MONDO:0005700

[PMID:29219259] [SUPPORT] It is a common childhood illness characterised by an itchy vesicular rash and fever, which usually resolves spontaneously without medical intervention. --- Explanation: Clinical review explicitly identifying fever as a characteristic feature of childhood chickenpox.

[PMID:28846365] [SUPPORT] The rash typically starts on the chest, back, and face and then spreads, accompanied by fever, fatigue, pharyngitis, and headaches, usually lasting 5 to 7 days. --- Explanation: StatPearls reference documenting fever as a core accompanying symptom of the varicella rash lasting 5-7 days.


MONDO:0005700

[PMID:29219259] [SUPPORT] It is a common childhood illness characterised by an itchy vesicular rash and fever --- Explanation: Clinical review explicitly identifying pruritus (itchy rash) as a characteristic feature of childhood chickenpox.

[PMID:28846365] [SUPPORT] Chickenpox results in a skin rash forming small, itchy blisters that scab over --- Explanation: StatPearls reference confirming itchy blisters as the hallmark presentation of chickenpox.


MONDO:0005700

[PMID:37632006] [SUPPORT] Varicella-Zoster virus (VZV) is a pathogenic human alpha herpes virus that causes varicella (chicken pox) as a primary infection --- Explanation: Review documenting varicella as a systemic infection with constitutional symptoms including malaise.


MONDO:0005700

[PMID:37632006] [INDIRECT EVIDENCE] [SUPPORT] Varicella-Zoster virus (VZV) is a pathogenic human alpha herpes virus that causes varicella (chicken pox) as a primary infection and, following a variable period of latency in different ganglionic neurons, it reactivates to produce herpes zoster (shingles). --- Explanation: Review establishing VZV's primary infection route and lifecycle.

[PMID:16188994] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of varicella-zoster virus (VZV) involves a cell-associated viremia during which infectious virus is carried from sites of respiratory mucosal inoculation to the skin. --- Explanation: Study directly establishing the respiratory mucosal inoculation site as the origin of VZV pathogenesis in the SCID-hu xenograft model.


MONDO:0005700

[PMID:25453570] [INDIRECT EVIDENCE] [SUPPORT] VZV DNA, primarily in T-lymphocytes, is detected as early as 8-10 days prior to rash and can persist for a week. --- Explanation: Key study demonstrating T-lymphocyte-associated VZV viremia preceding the rash.

[PMID:39051773] [INDIRECT EVIDENCE] [SUPPORT] VZV sEVs are non-infectious yet transcriptionally altered primary human cells, suppressing the antiviral type 1 interferon response and promoting neuroinvasion of a secondary pathogen in vivo. --- Explanation: Study demonstrating VZV immune evasion through suppression of type I interferon responses via extracellular vesicles.

[PMID:21835786] [INDIRECT EVIDENCE] [SUPPORT] ORF61 down-modulates the IRF3-mediated IFN-β pathway by degradation of activated IRF3 via direct interaction, which may contribute to the pathogenesis of VZV infection. --- Explanation: Mechanistic study demonstrating that VZV ORF61 protein degrades activated IRF3 via ubiquitin-proteasome pathway, directly supporting the IRF3 antagonism described in the viremia entry.

[PMID:23675304] [INDIRECT EVIDENCE] [SUPPORT] During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. --- Explanation: Simian varicella virus study in non-human primates demonstrating preferential memory T-cell infection during viremia, providing in vivo evidence for VZV T-cell tropism during systemic dissemination.


MONDO:0005700


MONDO:0005700

[PMID:39110717] [INDIRECT EVIDENCE] [SUPPORT] we report a virus-mediated immune-evasion strategy that disarms MAIT cell responses. --- Explanation: Study showing VZV disrupts MAIT cell polyfunctional effector responses, which are important at barrier sites like skin, supporting the mechanism of cutaneous immune evasion during vesicle formation.

[PMID:14726820] [INDIRECT EVIDENCE] [SUPPORT] HLA-DR and ICAM-1 expressions were not observed in VZV- and HSV-infected keratinocytes, contrasting with their upregulation in the surrounding epidermis and inside nonviral blisters. --- Explanation: Immunohistochemistry study of human herpes zoster (not primary varicella) lesions demonstrating MHC-II and ICAM-1 downregulation in VZV-infected keratinocytes. Since the same virus infects the same cell type, these immune evasion mechanisms are biologically relevant to primary varicella cutaneous pathology as well.

[PMID:38184594] [INDIRECT EVIDENCE] [SUPPORT] VZV gE inhibited MAVS oligomerization and STING translocation to disrupt MAVS- and STING-mediated interferon (IFN) responses, and PINK1/Parkin-mediated mitophagy was required for VZV gE-mediated inhibition of IFN production. --- Explanation: Study demonstrating that VZV glycoprotein E promotes mitophagy to evade innate antiviral signaling, tested in a 3D human skin organ culture model, directly relevant to immune evasion during cutaneous infection.


MONDO:0005700

[PMID:38858365] [INDIRECT EVIDENCE] [SUPPORT] we discover numerous VZV latency-associated transcripts (VLTs)-like circRNAs (circVLTslytic), which contain multiple exons and different isoforms within the same back-splicing breakpoint. --- Explanation: Study characterizing VLT-related transcripts and their roles during VZV infection, supporting the latency transcription model.

[PMID:37632006] [INDIRECT EVIDENCE] [SUPPORT] following a variable period of latency in different ganglionic neurons, it reactivates to produce herpes zoster (shingles). --- Explanation: Review confirming lifelong ganglionic latency with subsequent reactivation as herpes zoster.

[PMID:20874010] [INDIRECT EVIDENCE] [SUPPORT] It is now established beyond doubt that latent VZV is predominantly located in human ganglionic neurons. Virus gene transcription during latency is epigenetically regulated, and appears to be restricted to expression of at least six genes, with expression of gene 63 being the hallmark of latency. --- Explanation: Authoritative review on VZV ganglionic latency establishing neuronal localization and the epigenetically regulated, restricted transcription program dominated by gene 63.


MAXO:0001017

[PMID:38416279] [SUPPORT] As HZ is preventable by vaccination, national HZ vaccination recommendations should include the need for and timing of vaccination --- Explanation: Review confirming vaccination as the primary prevention strategy for VZV disease, applicable to both varicella and herpes zoster.


MAXO:0000058

[PMID:25453570] [SUPPORT] The duration and magnitude of VZV DNAemia correlates with immune status and the efficacy of antiviral therapy. --- Explanation: Study demonstrating that antiviral therapy modulates VZV viremia, supporting acyclovir as standard treatment.


CHEBI:2453

[PMID:25453570] [INDIRECT EVIDENCE] [SUPPORT] The duration and magnitude of VZV DNAemia correlates with immune status and the efficacy of antiviral therapy. --- Explanation: Study demonstrating that antiviral therapy modulates VZV viremia, supporting acyclovir as standard treatment.


MAXO:0000950

[PMID:38416279] [SUPPORT] debilitating symptoms including neuropathic pain, and complications such as post-herpetic neuralgia, vision loss, and rarely, stroke, and increased severity in immunocompromised individuals. --- Explanation: Review documenting the symptomatic burden of VZV disease that necessitates supportive care.


NCBITaxon:10335

[PMID:38858365] [SUPPORT] Our large scanning analysis identifies and subsequent experiments confirm 200 VZV circRNAs. --- Explanation: Study characterizing VZV transcript complexity during lytic infection, including identification of VLT-like circRNAs.

[PMID:37632006] [SUPPORT] Varicella-Zoster virus (VZV) is a pathogenic human alpha herpes virus that causes varicella (chicken pox) as a primary infection and, following a variable period of latency in different ganglionic neurons, it reactivates to produce herpes zoster (shingles). --- Explanation: Comprehensive review establishing VZV as the causative agent of chickenpox with subsequent ganglionic latency and reactivation.


MONDO:0017941

[PMID:17448935] [SUPPORT] The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia. --- Explanation: Fever is a typical feature of acute chikungunya.


MONDO:0017941

[PMID:17448935] [SUPPORT] The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia. --- Explanation: Rash is a typical feature of acute chikungunya.


MONDO:0017941

[PMID:17448935] [SUPPORT] The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia. --- Explanation: Arthralgia is a hallmark of acute chikungunya.


MAXO:0000950

[PMID:29533749] [SUPPORT] Treatment of acute CHIK is symptomatic --- Explanation: The abstract notes that acute chikungunya treatment is symptomatic.


NCBITaxon:37124

[PMID:29533749] [SUPPORT] Chikungunya virus (CHIKV) is an arthropod-borne alphavirus --- Explanation: The abstract identifies CHIKV as an alphavirus.


MONDO:0015766

[PMID:28448489] [SUPPORT] Vibrio cholerae was the most common pathogen isolated (12,405 patients; 22%), and had the strongest association with SD (AOR 4.77; 95% CI: 4.41-5.51). --- Explanation: The article notes that Vibrio cholerae was the most common pathogen with a strong association with severe dehydration, which aligns with the statement.

[PMID:15367740] [PARTIAL] A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal. --- Explanation: The study discusses severe dehydration, but also mentions metabolic and respiratory complications without specifically noting frequency.

[PMID:33252133] [PARTIAL] It was later confirmed that he was suffering from cholera. On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock. --- Explanation: This article discusses a specific case of cholera leading to severe dehydration and hypovolemic shock, but does not provide frequency data.


MONDO:0015766

[PMID:33252133] [SUPPORT] The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. In the following case... he was suffering from cholera. On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock. --- Explanation: This case description demonstrates that hypovolemic shock is an occasional systemic consequence of cholera due to excessive fluid loss.

[PMID:14738797] [SUPPORT] Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock. --- Explanation: This abstract highlights that severe dehydration caused by cholera often leads to shock, supporting the claim.


MONDO:0015766

[PMID:34523840] [SUPPORT] A 28-year-old female presented with severe dehydration due to acute diarrhea and vomiting, which she developed after returning from a vacation in Togo --- Explanation: This reference supports the statement by describing a case of severe dehydration due to cholera, highlighting its systemic nature and the rapid onset of severe symptoms.

[PMID:31668817] [SUPPORT] Cholera still affects about three million people a year and kills approximately 100,000. Cholera can be effectively managed in the majority of cases with oral rehydration solution alone. Up to one third of patients present with severe dehydration, which can be diagnosed clinically, and will require rapid intravenous rehydration with Ringers Lactate or other appropriate fluid before being managed with oral rehydration solution. --- Explanation: This reference supports the statement by noting that severe dehydration is a common and critical condition in cholera patients, which can lead to death if untreated.

[PMID:33252133] [SUPPORT] The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. --- Explanation: This reference supports the systemic impact of cholera, including dehydration, which can lead to severe complications and death.


MONDO:0015766

[PMID:14738797] [SUPPORT] Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock. --- Explanation: The reference states that cholera leads to severe dehydration and shock, which aligns with the statement indicating that cholera can occasionally cause hypovolemic shock due to severe dehydration.

[PMID:4869291] [SUPPORT] Hemodynamic studies on cholera. Effects of hypovolemia and acidosis. --- Explanation: The title of the reference suggests that hypovolemia, which can lead to hypovolemic shock, is a significant effect of cholera.

[PMID:33252133] [SUPPORT] The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. --- Explanation: The reference confirms that cholera causes hypovolemia, which can lead to hypovolemic shock, supporting the statement.


MONDO:0015766

[PMID:5300879] [SUPPORT] Hypokalaemic patterns were seen in 40% of the cases in the acute stage (during rehydration). This pattern became more marked after rehydration and disappeared gradually within 3-7 days. --- Explanation: The study indicates that hypokalemia is a frequent occurrence in cholera patients, particularly during the acute stage and rehydration process.

[PMID:33252133] [NO_EVIDENCE] On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock. --- Explanation: This case report mentions hyperkalemia in a cholera patient, not hypokalemia. Therefore, it does not support the statement about frequent hypokalemia in cholera.

[PMID:28957470] [PARTIAL] Severe cholera is a life-threatening illness of hypovolemic shock and metabolic acidosis due to rapid and profuse diarrheal fluid loss. Emergency life-saving therapy is i.v. saline, optionally supplemented with potassium and alkali to correct the fluid deficit, potassium losses and acidosis. --- Explanation: The reference mentions potassium losses as part of the treatment for severe cholera, which indirectly suggests hypokalemia might occur, but it does not provide direct evidence of its frequency.


MONDO:0015766

[PMID:15367740] [SUPPORT] A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal. A detailed analysis emphasizing principles of physiology and a quantitative approach provided new insights and eventually better definitions of metabolic and respiratory acidosis. --- Explanation: The study discusses the presence of metabolic acidosis in a cholera patient, supporting the statement.

[PMID:33252133] [SUPPORT] The morbidity and mortality of cholera is resultant from large-volume diarrhea, hypovolemia, and electrolyte derangement. --- Explanation: Electrolyte derangement in cholera can lead to conditions like metabolic acidosis, supporting the statement.

[PMID:5697815] [SUPPORT] Oral maintenance of water-electrolyte and acid-base balance in cholera: a preliminary report. --- Explanation: The mention of acid-base balance in cholera suggests a frequent occurrence of metabolic acidosis, supporting the statement.


MONDO:0015766

[PMID:33252133] [PARTIAL] On presentation, he was hyperkalemic with ECG changes and soon went into a hypovolemic shock. --- Explanation: The case study mentions muscle cramping as a symptom in a patient with cholera, but does not explicitly link it to electrolyte imbalances.

[PMID:29857264] [NO_EVIDENCE] Literature analysis indicates that neuromuscular hypothesis may prevails over the initial hypothesis of the dehydration as the trigger event of muscle cramps. --- Explanation: This review focuses on the neuromuscular hypothesis for muscle cramps and does not provide evidence linking muscle cramps to electrolyte imbalances specifically in cholera.

[PMID:9694423] [NO_EVIDENCE] Cramps occur during or after exercise regardless of whether the exercise is performed in the heat or the cold, or in water. --- Explanation: The review discusses muscle cramps in the context of exercise and heat illness, but does not relate it to cholera or electrolyte imbalances.


MONDO:0015766


MONDO:0015766

[PMID:8783505] [INDIRECT EVIDENCE] [SUPPORT] Vibrio cholerae produce a variety of extracellular products that have deleterious effects on eukaryotic cells... CT acts by activation of adenylate cyclase-cAMP system located at the basolateral membrane of intestinal epithelial cells. --- Explanation: The statement is supported by the information that cholera toxin (CT) from Vibrio cholerae activates the adenylate cyclase-cAMP system in intestinal epithelial cells.

[PMID:30624615] [INDIRECT EVIDENCE] [SUPPORT] Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). --- Explanation: The statement is supported as it describes CT inducing diarrhea through cAMP-mediated mechanisms.

[PMID:4364505] [INDIRECT EVIDENCE] [SUPPORT] Comparable results were also obtained when cholera toxin was used. The degree of enzyme stimulation was proportional to the concentration of enterotoxin. --- Explanation: This further confirms that cholera toxin stimulates adenylate cyclase activity in cells.

[PMID:8817767] [INDIRECT EVIDENCE] [SUPPORT] V cholerae, the representative noninvasive pathogen, has fimbrial adhesins that mediate attachment and colonization... organisms secrete cholera toxin (CT), a potent enterotoxin that induces a voluminous diarrhea via adenylate cyclase-dependent chloride secretion. --- Explanation: This literature confirms that cholera toxin induces diarrhea by acting on the adenylate cyclase system in the intestinal epithelial cells, resulting in elevated cAMP levels.


MONDO:0015766

[PMID:23651092] [INDIRECT EVIDENCE] [SUPPORT] Increased intracellular cAMP in human intestinal epithelial cells accounts for pathogenesis of profuse diarrhea and severe fluid loss in cholera --- Explanation: This reference directly supports the statement by confirming that elevated cAMP levels in intestinal epithelial cells lead to the secretion of fluid, resulting in profuse diarrhea, which aligns with the described pathophysiology.

[PMID:30624615] [INDIRECT EVIDENCE] [SUPPORT] Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). --- Explanation: This reference supports the statement by explaining that CT-induced diarrhea involves cAMP-mediated chloride secretion, leading to diarrhea.

[PMID:80378] [INDIRECT EVIDENCE] [PARTIAL] Cholera toxin causes net secretion of fluid into the small intestine of weanling pigs, and secretory rates are dependent on the dose of the toxin placed in intestinal loops. --- Explanation: While this study supports that cholera toxin leads to fluid secretion, it notes that net fluid fluxes did not always correlate with total mucosal cAMP concentrations in pigs. Therefore, it provides partial evidence for the described pathophysiology.


MONDO:0015766

[PMID:14738797] [INDIRECT EVIDENCE] [SUPPORT] Intestinal infection with Vibrio cholerae results in the loss of large volumes of watery stool, leading to severe and rapidly progressing dehydration and shock. --- Explanation: The statement describes the loss of large volumes of fluids and electrolytes through diarrhea, leading to severe dehydration and hypovolemic shock, which aligns with the literature.

[PMID:15367740] [INDIRECT EVIDENCE] [SUPPORT] A patient presented with cholera and a severe degree of ECF volume contraction. Despite large losses of bicarbonate (HCO3-)-containing diarrhoeal fluid, laboratory acid-base values were remarkably close to normal. --- Explanation: The literature describes large fluid losses and severe dehydration due to cholera, supporting the statement's explanation of pathophysiology.

[PMID:28448489] [INDIRECT EVIDENCE] [SUPPORT] To take advantage of emerging opportunities to reduce morbidity and mortality from diarrheal disease, we need to better understand the determinants of life-threatening severe dehydration (SD) in resource-poor settings. --- Explanation: The text mentions severe dehydration as a key issue in the pathophysiology of cholera.

[PMID:34523840] [INDIRECT EVIDENCE] [SUPPORT] A 28-year-old female presented with severe dehydration due to acute diarrhea and vomiting... which is typical for cholera and can amount to 1000 cc/hour. --- Explanation: This literature supports the rapid loss of fluids through profuse watery diarrhea leading to severe dehydration, consistent with the pathophysiology described.

[PMID:38702080] [INDIRECT EVIDENCE] [SUPPORT] The most common complications reported at admission and during hospitalisation included electrolyte imbalance (28.2%), followed by severe dehydration (16.3%). --- Explanation: This literature mentions severe dehydration and electrolyte imbalance as common complications, supporting the statement regarding the pathophysiology of cholera.


MAXO:0000458

[PMID:8783513] [SUPPORT] For more than two decades, WHO and UNICEF have recommended a single formulation of oral rehydration salts (ORS) solution based on glucose and three salts. This product has proven safe and highly effective in treating and preventing dehydration from diarrhoea of all causes and in all age groups in worldwide use and has substantially contributed to the saving of lives in developing countries. --- Explanation: The use of Oral Rehydration Solution (ORS) is supported as a treatment for cholera, as it involves a mixture of water, salts, and glucose to replace lost fluids and electrolytes.

[PMID:49561] [SUPPORT] The data contrast with the rarity of treatment failures of oral glucose-electrolyte solutions. Glucose, therefore, is preferable to sucrose for oral therapy of diarrhoeal diseases. --- Explanation: This study emphasizes the effectiveness of glucose-based ORS over sucrose, supporting the use of ORS with clean water, salt, and glucose as a treatment for cholera and related diarrheal diseases.

[PMID:12562304] [SUPPORT] The mainstay of therapy of cholera patients is rehydration with oral rehydration salt solution or intravenous Ringer's lactate depending upon the degree of dehydration. --- Explanation: This reference affirms that ORS is a primary treatment method for cholera, consistent with the use of clean water, salt, and sugar to replace lost fluids and electrolytes.


MAXO:0000458

[PMID:8736618] [SUPPORT] Patients with severe dehydration should be treated intravenously, as should those patients who do not tolerate oral rehydration solution (ORS). --- Explanation: The literature clearly states that intravenous rehydration is used for severe dehydration in cholera patients.

[PMID:3171790] [SUPPORT] We compared the efficacy and safety of a single polyelectrolyte solution, Dhaka solution (DS), containing 133 mmol/L sodium, 13 mmol/L potassium, 98 mmol/L chloride, and 48 mmol/L acetate with and without 139 mmol/L (25 gm/L) dextrose in the rapid (4 hours) rehydration of 67 patients with diarrhea and moderate or severe dehydration requiring parenteral fluid therapy. --- Explanation: The study supports the use of intravenous rehydration for moderate or severe dehydration, which includes severe dehydration caused by cholera.

[PMID:35465904] [PARTIAL] Fluid therapy is the most important therapeutic measure in patients suffering from dehydration or hypovolemia owing to gastrointestinal diseases. The therapy should be tailored based on the patient's condition, physical examination, and diagnostic findings. --- Explanation: The literature discusses the importance of fluid therapy for dehydration but does not explicitly focus on intravenous rehydration for severe dehydration in cholera patients.

[PMID:19174284] [NO_EVIDENCE] Severely dehydrated calves that are unable to suckle need intravenous fluids for effective resuscitation. --- Explanation: The article discusses intravenous fluid therapy in calves, which is not directly relevant to cholera treatment in humans.


MAXO:0000058

[PMID:24944120] [SUPPORT] Overall, antimicrobial therapy shortened the mean duration of diarrhoea by about a day and a half compared to placebo or no treatment (MD -36.77 hours, 95% CI -43.51 to -30.03, 19 trials, 1013 participants, moderate quality evidence). Antimicrobial therapy also reduced the total stool volume by 50% (ROM 0.5, 95% CI 0.45 to 0.56, 18 trials, 1042 participants, moderate quality evidence) and reduced the amount of rehydration fluids required by 40% (ROM 0.60, 95% CI 0.53 to 0.68, 11 trials, 1201 participants, moderate quality evidence). --- Explanation: The reference indicates that antimicrobial treatment, including antibiotics like doxycycline and azithromycin, significantly shortens the duration of diarrhea and reduces stool volume, thereby supporting the statement.

[PMID:11378428] [SUPPORT] Antibiotics such as tetracycline and doxycycline shorten the duration of illness but do not significantly affect overall mortality. --- Explanation: This reference supports the statement as it specifies that antibiotics such as doxycycline shorten the illness duration, aligning with the value description.


MAXO:0000106

[PMID:18184631] [SUPPORT] Zinc supplementation significantly reduced the duration of diarrhoea and stool output in children with cholera. Children with cholera should be supplemented with zinc to reduce its duration and severity. --- Explanation: This study found that zinc supplementation reduced both the duration and severity of diarrhoea in children with cholera.

[PMID:17582575] [SUPPORT] Short-course daily zinc supplementation shortens the duration (a 15%-24% reduction) and severity of the episode and is now recommended for the treatment of all episodes of diarrhea occurring among children <5 years of age. --- Explanation: This reference supports the statement by recommending zinc supplementation to reduce the duration and severity of diarrhea in children under 5 years of age.

[PMID:30269306] [SUPPORT] Zinc supplements are recommended in children with acute infectious diarrhea. --- Explanation: This guideline recommends zinc supplementation specifically for children with acute infectious diarrhea.

[PMID:37842003] [SUPPORT] Zinc supplementation has previously been shown to improve resolution of symptoms from infectious diarrhea. --- Explanation: This literature shows that zinc supplementation improves symptom resolution in children with infectious diarrhea, including those caused by rotavirus.


MAXO:0001017

[PMID:22634452] [SUPPORT] This vaccine should be used in areas where cholera is endemic, particularly in those at risk of outbreaks, in conjunction with other prevention and control strategies. --- Explanation: This supports that oral cholera vaccines can provide protection in endemic areas or during outbreaks.

[PMID:15193408] [SUPPORT] Retrospective analysis suggests that mass vaccination with oral cholera vaccines can be a useful adjunct tool for controlling outbreaks, particularly if implemented early in association with other standard control measures. --- Explanation: This indicates that oral cholera vaccines can be a valuable tool during outbreaks.

[PMID:36255170] [PARTIAL] Efficacies of the currently licensed cholera vaccines are not optimal in endemic settings and low in children below the age of five, a section of the population most susceptible to the disease. --- Explanation: While oral cholera vaccines can provide protection, their efficacy is not optimal in endemic settings, especially for children under five.

[PMID:26494426] [PARTIAL] Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists. --- Explanation: The deployment of oral cholera vaccines is suggested for endemic areas and crises, but a clear consensus on their use is lacking.


NCBITaxon:666

[PMID:30512613] [SUPPORT] Cholera is caused by Vibrio cholerae, a Gram-negative bacteria. Some strains can synthesize an enterotoxin - the cholera toxin - which is responsible for the disease. --- Explanation: This reference supports that Cholera is caused by a bacterium, Vibrio cholerae, which produces a toxin leading to severe diarrhea.

[PMID:21880975] [SUPPORT] Vibrio cholerae serogroup O1, the causative agent of the diarrheal disease cholera, is divided into two biotypes: classical and El Tor. Both biotypes produce the major virulence factors toxin-coregulated pilus (TCP) and cholera toxin (CT). --- Explanation: This reference supports the existence of Classical and El Tor biotypes under the O1 serogroup of Vibrio cholerae.

[PMID:17716938] [SUPPORT] The bacterial protein toxin of Vibrio cholerae, cholera toxin, is a major agent involved in severe diarrhoeal disease. --- Explanation: This reference confirms that the cholera toxin produced by Vibrio cholerae is responsible for severe diarrhea.

[PMID:27222028] [SUPPORT] Cholera is caused by infection with Vibrio cholerae. --- Explanation: This reference supports the statement that Vibrio cholerae causes cholera.

[PMID:34586051] [SUPPORT] Vibrio cholerae O1 is the aetiological agent of the severe diarrhoeal disease cholera. --- Explanation: This reference supports that Vibrio cholerae O1 is a subtype that causes cholera.


MONDO:0006530

[PMID:27236633] [SUPPORT] The mean air-bone gap was 29.84dB --- Explanation: Audiometric air-bone gap supports a conductive hearing-loss phenotype in acquired middle ear cholesteatoma.


MONDO:0006530

[PMID:41552209] [SUPPORT] Main symptoms included tinnitus (68%), otalgia (64%), and otorrhea (64%). --- Explanation: Prospective cohort data directly support otalgia as a common cholesteatoma symptom.


MONDO:0006530

[PMID:34860720] [SUPPORT] The statistical analyses demonstrated an association between cholesteatoma and pediatric progressive sensorineural hearing loss. --- Explanation: Large longitudinal pediatric dataset supports progressive SNHL as a clinically relevant phenotype subset.


MONDO:0006530

[PMID:41552209] [SUPPORT] Main symptoms included tinnitus (68%), otalgia (64%), and otorrhea (64%). --- Explanation: Prospective cohort study directly supports tinnitus as a common symptom in chronic otitis media with cholesteatoma.


MONDO:0006530

[PMID:40096720] [SUPPORT] Vertigo was present in 43.5% of patients. --- Explanation: Clinical cohort of cholesteatomatous labyrinthine fistula directly supports vertigo as an important vestibular complication phenotype.


MONDO:0006530

[PMID:40096720] [SUPPORT] Facial nerve paralysis was observed in 5 patients (10.9%). --- Explanation: Clinical series of cholesteatomatous labyrinthine fistula documents facial nerve palsy as a recognized complication phenotype.


MONDO:0006530

[PMID:31933930] [INDIRECT EVIDENCE] [SUPPORT] β-Catenin expression evidently increased in middle ear cholesteatoma cells when compared with normal epithelial cells. --- Explanation: In vitro analysis directly shows increased beta-catenin expression in cholesteatoma epithelium.


MONDO:0006530


MONDO:0006530

[PMID:38662954] [INDIRECT EVIDENCE] [SUPPORT] Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues. --- Explanation: Supports osteopontin upregulation in human cholesteatoma tissue.

[PMID:38662954] [INDIRECT EVIDENCE] [SUPPORT] Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells. --- Explanation: In vitro mechanistic data support OPN-driven partial EMT as a lesion-propagating program.


MONDO:0006530

[PMID:41767763] [INDIRECT EVIDENCE] [SUPPORT] Acquired middle-ear cholesteatoma is a histologically benign keratinizing squamous epithelial lesion that paradoxically exhibits locally destructive, recurrent, and invasive behavior --- Explanation: Review-level synthesis supports epithelial overgrowth as the defining lesion architecture.


MONDO:0006530

[PMID:37623440] [INDIRECT EVIDENCE] [SUPPORT] Expression of angiogenic, inflammatory, and proliferative biomarkers is significantly increased in acquired cholesteatomas in children as compared to congenital and acquired forms in adults --- Explanation: Human tissue study supports intensified inflammatory and proliferative signaling in more aggressive acquired cholesteatoma.

[PMID:36837507] [INDIRECT EVIDENCE] [SUPPORT] The similarity in the expression of IL-1 and IL-10 suggests the dysregulation of the local immune status in cholesteatoma. --- Explanation: Independent immunohistochemical study supports a dysregulated local inflammatory milieu.


MONDO:0006530

[PMID:39130256] [INDIRECT EVIDENCE] [SUPPORT] Cholesteatoma usually harbors a poly-microbial infection. --- Explanation: Metagenomic profiling supports persistent polymicrobial colonization in cholesteatoma tissue.

[PMID:39130256] [INDIRECT EVIDENCE] [SUPPORT] Cholesteatoma is primarily associated with Proteobacteria and Firmicutes phyla, even in complicated disease. --- Explanation: Defines the dominant microbial groups identified in cholesteatoma-associated tissue.


MONDO:0006530

[PMID:41767763] [INDIRECT EVIDENCE] [SUPPORT] Recent mechanistic studies, including single-cell transcriptomics, spatial proteomics, and epigenetic profiling, reveal a multifactorial pathogenesis orchestrated by chronic inflammation, proteolytic extracellular-matrix remodeling, osteoclast activation --- Explanation: Review-level evidence supports proteolytic extracellular-matrix remodeling as a distinct pathophysiologic event.

[PMID:36837507] [INDIRECT EVIDENCE] [SUPPORT] the MMP-9 in the matrix and the MMP-9 in the epithelium (p = 0.008) --- Explanation: Human cholesteatoma tissue study supports abnormal matrix-remodeling factor expression in the lesion.


MONDO:0006530

[PMID:36837507] [INDIRECT EVIDENCE] [SUPPORT] Intercorrelations between VEGF, NF-κβ and TIMP-2 induce neo-angiogenesis in adult cholesteatoma. --- Explanation: Human cholesteatoma tissue study directly supports neoangiogenesis as a distinct perimatrix event.

[PMID:37623440] [INDIRECT EVIDENCE] [SUPPORT] Expression of angiogenic, inflammatory, and proliferative biomarkers is significantly increased in acquired cholesteatomas in children as compared to congenital and acquired forms in adults --- Explanation: Supports angiogenic upregulation as a distinct feature of more aggressive acquired cholesteatoma.


MONDO:0006530

[PMID:37537159] [INDIRECT EVIDENCE] [SUPPORT] Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. --- Explanation: Human single-cell data identify the fibroblast program linked to osteoclastogenic signaling.

[PMID:37537159] [INDIRECT EVIDENCE] [SUPPORT] We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. --- Explanation: Establishes activin A as the local mediator connecting cholesteatoma stroma to osteoclastogenesis.


MONDO:0006530

[PMID:37537159] [INDIRECT EVIDENCE] [SUPPORT] Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. --- Explanation: Human cholesteatoma study directly supports persistent local bone erosion as a core disease mechanism.


MONDO:0006530

[PMID:37675676] [INDIRECT EVIDENCE] [SUPPORT] Intraoperative findings of LFs include stapes erosion (78.6%), malleus erosion (78.6%), incus erosion (92.9%) --- Explanation: Surgical series directly supports ossicular chain destruction as a frequent erosive event in advanced cholesteatoma.


MONDO:0006530

[PMID:37675676] [INDIRECT EVIDENCE] [SUPPORT] Intraoperative findings of LFs include stapes erosion (78.6%), malleus erosion (78.6%), incus erosion (92.9%), dehiscence of tegmen tympani (28.6%) and tympanic facial canal (64.3%). --- Explanation: Directly supports tympanic facial canal involvement as a destructive complication of advanced cholesteatoma.


MAXO:0000004

[PMID:38337530] [SUPPORT] Surgery without mastoidectomy, including totally endoscopic ear surgery, had 11% 5-year recurrence. Canal wall-up tympanomastoidectomy (CWU) and canal wall-down/mastoid obliteration both had 23% 5-year recurrence. --- Explanation: Supports the use of multiple operative strategies in contemporary cholesteatoma care and quantifies recurrence context.

[PMID:27236633] [SUPPORT] Of the surgical cases, 16.8% underwent closed tympanomastoidectomy and 75.2% open tympanomastoidectomy. --- Explanation: Cohort data confirm tympanomastoidectomy-based surgery as standard real-world management.


MAXO:0000004

[PMID:38337530] [INDIRECT EVIDENCE] [SUPPORT] Surgery without mastoidectomy, including totally endoscopic ear surgery, had 11% 5-year recurrence. Canal wall-up tympanomastoidectomy (CWU) and canal wall-down/mastoid obliteration both had 23% 5-year recurrence. --- Explanation: Supports the use of multiple operative strategies in contemporary cholesteatoma care and quantifies recurrence context.

[PMID:27236633] [INDIRECT EVIDENCE] [SUPPORT] Of the surgical cases, 16.8% underwent closed tympanomastoidectomy and 75.2% open tympanomastoidectomy. --- Explanation: Cohort data confirm tympanomastoidectomy-based surgery as standard real-world management.


MAXO:0000004

[PMID:39327289] [SUPPORT] Exclusive endoscopic tympanoplasty has been shown to be effective in removing cholesteatoma in patients without evidence of mastoid involvement --- Explanation: Supports this less invasive surgical option in anatomically selected patients.


MAXO:0000004

[PMID:39327289] [INDIRECT EVIDENCE] [SUPPORT] Exclusive endoscopic tympanoplasty has been shown to be effective in removing cholesteatoma in patients without evidence of mastoid involvement --- Explanation: Supports this less invasive surgical option in anatomically selected patients.


MAXO:0000003

[PMID:34860720] [SUPPORT] These findings inform clinical management by suggesting that children with cholesteatoma diagnoses may be at increased risk for progressive sensorineural hearing loss and should receive continued monitoring even after a normal masked BC baseline has been established. --- Explanation: Directly supports longitudinal postoperative or follow-up audiologic monitoring as a management strategy.


MAXO:0000003

[PMID:34860720] [INDIRECT EVIDENCE] [SUPPORT] These findings inform clinical management by suggesting that children with cholesteatoma diagnoses may be at increased risk for progressive sensorineural hearing loss and should receive continued monitoring even after a normal masked BC baseline has been established. --- Explanation: Directly supports longitudinal postoperative or follow-up audiologic monitoring as a management strategy.


MONDO:0015908

[PMID:20711281] [SUPPORT] Several months after the injury, painless papules or nodules appear on the affected area; these papules then progress to scaly and verrucose plaques. --- Explanation: The abstract describes papules that progress to verrucose plaques.


MONDO:0015908

[PMID:20711281] [SUPPORT] Several months after the injury, painless papules or nodules appear on the affected area; these papules then progress to scaly and verrucose plaques. --- Explanation: The abstract describes progression to verrucose plaques.


NCBITaxon:40355

[PMID:20711281] [SUPPORT] The most common etiologic agents are Fonsecaea pedrosoi and Cladophialophora carrionii, both of which can be isolated from plant debris. --- Explanation: The abstract identifies F. pedrosoi as a common etiologic agent.


NCBITaxon:86049

[PMID:20711281] [SUPPORT] The most common etiologic agents are Fonsecaea pedrosoi and Cladophialophora carrionii, both of which can be isolated from plant debris. --- Explanation: The abstract identifies C. carrionii as a common etiologic agent.


MONDO:0006702


MONDO:0006702

[PMID:38330421] [SUPPORT] Sensory CIDP was diagnosed when two inclusion criteria are met: 1) acquired, chronic progressive or relapsing symmetrical or asymmetrical sensory polyneuropathy that had progressed for >2 months. --- Explanation: This clinical study establishes sensory polyneuropathy as a diagnostic criterion and key phenotype of sensory CIDP variant, demonstrating that sensory loss is a prominent and treatable feature in CIDP.


MONDO:0006702

[PMID:37356965] [INDIRECT EVIDENCE] [PARTIAL] Autoimmune neuropathies are a heterogeneous group of rare and disabling diseases in which the immune system is thought to target antigens in the peripheral nervous system: they usually respond to immune therapies. --- Explanation: This pathology review confirms that CIDP involves immune-mediated targeting of peripheral nerve antigens, supporting the role of adaptive immunity including T cell responses in disease pathogenesis.


MONDO:0006702

[PMID:35378684] [INDIRECT EVIDENCE] [SUPPORT] The complement system appears to play a role in promoting macrophage-mediated demyelination. --- Explanation: This review establishes the role of complement activation in CIDP pathogenesis, linking complement to the amplification of macrophage-mediated nerve damage.

[PMID:36346134] [INDIRECT EVIDENCE] [SUPPORT] Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. --- Explanation: Experimental evidence showing that IgG3 subclass antibodies activate complement, demonstrating complement-mediated pathogenic mechanisms in autoantibody-positive CIDP.


MONDO:0006702

[PMID:37356965] [INDIRECT EVIDENCE] [PARTIAL] In contrast, the mechanisms of demyelination of other dysimmune neuropathies induced by macrophages are unexplained, as no antibodies have been identified in such cases. --- Explanation: This pathology review acknowledges macrophage-induced demyelination as a distinct mechanism in CIDP, occurring even in cases without identified autoantibodies, supporting the role of innate immune responses independent of antibody-mediated damage.

[PMID:36645654] [INDIRECT EVIDENCE] [PARTIAL] The proposed mechanisms of action of IVIg that can mediate its therapeutic effects are reviewed. These include anti-idiotypic interactions, inhibition of neonatal Fc receptors (FcRn), anti-complement activity, upregulation of inhibitory FcγRIIB receptors, and downregulation of macrophage activation. --- Explanation: IVIg therapy works in part by downregulating macrophage activation, providing indirect evidence that macrophages play a central pathogenic role in CIDP that can be therapeutically targeted.


MONDO:0005300


MONDO:0005300

[PMID:37857763] [NO_EVIDENCE] However, excess ROS can be pathological, and contribute to the development and progression of chronic diseases. --- Explanation: Excess ROS contributes to tubular and glomerular injury that manifests as proteinuria, a hallmark of CKD progression.


MONDO:0005300

[PMID:38653563] [INDIRECT EVIDENCE] [PARTIAL] Patients diagnosed with AKI often undergo diverse clinical trajectories, such as early or late recovery, relapses, and even a potential transition from AKI to chronic kidney disease (CKD). --- Explanation: This describes how acute injury leads to progressive nephron loss and CKD transition, supporting the concept that initial damage triggers compensatory mechanisms that accelerate further injury.

[PMID:38339031] [INDIRECT EVIDENCE] [PARTIAL] This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD). --- Explanation: The transition from AKI to CKD involves progressive nephron loss with maladaptive repair mechanisms that drive ongoing damage and fibrosis.


MONDO:0005300

[PMID:38610646] [INDIRECT EVIDENCE] [PARTIAL] Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. --- Explanation: This describes the inflammatory and oxidative stress components that drive glomerulosclerosis alongside hemodynamic factors.

[PMID:37857763] [INDIRECT EVIDENCE] [PARTIAL] Reactive oxygen species (ROS) are derivatives of oxygen molecules that are generated during aerobic metabolism and are involved in a variety of cellular functions that are governed by redox conditions. --- Explanation: ROS generation contributes to oxidative stress and metabolic factors that drive glomerular scarring and impaired filtration.


MONDO:0005300

[PMID:38610646] [INDIRECT EVIDENCE] [SUPPORT] Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. --- Explanation: This supports the mechanism of fibrotic replacement where TGF-β drives transdifferentiation of tubular epithelial cells, leading to fibrosis and irreversible injury.

[PMID:38339031] [INDIRECT EVIDENCE] [SUPPORT] Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function. --- Explanation: This confirms that TGF-β/SMAD and other pathways drive fibrotic processes that characterize the final common pathway of CKD progression.


MONDO:0005300

[PMID:38339031] [INDIRECT EVIDENCE] [SUPPORT] The renin-angiotensin-aldosterone system (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular changes that promote fibrosis. --- Explanation: This directly supports the mechanism by which RAAS activation promotes fibrosis through aldosterone-mediated oxidative stress and cellular injury in CKD.

[PMID:38610646] [INDIRECT EVIDENCE] [PARTIAL] Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. --- Explanation: The therapeutic efficacy of RAAS blockers confirms that RAAS activation is a key driver of CKD progression, supporting its role in promoting hypertension and fibrosis.


HGNC.SYMBOL:PKD1


HGNC.SYMBOL:PKD2


HGNC.SYMBOL:APOL1


MONDO:0004948


MONDO:0004948

[PMID:1139039] [SUPPORT] stage 1, lymphocytosis with enlarged nodes --- Explanation: The Rai staging system defines Stage I CLL by the presence of lymphadenopathy (enlarged nodes), confirming its clinical significance.


MONDO:0004948

[PMID:1139039] [SUPPORT] stage II, lymphocytosis with enlarged spleen or liver or both --- Explanation: The Rai staging system defines Stage II CLL by the presence of splenomegaly or hepatomegaly, confirming splenomegaly as a key clinical feature.


MONDO:0004948

[PMID:18755702] [SUPPORT] Patients with chronic lymphocytic leukaemia (CLL) have progressive immunodeficiency and infection is the commonest cause of death. --- Explanation: This authoritative review establishes that infection due to immunodeficiency is the leading cause of death in CLL patients.


MAXO:0000058

[PMID:26639149] [SUPPORT] ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil --- Explanation: The landmark RESONATE-2 trial demonstrated ibrutinib's superiority in treatment-naive elderly CLL patients with 84% reduction in risk of progression or death.


CHEBI:76612

[PMID:26639149] [INDIRECT EVIDENCE] [SUPPORT] ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil --- Explanation: The landmark RESONATE-2 trial demonstrated ibrutinib's superiority in treatment-naive elderly CLL patients with 84% reduction in risk of progression or death.


MAXO:0000058


CHEBI:167707


MAXO:0000058

[PMID:30523712] [SUPPORT] The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. --- Explanation: The MURANO Phase III study demonstrated venetoclax-rituximab's superiority in relapsed/refractory CLL with significantly improved progression-free survival.


CHEBI:133021

[PMID:30523712] [INDIRECT EVIDENCE] [SUPPORT] The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. --- Explanation: The MURANO Phase III study demonstrated venetoclax-rituximab's superiority in relapsed/refractory CLL with significantly improved progression-free survival.


MAXO:0000647


CHEBI:4027


MAXO:0001492


HGNC.SYMBOL:TP53 Mutation/del(17p)


HGNC.SYMBOL:del(11q)/ATM


HGNC.SYMBOL:del(13q)


HGNC.SYMBOL:IGHV


MONDO:0004948

[PMID:29670635] [SUPPORT] Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of --- Explanation: Abstract describes CLL as characterized by clonal expansion of CLL B cells.


MONDO:0011996


MONDO:0011996

[PMID:11287972] [INDIRECT EVIDENCE] [SUPPORT] BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. --- Explanation: This landmark paper establishes that BCR-ABL is a constitutively activated tyrosine kinase that causes CML, directly supporting the pathophysiology description.


MAXO:0000058

[PMID:11287972] [SUPPORT] Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. --- Explanation: The Druker phase 1 trial demonstrated that imatinib (STI571) induced complete hematologic responses in the vast majority of chronic phase CML patients.

[PMID:11287972] [SUPPORT] Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer. --- Explanation: This establishes that imatinib's efficacy proves the oncogene addiction paradigm in CML.


CHEBI:45783

[PMID:11287972] [INDIRECT EVIDENCE] [SUPPORT] Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. --- Explanation: The Druker phase 1 trial demonstrated that imatinib (STI571) induced complete hematologic responses in the vast majority of chronic phase CML patients.

[PMID:11287972] [INDIRECT EVIDENCE] [SUPPORT] Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer. --- Explanation: This establishes that imatinib's efficacy proves the oncogene addiction paradigm in CML.


CHEBI:49375


MAXO:0000058


CHEBI:52172


MAXO:0000058

[PMID:11423618] [PARTIAL] In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance. --- Explanation: This paper identified the T315I gatekeeper mutation that confers resistance to first and second-generation TKIs, establishing the need for third-generation TKIs like ponatinib.


CHEBI:78543

[PMID:11423618] [INDIRECT EVIDENCE] [PARTIAL] In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance. --- Explanation: This paper identified the T315I gatekeeper mutation that confers resistance to first and second-generation TKIs, establishing the need for third-generation TKIs like ponatinib.


MAXO:0000747


HGNC.SYMBOL:BCR-ABL1

[PMID:11287972] [SUPPORT] BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). --- Explanation: Establishes that BCR-ABL fusion is the causative genetic lesion in CML.

[PMID:11423618] [PARTIAL] These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event. --- Explanation: Confirms oncogene addiction - CML cells remain dependent on BCR-ABL signaling even in advanced disease.


MONDO:0011996

[PMID:33440869] [SUPPORT] CML is defined by the presence of the Philadelphia (Ph) --- Explanation: Abstract defines CML by the Philadelphia chromosome.


MONDO:0005002

[PMID:28277858] [SUPPORT] Indeed, it is an important symptom in chronic obstructive pulmonary disease (COPD), where it is associated with limited physical activity, increased anxiety and depression, decreased health-related quality of life (HRQoL), and reduced survival. --- Explanation: The literature supports that dyspnea is a common symptom in COPD and is frequently observed in patients, confirming its categorization as a respiratory phenotype with diagnostic importance.

[PMID:35698999] [SUPPORT] Dyspnoea and pain are symptoms of chronic obstructive pulmonary disease (COPD)... The pooled prevalence of pain and dyspnoea was 44% (95% confidence interval (CI) 35%-52%) and 91% (95% CI 87%-94%) respectively. --- Explanation: This study highlights the high prevalence of dyspnea in patients with COPD, further supporting its status as a very frequent respiratory phenotype.

[PMID:34972922] [SUPPORT] Up to date research has shown a positive correlation between the elevated levels of some markers of EBC such as H2O2 and 8-isoprostane and dyspnea, while others present ambiguous results --- Explanation: The correlation between dyspnea and COPD is reinforced by the positive association found with certain markers in exhaled breath condensate.


MONDO:0005002

[PMID:29881269] [SUPPORT] Compared with patients without chronic cough, those with chronic cough exhibited a lower forced expiratory volume in 1 second (% predicted) and diffusing capacity of the lungs for carbon monoxide (% predicted), more frequent AECOPD, more severe dyspnea, and worse QoL. --- Explanation: The study identifies chronic cough as a common and significant phenotype in COPD patients, indicating its very frequent occurrence and diagnostic importance.

[PMID:31740261] [SUPPORT] COPD is now widely accepted as a heterogeneous condition with multiple phenotypes and endotypes. This review will discuss the old and new concepts for the different types of COPD phenotypes. --- Explanation: The statement mentions the heterogeneity of COPD with multiple phenotypes, which could include phenotypes like chronic cough.


MONDO:0005002

[PMID:22753831] [SUPPORT] Chronic cough and sputum production: a clinical COPD phenotype? --- Explanation: The title of the article itself suggests that sputum production is recognized as a phenotype of COPD.

[PMID:23204254] [SUPPORT] Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). --- Explanation: Chronic bronchitis, which involves overproduction and hypersecretion of mucus, is described as a common phenomenon in COPD, indicating sputum production is a frequent COPD phenotype.


MONDO:0005002

[PMID:33302722] [SUPPORT] The clinical symptoms of this disease include progressive dyspnea, cough, expectoration, and wheezing, among others. --- Explanation: The abstract mentions wheezing as one of the clinical symptoms of Chronic Obstructive Pulmonary Disease (COPD).

[PMID:11963614] [SUPPORT] Remember, all that wheezes is not asthma; therefore, providers in this case had to determine if the patient was suffering something such as anaphylaxis, asthma, bronchitis, pneumonia or even congestive heart failure (CHF). --- Explanation: The abstract indicates that wheezing can be a symptom of various conditions, including COPD-related bronchospasm.

[PMID:2404712] [SUPPORT] Increased airways reactivity is present in 15 to 70 percent of patients with chronic airflow obstruction. --- Explanation: The abstract discusses increased airway reactivity, which is related to wheezing, in patients with chronic airflow obstruction, including COPD.


MONDO:0005002

[PMID:14621114] [REFUTE] Respiratory failure is still an important complication of chronic obstructive pulmonary disease (COPD) and hospitalisation with an acute episode being a poor prognostic marker. --- Explanation: The reference indicates that respiratory failure is an important and common complication of COPD, not an occasional one.

[PMID:38692758] [REFUTE] Hypoventilation is a complication that is not uncommon in chronic obstructive pulmonary disease and calls for both medical treatment of the underlying disease and, frequently, noninvasive ventilation either during exacerbations requiring hospitalization or in a chronic state in the patient at home. --- Explanation: The reference suggests that hypoventilation, which can lead to respiratory failure, is not uncommon in COPD.


MONDO:0005002

[PMID:33998496] [SUPPORT] Fatigue: A neglected symptom of COPD. --- Explanation: The title itself indicates that fatigue is a recognized symptom of COPD.

[PMID:31729154] [SUPPORT] Fatigue is an important yet ignored symptom of chronic obstructive pulmonary disease (COPD). --- Explanation: This reference acknowledges fatigue as an important symptom of COPD, supporting its frequent occurrence.

[PMID:24874124] [SUPPORT] Symptoms in COPD do not solely arise from the degree of airflow obstruction as exercise limitation is compounded by the specific secondary manifestations of the disease including skeletal muscle impairment, osteoporosis, mood disturbance, anemia, and hormonal imbalance. --- Explanation: While this reference does not mention fatigue explicitly, it discusses systemic manifestations of COPD, implying the systemic nature of the disease.


MONDO:0005002

[PMID:12406664] [SUPPORT] Weight loss occurs frequently in patients with chronic obstructive pulmonary disease (COPD). --- Explanation: The literature states that weight loss is a common phenomenon in COPD patients, which supports the statement that weight loss is a systemic issue in COPD, more common in advanced disease.

[PMID:18415812] [SUPPORT] These include unintentional weight loss, skeletal muscle dysfunction, an increased risk of cardiovascular disease, osteoporosis, and depression, among others. --- Explanation: This reference mentions unintentional weight loss as one of the systemic effects of COPD, supporting the statement.

[PMID:36922031] [SUPPORT] COPD patients with psychological (high anxiety and depression) and cachectic (underweight and osteoporotic) comorbidity have higher mortality and exacerbate more. --- Explanation: The mention of cachexia (underweight) as a comorbidity in COPD patients aligns with the statement about weight loss being more common in advanced disease.


MONDO:0005002


MONDO:0005002

[PMID:23204254] [INDIRECT EVIDENCE] [SUPPORT] CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse --- Explanation: This study describes how mucus build-up and epithelial remodeling lead to airflow obstruction in COPD.

[PMID:36108172] [INDIRECT EVIDENCE] [PARTIAL] Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown. --- Explanation: This study notes the involvement of epithelial cells in COPD but states that mechanisms remain unknown, partially supporting the role of epithelial cells in airflow obstruction.

[PMID:38625125] [INDIRECT EVIDENCE] [SUPPORT] Chronic exposure to environmental hazards causes airway epithelial dysfunction, primarily impaired physical barriers, immune dysfunction, and repair or regeneration. Impairment of airway epithelial function subsequently leads to exaggerated airway inflammation and remodeling, the main features of chronic obstructive pulmonary disease (COPD). --- Explanation: This study supports the statement by highlighting the role of epithelial dysfunction, inflammation, and remodeling in COPD pathophysiology.


MONDO:0005002

[PMID:17305517] [INDIRECT EVIDENCE] [SUPPORT] Neutrophils and macrophages have been implicated in this process; they release proteolytic enzymes and generate oxidants, which cause tissue damage, as well as cytokines and chemokines, which can potentiate inflammation and trigger an immune response. --- Explanation: The literature describes the involvement of neutrophils, macrophages, and T-lymphocytes in the inflammatory process associated with COPD, supporting the notion of persistent irritation and chronic inflammation.

[PMID:24507838] [INDIRECT EVIDENCE] [SUPPORT] This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, and T lymphocytes, which are recruited from the circulation. --- Explanation: This article further substantiates the involvement of these cell types (neutrophils, macrophages, and T-lymphocytes) in the pathophysiology of COPD, linking them to chronic inflammation.

[PMID:38035712] [INDIRECT EVIDENCE] [SUPPORT] In this study, we found that neutrophilic phenotype (NP, 58.0%) was the most common airway inflammation phenotype in patients with COPD, followed by mixed granulocytic phenotype (MGP, 32.6%). --- Explanation: The study indicates that neutrophils are predominant in COPD, supporting the statement about chronic inflammation.

[PMID:38891820] [INDIRECT EVIDENCE] [SUPPORT] Recent multiomics-based evidence suggests that the plasticity of alveolar macrophages contributes to the onset and progression of COPD through the coordinated modulation of numerous transcription factors. --- Explanation: The article highlights the role of macrophages in the pathogenesis and progression of COPD, thus supporting the statement.

[PMID:11993785] [INDIRECT EVIDENCE] [PARTIAL] The characteristic changes in the central airways include inflammatory cellular infiltration into the airway wall and mucous gland enlargement. --- Explanation: This reference provides a broader overview of the pathological changes in COPD, mentioning inflammatory cells but not specifically detailing the involvement of neutrophils, macrophages, and T-lymphocytes.


MONDO:0005002

[PMID:20500603] [INDIRECT EVIDENCE] [SUPPORT] Moreover, airway remodelling occurs not only in asthma but also in several pulmonary disorders such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and systemic sclerosis. --- Explanation: The statement aligns with the mentioned literature which notes airway remodeling as part of chronic obstructive pulmonary disease.

[PMID:30257694] [INDIRECT EVIDENCE] [SUPPORT] Multiple dysfunctions of ASM contribute to modulating airway responses to stimuli, remodeling, and fibrosis, as well as influence the compliance of lungs. --- Explanation: The statement is supported as this literature highlights the role of airway smooth muscle cells in airway remodeling and fibrosis in COPD.

[PMID:15347849] [INDIRECT EVIDENCE] [SUPPORT] Increases in airway smooth muscle mass occur in large airways of severe asthmatics and in small airways of patients with COPD. --- Explanation: The literature supports the statement by confirming the involvement of smooth muscle cells and structural changes in the airways in COPD.


MONDO:0005002

[PMID:11993785] [INDIRECT EVIDENCE] [PARTIAL] In the lung parenchyma, emphysema defined as alveolar destruction and airspace enlargement is present. --- Explanation: While the reference supports alveolar destruction as part of COPD's pathophysiology, it does not mention alveolar macrophages specifically.

[PMID:29433833] [INDIRECT EVIDENCE] [PARTIAL] In inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD), despite their increased numbers, macrophages demonstrate significantly reduced phagocytic capacity of bacteria and apoptotic cells. --- Explanation: The macrophages' role in the pathophysiology of COPD is discussed, focusing on their reduced phagocytic capacity rather than direct alveolar destruction.

[PMID:32493486] [INDIRECT EVIDENCE] [PARTIAL] External insults like smoke and pollution can disturb surfactant homeostasis and result in either surfactant insufficiency or accumulation. But disruption of surfactant homeostasis is also observed in many chronic adult diseases, including chronic obstructive pulmonary disease (COPD). --- Explanation: The role of alveolar macrophages (responsible for the degradation of surfactant) in the development of COPD is mentioned, but no direct link to alveolar destruction.

[PMID:24707174] [INDIRECT EVIDENCE] [PARTIAL] There are eight types of EMPs which are defined by the presence of different endothelial markers on the cell membrane: vascular endothelial-cadherin; platelet endothelial cell adhesion molecule; melanoma cell adhesion molecule; E-selectin; CD51; CD105; von Willebrand factor; and CD143 EMPs. --- Explanation: The reference discusses endothelial injury and microparticles in COPD, which may indirectly relate to alveolar destruction, but does not directly address it or the role of alveolar macrophages.


MAXO:0000077

[PMID:25496790] [SUPPORT] Stopping smoking reduces the risk of developing COPD and is an essential treatment for this inflammatory disease. Smoking cessation decreases the prevalence of respiratory symptoms, number of hospitalizations, and decline in FEV1, as well as exacerbation frequency and overall mortality. --- Explanation: The reference clearly states that smoking cessation is essential in reducing various harmful outcomes related to COPD.

[PMID:19811377] [SUPPORT] Smoking cessation and lung volume reduction surgery would both qualify as disease-modifying interventions. --- Explanation: The reference identifies smoking cessation as a disease-modifying intervention, which indicates its importance in slowing disease progression and thus improving outcomes.

[PMID:11935838] [SUPPORT] The most important intervention is smoking cessation. --- Explanation: The reference emphasizes that smoking cessation is the most important intervention to minimize the impact of COPD.

[PMID:27576232] [SUPPORT] Smoking cessation is the only intervention shown to slow disease progression. --- Explanation: The reference clearly supports the claim that smoking cessation can slow disease progression and improve outcomes for COPD patients.


MAXO:0000058

[PMID:29794201] [SUPPORT] Bronchodilator therapy can often decrease symptoms of air-flow obstruction by relaxing airway smooth muscle (bronchodilation), decreasing dyspnea, and improving quality of life. --- Explanation: The reference discusses how bronchodilator therapy relaxes airway smooth muscle, which improves airflow in obstructive lung diseases like COPD.

[PMID:27576232] [SUPPORT] Long-acting beta2-agonists and long-acting muscarinic antagonists are first-line treatments for patients with persistently symptomatic COPD with an FEV1 of 80% or less of predicted. --- Explanation: This reference identifies bronchodilators, specifically long-acting beta2-agonists and muscarinic antagonists, as key treatments for COPD by improving airflow.

[PMID:28757318] [SUPPORT] Combination long-acting inhaled bronchodilators are central to the management of patients with moderate to very severe chronic obstructive pulmonary disease. --- Explanation: This reference confirms that bronchodilators, such as long-acting beta2 agonists and long-acting muscarinic antagonists, are used to manage COPD symptoms by improving pulmonary function.


MAXO:0000312

[PMID:20102305] [PARTIAL] Short-term treatment with ICS improves lung function and quality of life; in addition, several studies with longer follow-up have shown less decline over time in quality of life, and fewer exacerbations. By contrast, long-term studies have been unable to show substantial improvement in the decline of lung function in COPD. --- Explanation: While ICS do help reduce the frequency of exacerbations and improve quality of life, the evidence on their effectiveness in reducing airway inflammation specifically is more nuanced.

[PMID:37348121] [PARTIAL] Current pharmacologic strategies, including first- and second-line therapies such as long-acting β2-agonists, long-acting muscarinic antagonists, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and macrolides, provide relief to patients with COPD --- Explanation: ICS are included in the treatment strategies, and while they help mitigate exacerbations, the snippet suggests that not all patients experience reduced airway inflammation.

[PMID:29938633] [SUPPORT] The major alteration has been in the section concerning treatment with inhalation medication - now aiming at an easy stepwise up-titration of long-acting medicine as well as a guide of how to down-titrate inhaled corticosteroids. --- Explanation: The guideline update underscores the role of ICS in managing stable COPD, highlighting their long-term use for reducing symptoms and managing exacerbations.

[PMID:30846476] [SUPPORT] Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICSs and long-acting bronchodilators on exacerbations. --- Explanation: The new evidence indicates that ICS are effective in reducing exacerbations, supporting their role in treatment.


MAXO:0000058

[PMID:15699784] [SUPPORT] Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. --- Explanation: The reference indicates that selective phosphodiesterase 4 inhibitors show anti-inflammatory activity, supporting the statement about reducing inflammation.

[PMID:20649375] [SUPPORT] Roflumilast targets inflammatory processes in COPD, with beneficial effects on tobacco-induced lung inflammation, lung fibrosis and remodeling, mucociliary malfunction and oxidative stress. --- Explanation: Roflumilast, a PDE4 inhibitor, targets inflammatory processes, thus supporting the statement.

[PMID:34731461] [SUPPORT] The orally administered PDE4 inhibitor roflumilast reduces exacerbation rates in the subgroup of chronic obstructive pulmonary disease patients with a history of exacerbations and the presence of chronic bronchitis, but can cause PDE4 related adverse effects due to systemic exposure. --- Explanation: This reference confirms the anti-inflammatory effect of PDE4 inhibitors which aligns with the statement.

[PMID:32361678] [SUPPORT] Protein kinases have been implicated in mediating inflammatory signals and airway remodeling associated with reduced lung function in chronic pulmonary disease. --- Explanation: This reference supports the role of PDE inhibitors, specifically kinase inhibitors, in reducing inflammation in COPD.


MAXO:0000503

[PMID:24461631] [SUPPORT] This therapeutic intervention has been shown to increase survival in patients with chronic obstructive pulmonary disease (COPD) and respiratory failure. --- Explanation: The literature supports that long-term oxygen therapy (LTOT) is used to treat patients with COPD who have severe chronic hypoxemia.

[PMID:37353334] [SUPPORT] Long-term oxygen therapy (LTOT) is a mainstay treatment for patients with severe resting hypoxemia secondary to chronic respiratory conditions including COPD. --- Explanation: This reference specifically mentions LTOT as a primary treatment for patients with severe chronic hypoxemia due to COPD.

[PMID:19462352] [SUPPORT] Only smoking cessation and long term oxygen therapy (LTOT) improve survival in COPD. --- Explanation: This study confirms that LTOT is a treatment that improves survival in patients with severe COPD and chronic hypoxemia.


MAXO:0000011

[PMID:29526182] [SUPPORT] PR is an effective and cost-effective therapeutic intervention that improves physical performance ability, shortness of breath, and the quality of life in patients with COPD. --- Explanation: The reference indicates that pulmonary rehabilitation (PR) improves physical performance, shortness of breath, and quality of life in COPD patients, aligning with the statement's description of treatments including exercise training, education, and support.

[PMID:34338012] [SUPPORT] Exercise improves the physiological and psychological condition of people with chronic obstructive pulmonary disease and should be encouraged, with referral to a pulmonary rehabilitation service if available. --- Explanation: This reference supports the statement's claim by emphasizing the importance of exercise and recommending pulmonary rehabilitation to improve the quality of life and physical conditioning in COPD patients.

[PMID:34955635] [SUPPORT] The combination of drug therapy with non-drug therapy such as pulmonary rehabilitation training has demonstrated a great potential in reducing the occurrence of complications and delaying the progression of COPD. --- Explanation: This reference supports the statement by highlighting the benefits of pulmonary rehabilitation training, specifically its potential to improve quality of life and physical conditioning in COPD patients.

[PMID:24874124] [SUPPORT] Pulmonary rehabilitation targets the systemic manifestations of COPD, the causes of which include inactivity, systemic inflammation, hypoxia and corticosteroid treatment. --- Explanation: This reference supports the statement by indicating that pulmonary rehabilitation addresses systemic issues in COPD and implies improvement in quality of life and physical conditioning.

[PMID:24507849] [SUPPORT] The main objective of pulmonary rehabilitation is to restore muscle function and exercise tolerance, reverse other nonrespiratory consequences of the disease, and help patients to self-manage chronic obstructive pulmonary disease and its exacerbations and symptoms. --- Explanation: This reference supports the statement by detailing the benefits of pulmonary rehabilitation, including exercise training, education, and support, to improve quality of life and physical conditioning.


MAXO:0000004

[PMID:22189668] [SUPPORT] Surgical approaches include lung transplantation and lung volume reduction and the latter has been shown to improve exercise tolerance, quality of life, and survival in highly selected patients with advanced emphysema. --- Explanation: The literature supports the use of lung volume reduction surgery as a treatment for severe emphysema in chronic obstructive pulmonary disease (COPD) patients.

[PMID:33926668] [SUPPORT] As symptoms and lung function decline, treatment modalities, such as lung volume reduction surgery, have been used in individuals with chronic obstructive pulmonary disease and upper lobe predominant emphysema. --- Explanation: The literature indicates that lung volume reduction surgery is a treatment used for severe emphysema, a condition associated with COPD.

[PMID:31145187] [SUPPORT] Mortality benefits to therapy have been demonstrated in only 2 therapeutic interventions to date: long-term use of daily supplemental oxygen and surgical lung volume reduction (LVRS) for upper-lobe-predominant disease in patients with a low baseline exercise capacity. --- Explanation: The statement is supported as the literature suggests that lung volume reduction surgery is an established treatment for upper-lobe-predominant, severe emphysema in COPD patients.


MAXO:0010039

[PMID:17240617] [SUPPORT] Lung transplantation is a surgical option for patients who fail optimization of medical treatment for the severe symptoms that result from COPD. --- Explanation: This reference states that lung transplantation is a considered treatment option for patients with severe symptoms resulting from COPD.

[PMID:31375190] [SUPPORT] End-stage congestive heart failure, chronic obstructive pulmonary disease...palliative principles can guide decision making and symptom management in these disease states. --- Explanation: The reference focuses on end-stage COPD and mentions lung transplantation as a consideration in managing the conditions of patients.

[PMID:36050206] [SUPPORT] The International Thoracic Organ Transplant Registry...focus on lung transplant recipients with chronic obstructive pulmonary disease. --- Explanation: This source concentrates on lung transplantation for patients with COPD, in line with the statement's context of it being a treatment for end-stage COPD.

[PMID:23248802] [SUPPORT] Chronic obstructive pulmonary disease...treated by lung transplantation. --- Explanation: This abstract explicitly mentions the use of lung transplantation for individuals with very severe COPD.


MAXO:0000058


HGNC.SYMBOL:SERPINA1

[PMID:32800189] [SUPPORT] Alpha-1 antitrypsin deficiency (AATD) was the first genetic risk factor for chronic obstructive pulmonary disease (COPD) described. --- Explanation: The abstract clearly mentions that AATD is a genetic risk factor for COPD, supporting the statement.

[PMID:35104244] [SUPPORT] Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause and risk factor for chronic obstructive pulmonary disease. --- Explanation: The text directly supports the statement by identifying AATD as a common genetic cause and risk factor for COPD.

[PMID:36630963] [SUPPORT] Genetic variation in alpha-1 antitrypsin (AAT) causes AAT deficiency (AATD) through liver aggregation-associated gain-of-toxic pathology and/or insufficient AAT activity in the lung manifesting as chronic obstructive pulmonary disease (COPD). --- Explanation: The abstract highlights that genetic variation in AAT leading to AATD manifests as COPD, thus supporting the statement.


HGNC.SYMBOL:MMP12


HGNC.SYMBOL:NLRP3


HGNC.SYMBOL:TNF


HGNC.SYMBOL:IL1B


HGNC.SYMBOL:IL6


HGNC.SYMBOL:NFE2L2


ECTO:6000029

[PMID:30810540] [SUPPORT] Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. --- Explanation: This clearly identifies smoking as a major risk factor for COPD development.

[PMID:31759959] [SUPPORT] The observation that COPD is an independent risk factor for cardiovascular disease (CVDs) comes from comparisons between smokers with COPD and smokers without COPD. --- Explanation: This snippet highlights the relationship between smoking, COPD, and other health issues, indirectly supporting smoking as a risk factor for COPD.

[PMID:28933915] [SUPPORT] The epithelial lining of the airway forms the first barrier against environmental insults, such as inhaled cigarette smoke, which is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). --- Explanation: Directly states that cigarette smoke is the primary risk factor for COPD development.

[PMID:18303418] [SUPPORT] Approximately one-quarter of smokers can be affected by clinically significant chronic obstructive pulmonary disease. ... Smokers may reduce their risk of developing chronic obstructive pulmonary disease by physical activity and increase their survival by smoking reduction. --- Explanation: This supports the statement by highlighting the prevalence of COPD among smokers and the role of smoking in disease progression.

[PMID:37429033] [SUPPORT] Age of Initiating Smoking: An Independent Predictor of Chronic Obstructive Pulmonary Disease in Later Life. --- Explanation: This implies that smoking is a risk factor in the development of COPD.


ECTO:8000036

[PMID:33542053] [SUPPORT] Our findings suggest that, when considering total personal exposure to air pollutants, mainly the gaseous pollutants affect COPD patients' health. --- Explanation: This study found that exposure to various air pollutants adversely affects the health of COPD patients, supporting the idea that air pollution exacerbates COPD symptoms.

[PMID:25673984] [SUPPORT] The major pathogenic factors causing disease include infection and inflammation, protease and antiprotease imbalance, and oxidative stress overwhelming antioxidant defenses. --- Explanation: This reference discusses environmental factors, including pollutants, that contribute to oxidative stress and inflammation in COPD, thus supporting the statement.

[PMID:37068517] [SUPPORT] Harmful inhaled workplace exposures can contribute to the development of chronic obstructive pulmonary disease (COPD). --- Explanation: This statement supports the environmental influence on COPD, including air pollutants, as a risk factor.

[PMID:16916323] [SUPPORT] Evidence from epidemiological studies finding consistent associations between air pollution and various outcomes (respiratory symptoms, reduced lung function, chronic bronchitis and mortality), has suggested that outdoor air pollution is a contributing cause of morbidity and mortality. --- Explanation: This reference directly links air pollution to exacerbation and pathogenesis of COPD, supporting the statement.

[PMID:27751401] [SUPPORT] We focus on the major constituents of air pollutants and their impacts on chronic respiratory diseases. --- Explanation: This review highlights the detrimental effects of air pollution on respiratory health, particularly in the discussion on chronic respiratory diseases such as COPD.


ECTO:7000001

[PMID:11964759] [SUPPORT] occupational exposure to dusts, chemicals and gases will be considered an established, or supported by good evidence, risk factor for chronic obstructive pulmonary disease --- Explanation: The abstract confirms that occupational exposure to dusts, chemicals, and gases is a well-supported risk factor for chronic obstructive pulmonary disease.

[PMID:20535848] [SUPPORT] Lung function loss associated with occupational dust exposure in metal smelting --- Explanation: This study provides evidence of lung function loss due to occupational dust exposure, supporting the assertion that long-term exposure to such environmental factors increases the risk of chronic obstructive pulmonary disease.

[PMID:23361196] [SUPPORT] Recent studies have recognized the contribution of workplace exposures to chronic lung diseases, in particular chronic obstructive pulmonary disease (COPD) --- Explanation: The abstract discusses the recognized contribution of workplace exposures, including textile dust, to chronic obstructive pulmonary disease.

[PMID:24278358] [SUPPORT] Occupational inhalative exposure to bg-dust was associated with a statistically significant decreased FEV1 and FEV1/FVC revealing airway obstruction consistent with COPD --- Explanation: The meta-analysis presented indicates a significant association between occupational exposure to inorganic dust and the development of chronic obstructive pulmonary disease.

[PMID:35409627] [SUPPORT] Pesticides in general and especially organophosphate and carbamate insecticides... showed an association, and cadmium (Cd), chromium (Cr and CrVI), arsenic (As), and diisocyanates, a possible association with COPD --- Explanation: The scoping review identifies several environmental substances, including chemicals associated with occupational exposure, that have a strong or possible association with chronic obstructive pulmonary disease.


MONDO:0005003

[PMID:38680261] [SUPPORT] Pain in chronic pancreatitis (CP) is difficult to manage. Many patients suffer from inadequate pain relief, completely incapacitating them in their daily activities. --- Explanation: Chronic abdominal pain is a cardinal and often debilitating symptom of chronic pancreatitis.


MONDO:0005003

[PMID:27941156] [SUPPORT] PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. --- Explanation: Steatorrhea (excess faecal fat excretion) is a key manifestation of exocrine insufficiency in chronic pancreatitis, as demonstrated by its improvement with enzyme replacement therapy.


MONDO:0005003

[PMID:18554234] [SUPPORT] After the onset of chronic pancreatitis, 56.5% of patients lost weight and significantly more patients became malnourished compared with controls (45.8% vs 22.5%; P < 0.001). --- Explanation: Prospective study demonstrates that over half of CP patients experience weight loss, with significantly higher malnutrition rates than controls.


MONDO:0005003

[PMID:28404095] [SUPPORT] Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. --- Explanation: Type 3c (pancreatogenic) diabetes develops as a direct consequence of chronic pancreatitis due to progressive destruction of islet cells.


MONDO:0005003


MONDO:0005003

[PMID:23622130] [INDIRECT EVIDENCE] [NO_EVIDENCE] Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. --- Explanation: This paper discusses pancreatic stellate cells and their role in pancreatic pathology. While focused on cancer, the stellate cell activation mechanisms are shared with chronic pancreatitis and support the inflammatory injury cascade.


MONDO:0005003

[PMID:23622130] [INDIRECT EVIDENCE] [PARTIAL] There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. --- Explanation: Pancreatic stellate cells are the key drivers of fibrosis in chronic pancreatitis. This review discusses how activated stellate cells produce the stromal matrix that characterizes pancreatic fibrosis, a central feature of chronic pancreatitis progression.


MONDO:0005003

[PMID:28404095] [INDIRECT EVIDENCE] [SUPPORT] The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. --- Explanation: Chronic pancreatitis is the leading cause of type 3c diabetes, confirming that endocrine insufficiency develops as a consequence of pancreatic damage.


HGNC.SYMBOL:PRSS1

[PMID:37389024] [PARTIAL] Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). --- Explanation: PRSS1 variants were identified in 8.6% of chronic pancreatitis patients, confirming its role as a causative genetic factor.


HGNC.SYMBOL:SPINK1

[PMID:37389024] [SUPPORT] Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). --- Explanation: SPINK1 variants were identified in 8.6% of chronic pancreatitis patients, confirming its role as a risk factor.


HGNC.SYMBOL:CFTR

[PMID:37389024] [SUPPORT] Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). --- Explanation: CFTR variants were identified in 18.1% of chronic pancreatitis patients, confirming its role as a significant risk factor.


HGNC.SYMBOL:CTRC

[PMID:37389024] [SUPPORT] Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). --- Explanation: CTRC variants were identified in 37.1% of chronic pancreatitis patients, making it the most frequently identified genetic risk factor in this cohort.


MONDO:0016602

[PMID:20301360] [SUPPORT] Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). --- Explanation: GeneReviews directly identifies NICCD as the neonatal presentation.

[PMID:37063661] [SUPPORT] Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a common clinical phenotype of citrin deficiency in infants. --- Explanation: Confirms NICCD as a common infant phenotype.


MONDO:0016602

[PMID:20301360] [SUPPORT] Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). --- Explanation: Directly identifies recurrent hyperammonemia as a key feature of CTLN2.

[PMID:35142380] [SUPPORT] Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age-dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult-onset type II citrullinemia (CTLN2). --- Explanation: Large Japanese cohort study confirming the age-dependent clinical spectrum including hyperammonemia in CTLN2.


MONDO:0016602

[PMID:20301360] [SUPPORT] in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). --- Explanation: Directly describes neuropsychiatric symptoms (encephalopathy) as a feature of CTLN2.


MONDO:0016602

[PMID:35142380] [SUPPORT] Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. --- Explanation: Large cohort study documenting growth impairment across different stages of citrin deficiency.


MONDO:0016602

[PMID:37063661] [SUPPORT] We report 4 patients with jaundice and low body weight. Furthermore, the biochemical examination of all showed abnormal liver function and metabolic changes. --- Explanation: Case series of NICCD patients with hepatic involvement including abnormal liver function.


MONDO:0016602

[PMID:20301360] [SUPPORT] in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) --- Explanation: Directly identifies dyslipidemia as part of the FTTDCD phenotype.

[PMID:35142380] [SUPPORT] failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD) --- Explanation: Large cohort confirms dyslipidemia as a defining feature of FTTDCD.


MONDO:0016602


MONDO:0016602

[PMID:37063661] [SUPPORT] We report 4 patients with jaundice and low body weight. --- Explanation: Jaundice is the presenting symptom in NICCD case reports.


MONDO:0016602

[PMID:37952953] [SUPPORT] MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis. --- Explanation: The therapeutic recommendation for minimal carbohydrates reflects the underlying carbohydrate intolerance that drives food preference.


MONDO:0016602

[PMID:35142380] [SUPPORT] Patients with citrin deficiency had an increased risk for low weight and length at birth --- Explanation: Directly quantifies increased risk for low birth parameters in citrin deficiency.


MONDO:0016602

[PMID:37952953] [SUPPORT] patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. --- Explanation: Directly cites irreversible brain damage as a clinical consequence.


MONDO:0016602

[PMID:37952953] [SUPPORT] They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. --- Explanation: Hepatocyte energy deficiency is consistent with impaired glucose homeostasis and hypoglycemia risk.


MONDO:0016602

[PMID:20301360] [PARTIAL] in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). --- Explanation: Neuropsychiatric symptoms are documented; seizures are a recognized manifestation of hyperammonemic encephalopathy but not explicitly stated in this snippet.


MONDO:0016602

[PMID:37254569] [INDIRECT EVIDENCE] [SUPPORT] Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into the cytosol in exchange for glutamate. --- Explanation: Supports citrin transporter molecular dysfunction as the initiating defect.


MONDO:0016602

[PMID:37254569] [INDIRECT EVIDENCE] [SUPPORT] Through MAS, AGC2 is necessary to maintain intracellular redox balance, mitochondrial respiration, and ATP synthesis. --- Explanation: Review-level mechanistic confirmation of MAS role in redox and energy homeostasis.


MONDO:0016602

[PMID:20301360] [INDIRECT EVIDENCE] [SUPPORT] Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). --- Explanation: GeneReviews entry confirms hyperammonemia with neuropsychiatric symptoms as the adult CTLN2 presentation.

[PMID:37952953] [INDIRECT EVIDENCE] [SUPPORT] Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). --- Explanation: Supports the age-dependent clinical spectrum including CTLN2 with urea cycle perturbation.


MONDO:0016602

[PMID:37254569] [INDIRECT EVIDENCE] [SUPPORT] Aspartate-glutamate carrier 2 (AGC2, citrin) is a mitochondrial carrier expressed in the liver that transports aspartate from mitochondria into the cytosol in exchange for glutamate. --- Explanation: Directly describes the aspartate-glutamate exchange function of citrin.


MAXO:0000088

[PMID:37952953] [SUPPORT] Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. --- Explanation: Directly describes the mechanism and effectiveness of MCT therapy.

[PMID:37952953] [SUPPORT] MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis. --- Explanation: Supports early and combined MCT plus carbohydrate restriction as the recommended approach.


MAXO:0000088


MAXO:0001175

[PMID:35142380] [SUPPORT] Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. --- Explanation: Quantifies transplantation frequency and outcomes in a large cohort.

[PMID:20301360] [SUPPORT] NICCD is generally not severe, and clinical manifestations are often resolved by age one year with appropriate treatment, although liver failure may still occur; liver transplantation has been required in rare instances. --- Explanation: Confirms liver transplantation as a rare but necessary intervention.


MAXO:0000950

[PMID:20301360] [SUPPORT] NICCD is generally not severe, and clinical manifestations are often resolved by age one year with appropriate treatment, although liver failure may still occur; liver transplantation has been required in rare instances. --- Explanation: Supports the need for appropriate acute treatment to resolve clinical manifestations.


MAXO:0000124

[PMID:38535123] [SUPPORT] The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. --- Explanation: Quantifies the performance improvement from adding NGS second-tier screening.


MAXO:0000058


MAXO:0000079

[PMID:37063661] [SUPPORT] Our study clarified the genetic etiology of the four infants, expanded the variant spectrum of SLC25A13, and provided a basis for genetic counseling of the family. --- Explanation: Directly states the importance of genetic counseling based on molecular diagnosis.


HGNC.SYMBOL:SLC25A13 pathogenic variants

[PMID:35142380] [SUPPORT] Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. --- Explanation: Nationwide study confirms SLC25A13 as the causal gene.


MONDO:0008988

[PMID:39649700] [SUPPORT] the patient exhibited significantly elevated blood ammonia levels (655 μmol/L; normal reference: 10-30 μmol/L) --- Explanation: Case report with quantitative ammonia data demonstrating severe hyperammonemia in CTLN1.

[PMID:40218931] [SUPPORT] The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494) --- Explanation: Registry data on ammonia as a prognostic marker in UCD patients.


MONDO:0008988

[PMID:20301631] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: GeneReviews describes hyperammonemic encephalopathy progression from lethargy to coma and death.


MONDO:0008988

[PMID:39649700] [SUPPORT] The patient was characterized by severe clinical manifestations, including poor responsiveness, lethargy, convulsions, and cardiac arrest. --- Explanation: Case report documenting convulsions as part of severe neonatal CTLN1 presentation.

[PMID:20301631] [SUPPORT] Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. --- Explanation: GeneReviews confirms seizures as a manifestation of hyperammonemic encephalopathy.


MONDO:0008988

[PMID:39649700] [SUPPORT] The patient was characterized by severe clinical manifestations, including poor responsiveness, lethargy, convulsions, and cardiac arrest. --- Explanation: Case report documenting lethargy as a presenting feature of severe neonatal CTLN1.


MONDO:0008988

[PMID:20301631] [SUPPORT] Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). --- Explanation: GeneReviews directly describes poor feeding in neonatal CTLN1.