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Biomolecules Sep 2023Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase... (Review)
Review
BACKGROUND
Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres on treatment response in adults with late-onset Pompe disease (LOPD) remains unclear but may contribute to interpatient variation. We therefore conducted a systematic review on this subject.
METHODS
A systematic search was performed in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Articles were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titres. In addition, articles mentioning dosages different from the standard recommended dosage were included.
RESULTS
Our literature search retrieved 2562 publications, and 17 fulfilled our selection criteria, describing 443 cases. Seven publications reported on anti-rhGAA antibody titres on a group level, with the percentage of patients with a high titre as defined in the included articles ranging from 0-33%. Six publications reported on the effect of anti-rhGAA antibody titre on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in Medical Research Council (MRC) score in patients with no detectable antibody titre. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titres. Seven publications reported on 17 individual patients with a high antibody titre (range 1:12,800-1:3,906,250). In only two cases were high-sustained neutralising antibodies reported to interfere with treatment efficacy.
CONCLUSIONS
No clear effect of anti-rhGAA IgG antibodies on treatment response could be established for the majority of LOPD patients with a high antibody titre. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described.
Topics: Humans; Adult; Glycogen Storage Disease Type II; alpha-Glucosidases; Treatment Outcome; Enzyme Replacement Therapy
PubMed: 37759814
DOI: 10.3390/biom13091414 -
Cancers Sep 2023Recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has poor survival rates. Immunotherapy is the standard of care for R/M HNSCC, but objective... (Review)
Review
BACKGROUND
Recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has poor survival rates. Immunotherapy is the standard of care for R/M HNSCC, but objective responses occur in a minority of patients. Toll-like receptor (TLR) agonists promote antitumor immune responses and have been explored in clinical trials.
METHODS
A search for clinical trials using TLR agonists in HNSCC was performed under PRISMA guidelines. Data on patient characteristics, safety, and efficacy were collected and analyzed.
RESULTS
Three phase 1b trials with 40 patients and three phase 2 trials with 352 patients studying TLR8 and TLR9 agonists in combination with other treatment regimens for HNSCC were included. In phase 2 trials, there was no significant change in the objective response rate (RR = 1.13, CI 0.80-1.60) or association with increased grade 3+ adverse events (RR = 0.91, CI 0.76-1.11) associated with TLR agonist use.
CONCLUSION
TLR agonists do not appear to provide additional clinical benefits or increase adverse events in the treatment of HNSCC. Given these results across multiple clinical trials and drug regimens, it is unlikely that additional trials of TLR agonists will demonstrate clinical benefits in HNSCC.
PubMed: 37686661
DOI: 10.3390/cancers15174386 -
Trauma, Violence & Abuse Apr 2024Informal supporters (friends, family, colleagues, and community members) play a crucial role in societal-wide responses to victim-survivors of domestic violence and... (Review)
Review
Informal supporters (friends, family, colleagues, and community members) play a crucial role in societal-wide responses to victim-survivors of domestic violence and abuse. Familial and social networks, however, report a sense of helplessness and difficulties in knowing how to respond. This mixed method systematic review examines the effectiveness, and perceived effectiveness, of training informal supporters to improve their responses to victim-survivors. A novel conceptual framework was developed to underpin the review. A systematic search of four electronic databases, specialist repositories, and websites were used to identify empirical research (in academic or gray literature). Eleven included studies examined educational interventions that aimed to improve responses from informal supporters. Quality appraisal was undertaken, and studies were judged to be "good enough" for synthesis. The studies in the review indicated that informal supporters recognized the value of training for building understanding and equipping them with the skills to respond to victim-survivors. The synthesis identified statistically significant improvements in the knowledge and attitudes of informal supporters in the immediate and short-term following training. Using a behavior change model to frame the evidence, the review found that training/educational activities prime informal supporters to respond to victim-survivors, as well as enhancing their capacity and motivation to do so. This increases the likelihood that informal supporters will take action to support victim-survivors of abuse. We don't know, however, what type of support they will provide and/or whether it would be judged to be helpful by victim-survivors.
Topics: Humans; Domestic Violence; Attitude; Friends; Survivors; Empirical Research
PubMed: 37649408
DOI: 10.1177/15248380231189191 -
Frontiers in Immunology 2023Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive... (Meta-Analysis)
Meta-Analysis
The benefit and risk of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small-cell lung cancer: a systematic review and single-arm meta-analysis of prospective clinical trials.
BACKGROUND
Previous studies revealed that Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus anti-angiogenic agents had extensive anti-tumor activities. However, almost all studies on the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer are non-randomized controlled trials with small sample sizes, which might lead to a lack of effective metrics to assess the effectiveness and safety of the therapeutic regimen. Here, this meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer.
METHODS
A single-arm meta-analysis was performed, and published literature from PubMed, Web of Science and Embase databases as of January 13, 2023, was systematically retrieved. We used the Cochrane risk of bias tool and methodological index for non-randomized studies (MINORS) Methodological items to evaluate the quality of eligible clinical trials. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. The random effect model is used to calculate the pooled parameters.
RESULTS
19 studies (16 were non-comparative single-arm clinical trials and 3 were randomized controlled trials) were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.4% (95% CI, 16.6-28.1%) and 76.8% (95% CI, 72.6-81.1%), respectively. With regard to survival analysis, the pooled PFS and OS were 5.20 (95% CI, 4.46-5.93) months and 14.09 (95% CI, 13.20-14.97) months, respectively. The pooled grade ≥3 adverse effect (AE) rate was 47.6% (95% CI, 33.1-62.0%).
CONCLUSION
PD-1/PD-L1 inhibitors plus anti-angiogenic agents has promising efficacy and safety as second or later-line treatment in patients with advanced non-small cell lung cancer.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42023407559.
Topics: Humans; Angiogenesis Inhibitors; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Programmed Cell Death 1 Receptor; Prospective Studies; Clinical Trials as Topic
PubMed: 37614237
DOI: 10.3389/fimmu.2023.1218258 -
The Journal of Infectious Diseases Nov 2023HIV poses significant challenges for vaccine development due to its high genetic mutation and recombination rates. Understanding the distribution of HIV subtypes... (Meta-Analysis)
Meta-Analysis
Geographic and Population Distributions of Human Immunodeficiency Virus (HIV)-1 and HIV-2 Circulating Subtypes: A Systematic Literature Review and Meta-analysis (2010-2021).
BACKGROUND
HIV poses significant challenges for vaccine development due to its high genetic mutation and recombination rates. Understanding the distribution of HIV subtypes (clades) across regions and populations is crucial. In this study, a systematic review of the past decade was conducted to characterize HIV-1/HIV-2 subtypes.
METHODS
A comprehensive search was performed in PubMed, EMBASE, and CABI Global Health, yielding 454 studies from 91 countries.
RESULTS
Globally, circulating recombinant forms (CRFs)/unique recombinant forms (URFs) accounted for 29% of HIV-1 strains, followed by subtype C (23%) and subtype A (17%). Among studies reporting subtype breakdowns in key populations, 62% of HIV infections among men who have sex with men (MSM) and 38% among people who inject drugs (PWIDs) were CRF/URFs. Latin America and the Caribbean exhibited a 25% increase in other CRFs (excluding CRF01_AE or CRF02_AG) prevalence between 2010-2015 and 2016-2021.
CONCLUSIONS
This review underscores the global distribution of HIV subtypes, with an increasing prevalence of CRFs and a lower prevalence of subtype C. Data on HIV-2 were limited. Understanding subtype diversity is crucial for vaccine development, which need to elicit immune responses capable of targeting various subtypes. Further research is needed to enhance our knowledge and address the challenges posed by HIV subtype diversity.
Topics: Male; Humans; HIV Infections; Homosexuality, Male; HIV-1; HIV-2; Genetic Variation; Phylogeny; Sexual and Gender Minorities; Prevalence; Genotype
PubMed: 37592824
DOI: 10.1093/infdis/jiad327 -
Frontiers in Public Health 2023Identifying SARS-CoV-2 infection risk factors allows targeted public health and social measures (PHSM). As new, more transmissible variants of concern (VoC) emerge,...
INTRODUCTION
Identifying SARS-CoV-2 infection risk factors allows targeted public health and social measures (PHSM). As new, more transmissible variants of concern (VoC) emerge, vaccination rates increase and PHSM are eased, it is important to understand any potential change to infection risk factors. The aim of this systematic literature review is to describe the risk factors for SARS-CoV-2 infection by VoC.
METHODS
A literature search was performed in MEDLINE, PubMed and Embase databases on 5 May 2022. Eligibility included: observational studies published in English after 1 January 2020; any age group; the outcome of SARS-CoV-2 infection; and any potential risk factors investigated in the study. Results were synthesized into a narrative summary with respect to measures of association, by VoC. ROBINS-E tool was utilized for risk of bias assessment.
RESULTS
Of 6,197 studies retrieved, 43 studies were included after screening. Common risk factors included older age, minority ethnic group, low socioeconomic status, male gender, increased household size, occupation/lower income level, inability to work from home, public transport use, and lower education level. Most studies were undertaken when the ancestral strain was predominant. Many studies had some selection bias due to testing criteria and limited laboratory capacity.
CONCLUSION
Understanding who is at risk enables the development of strategies that target priority groups at each of the different stages of a pandemic and helps inform vaccination strategies and other interventions which may also inform public health responses to future respiratory infection outbreaks. While it was not possible to determine changes to infection risk by recent VoC in this review, the risk factors identified will add to the overall understanding of the groups who are at greatest risk of infection in the early stages of a respiratory virus outbreak.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022330706, PROSPERO [CRD42022330706].
Topics: Humans; Male; Bias; COVID-19; Pandemics; Risk Factors; SARS-CoV-2
PubMed: 37583888
DOI: 10.3389/fpubh.2023.1178167 -
BMC Medical Education Aug 2023Health disparities experienced by LGBTQ + individuals have been partially attributed to health professionals' lack of cultural competence to work with them. Cultural...
BACKGROUND
Health disparities experienced by LGBTQ + individuals have been partially attributed to health professionals' lack of cultural competence to work with them. Cultural competence, the intricate integration of knowledge, skills, attitudes, and behaviors that improve cross-cultural communication and interpersonal relationships, has been used as a training framework to enhance interactions between LGBTQ + patients and health professionals. Despite multiple published LGBTQ + cultural competency trainings, there has been no quantitative appraisal and synthesis of them. This systematic review assessed articles evaluating the design and effectiveness of these trainings and examined the magnitude of their effect on cultural competence outcomes.
METHODS
Included studies quantitatively examined the effectiveness of LGBTQ + cultural competency trainings for health professionals across all disciplines in various healthcare settings. 2,069 citations were retrieved from five electronic databases with 44 articles meeting inclusion criteria. The risk of bias in the included studies was assessed by two authors utilizing the Joanna Briggs Institute critical appraisal checklists. Data extracted included study design, country/region, sample characteristic, training setting, theoretical framework, training topic, modality, duration, trainer, training target, measurement instrument, effect size and key findings. This review followed the PRISMA statement and checklist to ensure proper reporting.
RESULTS
75% of the studies were published between 2017 and 2023. Four study designs were used: randomized controlled trial (n = 1), quasi-experimental pretest-posttest without control (n = 39), posttest only with control (n = 1) and posttest only without control (n = 3). Training modalities were multiple modalities with (n = 9) and without simulation (n = 25); single modality with simulation (n = 1); and with didactic lectures (n = 9). Trainings averaged 3.2 h. Ten studies employed LGBTQ + trainers. The training sessions resulted in statistically significant improvements in the following cultural competence constructs: (1) knowledge of LGBTQ + culture and health (n = 28, effect size range = 0.28 - 1.49), (2) skills to work with LGBTQ + clients (n = 8, effect size range = 0.12 - 1.12), (3) attitudes toward LGBTQ + individuals (n = 14, effect size range = 0.19 - 1.03), and (4) behaviors toward LGBTQ + affirming practices (n = 7, effect size range = 0.51 - 1.11).
CONCLUSIONS
The findings of this review highlight the potential of LGBTQ + cultural competency training to enhance cultural competence constructs, including (1) knowledge of LGBTQ + culture and health, (2) skills to work with LGBTQ + clients, (3) attitudes toward LGBTQ + individuals, and (4) behaviors toward LGBTQ + affirming practices, through an interdisciplinary and multi-modal approach. Despite the promising results of LGBTQ + cultural competency training in improving health professionals' cultural competence, there are limitations in study designs, sample sizes, theoretical framing, and the absence of longitudinal assessments and patient-reported outcomes, which call for more rigorous research. Moreover, the increasing number of state and federal policies that restrict LGBTQ + health services highlight the urgency of equipping health professionals with culturally responsive training. Organizations and health systems must prioritize organizational-level changes that support LGBTQ + inclusive practices to provide access to safe and affirming healthcare services for LGBTQ + individuals.
Topics: Humans; Cultural Competency; Attitude; Health Personnel; Sexual and Gender Minorities
PubMed: 37559033
DOI: 10.1186/s12909-023-04373-3 -
The Cochrane Database of Systematic... Jul 2023Primary healthcare (PHC) integration has been promoted globally as a tool for health sector reform and universal health coverage (UHC), especially in low-resource... (Review)
Review
BACKGROUND
Primary healthcare (PHC) integration has been promoted globally as a tool for health sector reform and universal health coverage (UHC), especially in low-resource settings. However, for a range of reasons, implementation and impact remain variable. PHC integration, at its simplest, can be considered a way of delivering PHC services together that sometimes have been delivered as a series of separate or 'vertical' health programmes. Healthcare workers are known to shape the success of implementing reform interventions. Understanding healthcare worker perceptions and experiences of PHC integration can therefore provide insights into the role healthcare workers play in shaping implementation efforts and the impact of PHC integration. However, the heterogeneity of the evidence base complicates our understanding of their role in shaping the implementation, delivery, and impact of PHC integration, and the role of contextual factors influencing their responses.
OBJECTIVES
To map the qualitative literature on healthcare workers' perceptions and experiences of PHC integration to characterise the evidence base, with a view to better inform future syntheses on the topic.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 28 July 2020. We did not search for grey literature due to the many published records identified.
SELECTION CRITERIA
We included studies with qualitative and mixed methods designs that reported on healthcare worker perceptions and experiences of PHC integration from any country. We excluded settings other than PHC and community-based health care, participants other than healthcare workers, and interventions broader than healthcare services. We used translation support from colleagues and Google Translate software to screen non-English records. Where translation was not feasible we categorised these records as studies awaiting classification.
DATA COLLECTION AND ANALYSIS
For data extraction, we used a customised data extraction form containing items developed using inductive and deductive approaches. We performed independent extraction in duplicate for a sample on 10% of studies allowed for sufficient agreement to be reached between review authors. We analysed extracted data quantitatively by counting the number of studies per indicator and converting these into proportions with additional qualitative descriptive information. Indicators included descriptions of study methods, country setting, intervention type, scope and strategies, implementing healthcare workers, and client target population.
MAIN RESULTS
The review included 184 studies for analysis based on 191 included papers. Most studies were published in the last 12 years, with a sharp increase in the last five years. Studies mostly employed methods with cross-sectional qualitative design (mainly interviews and focus group discussions), and few used longitudinal or ethnographic (or both) designs. Studies covered 37 countries, with close to an even split in the proportions of high-income countries (HICs) and low- and middle-income countries (LMICs). There were gaps in the geographical spread for both HICs and LMICs and some countries were more dominant, such as the USA for HICs, South Africa for middle-income countries, and Uganda for low-income countries. Methods were mainly cross-sectional observational studies with few longitudinal studies. A minority of studies used an analytical conceptual model to guide the design, implementation, and evaluation of the integration study. The main finding was the various levels of diversity found in the evidence base on PHC integration studies that examined healthcare workers' perceptions and experiences. The review identified six different configurations of health service streams that were being integrated and these were categorised as: mental and behavioural health; HIV, tuberculosis (TB) and sexual reproductive health; maternal, women, and child health; non-communicable diseases; and two broader categories, namely general PHC services, and allied and specialised services. Within the health streams, the review mapped the scope of the interventions as full or partial integration. The review mapped the use of three different integration strategies and categorised these as horizontal integration, service expansion, and service linkage strategies. The wide range of healthcare workers who participated in the implementation of integration interventions was mapped and these included policymakers, senior managers, middle and frontline managers, clinicians, allied healthcare professionals, lay healthcare workers, and health system support staff. We mapped the range of client target populations.
AUTHORS' CONCLUSIONS
This scoping review provides a systematic, descriptive overview of the heterogeneity in qualitative literature on healthcare workers' perceptions and experience of PHC integration, pointing to diversity with regard to country settings; study types; client populations; healthcare worker populations; and intervention focus, scope, and strategies. It would be important for researchers and decision-makers to understand how the diversity in PHC integration intervention design, implementation, and context may influence how healthcare workers shape PHC integration impact. The classification of studies on the various dimensions (e.g. integration focus, scope, strategy, and type of healthcare workers and client populations) can help researchers to navigate the way the literature varies and for specifying potential questions for future qualitative evidence syntheses.
Topics: Child; Female; Humans; Cross-Sectional Studies; Family; Health Personnel; Health Services; Primary Health Care
PubMed: 37466272
DOI: 10.1002/14651858.CD013603.pub3 -
The Lancet. HIV Aug 2023Gay, bisexual, and other men who have sex with men (MSM) are disproportionately affected by HIV. In Africa, MSM face structural barriers to HIV prevention and treatment... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Gay, bisexual, and other men who have sex with men (MSM) are disproportionately affected by HIV. In Africa, MSM face structural barriers to HIV prevention and treatment that increase their vulnerability to HIV acquisition and transmission, and undermine the HIV response. In this systematic review, we aimed to explore progress towards increases in HIV testing, improving engagement in the HIV treatment cascade, and HIV incidence reductions among MSM in Africa.
METHODS
We searched Embase, MEDLINE, Global Health, Scopus, and Web of Science for cross-sectional and longitudinal studies reporting HIV testing, knowledge of status, care, antiretroviral therapy (ART) use, viral suppression, and HIV incidence among MSM in Africa published between Jan 1, 1980, and March 3, 2023. We pooled surveys using Bayesian generalised linear mixed-effects models, used meta-regression to assess time trends, and compared HIV incidence estimates among MSM with those of all men.
FINDINGS
Of 9278 articles identified, we included 152 unique studies published in 2005-23. In 2020, we estimate that 73% (95% credible interval [CrI] 62-87) of MSM had ever tested for HIV. HIV testing in the past 12 months increased over time in central, western, eastern, and southern Africa (odds ratio per year [OR] 1·23, 95% CrI 1·01-1·51, n=46) and in 2020 an estimated 82% (70-91) had tested in the past 12 months, but only 51% (30-72) of MSM living with HIV knew their HIV status. Current ART use increased over time in central and western (OR 1·41, 1·08-1·93, n=9) and eastern and southern Africa (OR 1·37, 1·04-1·84, n=17). We estimated that, in 2020, 73% (47-88) of all MSM living with HIV in Africa were currently on ART. Nevertheless, we did not find strong evidence to suggest that viral suppression increased, with only 69% (38-89) of MSM living with HIV estimated to be virally suppressed in 2020. We found insufficient evidence of a decrease in HIV incidence over time (incidence ratio per year 0·96, 95% CrI 0·63-1·50, n=39), and HIV incidence remained high in 2020 (6·9 per 100 person-years, 95% CrI 3·1-27·6) and substantially higher (27-199 times higher) than among all men.
INTERPRETATION
HIV incidence remains high, and might not be decreasing among MSM in Africa over time, despite some increases in HIV testing and ART use. Achieving the UNAIDS 95-95-95 targets for diagnosis, treatment, and viral suppression equitably for all requires renewed focus on this key population. Combination interventions for MSM are urgently required to reduce disparities in HIV incidence and tackle the social, structural, and behavioural factors that make MSM vulnerable to HIV acquisition.
FUNDING
US National Institutes of Health, UK Medical Research Council, Canadian Institutes of Health Research, and Fonds de Recherche du Québec-Santé.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Male; Humans; HIV Infections; Homosexuality, Male; Incidence; Cross-Sectional Studies; Bayes Theorem; Sexual and Gender Minorities; Canada; HIV Testing; Africa, Southern
PubMed: 37453439
DOI: 10.1016/S2352-3018(23)00111-X -
Journal of Crohn's & Colitis Jan 2024The aim of this systematic review and meta-analysis is to assess the efficacy and safety of faecal microbiota transplantation [FMT] in the treatment of chronic pouchitis. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The aim of this systematic review and meta-analysis is to assess the efficacy and safety of faecal microbiota transplantation [FMT] in the treatment of chronic pouchitis.
METHODS
A PRISMA-compliant systematic review and meta-analysis was conducted using the following databases and clinical trial registers: Medline, Embase, Scopus, Cochrane Database of Systematic Reviews [CENTRAL], clinical trials.gov, ScienceDirect, and VHL [virtual health library]. The primary outcome was clinical response/remission in patients treated with FMT. Secondary outcomes included safety profile, quality of life, and changes in the gut microbiome.
RESULTS
Seven observational cohort studies/case series and two randomised, controlled trials with a total of 103 patients were included. The route, preparation, and quantity of FMT administered varied among the included studies. Clinical response rate of 42.6% with a remission rate of 29.8% was estimated in our cohort following FMT therapy. Minor, self-limiting, adverse events were reported, and the treatment was well tolerated with good short- and long-term safety profiles. Successful FMT engraftment in recipients varied and, on average, microbial richness and diversity was lower in patients with pouchitis. In some instances, shifts with specific changes towards abundance of species, suggestive of a 'healthier' pouch microbiota, were observed following treatment with FMT.
CONCLUSION
The evidence for FMT in the treatment of chronic pouchitis is sparse, which limits any recommendations being made for its use in clinical practice. Current evidence from low-quality studies suggests a variable clinical response and remission rate, but the treatment is well tolerated, with a good safety profile. This review emphasises the need for rationally designed, well-powered, randomised, placebo-controlled trials to understand the efficacy of FMT for the treatment of pouchitis.
Topics: Humans; Fecal Microbiota Transplantation; Pouchitis; Quality of Life; Remission Induction; Gastrointestinal Microbiome; Treatment Outcome; Feces; Randomized Controlled Trials as Topic
PubMed: 37450947
DOI: 10.1093/ecco-jcc/jjad120