bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and Tolerability of Pimecrolimus and Tacrolimus in the Treatment of Atopic Dermatitis: Meta-analysis of Randomised Controlled Trials
Authors: Phipatanakul Wanda 
Published: September 2006

Purpose of the Study.
To determine the efficacy and tolerability of topical pimecrolimus and tacrolimus compared with other treatments for atopic dermatitis.

Methods.
Randomized, controlled trials of topical pimecrolimus or tacrolimus reporting efficacy outcomes or tolerability from the Cochrane Library, Medline, and Embase were identified. Eligible trials were evaluated for efficacy, identified as investigators’ global assessment of response; patients’ global assessment of response; proportions of patients with flares of atopic dermatitis; and improvements in quality of life. Trials were also evaluated for tolerability, identified as overall rates of withdrawal, withdrawal resulting from adverse events, and proportions of patients with burning of the skin and skin infections.

Results.
A total of 4186 of 6897 participants in 25 randomized, controlled trials received pimecrolimus or tacrolimus. Both drugs were significantly more effective than a vehicle control. Tacrolimus 0.1% was as effective as potent topical steroids at 3 weeks and more effective than combined treatment with hydrocortisone butyrate 0.1% plus hydrocortisone acetate 1% at 12 weeks (number needed to treat [NNT]: 6). Tacrolimus 0.1% was also more effective than hydrocortisone acetate 1% (NNT: 4). In comparison, tacrolimus 0.03% was more effective than hydrocortisone acetate 1% (NNT: 5) but less effective than hydrocortisone butyrate 0.1% (NNT: −8). Direct comparisons of tacrolimus 0.03% and tacrolimus 0.1% consistently favored the higher strength formulation. Pimecrolimus was far less effective than betamethasone valerate 0.1% (NNT: −3 at 3 weeks).

Conclusions.
Both topical pimecrolimus and topical tacrolimus are more effective than placebo treatments for atopic dermatitis, but in the absence of studies that show long-term safety gains, any advantage over topical corticosteroids is unclear. Topical tacrolimus is similar to potent topical corticosteroids and may have a place for long-term use in patients with resistant atopic dermatitis on sites at which adverse effects from topical corticosteroids might develop quickly. In the absence of key comparisons with mild corticosteroids, the clinical need for topical pimecrolimus is unclear. The usefulness of either treatment in patients whose conditions have failed to respond adequately to topical corticosteroids is also unclear.

Reviewer Comments.
With the recent worry of “black-box” warnings on these medications, it is useful to see a meta-analysis of controlled trials on pimecrolimus and tacrolimus as an alternative to steroids in the treatment of atopic dermatitis. The results of this study suggest that the usefulness of either treatment in patients whose conditions have failed to respond to topical corticosteroids is unclear but that they may provide an alternative to steroids in certain clinical scenarios. One should keep in mind the risk/benefit ratio of all immunosuppressive medications in the treatment of atopic dermatitis.
Titrating Steroids on Exhaled Nitric Oxide in Children With Asthma: A Randomized, Controlled Trial
Authors: Kelso John M. 
Published: September 2006

Purpose of the Study.
To evaluate whether titrating inhaled corticosteroids (ICSs) on the fraction of nitric oxide in exhaled air (FeNO) improves asthma management in children.

Study Population.
A total of 85 children (aged 6–18 years) with asthma who had been using ICSs at a constant dose for at least 3 months.

Methods.
Children were randomly allocated to 1 of 2 groups stratified for baseline FeNO and dose of ICSs. In one group, ICS doses were determined by FeNO and symptoms according to an algorithm; in the other group, only symptoms influenced ICS dosing. The study duration was 12 months, with 5 visits at 3-month intervals. FeNO was measured at each visit, and the ICS dose was then adapted to FeNO and/or symptom scores that were recorded during the previous 2 weeks.

Results.
The cumulative ICS dose was not different between groups. Within the FeNO group, no significant change in FeNO was found, whereas in the symptom group there was a significant increase in FeNO (P = .035). In the FeNO group, hyperresponsiveness improved more than in the symptom group (2.5 vs 1.1 methacholine doubling dose; P = .04). Eight prednisone courses were prescribed for 7 patients in the FeNO group versus 18 courses in 10 patients in the symptom group, but this difference was not statistically significant (P = .60). There was no difference between groups in forced expiratory volume in 1 second (FEV1) or symptom scores.

Conclusion.
In children with asthma, 1 year of steroid titration on FeNO did not result in higher steroid doses and did improve airway hyperresponsiveness and inflammation.

Reviewer Comments.
I am still not sure what to make of eNO. If monitoring FeNO and making treatment decisions on the basis of the values leads to better asthma outcomes, then it would be a useful tool. Because the FeNO group did not end up receiving a higher cumulative ICS dose, we have to assume that they got more when they needed it and less when they did not. However, the clinical results seem inconsistent. I suppose it is a good thing to have a higher methacholine PD20 (the dose provoking a 20% fall in FEV1) and a lower FeNO, but I would have been happier to see a difference in FEV1 and symptom scores, or if the difference in the number of episodes requiring prednisone courses had been statistically significant. Although I am not sure that I can share the authors’ conclusion that “the time has come to introduce FeNO in to the routine assessment of children with asthma,” I believe we should pay attention to future studies on FeNO monitoring and clinical asthma outcomes.
Pediatric Hypereosinophilic Syndrome (HES) Differs From Adult HES
Authors: James John 
Published: September 2006

Purpose of the Study.
To highlight specific differences between pediatric and adult patients with hypereosinophilic syndrome (HES).

Study Population.
The case report involved a 15-year-old male who presented with abdominal pain, diarrhea, and a 10-lb weight loss. Colonoscopy revealed colitis. A nonproductive cough, night sweats, and a diffuse pruritic, papular rash developed. His initial absolute eosinophil count was 1890/mm3 (reference: &lt;400/mm3), which increased to 52 000/mm3. Additional laboratory studies included: immunoglobulin E, 8561 U/mL (7–110 U/mL); alkaline phosphatase, 1149 U/mL (reference: 50–280 U/mL); γ-glutamyl transpeptidase, 193 (reference: 0–50 U/mL); and serum tryptase, 4.7 μg/L (reference: 1.9–13.5 μg/L). Ultrasound of the liver revealed an abnormal parenchymal pattern with dilated bile ducts. Molecular analysis of the patient’s peripheral blood for the Fip1-like-1 platelet-derived growth factor receptor α chain (FIP1L1-PDGFRA) fusion tyrosine kinase associated with HES in adults was negative. Open lung biopsy revealed patchy interstitial and intra-alveolar inflammation with a predominance of eosinophils. A skin biopsy showed acute neutrophilic folliculitis with perivascular dermatitis with eosinophils. Bone marrow biopsy demonstrated a hypercellular marrow with predominantly eosinophils, which is consistent with idiopathic HES.

Methods.
The investigators compared this case report of pediatric HES and additional published cases of pediatric and adult patients with HES.

Results.
Pediatric HES has only a slight male predominance (55.3% male vs 44.7% female), whereas adult HES is reported to be more common among males than females, with a ratio of 9 to 1. In adults, the frequencies of symptoms found on presentation are: fatigue (26%), cough (24%), dyspnea (16%), rash (12%), and fever (12%). Fever (58.8%), arthralgias (23%), and rash (23.5%) were more common in pediatric cases. As with adults, involvement of the cardiovascular system is the major source of morbidity and mortality. Pediatric HES is commonly associated with chromosomal abnormalities, and in ∼40% of the cases, it has been associated with acute leukemia. As opposed to the vast majority of adult HES cases, no pediatric case with the FIP1L1-PDGFRA fusion gene has been reported.

Conclusion.
There are several distinct features of pediatric, compared with adult, HES.

Reviewer Comments.
Most of the published information on the HES has focused on adult patients. This report compares a pediatric case report of HES and a review of published pediatric cases of this condition to adult patients with this syndrome. This is an insightful clinical report that should be useful in the overall workup of pediatric patients who present with dramatic eosinophilia (&gt;1500/mm3) for &gt;6 months’ duration without other known causes of eosinophilia and who have evidence of organ involvement that might be attributable to HES.
Breast-feeding Reduces the Risk for Childhood Eczema
Authors: Nowak-Wegrzyn Anna 
Published: September 2006

Purpose of the Study.
To investigate the effect of breastfeeding in various phenotypes of eczema.

Study Population.
A birth cohort of 4089 children followed up to 4 years of age.

Methods.
Data on breastfeeding, allergic symptoms, and potential confounders were obtained from questionnaires when the children were 2 months and 1, 2, and 4 years old. At 4 years, blood allergen-specific immunoglobulin E was analyzed. Children with symptoms of eczema and asthma during the period of breastfeeding were excluded in most analyses on risk assessment of eczema and asthma, respectively, to avoid disease-related modification of exposure.

Results.
Exclusive breastfeeding for ≥4 months reduced the risk for eczema at the age of 4 years (odds ratio [OR]: 0.78; 95% confidence interval [CI]: 0.63–0.96) irrespective of combination with asthma, sensitization to common allergens, or parental allergic disease. This decreased risk was most evident for children with onset of eczema during the first 2 years persisting to 4 years (OR: 0.59; 95% CI: 0.45–0.77). Among children with early-onset eczema, irrespective of persistency, followed by late onset of asthma or early-onset asthma, irrespective of persistency, followed by late-onset eczema to 4 years, a protective effect of breastfeeding was also seen (OR: 0.48; 95% CI: 0.30–0.76).

Conclusions.
Breastfeeding ≥4 months reduces the risk for eczema and asthma to 4 years of age.

Reviewer Comments.
Many studies to date have shown that breastfeeding confers a protective effect against early atopic diseases including eczema. This is yet another argument to support breastfeeding.
Patterns of Quick-Relief and Long-term Controller Medication Use in Pediatric Asthma
Authors: James John 
Published: September 2006

Purpose of the Study.
To simultaneously examine adherence to long-term controller and quick-relief medications and to contrast patterns of medication use in children with asthma.

Study Population.
There were 75 children aged 8 to 16 years diagnosed with persistent asthma and prescribed quick-relief and long-term medications by metered-dose inhaler. Participants were a subsample of a larger adherence study.

Methods.
This was a cross-sectional, 1-month follow-up study. The primary outcome measure was adherence to both medications as measured by electronic monitoring devices. A classification framework for contrasting adherence patterns between medication classes was developed to identify cases for individual analysis.

Results.
High levels of nonadherence to long-term controller medications (median: 46% of prescribed doses taken) and variable patterns of quick-relief medication use (range: 0–251 doses over the month) were documented, but consistent relationships between patterns of medication use across both classes were not found. Individual cases identified by the classification scheme illustrated the complexity and clinical utility of contrasting adherence patterns.

Conclusions.
Monitoring long-term controller medication adherence may be more predictive of morbidity than quick-relief medication use except in outlier cases, in which monitoring both medication types may be valuable for clinical and empirical purposes.

Reviewer Comments.
Medication adherence has long been identified as a key factor in overall asthma outcome. For example, self-reporting quick-relief and long-term controller medication use, canister weighing, pharmacy records, and electronic monitoring have all been used to assess medication adherence. Of these methods, electronic monitoring, which is the most costly and technologically complex, is generally accepted as the most accurate method for monitoring adherence. Inadequate daily medication adherence has been widely documented in patients with asthma and has been linked to morbidity and increased health care costs. Although it was not surprising that nonadherence to long-term controller medications was common in this investigation, it was very interesting that no statistically significant relationship was found between adherence with quick-relief and long-term controller medication classes. For example, the investigators’ hypothesis that quick-relief and long-term controller medication use would demonstrate an inverse relationship (eg, higher long-term controller medication use corresponding to lower reliance on quick-relief medications) was not confirmed. The investigators suggest that novel strategies to enhance appropriate medication use, such as better tracking the use of long-term controller medications and providing feedback regarding actual use, may be effective in improving adherence in asthma patients.
Emergence of Drug Resistant HIV-1 After Intrapartum Administration of Single-Dose Nevirapine Is Substantially Underestimated
Authors: Church Joseph A. 
Published: September 2006

Purpose of the Study.
An inexpensive, effective regimen to prevent perinatal HIV transmission in the developing world is highly desirable. Nevirapine, a nonnucleoside reverse transcriptase inhibitor, seems to provide such an intervention. However, drug-resistance mutations have been identified in up to 40% of women shortly after they received a single intrapartum nevirapine dose as part of a transmission-prevention strategy. This study was undertaken to reexamine the incidence of drug-resistant HIV-1 after single-dose nevirapine.

Study Population.
Fifty South African women infected with HIV subtype C.

Methods.
Sensitive, real-time polymerase chain reaction assays were sequentially performed for nonnucleoside reverse transcriptase inhibitor–resistance mutation, K103N and Y181C.

Results.
Resistance mutations emerged in 65% of women after a single dose of nevirapine.

Conclusions.
Single-dose nevirapine as used in the developing world for prevention of perinatal HIV transmission results in the development of resistance mutations in a very high percentage of women who receive this intervention.

Reviewer Comments.
Although single-dose nevirapine has been successfully implemented as a strategy to prevent perinatal HIV transmission, it is increasingly apparent that the women who are treated with this regimen more often than not develop resistance mutations to nevirapine. The clinical implications are clear: Will nevirapine work for future perinatal interventions for individual women with drug-resistance mutations? Will women with these drug-resistance mutations fail to respond to nevirapine as part of a highly active retroviral therapy intervention when they need treatment for their own HIV disease? In the same issue of The Journal of Infectious Diseases, Flys et al (J Infect Dis. 2005;192:24–29) demonstrated that drug-resistance variants of HIV may persist for &gt;1 year in this situation. In addition, Lee et al (J Infect Dis. 2005;192:1260–1264) showed that women who developed drug-resistant HIV after exposure to single-dose nevirapine shed drug-resistant HIV in their breast milk. This increases the risk of transmission of resistant virus to uninfected infants. Together, these studies demonstrate that single-dose nevirapine, although an effective strategy for reducing maternal-child transmission of HIV, also predisposes treated women to the development of drug-resistant virus as well as the potential for transmitting drug-resistant virus to their infants via breastfeeding.
Recognition, Evaluation, and Treatment of Anaphylaxis in the Child Care Setting
Authors: Skolnick Helen 
Published: September 2006

Purpose of the Study.
Although many young children with a history of allergic reactions or anaphylaxis spend considerable time in child care centers, little is known about the centers’ knowledge of, experience with, and capacity to treat anaphylaxis. The purpose of this study was to evaluate the ability of child care centers to recognize, evaluate, and treat anaphylaxis episodes.

Study Population.
Children aged 1 to 6 who attended child care center in the suburbs of Chicago, Illinois.

Methods.
Eighty-five independent child care centers in suburbs of Chicago were selected randomly. They were contacted by telephone and asked to join the study by completing an initial questionnaire about allergic reactions and anaphylaxis. The center directors and teachers were then offered an allergy seminar on anaphylaxis avoidance, recognition, evaluation, and treatment. After the seminar, center directors were given a posttest that included some of the questions from the original questionnaire.

Results.
Of the 85 centers, 44 agreed to participate. Forty-two centers completed the surveys before the seminar and 39 after the seminar. On average, each center had up to 7 children with an identifiable food allergy. The most commonly reported source of education concerning allergies was information provided by the parents. Before the seminar, 24% of child care centers would administer intramuscular epinephrine for a severe allergic reaction. After the seminar, 77% of centers stated they would administer intramuscular epinephrine (P &lt; .001). In addition, center staff significantly improved their knowledge of symptoms of allergic reactions and the correct methods of intramuscular epinephrine administration.

Conclusions.
There is a knowledge deficit in anaphylaxis education at child care centers for children 1 to 6 years old. Intervention with individual education seminars can significantly increase the ability of child care center staff to recognize, evaluate, and treat anaphylaxis.

Reviewer Comments.
Although it is encouraging that the staffs at child care centers seem to be able to learn how to recognize and treat allergic reactions and anaphylaxis, it is at the same time discouraging that such a small percentage would have done so correctly before the seminar. Most child care centers receive their education from discussions with parents. However, studies have shown that only 50% of parents could identify all the critical steps for proper usage of epinephrine. Therefore, I agree with the authors that it is critical that health care professionals become more involved in the education of parents and the staffs of child care centers. In addition, detailed treatment plans should be written to help guide centers in the proper care of allergic reactions.
Depletion of Latent HIV-1 Infection in Vivo: A Proof-of-Concept Study
Authors: Church Joseph A. 
Published: September 2006

Purpose of the Study.
Resting CD4+ T cells are a primary reservoir for HIV. In these cells the HIV is in a latent form and not a target of current antiviral agents. The chromatin-remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV. This study tested the hypothesis that an inhibitor of HDAC1, valproic acid, would result in depletion of latently infected resting CD4+ T cells.

Study Population.
Four human volunteers with HIV receiving highly active antiretroviral therapy.

Methods.
The individual subjects’ antiretroviral therapies were intensified with enfuvirtide, a fusion inhibitor, to minimize the spread of HIV during potential release from latency. The subjects then were treated with oral valproic acid, 500 to 750 mg twice daily, in addition to their antiretroviral therapy, and they were followed for 3 months. Latently infected resting T cells were quantified before and after augmentation of treatment with limiting-dilution culture of resting cells after ex vivo activation.

Results.
The frequency of resting CD4+ T-cell infection was stable before the addition of enfuvirtide and valproic acid but declined thereafter. This decline was significant in 3 or 4 patients, with a mean reduction of 75% in circulating HIV-infected resting CD4+ T cells. There were no complications of the additional treatments except for the expected injection-site reactions to enfuvirtide.

Conclusions.
Combination therapy with an HDAC inhibitor and very potent antiretroviral therapy accelerated the reduction in HIV-infected resting T cells. This suggests a new approach to the management of HIV that eventually may result in clearance of HIV from infected individuals.

Reviewer Comments.
This study received a fair amount of media coverage at the time it was published. It begs the question, can HIV be cured? A 75% reduction in the resting T-cell reservoir seems impressive. However, this was a very short-term study, and the kinetics and degree to which the resting T-cell reservoir was replenished after discontinuation of valproic acid was not reported. In addition, valproic acid, a widely used anticonvulsant, is potentially highly toxic and has “black-box” warnings for hepatotoxicity, teratogenicity, and pancreatitis. Despite the authors’ optimistic conclusions, “this finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future,” use of the “C word” is likely premature.