MONDO:0018076

[PMID:16882280] [SUPPORT] The findings of this study indicate that TB is a common cause of LBP that is liable to be overlooked in the differential diagnosis of LBP. --- Explanation: The study indicates that tuberculosis is a common cause of low back pain (LBP), supporting the statement that back pain may indicate spinal tuberculosis.

[PMID:29358061] [SUPPORT] We present a case report of a military veteran presenting with neck pain and initially diagnosed with cervical disc disease. The patient's pain progressed to the point of developing paresthesias in his bilateral upper extremities. Eventually, cervical spine radiographs were obtained that revealed complete cervical vertebral body destruction from spinal tuberculosis. --- Explanation: This case report supports the statement that back pain may indicate spinal tuberculosis, as it describes a patient whose neck pain was eventually diagnosed as spinal tuberculosis.

[PMID:19845697] [SUPPORT] In TB spondylitis, the lumbar (22.7%) and thoracic (50%) vertebrae were the most commonly involved sites. --- Explanation: This study supports the statement by indicating that the lumbar and thoracic vertebrae are commonly involved in TB spondylitis, which can manifest as back pain.

[PMID:33393654] [SUPPORT] In this article, we present a rare case of progressed tuberculous infection involving the respiratory and musculoskeletal system in a 36-year-old patient whose main complaints were non-specific and mild, and started only two weeks before his diagnosis, despite the advanced disease. --- Explanation: This case supports the statement by illustrating that tuberculosis can involve the musculoskeletal system, presenting as back pain.


MONDO:0018076

[PMID:30513392] [PARTIAL] TB can affect most organs in the head and neck region, such as the lymph nodes, larynx, middle ear, oral cavity and pharynx. In particular, as for cervical tuberculosis lymphadenopathy, a predominant involvement of the posterior triangle, supraclavicular, and internal jugular group of nodes bilaterally can be observed. --- Explanation: The literature supports that tuberculosis can cause lymphadenopathy, specifically in the neck region, but it does not provide a clear indication of frequency.

[PMID:38317037] [PARTIAL] Other major causes of lymphadenopathy were metastatic tumor deposits, reactive lymphoid hyperplasia, and tuberculous lymphadenitis. --- Explanation: The literature indicates that tuberculous lymphadenitis is one of the major causes of lymphadenopathy, but it does not specify how frequently this occurs.

[PMID:37743370] [PARTIAL] Close to half of patients with enlarged lymph nodes were positive for M. tuberculosis by the GeneXpert method in the study area. --- Explanation: The study shows a significant prevalence of TB lymphadenitis among patients with enlarged lymph nodes, but it does not provide a frequency classification such as 'occasional'.


MONDO:0018076

[PMID:14745511] [INDIRECT EVIDENCE] [PARTIAL] The immune response to Mycobacterium tuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual --- Explanation: This reference supports the claim that Mycobacterium tuberculosis infection leads to granuloma formation.

[PMID:30306257] [INDIRECT EVIDENCE] [SUPPORT] Phagocytosis refers to the process of internalization and degradation of particulate material... One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including modulation of the phagocytic pathway as well as interfering with a number of immune activation pathways that normally would lead to eradication of the internalized bacilli. --- Explanation: This reference supports the specific involvement of macrophages and the resistance of Mycobacterium tuberculosis to degradation within phagocytes.

[PMID:2425678] [INDIRECT EVIDENCE] [PARTIAL] The process of granuloma formation in the lung is mediated by an intimate interaction between macrophages and T cells, and this interaction provides the appropriate environment for granuloma formation and the development of fibrosis. --- Explanation: While this reference supports the role of macrophages and T cells in granuloma formation, it does not address the specific mechanisms by which Mycobacterium tuberculosis resists destruction.

[PMID:25607549] [INDIRECT EVIDENCE] [PARTIAL] Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. --- Explanation: This reference partially supports the claim by highlighting that M. tuberculosis avoids destruction within host cells, though it does not explicitly mention granuloma formation.


MONDO:0018076


MONDO:0018076

[PMID:23626591] [INDIRECT EVIDENCE] [SUPPORT] Granulomas are the hallmark of Mycobacterium tuberculosis (M.tb) infection and thus sit at the center of tuberculosis (TB) immunopathogenesis. --- Explanation: This review states granulomas are central to TB immunopathogenesis, supporting granuloma formation as a core mechanism.

[PMID:14745511] [INDIRECT EVIDENCE] [SUPPORT] The immune response to Mycobacterium tuberculosis (Mtb) infection is the formation of multicellular lesions, or granolomas, in the lung of the individual. --- Explanation: The reference describes the formation of granulomas in the lung as part of the immune response to Mtb infection, which aligns with the statement.

[PMID:28577054] [INDIRECT EVIDENCE] [SUPPORT] The typical composition is a center of macrophages/histiocytes with lymphocytes at the border. --- Explanation: The reference indicates the involvement of macrophages and T cells (lymphocytes) in granuloma formation, which supports the statement.

[PMID:36920308] [INDIRECT EVIDENCE] [PARTIAL] granulomas are pathologically diverse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. --- Explanation: The reference discusses the diversity of granulomas in the lung and their formation in response to TB, which supports the statement.

[PMID:25319335] [INDIRECT EVIDENCE] [PARTIAL] Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is an intracellular pathogen of mononuclear phagocytes. --- Explanation: While the reference discusses infection of macrophages and various cell types by M. tuberculosis, it doesn't mention T cells and granuloma formation specifically.

[PMID:33720848] [INDIRECT EVIDENCE] [SUPPORT] Granuloma formation is the pathologic hallmark of tuberculosis (TB). --- Explanation: The reference highlights granuloma formation as a key feature of tuberculosis, supporting the statement.


MONDO:0018076

[PMID:32482293] [INDIRECT EVIDENCE] [SUPPORT] Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance. --- Explanation: The reference explicitly mentions cavitation as a severe consequence of pulmonary tuberculosis, which aligns with the statement.

[PMID:27245780] [INDIRECT EVIDENCE] [SUPPORT] Human TB lesions are severely hypoxic and M.tb drives HIF-1alpha accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation. --- Explanation: This reference provides evidence that TB lesions result in hypoxia and enzymatic activity that contributes to the destruction of lung tissue and cavitation.

[PMID:16136463] [INDIRECT EVIDENCE] [SUPPORT] Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability. --- Explanation: This reference discusses the relationship between TB, cavitation, and lung tissue remodeling, underscoring the statement that active TB causes cavitation and tissue damage.

[PMID:25361920] [INDIRECT EVIDENCE] [SUPPORT] After many months, the affected lung suddenly undergoes caseation necrosis with vanishingly few MTB. The necrotic tissue fragments to produce a cavity or hardens to develop fibrocaseous disease. --- Explanation: This reference explains the process of caseation necrosis leading to cavity formation in the lung, which supports the statement regarding active TB causing cavitation and tissue destruction.


MAXO:0000058

[PMID:33106268] [SUPPORT] Isoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a prodrug which is activated by the intracellular KatG enzyme of Mycobacterium tuberculosis. --- Explanation: The description of Isoniazid as a first-line antibiotic for TB treatment and its activation by the KatG enzyme is supported. This aligns with the provided mechanism of prodrug activation.

[PMID:12164478] [SUPPORT] The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. --- Explanation: The inhibition of mycolic acid biosynthesis by Isoniazid aligns with the described mechanism of action in the statement.


CHEBI:6030

[PMID:33106268] [INDIRECT EVIDENCE] [SUPPORT] Isoniazid (INH), one of the first-line drugs used for the treatment of tuberculosis, is a prodrug which is activated by the intracellular KatG enzyme of Mycobacterium tuberculosis. --- Explanation: The description of Isoniazid as a first-line antibiotic for TB treatment and its activation by the KatG enzyme is supported. This aligns with the provided mechanism of prodrug activation.

[PMID:12164478] [INDIRECT EVIDENCE] [SUPPORT] The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. --- Explanation: The inhibition of mycolic acid biosynthesis by Isoniazid aligns with the described mechanism of action in the statement.


MAXO:0000058

[PMID:11290327] [SUPPORT] Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). --- Explanation: This reference explains that Rifampicin is a key component of anti-tuberculosis therapy due to its inhibition of bacterial RNA polymerase.

[PMID:27553018] [SUPPORT] For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide, and ethambutol is required for a long period of time to kill bacteria. --- Explanation: This reference confirms that rifampicin is used for the treatment of TB.

[PMID:34400805] [SUPPORT] Rifamycins exhibit bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting RNA polymerase (RNAP). --- Explanation: This reference supports the statement by confirming that Rifamycins, including rifampicin, exhibit bactericidal activity by inhibiting RNA polymerase.

[PMID:33199626] [SUPPORT] Rif targets the enzyme RNA polymerase (RNAP). --- Explanation: This reference affirms the mechanism of rifampicin targeting RNA polymerase, which validates its use in TB treatment.

[PMID:28803492] [SUPPORT] Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. --- Explanation: This reference supports the use of rifampicin (a Rifamycin antibiotic) for TB treatment due to its sterilizing activity against Mycobacterium tuberculosis.


CHEBI:28077

[PMID:11290327] [INDIRECT EVIDENCE] [SUPPORT] Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). --- Explanation: This reference explains that Rifampicin is a key component of anti-tuberculosis therapy due to its inhibition of bacterial RNA polymerase.

[PMID:27553018] [INDIRECT EVIDENCE] [SUPPORT] For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide, and ethambutol is required for a long period of time to kill bacteria. --- Explanation: This reference confirms that rifampicin is used for the treatment of TB.

[PMID:34400805] [INDIRECT EVIDENCE] [SUPPORT] Rifamycins exhibit bactericidal activity against many Gram-positive and Gram-negative bacteria by inhibiting RNA polymerase (RNAP). --- Explanation: This reference supports the statement by confirming that Rifamycins, including rifampicin, exhibit bactericidal activity by inhibiting RNA polymerase.

[PMID:33199626] [INDIRECT EVIDENCE] [SUPPORT] Rif targets the enzyme RNA polymerase (RNAP). --- Explanation: This reference affirms the mechanism of rifampicin targeting RNA polymerase, which validates its use in TB treatment.

[PMID:28803492] [INDIRECT EVIDENCE] [SUPPORT] Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. --- Explanation: This reference supports the use of rifampicin (a Rifamycin antibiotic) for TB treatment due to its sterilizing activity against Mycobacterium tuberculosis.


MAXO:0000058

[PMID:16209089] [SUPPORT] Ethambutol (EMB), the first line drug in the treatment of tuberculosis, is an inhibitor of the biosynthesis of the cell wall compound - arabinogalactan. --- Explanation: The literature states that ethambutol interferes with the biosynthesis of arabinogalactan, supporting the mechanism described in the statement.

[PMID:9949810] [PARTIAL] Isoniazid is the most widely used antituberculosis drug. --- Explanation: The statement specifies ethambutol as a bacteriostatic antibiotic used for TB treatment, whereas this reference talks about isoniazid. It is partially relevant since ethambutol is also an antituberculosis drug, but this reference does not fully address ethambutol's function.

[PMID:37289062] [SUPPORT] In combination with TB antibiotics, wollamide B1 synergistically enhances the activity of several antibiotics... and wollamide B1 did not compromise the antimycobacterial activity of the isoniazid/rifampicin/ethambutol combination. --- Explanation: This reference confirms that ethambutol is used in combination with other antitubercular drugs, aligning with the notes in the statement about preventing the emergence of drug resistance.


CHEBI:4877

[PMID:16209089] [INDIRECT EVIDENCE] [SUPPORT] Ethambutol (EMB), the first line drug in the treatment of tuberculosis, is an inhibitor of the biosynthesis of the cell wall compound - arabinogalactan. --- Explanation: The literature states that ethambutol interferes with the biosynthesis of arabinogalactan, supporting the mechanism described in the statement.

[PMID:9949810] [INDIRECT EVIDENCE] [PARTIAL] Isoniazid is the most widely used antituberculosis drug. --- Explanation: The statement specifies ethambutol as a bacteriostatic antibiotic used for TB treatment, whereas this reference talks about isoniazid. It is partially relevant since ethambutol is also an antituberculosis drug, but this reference does not fully address ethambutol's function.

[PMID:37289062] [INDIRECT EVIDENCE] [SUPPORT] In combination with TB antibiotics, wollamide B1 synergistically enhances the activity of several antibiotics... and wollamide B1 did not compromise the antimycobacterial activity of the isoniazid/rifampicin/ethambutol combination. --- Explanation: This reference confirms that ethambutol is used in combination with other antitubercular drugs, aligning with the notes in the statement about preventing the emergence of drug resistance.


MAXO:0000058

[PMID:17943789] [SUPPORT] Directly observed therapy (DOT), which involves people directly observing patients taking their antituberculous drugs. --- Explanation: The abstract clearly states that DOT involves someone directly observing patients taking their antituberculous drugs to ensure adherence.

[PMID:29461901] [SUPPORT] The World Health Organization (WHO) propagates Directly Observed Therapy Short-course (DOTS) as an effective way to stop the spread of TB in communities with a high burden. --- Explanation: The abstract indicates that DOTS is endorsed by WHO as a method to ensure patients adhere to TB treatment.

[PMID:28410705] [SUPPORT] A flexible, patient centered approach were a family member can act as the DOT provider with guidance from a trained health worker was evolved as the most acceptable and comfortable mode of treatment to majority of the TB patients --- Explanation: The abstract reinforces the involvement of a health worker in observing DOT, even if it's flexible to involve family members.

[PMID:27598709] [SUPPORT] To best ensure compliance, directly observed therapy (DOT) is considered the standard of practice. --- Explanation: Emphasizes DOT as a standard practice to ensure compliance by observing the patient directly.


MAXO:0000058

[PMID:29910114] [SUPPORT] The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates. --- Explanation: This source supports the statement mentioning that a regimen of isoniazid and rifapentine is used for latent TB infection.

[PMID:19496388] [SUPPORT] The treatment of choice for LTBI is isoniazid for nine months. --- Explanation: This source supports the use of isoniazid for the prevention of latent tuberculosis infection (LTBI).

[PMID:32551948] [SUPPORT] The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections. --- Explanation: This supports the statement by specifying that WHO recommends isoniazid and rifapentine for the treatment of latent tuberculosis infections.


MAXO:0000950


HGNC.SYMBOL:TREM2


HGNC.SYMBOL:APOE


HGNC.SYMBOL:NPC2


HGNC.SYMBOL:PLIN2


HGNC.SYMBOL:LIPA


HGNC.SYMBOL:TBK1


HGNC.SYMBOL:IRF3


NCBITaxon:1773

[PMID:27784885] [SUPPORT] Tuberculosis (TB) is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis complex. Although primarily a pulmonary pathogen, M. tuberculosis can cause disease in almost any part of the body. --- Explanation: The statement correctly identifies Mycobacterium tuberculosis as a bacterium that primarily affects the lungs but can affect other organs.

[PMID:37057936] [SUPPORT] Mycobacterium tuberculosis belongs to the group of mycobacteria, most of which can cause a delayed hypersensitivity reaction in the body and is a bacterium that causes tuberculosis. --- Explanation: This reference confirms that Mycobacterium tuberculosis is a bacterium that causes TB and can affect the lungs.

[PMID:33306806] [SUPPORT] Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). It spreads from one person to the another through the air while coughing, spitting, speaking or sneezing. TB most commonly affects lungs but it can affect any organ system. --- Explanation: This reference supports the claim that tuberculosis, caused by Mycobacterium tuberculosis, primarily affects the lungs but can also affect other organ systems.


MONDO:0001734

[PMID:27226234] [SUPPORT] Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. --- Explanation: Seizures are listed as a major feature of TSC.


MONDO:0001734

[PMID:32222129] [SUPPORT] TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. --- Explanation: Confirms intellectual disability as a significant TAND feature in TSC.


MONDO:0001734

[PMID:27226234] [SUPPORT] TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. --- Explanation: Autism spectrum disorder is identified as part of the TSC-associated neuropsychiatric disorder spectrum.


MONDO:0001734


MONDO:0001734

[PMID:27226234] [SUPPORT] Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders --- Explanation: Kidney tumors including angiomyolipomas are listed as a major feature of TSC.


MONDO:0001734

[PMID:27226234] [INDIRECT EVIDENCE] [SUPPORT] TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. --- Explanation: The Nature Reviews Disease Primers article confirms that the TSC1/TSC2 complex inhibits mTOR signaling and its loss leads to dysregulated cell growth.

[PMID:29478616] [INDIRECT EVIDENCE] [SUPPORT] These proteins form a complex to constitutively inhibit the mammalian target of rapamycin (mTOR) signaling cascade, and as a consequence, mTOR signaling is constitutively active within all TSC-associated lesions. --- Explanation: Confirms that mTOR signaling is constitutively active in all TSC lesions due to loss of TSC1/TSC2 complex function.


MAXO:0000058

[PMID:32222129] [SUPPORT] Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. --- Explanation: Confirms FDA approval of everolimus for three TSC indications.


MAXO:0000058


MAXO:0000004


MAXO:0000079


HGNC.SYMBOL:TSC1

[PMID:29478616] [SUPPORT] There are over 2000 known allelic variants for TSC, including nonsense and misssense mutation, and all pathogenic mutations are inactivating, leading to loss-of-function effects on the encoded proteins, TSC1 and TSC2. --- Explanation: Confirms TSC1 inactivating mutations as causative.


HGNC.SYMBOL:TSC2

[PMID:27226234] [SUPPORT] Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. --- Explanation: Confirms TSC1 and TSC2 as the causative genes.


MONDO:0019805

[PMID:23200164] [SUPPORT] The diagnosis of TTTS requires 2 criteria: (1) the presence of a MCDA pregnancy; and (2) the presence of oligohydramnios (defined as a maximal vertical pocket of <2 cm) in one sac, and of polyhydramnios (a maximal vertical pocket of >8 cm) in the other sac. --- Explanation: SMFM clinical guideline defining the diagnostic criteria for TTTS, with polyhydramnios in the recipient sac as one of the two required criteria.


MONDO:0019805

[PMID:23200164] [SUPPORT] The diagnosis of TTTS requires 2 criteria: (1) the presence of a MCDA pregnancy; and (2) the presence of oligohydramnios (defined as a maximal vertical pocket of <2 cm) in one sac, and of polyhydramnios (a maximal vertical pocket of >8 cm) in the other sac. --- Explanation: SMFM clinical guideline defining oligohydramnios in the donor sac as one of the two required diagnostic criteria for TTTS.


MONDO:0019805

[PMID:31484880] [SUPPORT] the donor develops oligohydramnios and intrauterine growth restriction. --- Explanation: Directly confirms that intrauterine growth restriction is a characteristic feature of the donor twin in TTTS.


MONDO:0019805

[PMID:10645517] [SUPPORT] stage IV, hydrops --- Explanation: Quintero staging system defines hydrops fetalis as the hallmark of Stage IV TTTS.


MONDO:0019805

[PMID:31484880] [SUPPORT] the recipient develops polyhydramnios, weight gain, cardiomegaly and hydrops fetalis in the uterus. --- Explanation: Directly confirms cardiomegaly as a characteristic manifestation of TTTS in the recipient twin.


MONDO:0019805

[PMID:36609186] [SUPPORT] Fetal anemia can occur in the context of twin anemia polycythemia sequence (TAPS), chronic twin-twin transfusion syndrome (TTTS) and acute peripartum TTTS --- Explanation: Directly confirms that fetal anemia occurs in the context of chronic TTTS, supporting its inclusion as a phenotype of the donor twin.


MONDO:0019805

[PMID:33851804] [SUPPORT] pPROM, chorioamniotic separation and iatrogenic preterm birth are among the most common complications of fetoscopic laser ablation, and the mean gestational age at delivery after laser procedure is about 31 weeks. --- Explanation: Confirms that preterm birth is a very common complication, with mean delivery at approximately 31 weeks after laser treatment.


MONDO:0019805

[PMID:21142846] [SUPPORT] characterized by the development of unbalanced chronic blood transfer from one twin, defined as donor twin, to the other, defined as recipient, through placental anastomoses --- Explanation: WAPM consensus document confirming that unbalanced chronic blood transfer through placental anastomoses is the defining pathological feature of TTTS.


MONDO:0019805

[PMID:23200164] [SUPPORT] The natural history of advanced (eg, stage ≥III) TTTS is bleak, with a reported perinatal loss rate of 70-100%, particularly when it presents <26 weeks. --- Explanation: Documents the very high perinatal loss rate in advanced untreated TTTS, with 70-100% mortality in Stage III and above.


MONDO:0019805

[PMID:22713499] [INDIRECT EVIDENCE] [SUPPORT] the presence of unbalanced placental vascular communications within a shared circulation has been implicated in its development --- Explanation: Review confirming that unbalanced placental vascular communications are central to TTTS pathophysiology.

[PMID:24858318] [INDIRECT EVIDENCE] [SUPPORT] TTTS results from progression of a chronic perfusion imbalance across unbalanced placental anastomoses, typically arising between 15 and 26 weeks gestation. --- Explanation: Confirms the chronic perfusion imbalance through unbalanced placental anastomoses as the mechanism of TTTS, with typical onset between 15 and 26 weeks.

[PMID:19255562] [INDIRECT EVIDENCE] [SUPPORT] The aetiology of TTTS relies in the presence of at least 1 arterio-venous placental anastomosis, through which unequal blood exchange from one twin (donor) to the co-twin (recipient) occurs. --- Explanation: Establishes that at least one arteriovenous placental anastomosis is required for TTTS development.


MONDO:0019805


MONDO:0019805

[PMID:31484880] [INDIRECT EVIDENCE] [SUPPORT] The donor has decreased renal blood flow due to decreased circulating blood volume. For this reason, the secretion of RAAS hormones is augmented in the fetal kidneys of the donor. --- Explanation: Describes the mechanism of RAAS activation in the donor due to decreased renal blood flow from hypovolemia.

[PMID:31484880] [INDIRECT EVIDENCE] [SUPPORT] In TTTS, these RAAS hormones from the donor transfer to the recipient through the anastomosed vessels. In addition to excess preload, the recipient heart is exposed to excess afterload due to systemic vasoconstriction through RAAS hormones. --- Explanation: Confirms the transfer of RAAS hormones from donor to recipient and the resulting cardiac afterload through systemic vasoconstriction.


MONDO:0019805

[PMID:31484880] [INDIRECT EVIDENCE] [SUPPORT] Commonly occurring complications in the recipient include myocardial hypertrophy, atrioventricular valve regurgitation, and pulmonary valve stenosis or pulmonary atresia. --- Explanation: Specifies the cardiac complications occurring in the recipient twin, including myocardial hypertrophy and valve abnormalities.

[PMID:27087122] [INDIRECT EVIDENCE] [SUPPORT] It focuses on the underlying cardiovascular pathophysiology of TTTS and the cardiovascular impact of TTTS for both the recipient and the donor twin. --- Explanation: Review dedicated to cardiovascular pathophysiology of TTTS, confirming the central role of cardiac dysfunction in disease progression.


MAXO:0001540

[PMID:15238624] [SUPPORT] As compared with the amnioreduction group, the laser group had a higher likelihood of the survival of at least one twin to 28 days of age (76 percent vs. 56 percent; relative risk of the death of both fetuses, 0.63; 95 percent confidence interval, 0.25 to 0.93; P=0.009) --- Explanation: The landmark Eurofetus randomized controlled trial demonstrating superiority of laser surgery over amnioreduction, with significantly higher survival rates.

[PMID:15238624] [SUPPORT] Infants in the laser group also had a lower incidence of cystic periventricular leukomalacia (6 percent vs. 14 percent, P=0.02) and were more likely to be free of neurologic complications at six months of age (52 percent vs. 31 percent, P=0.003). --- Explanation: The Eurofetus trial also demonstrated significantly better neurological outcomes with laser treatment compared to amnioreduction.

[PMID:30850326] [SUPPORT] High volume centers report up to 70% double survival and at least one survivor in >90%. --- Explanation: Documents the excellent outcomes achievable at high-volume fetal therapy centers.

[PMID:29436080] [SUPPORT] FLP has been established as the primary treatment for monochorionic twin pregnancy associated with TTTS at 16-26 weeks. --- Explanation: Confirms that fetoscopic laser photocoagulation is established as the primary treatment for TTTS between 16 and 26 weeks gestation.

[PMID:25677883] [SUPPORT] This systematic review of observational, comparative cohort and RCT data suggests a trend towards a reduction in TAPS and recurrent TTTS and an increase in twin survival, with no increase in the occurrence of complications or adverse events, when using the Solomon compared to the selective technique for the treatment of TTTS. --- Explanation: Systematic review supporting the Solomon technique over selective laser ablation for reducing recurrent TTTS and TAPS.


MAXO:0001425

[PMID:15238624] [PARTIAL] Endoscopic laser coagulation of anastomoses is a more effective first-line treatment than serial amnioreduction for severe twin-to-twin transfusion syndrome diagnosed before 26 weeks of gestation. --- Explanation: While amnioreduction is a valid treatment option, the Eurofetus trial demonstrated it is inferior to laser therapy for severe TTTS before 26 weeks.

[PMID:19255562] [SUPPORT] Treatment options for TTTS include serial amnioreduction, septostomy, selective feticide of the apparently sick twin, and selective photocoagulation of placental vessels (SLPCV). --- Explanation: Confirms amnioreduction as one of the established treatment options for TTTS.


MAXO:0000950

[PMID:29436080] [SUPPORT] However, there is still an 11-14% risk of long-term neurodevelopment impairment. --- Explanation: The significant risk of neurodevelopmental impairment in TTTS survivors underscores the need for ongoing neonatal and developmental follow-up care.


MAXO:0009012

[PMID:36609186] [SUPPORT] Management options include fetoscopic laser surgery, intrauterine blood transfusion, or expectant management, depending on the type of complication and the severity of the disease. --- Explanation: Review on fetal anemia in monochorionic twins confirming intrauterine blood transfusion as an established management option for fetal anemia in TTTS and TAPS.


MONDO:0005148

[PMID:29939616] [SUPPORT] This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia. --- Explanation: This describes how the failure of beta cells to compensate for insulin resistance results in hyperglycemia, the hallmark of type 2 diabetes.

[PMID:30150719] [SUPPORT] Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP). --- Explanation: This confirms that hyperglycemia in diabetes results from elevated hepatic glucose production and impaired glucose homeostasis.


MONDO:0005148

[PMID:9398128] [PARTIAL] Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia. --- Explanation: This establishes that polyuria results from glucose-induced osmotic diuresis in hyperglycemia, which in turn leads to polydipsia as a compensatory response to fluid loss.


MONDO:0005148

[PMID:9398128] [SUPPORT] Polyuria due to a glucose-induced osmotic diuresis is common in patients with hyperglycemia. This diuresis usually abates when the plasma glucose level approaches its renal threshold. --- Explanation: This describes the mechanism of polyuria in diabetes as glucose-induced osmotic diuresis when plasma glucose exceeds the renal threshold.


MONDO:0005148


MONDO:0005148

[PMID:12231074] [SUPPORT] Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin. --- Explanation: This establishes insulin resistance as a hallmark feature of T2D pathophysiology.


MONDO:0005148

[PMID:29939616] [SUPPORT] Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia. --- Explanation: This establishes hyperinsulinemia as a compensatory response to insulin resistance in T2D.


MONDO:0005148

[PMID:12231074] [INDIRECT EVIDENCE] [SUPPORT] Insulin resistance is caused by the decreased ability of peripheral target tissues (especially muscle) to respond properly to normal circulating concentrations of insulin. --- Explanation: This establishes that skeletal muscle is a key site of insulin resistance in type 2 diabetes, with impaired response to normal insulin levels.

[PMID:12231074] [INDIRECT EVIDENCE] [SUPPORT] These alterations in glucose transport activity are likely the result of dysregulation of intramyocellular fatty acid metabolism, whereby fatty acids cause insulin resistance by activation of a serine kinase cascade, leading to decreased insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and decreased IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. --- Explanation: This describes the molecular mechanism of insulin resistance involving fatty acid-induced serine kinase activation that impairs insulin receptor signaling through IRS-1 and PI3K.

[PMID:29939616] [INDIRECT EVIDENCE] [SUPPORT] Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia. --- Explanation: This confirms that insulin resistance leads to compensatory hyperinsulinemia as beta cells attempt to overcome impaired glucose disposal in peripheral tissues.


MONDO:0005148

[PMID:37035220] [INDIRECT EVIDENCE] [SUPPORT] Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). --- Explanation: This establishes beta cell dysfunction as a core pathological mechanism in type 2 diabetes development alongside insulin resistance.

[PMID:37035220] [INDIRECT EVIDENCE] [SUPPORT] Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. --- Explanation: This demonstrates that inflammatory markers are associated with beta cell failure, indicating inflammation contributes to beta cell dysfunction.

[PMID:37035220] [INDIRECT EVIDENCE] [SUPPORT] Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. --- Explanation: This confirms that oxidative stress, characterized by increased ROS and depleted antioxidants, contributes to pancreatic beta cell damage in type 2 diabetes.

[PMID:29939616] [INDIRECT EVIDENCE] [SUPPORT] This vicious cycle continues until pancreatic beta-cell activity can no longer adequately meet the insulin demand created by insulin resistance, resulting in hyperglycemia. --- Explanation: This describes the progression from compensatory beta cell hyperfunction to beta cell exhaustion and failure, leading to hyperglycemia.


MONDO:0005148

[PMID:30150719] [INDIRECT EVIDENCE] [SUPPORT] Diabetes is characterized by impaired glucose homeostasis partly due to abnormally elevated hepatic glucose production (HGP). --- Explanation: This establishes that elevated hepatic glucose production is a key feature of diabetes pathophysiology.

[PMID:30150719] [INDIRECT EVIDENCE] [SUPPORT] Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). --- Explanation: This confirms that hepatic glucose overproduction is central to diabetes hyperglycemia, as metformin's primary mechanism targets HGP suppression.

[PMID:30150719] [INDIRECT EVIDENCE] [SUPPORT] FBP1 catalyzes the irreversible hydrolysis of fructose-1,6-bisphosphate (F-1,6-P2) to fructose-6-phosphate (F6P) and inorganic phosphate (Pi) in the presence of divalent cations. FBP1 is a key rate-controlling enzyme in the gluconeogenic pathway. --- Explanation: This identifies fructose-1,6-bisphosphatase (FBP1) as a key rate-controlling enzyme in hepatic gluconeogenesis, the pathway responsible for glucose overproduction in diabetes.


MONDO:0005148

[PMID:38338783] [INDIRECT EVIDENCE] [SUPPORT] New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. --- Explanation: This establishes that mitochondrial dysfunction and oxidative damage occur early and may drive T2D progression regardless of whether insulin resistance or beta cell dysfunction is the primary event.

[PMID:38338783] [INDIRECT EVIDENCE] [SUPPORT] Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. --- Explanation: This describes the novel mechanism of extracellular vesicle-mediated oxidative stress propagation between tissues in T2D pathogenesis.

[PMID:37035220] [INDIRECT EVIDENCE] [SUPPORT] Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. --- Explanation: This confirms that oxidative stress characterized by increased ROS and depleted antioxidants contributes to beta cell damage.


MONDO:0005148

[PMID:38831203] [INDIRECT EVIDENCE] [PARTIAL] Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. --- Explanation: This establishes the importance of the GLP-1/GIP incretin axis in T2D pathophysiology and its targeting by dual agonist therapies.

[PMID:38831203] [INDIRECT EVIDENCE] [PARTIAL] Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. --- Explanation: This demonstrates the clinical relevance of incretin axis dysfunction by showing dual GLP-1/GIP agonism is effective for T2D treatment.


MAXO:0000058


CHEBI:6801


MAXO:0000088


MAXO:0000058

[PMID:38831203] [PARTIAL] Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. --- Explanation: This establishes GLP-1/GIP receptor agonists as effective pharmacological strategies for T2D treatment.


MAXO:0000058

[PMID:38831203] [SUPPORT] Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. --- Explanation: This confirms tirzepatide as an authorized dual GLP-1/GIP agonist for T2D and obesity treatment.


HGNC.SYMBOL:TCF7L2


HGNC.SYMBOL:PPARG


HGNC.SYMBOL:KCNJ11


HGNC.SYMBOL:SLC30A8


MONDO:0005147

[PMID:38272591] [PARTIAL] Type 1 diabetes is associated with both acute and chronic complications. Acute complications include diabetic ketoacidosis and severe hypoglycemia. Chronic complications can be microvascular or macrovascular. Microvascular complications include retinopathy, nephropathy, and neuropathy. --- Explanation: This source supports the statement by associating Type I Diabetes with hyperglycemia and chronic complications such as retinopathy and neuropathy, as well as acute complications like diabetic ketoacidosis.

[PMID:28544185] [PARTIAL] Participation in prospective follow-up studies reduces the frequency of DKA in children at diagnosis of T1D, but genetic screening alone does not decrease DKA risk. --- Explanation: This source supports the statement by confirming that Diabetic Ketoacidosis (DKA) is a frequent acute complication in Type 1 Diabetes at the time of diagnosis.

[PMID:34362315] [SUPPORT] Although SH was usually benign and long-term treatment was superfluous, it might be the first sign of insulinopenic status such as type 1 DM (T1DM) --- Explanation: This source supports the statement by describing stress hyperglycemia as a potential initial presentation of Type 1 Diabetes, thereby confirming hyperglycemia as a very frequent occurrence.


MONDO:0005147

[PMID:23075321] [PARTIAL] Immune-mediated (auto-immune) Type 1 diabetes mellitus is not a homogenous entity, but nonetheless has distinctive characteristics. In children, it may present with classical insulin deficiency and ketoacidosis at disease onset, whereas autoimmune diabetes in adults may not always be insulin dependent. --- Explanation: The source does indicate that Type 1 diabetes has varied presentations, including insulin deficiency and potentially weight loss due to failure to utilize glucose. However, the excerpt does not specifically mention weight loss as a frequent phenotype.

[PMID:37065759] [PARTIAL] The risk factors of weight gain included using exogenous insulin, intensifying insulin therapy, fear of hypoglycemia and related decrease in physical activity, and psychological factors, such as emotional eating and binge eating --- Explanation: This reference addresses weight gain in relation to Type 1 Diabetes but does not state that weight loss is a frequent phenotype.


MONDO:0005147

[PMID:35254878] [SUPPORT] Symptoms include polyuria, polydipsia, and weight loss. --- Explanation: This reference confirms that polyuria is a frequent symptom of Type I Diabetes.

[PMID:2923250] [SUPPORT] Poorly controlled insulin-dependent diabetes mellitus is associated with considerable elevations of plasma vasopressin concentrations, although well-controlled diabetics have normal osmoregulated thirst and vasopressin release. --- Explanation: This reference discusses the association of poorly controlled insulin-dependent diabetes mellitus (Type I Diabetes) with symptoms such as polyuria.


MONDO:0005147

[PMID:35254878] [SUPPORT] Symptoms include polyuria, polydipsia, and weight loss. --- Explanation: The reference clearly states that polydipsia is a symptom of Type 1 Diabetes Mellitus, supporting the statement that it is a frequent systemic occurrence.


MONDO:0005147

[PMID:12474677] [PARTIAL] Diabetic ketoacidosis is an emergency medical condition that can be life-threatening if not treated properly. Diabetic ketoacidosis occurs most often in patients with type 1 diabetes (formerly called insulin-dependent diabetes mellitus); however, its occurrence in patients with type 2 diabetes (formerly called noninsulin-dependent diabetes mellitus) is not as rare as was once thought. --- Explanation: The literature supports that diabetic ketoacidosis is a life-threatening complication of type 1 diabetes and mentions symptoms such as abdominal pain and vomiting. However, it does not specify the frequency as 'occasional'.

[PMID:17627511] [PARTIAL] A small group of patients affected by type 1 diabetes mellitus is characterized by a severe instability of glycemic values with frequent and unpredictable hypoglycemic and/or ketoacidosis episodes which cannot be explained by errors of patients or diabetologists. --- Explanation: This reference supports the occurrence of diabetic ketoacidosis in type 1 diabetes and mentions its life-threatening nature but does not confirm the frequency as 'occasional'.

[PMID:15137354] [PARTIAL] The article points out the signs and symptoms to be aware of when the person is in the acute state of diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic coma (or state), and severe hypoglycemia. --- Explanation: The reference confirms that diabetic ketoacidosis is a life-threatening complication of type 1 diabetes and includes symptoms like confusion and rapid breathing but does not specify the frequency as 'occasional'.

[PMID:35466445] [PARTIAL] Diabetic ketoacidosis as a unique initial presentation of cystic fibrosis. --- Explanation: This reference indicates that diabetic ketoacidosis can be a presentation in type 1 diabetes but does not address the frequency or the specific symptoms listed.


MONDO:0005147


MONDO:0005147

[PMID:38409439] [INDIRECT EVIDENCE] [SUPPORT] IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes. --- Explanation: This study identifies interferons as key drivers of beta cell inflammatory responses, upregulating antigen presentation and chemokine production.


MONDO:0005147

[PMID:12185667] [INDIRECT EVIDENCE] [PARTIAL] Type 1 diabetes mellitus is a T-cell-mediated autoimmune disease that results in the destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. --- Explanation: While T-cell mediated cytotoxicity is mentioned, there is no reference to autoantibody production.

[PMID:23774118] [INDIRECT EVIDENCE] [PARTIAL] Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. --- Explanation: Supports T cell-mediated cytotoxicity but does not discuss autoantibody production.

[PMID:27659143] [INDIRECT EVIDENCE] [PARTIAL] The autoimmune destruction of the pancreatic islet beta cells is due to a targeted lymphocyte attack. --- Explanation: Supports T cell-mediated cytotoxicity but does not mention autoantibody production.

[PMID:27017348] [INDIRECT EVIDENCE] [PARTIAL] Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells. --- Explanation: Describes immune-mediated destruction of beta cells but does not specifically mention autoantibody production.

[PMID:16280652] [INDIRECT EVIDENCE] [PARTIAL] Type 1 diabetes results from the destruction of insulin-producing pancreatic beta cells by a beta cell-specific autoimmune process. --- Explanation: Supports T cell-mediated cytotoxicity but does not address autoantibody production.

[PMID:34691077] [INDIRECT EVIDENCE] [PARTIAL] Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells. --- Explanation: Supports T cell-mediated cytotoxicity but lacks information on autoantibody production.

[PMID:33479911] [INDIRECT EVIDENCE] [PARTIAL] Type 1 diabetes is an organ-specific autoimmune disease characterized by immune-mediated beta cell destruction in pancreatic islets. --- Explanation: Describes immune-mediated destruction but not autoantibody production.

[PMID:28625830] [INDIRECT EVIDENCE] [PARTIAL] Type 1 diabetes is an autoimmune disease marked by the destruction of insulin-producing beta cells in the pancreatic islets. --- Explanation: Indicates immune destruction of beta cells but does not mention autoantibody production.


MONDO:0005147

[PMID:38409439] [INDIRECT EVIDENCE] [SUPPORT] IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes. --- Explanation: This study shows interferons drive beta cell stress responses including ER stress pathways that contribute to beta cell dysfunction and death.


MAXO:0000259

[PMID:21584767] [SUPPORT] Insulin therapy is a vital hormone replacement therapy in type 1 diabetes mellitus.

[PMID:36476434] [SUPPORT] The current standard method for type 1 diabetes (T1D) management majorly focuses on controlling blood glucose levels with exogeneous insulin administration.

[PMID:32342453] [SUPPORT] T1DM is caused by absolute lack of insulin secretion, so the current treatment for T1DM patients is exogenous insulin replacement therapy.

[PMID:31426099] [PARTIAL] Although a cure for T1D remains the ultimate goal, technology holds the promise of keeping youth with T1D in targeted control and minimize the burden of this chronic medical condition. --- Explanation: The reference acknowledges insulin therapy but focuses more on technological advancements rather than confirming insulin therapy as the essential treatment.

[PMID:28685788] [PARTIAL] Replacing C-peptide, a hormone normally co-secreted with insulin, has been shown to reduce diabetes-related complications. --- Explanation: This reference discusses auxiliary therapy but does not diminish the essential role of insulin therapy.

[PMID:33970586] [SUPPORT] The mainstay of management is a regimen of multiple daily injections of insulin or continuous subcutaneous insulin delivered via an insulin pump.

[PMID:15306833] [SUPPORT] There is, however, a limit to what can be achieved with existing exogenous insulin therapies due to their imperfect pharmacokinetic and pharmacodynamic profiles

[PMID:6749365] [SUPPORT] The results of epidemiological and clinical studies of diabetes in man and of studies of experimental diabetes in animals provide strong evidence: (1) that insulin-dependent diabetes mellitus is due to absolute or severe deficiency of insulin; (2) that replacement treatment with insulin is potentially capable of normalizing the metabolic abnormalities; and (3) that normalization of the metabolic abnormalities can be expected to prevent or ameliorate the complications of the disease

[PMID:20666700] [PARTIAL] Insulin is the primary medication in the treatment of type 1 diabetes. New therapeutic options and prevention strategies (cellular therapies, immunomodulation and vaccination) aim to preserve residual beta-cell function. --- Explanation: The focus on insulin as primary treatment supports the statement, despite mentioning new therapeutic options.


MAXO:0000088

[PMID:9314011] [PARTIAL] Nutrition therapy and physical activity can assist persons with diabetes to achieve metabolic goals. Several lifestyle strategies can be used. --- Explanation: The text supports the assertion that maintaining a balanced diet and regular physical activity can assist in managing diabetes through lifestyle modifications.

[PMID:16529680] [SUPPORT] The patient and physician must work together to optimize glucose control involving both insulin administration and caloric intake. Exercise has numerous benefits and the type 1 diabetic should take advantage of these benefits. --- Explanation: This supports the statement that lifestyle modifications, including diet and physical activity, are important in managing type 1 diabetes.

[PMID:24485215] [PARTIAL] Poor lifestyle habits (poor diet quality, sedentary behaviours and smoking) are known to be driving factors for increased CMR factors in the general population. --- Explanation: The text underlines the significance of maintaining a good lifestyle, including a balanced diet and physical activity, as part of diabetes management.

[PMID:32312302] [SUPPORT] Innovative, cost-effective interventions along with beneficial lifestyle modifications can improve home-based self-monitoring of blood glucose in T1D patients. --- Explanation: This reference highlights the role of lifestyle modifications in managing type 1 diabetes through controlling blood glucose levels.

[PMID:37820077] [NO_EVIDENCE] Weight loss treatments provide a wide-range of benefits in reducing both morbidity and mortality in those who are obese. --- Explanation: It mentions lifestyle interventions as a part of weight loss treatments that benefit T1D management, highlighting their efficacy and safety.


HGNC.SYMBOL:HLA-DQ2

[PMID:22184118] [SUPPORT] HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). --- Explanation: This study identifies HLA-DQ2 as a strongly predisposing haplotype for type 1 diabetes susceptibility.


HGNC.SYMBOL:HLA-DQ8

[PMID:22184118] [SUPPORT] HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). --- Explanation: This statement specifically mentions HLA-DQ8 as a strong predisposing haplotype for type 1 diabetes, supporting the association with susceptibility.

[PMID:26492519] [SUPPORT] The DR3-DQ2/DR4-DQ8 genotype conferred the highest detected risk for T1D. --- Explanation: This study identifies the DR4-DQ8 genotype as highly associated with a risk for developing type 1 diabetes, thus supporting the genetic susceptibility.

[PMID:34946827] [SUPPORT] The combination of HLA-DQA1*03:01 and DQB1*03:02 alleles (summarized as 'HLA-DQ8') is reported to be among the two most prevalent HLA class II haplotypes in Caucasian type 1 diabetes patients. --- Explanation: This reference confirms that HLA-DQ8 is one of the most prevalent haplotypes among type 1 diabetes patients in the studied population, supporting its association with susceptibility.


HGNC.SYMBOL:INS

[PMID:15529622] [SUPPORT] Our results indicate an exceptionally strong association of the class I INS-VNTR alleles with T1DM for the Romanian population. --- Explanation: The study presents evidence of a strong association between INS-VNTR alleles of the insulin gene and susceptibility to type 1 diabetes in the Romanian population.

[PMID:8934932] [SUPPORT] Genetic susceptibility predominantly results from specific alleles in the HLA complex and insulin gene region. --- Explanation: This paper states that genetic susceptibility to insulin-dependent diabetes mellitus predominantly results from specific alleles, including those in the insulin gene region.

[PMID:11845220] [PARTIAL] However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. --- Explanation: This study discusses the identification of susceptibility genes for type 1 diabetes, including the insulin gene.

[PMID:11921414] [SUPPORT] Because insulin has such a central role in the pathogenesis of both forms of diabetes, the insulin gene (INS) has always been considered a candidate susceptibility gene. --- Explanation: The paper directly states that the insulin gene is considered a candidate susceptibility gene.

[PMID:11347740] [SUPPORT] The disease-associated INS genotype (Hph I) was identified in 87.5% of the concordant twins but only in 59.5% (P = 0.005) of the discordant twins. --- Explanation: The study demonstrates the presence of a disease-associated INS genotype in a high percentage of concordant twins for type 1 diabetes.

[PMID:33483996] [SUPPORT] Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus. --- Explanation: This article attributes a significant portion of the genetic risk for type 1 diabetes to the insulin (INS) gene locus.


HGNC.SYMBOL:PTPN22

[PMID:15734872] [SUPPORT] The homozygous genotype for the T allele encoding the 620W residue is associated with an increased risk for developing type 1 diabetes --- Explanation: This study demonstrates that the PTPN22 R620W polymorphism confers significant genetic susceptibility to type 1 diabetes in Caucasian populations.


HGNC.SYMBOL:IL2RA

[PMID:22461703] [SUPPORT] CD4(+)CD25(+) regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1 diabetes, are deficient in their ability to control autologous proinflammatory responses --- Explanation: This study demonstrates that IL2RA variants associated with type 1 diabetes lead to diminished IL-2 responsiveness and impaired regulatory T cell function.


HGNC.SYMBOL:CTLA4

[PMID:9353155] [SUPPORT] the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers --- Explanation: This study demonstrates that CTLA4 gene polymorphisms confer susceptibility to type 1 diabetes independent of other genetic and immune markers.


HGNC.SYMBOL:TYK2


HGNC.SYMBOL:IFIH1


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:IRF4


HGNC.SYMBOL:IKZF1


ECTO:3000001

[PMID:23393684] [SUPPORT] One of the environmental risk factors identified by a series of independent studies is represented by viral infection, with strong evidence showing that viruses can indeed infect pancreatic beta cells with consequent effects ranging from functional damage to cell death. --- Explanation: This reference mentions that viral infections are a strong environmental risk factor for Type I Diabetes, affecting pancreatic beta cells which can lead to autoimmunity.

[PMID:22891485] [PARTIAL] Environmental factors must be involved such as viral infections, toxins from food, cow milk during childhood (instead of breast feeding) or vitamin D deficiency. --- Explanation: This reference suggests that viral infections are among several environmental factors associated with Type I Diabetes, but does not pinpoint them as the singularly most critical factor.

[PMID:34942009] [SUPPORT] Enteroviruses, especially CoxB and Echo, are most represented. --- Explanation: This reference supports the role of viral infections in Type I Diabetes, mentioning enteroviruses among others.

[PMID:18357774] [PARTIAL] The most often cited environmental agents implicated as initiators of T1D are the human enteroviruses, in particular the group B coxsackieviruses (CVB). --- Explanation: This reference supports the role of enteroviruses as environmental triggers for Type I Diabetes but notes that evidence is not firmly established.

[PMID:24003924] [PARTIAL] Enteroviruses are proposed candidate triggers due to temporal correlations between infection and T1D autoimmunity and to detection of viral proteins in diseased islets. --- Explanation: The reference suggests enteroviruses as potential triggers for Type I Diabetes but emphasizes the need for more robust evidence for a causative relationship.

[PMID:11334504] [SUPPORT] Congenital rubella is the only infection clearly associated with the development of type 1A diabetes. --- Explanation: This reference specifically mentions congenital rubella as an infection clearly associated with Type I Diabetes, supporting the statement.

[PMID:31401790] [PARTIAL] The natural history of human type 1 diabetes (T1D) and the documented associations between virus infections (in particular the enteroviruses) and disease development. --- Explanation: This reference discusses associations between viral infections, particularly enteroviruses, and Type I Diabetes development, but indicates a need for further studies.

[PMID:17691946] [SUPPORT] evidence from various animal models suggests that viruses can indeed initiate or accelerate autoimmune diseases, such as type 1 diabetes... --- Explanation: This reference provides evidence from animal models that support the initiation or acceleration of Type I Diabetes by viruses.

[PMID:36950864] [SUPPORT] Convincing evidence indicates that viruses are associated with T1D development and progression. --- Explanation: This reference provides convincing evidence that viral infections, including SARS-CoV-2, may trigger or unmask Type I Diabetes.


MONDO:0010161

[PMID:28771246] [SUPPORT] Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems --- Explanation: Directly supports hepatic failure as a primary manifestation.

[PMID:38505790] [SUPPORT] Patients failing medical treatment (eg, due to non-adherence), and who develop acute liver failure (ALF), have HCC or evidence of histologically proven dysplastic liver nodule(s) --- Explanation: Confirms acute liver failure as an indication for liver transplantation in HT-1.


MONDO:0010161

[PMID:38132825] [SUPPORT] Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). --- Explanation: Directly lists liver fibrosis as a significant risk in untreated HT-1.


MONDO:0010161

[PMID:38132825] [SUPPORT] A nine-year-old boy presented with HCC in a cirrhotic liver. --- Explanation: Documents cirrhosis in a missed NBS case of HT-1.

[PMID:39050308] [SUPPORT] A liver biopsy confirmed mixed nodular cirrhosis, and a subsequent whole exome sequencing revealed autosomal recessive inheritance of tyrosinemia type 1. --- Explanation: Confirms cirrhosis in a late-presenting HT-1 patient.


MONDO:0010161

[PMID:38505790] [SUPPORT] NTBC combined with dietary therapy, if initiated early, can provide liver transplant (LT) free survival and reduce the risk of hepatocellular carcinoma (HCC). --- Explanation: Confirms HCC as a recognized risk requiring monitoring.


MONDO:0010161

[PMID:38505790] [SUPPORT] This leads to the accumulation of toxic metabolites such as fumaryl and maleylacetoacetate, which can damage the liver, kidneys, and nervous system. --- Explanation: Confirms kidney damage from toxic metabolite accumulation.

[PMID:28771246] [SUPPORT] Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems --- Explanation: Renal involvement is a defining feature of hepatorenal tyrosinemia.


MONDO:0010161


MONDO:0010161

[PMID:28771246] [SUPPORT] Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems --- Explanation: Neurologic system involvement includes neuropathic crises.


MONDO:0010161

[PMID:38505790] [SUPPORT] They are also at risk of long-term neurocognitive impairment, which highlights the need for neurocognitive assessment and therapy. --- Explanation: Directly states neurocognitive impairment as a long-term risk in HT-1.


MONDO:0010161

[PMID:39050308] [SUPPORT] We present a case of HT-1 in a three-year-old female child characterized by abdominal distension, facial edema, lower limb edema, and an enlarged liver with parenchymal disease. --- Explanation: Case demonstrates growth and nutritional compromise in untreated HT-1.


MONDO:0010161

[PMID:39050308] [SUPPORT] We present a case of HT-1 in a three-year-old female child characterized by abdominal distension, facial edema, lower limb edema, and an enlarged liver with parenchymal disease. --- Explanation: Documents hepatomegaly in a late-presenting HT-1 patient.


MONDO:0010161

[PMID:28771246] [SUPPORT] Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure --- Explanation: Coagulopathy is a direct consequence of hepatic failure in HT-1.


MONDO:0010161

[PMID:39050308] [SUPPORT] We present a case of HT-1 in a three-year-old female child characterized by abdominal distension, facial edema, lower limb edema, and an enlarged liver with parenchymal disease. --- Explanation: Directly documents edema in an HT-1 patient with liver disease.


MONDO:0010161

[PMID:38505790] [INDIRECT EVIDENCE] [SUPPORT] Hepatorenal tyrosinemia type 1 (HT-1) is a rare autosomal recessive disease that results from a deficiency of fumaryl acetoacetate hydrolase (FAH), a critical enzyme in the catabolic pathway for tyrosine. --- Explanation: Directly supports FAH deficiency as the initiating molecular defect.


MONDO:0010161

[PMID:38505790] [INDIRECT EVIDENCE] [SUPPORT] This leads to the accumulation of toxic metabolites such as fumaryl and maleylacetoacetate, which can damage the liver, kidneys, and nervous system. --- Explanation: Directly supports toxic-metabolite accumulation downstream of FAH deficiency.


MONDO:0010161

[PMID:9689118] [INDIRECT EVIDENCE] [SUPPORT] Cytochrome c was released from mitochondria prior to liver failure in the Fah-/- Hpd-/- double-mutant mice after the administration of HGA. In a cell-free system, the addition of fumarylacetoacetate induced the release of cytochrome c from the mitochondria. --- Explanation: Demonstrates that FAA directly induces mitochondrial cytochrome c release in tyrosinemia model.

[PMID:9689118] [INDIRECT EVIDENCE] [SUPPORT] We also found that caspase inhibitors were highly effective in preventing the liver failure induced by HGA in the double-mutant mice. --- Explanation: Proves caspase-mediated apoptosis is the mechanism of hepatocyte injury in tyrosinemia.


MONDO:0010161

[PMID:36980965] [INDIRECT EVIDENCE] [SUPPORT] The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. --- Explanation: Demonstrates persistent HCC-related gene expression under NTBC therapy in mouse model.

[PMID:36980965] [INDIRECT EVIDENCE] [SUPPORT] NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. --- Explanation: Confirms NTBC does not cure the underlying enzymatic deficiency.


MAXO:0000058

[PMID:38505790] [SUPPORT] NTBC or nitisinone has significantly improved the management of HT-1, particularly when initiated before the onset of symptoms. --- Explanation: Supports NTBC as the transformative therapy for HT-1.

[PMID:36980965] [PARTIAL] Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC --- Explanation: Confirms NTBC efficacy but notes residual HCC risk.


MAXO:0000088

[PMID:28771246] [SUPPORT] There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. --- Explanation: Consensus recommendation for combined NTBC and dietary therapy.

[PMID:38505790] [SUPPORT] NTBC combined with dietary therapy, if initiated early, can provide liver transplant (LT) free survival and reduce the risk of hepatocellular carcinoma (HCC). --- Explanation: Confirms dietary therapy as part of the standard treatment combination.


MAXO:0010039

[PMID:38505790] [SUPPORT] Patients failing medical treatment (eg, due to non-adherence), and who develop acute liver failure (ALF), have HCC or evidence of histologically proven dysplastic liver nodule(s), or experience poor quality of life secondary to severe dietary restrictions are currently indicated for LT. --- Explanation: Lists specific indications for liver transplantation in HT-1.

[PMID:39050308] [SUPPORT] The patient is currently undergoing treatment with capsule nitisinone 5 mg, which inhibits the second step of tyrosine degradation to prevent tyrosinemia, along with a restricted protein diet, while awaiting liver transplantation. --- Explanation: Confirms liver transplantation as a treatment option for severe cases.


MAXO:0000124

[PMID:28771246] [SUPPORT] Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. --- Explanation: Strong consensus supporting SA-based NBS for HT-1.

[PMID:39728402] [SUPPORT] Overall positive predictive values were 27.3% for SUAC, 1.2% for Tyr solely, and 90.1% for Tyr + SUAC. --- Explanation: Provides worldwide performance data for NBS strategies.

[PMID:38132825] [PARTIAL] While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen. --- Explanation: Highlights that NBS can have rare false negatives requiring protocol optimization.


MAXO:0000950

[PMID:38505790] [SUPPORT] Children with HT-1 require frequent monitoring of liver and renal function to assess disease progression and treatment compliance. --- Explanation: Supports ongoing monitoring and supportive care in HT-1 management.


MAXO:0000079

[PMID:28771246] [SUPPORT] Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition --- Explanation: Autosomal recessive inheritance pattern supports the role of genetic counseling.


MAXO:0000950

[PMID:38505790] [SUPPORT] They are also at risk of long-term neurocognitive impairment, which highlights the need for neurocognitive assessment and therapy. --- Explanation: Directly recommends neurocognitive assessment and therapy for HT-1 patients.


HGNC.SYMBOL:FAH deficiency

[PMID:38505790] [SUPPORT] Hepatorenal tyrosinemia type 1 (HT-1) is a rare autosomal recessive disease that results from a deficiency of fumaryl acetoacetate hydrolase (FAH), a critical enzyme in the catabolic pathway for tyrosine. --- Explanation: Directly describes FAH deficiency as the genetic cause of HT-1.


MONDO:0005101

[PMID:38724705] [PARTIAL] Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. --- Explanation: Epithelial apoptosis and increased cell turnover in inflammatory colitis leads to mucosal ulceration and bleeding, which manifests as bloody diarrhea.


MONDO:0005101

[PMID:31272578] [SUPPORT] Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus. --- Explanation: Mayo Clinic Proceedings review confirms abdominal pain as a typical presenting symptom in UC.


MONDO:0005101

[PMID:30837080] [SUPPORT] The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation. --- Explanation: Rectal urgency is described as a classic presenting symptom of ulcerative colitis.


MONDO:0005101

[PMID:30837080] [SUPPORT] The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation. --- Explanation: Tenesmus is described as a classic presenting symptom of ulcerative colitis.


MONDO:0005101

[PMID:25506359] [SUPPORT] 51% of subjects with UC experienced significant weight loss prior to diagnosis (>5% BMI loss). --- Explanation: Weight loss is a significant and common symptom in ulcerative colitis patients, with over half experiencing significant weight loss prior to diagnosis.


MONDO:0005101

[PMID:27310658] [SUPPORT] more severe fatigue was associated with more ulcerative colitis symptoms --- Explanation: Fatigue is a common symptom in ulcerative colitis patients that correlates with disease activity and symptom severity.


MONDO:0005101

[PMID:25646159] [SUPPORT] Anemia is one of the most frequent complications and/or extraintestinal manifestations of inflammatory bowel disease (IBD). Iron deficiency is the most important cause of anemia in Crohn's disease and ulcerative colitis patients. --- Explanation: Anemia, particularly iron deficiency anemia, is one of the most frequent complications of ulcerative colitis due to chronic blood loss from the inflamed colonic mucosa.


MONDO:0005101

[PMID:38314135] [INDIRECT EVIDENCE] [PARTIAL] Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β, IL-18, NLRP3). --- Explanation: Pyroptosis-associated inflammatory cytokines IL-1β and IL-18 are produced in UC mucosa, contributing to the characteristic mucosal inflammation.

[PMID:39438660] [INDIRECT EVIDENCE] [PARTIAL] We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences. --- Explanation: Single-cell analysis of UC gut biopsies reveals disease-specific inflammatory cell states in the colonic mucosa.


MONDO:0005101


MONDO:0005101

[PMID:39438660] [INDIRECT EVIDENCE] [PARTIAL] A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. --- Explanation: Single-cell analysis demonstrates interferon-response signatures localize to T cell aggregates and epithelial damage in UC, revealing a key immune dysregulation mechanism.

[PMID:39438660] [INDIRECT EVIDENCE] [PARTIAL] Longitudinal comparisons demonstrated disease progression in nonremission: myeloid and T cell perturbations in CD and increased multi-cellular IFN signalling in UC. --- Explanation: Increased multi-cellular interferon signaling is associated with disease progression and non-remission in UC, indicating this is a critical pathway in dysregulated immune response.

[PMID:39461795] [INDIRECT EVIDENCE] [PARTIAL] Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response that extends dosing intervals up to 3 months. --- Explanation: IL-23 inhibitors target an upstream pathological mechanism in UC with high efficacy (up to 50% in IBD), supporting the role of aberrant immune signaling in disease pathogenesis.


MONDO:0005101

[PMID:39438660] [INDIRECT EVIDENCE] [PARTIAL] A systems biology-spatial analysis identified granuloma signatures in CD and interferon (IFN)-response signatures localising to T cell aggregates and epithelial damage in CD and UC. --- Explanation: Interferon-response signatures are spatially localized to epithelial damage sites in UC, directly linking immune responses to barrier disruption.

[PMID:38724705] [INDIRECT EVIDENCE] [PARTIAL] Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. --- Explanation: Epithelial cells express interferon-induced signatures associated with apoptosis and increased cell turnover, demonstrating the mechanism of barrier dysfunction in inflammatory colitis.

[PMID:38724705] [INDIRECT EVIDENCE] [PARTIAL] Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis. --- Explanation: Epithelial-immune crosstalk is critical to barrier function, confirming that disruption of this interaction underlies epithelial barrier dysfunction in colitis.

[PMID:39438660] [INDIRECT EVIDENCE] [PARTIAL] Pretreatment differences in epithelial and myeloid compartments were associated with remission outcomes in both diseases. --- Explanation: Epithelial compartment differences predict treatment outcomes, emphasizing the central role of epithelial dysfunction in UC pathogenesis.


MONDO:0005101

[PMID:25307765] [INDIRECT EVIDENCE] [PARTIAL] IBD has a consistent signature across studies and allows high classification accuracy of IBD from non-IBD subjects. --- Explanation: Meta-analysis confirms IBD has consistent microbiota signatures distinguishing patients from healthy controls.


MONDO:0005101

[PMID:23023125] [INDIRECT EVIDENCE] [NO_EVIDENCE] Patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens. --- Explanation: While this study focused on T2D, it demonstrates the general principle that dysbiosis involves loss of butyrate producers - a pattern also seen in IBD.


MONDO:0005101

[PMID:38314135] [INDIRECT EVIDENCE] [SUPPORT] SLC6A14 was increased and correlated with NLRP3 in UC tissues. --- Explanation: SLC6A14 expression is elevated and correlates with NLRP3 in UC tissues, establishing a molecular link between this transporter and inflammasome activation.

[PMID:38314135] [INDIRECT EVIDENCE] [SUPPORT] Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1β, IL-18, NLRP3). --- Explanation: Experimental reduction of SLC6A14 decreases pyroptosis-associated proteins including NLRP3, IL-1β, and IL-18, demonstrating the causal role of this pathway in UC.

[PMID:38314135] [INDIRECT EVIDENCE] [SUPPORT] SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis. --- Explanation: SLC6A14 promotes UC progression through NLRP3-mediated pyroptosis, identifying this as a key pathophysiological mechanism and potential therapeutic target.


MAXO:0000058

[PMID:21407188] [SUPPORT] 5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that doses of ≥ 2.0 g/day have greater efficacy --- Explanation: Systematic review and meta-analysis confirming 5-ASA efficacy in UC remission induction and relapse prevention.


MAXO:0000058

[PMID:31272578] [SUPPORT] Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission. --- Explanation: Review confirms corticosteroids are used to induce remission with goal of achieving corticosteroid-free maintenance.


MAXO:0000058

[PMID:31272578] [SUPPORT] In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors. --- Explanation: Review confirms thiopurines as a treatment class for moderate-severe UC.


MAXO:0000058

[PMID:26902011] [SUPPORT] Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy --- Explanation: Meta-analysis demonstrating significant efficacy of anti-TNF agents in UC clinical response induction.


MAXO:0000058

[PMID:31470005] [SUPPORT] clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively --- Explanation: Phase 3 RCT demonstrating vedolizumab efficacy with 46% clinical remission vs 14% placebo at week 52.


MAXO:0000058

[PMID:31272578] [SUPPORT] In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors. --- Explanation: Review confirms JAK inhibitors as approved treatment for moderate-severe UC.


MAXO:0000058

[PMID:39461795] [SUPPORT] Addressing an upstream pathological mechanism shared between these disorders, this drug class has high efficacy rates and a durable response --- Explanation: IL-23 inhibitors demonstrate high efficacy in UC by targeting upstream pathological mechanisms.


MAXO:0000004

[PMID:31272578] [SUPPORT] in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment. --- Explanation: Review confirms 15% of UC patients require colectomy for refractory disease or dysplasia.


HGNC.SYMBOL:IL23R


HGNC.SYMBOL:HNF4A


HGNC.SYMBOL:CDH1


HGNC.SYMBOL:HLA-DRB1


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:STAT3


HGNC.SYMBOL:IL10


HGNC.SYMBOL:CD28


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF8


HGNC.SYMBOL:SATB1


HGNC.SYMBOL:IKZF1


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:REL


HGNC.SYMBOL:PRDM1


HGNC.SYMBOL:PTPN22


MONDO:0008411

[PMID:9207801] [SUPPORT] Limb abnormalities of ulnar-mammary syndrome involve posterior elements --- Explanation: Confirms that UMS limb defects specifically affect posterior (ulnar) structures.

[PMID:16530712] [SUPPORT] typical UMS traits (hypoplasia of the breast and axillary hair, upper limbs and genital defects) --- Explanation: Lists upper limb defects as a typical feature of UMS.


MONDO:0008411

[PMID:16530712] [SUPPORT] typical UMS traits (hypoplasia of the breast and axillary hair, upper limbs and genital defects) --- Explanation: Breast hypoplasia listed as a typical UMS trait.

[PMID:9207801] [PARTIAL] Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development --- Explanation: Apocrine gland involvement (including breast) is a defining feature.


MONDO:0008411

[PMID:16530712] [PARTIAL] typical UMS traits (hypoplasia of the breast and axillary hair, upper limbs and genital defects) --- Explanation: Absent axillary hair is listed among typical UMS features.


MONDO:0008411

[PMID:10330342] [PARTIAL] Ulnar-mammary syndrome (UMS) is a pleiotropic disorder affecting limb, apocrine-gland, tooth, hair, and genital development --- Explanation: Genital development abnormalities including delayed puberty are part of the UMS phenotypic spectrum.


MONDO:0008411

[PMID:9207801] [INDIRECT EVIDENCE] [PARTIAL] mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome --- Explanation: Identifies TBX3 as the causative gene for UMS.

[PMID:9207801] [INDIRECT EVIDENCE] [SUPPORT] during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb --- Explanation: Establishes the evolutionary complementarity of TBX3 (posterior) and TBX5 (anterior) in limb development.

[PMID:16530712] [INDIRECT EVIDENCE] [SUPPORT] an association between mutations that disrupt the DNA-binding domain and a higher frequency of severe upper limb malformations and teeth defects --- Explanation: Demonstrates genotype-phenotype correlation with T-domain disrupting mutations causing more severe phenotypes.


MONDO:0008411


MONDO:0008411

[PMID:9207801] [INDIRECT EVIDENCE] [PARTIAL] mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome --- Explanation: TBX3 mutations underlie both limb and apocrine gland features of UMS.

[PMID:10330342] [INDIRECT EVIDENCE] [PARTIAL] five mutations downstream of the region encoding the T-box. This suggests that a domain(s) outside the T-box is highly conserved and important for the function of TBX3 --- Explanation: Functional domains outside the T-box contribute to TBX3 function in multiple tissues.


MAXO:0000004


MAXO:0000079


HGNC.SYMBOL:TBX3 Mutations

[PMID:10330342] [SUPPORT] Novel mutations have been found in all of eight newly reported families with UMS, including five mutations downstream of the region encoding the T-box --- Explanation: Demonstrates the range of TBX3 mutations in UMS families, including those outside the T-box.

[PMID:10330342] [SUPPORT] We found no obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts --- Explanation: Indicates that mutation type does not strongly predict phenotypic severity.

[PMID:16530712] [PARTIAL] mutations that do not disrupt the T-domain are associated with less severe limb defects --- Explanation: Partially refines the genotype-phenotype picture, suggesting T-domain mutations cause more severe limb involvement.


MONDO:0004739

[PMID:31110235] [SUPPORT] The urea cycle disorders (UCDs) comprise diseases presenting with hyperammonemia that arise in either the neonatal period (about 50% of cases) or later. --- Explanation: Confirms hyperammonemia as the defining clinical presentation across UCDs.

[PMID:30982989] [SUPPORT] UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death --- Explanation: Supports hyperammonemia as the core feature with variable age of onset.


MONDO:0004739

[PMID:37938118] [SUPPORT] Hyperammonemia, particularly if severe, causes time- and concentration-dependent neurologic injury. --- Explanation: Supports severity-dependent encephalopathy from hyperammonemia.

[PMID:30982989] [SUPPORT] UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death --- Explanation: Supports severe neurologic consequences from hyperammonemic episodes.


MONDO:0004739

[PMID:39121557] [SUPPORT] Seizures are observed in 13% of HA events. Among all HA events with concomitant EEG, subclinical seizures were identified in 27% of crises of encephalopathy without clinical seizures and 53% of crises with clinical seizures. --- Explanation: Quantifies seizure prevalence during UCD crises with EEG monitoring data.


MONDO:0004739

[PMID:31110235] [SUPPORT] The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. --- Explanation: Supports brain injury risk from ammonia exposure; cerebral edema is a key mechanism.


MONDO:0004739

[PMID:30982989] [SUPPORT] UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death --- Explanation: Directly supports intellectual disability as a major outcome of UCDs.


MONDO:0004739

[PMID:37938118] [SUPPORT] Hyperammonemia, particularly if severe, causes time- and concentration-dependent neurologic injury. --- Explanation: Lethargy and altered mental status are dose-dependent neurologic manifestations.


MONDO:0004739


MONDO:0004739

[PMID:31110235] [SUPPORT] excessive ammonia leads to life-threatening conditions --- Explanation: Supports life-threatening neurological deterioration from hyperammonemia.


MONDO:0004739

[PMID:30982989] [SUPPORT] UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death --- Explanation: Supports neurodevelopmental morbidity as a major UCD complication.


MONDO:0004739

[PMID:31110235] [SUPPORT] Nitrogen is essential for growth and life-maintenance, but excessive ammonia leads to life-threatening conditions. --- Explanation: Severe ammonia toxicity can cause basal ganglia injury leading to movement disorders.


MONDO:0004739

[PMID:31110235] [INDIRECT EVIDENCE] [SUPPORT] Congenital defects of the enzymes or transporters of the urea cycle cause the disease. --- Explanation: Directly supports primary upstream molecular defects in urea-cycle enzymes and transporters.


MONDO:0004739

[PMID:31110235] [INDIRECT EVIDENCE] [SUPPORT] The urea cycle is a metabolic pathway for the disposal of excess nitrogen, which arises primarily as ammonia. --- Explanation: Directly supports the urea cycle as the principal ammonia detoxification pathway.


MONDO:0004739

[PMID:31110235] [INDIRECT EVIDENCE] [SUPPORT] The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. --- Explanation: Supports ammonia-mediated brain toxicity as a central downstream mechanism.


MONDO:0004739

[PMID:31110235] [INDIRECT EVIDENCE] [SUPPORT] two of which, carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix --- Explanation: Supports the mitochondrial localization of proximal urea cycle enzymes where carbamoyl phosphate accumulates.


MAXO:0000088


MAXO:0000058

[PMID:31110235] [SUPPORT] We review here the current concepts of the pathogenesis, diagnostics, including genetics and treatment of UCDs. --- Explanation: Supports nitrogen scavenger therapy as part of standard UCD treatment.


MAXO:0000058


MAXO:0000058

[PMID:31110235] [SUPPORT] N-acetylglutamate synthase and at least two transporter proteins are essential to urea cycle function. --- Explanation: NAGS produces the obligate CPS1 activator; carglumic acid replaces this function.


MAXO:0000950

[PMID:31110235] [SUPPORT] The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. --- Explanation: Supports urgent ammonia-lowering treatment during crises.


MAXO:0010039


MAXO:0000124

[PMID:30982989] [SUPPORT] experience on newborn screening for some UCDs has widened --- Explanation: Confirms expanding newborn screening programs for UCD detection.


MAXO:0000079

[PMID:31110235] [SUPPORT] Severity and age of onset depend on residual enzyme or transporter function and are related to the respective gene mutations. --- Explanation: Genotype-phenotype correlations support the importance of genetic counseling.


HGNC.SYMBOL:Ornithine transcarbamylase (OTC) deficiency

[PMID:31110235] [SUPPORT] ornithine transcarbamylase are present in the mitochondrial matrix --- Explanation: Confirms OTC localization and its role in the urea cycle.


HGNC.SYMBOL:Carbamoyl phosphate synthetase I (CPS1) deficiency

[PMID:31110235] [SUPPORT] carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix --- Explanation: Directly identifies CPS1 as a mitochondrial urea cycle enzyme.


HGNC.SYMBOL:Argininosuccinate synthetase (ASS1) deficiency

[PMID:31110235] [SUPPORT] argininosuccinate synthetase, argininosuccinate lyase and arginase 1) are present in the cytoplasm --- Explanation: Directly identifies ASS1 as a cytosolic urea cycle enzyme.


HGNC.SYMBOL:Argininosuccinate lyase (ASL) deficiency

[PMID:31110235] [SUPPORT] argininosuccinate synthetase, argininosuccinate lyase and arginase 1) are present in the cytoplasm --- Explanation: Directly identifies ASL as a cytosolic urea cycle enzyme.


HGNC.SYMBOL:Arginase 1 (ARG1) deficiency

[PMID:31110235] [SUPPORT] arginase 1) are present in the cytoplasm --- Explanation: Identifies ARG1 as a cytosolic urea cycle enzyme.


HGNC.SYMBOL:N-Acetylglutamate synthase (NAGS) deficiency

[PMID:31110235] [SUPPORT] N-acetylglutamate synthase and at least two transporter proteins are essential to urea cycle function. --- Explanation: Directly identifies NAGS as essential for urea cycle function.


MONDO:0005492


MONDO:0005492

[PMID:40845419] [INDIRECT EVIDENCE] [SUPPORT] The central role of mast cells is being reinforced, but multiple cells, pathways, and mediators are involved in a complex interrelationship. --- Explanation: The review emphasizes mast cells as central effectors in urticaria pathogenesis.


MONDO:0006486


MONDO:0006486

[PMID:23877823] [INDIRECT EVIDENCE] [PARTIAL] Recently, major key genes involved in uveal melanoma development, GNAQ, GNA11, BAP1, SF3B1 and EIF1AX, have been identified. --- Explanation: Supports GNAQ and GNA11 as key genes in uveal melanoma development.


NCIT:C94208


MAXO:0000014


MAXO:0000004


MAXO:0000058


NCIT:C2654


NCIT:C68814


HGNC.SYMBOL:GNAQ Q209


HGNC.SYMBOL:GNA11 Q209


HGNC.SYMBOL:BAP1


HGNC.SYMBOL:SF3B1


HGNC.SYMBOL:EIF1AX


MONDO:0006486

[PMID:27268913] [SUPPORT] Malignant melanoma represents a neoplasm stemming from melanocytes --- Explanation: Abstract defines melanoma as a neoplasm stemming from melanocytes.


MONDO:0008723

[PMID:20301763] [SUPPORT] The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. --- Explanation: Directly supports hypoketotic hypoglycemia as a core VLCAD phenotype.

[PMID:37512487] [SUPPORT] Hypoketotic hypoglycemia is a feared clinical complication and the treatment focuses on avoiding hypoglycemia. --- Explanation: Confirms hypoketotic hypoglycemia as a feared complication of VLCAD.


MONDO:0008723

[PMID:20301763] [SUPPORT] The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy --- Explanation: Directly supports cardiomyopathy in severe VLCAD.


MONDO:0008723

[PMID:20301763] [SUPPORT] The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise --- Explanation: Directly supports recurrent rhabdomyolysis in later-onset VLCAD.

[PMID:38015438] [SUPPORT] Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L --- Explanation: Quantifies rhabdomyolysis frequency and severity in adult FAOD cohort.


MONDO:0008723

[PMID:20301763] [SUPPORT] The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly --- Explanation: Directly supports hepatomegaly as a feature of the hepatic VLCAD subtype.


MONDO:0008723

[PMID:38015438] [SUPPORT] The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. --- Explanation: Directly supports exercise intolerance as a principal symptom in adult VLCAD.

[PMID:20301763] [SUPPORT] The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. --- Explanation: Supports exercise intolerance in the myopathic form.


MONDO:0008723

[PMID:38015438] [SUPPORT] The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. --- Explanation: Directly supports myalgia as a principal symptom in adult FAOD including VLCAD.

[PMID:20301763] [SUPPORT] The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. --- Explanation: Supports muscle pain in the myopathic form.


MONDO:0008723

[PMID:38015438] [SUPPORT] The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. --- Explanation: Supports permanent muscle weakness as a complication of the myopathic form.


MONDO:0008723

[PMID:20301763] [SUPPORT] The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias --- Explanation: Directly supports arrhythmias in severe neonatal VLCAD.


MONDO:0008723

[PMID:20301763] [PARTIAL] The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life --- Explanation: Severe early multiorgan metabolic failure is consistent with lethargic crisis presentations.


MONDO:0008723


MONDO:0008723

[PMID:20301763] [PARTIAL] The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. --- Explanation: Multiorgan metabolic failure in severe VLCAD is consistent with lactic acidosis.


MONDO:0008723

[PMID:20301763] [SUPPORT] The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. --- Explanation: Directly supports hypotonia in severe neonatal VLCAD.


MONDO:0008723

[PMID:20301763] [PARTIAL] intermittent hypoglycemia --- Explanation: Severe hypoglycemia in VLCAD can precipitate seizures.


MONDO:0008723

[PMID:38015438] [SUPPORT] Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L --- Explanation: Quantifies elevated CK during rhabdomyolysis in adult FAOD cohort.


MONDO:0008723

[PMID:40149952] [INDIRECT EVIDENCE] [PARTIAL] Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000. --- Explanation: Provides disease-level context for VLCADD as an FAO disorder, but only partially supports the specific catalytic-activity claim.


MONDO:0008723

[PMID:40149952] [INDIRECT EVIDENCE] [SUPPORT] Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are crucial metabolic processes involved in generating ATP, with defects in these pathways causing mitochondrial disease. --- Explanation: Supports the central role of FAO in mitochondrial ATP generation.


MONDO:0008723

[PMID:20301763] [INDIRECT EVIDENCE] [SUPPORT] The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. --- Explanation: Supports high-energy-organ involvement including heart, liver, and systemic metabolic failure.

[PMID:37960342] [INDIRECT EVIDENCE] [SUPPORT] Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. --- Explanation: Demonstrates impaired metabolic flexibility and energy homeostasis in VLCAD deficiency.


MONDO:0008723

[PMID:37367883] [INDIRECT EVIDENCE] [SUPPORT] Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns. --- Explanation: Demonstrates widespread metabolic disruption from accumulated toxic intermediates.


MONDO:0008723

[PMID:40149952] [INDIRECT EVIDENCE] [SUPPORT] there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function. --- Explanation: Supports secondary OXPHOS dysfunction beyond the primary FAO defect.

[PMID:40149952] [INDIRECT EVIDENCE] [SUPPORT] we describe what is now known about the protein-protein interactions between VLCAD and the OXPHOS supercomplex and how their disruption contributes to overall VLCADD pathogenesis. --- Explanation: Directly supports VLCAD-OXPHOS supercomplex interaction disruption.


MONDO:0008723

[PMID:37367883] [INDIRECT EVIDENCE] [SUPPORT] Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns. --- Explanation: Metabolomics data consistent with oxidative stress in VLCADD newborns.


MONDO:0008723

[PMID:39399475] [INDIRECT EVIDENCE] [SUPPORT] The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. --- Explanation: Details specific TLR4 pathway impairment in VLCAD deficiency.


MAXO:0000088

[PMID:20301763] [SUPPORT] Agents/circumstances to avoid: Fasting --- Explanation: Directly supports fasting avoidance in VLCAD management.

[PMID:39203843] [SUPPORT] Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. --- Explanation: Expert nutritional review supports fasting avoidance as a primary intervention.