Reliable evidence from placebo-controlled, randomized, clinical trials for menopausal hormone therapy's influence on incidence and deaths from breast cancer.

In an invited editorial, Dr Shapiro proposes that vaginal bleeding leading to unblinding and subsequent detection bias explains the breast cancer increase seen with estrogen plus progestin in the Women's Health Initiative (WHI) clinical trial (1) . In the context of a uniform detection program of protocol-mandated annual mammography and breast examinations, such a proposal is medically implausible. Dr Shapiro suggests detection bias would identify a larger number of 'slowly growing tumors that would otherwise remain clinically silent'. The findings of more advanced cancers with increased deaths from breast cancer in the estrogen plus progestin group refute this conjecture. During early post-intervention phases of both WHI hormone therapy trials, when breast cancer detection bias is asserted by Dr Shapiro because participants had been informed of randomization assignment, breast cancer incidence rates were lower (rather than higher) than during intervention. Thus, Dr Shapiro's claims are directly refuted by findings from the WHI randomized clinical trials. Health-care providers should be aware that randomized clinical trial evidence supports estrogen plus progestin increasing breast cancer incidence and deaths from breast cancer. In contrast, among women with prior hysterectomy, randomized clinical trial evidence supports estrogen alone reducing breast cancer incidence and deaths from breast cancer.

Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study.

SUMMARY: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.

A collaborative and evolving response to the needs of frontline workers, patients and families during the COVID-19 pandemic at Tygerberg Hospital, Western Cape Province, South Africa.

The global devastation caused by the COVID-19 pandemic and its mental health impact is undeniable. The physical and psychological consequences are wide-ranging - affecting patients fighting the disease, frontline workers in the trenches with them, healthcare staff deployed in high-care settings, and families disconnected from their loved ones in their darkest hours. Within 6 weeks of the COVID-19 outbreak in South Africa, the Department of Psychiatry at Stellenbosch University established the TBH/SU COVID Resiliency Clinic to provide psychological support to frontline workers at Tygerberg Hospital. Identified barriers in healthcare workers accessing mental healthcare resulted in moving towards an on-site visibility to try to remove some of these barriers. This greater on-site presence enabled networking and building of relationships with frontline staff that over time highlighted other frontline needs, such as providing psychosocial and spiritual support to patients and their families. We share challenges, lessons learned and recommendations from two initiatives: the TBH/SU COVID-19 Resiliency Clinic, and an embedded COVID Care Team (CCT). We describe the establishment, roll-out and progress of the Clinic and the subsequent CCT.

Spotted fever rickettsiosis in South Africa: Evaluation of laboratory diagnostic capacity and inter-laboratory comparison of serological testing.

BACKGROUND: Spotted fever rickettsiosis, also known as tick bite fever (TBF), is a common infectious disease in South Africa (SA). Although the diagnosis of TBF is often based on clinical grounds only, laboratory testing is important to confirm the diagnosis and can contribute to case management in the light of a myriad of differential diagnoses, and in complicated cases. OBJECTIVES: To report on the availability and scope of laboratory tests for investigating suspected cases of TBF in SA, and the outcome of an inter-laboratory comparison (ILC) conducted for serological tests. METHODS: A self-administered questionnaire was circulated to major pathology laboratories in SA to determine what TBF tests they offered for TBF investigation. In addition, a clinical panel was provided to willing laboratories in order to perform an ILC of the serological tests. RESULTS: Serological tests for TBF were available from five laboratories serving both the private and state medical sectors in SA. There was no standardised testing platform or result interpretation across the different laboratories. Polymerase chain reaction (PCR) tests were less frequently available, and not available to state-operated facilities. The outcome of the ILC indicated varied performance and interpretation of serological results for TBF. CONCLUSIONS: Laboratory investigation for TBF is routinely and widely available in SA. Both serological and PCR-based methods were varied, and the lack of standardisation and interpretation of tests needs to be addressed to improve the overall quality of TBF diagnosis in SA. The utility of ILC to identify problem areas in serological testing for TBF is highlighted, and laboratories in SA are encouraged to use it to improve the quality of testing.

Vasomotor symptoms and the risk of incident venous thrombosis in postmenopausal women.

Essentials Vasomotor symptoms have been proposed as markers of changing cardiovascular risk. In this cohort study, we evaluated these symptoms as markers of venous thrombosis (VT) risk. We found no evidence that vasomotor symptom presence or severity were associated with VT risk. Among these postmenopausal women, vasomotor symptoms are not a useful marker of VT risk. SUMMARY: Background Vasomotor symptoms may be markers of changes in cardiovascular risk, but it is unknown whether these symptoms are associated with the risk of venous thrombosis (VT). Objective To evaluate the association of vasomotor symptom presence and severity with incident VT risk among postmenopausal women, independent of potential explanatory variables. Methods This cohort study included participants of the Women's Health Initiative (WHI) Hormone Therapy Trials (n = 24 508) and Observational Study (n = 87 783), analyzed separately. At baseline, women reported whether hot flashes or night sweats were present and, if so, their severity. Using Cox proportional hazards models, we estimated the VT risk associated with vasomotor symptom presence and severity, adjusted for potential explanatory variables: age, body mass index, smoking status, race/ethnicity, and time-varying current hormone therapy use. Results At baseline, WHI Hormone Therapy Trial participants were aged 64 years and WHI Observational Study participants were aged 63 years, on average. In the WHI Hormone Therapy Trials over a median of 8.2 years of follow-up, 522 women experienced a VT event. In the WHI Observational Study, over 7.9 years of follow-up, 1103 women experienced a VT event. In adjusted analyses, we found no evidence of an association between vasomotor symptom presence (hazard ratio [HR]adj  0.91, 95% confidence interval [CI] 0.75-1.1 in the WHI Hormone Therapy Trials; HRadj  1.1, 95% CI 0.99-1.3 in the WHI Observational Study) or severity (HRadj for severe versus mild 0.99, 95% CI 0.53-1.9 in the WHI Hormone Therapy Trials; HRadj  1.3, 95% CI 0.89-2.0) in the WHI Observational Study) and the risk of incident VT. Conclusions Although vasomotor symptoms have been associated with the risk of other cardiovascular events in published studies, our findings do not suggest that vasomotor symptoms constitute a marker of VT risk.

Kwashiorkor in North America.

The controversy regarding the relative importance of protein vs energy deficiency in the genesis of kwashiorkor has not been resolved by studies of protein-energy malnutrition (PEM) in developing countries. Cases of edematous PEM (n = 29) in North America on the other hand provide clear indications that protein deficiency is an essential prerequisite for the development of kwashiorkor and marasmic kwashiorkor. Energy intakes may vary from low to high and the main source of energy may be carbohydrate or fat. These findings are in keeping with experimental evidence that a low ratio of protein to energy disrupts the usual hypometabolic response to dietary deficiency and leads to hypoalbuminemia and consequent edema. Protein supplements should be a part of programs aimed at preventing kwashiorkor.

The effect of skim milk, yoghurt, and full cream milk on human serum lipids.

The hypothesis that certain milk products contain a cholesterol-lowering "milk factor" was tested in adolescent schoolboys whose diets were complemented with 2 L of skim milk, yoghurt, or full cream milk daily for 3 wk. After a fall in all serum lipids during the precomplementation wk, serum total cholesterol and low-density lipoprotein cholesterol continued to fall on skim milk; in contrast, it rose for the first 2 wk on yoghurt or full cream milk. These changes correlated with dietary fat and cholesterol intakes. Total cholesterol returned to base-line values during the 3rd wk on yoghurt or full cream milk. High-density lipoprotein cholesterol and percentage high-density lipoprotein/total cholesterol rose transiently in all three groups, with the highest levels being recorded on full cream milk. Serum triglycerides tended to decrease in all groups. No convincing evidence of a milk factor could be found, but skim milk appeared to have a cholesterol-lowering effect at least partly due to its low lipid content.

Promotion and regression of atherosclerosis in vervet monkeys by diets realistic for westernized people.

We have described and measured aortic and arterial atherosclerosis in adult female Vervet monkeys (n = 61) after application of dietary treatments for 47 months. The diets were compounded entirely of normal food items for westernized people, with no extra cholesterol added. A 'Western' diet (WD), known to induce hypercholesterolaemia, was found to be atherogenic in aortas and some arteries. A more 'prudent' diet (PD) induced much less lipid infiltration into aortic intimas and was not associated with serious atherosclerotic changes. However, when this PD was used as a treatment for 27 months, following 20 months of nutrition by the WD, minimal regression of cholesterol crystals and non-lipid components of atherosclerotic plaque was detected. There was no significant coronary artery or myocardial disease in these adult females after 47 months of feeding on the WD whereas males do develop coronary atherosclerosis and myocardial fibrosis. For this model the PD would be more effective in preventing atherosclerosis than treating advanced lesions. We believe this is the first time that the pathology of atherosclerosis promoted by realistic diets has been modelled in adult females of this species.

Does lowering serum cholesterol levels lower coronary heart disease risk?

Many lines of evidence converge toward the conclusion that low-density lipoprotein cholesterol (LDLC) is indeed a causal factor in the genesis of CHD. These range from animal studies, pathology studies, inborn errors of metabolism, clinical observations, and the existence of plausible biologic mechanisms, to the vast body of epidemiologic evidence. Observations of the association of LDLC with CHD hold between different populations, in the same population at different times, and to studies of individuals within populations. Finally, the clinical trials of cholesterol lowering, together with regression studies in animals and angiographic studies in humans, provide compelling evidence that the progress of atherosclerosis can be halted and the clinical sequelae can be reduced. The newly available results from more recent intervention studies have reinforced the validity of this conclusion. The intervention studies reduced the CHD incidence rate by approximately 2% for every 1% reduction in total cholesterol (TC) even though the studies were of relatively short duration (typically 5 years). More prolonged exposure to lower TC levels can be expected to yield even greater ultimate benefit. The benefit is most clearcut for men at highest risk. The combined data indicate that both fatal and nonfatal CHD can be reduced. More data on the extremes of age, on subjects with moderate elevations of TC, and on women would be valuable, but it is reasonable to proceed with advice to the general population aimed at reducing average cholesterol levels, and also to identify and treat those at high risk. There is good reason to expect that these measures will further reduce MI events and in all likelihood also MI deaths. Whether they will also reduce overall mortality is at present a moot point; however, a reduction in the burden of nonfatal MI would in itself be a very desirable objective.

Lipid-lowering interventions in angiographic trials.

This analysis examines the pooled data from all 14 published randomized angiographic trials (with 16 treatment arms) by type of cholesterol-lowering intervention evaluated, and for all the trials combined. All interventions reduced low density lipoprotein (LDL) cholesterol levels (average reduction, 26%), whereas the effects on high density lipoprotein (HDL) cholesterol and triglycerides varied by type of intervention. Meta-analyses of the angiographic outcomes indicated that treatment reduced the odds for disease progression by 49%, increased the odds for no change by 33%, and increased the odds for regression by 219%. Cardiovascular events were reduced by 47%. Thus, lipid reduction is effective for modifying the angiographic outcome and for reducing the incidence of coronary artery disease events. All types of intervention (lifestyle, drugs, or surgery) had overall favorable effects on angiographic and clinical outcomes. There was no class effect for the statin group of drugs. Surgery (partial ileal bypass) had the most favorable angiographic outcome, possibly because of a longer duration of therapy. Trials with higher baseline LDL levels tended to have more favorable angiographic outcomes. Analyses of in-trial levels of LDL were confounded by baseline levels, and analyses of change in LDL levels in the treatment groups were confounded by not including zero change (i.e., no treatment). It is hypothesized that lowering LDL levels by 30 mg/dl (0.8 mmol/liter) is sufficient on average to modify the angiographic outcome, with modest gains from further reductions in LDL levels.

Drop-out and newcomer bias in a community cardiovascular follow-up study.

Bias resulting from a loss of baseline subjects at follow-up (drop-out), and newcomer bias resulting from subjects entering the study at the follow-up stage, were investigated in a three-community coronary risk factor follow-up study. The study consisted of a cross-sectional baseline study on 7188 participants aged 15 to 64 years, a four-year intervention period and a follow-up cross-sectional study in the same communities on 6283 participants aged 19 to 68 years. The overall non-response rate of 45% in men and 42% in women varied from 30 to 79% in the various age and sex groups, with the biggest drop-out rate occurring in the youngest age group of 15 to 24 years. At baseline drop-outs were more likely to have lower educational qualifications than those who participated in both the baseline and follow-up studies (stayers) and included significantly more smokers than non-smokers. Coronary risk factors of newcomers were not different from that of the stayers at follow-up except for slightly, but not significantly, higher smoking rates in newcomers. These findings suggest that drop-out and newcomer bias need to be assessed and its effect studied before final evaluation of data in community follow-up studies.

Twelve-year results of the Coronary Risk Factor Study (CORIS).

BACKGROUND: After 4 years a coronary heart disease risk factor intervention programme produced equally large and significantly reduced risk profiles in two intervention towns compared with a control town. Intervention effects through community participation were assessed after cessation of the active intervention programme. The impact of secular trends was assessed in the control town and in two previously unstudied towns. METHODS: Cross-sectional surveys were done in a random sample of 1620 participants aged 15-64 years in the three original towns 12 years after the initial quasi-experimental study. Two years later 327 subjects, aged 35-44 years, were studied in the original control town and in two non-intervention towns. Risk factor knowledge, smoking and medical histories were determined by questionnaire. Blood pressure, anthropometry and blood lipids were recorded. Data were compared across towns, and with previous surveys. RESULTS: At 12 years the low intensity intervention town maintained a significantly better risk factor profile than the control town, while the high intensity intervention town now matched the control town. No differences in risk factor profiles were found between the control town and the two new towns. Deaths from coronary heart disease and strokes showed a downward trend in the study area. CONCLUSIONS: Outcome suggests large ongoing secular trends during the study could have overtaken the intervention effects in the high intensity town, but not in the low intensity intervention town, which showed an advantage over the control town. These results support the effectiveness of media-based, long term health promotion strategies to reduce cardiovascular disease risk profiles.

Community-based intervention: the Coronary Risk Factor Study (CORIS).

The Coronary Risk Factor Study (CORIS) examined the feasibility and effectiveness of a multifactorial community intervention programme to reduce coronary heart disease (CHD) risk factor levels. Three Afrikaner communities were surveyed before and after a 4-year intervention in two of the communities, the third serving as a control (C). Intervention was primarily by small mass media (low-intensity intervention, LII) or by small mass media plus interpersonal intervention to high-risk individuals (high-intensity intervention, HII). After allowing for change in C, significant net reductions in blood pressure, smoking, and risk score were obtained in LII and HII alike. Though the total cholesterol (TC) fell by 10-12%, there was no net reduction in favour of the intervention communities. However, LII and HII resulted in significant increases in high-density lipoprotein cholesterol (HDL-C) levels and HDL-C/TC ratios in comparison to C. Overall, the LII community fared almost as well as the HII community, and high-risk individuals did not show a greater change in risk factors than others. We conclude that community-based intervention works, and that in these particular communities a media-based health education programme was more cost-effective than one which adds a greater degree of interpersonal intervention.

Studies on the ultrastructure of blood cells and the microaggregate fraction in stored human blood.

Electron microscopy of citrate-phosphate-dextrose (CPD) buffered bank blood performed over 21 days shows that the normal architecture of erythrocytes, platelets and leucocytes disappears and that deformed organelles, leucocyte "ghosts", cell fragments and microaggregates accumulate. Leucocytes and platelets emerge as the most sensitive indicators of blood deterioration showing profound morphological changes from the first day. Microaggregates which passed through a 20-micrometer high capacity transfusion filter were identified as platelet conglomerates, leucocyte "ghost" and platelet-leucocyte "ghost" coaggregates with diameters of 6--20, 20--30 and 30--40 micrometers respectively. Of these aggregates present in the filtrate, 62% fell into the size range of 20--40 micrometers. The composition of microaggregates varies with storage time, the platelet conglomerates appear first during or after Day 1, leucocyte "ghosts" after Day 5 followed by platelet-leucocyte "ghost" coaggregate formation. At this stage the number of intact leucocytes and platelets is reduced and the filtrate shows an abundance of leucocyte debris. Microfiltration would thus appear to reduce but not eliminate the danger of microembolism and damage to capillary endothelium.

The effects of lowering serum cholesterol on coronary heart disease risk.

The clinical trials and angiographic studies of cholesterol lowering have been of decisive importance in persuading scientific and public opinion that elevated serum cholesterol is a causal element in the chain of events leading to CHD and that treatment by diet and drugs is effective in lowering the risk of CHD. The appropriateness of these opinions is well illustrated by the analyses of the combined trials, which show that the clinical event rate can be lowered by about 20% if cholesterol levels are lowered by 10%. The reduced risk for CHD applies to both primary and secondary prevention. Further, the angiographic studies have now demonstrated that vigorous lipid-lowering therapy leads to improvements in the angiographic appearance of coronary vessels, which are accompanied by large reductions in CHD risk. Diet and a variety of drugs appear to modify the risk of CHD. The results of studies using combinations of drugs, for example, bile acid-binding resins with either niacin or hydroxymethylglutaryl coenzyme A reductase inhibitors, are particularly impressive. The primary purpose of treatment remains the reduction of total and LDL cholesterol; however, the possibility of an additional benefit from improving other aspects of the lipid profile (such as raising HDL cholesterol levels) at the same time should not be ignored. In many instances, combinations of drugs are needed to achieve optimal lowering of serum cholesterol or to treat all elements of the disorder. Although the treatment of high-risk but apparently healthy individuals should not be neglected, it would be particularly appropriate to institute intensive diet and combination drug therapy in patients with existing CHD, in view of their high risk of reinfarction if left untreated. The secondary prevention trials provide evidence that clinical events can be reduced in such patients. The angiographic studies strongly suggest that large reductions in cholesterol to much lower levels (in-treatment LDL cholesterol levels below 100 mg/dL were frequently observed) than those achieved in the secondary prevention trials markedly reduce the rate of coronary events in patients with existing disease.

The nutrient intake of a group of older South African hospitalized persons.

Data from a dietary survey of patients in a rehabilitation hospital indicated that their nutrient intake was very low in comparison with the RDAs. Those patients are at risk of developing specific nutritional deficiencies. Recommendations to improve the nutrient intake of this group of elderly persons are given. Even if the "perfect diet" were served, however, a patient's food intake might not be sufficient to meet the RDAs because of lack of appetite or because of elevated requirements owing to various illnesses, multiple drug use, and physiological changes associated with aging. In such a patient, the potentially beneficial use of supplements must be considered.

Change in knowledge in a coronary heart disease risk factor intervention study in three communities.

We investigated health and diet knowledge as it relates to coronary heart disease (CHD) in three rural areas which participated in a community-oriented CHD risk factor intervention study. Knowledge of risk factors (risk knowledge) was fairly satisfactory at baseline, but diet knowledge was poor. Males, the young, and individuals with a lower level of education had less knowledge. Intervention consisted of a 3-year small mass media programme in one community (low-intensity intervention, LII), additional interpersonal intervention to high-risk individuals in the second (high-intensity intervention, HII), and no intervention in the control community (C). In the cohorts, with the baseline survey and the follow-up study 4 years apart, knowledge improved by 8.1% points in males (7.5% in females) in the HII community and by 7.1% (6.5%) in the LII community, compared to 5.5% (4.8%) in the C community (P less than 0.01). Diet knowledge improved more than risk knowledge, and individuals with lower initial scores benefitted most. Female scored highest. Educational level made a modest positive contribution to knowledge gain, after adjusting for differences in baseline knowledge. High-risk individuals did not have better knowledge at baseline, nor did they gain more from the intervention. We conclude that community intervention over a 4 year period, based on community diagnosis and tailored to the community's needs, can improve health knowledge.