Presentation of 493 Consecutive Girls with Idiopathic Central Precocious Puberty: A Single-Center Study

Background

Despite the number of reported data concerning idiopathic central precocious puberty (CPP) in girls, major questions remain including its diagnosis, factors, and indications of gonadotropin releasing hormone (GnRH) analog treatment.

Methods

A retrospective, single-center study was carried out on 493 girls with CPP.

Results

Eleven girls (2.2%) were aged less than 3 years. Breast development was either isolated (Group 0, n = 99), or associated with one sign, pubic hair development, growth rate greater than 2 standard deviation score (SDS) or bone age (BA) >2 years above chronological age, (Group 1, n = 187), two signs (Group 2, n = 142) or three signs (Group 3, n = 65). The interval between onset of puberty and evaluation, body mass index (BMI) SDS, plasma luteinising hormone (LH) concentrations (basal and peak) and LH/ follicle-stimulating hormone (FSH) peak ratio after GnRH test, plasma estradiol and uterus length were significantly greater in Groups 2 and 3 than in Groups 0 and 1 respectively. 211 (42.8%) patients were obese and/or had excessive weight gain during the year before puberty. Obese girls more often had BA advance of >2 years (p = 0.0004) and pubic hair development (p = 0.003) than the others. BMI did not correlate with LH or with LH/FSH peak ratio. Girls with familial history of early puberty (41.4%) had greater frequencies of pubertal LH/FSH peak ratios (p = 0.02) than the others. During the 31 years of the study, there was no increase in the frequency of CPP or variation in its characteristics.

Conclusion

Obesity is associated with a higher BA advance and higher frequency of pubic or axillary hair development but not with LH secretion, suggesting that obesity accelerates adrenarche but not the maturation of the hypothalamic-pituitary-ovarian axis. The LH/FSH peak ratio was more frequently pubertal in girls with a familial history of early puberty, suggesting that this maturation depends on genetic factors.     

Mucocolpos In A Toddler: Central Precocious Puberty With Vaginal Atresia

ObjectiveTo report the first case of imperforate hymen and vaginal atresia in a patient with mucocolpos during toddlerhood who was found to have central preco cious puberty.MethodsWe review the details of assessment of an 18-month-old girl who had the presence of pubic hair and breast enlargement. She underwent biochemical evaluation with serum follicle-stimulating hormone, luteinizing hor mone, and estradiol and radiologic evaluation with ultra sonography of the abdomen and pelvis as well as magnetic resonance imaging of the pelvis and brain.ResultsThis young female patient had clinical and imaging findings suggestive of idiopathic central preco cious puberty. Imaging also revealed imperforate hymen, vaginal atresia, and mucocolpos. She underwent surgical treatment to ensure an unobstructed vaginal opening before initiation of gonadotropin-releasing hormone agonist ther apy, since the latter may precipitate uterine bleeding and might have converted mucocolpos to a combination of mucocolpos and hematocolpos.ConclusionThis case highlights the need to suspect the presence of precocious puberty in all female patients in whom mucocolpos is detected beyond infancy but before adolescence. (Endocr Pract. 2012;18:e144-e146)     

A Rare Case of Central Precocious Puberty Due to Hypothalamic Hamartoma Diagnosed In Utero

ObjectiveTo report a rare case of central precocious puberty attributable to hypothalamic hamartoma that was diagnosed in utero.MethodsWe present the clinical, laboratory, and imaging data pertaining to our case and discuss the diagnostic features and recommended treatment of central precocious puberty in patients with hypothalamic hamartoma.ResultsA 3-month-old male child had had excessively rapid growth velocity and weight gain since birth. On investigation, the patient was diagnosed as having hypothalamic hamartoma with central precocious puberty. On inquiry, his mother described a history of prenatal ultrasonography and fetal magnetic resonance imaging suggesting the presence of a cystic lesion in his brain at 9 months of gestation. Because of continued rapid growth and acceleration of puberty during a 4-month observation period, we decided to treat the patient with leuprolide acetate. The patient responded well to treatment, with stabilization of growth.ConclusionTo the best of our knowledge, this patient is the youngest in the medical literature diagnosed to have central precocious puberty and also to receive treatment with leuprolide acetate. (Endocr Pract. 2010;16:237-240)     

Income Related Inequality of Health Care Access in Japan: A Retrospective Cohort Study

The purpose of this retrospective cohort study was to analyze the association between income level and health care access in Japan. Data from a total of 222,259 subjects (age range, 0–74 years) who submitted National Health Insurance claims in Chiba City from April 2012 to March 2014 and who declared income for the tax period from January 1 to December 31, 2012 were integrated and analyzed. The generalized estimating equation, in which household was defined as a cluster, was used to evaluate the association between equivalent income and utilization and duration of hospitalization and outpatient care services. A significant positive linear association was observed between income level and outpatient visit rates among all age groups of both sexes; however, a significantly higher rate and longer period of hospitalization, and longer outpatient care, were observed among certain lower income subgroups. To control for decreased income due to hospitalization, subjects hospitalized during the previous year were excluded, and the data was then reanalyzed. Significant inverse associations remained in the hospitalization rate among 40–59-year-old men and 60–69-year-old women, and in duration of hospitalization among 40–59 and 60–69-year-olds of both sexes and 70–74-year-old women. These results suggest that low-income individuals in Japan have poorer access to outpatient care and more serious health conditions than their higher income counterparts.     

Contraceptive Use and Pregnancy Outcomes among Opioid Drug-Using Women: A Retrospective Cohort Study

Objective

The contraceptive needs of illicit opioid users differ from non-drug users but are poorly understood. The aim of this study was to describe contraceptive use and pregnancy outcomes in opioid-using women, and to examine their association with a range of risk factors.

Method

This retrospective cohort study used UK general practice records, Treatment Outcomes Profile and National Drug Treatment Monitoring System data, and a nested data validation exercise. A cohort of 376 women aged 20–61 years were in active treatment for opioid addiction in October 2010 at two specialised primary care practices in North-East England. Outcomes were age-adjusted prevalence estimates for contraceptive use and pregnancy outcomes in users of illicit opioids. The association between lifestyle-related risk factors and contraception was explored.

Results

Drug-using women made lower use of planned (non-condom) contraception (24% vs 50%, p<0.001), had more frequent pregnancy terminations (0.46 vs. 0.025, p = 0.004) and higher annual incidence of chlamydia (1.1% vs. 0.33%, p<0.001), when compared with age-matched population data. Specifically, there was low use of oral contraceptives (4% vs. 25%, p<0.001), IUCD (1% vs. 6%, p<0.001), and sterilisation (7% vs. 6%, p = 0.053), but higher rates of injectable contraceptives (6% vs. 3%, p = 0.003). A total of 64% of children aged <16 years born to this group did not live with their mother. No individual risk factor (such as sex-working) significantly explained the lower use or type of non-condom contraception.

Conclusions

This is the first study to describe planned contraceptive use among drug-users, as well as the association with a range of risk factors and pregnancy outcomes. The low uptake of planned contraception, set against high rates of terminations and sexually transmitted disease demonstrates the urgent clinical need to improve contraceptive services, informed by qualitative work to explore the values and beliefs influencing low contraceptive uptake.     

The Use of Hypnotics and Mortality - A Population-Based Retrospective Cohort Study

Background

Sleep disorders, especially chronic insomnia, have become major health problem worldwide and, as a result, the use of hypnotics is steadily increasing. However, few studies with a large sample size and long-term observation have been conducted to investigate the relationship between specific hypnotics and mortality.

Methods

We conducted this retrospective cohort study using data from the National Health Insurance Research Database in Taiwan. Information from claims data including basic characteristics, the use of hypnotics, and survival from 2000 to 2009 for 1,320,322 individuals were included. The use of hypnotics was divided into groups using the defined daily dose and the cumulative length of use. Hazard ratios (HRs) were calculated from a Cox proportional hazards model, with two different matching techniques to examine the associations.

Results

Compared to the non-users, both users of benzodiazepines (HR = 1.81; 95% confidence interval [CI] = 1.78–1.85) and mixed users (HR = 1.44; 95% CI = 1.42–1.47) had a higher risk of death, whereas the users of other non-benzodiazepines users showed no differences. Zolpidem users (HR = 0.73; 95% CI = 0.71–0.75) exhibited a lower risk of mortality in the adjusted models. This pattern remained similar in both matching techniques. Secondary analysis indicated that zolpidem users had a reduced risk of major cause-specific mortality except cancer, and that this protective effect was dose-responsive, with those using for more than 1 year having the lowest risk.

Conclusions

The effects of different types of hypnotics on mortality were diverse in this large cohort with long-term follow-up based on representative claims data in Taiwan. The use of zolpidem was associated with a reduced risk of mortality.     

A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010

Background

Few studies have explored the trends in central precocious puberty (CPP) in Asian populations. This study assessed the prevalence and annual incidence of CPP among Korean children.

Methods

Using data from the Korean Health Insurance Review Agency from 2004 to 2010, we reviewed the records of 21,351 children, including those registered with a diagnosis of CPP for the first time and those diagnosed with CPP who were treated with gonadotropin-releasing hormone analogs.

Results

The prevalence of CPP was 55.9 per 100,000 girls and 1.7 per 100,000 boys, respectively. The overall incidence of CPP was 15.3 per 100,000 girls, and 0.6 per 100,000 boys. The annual incidence of CPP in girls significantly increased from 3.3 to 50.4 per 100,000 girls; whereas in boys, it gradually increased from 0.3 to 1.2 per 100,000 boys. The annual incidence of CPP in girls consistently increased at all ages year by year, with greater increases at older ages (≥6 years of age), and smaller increases in girls aged < 6 years. In contrast, the annual incidence remained relatively constant in boys aged < 8 years, while a small increase was observed only in boys aged 8 years. The increase of annual incidence showed significant differences depending on age and gender (P <0.0001).

Conclusions

The annual incidence of CPP has substantially increased among Korean girls over the past 7 years. Continued monitoring of CPP trends among Korean children will be informative.     

Comparative Efficacy and Safety of Three Current Clinical Treatments for Girls with Central Precocious Puberty: A Network Meta-Analysis

Objective: The optimal treatment for girls with central precocious puberty (CPP) is unknown. We conducted a network meta-analysis to evaluate the efficacy and safety of existing treatments to provide credible clinical guidelines.Methods: We compared gonadotropin-releasing hormone analogue (GnRHa) therapy, GnRHa plus growth hormone (GH) combination therapy, and no-treatment therapy for girls with CPP by performing an electronic search for studies in PubMed, Embase, Chinese National Knowledge Infrastructure databases, and Wanfang Data from their inception until September 30, 2018. Six outcomes, including bone maturation ratio, final height, final height compared with target height, growth velocity, height gain, and gain in predicted adult height (ΔPAH), were expressed as the mean difference with 95% confidence interval. The surface under the cumulative ranking curve (SUCRA) value illustrated the rank probability of each treatment under different outcomes.Results: Twenty-two studies with 1,268 patients were included. GnRHa plus GH had the best performance on final height, final height compared with target height, growth velocity, height gain, and ΔPAH, with the highest SUCRA values of 0.919, 0.975, 0.909, 0.999, and 0.957, respectively. For bone maturation ratio, GnRHa ranked the highest, with a SUCRA value of 0.663. No severe adverse effects were reported.Conclusion: For girls with CPP, GnRHa plus GH had the highest probability of being the optimal therapy for improving final height, and no severe adverse effects were reported.Abbreviations: BMI = body mass index; CI = confidence interval; CPP = central precocious puberty; GH = growth hormone; GnRHa = gonadotropin-releasing hormone analogue; HPG = hypothalamic-pituitary-gonadal; LH = luteinizing hormone; NMA = network meta-analysis; PAH = predicted adult height; PCOS = polycystic ovary syndrome; RCT = randomized controlled trial; SUCRA = surface under the cumulative ranking curve     

Hospitalisations for Pelvic Inflammatory Disease Temporally Related to a Diagnosis of Chlamydia or Gonorrhoea: A Retrospective Cohort Study

Objectives

The presence and severity of pelvic inflammatory disease (PID) symptoms are thought to vary by microbiological etiology but there is limited empirical evidence. We sought to estimate and compare the rates of hospitalisation for PID temporally related to diagnoses of gonorrhoea and chlamydia.

Methods

All women, aged 15–45 years in the Australian state of New South Wales (NSW), with a diagnosis of chlamydia or gonorrhoea between 01/07/2000 and 31/12/2008 were followed by record linkage for up to one year after their chlamydia or gonorrhoea diagnosis for hospitalisations for PID. Standardised incidence ratios compared the incidence of PID hospitalisations to the age-equivalent NSW population.

Results

A total of 38,193 women had a chlamydia diagnosis, of which 483 were hospitalised for PID; incidence rate (IR) 13.9 per 1000 person-years of follow-up (PYFU) (95%CI 12.6–15.1). In contrast, 1015 had a gonorrhoea diagnosis, of which 45 were hospitalised for PID (IR 50.8 per 1000 PYFU, 95%CI 36.0–65.6). The annual incidence of PID hospitalisation temporally related to a chlamydia or gonorrhoea diagnosis was 27.0 (95%CI 24.4–29.8) and 96.6 (95%CI 64.7–138.8) times greater, respectively, than the age-equivalent NSW female population. Younger age, socio-economic disadvantage, having a diagnosis prior to 2005 and having a prior birth were also associated with being hospitalised for PID.

Conclusions

Chlamydia and gonorrhoea are both associated with large increases in the risk of PID hospitalisation. Our data suggest the risk of PID hospitalisation is much higher for gonorrhoea than chlamydia; however, further research is needed to confirm this finding.     

Risk of Dementia in Patients with Insomnia and Long-term Use of Hypnotics: A Population-based Retrospective Cohort Study

Background

Hypnotics have been reported to be associated with dementia. However, the relationship between insomnia, hypnotics and dementia is still controversial. We sought to examine the risk of dementia in patients with long-term insomnia and the contribution of hypnotics.

Methods

Data was collected from Taiwan’s Longitudinal Health Insurance Database. The study cohort comprised all patients aged 50 years or older with a first diagnosis of insomnia from 2002 to 2007. The comparison cohort consisted of randomly selected patients matched by age and gender. Each patient was individually tracked for 3 years from their insomnia index date to identify whether the patient had a first diagnosis of dementia. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

We identified 5693 subjects with long-term insomnia and 28,465 individuals without. After adjusting for hypertension, diabetes mellitus, hyperlipidemia, and stroke, those with long-term insomnia had significantly higher risks of dementia (HR, 2.34; 95% CI, 1.92–2.85). Patients with long-term insomnia and aged 50 to 65 years had a higher increased risk of dementia (HR, 5.22; 95% CI, 2.62–10.41) than those older than 65 years (HR, 2.33; 95% CI, 1.90–2.88). The use of hypnotics with a longer half-life and at a higher prescribed dose predicted a greater increased risk of dementia.

Conclusions

Patients with long-term use of hypnotics have more than a 2-fold increased risk of dementia, especially those aged 50 to 65 years. In addition, the dosage and half-lives of the hypnotics used should be considered, because greater exposure to these medications leads to a higher risk of developing dementia.     

Retention in Care and Outpatient Costs for Children Receiving Antiretroviral Therapy in Zambia: A Retrospective Cohort Analysis

Background

There are few published estimates of the cost of pediatric antiretroviral therapy (ART) in Africa. Our objective was to estimate the outpatient cost of providing ART to children remaining in care at six public sector clinics in Zambia during the first three years after ART initiation, stratified by service delivery site and time on treatment.

Methods

Data on resource utilization (drugs, diagnostics, outpatient visits, fixed costs) and treatment outcomes (in care, died, lost to follow up) were extracted from medical records for 1,334 children at six sites who initiated ART at <15 years of age between 2006 and 2011. Fixed and variable unit costs (reported in 2011 USD) were estimated from the provider’s perspective using site level data.

Results

Median age at ART initiation was 4.0 years; median CD4 percentage was 14%. One year after ART initiation, 73% of patients remained in care, ranging from 60% to 91% depending on site. The average annual outpatient cost per patient remaining in care was $209 (95% CI, $199–$219), ranging from $116 (95% CI, $107–$126) to $516 (95% CI, $499–$533) depending on site. Average annual costs decreased as time on treatment increased. Antiretroviral drugs were the largest component of all outpatient costs (>50%) at four sites. At the two remaining sites, outpatient visits and fixed costs together accounted for >50% of outpatient costs. The distribution of costs is slightly skewed, with median costs 3% to 13% lower than average costs during the first year after ART initiation depending on site.

Conclusions

Outpatient costs for children initiating ART in Zambia are low and comparable to reported outpatient costs for adults. Outpatient costs and retention in care vary widely by site, suggesting opportunities for efficiency gains. Taking advantage of such opportunities will help ensure that targets for pediatric treatment coverage can be met.     

Use of Learning Media by Undergraduate Medical Students in Pharmacology: A Prospective Cohort Study

The ubiquity of the internet and computer-based technologies has an increasing impact on higher education and the way students access information for learning. Moreover, there is a paucity of information about the quantitative and qualitative use of learning media by the current student generation. In this study we systematically analyzed the use of digital and non-digital learning resources by undergraduate medical students. Daily online surveys and semi-structured interviews were conducted with a cohort of 338 third year medical students enrolled in a general pharmacology course. Our data demonstrate a predominant use of digital over non-digital learning resources (69 ± 7% vs. 31 ± 7%; p < 0.01) by students. Most used media for learning were lecture slides (26.8 ± 3.0%), apps (22.0 ± 3.7%) and personal notes (15.5 ± 2.7%), followed by textbooks (> 300 pages) (10.6 ± 3.3%), internet search (7.9 ± 1.6%) and e-learning cases (7.6 ± 3.0%). When comparing learning media use of teaching vs. pre-exam self-study periods, textbooks were used significantly less during self-study (-55%; p < 0.01), while exam questions (+334%; p < 0.01) and e-learning cases (+176%; p < 0.01) were utilized more. Taken together, our study revealed a high prevalence and acceptance of digital learning resources by undergraduate medical students, in particular mobile applications.     

Inadequate Dissemination of Phase I Trials: A Retrospective Cohort Study

Background

Drug development is ideally a logical sequence in which information from small early studies (Phase I) is subsequently used to inform and plan larger, more definitive studies (Phases II–IV). Phase I trials are unique because they generally provide the first evaluation of new drugs in humans. The conduct and dissemination of Phase I trials have not previously been empirically evaluated. Our objective was to describe the initiation, completion, and publication of Phase I trials in comparison with Phase II–IV trials.

Methods and Findings

We reviewed a cohort of all protocols approved by a sample of ethics committees in France from January 1, 1994 to December 31, 1994. The comparison of 140 Phase I trials with 304 Phase II–IV trials, showed that Phase I studies were more likely to be initiated (133/140 [95%] versus 269/304 [88%]), more likely to be completed (127/133 [95%] versus 218/269 [81%]), and more likely to produce confirmatory results (71/83 [86%] versus 125/175 [71%]) than Phase II–IV trials. Publication was less frequent for Phase I studies (21/127 [17%] versus 93/218 [43%]), even if only accounting for studies providing confirmatory results (18/71 [25%] versus 79/125 [63%]).

Conclusions

The initiation, completion, and publications of Phase I trials are different from those of other studies. Moreover, the results of these trials should be published in order to ensure the integrity of the overall body of scientific knowledge, and ultimately the safety of future trial participants and patients.     

Psychiatric Disorders after Epilepsy Diagnosis: A Population-Based Retrospective Cohort Study

Background

Psychiatric manifestations after occurrence of epilepsy have often been noted. However, the association between newly diagnosed epilepsy and psychiatric disorders afterward is not completely understood. We conducted two longitudinal cohorts for patients with and without epilepsy to investigate the risk factors and hazard ratios of developing psychiatric disorders after patients were newly diagnosed with epilepsy.

Methods

We identified 938 patients with a new diagnosis of epilepsy and 518,748 participants without epilepsy from the National Health Insurance Research Database in 2000–2002 and tracked them until 2008. We compared the incidence of developing psychiatric disorders between the two cohorts, evaluated risk factors and measured the associated hazard ratios (HRs) and 95% confidence intervals (CIs) of developing psychiatric disorders.

Findings

The incidences of psychiatric disorders for people with and without epilepsy were 94.1 and 22.6 per 1000 person-years, respectively. After adjusting the covariates, the epilepsy cohort showed the highest risks in mental retardation (HR 31.5, 95% CI 18.9 to 52.4), bipolar disorder (HR 23.5, 95% CI 11.4 to 48.3) and alcohol or drug psychosis (HR 18.8, 95% CI 11.1 to 31.8) among psychiatric complications developed after newly diagnosed epilepsy. The risk increased with epileptic general seizure and frequency of outpatient visits for epilepsy, as well as with emergency room visits and hospitalizations for epilepsy, and with older age. Chronologically, the highest risk occurred in the first year after epilepsy diagnosis (HR 11.4, 95% CI 9.88 to 13.2).

Conclusion

Various psychiatric disorders were demonstrated after newly diagnosed epilepsy and closely related to general seizure and use of medical services for epilepsy. This shows a need for integrated psychiatric care for patients newly diagnosed with epilepsy, especially in the first year.     

Evaluation of Epstein-Barr Virus Salivary Shedding in HIV/AIDS Patients and HAART Use: A Retrospective Cohort Study

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus(EBV) in saliva and relationship with highly active antiretroviral therapy(HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use(H) and non-HAART use(NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS(NH) group had the highest seropositive rate(IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS(H)(73.69%) and the HIV/AIDS(NH)(100%) groups showed significantly higher values than the HIV-negative control group(35.79%,[ twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS(H) group and the HIV/AIDS(NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.     

Symptomatic Dengue Infection during Pregnancy and Infant Outcomes: A Retrospective Cohort Study

Background

Dengue is a mosquito-borne disease that is common in many tropical and subtropical areas. Dengue infections can occur at any age and time in the lifespan, including during pregnancy. Few large scale studies have been conducted to determine the risk of preterm birth (PTB) and low birthweight (LBW) for infants born to women who had symptomatic dengue infection during pregnancy.

Methodology/Principal Findings

This study is a retrospective cohort study using medical records from 1992–2010 from pregnant women who attended a public regional referral hospital in western French Guiana. Exposed pregnancies were those with laboratory confirmed cases of dengue fever during pregnancy. Each of the 86 exposed infants was matched to the three unexposed births that immediately followed them to form a stratum. Conditional logistic regression was used to analyze these matched strata. Three groups were examined: all infants regardless of gestational age, only infants> = 17 weeks of gestational age and their strata, and only infants> = 22 weeks of age and their strata. Odds ratios were adjusted (aOR) for maternal age, maternal ethnicity, maternal gravidity, interpregnancy interval and maternal anemia. There was an increased risk of PTB among women with symptomatic dengue; (aOR all infants: 3.34 (1.13, 9.89), aOR 17 weeks: 1.89 (0.61, 5.87), aOR 22 weeks: 1.41 (0.39, 5.20)) but this risk was only statistically significant when all infants were examined (p value = 0.03). Adjusted results for LBW were similar, with an increased risk in the exposed group (aOR All infants: 2.23 (1.01, 4.90), aOR 17 weeks: 1.67 (0.71, 3.93), aOR 22 weeks: 1.43 (0.56, 3.70)) which was only statistically significant when all infants were examined (p value = 0.05).

Conclusions/Significance

Symptomatic dengue infection during pregnancy may increase the risk of PTB and LBW for infants. More research is needed to confirm these results and to examine the role of dengue fever in miscarriage.