on 27-Apr-2022 (Wed)

Whenever, do(𝑡) appears after the conditioning bar, it means that everything in that expression is in the post-intervention world where the intervention do(𝑡) occurs. For example, 𝔼[𝑌 | do(𝑡), 𝑍 = 𝑧] refers to the expected outcome in the subpopulation where 𝑍 = 𝑧 after the whole subpopulation has taken treatment 𝑡 . In contrast, 𝔼[𝑌 | 𝑍 = 𝑧] simply refers to the expected value in the (pre-intervention) population where individuals take whatever treatment they would normally take ( 𝑇 ). This distinction will become important when we get to counterfactuals in

The minimal building blocks of DAGs consist of chains, forks, immoralities, two unconnected nodes, and two connected nodes.

In defining the backdoor criterion (Definition 4.1) for the backdoor adjustment (Theorem 4.2), not only did we specify that the adjustment set 𝑊 blocks all backdoor paths, but we also specified that 𝑊 does not contain any descendants of 𝑇

This is known as M-bias due to the M shape that this non-causal association flows along when the graph is drawn with children below their parents.

Unfortunately, even if we only condition on pretreatment co- variates, we can still induce collider bias. Consider what would happen if we condition on the collider 𝑍 2 in Figure 4.16. Doing this opens up a backdoor path, along which non-causal association can flow

Whenever, do(𝑡) appears after the conditioning bar, it means that everything in that expression is in the post-intervention world where the intervention do(𝑡) occurs. For example, 𝔼[𝑌 | do(𝑡), 𝑍 = 𝑧] refers to the expected outcome in the subpopulation where 𝑍 = 𝑧 after the whole subpopulation has taken treatment 𝑡 .

Lesson 1: Causal DAGs | Causal Diagrams: Draw Your Assumptions Before Your Conclusions | edX

Accelerating AI with Synthetic Data Generating Data for AI Projects

Prediction: The future of CX

Synthetic Energy Data Generation Using Time Variant Generative Adversarial Network

Causal Inference and Data Fusion in Econometrics

Probability Calibration for Imbalanced Dataset - Towards Data Science

Generating synthetic data with referential integrity using GANs

Referential integrity is a structural element that ensures that the relationships among different sets of data are accurate. In order for synthetic data — completely artificial and private production data — to be useful, it must maintain these relationships among the data, including preserving the data links that can stretch across multiple tables.

In generating synthesised data, normally we use the finest granularity. For instance, order_id would represent a store managing orders, or person_id could represent a population. However, when we have multiple tables linked by foreign keys, then different levels of granularity emerge and the concept of finest granularity becomes ambiguous

The simple solution of left-joining the customer table with the order table, consolidating all the information and then synthesising this big table will not work.

For two reasons:

1. Each synthesised row will be a new customer and order. But in reality we have to fix the customer and only then generate details at the order level — in other words, fix the parent and generate the child. This would leave us unable to constrain the number of products in any order, which is a key feature of the data that needs to be preserved.

2. The assumption of independence of rows is no longer valid for the customer table — each customer is independent of each other. However, the order details — products bought — are not independent. Some of these fields may even have dependencies on time and should be treated as a sequence: A given Product X is dependent on the presence of other products in the basket.

To address this particular case, let's consider two levels:

1. Customer level (name, address, etc) - that we call the “parent level”

2. Order details level (products, suppliers, etc) - that we call the “child level” It is important to preserve this structure in the synthetic version because otherwise there could be misalignments and information leaks such as orders without customers or customers having unrealistic orders. This can be seen as a particular case of sequential data.

Some other examples where sequential data is common include:

electronic health records (EHR) data - diagnostics, exams

messages sent and received between two or many agents

measurements of physical systems taken over time

credit card transactions

Note that the finest grain may not be a sequence but the key insight is that data has a structure that has to be preserved — rows are not independent

Dozens of specific null mutants in a variety of pathways or for specific enzymes have been produced to examine their impact on the virulence composite of the yeast in several robust animal models, 133,137 including zebrafish, in which pathogenesis can visually be observed. 133,137,138

Proteomic and metabolomic approaches have also been used to study its pathophysiology. 143–145

Capsule The most distinctive feature of C. neoformans and C. gattii is a polysac- charide capsule containing an unbranched chain of α-1,3-linked mannose units substituted with xylosyl and β-glucuronyl groups

Capsular thickness, which varies between isolates, is regulated by several environmental cues, including ambient partial pressure of carbon dioxide, serum, urea, and low iron concentrations, which increase capsular size in many strains. These environmental signals appear to augment the yeast’s ability to produce disease and may help explain why the capsule may be small in in vitro cultures and the general environment but is much larger when observed within the mammalian host.

The impact of the capsular polysaccharide on host immunity can be profound at many pathophysiologic levels. For example, it has been shown to produce the following effects on the host 156 : (1) it acts as an antiphagocytosis barrier, (2) it depletes complement, (3) it produces antibody unresponsiveness, (4) it dysregulates cytokine secretion, (5) it interferes with antigen presentation, (6) it produces brain edema, (7) it creates selectin and tumor necrosis factor receptor loss, (8) it allows a highly negative charge around yeast cells, (9) it extrudes itself into the intracellular environment with the potential for local toxicity on cellular organelles, and (10) it enhances HIV replication.

Melanin The production of melanin is observed in many fungi, including some pathogenic species. 43 C. neoformans possesses a laccase, an enzyme that catalyzes the conversion of diphenolic compounds such as l-3,4- dihydroxyphenylalanine (DOPA), norepinephrine, epinephrine, and other related aromatic compounds to quinones, which rapidly autopolymerize to form melanin. The production of this pigment can help identify the yeast in the laboratory, but it is also a major virulence factor for the yeast.

One proposed mechanism by which melanin may protect the yeast is through its ability to act as an antioxidant, and it has been shown that yeast cells without the ability to form melanin are more susceptible to oxidative stress

It remains unclear whether the catecholamine-rich CNS, with its excellent substrates for melanin formation, provides some tissue tropism or a rich environment that enhances this yeast’s ability to produce disease. For instance, it has clearly been shown that melanin is formed in yeast cells within the brain. 162,163

High-Temperature Growth A basic trait of all pathogenic fungi is their ability to grow well at mammalian body temperature. For example, C. neoformans and C. gattii are the only cryptococcal species to grow consistently well at 37°C, and when mutants are made that cannot grow well at this body temperature, they are avirulent even when they possess the ability to make a capsule and produce melanin.

There has been progress in understanding the genetic controls for high-temperature growth in C. neoformans. First, signaling pathways such as calcineurin, RAS, and trehalose have been associated with the yeast’s ability to grow at mammalian body temperatures, and these are linked to its virulence composite. 164–167

Because serologic and skin hypersensitivity studies frequently identify cryptococcal infections and yet the incidence of cryptococcosis is low, it has been concluded that host immunity in humans is generally effective in controlling infection after initial exposure to this yeast. 179,180

Furthermore, there is general agreement among clinicians that a strong cellular immune response producing granulomatous inflammation is essential for contain- ment of infection. 180–183 Because granuloma formation is a result of a helper T cell 1 (Th1)–polarized response, cytokines such as tumor necrosis factor, interferon-γ, and interleukin (IL)-2 are required. 184,185

Several immune cell populations, such as natural killer cells, and certain types of lymphocytes have been shown to possess direct anti- cryptococcal effects. Human lymphocytes (CD4, CD8) inhibit growth of C. neoformans by direct contact. 188 A primary effector cell against C. neoformans is the macrophage, which produces anticryptococcal activity when it is “activated.” 189

It is not only the state of cellular activation or the type of host cell but also the number of cells at the site of infection that appear to provide an effective host immune response. It is clear from natural history studies in patients with AIDS that the risk of cryptococcal disease dramatically increases as total CD4 lymphocyte counts drop below 50 to 100 cells/μL of blood. 194

Phagocytosis of C. neoformans is optimally performed in the presence of complement or antibody. The intracellular fate of yeasts depends on cytokines such as interferon-γ or GM-CSF to improve intracellular inhibition or killing of the yeasts by either host oxidative or nonoxidative mechanisms. Human studies have consistently correlated a positive outcome with the presence and quantity of cytokines such as interferon-γ at the site of infection. 201

Human genome and immunogenetic studies in the future should reveal whether patients who have cryptococcosis, despite having an apparently normal immune system and no risk factors, might have subtle defects in innate or acquired immunity to this yeast.

The results of histologic examination of tissues and fluids range from virtual absence of an inflammatory reaction to intense granulomatous inflammation with caseous necrosis.

There is substantial evidence that the humoral immunity arm can contribute to an effective immune response, 207,208 including an immu- noglobulin M response. 209 Several groups have shown that preinfection monoclonal antibody strategies directed against the polysaccharide capsule can reduce the burden of yeasts and improve survival in animal models.

The pathogenesis of cryptococcosis is determined by three broad factors: (1) the status of the host defenses, (2) the virulence of the strain of C. neoformans and C. gattii, and (3) the size of the inoculum

A reasonable scenario for the pathophysiology of cryptococcosis is that the susceptible host comes into contact with cryptococci from the environment through inhalation of infectious propagules. In the alveoli, the yeasts contact the alveolar macrophages, which recruit other inflam- matory cells through cytokines/chemokines, and a proper Th1 response and granulomatous inflammation is elicited. The infection can then take one of three pathways: 1. In an immunosuppressed host, the yeast continues to proliferate and disseminate, causing clinical disease. 2. The effective immune response completely eliminates the yeast from the host. 3. The yeasts produce a small pulmonary lymph node complex and remain dormant in tissues but are not dead.

The yeasts remain dormant and the host is clinically asymptomatic until loss of local immunity occurs through, for example, corticosteroid use or progression of an HIV infection. Then the yeasts begin to replicate in the pulmonary lymph node complex and eventually disseminate into organs outside the lung. This pathophysiology is similar to the scenario proposed for reactivation of tuberculosis and histoplasmosis. Studies in France have given epidemiologic support for this concept of reactivation.

n African expatriates who lived in Europe for many years before their development of cryptococcosis, the infecting strain possessed a genotype consistent with strains from an African origin. 217

Although this evidence is indirect, there is also little evidence that cryptococcosis arises from a recent exposure, and only rare case clusters following a group exposure have been reported.

The two common sites for infection with this encapsulated yeast, the lung and the CNS, 218 were emphasized in a large review of cryptococcosis in HIV-negative patients. In this cohort, 109 patients (36%) were diagnosed with only pulmonary involvement and 157 (51%) presented with initial evidence of CNS disease. 67 Three other sites of infection (skin, prostate, and eye) have clinical features that are worthy of mention.

Cryptococcosis demonstrates a few differences depending on whether the patient has or does not have an underlying HIV infection. 125,219–222 HIV-infected patients present with more CNS and extrapulmonary infections, higher rates of positive India ink examinations, higher polysaccharide antigen titers, more frequent positive blood cultures, and fewer cerebrospinal fluid (CSF) inflammatory cells. These clinical distinctions are primarily a function of the severity of immunosuppression and the resulting high burden of yeasts. They most likely do not reflect a specific interaction between HIV and C. neoformans growth.

In at least one-third of normal hosts, the infection is asymptomatic on presentation and is detected by an abnormal chest radiograph. On the other hand, patients can present with acute symptoms of fever, chest pain, cough, weight loss, and sputum production. 227 Common and unusual pulmonary presentations are listed in Tab le 2 62 .2 .

Cryptococcosis occasionally occurs with another pathogen; coinfections of the lung have been reported with tuberculosis, nocardiosis, and echinococcosis. 228–230 There are rare cases of cryptococcosis associated with pulmonary alveolar proteinosis and autoantibodies against GM-CSF. 231,232

Also, C. neoformans may be isolated from the sputum repeatedly over months and years in patients with prior chronic lung disease but no immunosuppression, no evidence of active pulmonary parenchymal disease, negative serum cryptococcal antigen, and negative fungal cultures from urine and CSF. These patients are considered to have chronic endobronchial colonization

In normal hosts, chest radiographs commonly show well-defined, noncalcified single (Fig. 262.1) or multiple nodules. An initial presentation may be that of a radiographic lesion (or more than one) that is worrisome for a lung malignancy but then is proved by lung biopsy to be a cryptococ- cal infection. Other radiographic characteristics include indistinct masslike infiltrates, hilar lymphadenopathy, lobar infiltrates (Fig. 262.2), pleural effusions, and lung cavitation. 233

When infection is limited to the lung, the test for serum cryptococcal antigen is often negative. If there is pulmonary cryptococcosis with a positive test for serum cryptococcal antigen, it is prudent to consider an extrapulmonary source of infection, although workups may still be negative for another infection site (e.g., blood, skin, urine, CSF).

When C. neoformans has been isolated from the lung in patients at high risk for dissemination due to an underlying immunosuppressive disease or treatment, a lumbar puncture should be considered to rule out CNS infection, even in the absence of symptoms. Although it is rare, early, asymptomatic spread to the CNS may be manifested only by a positive CSF fungal culture, with otherwise normal CSF and a negative antigen test. The number of cryptococci may be so low that several milliliters of CSF must be cultured for a positive culture to be obtained.

In the severely immunosuppressed host with AIDS or receiving high-dose corticosteroids, cryptococcal pneumonia can progress more rapidly (over days instead of weeks). 224,226 Unlike immunocompetent hosts, most immunosuppressed individuals have constitutional symptoms such as fever, malaise, chest pain, shortness of breath, and weight loss. In these patients, pneumonia can progress to features of acute respiratory compromise even without evidence of CNS involvement

However, because of the ability of the yeast to disseminate outside the primary lung focus to the CNS, these very-high-risk patients frequently present with a meningeal rather than a pulmonary syndrome. In AIDS patients, cryptococcal pneumonia may not be symptomatic, and more than 90% may present with concomitant CNS infection at the initial diagnosis.

Chest radiographs in these immunocompromised hosts are similar in their range of presentations to those of immunocompetent hosts. However, alveolar and interstitial infiltrates are particularly common and thus might be confused with Pneumocystis infection.

Because the severely immunosuppressed patient with pulmonary cryptococcosis and AIDS generally has a CD4 count substantially below 100 cells/μL, it is always prudent to consider the possibility of coinfection with other opportunists such as typical and atypical mycobacterium, cytomegalovirus, Nocardia, and Pneumocystis

Most patients with cryptococcosis of the CNS present with signs and symptoms of subacute meningitis, such as headache, fever, cranial nerve palsies, lethargy, coma, or memory loss over several weeks (see Table 262.2). 218

Symptoms may not be typical, and patients may present with acute (several days) symptoms of severe headaches, with intermittent headaches, or even with no headache but with altered mental status. HIV-infected patients with cryptococcal meningitis exhibit few differences at presentation from those without HIV.

However, several clinical aspects may be more prominent in patients with AIDS. 67 First, the burden of yeasts is generally higher, and this may be reflected in higher polysaccharide antigen titers, slower conversion of CSF to sterilization during treatment, and a tendency toward a higher incidence of increased intracranial pressure. Second, there is a greater likelihood of finding the yeast in extracranial locations during the initial workup. Third, the possibility is greater that a second CNS event may occur, such as infection with Tox op la sma g on di i or development of a lymphoma. Fourth, the use of ART in AIDS patients has created a distinct immune reconstitution inflammatory syndrome (IRIS) in cryptococcal infections. 236–238

Fourth, the use of ART in AIDS patients has created a distinct immune reconstitution inflammatory syndrome (IRIS) in cryptococcal infections. 236–238 It appears in two forms: unmasking and paradoxical. In the unmasking form, after starting ART, some patients develop acute symptoms of cryptococcal meningitis or pain and swelling in peripheral, hilar, or mediastinal lymph nodes. In the paradoxical form, this syndrome may occur during treatment of cryptococcal meningitis in the first few weeks or months after ART is introduced. It appears to correlate with a significant drop in HIV load, but there may be only a modest rise in the number of CD4 cells. 239

During treatment for cryptococcal meningitis, IRIS may be marked by increasing headaches, new neurologic signs, appearance of more inflammatory cells in the CSF, and possibly increased intracranial pressure. 240 Distinction between immune reconstitution and progressive infection can be difficult, but cultures from the CSF and lymph node aspirates are generally negative in IRIS, even though cryptococci may be present on a smear and cryptococcal antigen titers tend to be lowering

There are still limited precise data that relate the severity of the meningitis to the particular infecting strain, but this is an area of active investigations. 20,170,241 In most cases the host defense responses determine the clinical manifestations.

C. neoformans can produce almost any type of skin lesion (see Table 262.2). A common lesion is a papule or maculopapule with a soft or ulcerated center (Fig. 262.4). A draining sinus usually originates in an underlying bone lesion or occasionally a subcutaneous abscess

Some lesions in severely immunosuppressed patients are easily mistaken for molluscum contagiosum, and lesions can mimic acne vulgaris, squamous carcinoma, or basal cell carcinoma.

After pulmonary and CNS sites of infection, the skin is the third most common organ for appearance of infection. Skin manifestations can be extraordinarily varied. 245–248

For example, in severely immunosuppressed patients, skin infections may present as a cellulitis (Fig. 262.5) or an abscess that mimics a bacterial skin infection in both appearance and rapidity of onset. 249,250

In most cases, the skin lesions represent a sentinel finding for dis- seminated cryptococcal infection.

In a large retrospective review of patients with cutaneous findings, a series of immunocompetent patients had: (1) solitary skin lesion(s) on unclothed areas of the skin; (2) a history of skin injury, participation in outdoor activities, or exposure to bird droppings; (3) isolation of C. neoformans; and (4) no evidence of disseminated disease. 252

Second, an observation made in a cohort of solid-organ transplant recipients suggests that patients receiving tacrolimus appeared to develop a higher ratio of skin and soft tissue infections to CNS infections when compared with previous immunosuppressive regimens. 107 Because tacrolimus has anticryptococcal activity at temperatures of 37° to 39°C 254 but loses its anticryptococcal activity at environmental temperatures, the skin involvement might result from the lower tem- peratures at this body site

Like Blastomyces and Mycobacterium tuberculosis, C. neoformans can invade the prostate gland, and in most cases of cryptococcal infection this involvement is asymptomatic. 255 In fact, asymptomatic or silent prostate infection may first be identified during urologic surgery and may spread into the bloodstream during surgery. 256

isolated cryptococcuria is a marker for disseminated disease.

Eye In the early reviews of cryptococcal meningitis, ocular signs and symptoms were reported in 45% of the cases. 261 The most common manifestations are ocular palsies and papilledema. Small white retinal exudates, without overlying vitritis, are probably the next most common finding

Third, there are reports of catastrophic loss of vision without evidence for endophthalmitis. 265,266 In these cases of blindness, which may occur while receiving therapy, two pathogenic processes have been identified. First, there is a visual loss secondary to an optic neuritis produced by infiltration of the optic nerve with yeasts, and, as for endophthalmitis, there are few options for successful management. Second, other patients present with visual loss in one or both eyes during antifungal therapy. In these patients, symptoms are probably related to the development of cerebral edema and unrelieved high intracranial pressure. The probable pathogenesis is compression of the ophthalmic artery within the optic sheath.

Once blindness has occurred, return of visual acuity is rare. A central scotoma or optic atrophy may be the only sequela of cured ocular cryptococcosis

Cryptococcemia rarely produces vascular instability, and only a few cases of native or prosthetic valve endocarditis have been described. 267

Before the AIDS epidemic, bone lesions were reported in up to 5% of disseminated cases. 268 Bone lesions are typically one or more well- circumscribed osteolytic lesions in almost any bone and may have a contiguous soft tissue abscess (“cold abscess”).

Bone lesions of sarcoidosis resemble cryptococcal lesions on radiographs but are more often on the hands or feet and have no contiguous soft tissue abscess. 269

Immune Reconstitution Inflammatory Syndrome IRIS and cryptococcosis are well described with HIV infection and its treatment, 237 but it also clearly occurs as a complication in solid-organ transplant recipients 272 and normal hosts. 273,274

In solid-organ transplant recipients, it occurs with those on potent antirejection regimens that have been reduced after initiation of antifungal therapy. It occurs at a mean period of 6 weeks after starting antifungal therapy and may be associated with organ graft loss.

IRIS in cryptococ- cosis with its dysregulated immune response needs to be identified by the clinician, because there are no specific tests for it, and the diagnosis relies on clinical guidelines and expert judgment. 279 It is so critically important to recognize IRIS because its management is different than for relapse or persistence of cryptococcosis