Effectiveness of vitamin D supplementation on knee osteoarthritis - A target trial emulation study using data from the Osteoarthritis Initiative cohort.

OBJECTIVE: To assess the real-world effectiveness of vitamin D supplementation in patients with knee osteoarthritis (KOA) by replicating a randomized controlled trial (RCT) design in an observational study. METHOD: This study emulated a target trial using data from the Osteoarthritis Initiative (OAI). Eligible participants were ≥45 years, had symptomatic KOA and did not take vitamin D supplements in the past 30 days. A participant can enter the trial more than once. Participants were included in vitamin D group if they took ≥1,000 IU/day for ≥4 days/week in the past 30 days at the first follow-up visit after baseline. The control group did not use vitamin D in the past 30 days. Optimal propensity score matching at 1:1 ratio was performed. The primary outcome was change in knee pain 2 years after baseline measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included WOMAC physical function and quantitative joint space width (JSW). Standardized mean difference (SMD) was used to compare the findings with previous RCTs. RESULTS: A total of 236 person-trials in the vitamin D group were pair-matched with a control. Compared to the control group, vitamin D supplementation did not reach significant changes in WOMAC pain (SMD = -0.04, 95%CI [-0.21, 0.13]), physical function and radiographic JSW over 2 years. The SMDs were consistent with the effect sizes reported in previous RCTs. CONCLUSION: Target trial emulation in the OAI cohort demonstrated findings close to published RCTs. This supports the future use of target trial emulation in evaluating other systemic therapies for KOA.

Efficacy and safety of a supplement combination on hand pain among people with symptomatic hand osteoarthritis an internet-based, randomised clinical trial the RADIANT study.

OBJECTIVE: The RADIANT study aimed to investigate the efficacy and safety of a complementary medicine supplement combination in people with hand osteoarthritis (HOA). METHOD: This was an internet-based, double-blind, randomised, placebo-controlled trial. Participants aged over 40 years with symptomatic HOA with radiographic confirmation (Kellgren Lawrence grade ≥ 2) throughout Australia were recruited and randomly assigned (1:1) to receive either a supplement combination composed of Boswellia serrata extract 250 mg/day, pine bark extract 100 mg/day, methylsulfonylmethane 1,500 mg/day and curcumin 168 mg/day or placebo for 12 weeks. The primary outcome was change in hand pain assessed using a visual analogue scale (VAS 0-100) from baseline to week 12. A range of secondary outcomes and additional measures were recorded. Adverse events were monitored weekly. RESULTS: One hundred and six participants were included with mean age 65.6 years and 81% were women. 45% of the participants were graded as KLG 4, 40% KLG three and 39 (37%) had erosive OA. There was no significant difference in pain VAS reduction between groups. The adjusted between group difference in means (95%CI) was 5.34 (-2.39 to 13.07). Five participants (10%) in the supplement combination group discontinued study treatment due to AE vs four participants (7%) in the placebo group. CONCLUSION: There were no significant differences in symptomatic relief between the two groups over 12 weeks. These findings do not support the use of the supplement combination for treating hand pain in people with HOA. REGISTRATION: Prospectively registered (Australian New Zealand Clinical Trials Registry ACTRN12619000835145, 31/05/2019).

The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial.

OBJECTIVE: Epidemiological data suggest low serum 25-hydroxyvitamin D3 (25-OH-D3) levels are associated with radiological progression of knee osteoarthritis (OA). This study aimed to assess whether vitamin D supplementation can slow the rate of progression. METHOD: A 3-year, double-blind, randomised, placebo-controlled trial of 474 patients aged over 50 with radiographically evident knee OA comparing 800 IU cholecalciferol daily with placebo. Primary outcome was difference in rate of medial joint space narrowing (JSN). Secondary outcomes included lateral JSN, Kellgren & Lawrence grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, stiffness and the Get up and Go test. RESULTS: Vitamin D supplementation increased 25-OH-D3 from an average of 20.7 (standard deviation (SD) 8.9) µg/L to 30.4 (SD 7.7) µg/L, compared to 20.7 (SD 8.1) µg/L and 20.3 (SD 8.1) µg/L in the placebo group. There was no significant difference in the rate of JSN over 3 years in the medial compartment of the index knee between the treatment group (average -0.01 mm/year) and placebo group (-0.08 mm/year), average difference 0.08 mm/year (95% confidence interval (CI) [-0.14-0.29], P = 0.49). No significant interaction was found between baseline vitamin D levels and treatment effect. There were no significant differences for any of the secondary outcome measures. CONCLUSION: Vitamin D supplementation did not slow the rate of JSN or lead to reduced pain, stiffness or functional loss over a 3-year period. On the basis of these findings we consider that vitamin D supplementation has no role in the management of knee OA.

OARSI guidelines for the non-surgical management of knee osteoarthritis.

OBJECTIVE: To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis (OA), intended to inform patients, physicians, and allied healthcare professionals worldwide. METHOD: Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the OA literature, 29 treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OA Research Society International (OARSI) evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using Assessment of Multiple Systematic Reviews (AMSTAR) criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical sub-phenotypes. Consensus recommendations were produced using the RAND/UCLA Appropriateness Method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical sub-phenotypes and accompanied by 1-10 risk and benefit scores. RESULTS: Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical sub-phenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral non-steroidal anti-inflammatory drugs (NSAIDs; COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical sub-phenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation). CONCLUSION: These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

Symptom and structure modification in osteoarthritis with pharmaceutical-grade chondroitin sulfate: what's the evidence?

OBJECTIVES: Osteoarthritis is a chronic disease characterized by irreversible damage to joint structures, including loss of articular cartilage, osteophyte formation, alterations in the subchondral bone and synovial inflammation. It has been shown that chondroitin sulfate interferes with the progression of structural changes in joint tissues and is used in the management of patients with osteoarthritis. METHODS: This review summarizes data from relevant reports describing the mechanisms of action of chondroitin sulfate that may explain the beneficial effects of the drug and examines the evidence for clinical efficacy of oral chondroitin sulfate in osteoarthritis. Data included in the review were derived from a literature search in PubMed. Literature searches were performed in PubMed using the search terms 'chondroitin sulfate', 'pharmaceutical-grade', 'osteoarthritis', 'randomized clinical trials', 'humans'. The MEDLINE database was searched from January 1996 through August 2012 for all randomized controlled trials, meta-analyses, systematic reviews, and review articles of chondroitin sulfate in osteoarthritis. RESULTS: Chondroitin sulfate exerts in vitro a beneficial effect on the metabolism of different cell lines: chondrocytes, synoviocytes and cells from subchondral bone, all involved in osteoarthritis. It increases type II collagen and proteoglycan synthesis in human articular chondrocytes and is able to reduce the production of some pro-inflammatory factors and proteases, to reduce the cellular death process, and improve the anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Clinical trials have reported a beneficial effect of chondroitin sulfate on pain and function. The structure-modifying effects of chondroitin sulfate have been reported and analyzed in recent meta-analyses. The results in knee osteoarthritis demonstrate a small but significant reduction in the rate of decline in joint space width. Because chondroitin sulfate quality of several nutraceuticals has been found to be poor, it is recommended that pharmaceutical-grade chondroitin sulfate is used rather than food supplements in the treatment of OA. Chondroitin sulfate is recommended by several guidelines from international societies in the management of knee and hip OA. Furthermore, its safety profile is favorable when compared with many other therapies used in OA. CONCLUSION: Chondroitin sulfate is an effective and safe treatment option for patients with osteoarthritis.

Lipid-soluble vitamins A, D, and E in HIV-infected pregnant women in Tanzania.

BACKGROUND/OBJECTIVES: There is limited published research examining lipid-soluble vitamins in human immunodeficiency virus (HIV)-infected pregnant women, particularly in resource-limited settings. SUBJECTS/METHODS: This is an observational analysis of 1078 HIV-infected pregnant women enrolled in a trial of vitamin supplementation in Tanzania. Baseline data on sociodemographic and anthropometric characteristics, clinical signs and symptoms, and laboratory parameters were used to identify correlates of low plasma vitamin A (<0.7 micromol/l), vitamin D (<80 nmol/l) and vitamin E (<9.7 micromol/l) status. Binomial regression was used to estimate risk ratios and 95% confidence intervals. RESULTS: Approximately 35, 39 and 51% of the women had low levels of vitamins A, D and E, respectively. Severe anemia (hemoglobin <85 g/l; P<0.01), plasma vitamin E (P=0.02), selenium (P=0.01) and vitamin D (P=0.02) concentrations were significant correlates of low vitamin A status in multivariate models. Erythrocyte Sedimentation Rate (ESR) was independently related to low vitamin A status in a nonlinear manner (P=0.01). The correlates of low vitamin D status were CD8 cell count (P=0.01), high ESR (ESR >81 mm/h; P<0.01), gestational age at enrollment (nonlinear; P=0.03) and plasma vitamins A (P=0.02) and E (P=0.01). For low vitamin E status, the correlates were money spent on food per household per day (P<0.01), plasma vitamin A concentration (nonlinear; P<0.01) and a gestational age <16 weeks at enrollment (P<0.01). CONCLUSIONS: Low concentrations of lipid-soluble vitamins are widely prevalent among HIV-infected women in Tanzania and are correlated with other nutritional insufficiencies. Identifying HIV-infected persons at greater risk of poor nutritional status and infections may help inform design and implementation of appropriate interventions.

OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.

PURPOSE: As a prelude to developing updated, evidence-based, international consensus recommendations for the management of hip and knee osteoarthritis (OA), the Osteoarthritis Research Society International (OARSI) Treatment Guidelines Committee undertook a critical appraisal of published guidelines and a systematic review (SR) of more recent evidence for relevant therapies. METHODS: Sixteen experts from four medical disciplines (primary care two, rheumatology 11, orthopaedics one and evidence-based medicine two), two continents and six countries (USA, UK, France, Netherlands, Sweden and Canada) formed the guidelines development team. Three additional experts were invited to take part in the critical appraisal of existing guidelines in languages other than English. MEDLINE, EMBASE, Science Citation Index, CINAHL, AMED, Cochrane Library, seven Guidelines Websites and Google were searched systematically to identify guidelines for the management of hip and/or knee OA. Guidelines which met the inclusion/exclusion criteria were assigned to four groups of four appraisers. The quality of the guidelines was assessed using the AGREE (Appraisal of Guidelines for Research and Evaluation) instrument and standardised percent scores (0-100%) for scope, stakeholder involvement, rigour, clarity, applicability and editorial independence, as well as overall quality, were calculated. Treatment modalities addressed and recommended by the guidelines were summarised. Agreement (%) was estimated and the best level of evidence to support each recommendation was extracted. Evidence for each treatment modality was updated from the date of the last SR in January 2002 to January 2006. The quality of evidence was evaluated using the Oxman and Guyatt, and Jadad scales for SRs and randomised controlled trials (RCTs), respectively. Where possible, effect size (ES), number needed to treat, relative risk (RR) or odds ratio and cost per quality-adjusted life year gained (QALY) were estimated. RESULTS: Twenty-three of 1462 guidelines or consensus statements retrieved from the literature search met the inclusion/exclusion criteria. Six were predominantly based on expert opinion, five were primarily evidence based and 12 were based on both. Overall quality scores were 28%, 41% and 51% for opinion-based, evidence-based and hybrid guidelines, respectively (P=0.001). Scores for aspects of quality varied from 18% for applicability to 67% for scope. Thirteen guidelines had been developed for specific care settings including five for primary care (e.g., Prodigy Guidance), three for rheumatology (e.g., European League against Rheumatism recommendations), three for physiotherapy (e.g., Dutch clinical practice guidelines for physical therapy) and two for orthopaedics (e.g., National Institutes of Health consensus guidelines), whereas 10 did not specify the target users (e.g., Ontario guidelines for optimal therapy). Whilst 14 guidelines did not separate hip and knee, eight were specific for knee but only one for hip. Fifty-one different treatment modalities were addressed by these guidelines, but only 20 were universally recommended. Evidence to support these modalities ranged from Ia (meta-analysis/SR of RCTs) to IV (expert opinion). The efficacy of some modalities of therapy was confirmed by the results of RCTs published between January 2002 and 2006. These included exercise (strengthening ES 0.32, 95% confidence interval (CI) 0.23, 0.42, aerobic ES 0.52, 95% CI 0.34, 0.70 and water-based ES 0.25, 95% CI 0.02, 0.47) and nonsteroidal anti-inflammatory drugs (NSAIDs) (ES 0.32, 95% CI 0.24, 0.39). Examples of other treatment modalities where recent trials failed to confirm efficacy included ultrasound (ES 0.06, 95% CI -0.39, 0.52), massage (ES 0.10, 95% CI -0.23, 0.43) and heat/ice therapy (ES 0.69, 95% CI -0.07, 1.45). The updated evidence on adverse effects also varied from treatment to treatment. For example, while the evidence for gastrointestinal (GI) toxicity of non-selective NSAIDs (RR=5.36, 95% CI 1.79, 16.10) and for increased risk of myocardial infarction associated with rofecoxib (RR=2.24, 95% CI 1.24, 4.02) were reinforced, evidence for other potential drug related adverse events such as GI toxicity with acetaminophen or myocardial infarction with celecoxib remained inconclusive. CONCLUSION: Twenty-three guidelines have been developed for the treatment of hip and/or knee OA, based on opinion alone, research evidence or both. Twenty of 51 modalities of therapy are universally recommended by these guidelines. Although this suggests that a core set of recommendations for treatment exists, critical appraisal shows that the overall quality of existing guidelines is sub-optimal, and consensus recommendations are not always supported by the best available evidence. Guidelines of optimal quality are most likely to be achieved by combining research evidence with expert consensus and by paying due attention to issues such as editorial independence, stakeholder involvement and applicability. This review of existing guidelines provides support for the development of new guidelines cognisant of the limitations in existing guidelines. Recommendations should be revised regularly following SR of new research evidence as this becomes available.

Multivitamin supplementation in HIV-positive pregnant women: impact on depression and quality of life in a resource-poor setting.

OBJECTIVES: The primary objective of this study was to examine the effect of vitamin supplementation on health-related quality of life and the risk of elevated depressive symptoms comparable to major depressive disorder (MDD) in HIV-positive pregnant women in Dar es Salaam, Tanzania. METHODS: From April 1995 to July 1997, 1078 HIV-positive pregnant women were enrolled in a randomized controlled trial. We examined the effects of vitamin supplementation on quality of life and the risk of elevated depressive symptoms, assessed longitudinally every 6-12 months. RESULTS: A substantial prevalence of elevated depressive symptoms (42%) was observed in HIV-positive pregnant women. Multivitamin supplementation (B-complex, C and E) demonstrated a protective effect on depression [relative risk (RR)=0.78; P=0.005] and quality of life [RR=0.72 for social functioning (P=0.001) and vitality (P=0.0001); RR=0.70 for role-physical (P=0.002)]; however, vitamin A showed no effect on these outcomes. CONCLUSIONS: Multivitamin supplementation (B-complex, C and E) resulted in a reduction in risk of elevated depressive symptoms comparable to MDD and improvement in quality of life in HIV-positive pregnant women in Tanzania.

Selenium levels in relation to morbidity and mortality among children born to HIV-infected mothers.

OBJECTIVE: To examine the relation between selenium status and child mortality and morbidity among children born to HIV-infected mothers. DESIGN: Prospective cohort study. METHODS: Study participants were originally part of a trial to study the effect of maternal vitamin supplements on maternal and child health outcomes. Morbidity information was collected during monthly clinic visits until the child reached 24 months of age. Out of 984 livebirths, 806 had morbidity information, and 610 also had data on plasma selenium levels available. SETTING: A study clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania, a tertiary-care hospital. RESULTS: The median age at baseline was 10.5 weeks. A total of 117 (19%) of the 610 study children died during follow-up. In a multivariate model, child plasma selenium levels were inversely associated with risk of all-cause mortality (P-value, test for trend=0.05). Plasma selenium levels were not significantly associated with risk of diarrhea or respiratory outcomes. CONCLUSIONS: Among infants born to HIV-infected women in sub-Saharan Africa, selenium status may be important to prevent child mortality. These preliminary findings warrant future reexamination.

Dietary intakes of vitamins A, C, and E and risk of melanoma in two cohorts of women.

Within the two Nurses' Health Study cohorts of US women, we examined whether higher intakes of vitamin C, vitamin E, retinol, or individual tocopherols or carotenoids are associated with a lower risk of melanoma. We confirmed 414 cases of invasive melanoma among over 162,000 Caucasian women aged 25-77 years during more than 1.6 million person-years of follow-up. Diet was measured every 4 years with a food frequency questionnaire and supplement use was reported every 2 years. Several measures of sun sensitivity were assessed and included in proportional hazards models. We found that vitamins A, C, E and their individual components were not associated with a lower risk of melanoma. Only retinol intake from foods plus supplements appeared protective within a subgroup of women who were otherwise at low risk based on nondietary factors (relative risk (RR)=0.39, 95% confidence interval (CI) 0.22-0.71 for >/=1,800 vs 400 microg day(-1), P for linear trend=0.01). Contrary to expectation, we observed higher risks of melanoma with greater intakes of vitamin C from food only (RR=1.43, 95% CI 1.01-2.00 for >/=175 vs <90 mg day(-1), P for linear trend=0.05) and a significant positive dose-response with frequency of orange juice consumption (P=0.008). Further research is needed to determine whether another component in foods such as orange juice may contribute to an increase in risk.

Risk of ovarian carcinoma and consumption of vitamins A, C, and E and specific carotenoids: a prospective analysis.

BACKGROUND: Antioxidant vitamins may decrease risk of cancer by limiting oxidative DNA damage leading to cancer initiation. Few prospective studies have assessed relations between antioxidant vitamins and ovarian carcinoma. METHODS: The authors prospectively assessed consumption of vitamins A, C, and E and specific carotenoids, as well as fruit and vegetable intake, in relation to ovarian carcinoma risk among 80,326 participants in the Nurses' Health Study who had no history of cancer other than nonmelanoma skin carcinoma. Women reported on known and suspected ovarian carcinoma risk factors including reproductive factors, smoking, and use of vitamin supplements on biennial mailed questionnaires from 1976 to 1996. Food frequency questionnaires were included in 1980, 1984, 1986, and 1990. The authors confirmed 301 incident cases of invasive epithelial ovarian carcinoma during 16 years of dietary follow-up (1980-1996). Pooled logistic regression was used to control for age, oral contraceptive use, body mass index, smoking history, parity, and tubal ligation. RESULTS: The authors observed no association between ovarian carcinoma risk and antioxidant vitamin consumption from foods, or foods and supplements together. The multivariate relative risks (95% confidence intervals [CIs]) for ovarian carcinoma among women in the highest versus lowest quintile of intake were 1.04 (95% CI, 0.72-1.51) for vitamin A from foods and supplements; 1.01 (95% CI, 0.69-1.47) for vitamin C; 0.88 (95% CI, 0.61-1.27) for vitamin E; and 1.10 (95% CI, 0.76-1.59) for beta-carotene. Among users of vitamin supplements, the authors found no evidence of an association between dose or duration of any specific vitamin and ovarian carcinoma risk, although the authors had limited power to assess these relations. No specific fruits or vegetables were associated significantly with ovarian carcinoma risk. The authors found no association between ovarian carcinoma and consumption of total fruits or vegetables, or specific subgroups including cruciferous vegetables, green leafy vegetables, legumes, or citrus fruits. Women who consumed at least 2.5 total servings of fruits and vegetables as adolescents had a 46% reduction in ovarian carcinoma risk (relative risk, 0.54, 95% CI, 0.29-1.03; P value for trend 0.04). CONCLUSIONS: These data do not support an important relation between consumption of antioxidant vitamins from foods or supplements, or intake of fruits and vegetables, and incidence of ovarian carcinoma in this cohort. However, modest associations cannot be excluded, and the authors' finding of an inverse association for total fruit and vegetable intake during adolescence raises the possibility that the pertinent exposure period may be much earlier than formerly anticipated.

Determinants of low birth weight among HIV-infected pregnant women in Tanzania.

BACKGROUND: Low birth weight (LBW) increases the risk of infant death, but little is known about its causes among HIV-infected populations in sub-Saharan Africa. OBJECTIVE: We assessed sociodemographic, nutritional, immunologic, parasitic, and infant risk factors for birth weight, LBW, and small-for-gestational-age (SGA) status in a cohort of 822 HIV-positive women enrolled in a clinical trial of vitamin supplementation and pregnancy outcomes in Dar es Salaam, Tanzania. DESIGN: Women were enrolled at prenatal care clinics during their second trimester, at which time blood, stool, urine, and genital specimens were collected, and anthropometric measurements and sociodemographic data were recorded. Birth weight was measured at hospital delivery. RESULTS: The mean (+/-SD) birth weight was 3015 +/- 508 g, 11.1% of newborns weighed <2500 g (LBW), and 11.5% were SGA. In multivariate analyses, maternal weight at enrollment and a low CD8 cell count were inversely associated with LBW. Advanced-stage HIV disease, previous history of preterm birth, Plasmodium falciparum malaria, and any helmintic infection were associated with higher risk of LBW. The intestinal parasites Entamoeba histolytica and Strongyloides stercoralis were predictors of LBW despite their low prevalence in the cohort. In a multivariate-adjusted linear regression model, BMI, midupper arm circumference, a CD4 cell count <200 x 10(6) cells/L (200 cells/mm(3)), primiparity, maternal literacy, and infant HIV infection at birth were significantly associated with birth weight in addition to risk factors included in the LBW model. Determinants of SGA included maternal weight, low serum vitamin E concentration, candidiasis, malaria, and infant HIV infection at birth. CONCLUSION: Prevention of HIV disease progression and vertical transmission, improved nutritional status, and better management of malaria and intestinal parasitic infections are likely to reduce the incidence of LBW in Tanzania.

Vitamin supplement use and the risk of non-Hodgkin's lymphoma among women and men.

The authors examined use of individual supplements of vitamins A, C, and E only and multivitamins in relation to risk of non-Hodgkin's lymphoma in prospective cohorts of 88,410 women in the Nurses' Health Study (1980-1996), with 261 incident cases during 16 years of follow-up, and of 47,336 men in the Health Professionals Follow-Up Study (1986-1996), with 111 incident cases during 10 years of follow-up. Multivitamin use was associated with a higher risk of non-Hodgkin's lymphoma among women but not among men; the multivariate relative risks for long-term duration (10 or more years) were 1.48 (95% confidence interval (CI): 1.01, 2.16) for women and 0.85 (95% CI: 0.45, 1.58) for men. The pooled multivariate relative risk from the two cohorts was 1.18 (95% CI: 0.70, 2.02). Use of individual supplements of vitamins A, C, and E only was not associated with risk among men. An increased risk associated with the use of individual supplements of vitamins A, C, and E only among women appeared to be secondary to the use of multivitamins by the same persons. Because an elevated risk among multivitamin users was not observed consistently in the two cohorts and the pooled data were not significant, the elevated risk among women may be the result of chance.

Nutritional factors and infectious disease contribute to anemia among pregnant women with human immunodeficiency virus in Tanzania.

The objective of this cross-sectional study was to identify risk factors for anemia among human immunodeficiency virus (HIV)-positive pregnant women in Dar es Salaam, Tanzania. Baseline data from 1064 women enrolled in a clinical trial on the effect of vitamin supplementation in HIV infection were examined to identify potential determinants of anemia. The mean hemoglobin (Hb) level was 94 g/L, and the prevalence of severe anemia (Hb < 85 g/L) was 28%; 83% of the women had Hb < 110 g/L. Iron deficiency and infectious disease appeared to be the predominant causes of anemia. Significant independent associations with severe anemia were observed for women with body mass index (BMI) < 19 kg/m(2) compared with women with BMI > 24 kg/m(2) [odds ratio (OR) 3.13, 95% confidence interval (CI): 1. 37-7.14); malaria parasite densities > 1000/mm(3) (OR 2.70, CI: 1. 58-4.61) compared with women with no parasites; eating soil during early pregnancy (OR 2.47, CI: 1.66-3.69); CD4+ cell count < 200/microL compared with CD4+ count > 500/microL (OR 2.70, CI: 1. 42-5.12); and serum retinol levels < 70 micromol/L (OR 2.45, CI: 1. 44-4.17) compared with women with retinol levels > 1.05 micromol/L. The most significant risk factors associated with severe anemia in this population are preventable. Public health recommendations include increasing the effectiveness of iron supplementation and malaria management during pregnancy, and providing health education messages that increase awareness of the potentially adverse nutritional consequences of eating soil during pregnancy.

Prospective study of smoking, antioxidant intake, and lung cancer in middle-aged women (USA).

BACKGROUND: Although substantial evidence suggests that higher intake of fruits and vegetables can reduce the adverse impact of smoking on lung cancer risk, great uncertainty exists regarding the specific foods and their constituents that are protective. We therefore examine prospectively the relation between cigarette smoking and lung cancer incidence among women, and quantify the associations between dietary antioxidants, other nutrients, and lung cancer risk. METHODS: In a 16-year prospective cohort study (the Nurses' Health Study), 593 cases of lung cancer were confirmed during 1,793,327 person-years of follow-up. Dietary data, including vitamin supplement use and food intake, were collected in 1980 using a validated semiquantitative food frequency questionnaire. RESULTS: The risk of lung cancer increased with the number of cigarettes smoked and with early onset of cigarette smoking. The risk decreased rapidly with the discontinuation of smoking but took 15 years to fall to about the level of risk for women who had never smoked. Dietary intake of fat was not related to the risk of lung cancer. Although beta-carotene intake was not related to risk, intake of carrots showed a strong inverse relation: women who reported consuming five or more carrots per week had a relative risk of 0.4 (95% CI = 0.2-0.8) compared with the risk for women who never ate carrots. CONCLUSIONS: Smoking is the most important risk factor for lung cancer in women, as it is in men. Higher vegetable consumption, particularly of carrots, may significantly reduce the risk of lung cancer, but dietary modification cannot be considered a substitute for smoking prevention and cessation.

A prospective study of folate intake and the risk of breast cancer.

CONTEXT: Folate is involved in DNA synthesis and methylation and may reduce breast cancer risk, particularly among women with greater alcohol consumption. OBJECTIVES: To assess the association between folate intake and risk of breast cancer and whether higher folate intake may reduce excess risk among women who consume alcohol. DESIGN: Prospective cohort study performed in 1980, with 16 years of follow-up. SETTING AND PARTICIPANTS: A total of 88818 women who completed the dietary questionnaire section of the Nurses' Health Study in 1980. MAIN OUTCOME MEASURE: Incidence of invasive breast cancer by levels of folate and alcohol intake. RESULTS: A total of 3483 cases of breast cancer were documented. Total folate intake was not associated with overall risk of breast cancer. However, among women who consumed at least 15 g/d of alcohol, the risk of breast cancer was highest among those with low folate intake. For total folate intake of at least 600 microg/d compared with 150 to 299 microg/d, the multivariate relative risk (RR) was 0.55 (95% confidence interval [CI], 0.39-0.76; P for trend = .001). This association was only slightly attenuated after additional adjustment for intake of beta carotene, lutein/zeaxanthin, preformed vitamin A, and total vitamins C and E. The risk of breast cancer associated with alcohol intake was strongest among women with total folate intake of less than 300 microg/d (for alcohol intake > or =15 g/d vs <15 g/d, multivariate RR, 1.32; 95% CI, 1.15-1.50). For women who consumed at least 300 microg/d of total folate, the multivariate RR for intake of at least 15 g/d of alcohol vs less than 15 g/d was 1.05 (95% CI, 0.92-1.20). Current use of multivitamin supplements, the major source of folate, was associated with lower breast cancer risk among women who consumed at least 15 g/d of alcohol (for current users of supplements vs never users, RR, 0.74; 95% CI, 0.59-0.93). CONCLUSIONS: Our findings suggest that the excess risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake.

Dietary carotenoids and vitamins A, C, and E and risk of breast cancer.

BACKGROUND: Data on intake of specific carotenoids and breast cancer risk are limited. Furthermore, studies of vitamins A, C, and E in relation to breast cancer risk are inconclusive. We have conducted a large, prospective study to evaluate long-term intakes of these nutrients and breast cancer risk. METHODS: We examined, by use of multivariate analysis, associations between intakes of specific carotenoids, vitamins A, C, and E , consumption of fruits and vegetables, and breast cancer risk in a cohort of 83234 women (aged 33-60 years in 1980) who were participating in the Nurses' Health Study. Through 1994, we identified 2697 incident cases of invasive breast cancer (784 premenopausal and 1913 postmenopausal). RESULTS: Intakes of beta-carotene from food and supplements, lutein/zeaxanthin, and vitamin A from foods were weakly inversely associated with breast cancer risk in premenopausal women. Strong inverse associations were found for increasing quintiles of alpha-carotene, beta-carotene, lutein/zeaxanthin, total vitamin C from foods, and total vitamin A among premenopausal women with a positive family history of breast cancer. An inverse association was also found for increasing quintiles of beta-carotene among premenopausal women who consumed 15 g or more of alcohol per day. Premenopausal women who consumed five or more servings per day of fruits and vegetables had modestly lower risk of breast cancer than those who had less than two servings per day (relative risk [RR] = 0.77; 95% confidence interval [CI] = 0.58-1.02); this association was stronger among premenopausal women who had a positive family history of breast cancer (RR = 0.29; 95% CI = 0.13-0.62) or those who consumed 15 g or more of alcohol per day (RR = 0.53; 95% CI = 0.27-1.04). CONCLUSIONS: Consumption of fruits and vegetables high in specific carotenoids and vitamins may reduce premenopausal breast cancer risk.

Association of dietary intake of fat and fatty acids with risk of breast cancer.

CONTEXT: High intakes of fat and specific fatty acids, including total, animal, saturated, polyunsaturated, and trans-unsaturated fats, have been postulated to increase breast cancer risk. OBJECTIVE: To determine whether intakes of fat and fatty acids are associated with breast cancer. DESIGN AND SETTING: Cohort study (Nurses' Health Study) conducted in the United States beginning in 1976. PARTICIPANTS: A total of 88795 women free of cancer in 1980 and followed up for 14 years. MAIN OUTCOME MEASURE: Relative risk (RR) of invasive breast cancer for an incremental increase of fat intake, ascertained by food frequency questionnaire in 1980, 1984, 1986, and 1990. RESULTS: A total of 2956 women were diagnosed as having breast cancer. Compared with women obtaining 30.1% to 35% of energy from fat, women consuming 20% or less had a multivariate RR of breast cancer of 1.15 (95% confidence interval [CI], 0.73-1.80). In multivariate models, the RR (95% CI) for a 5%-of-energy increase was 0.97 (0.94-1.00) for total fat, 0.98 (0.96-1.01) for animal fat, 0.97 (0.93-1.02) for vegetable fat, 0.94 (0.88-1.01) for saturated fat, 0.91 (0.79-1.04) for polyunsaturated fat, and 0.94 (0.88-1.00) for monounsaturated fat. For a 1% increase in energy from trans-unsaturated fat, the values were 0.92 (0.86-0.98), and for a 0.1% increase in energy from omega-3 fat from fish, the values were 1.09 (1.03-1.16). In a model including fat, protein, and energy, the RR for a 5% increase in total fat, which can be interpreted as the risk of substituting this amount of fat for an equal amount of energy from carbohydrate, was 0.96 (95% CI, 0.93-0.99). In similar models, no significant association of risk was evident with any major types of fat. CONCLUSION: We found no evidence that lower intake of total fat or specific major types of fat was associated with a decreased risk of breast cancer.

Rationale and design of the Tanzania Vitamin and HIV Infection Trial.

We present the rationale and design of a randomized, double-blind, placebo-controlled trial of vitamin supplements among HIV-positive pregnant women in Dar es Salaam, Tanzania. Higher levels of intake of vitamins A, B, C, and E may decrease the risk of vertical transmission and progression of HIV infection by enhancing maternal and infant immune function; by reducing viral load in the blood, breast milk, or lower genital tract secretions; and/or by strengthening the placental barrier to infection. Eligible pregnant women were randomized to receive vitamin A, multivitamins excluding A, vitamin A and multivitamins, or placebo. The main endpoints include vertical transmission of HIV infection, as assessed by examination of infection in infants using polymerase chain reaction (PCR), and progression of HIV disease as measured by the WHO clinical staging system. Over a period of 2 years, 13,876 women were tested for HIV infection, with appropriate pre- and posttest counseling, to enroll 1085 consenting HIV-positive women. The trial assesses women and their children once a month for a minimum of 18 months after delivery or up to the end of this 5-year study. We examine recruitment strategies and means of enhancing cohort retention in long-term follow-up. We assess compliance with the use of supplements by direct questioning, by counting pills, and biochemically by using serum beta-carotene and urine riboflavin levels. Briefly, we discuss ethical issues related to the conduct of AIDS prevention trials in this setting. In sub-Saharan Africa, most HIV-infected persons lack access to the relevant antiretroviral and prophylactic drugs, and the region urgently needs low-cost treatments and preventive strategies. The Tanzania trial should provide valuable data to address the effect of vitamin supplements in the transmission and progression of HIV infection.