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Mild analgesics such as acetylsalicylic acid (ASA) and acetaminophen (APAP) exert their pain-relieving effect in humans by inhibition of prostaglandin synthesis. Prostaglandins play key roles in developmental and reproductive processes in vertebrates, and in recent years, it has been suggested that weak analgesics might also act as endocrine disrupters. In a set of experiments we investigated if ASA and APAP affect well-established endocrine endpoints in zebrafish (Danio rerio), which is a commonly used model organism in the investigation of endocrine disrupting chemicals. Zebrafish were exposed to APAP (0.22, 2.3, and 30 mg L − 1) or ASA (0.2, 0.5, 1.7, and 8.2 mg L − 1) from hatch to sexual maturity in a test design resembling the OECD Fish Sexual Development Test. No effects on sex ratio and vitellogenin levels were observed. Adult zebrafish were exposed to high concentrations (mg L − 1) of ASA or APAP for eight or 14 days. ASA reduced the levels of prostaglandin E 2, but had no effect on the concentration of 11-ketotestosterone and vitellogenin. Overall, ASA decrease prostaglandin E 2 concentrations, but well-established endpoints for endocrine disruption in zebrafish are generally not affected by aquatic exposure neither during development nor adulthood. According to the WHO/IPCS definition of an endocrine disrupter, the present results do not define APAP and ASA as endocrine disrupters.

Background: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. Methods: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. Discussion: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. Trial registration: EU Clinical Trials Register: EudraCT 2016-001569-97, registered on 19-6-2017. Clinicaltrials.gov: NCT03192059, registered on 19-6-2017., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

Background: Recent studies suggest that aspirin use may improve survival in patients with prostate cancer.Objective: To assess the association between postdiagnosis use of low-dose aspirin and prostate cancer mortality.Design: Nationwide cohort study.Setting: Denmark.Patients: Men with incident prostate adenocarcinoma between 2000 and 2011.Measurements: Nationwide registry data on tumor characteristics, drug use, primary prostate cancer therapy, comorbidity, and socioeconomic parameters. Postdiagnosis use of low-dose aspirin (75 to 150 mg) was defined as 2 or more prescriptions filled within 1 year after prostate cancer diagnosis. Follow-up started 1 year after prostate cancer diagnosis. In secondary analyses, low-dose aspirin use was assessed within exposure periods of 5 or 7.5 years after prostate cancer diagnosis.Results: Of 29 136 patients (median age, 70 years), 7633 died of prostate cancer and 5575 died of other causes during a median follow-up of 4.9 years (interquartile range, 3.1 to 7.2 years), through 2015. Postdiagnosis low-dose aspirin use was associated with adjusted hazard ratios (HRs) of 0.95 (95% CI, 0.89 to 1.01) for prostate cancer-specific mortality and 1.12 (CI, 1.05 to 1.20) for other-cause mortality. The secondary analyses showed that prostate cancer mortality was slightly reduced with low-dose aspirin use after the 5-year (HR, 0.91 [CI, 0.83 to 1.01]) and 7.5-year (HR, 0.84 [CI, 0.72 to 0.97]) postdiagnosis exposure periods, notably among patients filling prescriptions for a large quantity of low-dose aspirin tablets during the 7.5-year period.Limitations: Data on over-the-counter aspirin use were unavailable. Some residual confounding was possible as a result of incomplete data on some prognostic factors.Conclusion: The study did not support an overall effect of postdiagnosis low-dose aspirin use on prostate cancer mortality. However, results for extended exposure periods suggest that low-dose aspirin use might be inversely associated with prostate cancer mortality after 5 years from cancer diagnosis.Primary Funding Source: Danish Cancer Society.

In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients ≥50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of ≥50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention. ispartof: CLINICAL CARDIOLOGY vol:42 issue:5 pages:498-505 ispartof: location:United States status: published

OBJECTIVES The number of elderly patients undergoing coronary revascularization is steadily increasing, and data on the impact of gender on outcomes are scarce. This study sought to assess gender-related differences in outcomes in elderly patients with acute coronary syndromes (ACS). METHODS We investigated outcomes in elderly ACS patients referred for coronary angiography and prospectively enrolled in the Swiss ACS Cohort between December 2009 and October 2012. Adjudicated major adverse cardiovascular and cerebrovascular events (MACCE) included all-cause death, non-fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke. RESULTS Among 2,168 patients recruited, 481 (22%) patients were >75 years of age (37% women). In patients >75 years, 1-year MACCE rates were 15% and 23% in women and men (OR 0.59, 95% CI 0.36-0.97, P = 0.04), respectively, and differences remained significant after adjustments for baseline variables (adjusted OR 0.48, 95% CI 0.26-0.90, P = 0.02). Women >75 years had a lower cardiovascular mortality (6% versus 12%, adjusted OR 0.31, 95% CI 0.12-0.81, P = 0.02). In patients ≤75 years, 1-year MACCE rates did not differ between gender (10% and 8% for women and men, adjusted OR 1.28, 95% CI 0.77-2.14, P = 0.34). Rates of TIMI major bleeding for women and men were 4% and 4% in patients >75 years (P = 0.96), and 5% and 3% in those ≤75 years (P = 0.11). CONCLUSIONS The low rates of MACCE observed in elderly women in this patient cohort suggest that with current interventional strategies the gender gap in ACS management has been attenuated.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, pINTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.FUNDING: Bayer AG.

Background: although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. Methods: in this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. Results: a total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P

Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-β-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age and sex matched controls treated with paclitaxel and low dose aspirin. By a cumulative dose of 1500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% CI, 0.9-3.0). Among those receiving a high dose paclitaxel regimen, the hazard ratio was 2.3 (95% CI, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high dose paclitaxel. This article is protected by copyright. All rights reserved.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

This article describes the mechanism of action, pharmacokinetics, and pharmacodynamics of aspirin at doses used for cardiovascular prevention and provides specific management recommendations for optimal use in clinical practice. The paper highlights practical aspects related to antiplatelet therapy, including the optimal dose of aspirin, concomitant treatment with other NSAIDs, and strategies for the prevention of gastrointestinal toxicity. Specifically, we revise the benefits and hazards in different clinical settings to help the clinician in the decision-making process for individuals who have different risks for cardiovascular and gastrointestinal bleeding events.

Background: Few studies have examined the association between use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and risk of glioma and the results have been equivocal. We therefore investigated the influence of NSAID use on glioma risk in a nationwide setting. Methods: We used national registries in Denmark to identify all patients aged 20-85 years with a first diagnosis of histologically verified glioma during 2000-2009. Each case was matched on birth year and sex to eight population controls using risk-set sampling. We used prescription data to assess NSAID use and classified exposure to low-dose aspirin or non-aspirin (NA) NSAIDs into ever use or long-term use, defined as continuous use for ≥5 years. Conditional logistic regression was used to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with NSAID use, adjusted for potential confounders.Results:A total of 2688 glioma cases and 18 848 population controls were included in the study. Ever use of low-dose aspirin (OR=0.90; 95% CI: 0.77-1.04) or NA-NSAIDs (OR=1.05; 95% CI: 0.96-1.14) was not associated with glioma risk. Compared with never use, long-term use of low-dose aspirin or of NA-NSAIDs was associated with ORs of 0.80 (95% CI: 0.53-1.21) and 1.11 (0.57-2.17), respectively. We observed no clear patterns of risk in stratified analysis according to estimated doses of low-dose aspirin (≤100 mg, 150 mg). Conclusion: We did not find any apparent association between aspirin or NA-NSAID use and risk of glioma, although our results may be consistent with a slight reduction in glioma risk with long-term use of low-dose aspirin.

Low-dose acetylsalicylic acid (ASA) is widely used as antithrombotic prophylaxis. Enteric coated ASA has been developed in order to decrease the risk of gastrointestinal side effects. The consequences of enteric coating on pharmacokinetics and antiplatelet effect of ASA have not systematically been assessed. This MiniReview demonstrates that data from clinical trials indicate that enteric coating can reduce the antiplatelet effect of ASA compared to plain ASA. This is possibly due to decreased bioavailability of ASA caused by prolonged solvation and absorption of the enteric coated formulations. Therefore, low dose enteric coated ASA might not be bioequivalent to plain ASA, entailing the risk of insufficient cardiovascular prophylaxis.

BACKGROUND: Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage.METHODS: 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266.FINDINGS: 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group).INTERPRETATION: Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes.FUNDING: Fondation Leducq.

Enterococcus faecalis and Streptococcus gallolyticus cause infective endocarditis (IE), which can originate from the continuous release or translocation of low bacterial numbers into the bloodstream. In this context, IE cannot be prevented with antibiotics. We previously demonstrated that aspirin plus ticlopidine protected rats from IE due to S. gordonii and Staphylococcus aureus. Here we showed that aspirin plus ticlopidine significantly reduced vegetation weight and protected 73 and 64% rats (P < 0.005) from IE due to E. faecalis and S. gallolyticus, respectively. These results further support the potential use of aspirin plus ticlopidine for a global prevention of IE in high-risk patients.

The use of high-dose aspirin therapy for Kawasaki disease,recommended by Dr Goel and his colleagues (June 25, p 144),requires comment. In the acute phase of the disease, high-doseaspirin is appropriate in an effort to ameliorate the acuteinflammatory response and reduce fever. The dose recommended,30 mg/kg/day, may be suitable, although this dose was no-better thana cephalosporin antibiotic in preventing the development ofcoronary-artery aneurysms. In the convalescent phase of theillness, when the incidence of sudden death is approximately 2%,the primary aim is to prevent death. Low-dose aspirin is likely tohave a role in preventing coronary-artery occlusion during thisphase.It is suggested that the reason why the dosage of aspirin is socritical in haemostasis is that it inhibits cyclo-oxygenase, which ispresent in both platelets and vessel walls. In the platelets theproducts of cyclo-oxygenase action include thromboxane A2 andmalondialdehyde, both of which aggregate platelets. In the vesselwall the same enzyme produces prostacyclin, which inhibits plateletaggregation. Thromboxane A2 is also a vasoconstrictor andprostacyclin a vasodilator. Several studies have shown that differentdoses of aspirin may swing the haemostatic mechanism in onedirection or the other by altering the balance of platelet aggregatingand aggregation-inhibiting influences. O’Grady and Moncadashowed that 0 - 3 g aspirin prolonged the bleeding time in 6 adult3 Hamashima Y, Kishi K, Tasaka K. Rickettsia like bodies in infantile mucocutaneouslymph node syndrome. Lancet 1973; ii: 42.1. Kato U, Koite S, Yokohama T. Kawasaki disease: effect of treatment on coronary arteryinvolvement. Pediatrics 1979; 63: 175-79.volunteers, whereas 3-9 g g had no effect.2 Masotti et al3 gavedifferent single doses of aspirin to 25 volunteers and measuredmalondialdehyde, platelet aggregation, and prostacyclin levels afterforearm ischaemia at different times. They found that the inhibitionof platelet aggregation was proportional to dose at 2-5 mg/kg andwas barely increased by larger doses, and that prostacyclinproduction was inhibited by larger doses (8 and 10 mg/kg). Largerdoses of aspirin therefore favour platelet aggregation. The durationof inhibition was less than 24 h for prostacyclin and longer than 72 hfor platelet aggregation. The reason for the differential effect isprobably that aspirin acetylates cyclo-oxygenase irreversibly inplatelets but reversibly in blood-vessel walls.4Clearly it would be unwise to rely on studies in healthy adults fortreatment recommendations in ill children with high platelet counts. The present recommendation of 30 mg/kg/day for threemonths is based on work presented at conference proceedings only. 5Further work needs to be done to examine the issue. Until then3’ 5-5 - 0 mg/kg of aspirin every second or third day would seem themost appropriate therapy for these children in the convalescentphase of the illness