<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Calcaneal spur and explain in detail? [/INST] A calcaneal spur (also known as a heel spur) is a bony outgrowth from the calcaneal tuberosity (heel bone). Calcaneal spurs are typically detected by x-ray examination. It is a form of exostosis.
When a foot is exposed to constant stress, calcium deposits build up on the bottom of the heel bone. Generally, this has no effect on a persons daily life. However, repeated damage can cause these deposits to pile up on each other, causing a spur-shaped deformity, called a calcaneal (or heel) spur.An inferior calcaneal spur is located on the inferior aspect of the calcaneus and is typically a response to plantar fasciitis over a period, but may also be associated with ankylosing spondylitis (typically in children). A posterior calcaneal spur develops on the back of the heel at the insertion of the Achilles tendon.An inferior calcaneal spur consists of a calcification of the calcaneus, which lies superior to the plantar fascia at the insertion of the plantar fascia. A posterior calcaneal spur is often large and palpable through the skin and may need to be removed as part of the treatment of insertional Achilles tendonitis.

Signs and symptoms
Major symptoms consist of pain in the region surrounding the spur, which typically increases in intensity after prolonged periods of rest. Patients may report heel pain to be more severe when waking up in the morning. Patients may not be able to bear weight on the affected heel comfortably. Running, walking, or lifting heavy weight may exacerbate the issue.

Causes
Plantar fasciitis is a common cause of calcaneal spurs. When stress is put on the plantar fascia ligament, it does not cause only plantar fasciitis, but causes a heel spur where the plantar fascia attaches to the heel bone. The considerations that affect plantar heel pain are the alignment of the foot with lower leg, foot and ankle mobility, strength and endurance of muscle. External influences on plantar heel pain are the amount of time spent on feet while exercising or standing, type of footwear used and type of floor surfaces.Calcaneal spur develops when proper care is not given to the foot and heels </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Male infertility and explain in detail? [/INST] Male infertility refers to a sexually mature males inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.

Age considerations
There is a decrease in sperm concentration as men age: 90% of seminiferous tubules in men in their 20s and 30s contain spermatids, whereas men in their 40s and 50s have spermatids in 50% of their seminiferous tubules, and only 10% of seminiferous tubules from men aged > 80 years contain spermatids. In a random international sample of 11,548 men confirmed to be biological fathers by DNA paternity testing, the oldest father was found to be 66 years old at the birth of his child; the ratio of DNA-confirmed versus DNA-rejected paternity tests around that age is in agreement with the notion of general male infertility above age 65–66.

Causes
Factors relating to male infertility include:

Immune infertility
Antisperm antibodies (ASA) have been considered as infertility cause in around 10–30% of infertile couples.  ASA production are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and acrosome reaction, impaired fertilization, influence on the implantation process, and impaired growth and development of the embryo. Risk factors for the formation of antisperm antibodies in men include the breakdown of the blood‑testis barrier, trauma and surgery, orchitis, varicocele, infections, prostatitis, testicular cancer, failure of immunosuppression and unprotected receptive anal or oral sex with men.

Genetics
Chromosomal anomalies and genetic mutations account for nearly 10–15% of all male infertility cases.

Klinefelter syndrome
One of the most commonly known causes of infertility is Klinefelter syndrome, which affects  one in 500–1000 newborn males. Klinefelter syndrome is a chromosomal defect that occurs during gamete formation due to a non-disjunction error during cell division. Resulting in males having smaller testes, reducing the amount of testosterone and sperm production. Males with this syndrome carry an extra X chromosome (XXY), meaning they have 47 chromosomes compared to the normal 46 in each cell. This extra chromosome directly affects sexual development before birth and during puberty. A variation of Klinefelter syndrome is when some cells in an individual have the extra X chromosome but others do not, referred to as mosaic Klinefelter syndrome. The reduction of testosterone in the male body normally results in an overall decrease in the production of viable sperm for these individuals thereby forcing them to turn to fertility treatments to father children.

Y chromosome deletions
Y chromosomal infertility is a direct cause of male infertility due to its effects on sperm production, occurring in approximately one in 2000 males. Usually, affected men show no symptoms, although they may have smaller testes. Men with this condition may exhibit azoospermia (no sperm production), oligozoospermia (small number of sperm production), or they may produce abnormally shaped sperm (teratozoospermia). This case of infertility occurs during the development of gametes in the male. Where a normal healthy male will have both an X and a Y chromosome, affected males have genetic deletions in the Y chromosome. These deletions affect protein production that is vital for spermatogenesis. Studies have shown that this is an inherited trait; if a male is fathered by a man who also exhibited Y chromosome deletions then this trait will be passed down. These individuals are thereby "Y-linked". Daughters are not affected and cannot be carriers due to their lack of a Y chromosome.

Other
Age group 12–49 (Paternal age effect)
Aneuploidy, an abnormal number of chromosomes
Centriole
Neoplasm, e.g. seminoma
Idiopathic failure
Cryptorchidism
Trauma
Hydrocele, particularly hydrocele testis
Hypopituitarism in adults, and hypopituitarism untreated in children (resulting in growth hormone deficiency and proportionate dwarfism.)
Mumps
Malaria
Testicular cancer
Defects in USP26 in some cases
Acrosomal defects affecting egg penetration
Idiopathic oligospermia – unexplained sperm deficiencies account for 30% of male infertility.

Pre-testicular causes
Pre-testicular factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including:

Varicocele
Varicocele is a condition of swollen testicle veins.It is present in 15% of normal men and in about 40% of infertile men.
It is present in up to 35% of cases of primary infertility and 69–81% of secondary infertility.
Hypogonadotropic hypogonadism due to various causes
Obesity increases the risk of hypogonadotropic hypogonadism. Animal models indicate that obesity causes leptin insensitivity in the hypothalamus, leading to decreased Kiss1 expression, which, in turn, alters the release of gonadotropin-releasing hormone (GnRH).
Undiagnosed and untreated coeliac disease (CD). Coeliac men may have reversible infertility. Nevertheless, CD can present with several non-gastrointestinal symptoms that can involve nearly any organ system, even in the absence of gastrointestinal symptoms. Thus, the diagnosis may be missed, leading to a risk of long-term complications. In men, CD can reduce semen quality and cause immature secondary sex characteristics, hypogonadism and hyperprolactinaemia, which causes impotence and loss of libido. The giving of gluten free diet and correction of deficient dietary elements can lead to a return of fertility.  It is likely that an effective evaluation for infertility would best include assessment for underlying celiac disease, both in men and women.
Drugs, alcohol
Strenuous riding (bicycle riding, horseback riding)
Medications, including those that affect spermatogenesis such as chemotherapy, fluoxetine, anabolic steroids, cimetidine, spironolactone; those that decrease FSH levels such as phenytoin; those that decrease sperm motility such as sulfasalazine and nitrofurantoin
Genetic abnormalities such as a Robertsonian translocation

Tobacco smoking
There is increasing evidence that the harmful products of tobacco smoking may damage the testicles and kill sperm, but their effect on male fertility is not clear. Some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes.

DNA damage
Common inherited variants in genes that encode enzymes employed in DNA mismatch repair are associated with increased risk of sperm DNA damage and male infertility.   As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage. The damage manifests by DNA fragmentation and by the increased susceptibility to denaturation upon exposure to heat or acid, the features characteristic of apoptosis of somatic cells. These findings suggest that DNA damage is an important factor in male infertility.

Epigenetic
An increasing amount of recent evidence has been recorded documenting abnormal sperm DNA methylation in association with abnormal semen parameters and male infertility. Until recently, scientists have thought that epigenetic markers only affect the individual and are not passed down due to not changing the DNA. New studies suggest that environmental factors that changed an individuals epigenetic markers can be seen in their grandchildren, one such study demonstrating this through rats and fertility disruptors. Another study bred rats exposed to an endocrine disruptor, observing effects up to generation F5 including decreased sperm motility and decreased sperm count. These studies suggest that environmental factors that influence fertility can be felt for generations even without changing the DNA.

Post-testicular causes
Post-testicular factors decrease male fertility due to conditions that affect the male genital system after testicular sperm production and include defects of the genital tract as well as problems in ejaculation:
Vas deferens obstruction
Lack of Vas deferens, often related to genetic markers for cystic fibrosis
Infection, e.g. prostatitis, male accessory gland infection
Retrograde ejaculation
Ejaculatory duct obstruction
Hypospadias
Impotence

Diagnostic evaluations
The diagnosis of infertility begins with a medical history and physical exam by a physician, physician assistant, or nurse practitioner. Typically two separate semen analyses will be required. The provider may order blood tests to look for hormone imbalances, medical conditions, or genetic issues.

Medical history
The history should include prior testicular or penile insults (torsion, cryptorchidism, trauma), infections (mumps orchitis, epididymitis), environmental factors, excessive heat, radiation, medications, and drug use (anabolic steroids, alcohol, smoking).Sexual habits, frequency and timing of intercourse, use of lubricants, and each partners previous fertility experiences are important.Loss of libido and headaches or visual disturbances may indicate a pituitary tumor.The past medical or surgical history may reveal thyroid or liver disease (abnormalities of spermatogenesis), diabetic neuropathy (retrograde ejaculation), radical pelvic or retroperitoneal surgery (absent seminal emission secondary to sympathetic nerve injury), or hernia repair (damage to the vas deferens or testicular blood supply).A family history may reveal genetic problems.

Physical examination
Usually, the patient disrobes completely and puts on a gown. The physician, physician assistant, or nurse practitioner will perform a thorough examination of the penis, scrotum, testicles, I vas deferens, spermatic cords, ejaculatory ducts, urethra, urinary bladder, anus and rectum. An orchidometer can measure testicular volume, which in turn is tightly associated with both sperm and hormonal parameters. A physical exam of the scrotum can reveal a varicocele, but the impact of detecting and surgically correct a varicocele on sperm parameters or overall male fertility is debated.

Sperm sample
Semen sample obtaining
Semen sample obtaining is the first step in spermiogram. The optimal sexual abstinence for semen sample obtaining is of 2–7 days. The first way to obtain the semen sample is through masturbation, and the best place to obtain it is in the same clinic, as this way temperature changes during transport can be avoided, which can be lethal for some spermatozoa.
A single semen sample is not determining for disease diagnosis, so two different samples have to be analyzed with an interval between them of seven days to three months, as sperm production is a cyclic process. It is prudent to ask about possible sample loss, as that could mask true results of spermiogram.
To obtain the sample, a sterile plastic recipient is put directly inside, always no more than one hour before being studied. Conventional preservatives shouldnt be used, as they have chemical substances as lubricants or spermicides that could damage the sample. If preservatives have to be used, for cases of religious ethics in which masturbation is forbidden, a preservative with holes is used. In case of paraplegia it is possible to use mechanic tools or electroejaculation.
The sample should never be obtained through coitus interruptus for several reasons:

Some part of ejaculation could be lost.
Bacterial contamination could happen.
The acid vaginal pH could be deleterious for sperm motility.Also is very important to label the sample correctly the recipient with patient identification, date, hour, abstinence days, among other data required to be known.

The volume of the semen sample (must be more than 1.5 ml), approximate number of total sperm cells, sperm motility/forward progression, and % of sperm with normal morphology are measured. It is possible to have hyperspermia (high volume more than 6 ml) or Hypospermia (low volume less than 0.5 ml). This is the most common type of fertility testing.
Semen deficiencies are often labeled as follows:

Oligospermia or oligozoospermia – decreased number of spermatozoa in semen
Aspermia – complete lack of semen
Hypospermia – reduced seminal volume
Azoospermia – absence of sperm cells in semen
Teratospermia – increase in sperm with abnormal morphology
Asthenozoospermia – reduced sperm motility
Necrozoospermia – all sperm in the ejaculate are dead
Leucospermia – a high level of white blood cells in semen
Normozoospermia or normospermia – It is a result of semen analysis that shows normal values of all ejaculate parameters by WHO but still there are chances of being infertile. This is also called as unexplained InfertilityThere are various combinations of these as well, e.g. Teratoasthenozoospermia, which is reduced sperm morphology and motility.
Low sperm counts are often associated with decreased sperm motility and increased abnormal morphology, thus the terms "oligoasthenoteratozoospermia" or "oligospermia" can be used as a catch-all.

Special obtaining
Psychological inhibition– Psychotherapy
– Intercourses with special preservatives without lubricants or spermicides. In case of religion limitations we should use a SCD, or Seminal Collection Device, such as preservatives with holes.
– Drug stimulation
– Percutaneous spermatozoa obtaining directly from epididymis, testes, etc.

Neurological injury– Vibro-stimulation
– Electro-stimulation

Retrograde ejaculationThis type of ejaculation happens when there is a defect on prostate, so the sample is not ejaculated outside but to the bladder. So, in that case, what we have to do to obtain the sample is:
– Intake bicarbonate, about 25 grams, the night before and the morning of the sample obtaining. This will neutralize acidic urine and will turn it alkaline, near semens pH, so spermatozoa can survive.
– Before masturbation we have to urinate to empty the bladder. This must go to the first recipient.
– Just after that, the subject has to masturbate and ejaculate, obtaining then a new urine sample with ejaculation that will be stored on the second recipient.
– Finally we have to obtain the next urine, 2nd urine, for potential ejaculation fraction, which will be stored in the third recipient. This may contain the most important fraction.

Blood sample
Common hormonal test include determination of FSH and testosterone levels. A blood sample can reveal genetic causes of infertility, e.g. Klinefelter syndrome, a Y chromosome microdeletion, or cystic fibrosis.

Ultrasonography
Scrotal ultrasonography is useful when there is a suspicion of some particular diseases. It may detect signs of testicular dysgenesis, which is often related to an impaired spermatogenesis and to a higher risk of testicular cancer. Scrotum ultrasonography may also detect testicular lesions suggestive of malignancy. A decreased testicular vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions such as lymphoma and leukemia. Doppler ultrasonography useful in assessing venous reflux in case of a varicocele, when palpation is unreliable or in detecting recurrence or persistence after surgery, although the impact of its detection and surgical correction on sperm parameters and overall fertility is debated.Dilation of the head or tail of the epididymis is suggestive of obstruction or inflammation of the male reproductive tract. Such abnormalities are associated with abnormalities in sperm parameters, as are abnormalities in the texture of the epididymis. Scrotal and transrectal ultrasonography (TRUS) are useful in detecting uni- or bilateral congenital absence of the vas deferens (CBAVD), which may be associated with abnormalities or agenesis of the epididymis, seminal vesicles or kidneys, and indicate the need for testicular sperm extraction. TRUS plays a key role in assessing azoospermia caused by obstruction, and detecting distal CBAVD or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied.

Prevention
Some strategies suggested or proposed for avoiding male infertility include the following:

Avoiding smoking as it damages sperm DNA
Avoiding heavy marijuana and alcohol use.
Avoiding excessive heat to the testes.
Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).
Wearing a protective cup and jockstrap to protect the testicles, in any sport such as baseball, football, cricket, lacrosse, hockey, softball, paintball, rodeo, motorcross, wrestling, soccer, karate or other martial arts or any sport where a ball, foot, arm, knee or bat can come into contact with the groin.
Diet: Healthy diets (i.e. the Mediterranean diet) rich in such nutrients as omega-3 fatty acids, some antioxidants and vitamins, and low in saturated fatty acids (SFAs) and trans-fatty acids (TFAs) are inversely associated with low semen quality parameters. In terms of food groups, fish, shellfish and seafood, poultry, cereals, vegetables and fruits, and low-fat dairy products have been positively related to sperm quality. However, diets rich in processed meat, soy foods, potatoes, full-fat dairy products, coffee, alcohol and sugar-sweetened beverages and sweets have been inversely associated with the quality of semen in some studies. The few studies relating male nutrient or food intake and fecundability also suggest that diets rich in red meat, processed meat, tea and caffeine are associated with a lower rate of fecundability. This association is only controversial in the case of alcohol. The potential biological mechanisms linking diet with sperm function and fertility are largely unknown and require further study.

Treatment
Treatments vary according to the underlying disease and the degree of the impairment of the males fertility. Further, in an infertility situation, the fertility of the female needs to be considered.Pre-testicular conditions can often be addressed by medical means or interventions.
Testicular-based male infertility tends to be resistant to medication. Usual approaches include using the sperm for intrauterine insemination (IUI), in vitro fertilization (IVF), or IVF with intracytoplasmatic sperm injection (ICSI). With IVF-ICSI even with a few sperm pregnancies can be achieved.
Obstructive causes of post-testicular infertility can be overcome with either surgery or IVF-ICSI. Ejaculatory factors may be treatable by medication, or by IUI therapy or IVF.
Vitamin E helps counter oxidative stress, which is associated with sperm DNA damage and reduced sperm motility. A hormone-antioxidant combination may improve sperm count and motility. Giving oral antioxidants to men in couples undergoing in vitro fertilisation for male factor or unexplained subfertility may lead to an increase in the live birth rate but overall the risk of adverse effects is unclear.

Hormonal therapy
Administration of luteinizing hormone (LH) (or human chorionic gonadotropin) and follicle-stimulating hormone (FSH) is very effective in the treatment of male infertility due to hypogonadotropic hypogonadism. Although controversial, off-label clomiphene citrate, an antiestrogen, may also be effective by elevating gonadotropin levels.Though androgens are absolutely essential for spermatogenesis and therefore male fertility, exogenous testosterone therapy has been found to be ineffective in benefiting men with low sperm count. This is thought to be because very high local levels of testosterone in the testes (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels) are required to mediate spermatogenesis, and exogenous testosterone therapy (which is administered systemically) cannot achieve these required high local concentrations (at least not without extremely supraphysiological dosages). Moreover, exogenous androgen therapy can actually impair or abolish male fertility by suppressing gonadotropin secretion from the pituitary gland, as seen in users of androgens/anabolic steroids (who often have partially or completely suppressed sperm production). This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes) and because FSH is independently critical for spermatogenesis. In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis. However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels. As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.Low-dose estrogen and testosterone combination therapy may improve sperm count and motility in some men, including in men with severe oligospermia.

Research
Researchers at Münster University developed in vitro culture conditions using a three-dimensional agar culture system which induces mouse testicular germ cells to reach the final stages of spermatogenesis, including spermatozoa generation. If reproduced in humans, this could potentially enable infertile men to father children with their own sperm.Researchers from Montana State University developed precursors of sperm from skin cells of infertile men.Sharpe et al. comment on the success of intracytoplasmic sperm injection (ICSI) in women saying, "[t]hus, the woman carries the treatment burden for male infertility, a fairly unique scenario in medical practice. Ironically, ICSIs success has effectively diverted attention from identifying what causes male infertility and focused research onto the female, to optimize the provision of eggs and a receptive endometrium, on which ICSIs success depends."

Prevalence
Currently, there are no solid numbers on how many couples worldwide experience infertility, but the World Health Organization estimates between 60 and 80 million couples are affected. The population in different regions have varying amounts of infertility.
Starting in the late 20th century, scientists have expressed concerns about the declining semen quality in men. A study was done in 1992 with men who had never experienced infertility showed that the amount of sperm in semen had declined by 1% per year since 1938. Further research a few years later also confirmed the decline in sperm count and also seminal volume. Various studies in Finland, Southern Tunisia, and Argentina also showed a decline in sperm count, motility, morphology, and seminal volume.
Males from India had a 30.3% decline in sperm count, 22.9% decline in sperm motility, and a 51% decrease in morphology over a span of a decade. Doctors in India disclosed that the sperm count of a fertile Indian male had decreased by a third over a span of three decades. Some factors may include exposure to high temperatures at places such as factories </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Circadian rhythm sleep disorder and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hypothalamic disease and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Diffuse large B-cell lymphoma and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Delta-beta thalassemia and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Varus deformity and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Nervous and explain in detail? [/INST]  </s>