The role of QRS complex prolongation in predicting severe toxicity in single-xenobiotic overdose.

OBJECTIVE: The QRS complex duration is commonly used to prognosticate severity, predict outcomes, and indicate treatment in overdose. However, literature to support this practice is mixed in tricyclic antidepressant overdoses and absent in non-tricyclic antidepressant overdoses. Our objective was to assess the validity of QRS complex duration as a prognostic marker in overdose. METHODS: This was a secondary analysis of cases reported to the Toxicology Investigators Consortium between January 1, 2010, and December 31, 2022. Cases were assessed to determine the six xenobiotics most associated with QRS complex prolongation. All cases involving these six xenobiotics, regardless of QRS complex duration, constituted the study cohort. Inclusion criteria were cases of patients older than 12 years old with single-xenobiotic exposures. Clinical outcomes evaluated were seizure, ventricular dysrhythmia, metabolic acidosis, and death. RESULTS: Of 94,939 total cases, diphenhydramine, amitriptyline, bupropion, quetiapine, nortriptyline, and cocaine were most associated with QRS complex prolongation. Inclusion criteria were met by 4,655 cases of exposure to these xenobiotics. QRS complex prolongation was associated with increased odds ratio of seizure in all included xenobiotics, of ventricular dysrhythmia in all included xenobiotics except nortriptyline, and of metabolic acidosis or death in all included xenobiotics except nortriptyline and quetiapine. A normal QRS complex duration had a negative predictive value of greater than or equal to 93.0 percent of developing metabolic acidosis and 98.0 percent of developing a ventricular dysrhythmia or death from the xenobiotics studied. DISCUSSION: This study demonstrates that patients with QRS complex prolongation from all six xenobiotics studied had an increased prevalence and odds of developing severe outcomes. Furthermore, patients who did not develop QRS complex prolongation were unlikely to develop a ventricular dysrhythmia, metabolic acidosis, or death. These findings were noted in six xenobiotics that mechanistically can cause QRS complex prolongation through sodium channel or gap junction inhibition. CONCLUSION: Identification of patients at risk for severe outcomes after overdose can be aided by measuring the QRS complex duration. If prospectively validated, these outcomes have implications on risk stratification, disposition level of care, and appropriateness of treatments.

The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers.

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine ß-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E. coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.

Bioelectrical impedance analysis as a clinical marker of health status in adult patients with benign gastrointestinal disease: A systematic review.

BACKGROUND: Body composition reflects nutritional status, disease status and progression, and treatment responses. Mounting evidence supports the use of bioelectrical impedance analysis (BIA) as a non-invasive tool to assess body composition. Patients with benign gastrointestinal (GI) disease experience disease-related alterations in their body composition, and bioimpedance outcomes in patients with benign GI diseases have not previously been summarized. We aimed to evaluate BIA as a clinical body composition marker for benign GI diseases and describe its association with physical health status. METHODS: We systematically searched PubMed, Scopus, Web of Science, Embase, and CINAHL from inception to October 2023 (PROSPERO registration: CRD42021265866). Of 971 screened studies, 26 studies were included in the final analysis, comprising a total of 2398 adult patients with benign GI disease. The main outcome was raw impedance data. RESULTS: The most frequently reported BIA outcome was phase angle (PhA) (reported in 18 of 26 studies), followed by fat-free-mass (FFM) (reported in 13 of 26 studies). The consensus view of the included studies illustrates that BIA can be a useful tool for evaluating body composition in patients with benign GI diseases, and low PhA and FFM were associated with increased nutritional risk, abnormal physical characteristics, and increased mortality risk. CONCLUSION: To fully utilize BIA as a clinical marker of health in patients with benign GI disease, standardized protocols specific to this population are needed and prospective studies testing cut-offs and ranges, accuracy, and other raw BIA parameters for classifying disease status.

Age-related changes in the endocranial capacity and surface area of ancient children from the Zaghunluq Cemetery (650-150 BCE) in Xinjiang, Northwestern China.

Early childhood is an important period for the rapid growth of the brain, which is crucial to neural connection and cognitive development. The purpose of this study is to characterize the age changes of endocasts in ancient children in Northwestern China (2600-2100 BP) to enrich our understanding of brain growth. 28 crania of ancient children excavated from the Zaghunluq cemetery were analyzed using endocasts generated from CT images. The endocast features of age-related changes were assessed by comparing the endocranial volume (cranial capacity), the intracranial surface area, and their ratios among different age groups: 2, 3-5, 6-7, 8-10, 12-15, and 17-19 years. The results demonstrated that with the increase of age, the volume and the surface area of children's endocasts seem to increase between age groups. The growth spurt periods of endocranial volume are 3-5 years old and 8-10 years old, and the growth spurt period of endocranial surface area is 3-5 years old, similar to the patterns in modern children. The increase of endocast surface area is smaller than that of volume, resulting in an overall increase in the ratio of endocranial volume to surface area, indicating a trend of gradual globularization of the brain.

A Case Report of Venezuelan Suntiger Tarantula (Psalmopoeus Irminia) Envenomation and Review of Tarantula Exposures.

BACKGROUND: Tarantula envenomations are encountered infrequently but may increase with increased exotic animal ownership. This case report presents the first documented toxicity from a Venezuelan suntiger tarantula (VST), Psalmopoeus irminia, and provides a general framework for approaching patients with tarantula exposures. CASE REPORT: A 35-year-old man presented to an emergency department 4 h after experiencing a bite from his pet VST. He developed erythema, pain, and edema to the bite site on the left thenar eminence that extended proximally. Within 4 h, he developed abdominal pain, nausea, vomiting, throat itching, and tightness. The patient had a blood pressure of 131/105 mm Hg, heart rate of 102 beats/min, 36.6°C, respiratory rate of 20 breaths/min, and SpO2 of 94%. Laboratory evaluations were within normal limits (other than chronically elevated but improved transaminases). The patient received 0.5 mg epinephrine intramuscularly, 50 mg diphenhydramine IV, 20 mg famotidine IV, 0.4 mg ondansetron IV, and 1 L of normal saline for a suspected anaphylactic reaction. Shortly after epinephrine administration, his gastrointestinal and upper airway symptoms resolved. All symptoms resolved within 1 week. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Little is known about VST toxicity. Therefore, providers should rely on a general framework for approaching patients with tarantula exposures. Morbidity from tarantula exposures is mediated by mechanical injury, venom effects, and hypersensitivity reactions. Typical clinical findings include local pain, pruritis, edema, erythema, and burning. Muscle cramping, ophthalmia nodosa, and hypersensitivity reactions may occur. Treatment is primarily supportive and includes decontamination, cool compresses, analgesia, treatment of anaphylaxis, and ophthalmology evaluation if ocular exposure.

Toxic Tetrahydrocannabinol (THC) Dose in Pediatric Cannabis Edible Ingestions.

OBJECTIVE: The study characterizes cannabis toxicity in relation to tetrahydrocannabinol (THC) dose in pediatric edible cannabis ingestions. METHODS: This is a retrospective review of children aged <6 years presenting with edible cannabis ingestions of known THC dose within a pediatric hospital network (January 1, 2015-October 25, 2022). Cannabis toxicity was characterized as severe if patients exhibited severe cardiovascular (bradycardia, tachycardia/hypotension requiring vasopressors or intravenous fluids, other dysrhythmias), respiratory (respiratory failure, apnea, requiring oxygen supplementation), or neurologic (seizure, myoclonus, unresponsiveness, responsiveness to painful stimulation only, requiring intubation or sedation) effects. Cannabis toxicity was characterized as prolonged if patients required >6 hours to reach baseline. The relationship between THC dose and severe and prolonged toxicity was explored using multivariable logistic regression and receiver operator characteristic curve analyses. RESULTS: Eighty patients met inclusion. The median age was 2.9 years. The median THC ingestion was 2.1 mg/kg. Severe and prolonged toxicity was present in 46% and 74%, respectively. THC dose was a significant predictor of severe (adjusted odds ratio 2.9, 95% confidence interval: 1.8-4.7) and prolonged toxicity (adjusted odds ratio 3.2, 95% confidence interval: 1.6-6.5), whereas age and sex were not. Area under the curve was 92.9% for severe and 87.3% for prolonged toxicity. THC ingestions of ≥1.7 mg/kg can predict severe (sensitivity 97.3%) and prolonged toxicity (sensitivity 75.4%). CONCLUSIONS: The THC dose of edible cannabis correlates to the degree of toxicity in children <6 years old. The threshold of 1.7 mg/kg of THC may guide medical management and preventive regulations.

Adverse Events in Pregnant Patients Treated with Coronavirus Disease 2019 Therapeutics.

BACKGROUND: Pregnant patients are at high risk of maternal and fetal complications from Coronavirus Disease 2019 (COVID-19) infections. The COVID-19 pandemic prompted a surge in the development and repurposing of therapies for the SARS-CoV-2 virus. Evidence is sparse on the efficacy and safety of these therapies in pregnant patients. Our objective was to describe adverse events (AEs) to COVID-19 therapeutics in pregnant patients. METHODS: This was a case series of AEs reported to the FDA ACMT COVID-19 ToxIC (FACT) Pharmacovigilance Project between November 23, 2020, and June 28, 2022. FACT is an ongoing toxicosurveillance project at 17 sites to proactively identify and report AEs associated with COVID-19 therapeutics. Abstracted information includes demographics, case narratives, exposure details, clinical information, pregnancy details, treatments, and outcomes. RESULTS: Forty-six COVID-19-positive pregnant patients who developed AEs following COVID-19 therapeutics were reported to the FACT Pharmacovigilance Project over 19 months. The most reported medications were remdesivir in 22 patients (47.8%) and casirivimab/imdevimab in 8 patients (17.4%). Four patients (8.7%) had life-threatening clinical manifestation, and 16 patients (34.8%) required intervention to prevent permanent damage. The most common maternal and fetal events were elevated serum alanine aminotransferase (26.1%) and non-reassuring fetal heart patterns (20.0%), respectively. CONCLUSIONS: This case series reports AEs of elevated serum alanine aminotransferase, maternal bradycardia, maternal hypothermia, non-reassuring fetal heart patterns, and emergent or unplanned cesarean sections following administration of several COVID-19 therapeutics. This study was not designed to definitely identify causation, and further study is needed to evaluate the causal role of these therapeutics in AEs affecting pregnant COVID-19 patients.

Are antimuscarinic effects common in hydroxyzine overdose? A cohort analysis of antimuscarinic effects in hydroxyzine and diphenhydramine-poisoned patients.

INTRODUCTION: Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine. METHODS: This was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry. RESULTS: There were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively. DISCUSSION: The clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures. CONCLUSIONS: Hydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.

A methodology for the systematic identification of naturally occurring radioactive materials (NORM).

Naturally occurring radioactive materials (NORM) are present worldwide and under certain circumstances (e.g., human activities) may give radiation exposure to workers, local public or occasional visitors and non-human biota (NHB) of the surrounding ecosystems. This may occur during planned or existing exposure situations which, under current radiation protection standards, require identification, management, and regulatory control as for other practices associated with man-made radionuclides that may result in the exposure of people and NHB. However, knowledge gaps exist with respect to the extent of global and European NORM exposure situations and their exposure scenario characteristics, including information on the presence of other physical hazards, such as chemical and biological ones. One of the main reasons for this is the wide variety of industries, practices and situations that may utilise NORM. Additionally, the lack of a comprehensive methodology for identification of NORM exposure situations and the absence of tools to support a systematic characterisation and data collection at identified sites may also lead to a gap in knowledge. Within the EURATOM Horizon 2020 RadoNorm project, a methodology for systematic NORM exposure identification has been developed. The methodology, containing consecutive tiers, comprehensively covers situations where NORM may occur (i.e., minerals and raw materials deposits, industrial activities, industrial products and residues and their applications, waste, legacies), and thus, allows detailed investigation and complete identification of situations where NORM may present a radiation protection concern in a country. Details of the tiered methodology, with practical examples on harmonised data collection using a variety of existing sources of information to establish NORM inventories, are presented in this paper. This methodology is flexible and thus applicable to a diversity of situations. It is intended to be used to make NORM inventory starting from the scratch, however it can be used also to systematise and complete existing data.

Fecal microbiota transplantation for recurrent C. difficile infection in patients with inflammatory bowel disease: A systematic review and meta-analysis.

Fecal microbiota transplantation (FMT) is known to be highly effective in patients with recurrent Clostridioides difficile infection (rCDI), but its role in patients who also suffer from inflammatory bowel disease (IBD) is unclear. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of FMT for the treatment of rCDI in patients with IBD. We searched the available literature until November 22, 2022 to identify studies that included patients with IBD treated with FMT for rCDI, reporting efficacy outcomes after at least 8 weeks of follow-up. The proportional effect of FMT was summarized with a generalized linear mixed-effect model fitting a logistic regression accounting for different intercepts among studies. We identified 15 eligible studies, containing 777 patients. Overall, FMT achieved high cure rates of rCDI, 81% for single FMT, based on all included studies and patients, and 92% for overall FMT, based on nine studies with 354 patients, respectively. We found a significant advantage of overall FMT over single FMT in improving cure rates of rCDI (from 80% to 92%, p = 0.0015). Serious adverse events were observed in 91 patients (12% of the overall population), with the most common being hospitalisation, IBD-related surgery, or IBD flare. In conclusion, in our meta-analysis FMT achieved high cure rates of rCDI in patients with IBD, with a significant advantage of overall FMT over single FMT, similar to data observed in patients without IBD. Our findings support the use of FMT as a treatment for rCDI in patients with IBD.

Frailty level at discharge predicts mortality in older patients with Clostridioides difficile more accurately than age or disease severity.

PURPOSE: Clostridioides difficile infection (CDI) has a high mortality among older patients. Identification of older patients with CDI in increased mortality risk is important to target treatment and thereby reduce mortality. The aim of this study was to investigate mortality rates and compare frailty levels at discharge, measured by the record-based Multidimensional Prognostic Index (MPI), with age and severity of CDI as mortality predictors in patients with CDI diagnosed during hospitalisation. METHODS: This was a population-based cohort study from Central Denmark Region, Denmark, including all patients ≥ 60 years with a positive CD toxin test without prior infection and diagnosed from 1 January to 31 December 2018. Frailty level, estimated from the electronic medical record, was defined as low, moderate, or severe frailty. CDI severity was graded according to international guidelines. Primary outcome was 90-day mortality. RESULTS: We included 457 patients with median age 77 years (interquartile range 69-84) and females (49%). Overall, 90-day mortality was 28%, and this was associated with age (hazard ratio (HR): 2.71 (95% confidence interval 1.64-4.47)), CDI severity (HR 4.58 (3.04-6.88)) and frailty (HR 10.15 (4.06-25.36)). Frailty was a better predictor of 90-day mortality than both age (p < 0.001) and CDI severity (p = 0.04) with a receiver operating characteristic curve area of 77%. CONCLUSION: The 90-day mortality among older patients with CDI in a Danish region is 28%. Frailty measured by record-based MPI at discharge outperforms age and disease severity markers in predicting mortality in older patients with CDI.

Left Atrioventricular Transvalvular Pressure Gradients Derived from Intraoperative and Postoperative Echocardiograms following Atrioventricular Septal Defect Repair.

BACKGROUND: Left atrioventricular valve (LAVV) stenosis following an atrioventricular septal defect (AVSD) repair is a rare but potentially life-threatening complication. While echocardiographic quantification of diastolic transvalvular pressure gradients is paramount in the evaluation of a newly corrected valve function, it is hypothesized that these measured gradients are overestimated immediately following a cardiopulmonary bypass (CPB) due to the altered hemodynamics when compared to postoperative valve assessments using awake transthoracic echocardiography (TTE) upon recovery after surgery. METHODS: Out of the 72 patients screened for inclusion at a tertiary center, 39 patients undergoing an AVSD repair with both intraoperative transesophageal echocardiograms (TEE, performed immediately after a CPB) and an awake TTE (performed prior to hospital discharge) were retrospectively selected. The mean (MPGs) and peak pressure gradients (PPGs) were quantified using a Doppler echocardiography and other measures of interest were recorded (e.g., a non-invasive surrogate of the cardiac output and index (CI), left ventricular ejection fraction, blood pressures and airway pressures). The variables were analyzed using the paired Student's t-tests and Spearman's correlation coefficients. RESULTS: The MPGs were significantly higher in the intraoperative measurements when compared to the awake TTE (3.0 ± 1.2 vs. 2.3 ± 1.1 mmHg; p < 0.01); however, the PPGs did not significantly differ (6.6 ± 2.7 vs. 5.7 ± 2.8 mmHg; p = 0.06). Although the assessed intraoperative heart rates (HRs) were also higher (132 ± 17 vs. 114 ± 21 bpm; p < 0.001), there was no correlation found between the MPG and the HR, or any other parameter of interest, at either time-point. In a further analysis, a moderate to strong correlation was observed in the linear relationship between the CI and the MPG (r = 0.60; p < 0.001). During the in-hospital follow-up period, no patients died or required an intervention due to LAVV stenosis. CONCLUSIONS: The Doppler-based quantification of diastolic transvalvular LAVV mean pressure gradients using intraoperative transesophageal echocardiography seems to be prone to overestimation due to altered hemodynamics immediately after an AVSD repair. Thus, the current hemodynamic state should be taken into consideration during the intraoperative interpretation of these gradients.

Risk of Helicobacter pylori transmission by faecal microbiota transplantation via oral capsules.

OBJECTIVES: The aim was to determine if Helicobacter pylori is transmitted from donors to recipients by faecal microbiota transplantation (FMT) via oral capsules. METHODS: In a cohort of faeces donors not primarily screened for H. pylori, consecutive stool samples were retrospectively analysed by the H. pylori stool antigen test (SAT). Subsequently, we analysed recipient stool samples collected before and after receiving faeces donated by H. pylori SAT-positive donors, and we recorded recipient use of antibiotics and proton pump inhibitors. All stool samples were frozen upon collection and stored at -80°C until use. RESULTS: Thirteen out of 40 faeces donors (33%; 95% CI, 20-48%) were H. pylori SAT-positive. Among those positive, five donors donated faeces for 28 capsule-based FMTs performed in 26 recipients with stool samples collected before and after FMT. At a median of 59 days (range, 7-84 days) after FMT, no recipients (0%; 95% CI, 0-11%) were H. pylori SAT-positive. DISCUSSION: We found no occurrence of H. pylori transmission from healthy, asymptomatic donors to recipients by oral capsule-based FMT, although with a wide CI.

US Medical School Admissions Leaders' Experiences With Barriers to and Advancements in Diversity, Equity, and Inclusion.

Importance: Despite decades-long calls for increasing racial and ethnic diversity, the medical profession continues to exclude members of Black or African American, Hispanic or Latinx, and Indigenous groups. Objective: To describe US medical school admissions leaders' experiences with barriers to and advances in diversity, equity, and inclusion. Design, Setting, and Participants: This qualitative study involved key-informant interviews of 39 deans and directors of admission from 37 US allopathic medical schools across the range of student body racial and ethnic composition. Interviews were conducted in person and online from October 16, 2019, to March 27, 2020, and analyzed from October 2019 to March 2021. Main Outcomes and Measures: Participant experiences with barriers to and advances in diversity, equity, and inclusion. Results: Among 39 participants from 37 medical schools, admissions experience ranged from 1 to 40 years. Overall, 56.4% of participants identified as women, 10.3% as Asian American, 25.6% as Black or African American, 5.1% as Hispanic or Latinx, and 61.5% as White (participants could report >1 race and/or ethnicity). Participants characterized diversity broadly, with limited attention to racial injustice. Barriers to advancing racial and ethnic diversity included lack of leadership commitment; pressure from faculty and administrators to overemphasize academic scores and school rankings; and political and social influences, such as donors and alumni. Accreditation requirements, holistic review initiatives, and local policy motivated reforms but may also have inadvertently lowered expectations and accountability. Strategies to overcome challenges included narrative change and revision of school leadership structure, admissions goals, practices, and committee membership. Conclusions and Relevance: In this qualitative study, admissions leaders characterized the ways in which entrenched beliefs, practices, and power structures in medical schools may perpetuate institutional racism, with far-reaching implications for health equity. Participants offered insights on how to remove inequitable structures and implement process changes. Without such action, calls for racial justice will likely remain performative, and racism across health care institutions will continue.

Gut microbiota differs between treatment outcomes early after fecal microbiota transplantation against recurrent Clostridioides difficile infection.

AbstarctIn fecal microbiota transplantation (FMT) against recurrent Clostridioides difficile infection (CDI), clinical outcomes are usually determined after 8 weeks. We hypothesized that the intestinal microbiota changes earlier than this timepoint, and analyzed fecal samples obtained 1 week after treatment from 64 patients diagnosed with recurrent CDI and included in a randomized clinical trial, where the infection was treated with either vancomycin-preceded FMT (N = 24), vancomycin (N = 16) or fidaxomicin (N = 24). In comparison with non-responders, patients with sustained resolution after FMT had increased microbial alpha diversity, enrichment of Ruminococcaceae and Lachnospiraceae, depletion of Enterobacteriaceae, more pronounced donor microbiota engraftment, and resolution of gut microbiota dysbiosis. We found that a constructed index, based on markers for the identified genera Escherichia and Blautia, successfully predicted clinical outcomes at Week 8, which exemplifies a way to utilize clinically feasible methods to predict treatment failure. Microbiota changes were restricted to patients who received FMT rather than antibiotic monotherapy, indicating that FMT confers treatment response in a different way than antibiotics. We suggest that early identification of microbial community structures after FMT is of clinical value to predict response to the treatment.

Cross-generational bacterial strain transfer to an infant after fecal microbiota transplantation to a pregnant patient: a case report.

BACKGROUND: Fecal microbiota transplantation (FMT) effectively prevents the recurrence of Clostridioides difficile infection (CDI). Long-term engraftment of donor-specific microbial consortia may occur in the recipient, but potential further transfer to other sites, including the vertical transmission of donor-specific strains to future generations, has not been investigated. Here, we report, for the first time, the cross-generational transmission of specific bacterial strains from an FMT donor to a pregnant patient with CDI and further to her child, born at term, 26 weeks after the FMT treatment. METHODS: A pregnant woman (gestation week 12 + 5) with CDI was treated with FMT via colonoscopy. She gave vaginal birth at term to a healthy baby. Fecal samples were collected from the feces donor, the mother (before FMT, and 1, 8, 15, 22, 26, and 50 weeks after FMT), and the infant (meconium at birth and 3 and 6 months after birth). Fecal samples were profiled by deep metagenomic sequencing for strain-level analysis. The microbial transfer was monitored using single nucleotide variants in metagenomes and further compared to a collection of metagenomic samples from 651 healthy infants and 58 healthy adults. RESULTS: The single FMT procedure led to an uneventful and sustained clinical resolution in the patient, who experienced no further CDI-related symptoms up to 50 weeks after treatment. The gut microbiota of the patient with CDI differed considerably from the healthy donor and was characterized as low in alpha diversity and enriched for several potential pathogens. The FMT successfully normalized the patient's gut microbiota, likely by donor microbiota transfer and engraftment. Importantly, our analysis revealed that some specific strains were transferred from the donor to the patient and then further to the infant, thus demonstrating cross-generational microbial transfer. CONCLUSIONS: The evidence for cross-generational strain transfer following FMT provides novel insights into the dynamics and engraftment of bacterial strains from healthy donors. The data suggests FMT treatment of pregnant women as a potential strategy to introduce beneficial strains or even bacterial consortia to infants, i.e., neonatal seeding. Video Abstract.

Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Clostridioides difficile infection is an urgent antibiotic-associated health threat with few treatment options. Microbiota restoration with faecal microbiota transplantation is an effective treatment option for patients with multiple recurring episodes of C difficile. We compared the efficacy and safety of faecal microbiota transplantation compared with placebo after vancomycin for first or second C difficile infection. METHODS: We did a randomised, double-blind, placebo-controlled trial (EarlyFMT) at a university hospital in Aarhus, Denmark. Eligible patients were aged 18 years or older with first or second C difficile infection (defined as ≥3 watery stools [Bristol stool chart score 6-7] per day and a positive C difficile PCR test). Patients were randomly assigned (1:1) to faecal microbiota transplantation or placebo administered on day 1 and between day 3 and 7, after they had received 125 mg oral vancomycin four times daily for 10 days. Randomisation was done by investigators using a computer-generated randomisation list provided by independent staff. Patients and investigators were masked to the treatment group. The primary endpoint was resolution of C difficile-associated diarrhoea (CDAD) 8 weeks after treatment. We followed up patients for 8 weeks or until recurrence. We planned to enrol 84 patients with a prespecified interim analysis after 42 patients. The primary outcome and safety outcomes were analysed in the intention-to-treat population, which included all randomly assigned patients. The trial is registered with ClinicalTrials.gov, NCT04885946. FINDINGS: Between June 21, 2021, and April 1, 2022, we consecutively screened 86 patients, of whom 42 were randomly assigned to faecal microbiota transplantation (n=21) or placebo (n=21). The trial was stopped after the interim analysis done on April 7, 2022 for ethical reasons because a significantly lower rate of resolution was identified in the placebo group compared with the faecal microbiota transplantation group (Haybittle-Peto boundary limit p<0·001). 19 (90%; 95% CI 70-99) of 21 patients in the faecal microbiota transplantation group and seven (33%, 95% CI 15-57) of 21 patients in the placebo group had resolution of CDAD at week 8 (p=0·0003). The absolute risk reduction was 57% (95% CI 33-81). Overall, 204 adverse events occurred, with one or more adverse events being reported in 20 of 21 patients in the faecal microbiota transplantation group and all 21 patients in the placebo group. Diarrhoea (n=23 in the faecal microbiota transplantation group; n=14 in the placebo group) and abdominal pain (n=14 in the faecal microbiota transplantation group; n=11 in the placebo group) were the most common adverse events. Three serious adverse events possibly related to study treatment occurred (n=1 in the faecal microbiota transplantation group; n=2 in the placebo group), but no deaths or colectomies during the 8-week follow-up. INTERPRETATION: In patients with first or second C difficile infection, first-line faecal microbiota transplantation is highly effective and superior to the standard of care vancomycin alone in achieving sustained resolution from C difficile. FUNDING: Innovation Fund Denmark.