Fecal Microbiota Transplant in Pediatric Solid Organ Transplant Recipients.

BACKGROUND: Fecal microbiota transplant (FMT) is an effective treatment for recurrent Clostridioides difficile infection (CDI). Safety concerns around FMT are increased in immunocompromised populations, such as solid organ transplant (SOT) recipients. Outcomes among adult SOT recipients suggest FMT is efficacious and safe; however, pediatric SOT data are lacking. METHODS: We describe the efficacy and safety of FMT among pediatric SOT recipients in a single-center retrospective study from March 2016 to December 2019. Successful FMT was defined as no recurrence of CDI within 2 mo of FMT. We identified 6 SOT recipients ages 4-18 y who received FMT a median of 5.3 y post-SOT. RESULTS: Success after a single FMT was 83.3%. One liver recipient did not achieve cure after 3 FMTs and remains on low-dose vancomycin. One serious adverse event (SAE) occurred; cecal perforation and bacterial peritonitis occurred following colonoscopic FMT coordinated with intestinal biopsy in a kidney transplant recipient. He achieved full recovery and CDI cure. There were no other SAEs. There were no adverse events related to immunosuppression or transplantation status including: bacteremia, cytomegalovirus activation or reactivation, allograft rejection, or allograft loss. CONCLUSIONS: In this limited series, efficacy of FMT in pediatric SOT is comparable to efficacy in the general pediatric recurrent CDI population. There may be an increased risk of procedure-related SAE in SOT patients and larger cohort studies are needed.

Higher alpha diversity and Lactobacillus blooms are associated with better engraftment after Fecal Microbiota Transplant in Inflammatory Bowel Disease.

Background: Fecal Microbiota Transplant (FMT) has proven effective in treating recurrent Clostridioides difficile infection (rCDI) and has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. However, there is little known regarding predictors of engraftment. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Results: Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. The treatment arm received seven days of antibiotics followed by FMT enema and then capsules weekly for seven weeks. We enrolled four subjects with CD and 11 with UC, ages 14-29 years. Due to weekly stool sampling, we were able to create a time series of alpha diversity, beta diversity and engraftment as they related to clinical response. Subjects exhibited a wide range of microbial diversity and donor engraftment as FMT progressed. Specifically, engraftment ranged from 26% to 90% at week 2 and 3% to 92% at two months. Consistent with the current literature, increases over time of both alpha diversity (p< 0.05) and donor engraftment (p< 0.05) correlated with improved clinical response. Additionally, our weekly time series enabled an investigation into the clinical and microbial correlates of engraftment at various time points. We discovered that the post-antibiotic but pre-FMT time point, often overlooked in FMT trials, was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial with publicly available weekly sequencing data. Conclusions: We found that higher residual alpha diversity and Lactobacillus blooms after antibiotic treatment correlated with improved engraftment and clinical response to FMT. Future studies should closely examine the host microbial communities pre-FMT and the impact of antibiotic preconditioning on engraftment and response.

High functional load inhibits phonological contrast loss: a corpus study.

For nearly a century, linguists have suggested that diachronic merger is less likely between phonemes with a high functional load--that is, phonemes that distinguish many words in the language in question. However, limitations in data and computational power have made assessing this hypothesis difficult. Here we present the first larger-scale study of the functional load hypothesis, using data from sound changes in a diverse set of languages. Our results support the functional load hypothesis: phoneme pairs undergoing merger distinguish significantly fewer minimal pairs in the lexicon than unmerged phoneme pairs. Furthermore, we show that higher phoneme probability is positively correlated with merger, but that this effect is stronger for phonemes that distinguish no minimal pairs. Finally, within our dataset we find that minimal pair count and phoneme probability better predict merger than change in system entropy at the lexical or phoneme level.

Functional load and the lexicon: Evidence that syntactic category and frequency relationships in minimal lemma pairs predict the loss of phoneme contrasts in language change.

All languages use individually meaningless, contrastive categories in combination to create distinct words. Despite their central role in communication, these "phoneme" contrasts can be lost over the course of language change. The century-old functional load hypothesis proposes that loss of a phoneme contrast will be inhibited in relation to the work that it does in distinguishing words. In a previous work we showed for the first time that a simple measure of functional load does significantly predict patterns of contrast loss within a diverse set of languages: the more minimal word pairs that a phoneme contrast distinguishes, the less likely those phonemes are to have merged over the course of language change. Here, we examine several lexical properties that are predicted to influence the uncertainty between word pairs in usage. We present evidence that (a) the lemma rather than surface-form count of minimal pairs is more predictive of merger; (b) the count of minimal lemma pairs that share a syntactic category is a stronger predictor of merger than the count of those with divergent syntactic categories, and (c) that the count of minimal lemma pairs with members of similar frequency is a stronger predictor of merger than that of those with more divergent frequencies. These findings support the broad hypothesis that properties of individual utterances influence long-term language change, and are consistent with findings suggesting that phonetic cues are modulated in response to lexical uncertainty within utterances.

Perceptual pressures on lenition.

The phonological processes known as 'lenition' have traditionally been explained as articulatory effort reduction. However, such a motivation for lenition has never been directly demonstrated; in addition, there are reasons to doubt the articulatory explanation. This paper focuses on a particular type of lenition (intervocalic spirantization of voiced stops) and presents two experiments that investigate what role, if any, perceptual considerations might play in lenition. Experiment I shows that spirantization of intervocalic voiced stops is a less perceptually salient change than devoicing of intervocalic voiced stops (an unattested process). Using the line of reasoning of Steriade's P-map hypothesis, perceptual facts offer an alternative to the articulatory account: lenition of intervocalic voiced stops yields spirants rather than voiceless stops because the latter change is perceptually highly salient. The results of Experiment 2 show that the perceptual facts differ by place of articulation, such that the difference between stops and spirants is greater for labials than for dorsals. These results do not match the attested typology; if anything, languages are more likely to spirantize labials than they are to spirantize dorsals. Thus, perceptual facts have the potential to explain some, but not all, of the typology of lenition.