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PloS One 2020Conduct a systematic review and meta-analysis to estimate the impact of pharmacy-supported interventions on the proportion of patients discharged from the hospital on... (Meta-Analysis)
Meta-Analysis
Impact of pharmacy-supported interventions on proportion of patients receiving non-indicated acid suppressive therapy upon discharge: A systematic review and meta-analysis.
OBJECTIVE
Conduct a systematic review and meta-analysis to estimate the impact of pharmacy-supported interventions on the proportion of patients discharged from the hospital on inappropriate acid suppressive therapy (AST).
METHODS
To identify studies, the following databases were systematically searched on October 14th, 2018 and repeated on September 12th, 2019: Ovid MEDLINE(R) and In-Process & Other Non-Indexed Citations and Daily, Embase.com, CINAHL, Web of Science, Cochrane CENTRAL (EBSCO), and ClinicalTrials.gov. Eligible studies consisted of adults, intervention and historical/usual care groups, description of active pharmacy-supported intervention, and proportion of patients discharged on inappropriate AST. Qualitative assessments and quantitative analyses were performed. Modified funnel plot analysis assessed heterogeneity. Preferred reporting items of systematic reviews and meta-analyses (PRISMA) methodology was used to evaluate studies in this review.
RESULTS
Seventeen publications resulting in 16 studies were included in the review. Using random effects model, meta-analysis showed a significant reduction in the odds of being discharged on inappropriate AST from the hospital in the pharmacist-supported intervention arm versus comparator (Odds Ratio 0.33 [95%CI 0.20 to 0.53]), with significant heterogeneity (I2 = 86%). Eleven studies favored pharmacy-supported interventions, four were inconclusive and one favored usual care. Using modified funnel plot analysis, our final evaluation was distilled to 11 studies and revealed a similar outcome (OR 0.36 [95%CI 0.27 to 0.48]), but with less heterogeneity (I2 = 36%).
CONCLUSION
This systematic review and meta-analysis showed that pharmacy-supported interventions were associated with a significantly reduced probability of patients discharged on inappropriate AST. However, heterogeneity was high and may affect interpretation of results. Using funnel plot optimization method, three positive and two negative studies were objectively removed from analyses, resulting in a similar effect size, but with less heterogeneity. To improve study quality, future researchers should consider utilizing a pre-post, multi-arm, prospective design with sampling randomization, training of data extractors (preferably two extractors), re-evaluating a small dataset to check for agreement and providing a comprehensive methodology in subsequent publications.
Topics: Antacids; Anti-Ulcer Agents; Humans; Intensive Care Units; Patient Discharge; Pharmacies; Pharmacists; Proton Pump Inhibitors
PubMed: 33270710
DOI: 10.1371/journal.pone.0243134 -
Clinical and Experimental Allergy :... Mar 2021Hard domestic water has been reported to worsen atopic eczema (AE) and may contribute to its development in early life. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hard domestic water has been reported to worsen atopic eczema (AE) and may contribute to its development in early life.
OBJECTIVE
To review the literature on the relationship between the effect of water hardness (high calcium carbonate; CaCO ) on (a) the risk of developing AE, (b) the treatment of existing AE and (c) skin barrier function in human and animal studies.
DESIGN , DATA SOURCES AND ELIGIBILITY CRITERIA
We systematically searched databases (MEDLINE, Embase, Cochrane CENTRAL, GREAT and Web of Science) from inception until 30/6/2020. Human and animal observational and experimental studies were included. The primary outcomes were risk of AE and skin barrier function. Studies were meta-analysed using a random effects model. Evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.
RESULTS
Sixteen studies were included. Pooled observational data from seven studies on 385,901 participants identified increased odds of AE in children exposed to harder versus softer water (odds ratio 1.28, 95% CI 1.09, 1.50; GRADE certainty: very low). Two mechanistic studies in humans reported higher deposition of the detergent sodium lauryl sulphate in those exposed to harder versus softer water. Two randomized controlled trials comparing water softeners with standard care did not show a significant difference in objective AE severity with softened water (standardized mean difference 0.06 standard deviations higher, 95% CI 0.16 lower to 0.27 higher; GRADE certainty: moderate).
CONCLUSIONS & CLINICAL RELEVANCE
There was a positive association between living in a hard water (range: 76 to > 350 mg/L CaCO ) area and AE in children. There is no evidence that domestic water softeners improve objective disease severity in established AE. There may be a role of water hardness in the initiation of skin inflammation in early life, but there is a need for further longitudinal and interventional studies.
Topics: Animals; Calcium Carbonate; Dermatitis, Atopic; Detergents; Humans; Severity of Illness Index; Skin; Sodium Dodecyl Sulfate; Surface-Active Agents; Water; Water Softening
PubMed: 33259122
DOI: 10.1111/cea.13797 -
Microbial Pathogenesis Mar 2021Bismuth-containing quadruple treatment (BQT) and concomitant treatment (CT) were recommended as alternative first-line treatments of Helicobacter pylori (H. Pylori). A... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of bismuth-containing quadruple treatment and concomitant treatment for first-line Helicobacter pylori eradication: A systematic review and meta-analysis.
Bismuth-containing quadruple treatment (BQT) and concomitant treatment (CT) were recommended as alternative first-line treatments of Helicobacter pylori (H. Pylori). A meta-analysis was performed to evaluate the cure rates and compare efficacy and safety of BQT and CT for H. Pylori eradication. PubMed, Cochrane Library, and Embase databases were searched on June 16, 2020. Meta-analysis, sensitivity analysis, and subgroup analysis were conducted by Review Manager 5.3 and Stata 11.0. Ten studies were collected. We found no difference of cure rate between BQT and CT in intention-to-treat (ITT) analysis (84.6% vs. 82.9%, OR = 1.14, 95% CI: 0.94-1.38; P = 0.19) and marginally statistical difference in per-protocol (PP) analysis (92.4% vs 90.1%, OR = 1.32, 95% CI: 1.00-1.73; P = 0.05). Based on the results of subgroup analyses, we found statistical difference of eradication rate between BQT and CT (amoxicillin + clarithromycin + metronidazole + PPI treatment) according to PP analysis (94.3% vs. 91.5%, OR = 1.49, 95% CI:1.03-2.15; P = 0.03) and marginally statistical difference according to ITT analysis (87.5% vs. 84.6%, OR = 1.28, 95% CI:1.00-1.65; P = 0.05). BQT and CT may be both good treatment options for H. pylori infection. However, BQT was superior to current scheme of CT (amoxicillin + clarithromycin + metronidazole + PPI treatment) in subgroup analysis. It is very necessary to choose tailored therapy as an outstanding way to reduce the impact of antibiotic.
Topics: Amoxicillin; Anti-Bacterial Agents; Bismuth; Drug Therapy, Combination; Helicobacter Infections; Helicobacter pylori; Humans; Proton Pump Inhibitors; Treatment Outcome
PubMed: 33249167
DOI: 10.1016/j.micpath.2020.104661 -
Surgical Oncology Dec 2020Selective Internal Radiation Therapy (SIRT) is a therapeutic modality in patients with hepatocellular carcinoma or liver metastases. Complications due to SIRT-induced...
BACKGROUND
Selective Internal Radiation Therapy (SIRT) is a therapeutic modality in patients with hepatocellular carcinoma or liver metastases. Complications due to SIRT-induced gastric ulcers are seen in less than 5% of patients but there is no consensus for management of this rare side effect. We conducted a systematic review to analyze the efficacy of medical treatment of SIRT-induced ulcers.
METHODS
This systematic review was conducted in accordance with the PRISMA guidelines. We developed the research question following the population, intervention, comparison, outcome, and study design (PICOS) format. We identified studies and cases reporting patients with gastric and/or duodenal (=population) ulcers treated with medical therapy with proton pump inhibitor (PPI), antacid, or sucralfate, alone or in combination (=intervention). We did not require that studies include a control group. We included studies reporting the evaluation of the medical and/or surgical treatment (=outcomes).
RESULTS
Out of 219 articles, 29 articles were included, resulting in analysis of data for a total of 51 patients who had a SIRT-induced gastric and/or duodenal ulcer treated with medication, surgery, or both. Twenty-eight patients (55%) were reported to have SIRT-induced ulcers that improved after initiation of PPI, antacid, or sucralfate treatment (alone or in combination). Twenty-three patients (45%) were reported to be refractory to medical treatment and surgery was performed in 7 out of 23 patients (30%).
CONCLUSIONS
About 45% of SIRT-induced gastroduodenal ulcers are refractory to medical treatment with PPI, antacid, or sucralfate, alone or in combination. Surgery is an effective treatment in patients who are refractory to medical treatment and who have intense symptoms.
Topics: Anti-Ulcer Agents; Humans; Liver Neoplasms; Peptic Ulcer; Radiotherapy
PubMed: 33157433
DOI: 10.1016/j.suronc.2020.10.014 -
BMJ Open Gastroenterology Sep 2020Current guidelines recommend bismuth-containing quadruple therapy (BQT) and quinolone-containing therapy after failure of first-line eradication therapy. However, the... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
Current guidelines recommend bismuth-containing quadruple therapy (BQT) and quinolone-containing therapy after failure of first-line eradication therapy. However, the optimum regimen of second-line eradication therapy remains elusive. We conducted a network meta-analysis to compare the relative efficacy of 16 second-line eradication regimens.
METHODS
Three major bibliographic databases were reviewed to enrol relevant randomised controlled trials between January 2000 and September 2018. Network meta-analysis was conducted by STATA software and we performed subgroup analysis in countries with high clarithromycin resistance and high levofloxacin resistance, and in patients with documented failure of first-line triple therapy.
RESULTS
Fifty-four studies totalling 8752 participants who received 16 regimens were eligible for analysis. Compared with a 7-day BQT, use of probiotic add-on therapy during, before, and after second-line antibiotic regimens, quinolone-based sequential therapy for 10-14 days, quinolone-based bismuth quadruple therapy for 10-14 days, bismuth quadruple therapy for 10-14 days, and quinolone-based triple therapy for 10-14 days were significantly superior to the other regimens. Subgroup analysis of countries with high clarithromycin resistance and high levofloxacin resistance revealed that the ranking of second-line eradication regimens was distributed similarly in each group, as well as in patients with failure of first-line triple therapy.
CONCLUSION
We conducted a detailed comparison of second-line regimens according to different antibiotic resistance rates and the results suggest alternative treatment choices with potential benefits beyond those that could be achieved using salvage therapies recommended by guidelines.
Topics: Adult; Antacids; Anti-Bacterial Agents; Bismuth; Clarithromycin; Drug Resistance, Multiple; Drug Therapy, Combination; Female; Helicobacter Infections; Helicobacter pylori; Humans; Levofloxacin; Male; Metronidazole; Middle Aged; Network Meta-Analysis; Outcome Assessment, Health Care; Practice Guidelines as Topic; Proton Pump Inhibitors; Quinolones; Randomized Controlled Trials as Topic; Tetracycline
PubMed: 32883715
DOI: 10.1136/bmjgast-2020-000472 -
Digestive Diseases and Sciences Jul 2021A large number of studies have evaluated the pharmacology, safety, and/or efficacy of bismuth subsalicylate for the relief of common gastrointestinal symptoms, diarrhea... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A large number of studies have evaluated the pharmacology, safety, and/or efficacy of bismuth subsalicylate for the relief of common gastrointestinal symptoms, diarrhea and vomiting due to acute gastroenteritis. In addition, short-term (48 h) medication with bismuth subsalicylate is known to be effective against infectious gastroenteritis such as travelers' diarrhea.
AIMS
Previous studies have documented the bacteriostatic/bactericidal effects of bismuth subsalicylate against a variety of pathogenic gastrointestinal bacteria. However, meta-analyses of the clinical efficacy of bismuth subsalicylate for both prevention and treatment of travelers' diarrhea have not yet been published.
METHODS
A total of 14 clinical studies (from 1970s to 2007) comprised the core data used in this assessment of efficacy of bismuth subsalicylate against infectious (including travelers') diarrhea. These studies allowed for statistical meta-analyses regarding prevention (three travelers' diarrhea studies) and treatment of infectious diarrhea (11 studies [five travelers' diarrhea]).
RESULTS
The results show that subjects treated with bismuth subsalicylate for up to 21 days have 3.5 times greater odds of preventing travelers' diarrhea compared with placebo (95% CI 2.1, 5.9; p < 0.001). In addition, subjects with infectious diarrhea treated with bismuth subsalicylate had 3.7 times greater odds of diarrhea relief (recorded on diaries as subjective symptomatic improvement) compared to those receiving placebo (95% CI 2.1, 6.3; p < 0.001).
CONCLUSIONS
This systematic review and meta-analysis suggests that bismuth subsalicylate can be beneficial for those at risk or affected by food and waterborne diarrheal disease such as traveler's (infectious) diarrhea, and may decrease the risk of inappropriate antibiotic utilization.
Topics: Bismuth; Communicable Diseases; Diarrhea; Humans; Organometallic Compounds; Salicylates; Travel
PubMed: 32772204
DOI: 10.1007/s10620-020-06509-7 -
The Cochrane Database of Systematic... Jul 2020Foot ulcers in people with diabetes are non-healing, or poorly healing, partial, or full-thickness wounds below the ankle. These ulcers are common, expensive to manage... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Foot ulcers in people with diabetes are non-healing, or poorly healing, partial, or full-thickness wounds below the ankle. These ulcers are common, expensive to manage and cause significant morbidity and mortality. The presence of a wound has an impact on nutritional status because of the metabolic cost of repairing tissue damage, in addition to the nutrient losses via wound fluid. Nutritional interventions may improve wound healing of foot ulcers in people with diabetes.
OBJECTIVES
To evaluate the effects of nutritional interventions on the healing of foot ulcers in people with diabetes.
SEARCH METHODS
In March 2020 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that evaluated the effect of nutritional interventions on the healing of foot ulcers in people with diabetes.
DATA COLLECTION AND ANALYSIS
Two review authors, working independently, assessed included RCTs for their risk of bias and rated the certainty of evidence using GRADE methodology, using pre-determined inclusion and quality criteria.
MAIN RESULTS
We identified nine RCTs (629 participants). Studies explored oral nutritional interventions as follows: a protein (20 g protein per 200 mL bottle), 1 kcal/mL ready-to-drink, nutritional supplement with added vitamins, minerals and trace elements; arginine, glutamine and β-hydroxy-β-methylbutyrate supplement; 220 mg zinc sulphate supplements; 250 mg magnesium oxide supplements; 1000 mg/day omega-3 fatty acid from flaxseed oil; 150,000 IU of vitamin D, versus 300,000 IU of vitamin D; 250 mg magnesium oxide plus 400 IU vitamin E and 50,000 IU vitamin D supplements. The comparator in eight studies was placebo, and in one study a different dose of vitamin D. Eight studies reported the primary outcome measure of ulcer healing; only two studies reported a measure of complete healing. Six further studies reported measures of change in ulcer dimension, these studies reported only individual parameters of ulcer dimensions (i.e. length, width and depth) and not change in ulcer volume. All of the evidence identified was very low certainty. We downgraded it for risks of bias, indirectness and imprecision. It is uncertain whether oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements, increases the proportion of ulcers healed at six months more than placebo (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.42 to 1.53). It is also uncertain whether arginine, glutamine and β-hydroxy-β-methylbutyrate supplement increases the proportion of ulcers healed at 16 weeks compared with placebo (RR 1.09, 95% CI 0.85 to 1.40). It is uncertain whether the following interventions change parameters of ulcer dimensions over time when compared with placebo; 220 mg zinc sulphate supplement containing 50 mg elemental zinc, 250 mg magnesium oxide supplement, 1000 mg/day omega-3 fatty acid from flaxseed oil supplement, magnesium and vitamin E co-supplementation and vitamin D supplementation. It is also uncertain whether 150,000 IU of vitamin D, impacts ulcer dimensions when compared with 300,000 IU of vitamin D. Two studies explored some of the secondary outcomes of interest for this review. It is uncertain whether oral nutritional supplement with 20 g protein per 200 mL bottle, 1 kcal/mL, nutritional supplement with added vitamins, minerals and trace elements, reduces the number of deaths (RR 0.96, 95% CI 0.06 to 14.60) or amputations (RR 4.82, 95% CI 0.24 to 95.88) more than placebo. It is uncertain whether arginine, glutamine and β-hydroxy-β-methylbutyrate supplement increases health-related quality of life at 16 weeks more than placebo (MD -0.03, 95% CI -0.09 to 0.03). It is also uncertain whether arginine, glutamine and β-hydroxy-β-methylbutyrate supplement reduces the numbers of new ulcers (RR 1.04, 95% CI 0.71 to 1.51), or amputations (RR 0.66, 95% CI 0.16 to 2.69) more than placebo. None of the included studies reported the secondary outcomes cost of intervention, acceptability of the intervention (or satisfaction) with respect to patient comfort, length of patient hospital stay, surgical interventions, or osteomyelitis incidence. One study exploring the impact of arginine, glutamine and β-hydroxy-β-methylbutyrate supplement versus placebo did not report on any relevant outcomes.
AUTHORS' CONCLUSIONS
Evidence for the impact of nutritional interventions on the healing of foot ulcers in people with diabetes compared with no nutritional supplementation, or compared with a different dose of nutritional supplementation, remains uncertain, with eight studies showing no clear benefit or harm. It is also uncertain whether there is a difference in rates of adverse events, amputation rate, development of new foot ulcers, or quality of life, between nutritional interventions and placebo. More research is needed to clarify the impact of nutritional interventions on the healing of foot ulcers in people with diabetes.
Topics: Arginine; Diabetic Foot; Dietary Proteins; Dietary Supplements; Fatty Acids, Omega-3; Female; Glutamine; Humans; Magnesium; Magnesium Oxide; Male; Middle Aged; Minerals; Randomized Controlled Trials as Topic; Trace Elements; Valerates; Vitamins; Wound Healing; Zinc Sulfate
PubMed: 32677037
DOI: 10.1002/14651858.CD011378.pub2 -
Animal Health Research Reviews Dec 2019A systematic review and network meta-analysis were conducted to assess the relative efficacy of internal or external teat sealants given at dry-off in dairy cattle.... (Meta-Analysis)
Meta-Analysis
A systematic review and network meta-analysis were conducted to assess the relative efficacy of internal or external teat sealants given at dry-off in dairy cattle. Controlled trials were eligible if they assessed the use of internal or external teat sealants, with or without concurrent antimicrobial therapy, compared to no treatment or an alternative treatment, and measured one or more of the following outcomes: incidence of intramammary infection (IMI) at calving, IMI during the first 30 days in milk (DIM), or clinical mastitis during the first 30 DIM. Risk of bias was based on the Cochrane Risk of Bias 2.0 tool with modified signaling questions. From 2280 initially identified records, 32 trials had data extracted for one or more outcomes. Network meta-analysis was conducted for IMI at calving. Use of an internal teat sealant (bismuth subnitrate) significantly reduced the risk of new IMI at calving compared to non-treated controls (RR = 0.36, 95% CI 0.25-0.72). For comparisons between antimicrobial and teat sealant groups, concerns regarding precision were seen. Synthesis of the primary research identified important challenges related to the comparability of outcomes, replication and connection of interventions, and quality of reporting of study conduct.
Topics: Animals; Antacids; Anti-Bacterial Agents; Bismuth; Cattle; Female; Mammary Glands, Animal; Mastitis, Bovine; Network Meta-Analysis
PubMed: 32081124
DOI: 10.1017/S1466252319000276 -
Clinical Therapeutics Mar 2020Acid-suppressive medications are widely used in non-intensive care unit (non-ICU) patients for stress ulcer (SU) prophylaxis. However, SU prophylaxis in this population... (Meta-Analysis)
Meta-Analysis
PURPOSE
Acid-suppressive medications are widely used in non-intensive care unit (non-ICU) patients for stress ulcer (SU) prophylaxis. However, SU prophylaxis in this population is still controversial. The purpose of this study was to systematically evaluate the efficacy and tolerability of these agents for SU prophylaxis in non-ICU patients.
METHODS
Electronic databases including Cochrane, ClinicalTrials.gov, Ovid-Medline, Embase, Chinese CNKI, and Wanfang Data were systematically searched on July 10, 2019, for randomized controlled trials (RCTs) that evaluated acid-suppressive medications in non-ICU patients. Network meta-analysis and pairwise meta-analysis were performed to calculate odds ratios (ORs) and 95% CIs. A random-effects model was used for generating pooled estimates. The primary outcome was occurrence of SU bleeding, and the adverse drug events (ADEs) were described as the secondary outcome.
FINDINGS
A total of 17 RCTs involving 1985 patients were eligible. Meta-analysis results indicated that the occurrence of SU bleeding was significantly decreased with all acid-suppressive medications compared with placebos (gastric mucosa protectants, OR = 0.29 [95% CI, 0.14-0.61]; H2-receptor antagonists, OR = 0.3 [95% CI, 0.18-0.50]; proton pump inhibitors [PPIs]: OR = 0.08 [95% CI, 0.04-0.16]). The occurrence of SU bleeding was significantly decreased with PPIs compared with gastric mucosa protectants (OR = 0.29; 95% CI, 0.12-0.72) and H2-receptor antagonists (OR = 0.28; 95% CI, 0.16-0.48). There was no significant difference between any 2 classes of PPIs on SU bleeding or any 2 acid-suppressive medications on ADEs.
IMPLICATIONS
PPIs could significantly decrease SU bleeding risk without increasing ADEs than other acid-suppressive medications for SU prophylaxis in non-ICU patients. However, RCTs of high quality were required to confirm the findings of this investigation.
Topics: Antacids; Histamine H2 Antagonists; Humans; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Stomach Ulcer
PubMed: 32046894
DOI: 10.1016/j.clinthera.2020.01.008 -
PloS One 2019Several clinical prediction rules (CPRs) for complications and mortality of Clostridioides difficile infection (CDI) have been developed but only a few have gone through...
BACKGROUND
Several clinical prediction rules (CPRs) for complications and mortality of Clostridioides difficile infection (CDI) have been developed but only a few have gone through external validation, and none is widely recommended in clinical practice.
METHODS
CPRs were identified through a systematic review. We included studies that predicted severe or complicated CDI (cCDI) and mortality, reported at least an internal validation step, and for which data were available with minimal modifications. Data from a multicenter prospective cohort of 1380 adults with confirmed CDI were used for external validation. In this cohort, cCDI occurred in 8% of the patients and 30-day all-cause mortality occurred in 12%. The performance of each tool was assessed using individual outcomes, with the same cut-offs and standard parameters.
RESULTS
Seven CPRs were assessed. Three predictive scores for cCDI showed low sensitivity (25-61%) and positive predictive value (PPV; 9-31%), but moderate specificity (54-90%) and negative predictive value (NPV; 82-95%). One model [using age, white blood cell count (WBC), narcotic use, antacids use, and creatinine ratio > 1.5× the normal level as covariates] showed a probability of 25% of cCDI at the optimal cut-off point with 36% sensitivity and 84% specificity. Two scores for mortality had low sensitivity (4-55%) and PPV (25-31%), and moderate specificity (71-78%) and NPV (87-92%). One predictive model for 30-day all-cause mortality [Charlson comorbidity index, WBC, blood urea nitrogen (BUN), diagnosis in ICU, and delirium] showed an AUC-ROC of 0.74. All other CPRs showed lower AUC values (0.63-0.69). Errors in calibration ranged from 12%- 27%.
CONCLUSIONS
Included CPRs showed moderate performance for clinical use in a large validation cohort with a majority of patients infected with ribotype 027 strains and a low rate of cCDI and mortality. These data show that better CPRs need to be developed and validated.
Topics: Clinical Decision Rules; Clostridioides difficile; Clostridium Infections; Humans; Predictive Value of Tests; Sensitivity and Specificity
PubMed: 31846487
DOI: 10.1371/journal.pone.0226672