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Background & aimsFecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers.MethodsPatients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes.ResultsOf the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%).ConclusionsThis prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT.

Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218 084 men in the population-based UK Biobank cohort, aged 40 to 69 at study entry between 2006 and 2010, with follow-up through mid-2015. We assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of PC and previous prostate-specific antigen testing. Mean age at study entry was 56 years, 94% of the men were white, and 1.1% (n = 2311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.03-1.67, P = .029). The association with PC was only among men with the ulcerative colitis (UC; aHR = 1.47, 95% CI = 1.11-1.95, P = .0070), and not Crohn's disease (aHR 1.06, 95% CI = 0.63-1.80, P = .82). Results are limited by lack of data on frequency of health care interactions. In a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis.

PurposeWild-type isocitrate dehydrogenase-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of

Functional neuroimaging studies have consistently implicated the left rostrolateral prefrontal cortex (RLPFC) as playing a crucial role in the cognitive operations supporting episodic memory and analogical reasoning. However, the degree to which the left RLPFC causally contributes to these processes remains underspecified. We aimed to assess whether targeted anodal stimulation-thought to boost cortical excitability-of the left RLPFC with transcranial direct current stimulation (tDCS) would lead to augmentation of episodic memory retrieval and analogical reasoning task performance in comparison to cathodal stimulation or sham stimulation. Seventy-two healthy adult participants were evenly divided into three experimental groups. All participants performed a memory encoding task on Day 1, and then on Day 2, they performed continuously alternating tasks of episodic memory retrieval, analogical reasoning, and visuospatial perception across two consecutive 30-min experimental sessions. All groups received sham stimulation for the first experimental session, but the groups differed in the stimulation delivered to the left RLPFC during the second session (either sham, 1.5 mA anodal tDCS, or 1.5 mA cathodal tDCS). The experimental group that received anodal tDCS to the left RLPFC during the second session demonstrated significantly improved episodic memory source retrieval performance, relative to both their first session performance and relative to performance changes observed in the other two experimental groups. Performance on the analogical reasoning and visuospatial perception tasks did not exhibit reliable changes as a result of tDCS. As such, our results demonstrate that anodal tDCS to the left RLPFC leads to a selective and robust improvement in episodic source memory retrieval.

Over the last decades, the treatment of schizophrenia has shifted fundamentally from a focus on symptom reduction to a focus on recovery and improving aspects of functioning. In this study, we examined the effect of transcranial direct current stimulation (tDCS) on social cognitive and nonsocial neurocognitive functions, as well as on electroencephalogram (EEG) measures, in individuals with schizophrenia. Thirty-seven individuals with schizophrenia were administered one of three different tDCS conditions (cathodal, anodal, and sham) per visit over the course of three visits, with approximately one week between each visit. Order of conditions was randomized and counterbalanced across subjects. For the active conditions, the electrode was placed over the left dorsolateral prefrontal cortex with the reference electrode over right supraorbital cortex. Current intensity was 2 mA and was maintained for two 20-minute sessions, with a one hour break between the sessions. Assessments were conducted immediately following each session, in a counterbalanced order of administration. No systematic effects were found across the social and nonsocial cognitive domains, and no significant effects were detected on event-related potentials (ERPs). The very small effect sizes, further validated by post-hoc power analyses (large Critical Ns), demonstrated that these findings were not due to lack of statistical power. Except for mild local discomfort, no significant side effects were reported. Findings demonstrate the safety and ease of administration of this procedure, but suggest that a single dose of tDCS over these areas does not yield a therapeutic effect on cognition in schizophrenia.Trial registrationClinicalTrials.gov NCT02539797.

BackgroundHuman milk oligosaccharides (HMOs) and bioactive proteins are beneficial to infant health. Recent evidence suggests that maternal nutrition may affect the amount of HMOs and proteins in breast milk; however, the effect of nutrient supplementation on HMOs and bioactive proteins has not yet been well studied.ObjectiveWe aimed to determine whether lipid-based nutrient supplements (LNSs) affect milk bioactive protein and HMO concentrations at 6 mo postpartum in women in rural Malawi. These are secondary outcomes of a previously published randomized controlled trial.MethodsWomen were randomly assigned to consume either an iron and folic acid capsule (IFA) daily from ≤20 wk gestation until delivery, followed by placebo daily from delivery to 6 mo postpartum, or a multiple micronutrient (MMN) capsule or LNS daily from ≤20 wk gestation to 6 mo postpartum. Breast milk concentrations of total HMOs, sialylated HMOs, fucosylated HMOs, lactoferrin, lactalbumin, lysozymes, antitrypsin, immunoglobulin A, and osteopontin were analyzed at 6 mo postpartum (n = 647). Between-group differences in concentrations and in proportions of women classified as having low concentrations were tested.ResultsHMO and bioactive protein concentrations did not differ between groups (P > 0.10 for all comparisons). At 6 mo postpartum, the proportions of women with low HMOs or bioactive proteins were not different between groups except for osteopontin. A lower proportion of women in the IFA group had low osteopontin compared with the LNS group after adjusting for covariates (OR: 0.5; 95% CI: 0.3, 0.9; P = 0.016).ConclusionThe study findings do not support the hypothesis that supplementation with an LNS or MMN capsule during pregnancy and postpartum would increase HMO or bioactive milk proteins at 6 mo postpartum among Malawian women. This trial was registered at clinicaltrials.gov as NCT01239693.

The cerebellum has been shown to be important for skill learning, including the learning of motor sequences. We investigated whether cerebellar transcranial direct current stimulation (tDCS) would enhance learning of fine motor sequences. Because the ability to generalize or transfer to novel task variations or circumstances is a crucial goal of real world training, we also examined the effect of tDCS on performance of novel sequences after training. In Study 1, participants received either anodal, cathodal or sham stimulation while simultaneously practising three eight-element key press sequences in a non-repeating, interleaved order. Immediately after sequence practice with concurrent tDCS, a transfer session was given in which participants practised three interleaved novel sequences. No stimulation was given during transfer. An inhibitory effect of cathodal tDCS was found during practice, such that the rate of learning was slowed in comparison to the anodal and sham groups. In Study 2, participants received anodal or sham stimulation and a 24 h delay was added between the practice and transfer sessions to reduce mental fatigue. Although this consolidation period benefitted subsequent transfer for both tDCS groups, anodal tDCS enhanced transfer performance. Together, these studies demonstrate polarity-specific effects on fine motor sequence learning and generalization.This article is part of the themed issue 'New frontiers for statistical learning in the cognitive sciences'.

Intense interest centers on the role of the human gut microbiome in health and disease, but optimal methods for analysis are still under development. Here we present a study of methods for surveying bacterial communities in human feces using 454/Roche pyrosequencing of 16S rRNA gene tags. We analyzed fecal samples from 10 individuals and compared methods for storage, DNA purification and sequence acquisition. To assess reproducibility, we compared samples one cm apart on a single stool specimen for each individual. To analyze storage methods, we compared 1) immediate freezing at -80 degrees C, 2) storage on ice for 24 or 3) 48 hours. For DNA purification methods, we tested three commercial kits and bead beating in hot phenol. Variations due to the different methodologies were compared to variation among individuals using two approaches--one based on presence-absence information for bacterial taxa (unweighted UniFrac) and the other taking into account their relative abundance (weighted UniFrac). In the unweighted analysis relatively little variation was associated with the different analytical procedures, and variation between individuals predominated. In the weighted analysis considerable variation was associated with the purification methods. Particularly notable was improved recovery of Firmicutes sequences using the hot phenol method. We also carried out surveys of the effects of different 454 sequencing methods (FLX versus Titanium) and amplification of different 16S rRNA variable gene segments. Based on our findings we present recommendations for protocols to collect, process and sequence bacterial 16S rDNA from fecal samples--some major points are 1) if feasible, bead-beating in hot phenol or use of the PSP kit improves recovery; 2) storage methods can be adjusted based on experimental convenience; 3) unweighted (presence-absence) comparisons are less affected by lysis method.

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.

Introduction and objectiveSpecimen morcellation during laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) is controversial. We seek to evaluate the safety and efficacy of specimen morcellation and LRN for treatment of presumed malignant renal lesions.MethodsWe retrospectively reviewed all patients who underwent LRN at three academic institutions from 1996 to 2007. One hundred eighty-eight patients underwent specimen morcellation after LRN for enhancing solid or cystic renal masses.ResultsLRN was successfully performed on all the patients. Patient age ranged from 36 to 94. One hundred sixty-seven patients were in clinical stage T1, 19 patients T2, and unknown in two. The specimen was manually morcellated within a Cook Lap Sac or Endocatch II bag under laparoscopic or direct observation. On histological review of morcellated specimens, 165 patients were confirmed to have RCC, 17 had an oncocytoma, and 2 had benign cysts. At least 13 patients with RCC were pathologically upgraded to stage T3. Mean operative time was 225 minutes (range 94-650). Mean hospital stay was 2.5 days (range 1-8). In patients with RCC, 11 developed recurrent disease with mean follow-up of 21 months (range 0.3-111). In one patient, a port site recurrence occurred in concert with renal fossa and lymph node metastases.ConclusionsIntracorporeal mechanical morcellation after LRN appears to be safe and effective in clinical stage T1 and T2 RCC. This supports the use of morcellation as an alternative for intact specimen removal in properly selected patients.