Search

Background Acute pancreatitis (AP) is a frequent cause of hospitalization with long-term health consequences, including type 3c diabetes mellitus (DM). The incidence and risk factors for new-onset morbidities after AP need to be clarified to inform a personalized medicine approach. Methods Using a longitudinal electronic healthcare record-linkage analysis, all patients admitted to hospital in Scotland with a first episode of AP between 1 April 2009 and 31 March 2012 and followed for a minimum of 5 years after their index AP admission were identified. All new-onset morbidity with specific focus on type 3c DM were analysed and, using time-split multiple regression. Results A total of 2047 patients were included. AP requiring critical care was followed by 2 years of heightened risk (HR 5.24) of developing type 3c DM, increased risk of new-onset cardiac disease (HR 1.61), and renal disease (HR 2.96). The additional risk conferred by critical care AP had a negative interaction with time, whereas additional risk associated with male sex and a non-gallstone aetiology was long lasting. Conclusion Based on these findings, a personalized approach to include type 3c DM screening for a minimum of 2 years for individuals who required critical care when hospitalized with AP is recommended. [ABSTRACT FROM AUTHOR]

Background: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up.Methods: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs.Results: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24).Conclusions: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study. [ABSTRACT FROM AUTHOR]

Cinnamyl alcohol dehydrogenase (CAD) catalyzes the final step in monolignol biosynthesis, reducing sinapaldehyde, coniferaldehyde, and p-coumaraldehyde to their corresponding alcohols in an NADPH-dependent manner. Because of its terminal location in monolignol biosynthesis, the variation in substrate specificity and activity of CAD can result in significant changes in overall composition and amount of lignin. Our in-depth characterization of two major CAD isoforms, SbCAD2 (Brown midrib 6 [bmr6]) and SbCAD4, in lignifying tissues of sorghum (Sorghum bicolor), a strategic plant for generating renewable chemicals and fuels, indicates their similarity in both structure and activity to Arabidopsis (Arabidopsis thaliana) CAD5 and Populus tremuloides sinapyl alcohol dehydrogenase, respectively. This first crystal structure of a monocot CAD combined with enzyme kinetic data and a catalytic model supported by site-directed mutagenesis allows full comparison with dicot CADs and elucidates the potential signature sequence for their substrate specificity and activity. The L119W/G301F-SbCAD4 double mutant displayed its substrate preference in the order coniferaldehyde > p-coumaraldehyde > sinapaldehyde, with higher catalytic efficiency than that of both wild-type SbCAD4 and SbCAD2. As SbCAD4 is the only major CAD isoform in bmr6 mutants, replacing SbCAD4 with L119W/G301F-SbCAD4 in bmr6 plants could produce a phenotype that is more amenable to biomass processing. [ABSTRACT FROM AUTHOR]

Cinnamoyl-coenzyme A reductase (CCR) catalyzes the reduction of hydroxycinnamoyl-coenzyme A (CoA) esters using NADPH to produce hydroxycinnamyl aldehyde precursors in lignin synthesis. The catalytic mechanism and substrate specificity of cinnamoyl-CoA reductases from sorghum (Sorghum bicolor), a strategic plant for bioenergy production, were deduced from crystal structures, site-directed mutagenesis, and kinetic and thermodynamic analyses. Although SbCCR1 displayed higher affinity for caffeoyl-CoA or p-coumaroyl-CoA than for feruloyl-CoA, the enzyme showed significantly higher activity for the latter substrate. Through molecular docking and comparisons between the crystal structures of the Vitis vinifera dihydroflavonol reductase and SbCCR1, residues threonine-154 and tyrosine-310 were pinpointed as being involved in binding CoA-conjugated phenylpropanoids. Threonine-154 of SbCCR1 and other CCRs likely confers strong substrate specificity for feruloyl-CoA over other cinnamoyl-CoA thioesters, and the T154Y mutation in SbCCR1 led to broader substrate specificity and faster turnover. Through data mining using our structural and biochemical information, four additional putative CCR genes were discovered from sorghum genomic data. One of these, SbCCR2, displayed greater activity toward p-coumaroyl-CoA than did SbCCR1, which could imply a role in the synthesis of defense-related lignin. Taken together, these findings provide knowledge about critical residues and substrate preference among CCRs and provide, to our knowledge, the first three-dimensional structure information for a CCR from a monocot species. [ABSTRACT FROM AUTHOR]

Background: Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice.Methods: MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis.Results: There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators.Conclusion: For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications. [ABSTRACT FROM AUTHOR]

Caffeoyl-coenzyme A 3-O-methyltransferase (CCoAOMT) is an S-adenosyl methionine (SAM)-dependent O-methyltransferase responsible for methylation of the meta-hydroxyl group of caffeoyl-coenzyme A (CoA) on the pathway to monolignols, with their ring methoxylation status characteristic of guaiacyl or syringyl units in lignin. In order to better understand the unique class of type 2 O-methyltransferases from monocots, we have characterized CCoAOMT from sorghum (Sorghum bicolor; SbCCoAOMT), including the SAM binary complex crystal structure and steady-state enzyme kinetics. Key amino acid residues were validated with site-directed mutagenesis. Isothermal titration calorimetry data indicated a sequential binding mechanism for SbCCoAOMT, wherein SAM binds prior to caffeoyl-CoA, and the enzyme showed allosteric behavior with respect to it. 5-Hydroxyferuloyl-CoA was not a substrate for SbCCoAOMT. We propose a catalytic mechanism in which lysine-180 acts as a catalytic base and deprotonates the reactive hydroxyl group of caffeoyl-CoA. This deprotonation is facilitated by the coordination of the reactive hydroxyl group by Ca2+ in the active site, lowering the pKa of the 3'-OH group. Collectively, these data give a new perspective on the catalytic mechanism of CCoAOMTs and provide a basis for the functional diversity exhibited by type 2 plant OMTs that contain a unique insertion loop (residues 208-231) conferring affinity for phenylpropanoid-CoA thioesters. The structural model of SbCCoAOMT can serve as the basis for protein engineering approaches to enhance the nutritional, agronomic, and industrially relevant properties of sorghum. [ABSTRACT FROM AUTHOR]

Introduction Nonarteritic anterior ischemic optic neuropathy ( NAION), a rare visual disorder, has been reported in men using phosphodiesterase type 5 inhibitors ( PDE5i) for erectile dysfunction. Aim We examined whether intermittent use of PDE5i is associated with acute NAION onset within approximately five half-lives following drug ingestion. Methods One hundred two ophthalmology centers in the United States and Europe identified potential cases of NAION. An expert adjudication committee conducted a blind review of the records of those with recent PDE5i use to classify cases as Definite, Possible, or not NAION. Subjects provided information on PDEi use via telephone interview. Each NAION case's PDE5i exposure immediately prior to onset was compared against his recent patterns of use in an observational case-crossover design. A sample size of 40 cases with intermittent PDE5i exposure in the 30 days prior to NAION onset was needed to detect an odds ratio ( OR) of 3.0 with 80% power. Main Outcome Measures The daily relative risk for acute NAION on days within five half-lives of PDE5i use vs. other days was estimated via an OR obtained from conditional logistic regression. Results Among 43 Definite NAION cases with PDE5i exposure in the prior 30 days, the OR was 2.15 (95% confidence interval [ CI]: 1.06, 4.34). When 21 Possible NAION cases were included (n = 64), the OR was 2.36 (95% CI: 1.33, 4.19). Conclusions We found an approximately twofold increased risk of acute NAION within five half-lives of PDE5i use compared with use in a more prior time period. Bias from inaccurate recall of exposure was unlikely to have substantially affected the results. Based on our results, we estimate that weekly use of PDE5i adds three NAION cases per 100,000 men 50 years and older annually. Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D, Quinn S, Klein BEK, Laties AM, Lewis M, Sharlip ID, Kolitsopoulos F, Klee BJ, Mo J, and Reynolds RF. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med 2015;12:139-151. [ABSTRACT FROM AUTHOR]

Hydroxycinnamoyltransferase (HCT) from sorghum (Sorghum bicolor) participates in an early step of the phenylpropanoid pathway, exchanging coenzyme A (CoA) esterified to p-coumaric acid with shikimic or quinic acid as intermediates in the biosynthesis of the monolignols coniferyl alcohol and sinapyl alcohol. In order to elucidate the mode of action of this enzyme, we have determined the crystal structures of SbHCT in its apo-form and ternary complex with shikimate and p-coumaroyl-CoA, which was converted to its product during crystal soaking. The structure revealed the roles of threonine-36, serine-38, tyrosine-40, histidine-162, arginine-371, and threonine-384 in catalysis and specificity. Based on the exact chemistry of p-coumaroyl-CoA and shikimic acid in the active site and an analysis of kinetic and thermodynamic data of the wild type and mutants, we propose a role for histidine-162 and threonine-36 in the catalytic mechanism of HCT. Considering the calorimetric data, substrate binding of SbHCT should occur sequentially, with p-coumaroyl-CoA binding prior to the acyl acceptor molecule. While some HCTs can use both shikimate and quinate as an acyl acceptor, SbHCT displays low activity toward quinate. Comparison of the structure of sorghum HCT with the HCT involved in chlorogenic acid synthesis in coffee (Coffea canephora) revealed many shared features. Taken together, these observations explain how CoA-dependent transferases with similar structural features can participate in different biochemical pathways across species. [ABSTRACT FROM AUTHOR]

Estimating risks associated with the use of childhood vaccines is challenging. The authors propose a new approach for studying short-term vaccine-related risks. The method uses a cubic smoothing spline to flexibly estimate the daily risk of an event after vaccination. The predicted incidence rates from the spline regression are then compared with the expected rates under a log-linear trend that excludes the days surrounding vaccination. The 2 models are then used to estimate the excess cumulative incidence attributable to the vaccination during the 42-day period after vaccination. Confidence intervals are obtained using a model-based bootstrap procedure. The method is applied to a study of known effects (positive controls) and expected noneffects (negative controls) of the measles, mumps, and rubella and measles, mumps, rubella, and varicella vaccines among children who are 1 year of age. The splines revealed well-resolved spikes in fever, rash, and adenopathy diagnoses, with the maximum incidence occurring between 9 and 11 days after vaccination. For the negative control outcomes, the spline model yielded a predicted incidence more consistent with the modeled day-specific risks, although there was evidence of increased risk of diagnoses of congenital malformations after vaccination, possibly because of a “provider visit effect.” The proposed approach may be useful for vaccine safety surveillance. [ABSTRACT FROM PUBLISHER]

Observational studies often provide the only available information about treatment effects. Control of confounding, however, remains challenging. The authors compared five methods for evaluating the effect of tissue plasminogen activator on death among 6,269 ischemic stroke patients registered in a German stroke registry: multivariable logistic regression, propensity score–matched analysis, regression adjustment with the propensity score, and two propensity score–based weighted methods—one estimating the treatment effect in the entire study population (inverse-probability-of-treatment weights), another in the treated population (standardized-mortality-ratio weights). Between 2000 and 2001, 212 patients received tissue plasminogen activator. The crude odds ratio between tissue plasminogen activator and death was 3.35 (95% confidence interval: 2.28, 4.91). The adjusted odds ratio depended strongly on the adjustment method, ranging from 1.11 (95% confidence interval: 0.67, 1.84) for the standardized-mortality-ratio weighted to 10.77 (95% confidence interval: 2.47, 47.04) for the inverse-probability-of-treatment-weighted analysis. For treated patients with a low propensity score, risks of dying were high. Exclusion of patients with a propensity score of <5% yielded comparable odds ratios of approximately 1 for all methods. High levels of nonuniform treatment effect render summary estimates very sensitive to the weighting system explicit or implicit in an adjustment technique. Researchers need to be clear about the population for which an overall treatment estimate is most suitable. [ABSTRACT FROM AUTHOR]

Objective. To quantify resource utilization and costs incurred for patients who received transdermal fentanyl as their first long-acting analgesic for non-malignant pain, and to compare these with utilization and costs for similar patients dispensed other long-acting oral opioids. Design. A retrospective matched cohort study using medical claims data from a large New England Insurer. Patients. We identified 478 patients without cancer who received transdermal fentanyl during 1995-1998. We selected patients who had no previous long-acting opioid dispensings and were enrolled during the 180 days before and 30 days following the initial dispensing. We used propensity scores to identify a matched comparison group of 478 long-acting oral opioid users. Results. Transdermal fentanyl and matched long-acting oral opioid users incurred identical median costs for outpatient medical services and prescriptions during 2 years of follow-up. A larger proportion of transdermal fentanyl patients were still taking their initial opioid analgesic at the end of the 2-year follow-up than were patients initially taking other long-acting opioids. Use of short-acting opioids tapered off more slowly among transdermal fentanyl patients than among long-acting opioid patients. In the first 6 months, the transdermal fentanyl patients had more hospital discharges than the long-acting oral opioid patients, but this difference appeared to reflect preexisting conditions. Conclusions. Users of fentanyl transdermal system and other long-acting opioids experienced essentially identical evolution of health services utilization and costs over a 2-year period. The choice of long-acting opioid analgesia does not appear to be a determinant of future medical costs. [ABSTRACT FROM AUTHOR]

Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTDs). To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (spina bifida, anencephaly, and encephalocele) with data from a control group of 6,660 infants with malformations not related to vitamin supplementation. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors and about medication use. The adjusted odds ratios of NTDs related to exposure to FAAs (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) during the first or second months after the last menstrual period, compared with no use in either month, were 2.8 (95% confidence interval: 1.7, 4.6) for FAAs as a group, 4.8 (95% confidence interval: 1.5, 16.1) for trimethoprim (based on five exposed cases), and 6.9 (95% confidence interval: 1.9, 25.7) for carbamazepine (six exposed cases). These results are adjusted for region, interview year, periconceptional folic acid supplementation, maternal age, weight, education, and infections early in pregnancy. These findings suggest that a number of FAAs may increase NTD risk, and they provide estimates of risk for selected drugs. Am J Epidemiol 2001;153:961-8. [ABSTRACT FROM AUTHOR]

Prevalences of bowing and knock knee, measured at a standard stance, have been obtained on Negro, Coloured, Indian and Caucasian schoolchildren aged 7, 12, and 16-17 years. These two abnormalities were unexpectedly common, affecting about one-fifth and one-third of all children respectively. Ranges of prevalences of chest abnormalities were—Harrison's sulcus, 0-5%, and pigeon chest, 0-2%. Prevalence of bowing increased with age. That of knock knee was little affected by age, but increased markedly with body mass. There was no age trend with prevalences of chest abnormalities. Prevalences appeared unrelated to vitamin D intake. As to sunshine, the annual mean for the Transvaal is 8·4 hr daily. Results from radiological, skin pigmentation, and biochemical studies were non-contributory. Since a primary deficiency of vitamin D is evidently not the causal factor, one explanation is that a secondary deficiency is involved, arising from an impairment in metabolic availability. Further, a proportion of leg abnormalities may be physiological variants; moreover, it cannot be excluded that unknown factors may bear, or share, in responsibility. Elucidation may be forthcoming by investigating the interrelationship between vitamin D status and frequency of leg abnormalities during and after puberty; in addition, results of serial studies of prevalences of abnormalities from birth to post-adolescence would be illuminating. [ABSTRACT FROM PUBLISHER]

Whereas expectation of life at birth invariably is greater in more privileged populations, the respective survival patterns at middle age can be entirely different. Comparisons have been made between South African and other populations, using, as a survival index, the number who are 70 years or more at present, as a percentage of the number who were 50 years or more 19 years earlier (data for the desired 20-year period were not available for all populations). Briefly (1) South African Negroes had the highest index; Indians both in India and South Africa the lowest; Caucasian populations in South Africa, United States, and England and Wales, were intermediate. (2) Indices for females were higher than for males; the disparity was least in Indians, but greatest for the population of England and Wales. Evidently, with progressive sophistication of diet and manner of life, the concomitant change from infections to degenerative diseases, as main causes of death at middle age and beyond, reduces rather than increases chances of survival. [ABSTRACT FROM PUBLISHER]

In vitro mutagenic activity and carcinogenic potential of metronidazole in certain animals raised concerns about its possible carcinogenicity in humans. We studied the late incidence of cancer after metronidazole use among persons enrolled in the Group Health Cooperative of Puget Sound, Seattle, a health maintenance organization. Randomly selected nonusers were matched on a one-to-one basis for age, gender, and year of enrollment to persons who used metronidazole on an outpatient basis during the period January 1975 to December 1983; 5,222 metronidazole user/nonuser pairs, for whom the median follow-up was 12.6 years, were analyzed. Forty-nine percent, 39.2%, 9.8%, and 2% of users had 1, 2–4, 5–9, and ⩾10 prescriptions or refills of metronidazole filled, respectively. The late (after the first 7 years of follow-up) incidence of cancer was nearly identical among users and nonusers (652 and 662 per 100,000 person-years, respectively; relative risk, 0.98; 95% confidence interval, 0.80–1.20). Age-gender stratified analysis did not reveal any association between metronidazole use and cancer. These data support no association between short-term exposure to metronidazole and cancer in humans. Although the results are reassuring, they may not extend to subjects who have used metronidazole for prolonged periods; further epidemiological studies should focus on these individuals. [ABSTRACT FROM PUBLISHER]

Multilayer neural networks have been faulted for functioning as “black boxes” and for failing to assess the relative importance of the input factors. The aim of this paper is to illustrate how neural networks can classify individuals. The authors investigated the role of weights in the formation of neural networks‘ decision surfaces and decision regions. The data used were from a case-control study. Two strong determinants of case status were used as input “neurons.” Zero, three, and five hidden neurons were used to explore the effect of the number of hidden neurons on the decision surfaces and regions. Mapping of input and output spaces revealed that three hidden neurons were insufficient to fully discriminate cases from controls. Five hidden neurons may be optimal, but at the cost of possible over-fitting. The more complex neural networks were very effective at defining regions of uniform risk in the plane of the initial covariates, and at assigning risk levels. The authors speculate that neural networks will prove useful in epidemiologic problems that require pattern recognition or complicated classification techniques, and that they will be unfavorable in problems that involve distinct effects of distinguishable predictors. Am J Epidemiol 1998; 147: 1112–22. [ABSTRACT FROM PUBLISHER]

The authors developed and cross-validated prediction models for newty diagnosed cases of liver disorders by using logistic regression and neural networks. Computerized files of health care encounters from the Fallon Community Health Plan were used to identify 1,674 subjects who had had liver-related health services between July 1,1992, and June 30, 1993. A total of 219 subjects were confirmed by review of medical records as incident cases. The 1, 674 subjects were randomly and evenly divided into training and test sets. The training set was used to derive prediction algorithms based solely on the automated data; the test set was used for cross-validation. The area under the Receiver Operating Characteristic curve for a neural network model was significantly larger than that for logistic regression in the training set (p = 0.04). However, the performance was statistically equivalent in the test set (p = 0.45). Despite its superior performance in the training set, the generalizability of the neural network model is limited. Logistic regression may therefore be preferred over neural network on the basis of its established advantages. More generalizable modeling techniques for neural networks may be necessary before they are practical for medical research. Am J Epidemiol 1998; 147: 407–13. [ABSTRACT FROM AUTHOR]

SUMMARY The simulated small-sample behaviours of several estimators of a common hazard ratio are compared. In most circumstances, a modified version of the empirical logit (Haldane 1955; Anscombe 1956) seems to be the analytic technique of choice. The performance of the Standardized Mortality Ratio (SMR) is indistinguishable from that of the ML estimator when the denominator experience is much larger than that of the numerator experience. When many cells have small expectations, then the empirical logit becomes biased, and a variant of the Mantel-Haenszel estimator (Mantel and Haenszel, 1959) is the most widely reliable non-iterative estimator. [ABSTRACT FROM AUTHOR]

When matched sets of individuals are entered into follow-up studies, data collection on many covariates can be eliminated without loss of relevant information. In a proportional hazards model with risk sets restricted by a matching factor, no individual's data enter into the likelihood function unless some member of his matched set experiences an event. In many epidemiological studies, the probability of an event in any given matched set is small, as a result most sets, having no event, make no contribution to effect estimates and data collection in these sets can be avoided. [ABSTRACT FROM AUTHOR]

A multiplicative model was fitted to incidence rates of nervous system tumours cross-tabulated for each sex by fiveyear age groups between ages 35–64 and 51 populations in which at least ten cases had been observed and 60% of cases histologically verified. There was no significant departure from a model in which the age curve was assumed to have the same shape but a different level in each population. On log-log scale this shape was a straight line with identical slope (2.6) for males and females. Population-specific multipliers were highest in Israel and lowest in Asia. Within the US, rates were significantly lower among blacks. Hispanics, Chinese and Japanese compared to whites. A model for both sexes combined showed that sex ratios were rarely below unity but varied significantly between populations. Exposure for susceptibility) to as yet unidentified aetiological factors appears to be higher in males and whites than in females and non-whites. [ABSTRACT FROM PUBLISHER]

This paper persents a technique for the analysis of interaction which is based upon the additivity of attributable risks. Such an approach is justified when the purpose is to provide a basis for making decisions about personal risk or public health intervention. [ABSTRACT FROM PUBLISHER]

At present there is considerable controversy over many aspects of iron nutrition, including: (1) iron needs and intake levels; (2) the bearing of iron intake on haematological levels; (3) iron deficiency anaemia and deficiency stigmata; and (4) iron therapy, prophylaxis, and the haematological and clinical benefits accruing. Differences of opinion prevail because of inadequacies of knowledge of the level of haemoglobin (or other parameter of iron status) below which unequivocal signs and symptoms of ill-health become manifest in the major proportion of those affected. Difficulties arise equally from lack of knowledge of the level of haemoglobin above which no clinical benefit, short-term or long-term, can be detected from iron supplementation. Clarification of the situation can be obtained only by carrying out the same meticulous and time-consuming procedures that have been used in respect of requirements and deficiency stigmata of other nutrients. Comprehensive iron depletion studies, real and simulated, and repletion studies, including the use of placebos, will be required. Epidemiological investigations bearing on haematological status and morbidity will also need to be undertaken, and include groups of subjects in both Western, and developing countries. [ABSTRACT FROM PUBLISHER]

Information on appendicectomy-prevalence was secured on 15,317 16-20-year-old South African pupils and students—Negroes, Coloureds (Eurafricans), Indians and Caucasians. Data were also obtained on crude fibre-intake, frequency of defaecation, and transit-time of digesta. Among students, 18-20 years, appendicectomy was very uncommon in rural Negroes (0·5%) and periurban Negroes (0·9%), slightly more common in urban Negroes (1·4%), but very common in Caucasians (16·5%); prevalences in Coloured and Indian groups were low (1·7 and 2·9%). Rural Negroes had a far larger fibre-intake, greater frequency of defaecation, and much shorter transit-time; yet, in the four ethnic groups in urban areas, despite wide differences in appendicectomy-prevalence, data on these variables were similar. Differences in other aspects of the bowel milieu intérieur must therefore be sought. Corresponding studies were made on 1325 Caucasian pupils in Homes; their diet is less sophisticated (in respect of fibre, sugar and fat-intakes) than that of the general population. Pupils had slightly greater defaecation-frequency, lesser transit-time, and an appendicectomy-incidence only 23% of that of an appropriate control-group. The conclusion is reached that the causes of appendicitis are wholly environmental. [ABSTRACT FROM PUBLISHER]

Negro groups in West, Central and Southern Africa, also in Jamaica, have mean cardio-thoracic ratios significantly greater than those in corresponding age-sex groups of Caucasians. To throw more light on the situation, studies on young and elderly Negroes have been made in certain groups in Southern Africa, also on local Caucasian groups. Only slight differences in ratio were found between local Negro groups, and Caucasian groups in South Africa, also in Wales and Tecumseh (U.S.A.). Yet ratios in Negro males from Malawi and Mozambique, resident in South Africa, were significantly greater than values in local Negroes. High ratios are not therefore invariable for Negroes. The difference observed relates to heart, not thoracic diameter. Since the phenomenon, which concerns heart position, is apparent in the young, almost certainly it is of ethnic origin. Investigations on cardiomegaly in African populations must take this factor into reckoning. Its presence or absence locally may readily be assessed by determining ratios in relatively small numbers of young people of both sexes. [ABSTRACT FROM PUBLISHER]

Groups of South African Bantu boys and girls of 14 years, compared with local Caucasian children, have lower cortical thickness, cortical score, and crosssection and volume scores for second metacarpal. Yet, when these parameters on groups of aged Bantu men and women, 70-79 years, are compared with published values on corresponding Caucasians, there are no significant differences. Further, aged Bantu have lower prevalences of hip fracture and severe collapse of vertebral bodies. Since a low calcium intake, and in aged Bantu women numerous pregnancies and long lactations, are compatible with satisfactory bone data, it is questioned whether the present insistence on a high calcium intake is justified. [ABSTRACT FROM PUBLISHER]

A review of the article "The Failure of Academic Epidemiology: Witness for the Prosecution," by C.M. Shy in a previous issue is presented.