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PubMed2026

Genome-resolved analysis reveals disruption of gut microbial vitamin B and K2 biosynthesis during Toxoplasma gondii infection in mice.

UNLABELLED: Toxoplasma gondii infection remodels the gut microbiome, yet its impact on microbial vitamin biosynthetic potential and host redox metabolism remains unclear. Here, we integrated mouse gut metagenomes with publicly available metagenome-assembled genomes (MAGs) to construct a genome-resolved atlas of B-vitamin and vitamin K2 biosynthesis. From 45,697 MAGs, we curated 4,771 representative genomes, of which 2,682 met high-quality criteria (completeness ≥90%, contamination <5%). Functional annotation identified 229,717 vitamin-related genes corresponding to 177 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs across de novo pathways for eight B vitamins, thiamine (B1), riboflavin (B2), niacin (B3), pantothenate (B5), pyridoxine (B6), biotin (B7), folate (B9), cobalamin (B12), and vitamin K2. Among the high-quality genomes, 1,665 encoded complete de novo pathways for at least one vitamin, highlighting functional specialization and community-level complementarity. Transcripts per million-normalized metagenomic read counts revealed significant differences in KEGG ortholog abundances across six of the nine vitamin pathways. Reanalysis of metagenomic data from infected mice (acute, chronic, and control; n = 10 per group) revealed a stage-dependent reduction in α-diversity of vitamin biosynthesis pathways during acute infection, and a clear β-diversity separation from chronic and control groups. Core niacin biosynthesis genes (nadB, nadA, nadC) displayed phylum-specific redistribution, indicating selective remodeling of microbial NAD+ precursor production under infection-induced metabolic stress. These results suggest that T. gondii infection disrupts cooperative vitamin biosynthetic networks while specifically modulating niacin pathways linked to host NAD+ metabolism. IMPORTANCE: Gut microbes can synthesize essential vitamins, but how infection alters this function is poorly understood. By integrating mouse gut metagenomes with genome-resolved microbial data, we show that Toxoplasma gondii infection reshapes the vitamin biosynthetic potential of the gut microbiome in a stage-dependent manner. Acute infection reduces the diversity of vitamin biosynthesis pathways and shifts the taxonomic distribution of key niacin biosynthesis genes involved in microbial NAD+ precursor production. These findings identify vitamin metabolism, especially niacin-related pathways, as a sensitive functional axis of microbiome remodeling during infection. Our work links microbial taxonomic changes to functional metabolic consequences and suggests that microbiome-mediated regulation of NAD+-related metabolism may contribute to host redox adaptation during T. gondii infection.

B vitamins↗

PubMed1983

Sex ratio and heterozygote advantage in cystic fibrosis families.

The families of aunts and uncles of cystic fibrosis (CF) patients were compared with one another and with controls in order to test claims of increased fertility and sex ratio in families containing the CF allele and to identify the more fertile sex. Uncles' families were found to contain a significant excess of sons, particularly at primiparous births, as well as a significantly increased sex ratio. Reanalysis of published records of CF sibships confirmed the effect of parity on sex ratio. The families of uncles were also exceptional in exceeding the size intended, although their mean size was not raised significantly. It is suggested that these effects could be related to an interaction between CF-related, paternally-derived antigens and the maternal immune system.

Alleles↗

PubMed1993

Health inequalities: new concerns about the children of single mothers.

OBJECTIVES: To show that the exclusion from conventional class based analyses of child mortality of children whose parents are classified as "unoccupied" produces a misleading picture of health inequalities. DESIGN: Reanalysis of data published in the childhood supplement of the registrar general's decennial supplement on occupational mortality in England and Wales, which compares numerator data for registrations of deaths in children over the age of 1 but below their 16th birthday in 1979, 1980, 1982, and 1983 with data about children aged 1-15 who were enumerated at the 1981 census. RESULTS: Parents who are classified as "unoccupied" largely consist of economically inactive single mothers. Their children are estimated to represent 89% of the 614,000 aged 1-15 classified as "unoccupied" in the childhood supplement. They have the worst mortality record of all social groups--an age specific death rate of 68.8/100,000 a year, 42% worse than in social class V (48.4/100,000) and worse than that of social class I (22.8) by a factor of 3. At older ages (10-15 years) these children have a relative risk of death of 4.14 relative to classes I and II; the risk is 2.58 in children 0-4 and 2.56 in those 5-9. Relative risks of child mortality in social classes I and II in comparison to classes IV and V suggests a progressive shallowing from 2.08 at ages 1-4 to 1.37 at ages 10-15. When unoccupied parents were combined with classes IV and V and compared with classes I and II, however, inequalities seemed to be pervasive throughout childhood; the relative risks were 2.21 for those aged 1-4 and 1.98 for those aged 10-15. CONCLUSION: Children classified as unoccupied are almost certainly living in poverty as well as experiencing relatively high risks of mortality. Class based analyses which exclude them therefore produce a misleading picture of inequalities in child health. The implications for health policy are profound. Strategies to promote the nation's health should acknowledge the importance of material and social deprivation more explicitly.

Adolescent↗

PubMed1994

Invasive cancer of the cervix in women with mild dyskaryosis followed up cytologically.

Mildly dyskaryotic smears are common, and women with such results are often followed up with further cervical smear tests. An important consideration in evaluating this practice would be the annual incidence of invasive cervical cancer. A reanalysis of five previous studies of the cytological follow up of women with mildly abnormal smear test results was undertaken to calculate this incidence. The annual incidence of invasive cancer in these women ranged from 0 to 420 per 100,000 women years. The large studies providing the most precise estimates had annual rates of 143 to 420 per 100,000 women years. This is 16 to 47 times greater than in women aged 15-34 years in England and Wales. The average rate was 208 per 100,000 women years. Women with mild dyskaryosis are at high risk of developing invasive cervical cancer despite cytological follow up. A full appraisal of the costs and benefits of colposcopy in this situation is urgently required.

Adolescent↗

PubMed1996

Marginal costs and benefits.

Decision makers are interested in measuring the costs and benefits of various interventions, and sometimes they are presented with the average costs and benefits of alternative interventions and asked to compare these. Usually a newer intervention is being compared with an existing one, and the most appropriate comparison is not of average costs (and benefits) but of the extra--or marginal--costs (and benefits) of the new intervention. Reanalysis of the cost effectiveness ratio of biochemical screening of all women for Down's syndrome compared with age based screening shows that the marginal cost effectiveness of biochemical screening is 47,786 pounds, compared with an average cost effectiveness of 37,591 pounds. It may sometimes be difficult or costly to calculate marginal costs and benefits, but this should be done whenever possible.

Adult↗

PubMed1998

Using epidemiological data to guide clinical practice: review of studies on cardiovascular disease and use of combined oral contraceptives.

OBJECTIVE: To explore the usefulness of epidemiological data to guide clinical practice by seeking an answer to the question "What is the risk of cardiovascular disease among users of currently available, low dose, combined oral contraceptives who are aged less than 35 years, do not smoke, and do not have a medical condition known to increase the risk of vascular disease?" DESIGN: Review of all relevant published studies identified from the library of references held by Royal College of General Practitioners' Manchester Research Unit, checking of reference lists of identified studies, and Medline search. MAIN OUTCOME MEASURES: Identification of methodologically sound studies able to address the specific clinical question. RESULTS: Our literature search identified 74 papers about the relation between current use of combined oral contraceptives and cardiovascular disease: 23 papers reporting risk of venous thromboembolism, 22 on ischaemic stroke, 13 on haemorrhagic stroke or subarachnoid haemorrhage, 13 on all stroke, and 33 on myocardial infarction. Only five papers provided information that directly addressed our clinical question; all related to the risk of venous thromboembolism. Fourteen of the discarded papers probably had the potential to answer our clinical question. CONCLUSIONS: Much of the epidemiological data about the risk of cardiovascular disease in users of combined oral contraceptives is not useful to clinicians. Some of the discarded data could be made more useful to clinicians by reanalysis. This situation is unlikely to be unique to use of contraceptives.

Adolescent↗

PubMed2006

Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study.

OBJECTIVE: To perform prion protein gene (PRNP) codon 129 analysis in DNA extracted from appendix tissue samples that had tested positive for disease associated prion protein. DESIGN: Reanalysis of positive cases identified in a retrospective anonymised unlinked prevalence study of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom. STUDY SAMPLES: Three positive appendix tissue samples out of 12,674 samples of appendix and tonsil tested for disease associated prion protein. The patients from whom these samples were obtained were aged 20-29 years at the time of surgery, which took place in 1996-9. SETTING: Pathology departments in two tertiary centres in England and Scotland. RESULTS: Adequate DNA was available for analysis in two of the three specimens, both of which were homozygous for valine at codon 129 in the PRNP. CONCLUSIONS: This is the first indication that the valine homozygous subgroup at codon 129 in the PRNP is susceptible to vCJD infection. All tested clinical cases of vCJD have so far occurred in the methionine homozygous subgroup, and a single case of probable iatrogenic vCJD infection has been identified in one patient who was a methionine/valine heterozygote at this genetic locus. People infected with vCJD with a valine homozygous codon 129 PRNP genotype may have a prolonged incubation period, during which horizontal spread of the infection could occur either from blood donations or from contaminated surgical instruments used on these individuals during the asymptomatic phase of the illness.

Adolescent↗

PubMed1987

Variceal bleeding: does variable delay in trial entry invalidate comparison between trials?

Variation in time of patient admission to studies of prognosis after variceal haemorrhage has been proposed as a major factor in the wide range of reported results. A study of 144 unselected subjects with a low initial mortality (3% at two days) suggests that the effect has been overemphasised and studies in which time of entry is later than the date of bleeding may be usefully compared. Reanalysis of previous work suggests that even in populations with a high initial mortality limited comparisons between studies can still be usefully made. It is stressed that survival analysis must be started from the date of study entry and not from the date of the index bleed which involves incorporating a retrospective period of survivorship.

Clinical Trials as Topic↗

PubMed1988

Arrival-time analysis of intravenous digital aortograms in aortic dissection.

Arrival-time analysis was applied to intravenous digital aortograms. A single static image was produced by representing the time to 90% maximum density for each image pixel on a grey scale. Arrival-time analysis confirmed the diagnosis in four of six patients with aortic dissection that had been shown by image subtraction. In a further three patients with no dissection the arrival-time images were normal. In two patients with surgical repair of the ascending aorta, residual false lumens were shown by both subtraction and arrival-time analysis. In one of these cases arrival-time analysis prompted reanalysis of the subtraction image that had previously been interpreted as showing a normal aorta. Arrival-time analysis provides a static image of aortic dissection, which helps to overcome subtraction artefact.

Aortic Dissection↗

PubMed1990

Mechanism of the increased ventilatory response to exercise in patients with chronic heart failure.

Minute ventilation, respiratory rate, and metabolic gas exchange were measured continuously during maximal symptom limited treadmill exercise in 30 patients with stable chronic heart failure. The ventilatory response to exercise was assessed by calculation of the slope of the relation between minute ventilation and rate of carbon dioxide production. There was a close correlation between the severity of heart failure, determined as the maximal rate of oxygen consumption, and the ventilatory response to exercise. Reanalysis of the data after correction for ventilation of anatomical dead space did not significantly weaken the correlation but reduced the slope of the relation by approximately one third. These results show that the increased ventilatory response to exercise in patients with chronic heart failure is largely caused by mechanisms other than increased ventilation of anatomical dead space. This finding supports the concept that a significant pulmonary ventilation/perfusion mismatch develops in patients with chronic heart failure and suggests that the magnitude of this abnormality is directly related to the severity of chronic heart failure.

Adult↗

PubMed1997

Caregiver factors and pool fencing: an exploratory analysis.

OBJECTIVES: To explore the relationship between caregiver characteristics and the adequacy of domestic swimming pool fencing. SETTING: A typical metropolitan area of a large Australian capital city, Brisbane. METHODS: From a reanalysis of the dataset of the 1989 Brisbane Home Safety Survey of 1050 householders, associations between 10 caregiver factors, pool ownership, and quality of pool fencing, were analysed. Household characteristics relating to toddlers (children < or = 4 years), and socioeconomic measures were also included in the analyses. Pool fencing quality was measured on an ordinal scale derived from Australian Standards Association guidelines, confirmed through home visits by trained inspectors. RESULTS: Caregiver factors did not distinguish households with a swimming pool from those without, nor were they associated with adequacy of pool fencing among pool owners. Pool owners, with or without children, were less likely to perceive having a childproof fence as being important. Strongest correlates of adequacy of pool fencing were socioeconomic indicators of surrounding districts. CONCLUSIONS: These results do not support the arguments of opponents of compulsory pool fencing that caregiver factors are adequate to prevent toddler drownings and obviate the need for a pool fence. Pool owners do not appear to perceive their pool as a hazard for young children, and complacency about the adequacy of pool fencing needs to be replaced by increased caregiver health beliefs, skills, and perceptions.

Accident Prevention↗

PubMed2004

Supervised automated microscopy increases sensitivity and efficiency of detection of sentinel node micrometastases in patients with breast cancer.

AIMS: To investigate the practicality and sensitivity of supervised automated microscopy (AM) for the detection of micrometastasis in sentinel lymph nodes (SLNs) from patients with breast carcinoma. METHODS: In total, 440 SLN slides (immunohistochemically stained for cytokeratin) from 86 patients were obtained from two hospitals. Samples were selected on the basis of: (1) a pathology report mentioning micrometastases or isolated tumour cells (ITCs) and (2) reported as negative nodes (N0). RESULTS: From a test set of 29 slides (12 SLN positive patients, including positive and negative nodes), 18 slides were scored positive by supervised AM and 11 were negative. Routine examination revealed 17 positive slides and 12 negative. Subsequently, automated reanalysis of 187 slides (34 patients; institute I) and 216 slides (40 patients; institute II) from reported node negative (N0) patients showed that two and seven slides (from two and five patients, respectively) contained ITCs, respectively, all confirmed by the pathologists, corresponding to 5.9% and 12.5% missed patients. In four of the seven missed cases from institute II, AM also detected clusters of four to 30 cells, but all with a size < or = 0.2 mm. CONCLUSIONS: Supervised AM is a more sensitive method for detecting immunohistochemically stained micrometastasis and ITCs in SLNs than routine pathology. However, the clinical relevance of detecting cytokeratin positive cells in SLNs of patients with breast cancer is still an unresolved issue and is at the moment being validated in larger clinical trials.

Automation↗

PubMed1991

Practice of breast self examination: disease extent at diagnosis and patterns of surgical care. A report from an Italian study. GIVIO (Interdisciplinary Group for Cancer Care Evaluation).

STUDY OBJECTIVE: The aim was to determine whether breast self examination leads to earlier diagnosis and whether this translates into a larger utilisation of conservative surgical procedures. DESIGN: The study was a survey of a cohort of breast cancer patients diagnosed over the period September 1986-July 1988. SUBJECTS: Participants were 1315 women enrolled in a clinical trial testing the effectiveness of two follow up regimens by 30 general hospitals throughout Italy. MEASUREMENTS AND MAIN RESULTS: Overall, 511 patients (39%) reported some breast self examination practice, but only 109 (8%) did this regularly and in a way deemed correct by their physicians. Breast self examination practice was positively associated with patients' education and past history of benign breast disease and negatively with age. Self examiners were found to have a significantly greater chance of being diagnosed with a primary tumour coded as pT1 according to the 1982 TNM classification (odds ratio = 1.42, 95% CI = 1.13-1.79). This protective effect was mostly evident in the subgroup of optimal performers (odds ratio = 1.54, CI = 1.01-2.34). Nearly half the patients (319/655) eligible for conservative surgery still had an unnecessary radical procedure. CONCLUSIONS: Premorbid breast self examination seems to have a modest effect on the extent of disease at diagnosis. The still widespread use of radical surgery suggests that a careful reanalysis of priorities among possible public interventions is needed before launching massive educational campaigns targeted exclusively at consumers.

Adult↗

PubMed1995

Is enumeration district level an improvement on ward level analysis in studies of deprivation and health?

AIM: To investigate whether enumeration district (ED) level data reflect the aggregate characteristics of people living in that district better than ward level analysis. DESIGN AND SETTING: Reanalysis of the fourth national morbidity survey in general practice (MSGP4). Socioeconomic data on patients who had consulted 60 practices over one year were linked via postcode to ED and thence to small area statistics data for that ED and to the corresponding electoral ward. RESULTS AND CONCLUSIONS: There was no evidence that patients were likely to be more representative samples of the population of an ED than of a ward.

Data Interpretation, Statistical↗

PubMed1977

Colchester revisited: a genetic study of mental defect.

This reanalysis of a classic survey leads to inferences about design of genetic studies, resolution of heterogeneity, and the role of autosomal and sex-linked genes in mental retardation, which is no longer refractory to segregation analysis. By discriminating between sociofamilial and biological types we estimate that at least 351 autosomal loci can produce mental retardation, with an inbred load of 0.83 detrimental equivalents and a mutation rate of 0.008 per gamete, or less than 2.4 X 10(-5) per locus. The distribution of probands was estimated as: 7 per cent medical, 60 per cent sociofamilial, and 33 per cent biological. Simple genetic mechanisms account for virtually all the biological category. Within the sociofamilial group cultural inheritance and polygenes could not be resolved.

Consanguinity↗

PubMed1991

Genetic aspects of antibiotic induced deafness: mitochondrial inheritance.

Analysis of 36 pedigrees with a positive family history of aminoglycoside antibiotic induced deafness, ascertained in a population of 483,611 in Zhabei District in Shanghai, showed that the susceptibility to antibiotic ototoxicity was transmitted by females exclusively, indicating mitochondrial inheritance. Reanalysis of 18 other published pedigrees confirmed this conclusion.

Aminoglycosides↗

PubMed1998

General practitioner screening for melanoma: sensitivity, specificity, and effect of training.

OBJECTIVE: To measure the performance of trained and untrained general practitioners (GPs) in screening men and women aged 50 or more for melanomas. METHODS: GPs trained in melanoma diagnosis, untrained GPs, and skin cancer specialists examined groups of volunteers, each of which included a small number of subjects with prediagnosed suspicious pigmented lesions (SPLs) that were subsequently excised for histopathological examination. RESULTS: Trained and untrained GPs achieved mean sensitivities of 0.73 and 0.71, and mean predictive values of 0.40 and 0.37, respectively, for the detection of prediagnosed SPLs. When the SPLs had been excised and examined histopathologically, reanalysis showed mean sensitivities of 0.98 and 0.95, mean specificities of 0.52 and 0.49, and mean positive predictive values of 0.24 and 0.22 for the detection of subjects with melanomas by trained and untrained GPs respectively. Trained GPs were significantly better than untrained GPs at diagnosing as melanomas SPLs that subsequently proved to be melanomas (p = 0.04). CONCLUSIONS: GPs in this study achieved high sensitivities in screening older Australian men and women for melanomas, but at the cost of low specificities and positive predictive values. Training in melanoma diagnosis had no significant effect on sensitivity, specificity, and positive predictive value for screening. Data from the study were tested in a model of population screening for melanomas, and costs per life year saved for men aged 50-70 ranged from $A11,852 to $A40,259 depending upon the screening interval and whether the GPs excised the SPLs diagnosed, or referred all patients to skin cancer specialists; this would be as cost effective as cervical cancer screening.

Female↗

PubMed1998

Obstacles to timely neonatal screening in North Thames.

OBJECTIVE: To assess the timeliness of neonatal (Guthrie card) screening in North Thames, and to identify the most effective ways of improving it. DESIGN: Analysis of information routinely collected in the course of neonatal screening; reanalysis of published data on blood phenylalanine concentration in phenylketonuria (PKU) over the first two weeks; simulation studies on the impact of different interventions. SUBJECTS: 100,690 infants born over one year and screened at Great Ormond Street Hospital NHS Trust. OUTCOME MEASURE: Interval between birth and reading PKU screen results. RESULTS: Although 75% of samples (district range 55-91%) were collected by day 7, only 81% had arrived in the laboratory seven days later (range 57-96%). The average interval between birth and reading results was 14.5 days, with only 9.7% read by day 10. Samples could be collected from day 4 without significant impact on false negative rates for PKU. If samples were collected from day 4 and posted promptly (second class), the average interval between birth and reading results could be reduced to 9.3 days. If first class mail were used and the laboratory operated on Saturdays, and used assays that could be read the same day rather than bacterial inhibition assays, the average would be 7.8 days, with 96% read by day 10. CONCLUSION: Timeliness of neonatal screening shows unacceptable variation between districts, and delays in dispatch of specimens to the laboratory. Same day, first class posting should be introduced, and samples could be collected between days 4 and 8.

Blood Specimen Collection↗