The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

The European Hernia Society classification applied to the rare cases of parastomal hernia after ileal conduit urinary diversion: a retrospective cohort of 96 patients.

INTRODUCTION: To determine the incidence and classification of parastomal hernia (PH) following ileal conduit urinary diversion and to identify risk factors for PH development. METHODS: We performed a retrospective review of our cystectomy database which includes benign and malignant cases from 2011-2016. Patients with an abdominal CT at 24 ± 2 months post-operation were included. PH were classified according to the European Hernia Society (EHS) system. Regression analyses were performed on variables associated with parastomal hernia. RESULTS: A total of 96 patients were included in the study. The incidence of PH on CT is 20.2% at one year and 28.1% at two years. Using the EHS classification, the majority of PH was small (≤ 5 cm), but up to 50% were associated with a concomitant incisional hernia. On multivariable analysis, (C-index = 0.71), obesity was associated with a higher risk of PH (OR = 2.8, 95% CI 1.06-7.42, p = 0.04), whereas prior tobacco use was associated with a lower risk of PH at 2 years (OR = 0.23, 95% CI 0.09-0.63, p < 0.01). CONCLUSIONS: Hernia after ileal conduit is common with radiographic rates approaching 30% at two years, with obesity being an independent risk factor. The relationship between prior tobacco use and a lower hernia rate may be limited to this study but presents an opportunity for future investigation. No difference in PH rates were observed between open and minimally invasive surgery and between intracorporeal and extracorporeal conduits.

Genomic analysis to assess disease progression and recurrence in patients with oral squamous cell carcinoma: - a preliminary study.

We studied the progression from dysplasia to invasive carcinoma and subsequent second primaries or locoregional recurrences in 11 patients with recurrent squamous cell carcinoma (SCC). Between one and six samples were sequenced/patient. DNA samples were prepared, and libraries multiplexed to between 40 and 80 samples/lane of an Illumina HiSeq 3000 and sequenced with 2×100bp paired end sequencing. Copy number data were generated by CNAnorm (Bioconductor package). Samples of recurrent SCC showed unique patterns of descent when compared with earlier samples from the primary tumour, and three main patterns emerged. In four patients there was convincing evidence that the later lesion was descended directly from cells from the first, and in a further four there were no detectable genomic events between the two lesions. Three patients had some shared events between the early and later lesions, but although there were enough differences to deduce that the two lesions had a shared ancestor, they were not directly descended from each other. We present the patients' characteristics in detail, including the overall survival in each group. There was a distinct genomic pattern after a second episode of SCC in all the groups. A larger study that uses similar methods and a longer duration could provide reliable conclusions with respect to survival. With the use of new techniques, genomic data can be available to clinical teams during the planning of treatment.

Diagnosis of copy number variation by Illumina next generation sequencing is comparable in performance to oligonucleotide array comparative genomic hybridisation.

Array comparative genomic hybridisation (aCGH) profiling is currently the gold standard for genetic diagnosis of copy number. Next generation sequencing technologies provide an alternative and adaptable method of detecting copy number by comparing the number of sequence reads in non-overlapping windows between patient and control samples. Detection of copy number using the BlueGnome 8×60k oligonucleotide aCGH platform was compared with low resolution next generation sequencing using the Illumina GAIIx on 39 patients with developmental delay and/or learning difficulties who were referred to the Leeds Clinical Cytogenetics Laboratory. Sensitivity and workflow of the two platforms were compared. Customised copy number algorithms assessed sequence counts and detected changes in copy number. Imbalances detected on both platforms were compared. Of the thirty-nine patients analysed, all eleven imbalances detected by array CGH and confirmed by FISH or Q-PCR were also detected by CNV-seq. In addition, CNV-seq reported one purported pathogenic copy number variant that was not detected by array CGH. Non-pathogenic, unconfirmed copy number calls were detected by both platforms; however few were concordant between the two. CNV-seq offers an alternative to array CGH for copy number analysis with resolution and future costs comparable to conventional array CGH platforms and with less stringent sample requirements.

Knowledge of signs, treatment and need for urgent management in patients presenting with an acute ischaemic stroke or transient ischaemic attack: a prospective study.

OBJECTIVE: To assess stroke awareness among patients presenting to the emergency department with an acute ischaemic stroke or transient ischaemic attack (TIA). METHODS: A consecutive cohort of patients presenting with a cerebrovascular event was prospectively enrolled over a 15-month period and questionnaires were administered. If the patient was unable to respond to the questions or answer the questionnaire, it was administered to the primary caregiver. Comprehension of having a cerebrovascular event, reason for delay in presentation, mode of arrival and knowledge of treatment modalities were determined. RESULTS: Only 42% of 400 patients thought they were having a stroke or TIA. The median time to presentation was 3.4 h. Delayed presentation was almost equal in men and women. When asked about onset, 19.4% thought that a stroke came on gradually and only 51.9% thought immediate presentation was crucial. 20.8% of patients had heard of thrombolysis. CONCLUSION: Community knowledge of ischaemic stroke needs to be enhanced so that individuals present earlier, leading to timely management.

Cloning of the CYP51 gene from the eyespot pathogen Tapesia yallundae indicates that resistance to the DMI fungicide prochloraz is not related to sequence changes in the gene encoding the target site enzyme.

Resistance to sterol 14 alpha-demethylase inhibitor (DMI) fungicides has been correlated with mutations in the CYP51 gene encoding the target enzyme eburicol 14 alpha-demethylase. CYP51 was isolated from the eyespot pathogen Tapesia yallundae revealing a predicted 526-amino acid product exhibiting homology to other fungal CYP51s. CYP51 was sequenced from four field isolates sensitive or resistant to the DMI fungicide prochloraz and partially sequenced from two further isolates and eight progeny from a cross between prochloraz-sensitive and -resistant parents. Two alleles of the gene were detected termed CYP51-1 and CYP51-2. No correlation was found between sequence change and fungicide sensitivity. Therefore prochloraz resistance involved a mechanism other than mutation in the target site gene.

Differences in visuospatial judgement in reading-disabled and normal children.

Both visual and verbal impairments have been reported in two independent streams of research into the etiology of dyslexia or reading-disability. To address the question of the presence of either abnormality in reading-disabled children, visuospatial and phonological ability were assessed and contrasted in 39 Normal and 26 Reading-disabled children. To assess whether these deficits are unique to dyslexia, scores were also compared to those of a group of 12 Poor Readers ("garden-variety" backward readers with low IQs). The Benton Judgement of Line Orientation Test was used for its simplicity and clinical reliability: Reading-disabled subjects performed significantly worse than Normal readers (but similar to Poor Readers). Reading-disabled subjects performed worse for lines in the left-hemifield compared to Normal subjects and also had a greater tendency to scan the task in reverse order (left-to-right) from the usual right-to-left scanning pattern observed in the Normal group when performing this test. When both verbal and visuospatial variables were combined in a multiple regression analysis, 71% of reading variance could be accounted for. These results suggest that Reading-disabled children not only have poor phonological awareness, but they also show visuospatial deficits. However, poor performance on both these tasks was also observed in the group of Poor Readers, suggesting that these deficits are not unique to children with specific reading disability. The results lend further evidence to the hypothesis that reading disability cannot solely be attributed to left-hemisphere dysfunction resulting in phonological impairment. There are other behavioral deficits, possibly caused by a common mechanism, some of which, like visuospatial ability, can be measured by simple behavioral tests such as the Judgment of Line Orientation Test.

Temporal and spatial processing in reading disabled and normal children.

The ability to process temporal and spatial visual stimuli was studied to investigate the role these functions play in the reading process. Previous studies of this type have often been confounded by memory involvement, or did not take into account the evidence which suggests a visual transient deficient in some dyslexics. Normal (n = 39), reading disabled (n = 26), and backward reading children (n=12) were compared on a visual computer game, which consisted of a temporal and a analogous spatial dot counting task. Reading disabled children performed significantly worse than normal children on the Temporal Dot Task, but were only mildly impaired on the Spatial Dot Task, Backward readers were not significantly better than the reading disabled group on either task, suggesting that poor poor visual temporal processing is not specific to dyslexia. In a group of 93 children, a regression model including age, verbal IQ, phonological awareness, and visual temporal processing ability, predicted 73% of the variance of reading ability. The results suggest that dyslexics perform worse in tasks that require fast, sequential processing and that this impairment may be partially responsible for their reading difficulties.

Promotion of women physicians in academic medicine. Glass ceiling or sticky floor?

OBJECTIVE: To assess possible explanations for the finding that the percentage of women medical school faculty members holding associate or full professor rank remains well below the percentage of men. DESIGN: Cross-sectional survey of physician faculty of US medical schools using the Association of American Medical Colleges (AAMC) database. SUBJECTS: Surveyed were 153 women and 263 men first appointed between 1979 and 1981, matched for institutions of original faculty appointment. MAIN OUTCOME MEASURES: Academic rank achieved, career preparation, academic resources at first appointment, familial responsibilities, and academic productivity. RESULTS: After a mean of 11 years on a medical school faculty, 59% of women compared with 83% of men had achieved associate or full professor rank, and 5% of women compared with 23% of men had achieved full professor rank. Women and men reported similar preparation for an academic career, but women began their careers with fewer academic resources. The number of children was not associated with rank achieved. Women worked about 10% fewer hours per week and had authored fewer publications. After adjustment for productivity factors, women remained less likely to be associate or full professors (adjusted odds ratio [OR] = 0.37; 95% confidence interval [CI], 0.21 to 0.66) or to achieve full professor rank (adjusted OR = 0.27; 95% CI, 0.12 to 0.63). Based on the AAMC database, 50% of both women and men originally appointed as faculty members between 1979 and 1981 had left academic medicine by 1991. CONCLUSION: Women physician medical school faculty are promoted more slowly than men. Gender differences in rank achieved are not explained by productivity or by differential attrition from academic medicine.

Differences in eye movements and reading problems in dyslexic and normal children.

It has been suggested that eye movement abnormalities seen in dyslexics are attributable to their language problems. In order to investigate this claim, we studied eye movements in dyslexic children, during several non-reading tasks. Dyslexic children were compared to normal and backward readers on measures of fixation, vergence amplitude, saccade and smooth pursuit. The results were compared to the children's phonological ability. Dyslexic children (n = 26) had significantly worse eye movement stability during fixation of small targets than normal children (n = 39). Vergence amplitudes were lower for dyslexics than for controls. A qualitative assessment of saccadic eye movements revealed that dyslexics exhibit fixation instability at the end of saccades. Assessment of smooth pursuit revealed poor smooth pursuit in the dyslexic group, particularly when pursuing a target moving from left to right. Dyslexic children also performed significantly worse than normal children on a test of phonological awareness (Pig Latin). Eye movement results were studied in the light of the findings on phonological awareness: dyslexics with small vergence amplitudes also always have poor phonemic awareness. However, poor fixation control is found in dyslexics with or without poor phonological ability. The backward reading children performed similar to the dyslexics on all tests, suggesting that the deficiencies observed in this study are not specific to children with dyslexia. The problems experienced by the children (revealed by a questionnaire) are in agreement with those measured in terms of eye movement recordings and phonemic awareness. Sex, handedness, IQ or the presence of attention deficit disorder (ADD) did not appear to influence the children's performances on any of the eye movement tasks. The presence of oculomotor abnormalities in a non-reading task strongly suggests that the underlying deficit in the control of eye movements seen in dyslexics is not caused by language problems alone.

Confirmation of linear system theory prediction: Rate of change of Herrnstein's kappa as a function of response-force requirement.

Four human subjects worked on all combinations of five variable-interval schedules and five reinforcer magnitudes ( cent/reinforcer) in each of two phases of the experiment. In one phase the force requirement on the operandum was low (1 or 11 N) and in the other it was high (25 or 146 N). Estimates of Herrnstein's kappa were obtained at each reinforcer magnitude. The results were: (1) response rate was more sensitive to changes in reinforcement rate at the high than at the low force requirement, (2) kappa increased from the beginning to the end of the magnitude range for all subjects at both force requirements, (3) the reciprocal of kappa was a linear function of the reciprocal of reinforcer magnitude for seven of the eight data sets, and (4) the rate of change of kappa was greater at the high than at the low force requirement by an order of magnitude or more. The second and third findings confirm predictions made by linear system theory, and replicate the results of an earlier experiment (McDowell & Wood, 1984). The fourth finding confirms a further prediction of the theory and supports the theory's interpretation of conflicting data on the constancy of Herrnstein's kappa.

Confirmation of linear system theory prediction: Changes in Herrnstein's k as a function of changes in reinforcer magnitude.

Eight human subjects pressed a lever on a range of variable-interval schedules for 0.25 cent to 35.0 cent per reinforcement. Herrnstein's hyperbola described seven of the eight subjects' response-rate data well. For all subjects, the y-asymptote of the hyperbola increased with increasing reinforcer magnitude and its reciprocal was a linear function of the reciprocal of reinforcer magnitude. These results confirm predictions made by linear system theory; they contradict formal properties of Herrnstein's account and of six other mathematical accounts of single-alternative responding.