Yin Bun Cheung

Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2).

PURPOSE Our previous study, Atropine for the Treatment of Myopia 1 (ATOM1), showed that atropine 1% eyedrops were effective in controlling myopic progression but with visual side effects resulting from cycloplegia and mydriasis. The aim of this study was to compare efficacy and visual side effects of 3 lower doses of atropine: 0.5%, 0.1%, and 0.01%. DESIGN Single-center, double-masked, randomized study. PARTICIPANTS A total of 400 children aged 6-12 years with myopia of at least -2.0 diopters (D) and astigmatism of -1.50 D or less. INTERVENTION Children were randomly assigned in a 2:2:1 ratio to 0.5%, 0.1%, and 0.01% atropine to be administered once nightly to both eyes for 2 years. Cycloplegic refraction, axial length, accommodation amplitude, pupil diameter, and visual acuity were noted at baseline, 2 weeks, and then every 4 months for 2 years. MAIN OUTCOME MEASURES Myopia progression at 2 years. Changes were noted and differences between groups were compared using the Huber-White robust standard error to allow for data clustering of 2 eyes per person. RESULTS The mean myopia progression at 2 years was -0.30±0.60, -0.38±0.60, and -0.49±0.63 D in the atropine 0.5%, 0.1%, and 0.01% groups, respectively (P=0.02 between the 0.01% and 0.5% groups; between other concentrations P > 0.05). In comparison, myopia progression in ATOM1 was -1.20±0.69 D in the placebo group and -0.28±0.92 D in the atropine 1% group. The mean increase in axial length was 0.27±0.25, 0.28±0.28, and 0.41±0.32 mm in the 0.5%, 0.1%, and 0.01% groups, respectively (P < 0.01 between the 0.01% and 0.1% groups and between the 0.01% and 0.5% groups). However, differences in myopia progression (0.19 D) and axial length change (0.14 mm) between groups were small and clinically insignificant. Atropine 0.01% had a negligible effect on accommodation and pupil size, and no effect on near visual acuity. Allergic conjunctivitis and dermatitis were the most common adverse effect noted, with 16 cases in the 0.1% and 0.5% atropine groups, and no cases in the 0.01% group. CONCLUSIONS Atropine 0.01% has minimal side effects compared with atropine at 0.1% and 0.5%, and retains comparable efficacy in controlling myopia progression.

Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial

BACKGROUND Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever. METHODS To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969. FINDINGS We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups. INTERPRETATION Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue. FUNDING STOP Dengue Translational Clinical Research.

CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations

ObjectiveTo determine the frequencies of two functional single nucleotide polymorphisms, CYP3A5*3 and CYP3A5*6, in the CYP3A5 gene in three distinct Asian ethnic groups, namely, the Chinese, Malays and Indians.MethodsSingle nucleotide polymorphism analyses of CYP3A5*1, *3 and *6 were performed in 296 healthy subjects (108 Chinese, 98 Malays and 90 Indians) using the polymerase chain reaction-restriction fragment length polymorphism method.ResultsThe *1 allele frequency was 25% in Chinese compared with 40% in Malays and Indians (P=0.001). The *3 allele frequency was also higher in the Chinese population, being 76% versus 60% in the Malays and Indians (P=0.001). The Malays and Indians also had allele frequencies significantly different from Caucasian, Japanese and African-American populations (each P≤0.001) previously published in the literature. The *6 allele was not detected in any the three Asian ethnic groups analysed.ConclusionThese results seem to suggest that genetic polymorphisms in CYP3A5 in Asians, in particular Malays and Indians but also Chinese although to a lesser extent, may be an important genetic contributor to interindividual as well as interethnic differences in clearance of CYP3A substrates.

Adoptive T-cell Transfer and Chemotherapy in the First-line Treatment of Metastatic and/or Locally Recurrent Nasopharyngeal Carcinoma

The outcomes for patients with metastatic or locally recurrent Epstein–Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) remain poor. Adoptive immunotherapy with EBV-specific cytotoxic T lymphocytes (EBV-CTLs) has proven clinical efficacy, but it has never been evaluated in the first-line treatment setting in combination with chemotherapy. To evaluate the safety and efficacy of a chemotherapy in combination with adoptive EBV-CTL transfer, we conducted a phase 2 clinical trial consisting of four cycles of gemcitabine and carboplatin (GC) followed by up to six doses of EBV-CTL. Thirty-eight patients were enrolled, and 35 received GC and EBV-CTL. GC-CTL therapy resulted in a response rate of 71.4% with 3 complete responses and 22 partial responses. With a median follow up of 29.9 months, the 2-year and 3-year overall survival (OS) rate was 62.9 and 37.1%, respectively. Five patients did not require further chemotherapy for more than 34 months since initiation of CTL. Infusion of CTL products containing T cells specific for LMP2 positively correlated with OS (hazard ratio: 0.35; 95% confidence interval: 0.14–0.84; P = 0.014). Our study achieved one of the best survival outcomes in patients with advanced NPC, setting the stage for a future randomized study of chemotherapy with and without EBV-CTL.

The impact of lipid-based nutrient supplement provision to pregnant women on newborn size in rural Malawi: a randomized controlled trial

BACKGROUND Small birth size, often associated with insufficient maternal nutrition, contributes to a large share of global child undernutrition, morbidity, and mortality. We developed a small-quantity lipid-based nutrient supplement (SQ-LNS) to enrich the diets of pregnant women. OBJECTIVE The objective was to test a hypothesis that home fortification of pregnant womens diets with SQ-LNS would increase birth size in an African community. DESIGN We enrolled 1391 women with uncomplicated pregnancies (<20 gestational weeks) in a randomized controlled trial in Malawi. The women were provided with one daily iron-folic acid (IFA) capsule, one capsule containing multiple micronutrients (MMNs), or one 20-g sachet of SQ-LNS (LNS, containing 118 kcal, protein, carbohydrates, essential fatty acids, and 21 micronutrients). Primary outcomes were birth weight and newborn length. Secondary outcomes included newborn weight, head and arm circumference, and pregnancy duration. Analysis was by intention to treat. RESULTS The mean ± SD birth weight and newborn length were 2948 ± 432, 2964 ± 460, and 3000 ± 447 g (P = 0.258) and 49.5 ± 2.4, 49.7 ± 2.2, and 49.9 ± 2.1 cm (P = 0.104) in the IFA, MMN, and LNS groups, respectively. For newborn weight-for-age, head circumference, and arm circumference, the point estimate for the mean was also highest in the LNS group, intermediate in the MMN group, and lowest in the IFA group, but except for midupper arm circumference (P = 0.024), the differences were not statistically significant. The prevalence of low birth weight (<2500 g) was 12.7%, 13.5%, and 12.1% (P = 0.856), respectively; newborn stunting (length-for-age z score < -2) was 19.2%, 14.0%, and 14.9% (P = 0.130), respectively; and newborn small head circumference (head circumference-for-age z score < -2) was 5.8%, 3.0%, and 3.1% (P = 0.099), respectively. The associations between the intervention and the outcomes were not modified by maternal parity, age, or nutritional status (P > 0.100). CONCLUSION The study findings do not support a hypothesis that provision of SQ-LNS to all pregnant women would increase the mean birth size in rural Malawi. The trial was registered at clinicaltrials.gov as NCT01239693.

Postintervention growth of Malawian children who received 12-mo dietary complementation with a lipid-based nutrient supplement or maize-soy flour

BACKGROUND Therapeutic feeding with micronutrient-fortified lipid-based nutrient supplements (LNSs) has proven useful in the rehabilitation of severely malnourished children. We recently reported that complementary feeding of 6-18-mo-old infants with an LNS known as FS50 was associated with improved linear growth and a reduction in the incidence of severe stunting during the supplementation period. OBJECTIVE Our objective was to assess whether a reduction in stunting seen with 12-mo LNS supplementation was sustained over a subsequent 2-y nonintervention period. DESIGN One hundred eighty-two 6-mo-old healthy rural Malawian infants were randomly assigned to receive daily supplementation for 12 mo with 71 g of maize-soy flour [likuni phala (LP); control group, 282 kcal] or either 50 g of FS50 (264 kcal; main intervention group), or 25 g of FS25 (130 kcal). Main outcome measures were incidence of severe stunting and mean z score changes in weight-for-age, length-for-age, and weight-for-length during a 36-mo follow-up period. RESULTS The cumulative 36-mo incidence of severe stunting was 19.6% in LP, 3.6% in FS50, and 10.3% in FS25 groups (P = 0.03). Mean weight-for-age changes were -1.09, -0.76, and -1.22 (P = 0.04); mean length-for-age changes were -0.47, -0.37, and -0.71 (P = 0.10); and mean weight-for-length changes were -1.52, -1.18, and -1.48 (P = 0.27). All differences were more marked among individuals with baseline length-for-age below the median. Differences in length developed during the intervention at age 10-18 mo, whereas weight differences continued to increase after the intervention. CONCLUSIONS Twelve-month-long complementary feeding with 50 g/d FS50 is likely to have a positive and sustained impact on the incidence of severe stunting in rural Malawi. Half-dose intervention may not have the same effect. This trial was registered at (clinicaltrials.gov) as NCT00131209.

Effect of Repeated Treatment of Pregnant Women with Sulfadoxine-Pyrimethamine and Azithromycin on Preterm Delivery in Malawi: A Randomized Controlled Trial

Preterm delivery, which is associated with infections during pregnancy, is common in sub-Saharan Africa. We enrolled 1,320 pregnant women into a randomized, controlled trial in Malawi to study whether preterm delivery and low birth weight (LBW) incidence can be reduced by intermittent preventive treatment of maternal malaria and reproductive tract infections. The participants received either sulfadoxine-pyrimethamine (SP) twice (controls), monthly SP, or monthly SP and two doses of azithromycin (AZI-SP). The incidence of preterm delivery was 17.9% in controls, 15.4% in the monthly SP group (P = 0.32), and 11.8% in AZI-SP group (risk ratio = 0.66, P = 0.01). Compared with controls, those in AZI-SP group had a risk ratio of 0.61 (P = 0.02) for LBW. Incidence of serious adverse events was low in all groups. In conclusion, the incidence of preterm delivery and LBW can in some conditions be reduced by treating pregnant women with monthly SP and two azithromycin doses.

Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma.

This Phase II study was designed to evaluate the efficacy and safety of irinotecan in patients with advanced nasopharyngeal carcinoma (NPC).

Supplementation of Maternal Diets during Pregnancy and for 6 Months Postpartum and Infant Diets Thereafter with Small-Quantity Lipid-Based Nutrient Supplements Does Not Promote Child Growth by 18 Months of Age in Rural Malawi: A Randomized Controlled Trial

BACKGROUND Intrauterine growth restriction may be reduced by supplementing maternal diets during pregnancy, but few studies have assessed the impact of combined prenatal and postnatal interventions on child growth. OBJECTIVE We tested a hypothesis that provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) to mothers in pregnancy and 6 mo postpartum and to their infants from 6 to 18 mo of age would promote infant and child growth in the study area in rural Malawi. METHODS We enrolled 869 pregnant women in a randomized trial in Malawi. During pregnancy and 6 mo thereafter, the women received daily 1 capsule of iron-folic acid (IFA), 1 capsule containing 18 micronutrients (MMN), or one 20-g sachet of SQ-LNS [lipid-based nutrient supplements (LNS), containing 21 MMN, protein, carbohydrates, essential fatty acids, and 118 kcal]. Children in the IFA and MMN groups received no supplementation; children in the LNS group received SQ-LNSs from 6 to 18 mo. Primary outcome was child length at 18 mo. RESULTS At 18 mo, the mean length in the IFA, MMN, and LNS groups was 77.0, 76.9, and 76.8 cm (P = 0.90), respectively, and the prevalence of stunting was 32.7%, 35.6%, and 37.9% (P = 0.54), respectively. No intergroup differences were found in the mean weight, head circumference, or midupper arm circumference or the proportions with low z scores for these variables (P > 0.05). Covariate adjustment did not change the analysis results, and the associations between the intervention and child length were not modified by maternal parity, age, or nutritional status (P > 0.10). CONCLUSIONS The findings do not support a hypothesis that provision of SQ-LNSs to women in pregnancy and postpartum and to children from 6 to 18 mo of age would promote child growth in this Malawian study area. This trial was registered at clinicaltrials.gov as NCT01239693.

“A Body Shape Index” in Middle-Age and Older Indonesian Population: Scaling Exponents and Association with Incident Hypertension

Background “A Body Shape Index” (ABSI) is a recently proposed index that standardizes waist circumference for body mass index (BMI) and height. This study aims to: (a) examine if the ABSI scaling exponents for standardizing waist circumference for BMI and height are valid in middle-aged and older Indonesian population, and (b) compare the association between incident hypertension and ABSI and other anthropometric measures. Methods and Findings The Indonesian Family Life Survey Wave 3 measured anthropometric variables and blood pressure of 8255 adults aged between 40 to 85 years in 2000. The relationship between two anthropometric quantities, e.g. weight (w) and height (h), can be expressed as the power law-equivalent , where p = 2 is the scaling exponent in the derivation of the BMI and can be estimated by linear regression analysis. This was extended to the regression analysis of the log-transformed waist circumference, weight and height to establish the scaling exponents in the ABSI. The values for men were similar to those developed by the previous American study, which were 2/3 (BMI) and 1/2 (height). Those for women were somewhat smaller, at 3/5 (BMI) and 1/5 (height). The original (American) ABSI leads to mild negative correlation with BMI (−0.14) and height (−0.12) in the female population. Analysis of the development of hypertension between Waves 3 and 4 (average interval 7.5 years) in relation to ABSI measured at Wave 3 showed stronger association if the locally derived (Indonesian) scaling exponents were used. However, both versions of the ABSI were less associated with incident hypertension than waist circumference and BMI. Conclusions The values for the scaling exponents for ABSI are roughly similar between the American population and the middle-aged and older Indonesian population, although larger discrepancy was found in women. The ABSI is less associated with incident hypertension than waist circumference and BMI.