<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Circadian rhythm sleep disorder and can you explain it in depth? [/INST] Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in ones biological clock system, or by misalignment between ones endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Delayed sleep phase disorder, advanced sleep phase disorder, non-24-hour sleep–wake disorder and irregular sleep–wake rhythm disorder represents the four main types of CRSD.

Overview
Humans, like most living organisms, have various biological rhythms. These biological clocks control processes that fluctuate daily (e.g., body temperature, alertness, hormone secretion), generating circadian rhythms. Among these physiological characteristics, the sleep-wake propensity can also be considered one of the daily rhythms regulated by the biological clock system. Humans sleeping cycles are tightly regulated by a series of circadian processes working in tandem, allowing for the experience of moments of consolidated sleep during the night and a long wakeful moment during the day. Conversely, disruptions to these processes and the communication pathways between them can lead to problems in sleeping patterns, which are collectively referred to as circadian rhythm sleep disorders.

Normal rhythm
A circadian rhythm is an entrainable, endogenous, biological activity that has a period of roughly twenty-four hours. This internal time-keeping mechanism is centralized in the suprachiasmatic nucleus (SCN) of humans, and allows for the internal physiological mechanisms underlying sleep and alertness to become synchronized to external environmental cues, like the light-dark cycle. The SCN also sends signals to peripheral clocks in other organs, like the liver, to control processes such as glucose metabolism. Although these rhythms will persist in constant light or dark conditions, different Zeitgebers (time givers such as the light-dark cycle) give context to the clock and allow it to entrain and regulate expression of physiological processes to adjust to the changing environment. Genes that help control light-induced entrainment include positive regulators BMAL1 and CLOCK and negative regulators PER1 and CRY. A full circadian cycle can be described as a twenty-four hour circadian day, where circadian time zero (CT 0) marks the beginning of a subjective day for an organism and CT 12 marks the start of subjective night.Humans with regular circadian function have been shown to maintain regular sleep schedules, regulate daily rhythms in hormone secretion, and sustain oscillations in core body temperature. Even in the absence of Zeitgebers, humans will continue to maintain a roughly 24-hour rhythm in these biological activities. Regarding sleep, normal circadian function allows people to maintain balance rest and wakefulness that allows people to work and maintain alertness during the days activities, and rest at night.Some misconceptions regarding circadian rhythms and sleep commonly mislabel irregular sleep as a circadian rhythm sleep disorder. In order to be diagnosed with CRSD, there must be either a misalignment between the timing of the circadian oscillator and the surrounding environment, or failure in the clock entrainment pathway. Among people with typical circadian clock function, there is variation in chronotypes, or preferred wake and sleep times, of individuals. Although chronotype varies from individual to individual, as determined by rhythmic expression of clock genes, people with typical circadian clock function will be able to entrain to environmental cues. For example, if a person wishes to shift the onset of a biological activity, like waking time, light exposure during the late subjective night or early subjective morning can help advance ones circadian cycle earlier in the day, leading to an earlier wake time.

Diagnosis
The International Classification of Sleep Disorders classifies Circadian Rhythm Sleep Disorder as a type of sleep dyssomnia. Although studies suggest that 3% of the adult population has a CRSD, many people are often misdiagnosed with insomnia instead of a CRSD. Of adults diagnosed with sleep disorders, an estimated 10% have a CRSD and of adolescents with sleep disorders, an estimated 16% may have a CRSD. Patients diagnosed with circadian rhythm sleep disorders typically express a pattern of disturbed sleep, whether that be excessive sleep that intrudes on working schedules and daily functions, or insomnia at desired times of sleep. Note that having a preference for extreme early or late wake times are not related to a circadian rhythm sleep disorder diagnosis. There must be distinct impairment of biological rhythms that affects the persons desired work and daily behavior. For a CRSD diagnosis, a sleep specialist gathers the history of a patients sleep and wake habits, body temperature patterns, and dim-light melatonin onset (DLMO). Gathering this data gives insight into the patients current schedule, as well as the physiological phase markers of the patients biological clock.The start of the CRSD diagnostic process is a thorough sleep history assessment. A standard questionnaire is used to record the sleep habits of the patient, including typical bedtime, sleep duration, sleep latency, and instances of waking up. The professional will further inquire about other external factors that may impact sleep. Prescription drugs that treat mood disorders like tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants are associated with abnormal sleep behaviors. Other daily habits like work schedule and timing of exercise are also recorded—because they may impact an individuals sleep and wake patterns. To measure sleep variables candidly, patients wear actigraphy watches that record sleep onset, wake time, and many other physiological variables. Patients are similarly asked to self-report their sleep habits with a week-long sleep diary to document when they go to bed, when they wake up, etc. to supplement the actigraphy data. Collecting this data allows sleep professionals to carefully document and measure patients sleep habits and confirm patterns described in their sleep history.Other additional ways to classify the nature of a patients sleep and biological clock are the morningness-eveningness questionnaire (MEQ) and the Munich ChronoType Questionnaire, both of which have fairly strong correlations with accurately reporting phase advanced or delayed sleep. Questionnaires like the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) help gauge the severity of sleep disruption. Specifically, these questionnaires can help the professional assess the patients problems with sleep latency, undesired early-morning wakefulness, and problems with falling or staying asleep.Tayside childrens sleep questionnaire is a ten-item questionnaire for sleep disorders in children aged between one and five years old.

Types
Currently, the International Classification of Sleep Disorders (ICSD-3) lists 6 disorders under the category of circadian rhythm sleep disorders.CRSDs can be categorized into two groups based on their underlying mechanisms: The first category is composed of disorders where the endogenous oscillator has been altered, known as intrinsic type disorders. The second category consists of disorders in which the external environment and the endogenous circadian clock are misaligned, called extrinsic type CRSDs.

Intrinsic
Delayed sleep phase disorder (DSPD): Individuals who have been diagnosed with delayed sleep phase disorder have sleep-wake times which are delayed when compared to normal functioning individuals. People with DSPD typically have very long periods of sleep latency when they attempt to go to sleep during conventional sleeping times. Similarly, they also have trouble waking up at conventional times.
Advanced sleep phase disorder (ASPD): People with advanced sleep phase disorder exhibit characteristics opposite to those with delayed sleep phase disorder. These individuals have advanced sleep wake times, so they tend to go to bed and wake up much earlier as compared to normal individuals. ASPD is less common than DSPD, and is most prevalent within older populations.Familial Advanced Sleep Phase Syndrome (FASPS) is linked to an autosomal dominant mode of inheritance. It is associated with a missense mutation in human PER2 that replaces Serine for a Glycine at position 662 (S662G). Families that have this mutation in PER2 experience extreme phase advances in sleep, waking up around 2 AM and going to bed around 7 PM.
Irregular sleep–wake rhythm disorder (ISWRD) is characterized by a normal 24-hr sleeping period. However, individuals with this disorder experience fragmented and highly disorganized sleep that can manifest in the form of waking frequently during the night and taking naps during the day, yet still maintaining sufficient total time asleep. People with ISWRD often experience a range of symptoms from insomnia to excessive daytime sleepiness.
Non-24-hour sleep–wake disorder (N24SWD): Most common in individuals that are blind and unable to detect light, is characterized by chronic patterns of sleep/wake cycles which are not entrained to the 24-hr light-dark environmental cycle. As a result of this, individuals with this disorder will usually experience a gradual yet predictable delay of sleep onset and waking times. Patients with DSPD may develop this disorder if their condition is untreated.

Extrinsic
Shift work sleep disorder (SWSD): Approximately 9% of Americans who work night or irregular work shifts are believed to experience shift work sleep disorder. Night shift work directly opposes the environmental cues that entrain our biological clock, so this disorder arises when an individuals clock is unable to adjust to the socially imposed work schedule. Shift work sleep disorder can lead to severe cases of insomnia as well as excessive daytime sleepiness.
Jet lag: Jet lag is best characterized by difficulty falling asleep or staying asleep as a result of misalignment between ones internal circadian system and external, or environmental cues. It is typically associated with rapid travel across multiple time zones.

Alzheimers disease
CRSD has been frequently associated with excessive daytime sleepiness and nighttime insomnia in patients diagnosed with Alzheimers disease (AD), representing a common characteristic among AD patients as well as a risk factor of progressive functional impairments. On one hand, it has been stated that people with AD have melatonin alteration and high irregularity in their circadian rhythm that lead to a disrupted sleep-wake cycle, probably due to damage on hypothalamic SCN regions typically observed in AD. On the other hand, disturbed sleep and wakefulness states have been related to worsening of an AD patients cognitive abilities, emotional state and quality of life. Moreover, the abnormal behavioural symptoms of the disease negatively contribute to overwhelming patients relatives and caregivers as well.However, the impact of sleep-wake disturbances on the subjective experience of a person with AD is not yet fully understood. Therefore, further studies exploring this field have been highly recommended, mainly considering the increasing life expectancy and significance of neurodegenerative diseases in clinical practices.

Treatment
Possible treatments for circadian rhythm sleep disorders include:

Chronotherapy, best shown to effectively treat delayed sleep phase disorder, acts by systematically delaying an individuals bedtime until their sleep-wake times coincide with the conventional 24-hr day.
Light therapy utilizes bright light exposure to induce phase advances and delays in sleep and wake times. This therapy requires 30–60 minutes of exposure to a bright (5,000–10,000 lux) white, blue, or natural light at a set time until the circadian clock is aligned with the desired schedule </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hypothalamic disease and can you explain it in depth? [/INST] Hypothalamic disease is a disorder presenting primarily in the hypothalamus, which may be caused by damage resulting from malnutrition, including anorexia and bulimia eating disorders, genetic disorders, radiation, surgery, head trauma, lesion, tumour or other physical injury to the hypothalamus. The hypothalamus is the control center for several endocrine functions. Endocrine systems controlled by the hypothalamus are regulated by antidiuretic hormone (ADH), corticotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, oxytocin, all of which are secreted by the hypothalamus. Damage to the hypothalamus may impact any of these hormones and the related endocrine systems. Many of these hypothalamic hormones act on the pituitary gland. Hypothalamic disease therefore affects the functioning of the pituitary and the target organs controlled by the pituitary, including the adrenal glands, ovaries and testes, and the thyroid gland.Numerous dysfunctions manifest as a result of hypothalamic disease. Damage to the hypothalamus may cause disruptions in body temperature regulation, growth, weight, sodium and water balance, milk production, emotions, and sleep cycles. Hypopituitarism, neurogenic diabetes insipidus, tertiary hypothyroidism, and developmental disorders are examples of precipitating conditions caused by hypothalamic disease.

Hypopituitarism
The hypothalamus and pituitary gland are tightly integrated </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Diffuse large B-cell lymphoma and can you explain it in depth? [/INST] Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a malignant transformation of other types of lymphoma (particularly marginal zone lymphomas) or, in rare cases termed Richters transformation, chronic lymphocytic leukemia. An underlying immunodeficiency is a significant risk factor for development of the disease. Infections with the Epstein–Barr virus (EBV), Kaposis sarcoma-associated herpesvirus, human immunodeficiency virus (i.e. HIV), and the Helicobacter pylori bacterium  are also associated with the development of certain subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained step-wise acquisition of increasing numbers of gene mutations and changes in gene expression that occur in, and progressively promote the malignant behavior of, certain B-cell types.Diagnosis of DLBCL is made by removing a portion of the tumor through a biopsy, and then examining this tissue using a microscope. Usually a hematopathologist makes this diagnosis. Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses, and recommended treatments. However, the usual treatment for most subtypes of DLBCL is chemotherapy combined with a monoclonal antibody drug that targets the diseases cancerous B-cells, usually rituximab. Through these treatments, more than half of all patients with DLBCL can be cured; the overall cure rate for older adults is less than this but their five-year survival rate has been around 58%.

Subtypes of diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes, many of which are difficult to separate from one another based on well-defined and widely accepted criteria. The World Health Organization, 2008, classification system defined more than a dozen subtypes, each of which was identified based on the location of the tumor, the presence of other cell types such as T cells in the tumor, and whether the patient had certain other illnesses related to DLBCL. Based on further research, the World Health Organization, 2016, reclassified DLBCL into its most common subtype, diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). DLBCL, NOS represents 80–85% of all DLBCL. The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology, (i.e. microscopic appearance), immunophenotype, (i.e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses. Some cases of DLBCL, NOS, while not included in the 2016 World Health Organizations classification, are clearly associated with, and caused by, chronic infection by the bacterium, Helicobacter pylori.

Diffuse large B-cell lymphoma, not otherwise specified
DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype, and/or pathogen-associated criteria of other DLBCL subtypes are termed Diffuse large B-cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases, is a diagnosis of exclusion. In general, DLBCL, NOS is an aggressive disease with an overall long-term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment.

Presenting signs and symptoms
About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases, the most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach, or, less commonly, in other sites such as the testicles, breasts, uterus, ovaries, kidneys, adrenal glands, thyroid gland, or bone. The presenting signs and symptoms in these cases reflect the presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction. Individuals with nodal or extranodal disease also present with: systemic B symptoms such as weight loss, night sweats, fevers, and/or fatigue in ~33% of cases; unexplained elevations in their blood levels of lactic acid dehydrogenase and beta-2 microglobulin in many cases; malignant cells infiltrating their bone marrow in 10–20% of cases; and/or localized Stage I or II disease in up to 50% of cases and disseminated Stage III or IV disease in the remaining cases. Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis. Uncommonly, DLBCL may arise as a transformation of marginal zone lymphoma (MZL) in individuals who have been diagnosed with this indolent cancer 4–5 years (median times) previously.

Prognostic indicators based on clinical presentation
The International Prognostic Index and more recently, the Indexs age-adjusted variant use age >60 years, elevated serum lactate dehydrogenase levels, low performance status, and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS. In addition, disease that initially involves the testes, breast, or uterus has a relatively high rate of spreading to the central nervous system while disease initially involving the kidneys, adrenal glands, ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses.

Pathophysiology
Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of gene changes such as mutations, altered expressions, amplifications (i.e. increases in the number of copies of specific genes), and tranlocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate the maturation, proliferation, survival, spread, evasion of the immune system, and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this diseases development and/or progression.
BCL2: This gene is a protooncogene, i.e. a normal gene that can become cancer-causing when mutated or overexpressed. Its product, Bcl-2 protein, regulates cellular apoptosis (i.e. survival) by inhibiting the apoptosis-causing proteins, Bcl-2-associated X protein and Bcl-2 homologous antagonist killer.
BCL6: This genes product, Bcl-6, is a repressor of transcription that regulates the expression of other genes which control cell maturation, proliferation, and survival.
MYC: This protooncogenes product, Myc, encodes a transcription factor which regulates the expression of other genes whose products stimulate cell proliferation and expansion to extra-nodal tissues.
EZH2: This genes product, the EZH2 protein, is a histone-lysine N-methyltransferase. It thereby regulates the expression of other genes which control lymphocyte maturation.
MYD88: This genes product is a signal transducing adaptor protein essential for the transduction of interleukin-1 and toll-like receptor signaling pathways. It thereby regulates NF-κB and MAPK/ERK signaling pathways that control cell proliferation and survival.
CREBBP: This genes product is a transcriptional coactivator; it activates numerous transcription factors, some of which control cell proliferation.
CD79A and CD79B: these genes products are critical components of the B-cell receptor. Mutations in either gene can cause uncontrolled cell activation and proliferation.
PAX5: this genes product, Pax-5, is a transcription factor that controls the development, maturation, and survival of B-cells; it also controls expression of the MYC gene in these cells.As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF-κB, PI3K/AKT/mTOR, JAK-STAT0, MAPK/ERK, B-cell receptor, toll-like receptor, and NF-κB signaling pathways and thereby uncontrolled pro-malignant behaviors.

Diagnosis
Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins (e.g. CD20, CD19, CD22, CD79, PAX5, BOB1, OCT2, an immunoglobulin [usually IgM but occasionally IgG or IgA)], CD30, and in ~20–25% of cases PD-L1 or PD-L2 (PD-L1 and PD-L2 are transmembrane proteins that normally function to suppress attack by the immune system). These cells arrange in a diffuse pattern, efface the tissues architecture, and resemble Centroblast cells (80% of cases), Immunoblast cells (8–10% of cases), or anaplastic cells (9% of cases; anaplastic cells have bizarre nuclei and other features that may mimic the Reed–Sternberg cells of Hodgkin disease or the neoplastic cells of anaplastic large cell lymphoma). Rarely, these neoplastic cells are characterized as having signet ring or spindle shaped nuclei, prominent cytoplasmic granules, multiple microvillus projections, or, when viewed by electron microscopy, tight junctions with other cells. These neoplastic tissue infiltrates are often accompanied by small non-malignant T-cell lymphocytes and histiocytes that have a reactive morphology.

Variants of DLBCL, NOS
The World Health Organization, 2016, requires that the neoplastic cells in DLBCL, NOS be further defined based on whether they are derived from germinal center B-cells (i.e. GBC) or activated B-cells (i.e. ABC) as identified by gene expression profiling (GEP) or are GBC or non-GBC as identified by immunohistochemical (IHC) analyses. As identified by GEP, which measures all cellular messenger RNAs, GBC and ABC represent about 50 and ~35% of DLBCL, NOS cases, respectively, with ~15% of cases being unclassifiable. IHC analyses measure the cellular expression of specific proteins using a panel of fluorescent antibodies that bind to and therefore stain a set of key proteins. For example, one commercially available panel uses three antibodies to detect CD10, BCL6, and MUM1 proteins; GBC express whereas ABC and unidentified cells do not express these proteins; accordingly, this as well as other IHC panels classify ABC and undetermined neoplastic cell types together as non-GBC. Individuals with the ABC, unclassifiable, and non-GBC variants have significantly worse prognoses than individuals with the GBC variant: respective 5 year progression-free and overall survival rates have been reported to be 73–80% for GBC variants and 31–56% for ABC variants. Clinically, however, most DLBCL, NOS cases are analyzed by IHC and therefore classified as either GBC or non-GBC variants with non-GBC variants having progression-free and overall survival rates similar to those of the ABC variants.Gene and protein markers in the neoplastic cells of DLBCL, NOS that have clinical significance include CD5, MYC, BCL2, BCL6, CD20, CD19, CD22, CD30, PD-L1, and PD-L2. The 5–10% of DLBCL, NOS cases in which the neoplastic cells express CD5 have a very poor prognosis that is not improved by even aggressive treatment regimens. Cases in which fluorescence in situ hybridization analysis show that the neoplastic cells in this disease bear translocations in both the MYC and BCL2 genes or MYC and BCL6 genes (termed double hit lymphomas) or in all three genes (termed triple hit lymphomas) are associated with advanced disease that spreads to the central nervous system. These lymphomas, termed high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements or, more simply, DH/THL, are regarded as borderline DLBCL,NOS. They represent 6–14% of all DLBCL, NOS and have had long-term survival rates of only 20–25%. Another variant B-cell lymphoma that is also considered to be a borderline DLBCL, NOS is termed high-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS). These two aggressive borderline B-cell lymphomas were previously grouped together as "B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma" (i.e. BCLU) but were separated into DH/THL and HGBC, NOS by the World Health Organization, 2016. The neoplastic cells in a related variant, double expresser lymphoma (i.e. DEL), express the products of MYC and BCL2 genes, i.e. c-Myc and bcl-2 proteins, respectively, but do not have translocations in either of their genes. DEL, which represents about one-third of all DLBCL, NOS cases, has a poorer prognosis than standard DLBCL, NOS but not as poor as DH/THL cases. Cases in which the neoplastic cells have alterations in the MYC gene or its expression without changes in BLC2 or BLC6 also have a poor prognosis, particularly in cases where the MYC gene translocates (i.e. rearranges) with one of the immunoglobulin gene loci. DLBCL that begin in the testicles are a variant of DLBCL, NOS that some authors suggest should be classified as a distinct DLBCL subtype. This variant, termed Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), is a DLBCL, NOS that in >75% of cases involves activated B-cells, i.e. ABC. These cells, which typically have a centroblast-like morphology, infiltrate one or, in ~6% of cases, both testicles. PT-DLBCL is an aggressive disease that often spreads to the central nervous system and has median overall survival and progression-free survival times of 96 and 49 months, respectively.The neoplastic cells in almost all cases of DLBCL, NOS express CD20. Commercially available anti-CD20 antibody agents such as rituximab or Obinutuzumab (which is sometimes used in place of rituximab) kill cells that express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts adaptive immune system. The addition of one of these immunotherapy agents to chemotherapy protocols has greatly improved the prognosis of most DLBCL, NOS variants. Neoplastic cell expression of CD30, found in 10–15% of DLBCL, NOS cases is a favorable prognostic indicator. As indicated in the following Treatments and prognoses section, expression of the CD20 and CD30 proteins as well as the CD19, CD20 CD22, CD30, CD79A, CD79B, and D-L1 proteins, expression of the MYC, BCL2, MYD88nd, and CREBBP genes, and expression of the PI3K/AKT/mTOR, JAK-STAT, B-cell receptor, toll-like receptor, and NF-κB signaling pathways are being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC DLBCL, NOS cases.

Treatments and prognoses
First-line therapy
First-line therapy for patients with the GBC variant of DLBCL, NOS is R-CHOP. R-CHOP consists of rituximab, three chemotherapy drugs (cyclophosphamide, doxorubicin, and vincristine) and a glucocorticoid (either prednisone or prednisolone). The regimen achieves cure, relapse following remission, and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in GBC variant cases. Relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R-CHOP have poorer prognoses. R-CHOP is less effective and not recommended for patients who have MYC, BL2, and/or BL6 rearrangements regardless of their GBC, ABC, or non-GBC type. One recommendation for treating these DH/THL cases is the DA-R-EPOCH regimen (dose-adjusted rituximab, etoposide, prednisolone, oncovin, cyclophosphamide, and hydroxydaunorubicin). S-R-EPOCH achieves 2 year survival rates of 40–67% compared to a ~25% survival rate for R-CHOP in these cases. DA-R-EPOCH has also been recommended for patients with double expresser lymphoma although some experts recommend treating this variant more like a typical DLCBL, NOS. First-line therapy for patients with the ABC, undetermined, or non-GBC variants has been the DA-R-EPOCH regimen. Patients with these variants (including those with double expresser lymphoma) have had a ~40% cure rate when treated with it. A randomized clinical trial conducted in France reported that a R-ACVBP chemotherapy regimen (rituximab, adriamycin, cyclophosphamide, vindesine, bleomycin, and cytarabine followed by sequential consolidation therapy with systemic methotrexate, ifosfamide, and etoposide, and then cytarabine) achieved significantly better response rates than R-CHOP in ABC/NGC variant cases lymphoma. In DLBCL, NOS variants which trend to spread or to the central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as prophylaxis to reduce the incidence of this complication. The role of Autologous stem-cell transplantation as an addition to first-line therapy in the treatment of DLBCL, NOS, including cases with a poor prognosis, is unclear.A phase I clinical research trial found that the addition of lenalidomide to the R-CHOP regimen produce an ~80% complete response rate in GBC as well as non- GBC DLBCL, NOS variants. Two phase III clinical research trials are underway to confirm these results and determine if the R-CHOP + lenalidomide regimen is superior to R-CHOP in the up-front treatment of GBC and/or non-GBC variants.

Treatment of recurrent and refractory DLBCL, NOS
Patients with DLBCL, NOS who relapse or progress following first-line therapy have been treated with "salvage regimens" consisting of high-dose (also termed high-intensity) chemotherapy conditioning drugs followed by autologous stem cell transplantation. This regimen has attained 3-year progression-free survival rates of 21–37%. Relapse following this treatment carries a very poor prognosis with median overall survival times of ~10 months. Patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by allogeneic stem cell transplantation. This regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively. Further studies are underway to determine the best treatment regimens for these cases. Patients refractory to first-line therapy or who relapse within 12 months of receiving salvage therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively. The prognosis of these patients appears to be improved by using CAR-T therapy.
Chimeric antigen receptor T cell (i.e. CAR-T) adoptive cellular immunotherapy has emerged as a recent advance in treating refractory and relapsed DLBCL, NOS (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel). Chimeric antigen receptor T cells are genetically engineered to express: 1) an artificial T-cell receptor consisting of antigen-recognition and attached hinge domains expressed on their surface membranes; 2) a surface membrane-spanning domain; 3) an intracellular domain which, when the antigen-recognition domain binds its targeted antigen, activates signaling pathways that cause the T-cell to attack and kill cells that bear the recognized antigen on their surface membranes; and 4), in more recently devised second generation CAR-T strategies, an associated intracellular co-stimulating molecule (e.g. CD28 or 4-1BB) which augments activation of the cell-killing signaling pathways. CAR-T therapy, as it pertains to DLBCL, NOS, kills a patients neoplastic B-cells by isolating this patients T-cells; genetically engineering these cells to express an artificial T-cell receptor designed to bind an antigen expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been CD19, a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS. However, design of CARs as well as the antigens chosen to be their targets  are constantly being changed in order to improve the efficacy of this therapeutic strategy.
CAR-T therapy for DLBCL, NOS has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. Patients are treated first with a conditioning chemotherapy regimen, usually cyclophosphamide and fludarabine, and then infused with their own T-cells that have been engineered to attack CD19-bearing or, rarely, CD20-bearing cells. A meta-analysis of 17 studies using this or very similar approaches to treat DLBCL, NOS found the treatments gave complete and partial responses rates of 61% and 43%, respectively. While these studies did not have control groups and were too recent for meaningful estimates of remission durations, the remission rates were higher than expected using other treatment approaches. Significant and potentially lethal therapeutic complications of this therapy included development of the cytokine release syndrome (21% of cases), neurotoxicity, i.e. the CAR-T cell-related encephalopathy syndrome (9% of cases), and the hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (i.e. a form of Hemophagocytic lymphohistiocytosis). Individual studies within and outside of this meta-analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and neurotoxicity responses to this therapy. As a consequence of these studies, the Committee for Advanced Therapies and the Committee for Medicinal Products for Human Use of the European Medicines Agency recommend granting marketing authorization for tisagenlecleucel (i.e. chimeric antigen receptor T cells directed against CD19) in adult patients with DLBCL, NOS who have relapsed after or are refractory to two or more lines of systemic therapy. The Committee for Orphan Medicinal Products of the European Medicines Agency recommends tisagenlecleucel retain its orphan drug designation. The USA Food and Drug Administration (FDA) has also approved the use of this drug for relapsed or refractory DLBCL of the large B-cell lymphoma subtype in patients who have failed after two or more lines of systemic therapy. Monoclonal antibodies directed against CD19, CD22, CD30, and PD-L1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in DLBCL, NOS. In August 2020, the FDA approved the humanized Fc-modified cytolytic CD19 targeting monoclonal antibody tafasitamab in combination with lenalidomide as a treatment for adult patients with relapsed or refractory DLBCL. In April 2021, the FDA approved the CD19-directed antibody-drug conjugate loncastuximab tesirine as a treatment for adult patients with relapsed or refractory DLBCL after systemic therapy.

Emerging therapies
Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, brentuximab vedotin may be a useful addition to chemotherapy treatment protocols. This agent is a CD30-targeting antibody that delivers a toxin, monomethyl auristatin E, to CD30-expressing cells, has therapeutic efficacy against other CD30-expressing lymphomas, and may prove useful in treating the 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the EZH2, BCL2 and CREBBP genes and overactive PI3K/AKT/mTOR and JAK-STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the MYD88, CD79A and CD79B (polatuzumab vedotin) genes and overactive B-cell receptor, toll-like receptor, and NF-κB signaling pathways. These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC cases. CUDC-907, an inhibitor of PI3K and histone deacetylases, is being evaluated in two separate clinical trials for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene. GSK525762, an inhibitor of the BET family of proteins, suppresses expression of the MYC gene and is undergoing a phase I clinical trial for the treatment of high-grade B-cell lymphoma with MYC, BL2, and/or BL6 rearrangements (i.e. DH/THL). RO6870810, another BET inhibitor, in combination with Venetoclax, an inhibitor of the Bcl-2 protein, is likewise in a phase I clinical trial for the treatment of DH/THL. Pharmacological inhibition of BCL-2 is effective in most B cell lymphomas, but often leads to acquired resistance due to the expression of other major anti-apoptotic BCL-2 family proteins like BCL-XL and MCL-1. Combined therapy using MCL-1 inhibitor (S63845) or BCL-XL inhibitor (A-1331852) in addition to Venetoclax can be a solution to overcome this issue.

Subtypes of diffuse large B-cell lymphoma
DLBCL subtypes have been sorted into groups based on their distinctive morphology or immunophenotype, distinctive clinical issues, and distinctive virus-driven etiology. The prognoses and treatment of these subtypes varies with their severity. Most subtypes are aggressive diseases and consequently treated in a manner similar to DLBCL,NOS. Further details on these subtypes, including their treatments, can be found in their respective main article linkages.

DLBCL with a distinctive morphology or immunophenotype
T cell/histiocyte-rich large B-cell lymphoma
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a DLBCL in which tumors containing small numbers of usually large neoplastic B-cells embedded in a background of reactive T-cells and histiocytes develop in the liver, spleen, bone marrow and/or, rarely other sites. Patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%.

ALK+ large B-cell lymphoma
ALK+ large B-cell lymphoma (ALK+ LBCL) is a DLBCL in which neoplastic lymphocytes that express the ALK tyrosine kinase receptor protein infiltrate lymph nodes as well as extranodal sites, e.g. the mediastinum, bones, bone marrow, nasopharynx, tongue, stomach, liver, spleen, and skin. About 60% of these individuals present with advanced disease. ALK+ LBCL has an overall 5 year survival rate of ~34%.

Plasmablastic lymphoma
Plasmablastic lymphoma (PBL) is a DLBCL in which neoplastic immunoblastic or plasmablastic cells embedded in a background of other cell types infiltrate the oral/nasal cavity or much less often the gastrointestinal tract. Some 70% of individuals with PBL are infected with EBV and/or (particularly those with oral/nasal cavity disease) human immunodeficiency virus (HIV). PBL is an aggressive disease with a median survival time of ~15 months.

Intravascular large B-cell lymphoma
Intravascular large B-cell lymphoma (IVLBCL) is a DLBCL in which medium- to large-sized neoplastic B-cells infiltrate small- to medium-sized blood vessels and sinusoids in the liver, spleen, and/or bone marrow. IVLBCL may be associated with the hemophagic syndrome (i.e. excessive cytokine secretion and systemic inflammation). Patients with the latter syndrome have very short survival times. The poor prognosis of this disease has been significantly improved by rituximab or similar immunochemotherapy drugs but significant proportions of these responding cases relapse, often with central nervous system involvement.

Large B-cell lymphoma with IRF4 rearrangement
Large B-cell lymphoma with IRF4 rearrangement (LBCL with IRF4 rearrangement) is a DLBCL in which tissue infiltrates containing intermediate- or large-sized neoplastic B-cells strongly express a chromosomal translocation involving the IRF4 gene on the short arm of chromosome 6. These cells form follicular, follicular and diffuse, or entirely diffuse infiltrates in Waldeyers tonsillar ring or other regions of the head and neck. The disease, which represents ~0.05% of all DLBCL, occurs primarily in children and young adults and typically has a good prognoses. Cases with a follicular pattern of tissue infiltrates often have indolent disease and an excellent prognosis following excision and may not need chemotherapy. Cases with a purely diffuse tissue infiltrate pattern, in contrast, often do require chemotherapy.

DLBCL with distinctive clinical issues
Primary mediastinal large B-cell lymphoma
Primary mediastinal large B-cell lymphoma (PMBL), also termed primary mediastinal (thymic) large B-cell lymphoma, is a DLBCL in which neoplastic B-cells infiltrates are commonly located in sclerotic/fibrous tissues of the thymus and mediastinal lymph nodes. The disease represents 6–10% of all DLBCL cases, presents with early stage disease in ~80% of cases, and has an overall survival rate at 5 years of 75–85%.

Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a DLBCL in which diffuse patterns of immunoblastic and/or centroblastic B-cells infiltrate the dermis and/or subcutaneous tissue principally, but not exclusively, of the legs. This diseases 5-year overall survival rate is 50–60%.

Primary diffuse large B-cell lymphoma of the central nervous system
Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS, also termed primary central nervous system lymphoma [PCNSL]) is a DLBCL in which diffuse patterns of neoplastic B-cells with centroblastic, immunoblastic, or poorly differentiated features infiltrate the brain, spinal cord, leptomeninges, or eye. The disease usually presents as a single lesion with a predilection for the supratentorial region of the brain but may involve the eye in 15–25% of cases, the cerebrospinal fluid in 7–42% of cases, and the spinal cord in ~1% of cases. The disease has a 5-year overall survival rate of ~30%.

Diffuse large B-cell lymphoma associated with chronic inflammation
Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is an Epstein–Barr virus-associated lymphoproliferative disease arising in persons with a long and persistent history of chronic inflammation. The diseases lesions consist of large, mature-appearing B-cells infiltrating the lungs pleura and nearby tissues. Most cases have occurred in patients who were given a pneumothorax (i.e. therapeutic introduction of air into the chest cavity in order to collapse and thereby "rest" the lung) to treat pulmonary tuberculosis that had progressed to a pyothorax (i.e. pus in the pleural cavity). Fibrin-associated large B-cell lymphoma (FA-DLBCL), often considered a sub-type of DLBCL-CI, is an infiltration of large neoplastic B-cells and fibrin affix to a prosthesis (e.g., cardiac valve, orthopaedic device) or accumulate within a hydrocele, pseudocyst, cardiac myxoma, or chronic subdural hematoma. The B-cells in these lesions are often but not always infected with the Epstein–Barr virus. DLBCL-CI occurring in cases of pleural empyema (sometimes termed pyothorax-associated lymphoma, i.e. PAL) is an aggressive lymphoma with a five-year overall survival rate of 20–35%; FA-DLBCL, when involving the heart (e.g. occurring on myxommas or prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), may involve life-threatening cardiovascular complications, particularly strokes. Outside of these complications, however, DLBCL-CI usually has a highly favorable outcome.

Lymphomatoid granulomatosis
Lymphomatoid granulomatosis (LYG) is a DLBCL in which large, atypical B-cells with immunoblastic or Hodgkin disease-like features that are infected by the Epstein-Barr virus center around and destroy the microvasculature. Lymphomatoid granulomatosis almost always involves the lung but may concurrently involve the brain, peripheral nervous system, skin, kidneys, liver, gastrointestinal tract, and/or upper respiratory tract; LYG has an increased incidence in persons with Wiskott–Aldrich syndrome or HIV or who are immunosuppression due to chemotherapy or organ transplantation. The diseases prognosis is highly variable: patients with low grade disease often require no therapy except watchful waiting while patients with high grade disease usually require chemotherapy.

Primary effusion lymphoma
Primary effusion lymphoma (PEL) is a DLBCL in which neoplastic B cells that resemble immunoblasts, plasmablasts, or Reed–Sternberg cells infiltrate the pleural, pericardial, or peritoneal membranes that surround the lungs, heart, and abdominal organs, respectively. This infiltration leads to the seeping of fluid into the cavities which are encased by these membranes, i.e. it leads to pleural effusions, pericardial effusions, and abdominal ascites. Some cases of PEL also involve the gastrointestinal tract and lymph nodes. The disease occurs primarily in people who are immunosuppressed or test positive for HIV and are also latently infected with Kaposis sarcoma-associated herpesvirus; PEL is an aggressive disease with an overall 1 year survival rate of ~30%.

DLBCL driven by viruses
Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified
Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) is a B-cell lymphoma in which neoplastic B-cells that are infected with the Epstein-Barr virus cause a disease that does not fit into other subtypes of DLBCL. In EBV+ DLBCL, small neoplastic B-cells, other lymphocyte typess, plasma cells, histiocytes and epithelioid cells interspersed with Reed–Sternberg-like cells infiltrate, almost exclusively, lymph nodes. Elderly patients with the disease have median survival times of ~2 years while young patients have long-term treatment-related remissions in >80% of cases.

HHV8-positive diffuse large B-cell lymphoma, NOS
HHV8-positive diffuse large B-cell lymphoma, NOS (HHV8+ DLBCL, NOS; also termed HHV8-positive diffuse large B-cell lymphoma [HHV8+ DLBCL]) is a DLBCL in which Kaposis sarcoma-associated herpesvirus-infected, medium- to large-size neoplastic B-cells that resemble lymphocytes or immunoblasts infiltrate lymph nodes (~80% of cases) and, when disseminated (20% of cases), the liver and spleen. This infiltration usually disrupts the normal architecture of the involved tissues. HHV8+ DLBCL develops in HIV-infected individuals in ~50% of cases, in individuals with multicentric Castleman disease, plasma cell variant in uncommon cases, and in individuals with Kaposi sarcoma in rare cases. HHV8+ DLBCL commonly takes an aggressive course and has a poor prognosis.

Related disorders
Helicobactor pylori associated diffuse large B-cell lymphoma
Rare cases of DLBCL are associated with the presence of the bacterium, Helicobacter pylori, in the neoplastic B-cells. While the histology of Helicobactor pylori-associated diffuse large B-cell lymphoma (H. pylori+ DLBCL) is typical of DLBCL, the disease is sometimes a progression of mantle cell lymphoma, is often restricted to the stomach, is less aggressive that most DLBCL cases, and may respond to a drug regimen consisting of antibiotics and proton pump inhibitors directed at killing the bacterium. Perhaps because of these features of the disease, H. pylori+ DLBCL has not been classified as a DLBCL by the World Health Organization, 2016.Recent studies suggest that localized, early-stage H. pylori+ DLBCL, when limited to the stomach, is successfully treated with H. pylori eradication protocols consisting of two or more antibiotics plus a proton pump inhibitor. However, these studies also agree that patients treated with one of these H. pylori eradication regimes need to be carefully followed: those unresponsive to, or worsening on, these regimens should be switched to a chemotherapy regimen (e.g. R-CHOP) and/or, for complicated bulky disease, surgery and/or local radiotherapy.

Epstein–Barr virus-positive mucocutaneous ulcer
Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in which Epstein–Barr virus-infected B-cells proliferate and cause ulcerations in the mucous membranes and skin of immunosuppressed individuals. Its lesions consist of Epstein–Barr virus-positive, variable-sized, atypical B-cells that by conventional histopathologic criteria indicate the lesions are a form of DLBCL. Since these lesions regress spontaneously without anti-cancer treatment, EBVMCU is now considered a pseudo-malignant disorder. Elderly individuals that evidence the disease but have no other cause for immunosuppression may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously. Persistent and/or severely symptomatic cases have had excellent responses to rituximab. Individuals developing these ulcers as a consequence of immunosuppressive therapy generally have a remission after the dosage of the drugs used in their immunosuppressive treatments are reduced </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Delta-beta thalassemia and can you explain it in depth? [/INST] Delta-beta thalassemia is a rare form of thalassemia in which there is a reduced production of hemoglobin subunit delta and hemoglobin subunit beta and raised levels of hemoglobin subunit gamma. It is an autosomal recessive disorder.

Signs and symptoms
An individual with delta-beta thalassemia is usually asymptomatic, however  microcytosis can occur where the  red blood cells are abnormally small.

Mechanism
Delta-beta thalassemia is autosomal recessive disorder, which means both parents are affected and two copies of the gene must be present. A carrier gets a normal gene to produce hemoglobin A, from one parent and the other parent supplies a gene which makes no hemoglobin A. Delta-beta thalassemia is considered rare.Delta-beta-thalassemia is caused by deletions of the entire delta and beta genes sequences and only gamma-globin and HbF are formed. Rarely, non-deletional forms have been reported.When two delta0 mutations are inherited, no hemoglobin A2 (alpha2, delta2) are formed.  This is innocuous because only 2-3% of normal adult hemoglobin is hemoglobin A2.  The individual will have normal hematological parameters (erythrocyte count, total hemoglobin, mean corpuscular volume).  The delta-beta thalassemia demonstrates one mutation is at the +69 position.

Relation to beta thalassemia
Delta-beta thalassemia can mask the diagnosis of beta thalassemia trait.  In beta thalassemia, an increase in hemoglobin A2 results, but the co-existence of a delta-beta thalassemia mutation will decrease the value of the hemoglobin A2 into the normal range, thereby obscuring the diagnosis of beta thalassemia trait

Diagnosis
Following the detection of hypochromic microcytic red blood cells, delta-beta thalassemia is confirmed by high-performance liquid chromatography.

Treatment
When needed, treatment for anemia, such as blood transfusions are used.Stem cell transplant is another option, but the donor and the individual who will receive the bone marrow transplant must be compatible, the risks involved should be evaluated.

See also
Alpha thalassemia
Beta-thalassemia
Hemoglobinopathy

References
Further reading
Verma, S; Bhargava, M; Mittal, SK; Gupta, R (1 January 2013). "Homozygous delta-beta Thalassemia in a Child: a Rare Cause of Elevated Fetal Hemoglobin". Iranian Journal of Pediatric Hematology and Oncology. 3 (1): 222–227. ISSN 2008-8892. PMC 3915439. PMID 24575268.
Kumar, B </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Varus deformity and can you explain it in depth? [/INST] A varus deformity is an excessive inward angulation (medial angulation, that is, towards the bodys midline) of the distal segment of a bone or joint.  The opposite of varus is called valgus.  EX: Varus deformity results in a decreased Q angle of the knee joint.
The terms varus and valgus always refer to the direction that the distal segment of the joint points.
For example, in a valgus deformity of the knee, the distal part of the leg below the knee is deviated outward, in relation to the femur, resulting in a knock-kneed appearance </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Nervous and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Animal and can you explain it in depth? [/INST] Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in which their body consists of a hollow sphere of cells, the blastula, during embryonic development. Over 1.5 million living animal species have been described—of which around 1 million are insects—but it has been estimated there are over 7 million animal species in total. Animals range in length from 8.5 micrometres (0.00033 in) to 33.6 metres (110 ft). They have complex interactions with each other and their environments, forming intricate food webs. The scientific study of animals is known as zoology.
Most living animal species are in Bilateria, a clade whose members have a bilaterally symmetric body plan. The Bilateria include the protostomes, containing animals such as nematodes, arthropods, flatworms, annelids and molluscs, and the deuterostomes, containing the echinoderms and the chordates, the latter including the vertebrates. Life forms interpreted as early animals were present in the Ediacaran biota of the late Precambrian. Many modern animal phyla became clearly established in the fossil record as marine species during the Cambrian explosion, which began around 539 million years ago. 6,331 groups of genes common to all living animals have been identified; these may have arisen from a single common ancestor that lived 650 million years ago.
Historically, Aristotle divided animals into those with blood and those without. Carl Linnaeus created the first hierarchical biological classification for animals in 1758 with his Systema Naturae, which Jean-Baptiste Lamarck expanded into 14 phyla by 1809. In 1874, Ernst Haeckel divided the animal kingdom into the multicellular Metazoa (now synonymous for Animalia) and the Protozoa, single-celled organisms no longer considered animals. In modern times, the biological classification of animals relies on advanced techniques, such as molecular phylogenetics, which are effective at demonstrating the evolutionary relationships between taxa.
Humans make use of many animal species, such as for food (including meat, milk, and eggs), for materials (such as leather and wool), as pets, and as working animals including for transport. Dogs have been used in hunting, as have birds of prey, while many terrestrial and aquatic animals were hunted for sports. Nonhuman animals have appeared in art from the earliest times and are featured in mythology and religion.

Etymology
The word "animal" comes from the Latin animalis, meaning having breath, having soul or living being. The biological definition includes all members of the kingdom Animalia. In colloquial usage, the term animal is often used to refer only to nonhuman animals. The term "metazoa" is from  Ancient Greek μετα (meta, used to mean "later") and ζῷᾰ (zōia, plural of ζῷον zōion "animal").

Characteristics
Animals have several characteristics that set them apart from other living things. Animals are eukaryotic and multicellular. Unlike plants and algae, which produce their own nutrients, animals are heterotrophic, feeding on organic material and digesting it internally. With very few exceptions, animals respire aerobically. All animals are motile (able to spontaneously move their bodies) during at least part of their life cycle, but some animals, such as sponges, corals, mussels, and barnacles, later become sessile. The blastula is a stage in embryonic development that is unique to animals, allowing cells to be differentiated into specialised tissues and organs.

Structure
All animals are composed of cells, surrounded by a characteristic extracellular matrix composed of collagen and elastic glycoproteins. During development, the animal extracellular matrix forms a relatively flexible framework upon which cells can move about and be reorganised, making the formation of complex structures possible. This may be calcified, forming structures such as shells, bones, and spicules. In contrast, the cells of other multicellular organisms (primarily algae, plants, and fungi) are held in place by cell walls, and so develop by progressive growth. Animal cells uniquely possess the cell junctions called tight junctions, gap junctions, and desmosomes.With few exceptions—in particular, the sponges and placozoans—animal bodies are differentiated into tissues. These include muscles, which enable locomotion, and nerve tissues, which transmit signals and coordinate the body. Typically, there is also an internal digestive chamber with either one opening (in Ctenophora, Cnidaria, and flatworms) or two openings (in most bilaterians).

Reproduction and development
Nearly all animals make use of some form of sexual reproduction. They produce haploid gametes by meiosis; the smaller, motile gametes are spermatozoa and the larger, non-motile gametes are ova. These fuse to form zygotes, which develop via mitosis into a hollow sphere, called a blastula. In sponges, blastula larvae swim to a new location, attach to the seabed, and develop into a new sponge. In most other groups, the blastula  undergoes more complicated rearrangement. It first invaginates to form a gastrula with a digestive chamber and two separate germ layers, an external ectoderm and an internal endoderm. In most cases, a third germ layer, the mesoderm, also develops between them. These germ layers then differentiate to form tissues and organs.Repeated instances of mating with a close relative during sexual reproduction generally leads to inbreeding depression within a population due to the increased prevalence of harmful recessive traits. Animals have evolved numerous mechanisms for avoiding close inbreeding.
Some animals are capable of asexual reproduction, which often results in a genetic clone of the parent. This may take place through fragmentation; budding, such as in Hydra and other cnidarians; or parthenogenesis, where fertile eggs are produced without mating, such as in aphids.

Ecology
Animals are categorised into ecological groups depending on how they obtain or consume organic material, including carnivores, herbivores, omnivores, detritivores, and parasites. Interactions between animals form complex food webs. In carnivorous or omnivorous species, predation is a consumer–resource interaction where a predator feeds on another organism (called its prey). Selective pressures imposed on one another lead to an evolutionary arms race between predator and prey, resulting in various anti-predator adaptations. Almost all multicellular predators are animals. Some consumers use multiple methods; for example, in parasitoid wasps, the larvae feed on the hosts living tissues, killing them in the process, but the adults primarily consume nectar from flowers. Other animals may have very specific feeding behaviours, such as hawksbill sea turtles primarily eating sponges.

Most animals rely on the biomass and energy produced by plants through photosynthesis. Herbivores eat plant material directly, while carnivores, and other animals on higher trophic levels typically acquire it indirectly by eating other animals. Animals oxidize carbohydrates, lipids, proteins, and other biomolecules, which allows the animal to grow and to sustain biological processes such as locomotion. Animals living close to hydrothermal vents and cold seeps on the dark sea floor consume organic matter of archaea and bacteria produced in these locations through chemosynthesis (by oxidizing inorganic compounds, such as hydrogen sulfide).Animals originally evolved in the sea. Lineages of arthropods colonised land around the same time as land plants, probably between 510 and 471 million years ago during the Late Cambrian or Early Ordovician. Vertebrates such as the lobe-finned fish Tiktaalik started to move on to land in the late Devonian, about 375 million years ago. Animals occupy virtually all of earths habitats and microhabitats, including salt water, hydrothermal vents, fresh water, hot springs, swamps, forests, pastures, deserts, air, and the interiors of animals, plants, fungi and rocks. Animals are however not particularly heat tolerant; very few of them can survive at constant temperatures above 50 °C (122 °F). Only very few species of animals (mostly nematodes) inhabit the most extreme cold deserts of continental Antarctica.

Diversity
Size
The blue whale (Balaenoptera musculus) is the largest animal that has ever lived, weighing up to 190 tonnes and measuring up to 33.6 metres (110 ft) long. The largest extant terrestrial animal is the African bush elephant (Loxodonta africana), weighing up to 12.25 tonnes and measuring up to 10.67 metres (35.0 ft) long. The largest terrestrial animals that ever lived were titanosaur sauropod dinosaurs such as Argentinosaurus, which may have weighed as much as 73 tonnes. Several animals are microscopic; some Myxozoa (obligate parasites within the Cnidaria) never grow larger than 20 µm, and one of the smallest species (Myxobolus shekel) is no more than 8.5 µm when fully grown.

Numbers and habitats
The following table lists estimated numbers of described extant species for all the animal groups, along with their principal habitats (terrestrial, fresh water, and marine), and free-living or parasitic ways of life. Species estimates shown here are based on numbers described scientifically; much larger estimates have been calculated based on various means of prediction, and these can vary wildly. For instance, around 25,000–27,000 species of nematodes have been described, while published estimates of the total number of nematode species include 10,000–20,000; 500,000; 10 million; and 100 million. Using patterns within the taxonomic hierarchy, the total number of animal species—including those not yet described—was calculated to be about 7.77 million in 2011.

Evolutionary origin
Animals are found as long ago as the Ediacaran biota, towards the end of the Precambrian, and possibly somewhat earlier. It had long been doubted whether these life-forms included animals, but the discovery of the animal lipid cholesterol in fossils of Dickinsonia establishes their nature. Animals are thought to have originated under low-oxygen conditions, suggesting that they were capable of living entirely by anaerobic respiration, but as they became specialized for aerobic metabolism they became fully dependent on oxygen in their environments.Many animal phyla first appear in the fossil record during the Cambrian explosion, starting about 539 million years ago, in beds such as the Burgess shale. Extant phyla in these rocks include molluscs, brachiopods, onychophorans, tardigrades, arthropods, echinoderms and hemichordates, along with numerous now-extinct forms such as the predatory Anomalocaris. The apparent suddenness of the event may however be an artefact of the fossil record, rather than showing that all these animals appeared simultaneously.
That view is supported by the discovery of Auroralumina attenboroughii, the earliest known Ediacaran crown-group cnidarian (557–562 mya, some 20 million years before the Cambrian explosion) from Charnwood Forest, England. It is thought to be one of the earliest predators, catching small prey with its nematocysts as modern cnidarians do.Some palaeontologists have suggested that animals appeared much earlier than the Cambrian explosion, possibly as early as 1 billion years ago. Early fossils that might represent animals appear for example in the 665-million-year-old rocks of the Trezona Formation of South Australia. These fossils are interpreted as most probably being early sponges.Trace fossils such as tracks and burrows found in the Tonian period (from 1 gya) may indicate the presence of triploblastic worm-like animals, roughly as large (about 5 mm wide) and complex as earthworms. However, similar tracks are produced today by the giant single-celled protist Gromia sphaerica, so the Tonian trace fossils may not indicate early animal evolution. Around the same time, the layered mats of microorganisms called stromatolites decreased in diversity, perhaps due to grazing by newly evolved animals. Objects such as sediment-filled tubes that resemble trace fossils of the burrows of wormlike animals have been found in 1.2 gya rocks in North America, in 1.5 gya rocks in Australia and North America, and in 1.7 gya rocks in Australia. Their interpretation as having an animal origin is disputed, as they might be water-escape or other structures.

Phylogeny
Animals are monophyletic, meaning they are derived from a common ancestor. Animals are sister to the Choanoflagellata, with which they form the Choanozoa. The most basal animals, the Porifera, Ctenophora, Cnidaria, and Placozoa, have body plans that lack bilateral symmetry. Their relationships are still disputed; the sister group to all other animals could be the Porifera or the Ctenophora, both of which lack hox genes, important in body plan development.These genes are found in the Placozoa and the higher animals, the Bilateria. 6,331 groups of genes common to all living animals have been identified; these may have arisen from a single common ancestor that lived 650 million years ago in the Precambrian. 25 of these are novel core gene groups, found only in animals; of those, 8 are for essential components of the Wnt and TGF-beta signalling pathways which may have enabled animals to become multicellular by providing a pattern for the bodys system of axes (in three dimensions), and another 7 are for transcription factors including homeodomain proteins involved in the control of development.The phylogenetic tree indicates approximately how many millions of years ago (mya) the lineages split.

Non-Bilateria
Several animal phyla lack bilateral symmetry. Among these, the sponges (Porifera) probably diverged first, representing the oldest animal phylum. Sponges lack the complex organization found in most other animal phyla; their cells are differentiated, but in most cases not organised into distinct tissues. They typically feed by drawing in water through pores.The Ctenophora (comb jellies) and Cnidaria (which includes jellyfish, sea anemones, and corals) are radially symmetric and have digestive chambers with a single opening, which serves as both mouth and anus. They are sometimes placed together in the group Coelenterata because of common traits, not because of close relationships. Animals in both phyla have distinct tissues, but these are not organised into organs. They are diploblastic, having only two main germ layers, ectoderm and endoderm. The tiny placozoans are similar, but they do not have a permanent digestive chamber.

Bilateria
The remaining animals, the great majority—comprising some 29 phyla and over a million species—form a clade, the Bilateria, which have a bilaterally symmetric body plan. The Bilateria are triploblastic, with three well-developed germ layers, and their tissues form distinct organs. The digestive chamber has two openings, a mouth and an anus, and there is an internal body cavity, a coelom or pseudocoelom. These animals have a head end (anterior) and a tail end (posterior),  a back (dorsal) surface and a belly (ventral) surface, and a left and a right side.Having a front end means that this part of the body encounters stimuli, such as food, favouring cephalisation, the development of a head with sense organs and a mouth. Many bilaterians have a combination of circular muscles that constrict the body, making it longer, and an opposing set of longitudinal muscles, that shorten the body; these enable soft-bodied animals with a hydrostatic skeleton to move by peristalsis. They also have a gut that extends through the basically cylindrical body from mouth to anus. Many bilaterian phyla have primary larvae which swim with cilia and have an apical organ containing sensory cells. However, over evolutionary time, descendant spaces have evolved which have lost  one or more of each of these characteristics. For example, adult echinoderms are radially symmetric (unlike their larvae), while some parasitic worms have extremely simplified body structures.Genetic studies have considerably changed zoologists understanding of the relationships within the Bilateria. Most appear to belong to two major lineages, the protostomes and the deuterostomes. The basalmost bilaterians are the Xenacoelomorpha.

Protostomes and deuterostomes
Protostomes and deuterostomes differ in several ways. Early in development, deuterostome embryos undergo radial cleavage during cell division, while many protostomes (the Spiralia) undergo spiral cleavage.
Animals from both groups possess a complete digestive tract, but in protostomes the first opening of the embryonic gut develops into the mouth, and the anus forms secondarily. In deuterostomes, the anus forms first while the mouth develops secondarily. Most protostomes have schizocoelous development, where cells simply fill in the interior of the gastrula to form the mesoderm. In deuterostomes, the mesoderm forms by enterocoelic pouching, through invagination of the endoderm.The main deuterostome phyla are the Echinodermata and the Chordata. Echinoderms are exclusively marine and include starfish, sea urchins, and sea cucumbers. The chordates are dominated by the vertebrates (animals with backbones), which consist of fishes, amphibians, reptiles, birds, and mammals. The deuterostomes also include the Hemichordata (acorn worms).

Ecdysozoa
The Ecdysozoa are protostomes, named after their shared trait of ecdysis, growth by moulting. They include the largest animal phylum, the Arthropoda, which contains insects, spiders, crabs, and their kin. All of these have a body divided into repeating segments, typically with paired appendages. Two smaller phyla, the Onychophora and Tardigrada, are close relatives of the arthropods and share these traits. The ecdysozoans also include the Nematoda or roundworms, perhaps the second largest animal phylum. Roundworms are typically microscopic, and occur in nearly every environment where there is water; some are important parasites. Smaller phyla related to them are the Nematomorpha or horsehair worms, and the Kinorhyncha, Priapulida, and Loricifera. These groups have a reduced coelom, called a pseudocoelom.

Spiralia
The Spiralia are a large group of protostomes that develop by spiral cleavage in the early embryo. The Spiralias phylogeny has been disputed, but it contains a large clade, the superphylum Lophotrochozoa, and smaller groups of phyla such as the Rouphozoa which includes the gastrotrichs and the flatworms. All of these are grouped as the Platytrochozoa, which has a sister group, the Gnathifera, which includes the rotifers.The Lophotrochozoa includes the molluscs, annelids, brachiopods, nemerteans, bryozoa and entoprocts. The molluscs, the second-largest animal phylum by number of described species, includes snails, clams, and squids, while the annelids are the segmented worms, such as earthworms, lugworms, and leeches. These two groups have long been considered close relatives because they share trochophore larvae.

History of classification
In the classical era, Aristotle divided animals, based on his own observations, into those with blood (roughly, the vertebrates) and those without. The animals were then arranged on a scale from man (with blood, 2 legs, rational soul) down through the live-bearing tetrapods (with blood, 4 legs, sensitive soul) and other groups such as crustaceans (no blood, many legs, sensitive soul) down to spontaneously generating creatures like sponges (no blood, no legs, vegetable soul). Aristotle was uncertain whether sponges were animals, which in his system ought to have sensation, appetite, and locomotion, or plants, which did not: he knew that sponges could sense touch, and would contract if about to be pulled off their rocks, but that they were rooted like plants and never moved about.In 1758, Carl Linnaeus created the first hierarchical classification in his Systema Naturae. In his original scheme, the animals were one of three kingdoms, divided into the classes of Vermes, Insecta, Pisces, Amphibia, Aves, and Mammalia. Since then the last four have all been subsumed into a single phylum, the Chordata, while his Insecta (which included the crustaceans and arachnids) and Vermes have been renamed or broken up. The process was begun in 1793 by Jean-Baptiste de Lamarck, who called the Vermes une espèce de chaos (a chaotic mess) and split the group into three new phyla: worms, echinoderms, and polyps (which contained corals and jellyfish). By 1809, in his Philosophie Zoologique, Lamarck had created 9 phyla apart from vertebrates (where he still had 4 phyla: mammals, birds, reptiles, and fish) and molluscs, namely cirripedes, annelids, crustaceans, arachnids, insects, worms, radiates, polyps, and infusorians.In his 1817 Le Règne Animal, Georges Cuvier used comparative anatomy to group the animals into four embranchements ("branches" with different body plans, roughly corresponding to phyla), namely vertebrates, molluscs, articulated animals (arthropods and annelids), and zoophytes (radiata) (echinoderms, cnidaria and other forms). This division into four was followed by the embryologist Karl Ernst von Baer in 1828, the zoologist Louis Agassiz in 1857, and the comparative anatomist Richard Owen in 1860.In 1874, Ernst Haeckel divided the animal kingdom into two subkingdoms: Metazoa (multicellular animals, with five phyla: coelenterates, echinoderms, articulates, molluscs, and vertebrates) and Protozoa (single-celled animals), including a sixth animal phylum, sponges. The protozoa were later moved to the former kingdom Protista, leaving only the Metazoa as a synonym of Animalia.

In human culture
Practical uses
The human population exploits a large number of other animal species for food, both of domesticated livestock species in animal husbandry and, mainly at sea, by hunting wild species. Marine fish of many species are caught commercially for food. A smaller number of species are farmed commercially. Humans and their livestock make up more than 90% of the biomass of all terrestrial vertebrates, and almost as much as all insects combined.Invertebrates including cephalopods, crustaceans, and bivalve or gastropod molluscs are hunted or farmed for food. Chickens, cattle, sheep, pigs, and other animals are raised as livestock for meat across the world.
Animal fibres such as wool are used to make textiles, while animal sinews have been used as lashings and bindings, and leather is widely used to make shoes and other items. Animals have been hunted and farmed for their fur to make items such as coats and hats. Dyestuffs including carmine (cochineal), shellac, and kermes have been made from the bodies of insects. Working animals including cattle and horses have been used for work and transport from the first days of agriculture.Animals such as the fruit fly Drosophila melanogaster serve a major role in science as experimental models. Animals have been used to create vaccines since their discovery in the 18th century </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Diphyllobothriasis and can you explain it in depth? [/INST] Diphyllobothriasis is the infection caused by tapeworms of the genus Diphyllobothrium (commonly D. latum and D. nihonkaiense).
Diphyllobothriasis mostly occurs in regions where raw fish is regularly consumed; those who consume raw fish are at risk of infection. The infection is often asymptomatic and usually presents only with mild symptoms, which may include gastrointestinal complaints, weight loss, and fatigue. Rarely, vitamin B12 deficiency (possibly leading to anaemia) and gastrointestinal obstructions may occur. Infection may be long-lasting in absence of treatment. Diphyllobothriasis is generally diagnosed by looking for eggs or tapeworm segments in passed stool. Treatment with antiparasitic medications is straightforward, effective, and safe.

Signs and symptoms
Most infections (~80%) are asymptomatic. Infections may be long-lasting, persisting for many years or decades (up to 25 years) if untreated.
Symptoms (when present) are generally mild. Manifestations may include abdominal pain and discomfort, diarrhea, vomiting, constipation, weight loss, and fatigue.
Additional symptoms have been reported/described, including dyspepsia, abdominal distension (commonly as presenting complaint), headache, myalgia, and dizziness.

Complications
While the infection is generally mild, complications may occur. Complications are predicated on parasite burden, and are generally related to vitamin B12 deficiency and related health conditions.

Vitamin B12 deficiency and anaemia
Vitamin B12 deficiency with subsequent megaloblastic anaemia (which is indistinguishable from pernicious anaemia) may occur in some instances of the disease. Anaemia may in turn result in subacute combined degeneration of the spinal cord and cognitive decline.D. latum competes with the host for vitamin B12 absorption, absorbing some 80% of dietary intake and causing deficiency and megaloblastic anaemia in some 40% of cases. Vitamin B12 uptake is enabled by the position of the parasite which usually lodges in the jejunum. Vitamin B12 deficiency is - according to research - conversely seldom seen in D. pacificum infection.

Gastrointestinal obstructions
Rarely, massive infections may result in intestinal obstruction. Migration of proglottids can cause cholecystitis or cholangitis.

Cause
Diphyllobothriasis is caused by infection by several species of the Diphyllobothrium genus.

Transmission
Humans are one of the definitive hosts of Diphyllobothrium tapeworms, along with other carnivores; fish-eating mammals (including canids, felids, and bears), marine mammals (dolphins, porpoises, and whales), and (a few) birds (e.g. gulls) may also serve as definitive hosts.Definitive hosts release eggs in faeces; the eggs then mature in ~18–20 days if under favourable conditions. Crustaceans serve as the first intermediate hosts, and Diphyllobothrium larvae develop. The larvae are released when crustaceans are consumed by predators, which serve as second intermediate hosts (these are mostly small fish). Larvae move into deeper tissues in the second intermediate host. Second intermediate hosts do not serve as an important source of infection of humans as these are not regularly consumed raw. Consumption of infected second intermediate hosts by larger predatory fish, which serve as paratenic hosts; the parasites thereupon migrate into the musculature awaiting consumption by definitive hosts in which adult tapeworms will then finally develop in the small intestine to release up to a million immature eggs per day per parasite. Hosts begin to release eggs 5–6 weeks after infection.

Pathophysiology
Tapeworms develop in the small intestine. Adults attach to the intestinal mucosa. Adult tapeworms may grow to over 10m in length and may constitute of over 3,000 proglottids which contain sets of male and female reproductive organs, allowing for high fecundity. Eggs appear in the faeces 5–6 weeks after infection.D. latum tapeworms are the longest and typically reach a length of 4-15m, but may grow up to 25m in length within the human intestine. Growth rate may exceed 22 cm/day. D. latum tapeworms feature an anterior end (scolex) equipped with attachment grooves on the dorsal and ventral surfaces.

Host-parasite interactions
Diphyllobothriasis is postulated to cause changes in neuromodulator concentrations in host tissue and serum. D. latum infection has been shown to cause local changes in the host, leading to altered GI function (including motility) via neuroendocrine modulation.Diphyllobothriasis causes mast cell and eosinophil degranulation, leading to pro-inflammatory cytokine release.

Diagnosis
Infection may be suspected based upon a patients occupation, hobbies, eating habits, and travel history. During diagnostic procedures, standard safety precautions apply. Eggs are not directly infectious to humans (in contrast to some other tapeworm species).

Microscopy
Diagnosis is usually made by identifying proglottid segments, or characteristic eggs in the faeces. Eggs are usually numerous and can be demonstrated without concentration techniques. Morphologic comparison with other intestinal parasites may be employed as a further diagnostic approach.These simple diagnostic techniques are able to identify the nature of the infection to the genus level, which is usually sufficient in a clinical setting. Though it is difficult to identify the eggs or proglottids to the species level, the distinction is of little clinical importance because - like most adult tapeworms in the intestine - all members of the genus respond to the same treatments. Treatment may distort morphological features of expelled pathogen tissues and complicate subsequent morphological diagnosis attempts.

Genetic identification
When the exact species need be determined (e.g. in epidemiological studies), restriction fragment length polymorphisms can be effectively used. PCR can be performed on samples of purified eggs, or on native fecal samples following sonication of the eggs to release their contents. Molecular identification is currently generally only used in research.

Radiography
A potential diagnostic tool and treatment is the contrast medium gastrografin which, when introduced into the duodenum, allows both visualization of the parasite, and has also been shown to cause detachment and passing of the whole parasite.

Prevention
Ingestion of raw freshwater fish should be avoided. Adequate cooking or freezing of freshwater fish will destroy the encysted fish tapeworm larvae. Fish that is thoroughly cooked, brined, or frozen at -10 °C for 24–48 hours can also be consumed without risk of D. latum infection. Public health information campaigns may be employed to educate the public about the risks of consuming improperly prepared fish.
Because human feces are an important mechanism for spreading eggs, proper disposal of sewage can reduce fish (and therefore human) infections. Prevention of water contamination may be achieved both by raising public awareness of the dangers of defecating in recreational bodies of water and by implementation of basic sanitation measures and screening and successful treatment of people infected with the parasite.

Treatment
Upon diagnosis, treatment is simple and effective.Praziquantel
The standard treatment for diphyllobothriasis (as well as many other tapeworm infections) is a single dose of praziquantel, 5–10 mg/kg orally once for both adults and children. Praziquantel is not FDA-approved for this indication. Praziquantel has few side effects, many of which are similar to the symptoms of diphyllobothriasis.Niclosamide
An alternative treatment is niclosamide, 2 g orally once for adults or 50 mg/kg (max 2 g) for children. Niclosamide is not available for human or even animal use in the United States. Side effects of niclosamide are very rare due to the fact that the medication is not absorbed in the gastrointestinal tract.Other
Reportedly, albendazole can also be effective.  Gastrografin may be potentially used both as a diagnostic and therapeutic; when introduced into the duodenum it allows for the visualization of the parasite, and has also been shown to cause detachment and passing of the whole worm.  During the 1940s, the preferred treatment was 6 to 8 grams of oleoresin of aspidium, which was introduced into the duodenum via a Rehfuss tube.

Epidemiology
People at high risk for infection have traditionally been those who regularly consume raw fish. While people of any gender or age may fall sick, the majority of identified cases occurred in middle-aged men.

Geographical distribution
Diphyllobothriasis occurs in areas where lakes and rivers coexist with human consumption of raw or undercooked freshwater fish. Such areas are found in Europe, newly independent states of the former Soviet Union, North America, Asia, Uganda, Peru (because of ceviche), and Chile. Many regional cuisines include raw or undercooked food, including sushi and sashimi in Japanese cuisine, carpaccio di persico in Italian, tartare maison in French-speaking populations, ceviche in Latin American cuisine and marinated herring in Scandinavia. With emigration and globalization, the practice of eating raw fish in these and other dishes has brought diphyllobothriasis to new parts of the world and created new endemic foci of disease.Infections in Europe and North America were traditionally associated with Jewish women due to the practice of tasting bits of uncooked fish during preparation of the gefilte fish dish, and also occurred in Scandinavian women for the same reason. Diphyllobothriasis was thus also referred to as the "Jewish housewifes disease" or the "Scandinavian housewifes disease".

Japan
Diphyllobothriasis nihonkaiense was once endemic to coastal provinces of central and northern Japan, where salmon fisheries thrived. In recent decades, regions with endemic diphyllobothriasis nihonkaiense have disappeared from Japan, though cases continue to be reported among urbanites who consume sushi or sashimi. In Kyoto, it is estimated that the average annual incidence in the past 20 years was 0.32/100,000, and that in 2008 was 1.0 case per 100,000 population, suggesting that D. nihonkaiense infection is equally as prevalent in Japan as D. latum is in some European countries.

United States
The disease is rare in the United States.

History
The fish tapeworm has a long documented history of infecting people who regularly consume fish and especially those whose customs include the consumption of raw or undercooked fish </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sequela and can you explain it in depth? [/INST] A sequela (UK: , US: ; usually used in the plural, sequelae ) is a pathological condition resulting from a disease, injury, therapy, or other trauma. Derived from the Latin word, meaning “sequel”, it is used in the medical field to mean a complication or condition following a prior illness or disease.A typical sequela is a chronic complication of an acute condition—in other words, a long-term effect of a temporary disease or injury—which follows immediately from the condition. Sequelae differ from late effects, which can appear long after—even several decades  after—the original condition has resolved.
In general, non-medical usage, the terms sequela and sequelae mean consequence and consequences.

Examples and uses
Chronic kidney disease, for example, is sometimes a sequela of diabetes; "chronic constipation" or more accurately "obstipation"  (that is, inability to pass stool or gas) is a sequela to an intestinal obstruction; and neck pain is a common sequela of whiplash or other trauma to the cervical vertebrae. Post-traumatic stress disorder may be a psychological sequela of rape. Sequelae of traumatic brain injury include headache, dizziness, anxiety, apathy, depression, aggression, cognitive impairments, personality changes, mania, and psychosis.
COVID-19 is also known to cause post-acute sequelae, known as long COVID, post-COVID syndrome, or post-acute sequelae of COVID-19 (PASC). This refers to the continuation of COVID-19 symptoms or the development of new ones, four or more weeks after the initial infection; these symptoms may persist for weeks and months. Post-COVID syndrome can occur in individuals who were asymptomatic for COVID, as well as those ranging from mild illness to severe hospitalization. These most commonly reported sequelae include fatigue, shortness of breath, chest pain, loss of smell, and brain fog; symptoms drastically range, from mild illness to severe impairment.Some conditions may be diagnosed retrospectively from their sequelae. An example is pleurisy.
Other examples of sequelae include those following neurological injury; including aphasia, ataxia, hemi- and quadriplegia, and any number of other changes that may be caused by neurological trauma </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Buried penis and can you explain it in depth? [/INST] Buried penis (also known as hidden penis or retractile penis) is a congenital or acquired condition in which the penis is partially or completely hidden below the surface of the skin. A buried penis can lead to urinary difficulties, poor hygiene, infection, and inhibition of normal sexual function.Buried penis is different than micropenis, which is an abnormally small, normally structured penis with a stretched penile length of less than 2.5 standard deviations below the mean for age or stage of sexual development of the patient.

History
Buried penis was first described by Edward Lawrence Keyes in 1919 as the apparent absence of the penis due to the penis being buried beneath the skin of the abdomen, thigh, or scrotum. Further research was done by Maurice Campbell in 1951, when he reported on the penis being buried beneath subcutaneous fat of the scrotum, perineum, hypogastrium, and thigh.

Causes
Congenital
Congenital causes can include the maldevelopment of the penile shaft with a lack of attachments of the shaft skin to the penile shaft. While rare, it can include an abnormally large pubic fat pad and firm tissue that pulls the penis inward.

Acquired
Obesity
While not every obese male has the buried penis condition, 87% of men that received surgical treatment for buried penis were reported to be obese. Significant overlying abdominal fat can also create an environment that encourages bacterial and fungal growth. Obesity can also increase the likelihood of the development of type II diabetes mellitus, which is characterized by increase susceptibility to infections, making it difficult to successfully and promptly manage the buried penis condition </s>