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Cell May 2020There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19....
There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
Topics: Adolescent; Alveolar Epithelial Cells; Angiotensin-Converting Enzyme 2; Animals; Betacoronavirus; COVID-19; Cell Line; Cells, Cultured; Child; Coronavirus Infections; Enterocytes; Goblet Cells; HIV Infections; Humans; Influenza, Human; Interferon Type I; Lung; Macaca mulatta; Mice; Mycobacterium tuberculosis; Nasal Mucosa; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Receptors, Virus; SARS-CoV-2; Serine Endopeptidases; Single-Cell Analysis; Tuberculosis; Up-Regulation
PubMed: 32413319
DOI: 10.1016/j.cell.2020.04.035 -
Digestive Diseases (Basel, Switzerland) 2021Chronic diarrhea is defined as more than 3 bowel movements per day, or loose stools, or stool weight >200 g/day for at least 4 weeks. Accompanying symptoms may include...
BACKGROUND
Chronic diarrhea is defined as more than 3 bowel movements per day, or loose stools, or stool weight >200 g/day for at least 4 weeks. Accompanying symptoms may include urgency, abdominal pain, or cramps.
SUMMARY
A number of causes have to be considered, including inflammatory, neoplastic, malabsorptive, infective, vascular, and functional gastrointestinal diseases. Other causes include food intolerances, side effects of drugs, or postsurgical conditions. Diarrhea may also be symptom of a systemic disease, like diabetes or hyperthyroidism. Special patient groups, like the very elderly and immunocompromised patients, pose special challenges. This review follows a question-answer style and addresses questions raised on the intersection of primary and secondary care. What do you mean by diarrhea? Why is it important to distinguish between acute or chronic diarrhea? How shall the patient with chronic diarrhea be approached? How can history and physical exam help? How can routine laboratory tests help in categorizing diarrhea? Which additional laboratory tests may be helpful? How to proceed in undiagnosed or intractable diarrhea? What are the treatment options in patients with chronic diarrhea? Key Messages: Acute diarrhea is usually of infectious origin with the main treatment goal of preventing water and electrolyte disturbances. Chronic diarrhea is usually not of infectious origin and may be the symptom of a large number of gastrointestinal and general diseases or drug side effects. In undiagnosed or intractable diarrhea, the question shall be raised whether the appropriate tests have been performed and interpreted correctly.
Topics: Aged; Chronic Disease; Defecation; Diarrhea; Feces; Gastroenterologists; Humans; Primary Health Care
PubMed: 33588424
DOI: 10.1159/000515219 -
Journal of Crohn's & Colitis Apr 2023As more therapeutic options with their own characteristics become available for inflammatory bowel disease [IBD], drug development and individual treatment... (Review)
Review
BACKGROUND AND AIMS
As more therapeutic options with their own characteristics become available for inflammatory bowel disease [IBD], drug development and individual treatment decision-making needs to be tailored towards patients' preferences and needs. This study aimed to understand patient preferences among IBD patients, and their most important treatment outcomes and unmet needs.
METHODS
This qualitative study consisted of [1] a scoping literature review, [2] two focus group discussions [FGDs] with IBD patients [n = 11] using the nominal group technique, and [3] two expert panel discussions.
RESULTS
IBD patients discussed a multitude of unmet needs regarding their symptoms, side-effects, and psychological and social issues for which they would welcome improved outcomes. In particular, IBD patients elaborated on the uncertainties and fears they experienced regarding the possible need for surgery or an ostomy, the effectiveness and onset of action of their medication, and the medication's long-term effects. Furthermore, participants extensively discussed the mental impact of IBD and their need for more psychological guidance, support, and improved information and communication with healthcare workers regarding their disease and emotional wellbeing. The following five characteristics were identified during the attribute grading as most important: prevent surgery, long-term clinical remission, improved quality of life [QoL], occurrence of urgency and improved labour rate.
CONCLUSIONS
This study suggests that IBD drug development and treatment decision-making are needed to improve IBD symptoms and adverse events that significantly impact IBD patients' QoL. Furthermore, this study underlines patients' need for a shared decision-making process in which their desired treatment outcomes and uncertainties are explicitly discussed and considered.
Topics: Humans; Decision Making; Inflammatory Bowel Diseases; Patient Preference; Quality of Life; Treatment Outcome; Focus Groups
PubMed: 36165579
DOI: 10.1093/ecco-jcc/jjac145 -
Annals of Gastroenterological Surgery Sep 2023Low anterior resection syndrome (LARS) is the distressful defecatory functional problem after sphincter-saving surgery for rectal cancer. Although the symptoms of fecal... (Review)
Review
Low anterior resection syndrome (LARS) is the distressful defecatory functional problem after sphincter-saving surgery for rectal cancer. Although the symptoms of fecal urgency, frequency, and incontinence may develop in most of the patients after surgery, there is no definitive treatments for LARS. Multifactorial etiologies and various risk factors have been identified, but the reduction of storage capacity in the rectum is one of the main reasons for LARS. Anal sphincter muscle or nerve damage during rectoanal resection or anastomosis construction, and intersphincteric resection for low-lying tumors or hand-sewing anastomosis, are the absolute risk factors for LARS. Preoperative radiotherapy, postoperative complications, such as anastomosis leakage, or longer duration of stoma, are also risk factors. The severity of LARS can be confirmed using the LARS score questionnaire. The questionnaire has been translated to numerous language versions including Korean and have been validated. Diverse empirical treatments, such as loperamide, fiber, probiotics, or enema, have been tried, but the safety and efficacy have not been verified yet. The 5-Hydroxytryptamine (5-HT) receptor antagonist, ramosetron, used for diarrhea-dominant irritable bowel syndrome, is one potential drug for relieving the symptoms of major LARS. A randomized-controlled trial suggested the use of ramosetron could be safe and efficacious for patients who have major LARS after sphincter-saving rectal cancer surgery. Novel techniques or drugs for relieving the symptoms of LARS should be developed more and further studies are necessary.
PubMed: 37663958
DOI: 10.1002/ags3.12695 -
Clinical Gastroenterology and... Jun 2023Fecal urgency, which is defined by the sudden need to rush to the bathroom to empty one's bowel, is one of the common and distressing symptoms experienced by patients... (Review)
Review
BACKGROUND & AIMS
Fecal urgency, which is defined by the sudden need to rush to the bathroom to empty one's bowel, is one of the common and distressing symptoms experienced by patients with inflammatory bowel disease.
METHODS
We performed a narrative review to investigate the definition, pathophysiology, and therapeutic management of fecal urgency.
RESULTS
Definitions of fecal urgency in inflammatory bowel disease, but also in irritable bowel syndrome, oncology, nononcologic surgery, obstetrics and gynecology, and in proctology, are empirical and heterogenous, lacking standardization. In the majority of these studies, nonvalidated questionnaires were used. When nonpharmacologic measures (dietary regimen, cognitive behavioral program) fail, medications such as loperamide, tricyclic antidepressants, or biofeedback therapy may become necessary. Medical management of fecal urgency may be challenging, in part because only limited data are available regarding the treatment of this symptom in randomized clinical trials of biologics in patients with inflammatory bowel disease.
CONCLUSIONS
There is an urgent need for a systematic approach to assessment of fecal urgency in inflammatory bowel disease. It is time to consider fecal urgency as an outcome in clinical trials to remedy this disabling symptom.
Topics: Pregnancy; Female; Humans; Inflammatory Bowel Diseases; Fecal Incontinence; Irritable Bowel Syndrome; Surveys and Questionnaires; Colitis, Ulcerative
PubMed: 36906079
DOI: 10.1016/j.cgh.2023.02.029 -
Crohn's & Colitis 360 Jul 2022Bowel urgency is commonly experienced by patients with ulcerative colitis (UC) and is associated with reduced health-related quality of life (QoL). Mirikizumab, a...
BACKGROUND
Bowel urgency is commonly experienced by patients with ulcerative colitis (UC) and is associated with reduced health-related quality of life (QoL). Mirikizumab, a humanized monoclonal antibody directed against the p19 subunit of IL-23, significantly reduced bowel urgency in a double-blind, randomized, placebo-controlled Phase 2 clinical trial in patients with moderate-to-severe UC (NCT02589665).
METHODS
All patients ( = 249) reported symptoms including absence or presence of bowel urgency. Absence of urgency was defined as no urgency for the 3 consecutive days prior to each scheduled visit. Missing urgency data were imputed as present. After 12 weeks of induction treatment, patients who achieved clinical response continued maintenance mirikizumab treatment through Week 52. We assessed the relationship of urgency with QoL, clinical outcomes, and inflammatory biomarkers at Weeks 12 and 52.
RESULTS
Patients with absence of urgency demonstrated significantly greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) scores even after adjusting for rectal bleeding (RB) and stool frequency (SF), significantly higher rates of all clinical outcomes at Weeks 12 and 52, and a greater decrease in inflammatory biomarkers C-reactive protein and fecal calprotectin compared to those with presence of urgency. Absence of urgency at Week 12 was associated with improved IBDQ scores at Week 52, while Week 12 RB or SF status was not.
CONCLUSIONS
Absence of urgency is strongly associated with improvement in QoL as well as clinical measures of UC disease activity. These findings suggest urgency may be a useful surrogate marker of disease activity and an important treatment target for UC.
PubMed: 36777426
DOI: 10.1093/crocol/otac016 -
Gastroenterology & Hepatology Feb 2023Bowel urgency, the sudden and immediate need to have a bowel movement, is one of the most widely reported and debilitating symptoms of ulcerative colitis. Urgency has a...
Bowel urgency, the sudden and immediate need to have a bowel movement, is one of the most widely reported and debilitating symptoms of ulcerative colitis. Urgency has a profound impact on patient well-being, often resulting in patient disengagement from education, employment, and social activities. Although its prevalence correlates with disease activity, it is present in states of both disease flare and remission. Postulated pathophysiologic mechanisms are complex, but urgency is likely a consequence of both acute inflammation and structural sequelae of chronic inflammation. Bowel urgency is not widely incorporated into clinical assessment indices or clinical trial endpoints, despite being a pivotal symptom influencing patient health-related quality of life. Addressing urgency can be challenging owing to the associated embarrassment for patients in volunteering this symptom, and its management can be nuanced in the context of a paucity of specific evidence to target it, independently of disease activity. Explicitly inquiring about urgency and integrating it into a multidisciplinary team combining gastroenterologists, psychological support, and continence services is essential to achieving shared satisfaction from treatment. This article outlines the prevalence of urgency and its impact on the quality of life of patients, describes postulated driving mechanisms, and makes recommendations for its inclusion in clinical care and research.
PubMed: 36866112
DOI: No ID Found -
Clinical Medicine Insights. Pediatrics 2020Voiding disorders result usually from functional disturbance. However, relevant organic diseases must be excluded prior to diagnosis of functional disorders. Additional... (Review)
Review
Voiding disorders result usually from functional disturbance. However, relevant organic diseases must be excluded prior to diagnosis of functional disorders. Additional tests, such as urinalysis or abdominal ultrasound are required. Further diagnostics is necessary in the presence of alarm symptoms, such as secondary nocturnal enuresis, weak or intermittent urine flow, systemic symptoms, glucosuria, proteinuria, leukocyturia, erythrocyturia, skin lesions in the lumbar region, altered sensations in the perineum. Functional micturition disorders were thoroughly described in 2006, and revised in 2015 by ICCS (International Children's Continence Society) and are divided into storage symptoms (increased and decreased voiding frequency, incontinence, urgency, nocturia), voiding symptoms hesitancy, straining, weak stream, intermittency, dysuria), and symptoms that cannot be assigned to any of the above groups (voiding postponement, holding maneuvers, feeling of incomplete emptying, urinary retention, post micturition dribble, spraying of the urinary stream). Functional voiding disorders are frequently associated with constipation. Bladder and bowel dysfunction (BBD) is diagnosed when lower urinary tract symptoms are accompanied by problems with defecation. Monosymptomatic enuresis is the most common voiding disorder encountered by pediatricians. It is diagnosed in children older than 5 years without any other lower urinary tract symptoms. Other types of voiding disorders such as: non-monosymptomatic enuresis, overactive and underactive bladder, voiding postponement, bladder outlet obstruction, stress or giggle incontinence, urethrovaginal reflux usually require specialized diagnostics and therapy. Treatment of all types of functional voiding disorders is based on non-pharmacological recommendations (urotherapy), and such education should be implemented by primary care pediatricians.
PubMed: 33293883
DOI: 10.1177/1179556520975035 -
Journal of Crohn's & Colitis Oct 2023To evaluate the effect of mirikizumab, a p19-targeted anti-interleukin-23, on histological and/or endoscopic outcomes in moderately-to-severely active ulcerative colitis... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
To evaluate the effect of mirikizumab, a p19-targeted anti-interleukin-23, on histological and/or endoscopic outcomes in moderately-to-severely active ulcerative colitis [UC].
METHODS
Endoscopic remission [ER], histological improvement [HI], histological remission [HR], histological-endoscopic mucosal improvement [HEMI], and histological-endoscopic mucosal remission [HEMR] were assessed at Week [W]12 [LUCENT-1: N = 1162, induction] and W40 [LUCENT-2: N = 544, maintenance] for patients randomised to mirikizumab or placebo. Analyses were performed to evaluate predictors of: HEMI at W12 with mirikizumab and HEMR at W40 in patients re-randomised to subcutaneous [SC] mirikizumab; associations between W12 histological/endoscopic endpoints and W40 outcomes in mirikizumab responders re-randomised to mirikizumab SC; and associations between W40 endoscopic normalisation [EN] with/without HR.
RESULTS
Significantly more patients treated with mirikizumab achieved HI, HR, ER, HEMI, and HEMR vs placebo [p <0.001], irrespective of prior biologic/tofacitinib failure [p <0.05]. Lower clinical baseline disease activity, female sex, no baseline immunomodulator use, and no prior biologic/tofacitinib failure were predictors of HEMI at W12 [p <0.05]. Corticosteroid use and longer disease duration were negative predictors of achieving HEMR at W40 [p <0.05]. W12 HI, HR, or ER was associated with W40 HEMI or HEMR [p <0.05]; ER at W12 was associated with clinical remission [CR] [p <0.05] and corticosteroid-free remission [CSFR] at W40 [p = 0.052]. HR and HEMR at W12 were associated with CSFR, CR, and symptomatic remission at W40. Alternate HEMR [EN + HR] at W40 was associated with bowel urgency remission at W40 [p <0.05].
CONCLUSIONS
Early resolution of endoscopic and histological inflammation with mirikizumab is associated with better UC outcomes. Clinicaltrials.gov: LUCENT-1, NCT03518086; LUCENT-2, NCT03524092.
Topics: Humans; Female; Colitis, Ulcerative; Inflammation; Adrenal Cortex Hormones; Biological Products; Remission Induction; Sulfonamides; Antibodies, Monoclonal, Humanized
PubMed: 37057827
DOI: 10.1093/ecco-jcc/jjad050