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Biomedical subjects

J K Morris

Publications and source records attributed to J K Morris.

At least 19 recordsLinked to original sources
PubMed2003

Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials.

OBJECTIVE: To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. DESIGN: Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. SUBJECTS: 40,000 treated patients and 16,000 patients given placebo. MAIN OUTCOME MEASURES: Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. RESULTS: All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, beta blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. CONCLUSIONS: Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.

Antihypertensive Agents↗
PubMed2003

Comparison of models of maternal age-specific risk for Down syndrome live births.

OBJECTIVES: To display and compare the different published formulae that specify the association between maternal age and the risk of a Down syndrome live birth. METHODS: Papers published since 1987 on the prevalence of Down syndrome live births in relation to maternal age were located using MEDLINE and the references given in other papers. The data series and the models fitted to them were plotted to obtain a visual idea of their similarities and differences. RESULTS: The observed and modelled age-specific rates for Down syndrome births were remarkably similar in all published series of data for women up to the age of 35, were reasonably similar for women aged 35 to 45, but differed for women older than 45. CONCLUSION: In practice, the overall small differences in age-related risk between the different studies did not materially affect the performance of antenatal screening for Down syndrome. If a choice is to be made, the analysis based on the National Down Syndrome Cytogenetic Register (NDSCR) has marginal advantages since it is based on the largest data set and the corresponding model fits the data well. More data is needed to clarify the pattern of risk with maternal age among women over 45 years of age.

Adult↗
PubMed2003

A new approach to antenatal screening for Fragile X syndrome.

OBJECTIVES: To describe a new approach to antenatal screening for Fragile X syndrome and to evaluate its effectiveness. METHODS: We propose that Fragile X syndrome should be considered as a different disorder in males and in females. We also propose that only male Fragile X syndrome should be screened for, so the initial screening test would be the determination of fetal sex. This can now be performed from eight-weeks gestation using a polymerase chain reaction (PCR) analysis on maternal serum. If this test reveals a male fetus, then the same blood sample can be used to determine the CGG repeat length in the DNA of the mother, again using the PCR technique and a Southern blot analysis where necessary. Mothers with positive results (>58 repeats) would be offered antenatal diagnosis (chorionic villus sampling or amniocentesis) to determine the CGG repeat length in cells from the fetus. The screening performance of this strategy was determined using the performance of the component tests. RESULTS: The proposed strategy for screening for male Fragile X syndrome would have a 99% detection rate and a 0.1% false-positive rate. CONCLUSION: After antenatal screening for Down syndrome, the proposed screening strategy would be the most effective method of preventing the birth of males with severe mental retardation. It would have a higher detection rate and a lower false-positive rate than any other antenatal screening programme currently being undertaken, and there would be virtually no prenatal diagnosis of female Fragile X syndrome, which, because such a high proportion are phenotypically normal, has been a barrier to the introduction of screening.

Adult↗
PubMed2003

Cystic fibrosis: selecting the prenatal screening strategy of choice.

Cystic fibrosis is a serious disorder. Research into the treatment of affected individuals is in progress, but a cure is not expected in the near future. In this review, we demonstrate that prenatal screening for cystic fibrosis meets the requirements for a worthwhile screening programme. We explain the reasons that have led us to conclude that one approach ('couple screening') is the method of choice. The couple-based approach calls for reporting results to the couple as a unit. Only if both parents are found to be carriers is the result designated screen-positive and an amniocentesis or chorionic villus sampling offered. This offers a substantial reduction in the proportion of women with unaffected pregnancies with positive results (the false-positive rate) compared with other methods without reducing the detection of affected pregnancies. It also avoids creating a screen-positive group for which no definitive diagnosis is available. This is a problem with other screening methods. The couple method can achieve a 72% detection rate for a 0.1% false-positive rate. The screening method is simple, non-invasive, reliable, safe and reasonably cost effective. Existing programmes have shown that screening using this method is acceptable to health care professionals and patients. Setting up a national prenatal screening programme for cystic fibrosis is timely and should be implemented using the couple screening method.

Adult↗
PubMed2002

Revised estimates of the maternal age specific live birth prevalence of Down's syndrome.

OBJECTIVES: To revise the estimates of maternal age specific live birth prevalence of Down's syndrome in the absence of antenatal screening and selective termination using newly available data. SETTING AND DESIGN: Data were used from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all antenatally or postnatally diagnosed cases of Down's syndrome in which a karyotype was confirmed between 1989 and 1998 in England and Wales. It is the largest single series of data on the prevalence of Down's syndrome. RESULTS AND CONCLUSION: The prevalence does not continue increasing at an increasing rate with age above age 45 as has been previously assumed. Above this age the rate of increase declines with increasing age. The overall age pattern is sigmoidal. A new logit logistic model is proposed which fits the data well. The risk of a Down's syndrome live birth is given by: risk=1/(1+exp(7.330-4.211/(1+exp(-0.282x(age-37.23))))).

Down Syndrome↗
PubMed2001

Quantifying the effect of folic acid.

BACKGROUND: Folic acid is known to prevent neural-tube defects (NTDs) but the size of the effect for a given dose is unclear. We aimed to quantify such an effect. METHODS: We used published data from 13 studies of folic acid supplementation on serum folate concentrations and results from a large cohort study of the risk of NTDs according to serum folate, to measure the preventive effect of specified increases in intake of folic acid. FINDINGS: Serum folate concentrations increase by 0.94 ng/mL (95% CI 0.77-1.10) for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, and about double that in people aged 40-65. Every doubling of serum folate concentration roughly halves the risk of an NTD. These two effects can be combined to predict the reduction in risk according to intake of extra folic acid and background serum folate concentration. Such results predict that the preventive effect is greater in women with low serum folate than in those with higher concentrations. The results have also been used to predict direct observations from large randomised trials and the effect of food fortification. From a typical western background serum folate of 5 ng/mL, about 0.2 mg/day (the US level of folic acid fortification) would be expected to reduce NTDs by about 20%; a similar effect can be expected from the current British recommendation (0.24 mg/day). An increase of 0.4 mg/day would reduce risk by about 36%, of 1 mg/day by 57%, and taking a 5-mg tablet daily would reduce risk by about 85%. INTERPRETATION: Folic acid fortification levels should be increased. Additionally women planning a pregnancy should take 5 mg folic acid tablets daily, instead of the 0.4 mg dose presently recommended.

Adult↗
PubMed2001

Multiple marker second trimester serum screening for pre-eclampsia.

OBJECTIVE: To investigate whether an appropriate combination of maternal serum inhibin A, free beta-human chorionic gonadotropin (free beta-hCG), unconjugated estriol (uE3), and alpha-fetoprotein (AFP) may be an effective means of screening for pre-eclampsia in the second trimester of pregnancy. SETTING: Women who attended an antenatal clinic in Oxford, from whom serum samples were stored, 19 of whom subsequently developed pre-eclampsia. METHODS: Serum inhibin A, free beta-hCG, uE3, and AFP were measured in 32 serum samples collected from the 19 women who developed pre-eclampsia and, for each sample, in three control samples collected from women with unaffected pregnancies matched for gestational age and maternal age. RESULTS: In pregnancies that developed pre-eclampsia the median inhibin A value was raised (1.7 multiples of the median (MoM) for unaffected pregnancies (95% confidence interval (95% CI) 1.1 to 2.7 MoM), the median free beta-hCG was raised (2.1, 1.4 to 3.3 MoM) and the median uE3 was lowered (0.8, 0.6 to 0.98 MoM) after 19 completed weeks of gestation and at least 2 weeks before the onset ofproteinuria. Values of AFP were similar in affected and unaffected pregnancies. Combining the values ofinhibin A, free beta-hCG, and uE3 to form a screening test would detect an estimated 55% of affected pregnancies with a false positive rate of 5%. CONCLUSIONS: Inhibin A, free beta-hCG, and uE3 in combination may be a useful screening test during the second trimester for pre-eclampsia.

Biomarkers↗
PubMed2000

Chlamydia pneumoniae infection and mortality from ischaemic heart disease: large prospective study.

OBJECTIVE: To determine whether there is an independent association between infection with Chlamydia pneumoniae and ischaemic heart disease. DESIGN: Prospective study using a nested case-control design. SETTING: Medical centre in London run by BUPA, a private medical organisation. PARTICIPANTS: 21 520 professional men aged 35-64 who attended for a medical examination in London between 1975 and 1982. MAIN OUTCOME MEASURE: Death from ischaemic heart disease. RESULTS: The distributions of concentrations of IgG and IgA antibodies to C pneumoniae were similar in the 647 men who subsequently died of ischaemic heart disease and in 1294 age matched controls who did not. There was no material association with heart disease irrespective of the cut-off point chosen to define seropositivity. At a cut-off point that defines 15% of controls as positive, for example, the odds ratios were 1.26 (95% confidence interval 0.95 to 1.68) for IgG and 1.09 (0.82 to 1.43) for IgA. CONCLUSIONS: No material association was found between infection with C pneumoniae and ischaemic heart disease. The size and prospective design of the study and the socioeconomic homogeneity of the cohort minimise both random and systematic error.

Adult↗
PubMed2000

Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice.

Receptor tyrosine kinase erbB2, which is activated by neuregulin, is expressed in Schwann and muscle cells in the developing neuromuscular junction (NMJ). In vitro studies have shown that neuregulin promotes the survival and migration of Schwann cells and stimulates acetylcholine receptor gene transcription in cultured muscle cells. These findings suggest an important role for erbB2 in the development of the NMJ. Here we examine erbB2-deficient mice to determine whether erbB2 is required for NMJ development in vivo. Our analysis shows that there are pre- and postsynaptic defects of developing NMJ in erbB2-deficient embryos. The presynaptic defects include defasciculation and degeneration of the motor nerves, and an absence of Schwann cells. The postsynaptic defect features an impairment of junctional folds at the neuromuscular synapse in the mutants. These results demonstrate that erbB2 is essential for in vivo development of the NMJ.

Animals↗
PubMed1999

Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development.

ErbB2 receptor tyrosine kinase plays a role in neuregulin signaling and is expressed in the developing nervous system. We genetically rescued the cardiac defect of erbB2 null mutant embryos, which otherwise died at E11. These rescued erbB2 mutant mice die at birth and display a severe loss of both motor and sensory neurons. Motor and sensory axons are severely defasciculated and aberrantly projected within their final target tissues. Schwann cells are completely absent in the peripheral nerves. Schwann cell precursors are present within the DRG and proliferate normally, but their ability to migrate is decreased. Acetylcholine receptors cluster within the central band of the mutant diaphragm muscle. However, these clusters are dispersed and morphologically different from those in control muscle. Our results reveal an important role for erbB2 during normal peripheral nervous system development.

Animals↗
PubMed1999

Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening.

To examine the Down's syndrome screening positive rate among in vitro fertilisation (IVF) pregnancies, we measured second trimester serum marker levels in singleton IVF pregnancies (cases) and in five non-IVF pregnancies (controls) matched to each case for gestational age, age of mother, and duration of storage of the serum sample. There were 151 IVF pregnancies in which alpha fetoprotein, unconjugated oestriol (uE3), free beta-human chorionic gonadotrophin (hCG) and total hCG were measured, 104 IVF pregnancies in which free alpha-hCG was measured, and 39 IVF pregnancies in which inhibin A was measured. Median uE3 levels were 6% lower (P = 0.003), median free beta-hCG 9% higher (P = 0.024), and median total hCG 14% higher (P = 0.026) in IVF pregnancies compared with controls. The screen positive rate in the IVF pregnancies (28%) was about twice as high as that in controls (17%). High hCG levels may be explained by progesterone remaining high in IVF pregnancies. The low uE3 levels remain unexplained. In Down's syndrome screening in IVF pregnancies hCG and uE3 values should be adjusted to avoid the high screen positive rate.

Biomarkers↗
PubMed1999

The importance of age in screening for cancer.

OBJECTIVE: To derive a rational method of selecting the age range over which screening tests for cancer should be offered (that is, over which they would be most effective in saving life). MAIN OUTCOME MEASURE: The number of person-years of life that are lost through deaths occurring at each year of age from each of six cancers. RESULTS: For each cancer the number of years of life lost to age 80, plotted against age at death, showed a rise followed by a fall. The peak indicates the age at which deaths from the cancer result in most years of life lost. Special screening tests, such as mammography for breast cancer, will be most effective in saving life shortly before that age. The peak (as a five year age span) occurs at age 55-59 for breast cancer (189 years of life lost per 10,000 women per year), 70-74 for prostate cancer (114), 65-69 for colorectal cancer (96), 55-59 for ovarian cancer (61), 50-54 for cervical cancer (47), and 45-50 for melanoma (8). The precise interval by which special screening tests should precede the peak age is not critical; five years would be appropriate. Given current evidence on the efficacy of cancer screening, if it were stipulated that screening could only be performed when at least 50 years of life were to be gained per 10,000 persons screened, only mammography for breast cancer would be conducted, between the ages of 50 and 59. If the stipulation was 25 or more years of life gained mammography would be offered to women aged 40-69 and cervical smears to women aged 35-59. With only 10 or more years of life gained (unlikely to be worthwhile) mammography would be extended to women aged 30-74, cervical smears to 25-69, and faecal occult blood testing for colorectal cancer offered to those aged 45-74. Extending cervical cancer screening to age 69 would save more years of life than the present policy of screening women aged 20-29. Extending breast cancer screening to the age of 74 would be more effective than cervical screening at any age. CONCLUSIONS: Determining the number of years of life lost through deaths from a particular cancer at each age is useful in public health screening policy, both in selecting the age range over which special screening tests of proven efficacy should be offered and in quantitatively comparing the value of screening for different cancers.

Adolescent↗
PubMed1999

Quantifying the decline in the birth prevalence of neural tube defects in England and Wales.

In England and Wales there has been a large decline in the birth prevalence of neural tube defects (NTDs) from the early 1970s (reported rates of about 3.2 per 1000 births) to the present (0.1 per 1000 births in 1997). The reported number of terminations of NTD pregnancies increased from 0.02 per 1000 in 1970 to 0.66 per 1000 in 1997, much too small an increase to explain the decline in NTD births. Some underreporting of NTD terminations is recognised. We estimated its extent using 1976-80 data on reported central nervous system (CNS) defect terminations and NTD births in an analysis in which the true total number of NTD pregnancies during this short period was assumed to have either remained constant or else to have been changing by a constant amount per year. The estimate was that 56% of NTD terminations were not reported as such and this fitted the data well. In 1997 the estimated birth prevalence of NTDs was 0.14 per 1000 births, a fall of 96% since 1970. This 96% was apportioned as 40% due to antenatal screening and termination of pregnancy and 56% due to a decline in incidence. Over the period 1970-97 there was an increase in dietary folate, and this will have at least in part caused the decline in incidence of NTDs.

Abortion, Induced↗
PubMed1999

Fetal loss in Down syndrome pregnancies.

It is recognized that pregnancies with Down syndrome are liable to end in spontaneous fetal loss. It is important to determine the magnitude of this effect so that it can be taken into account when assessing the results of antenatal screening programmes for Down syndrome. Failure to do so will tend to overestimate the detection rate in intervention studies in which the screening results are used to identify women for a diagnostic test and the offer of a termination of pregnancy if indicated. We present new data on the spontaneous fetal loss in Down syndrome pregnancies from the National Down Syndrome Cytogenetic Register (1989-1996). We compare our results with published results of other studies on the subject to obtain a summary estimate. We exclude one study from the meta analysis due to incorrect methodology resulting in an overestimate of fetal loss. Based on the combined data (i) between the time of chorionic villus sampling and term an estimated 43 per cent (95 per cent CI: 31-54 per cent) of pregnancies ended in a miscarriage or still birth, (ii) between the time of amniocentesis and term an estimated 23 per cent (95 per cent CI: 19 28 per cent) of pregnancies ended in a miscarriage or still birth, and (iii) 12 per cent (95 per cent CI: 2-23 per cent) of births were stillborn or resulted in a neonatal death.

Abortion, Spontaneous↗
PubMed1998

Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization.

BACKGROUND: In vitro fertilization is associated with a high risk of multiple births, which is a direct consequence of the number of embryos transferred. However, other factors that contribute to the risk are not well defined. METHODS: Using the data base established by the Human Fertilization and Embryology Authority in the United Kingdom, we studied the factors associated with an increased risk of multiple births in 44,236 cycles in 25,240 women. The factors included the woman's age, the cause and duration of infertility, previous attempts at in vitro fertilization, previous live births, number of eggs fertilized, and number of embryos transferred. RESULTS: Older age, tubal infertility, longer duration of infertility, and a higher number of previous attempts at in vitro fertilization were all associated with a significantly decreased chance of a birth and of multiple births. Previous live birth was associated with an increased chance of a birth but not of multiple births. The higher the number of eggs fertilized, the higher the likelihood of a live birth. When more than four eggs were fertilized, there was no increase in the birth rate for women receiving three transferred embryos as compared with those receiving two, but there was a considerable increase in the rate of multiple births when three were transferred (odds ratio, 1.6; 95 percent confidence interval, 1.5 to 1.8). CONCLUSIONS: Among women undergoing in vitro fertilization, the chances of a live birth are related to the number of eggs fertilized, presumably because of the greater selection of embryos for transfer. When more than four eggs are fertilized and available for transfer, the woman's chance of a birth is not diminished by transferring only two embryos. Transferring more embryos increases the risk of multiple births.

Adult↗
PubMed1998

By how much does fruit and vegetable consumption reduce the risk of ischaemic heart disease?

OBJECTIVE: To quantify the relationship between fruit and vegetable consumption and the incidence of ischaemic heart disease. DESIGN: A meta-analysis of cohort studies of the relationship between ischaemic heart disease and markers of fruit and vegetable consumption, namely dietary intake of fruit, vegetables, carotenoids, vitamin C, fruit fibre and vegetable fibre, and serum concentration of carotenoids and vitamin C, adjusted for other risk factors. MAIN OUTCOME MEASURES: Risk of ischaemic heart disease at the 90th centile of consumption relative to that at the 10th, equivalent to about a four-fold difference in fruit consumption and a doubling of vegetable consumption. RESULTS: The association with ischaemic heart disease was of similar magnitude for all six dietary markers of fruit and vegetable consumption. The median of the six estimates was that risk was 15% (range 12-19%) lower at the 90th centile of consumption than at the 10th. The estimates were generally adjusted for the possible confounding effect of other heart disease risk factors. The serum studies of vitamin C were consistent with this; those of carotenoids suggested a larger difference (43%) but were not adjusted for the important confounding effect of smoking. The substances in fruit and vegetables responsible for the protective effect on heart disease are uncertain but the effect is commensurate with the estimated protective effects of the potassium and folate in fruit and vegetables. Beta-carotene or vitamin E are not likely to be important because randomised trials of these vitamins in large doses have shown no reduction in heart disease mortality. CONCLUSIONS: The risk of ischaemic heart disease is about 15% lower at the 90th than the 1Oth centile of fruit and vegetable consumption.

Adult↗