Bronchoalveolar uid shows increased cellularity with lymphocytosis in most and, less commonly, increased macrophages (Cummings et al. Ground-glass opacities, interlobular septal thickening, traction bronchiectasis, sub-pleural disease, hilar retraction and honeycombing are described, but vary between cases. Prognosis Clearance from the lungs is slow, and of ten reviewed cases, lung disease progressed after being removed from exposure in eight and was fatal in two (Cummings et al. Images (a) and (b) show high-resolution computed tomography scans of a left and right lung showing bilateral ground-glass opacities, centrilobular nodules and intra-lobular and extra-lobular septal thickening. More recently, tin alloy associated with indium has been used in at-screen technology (see above). The chief ore is cassiterite, a tin oxide from which tin must be recovered by smelting. The proportion of tin in crude ore is generally low and extraction procedures such as crushing and screening are unlikely to yield high exposures, although they are associated with high exposures to silicacious dust. Processes that are likely to produce tin dust or fumes include the emptying of bags of crude ore, its milling and grinding, tipping it into furnaces and chronic exposure to welding tin oxide (Giraldo et al. Pathology Tin oxide does not cause brosis in animal experiments (Robertson, 1960). Microscopic appearances show macrophages that contain tin oxide dust particles in the alveolar walls and spaces, peri-vascular lymphatics and interlobular septa; macules consist of dense peri-vascular and peribronchiolar aggregations of dust-laden macrophages. X-ray diffraction gives de nitive identi cation; the tetragonal crystals of tin oxide exhibit strong birefringence, unlike crystals of quartz, which are poorly birefringent. Symptoms, Radiology and Lung Function There are no symptoms or abnormal physical signs due to the inhalation and retention of tin oxide dust. Lung function is unaffected (Robertson, 1960) unless there is coexisting disease from some other cause. Chest radiographs show numerous small and very dense opacities scattered evenly throughout the lung elds. The mining of antimony can yield high exposures to quartz; thus, antimony pneumoconiosis can be confounded by coexistent crystalline silica exposure (Potkonjak and Pavlovich, 1983), although pneumoconiosis due to the inhalation of quartz-free powdered antimony trioxide has been described (Klucik et al. Pathology Antimony dust particles are seen in dust-laden macrophages in alveolar walls and in perivascular regions of the lungs, but there is no brosis or in ammatory reaction (McCallum, 1967). The dust of antimony ore or its trioxide does not cause brosis of the lungs in experimental animals (Cooper et al. Symptoms, Radiology and Lung Function Orange staining of the front teeth is characteristic of exposure to antimony oxide in workers with poor oral hygiene (Potkonjak and Pavlovich, 1983). Texts vary, detailing no respiratory symptoms in some workers and non-speci c respiratory symptoms including cough, wheeze, bronchitis and upper-airway in ammation in others. No abnormal physical signs or changes in lung function are associated with the radiographic changes. Acute pulmonary oedema or acute chemical pneumonia is described rarely (Renes, 1953). Metallic antimony is used as an alloy for lead and tin in the manufacture of lead acid batteries, solders, pewter, bullets and bearings, re-retardant materials and microelectronics. Antimony compounds have been used in the treatment of leishmaniasis and schistosomiasis. Larger component shadows are not seen, but the hilar regions may be denser than normal. The opacities appear only after 10 or more years of exposure (Potkonjak and Pavlovich, 1983). Prognosis There is no known detrimental effect upon health or life expectancy, but radiographic appearances persist. Hilar lymph nodes may be opaque but not enlarged and Kerley B-lines are often prominent. The chemically similar elements scandium and yttrium make up the rare earth group; their uses are varied and widespread (Table 20. It is also used in paints, plastics, engine compartments, friction products for automobiles and trucks, electronics, glass, ceramics and medical applications. Exposure via dust inhalation can occur during the drying and bagging of ground barytes. Barytes in some areas will contain variable and often signi cant quantities of free silica. A survey of a barium plant revealed the presence of baritosis in 48% of 118 workers (Levi-Valensi et al. Pneumoconiosis in barytes miners is likely to be predominantly silicosis (Seaton et al. Pathology Macroscopic appearances are of discrete grey macules in the pulmonary pleura and cut surface of the lungs; if nodular changes occur, this is usually due to the presence of silica. There is no evidence of brosis or conuent massing, and hilar lymph nodes are not enlarged.

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