On summary ROC curve for dichotomous diagnostic studies: an application to meta-analysis of COVID-19.

In a systematic review of a diagnostic performance, summarizing performance metrics is crucial. There are various summary models in the literature, and hence model selection becomes inevitable. However, most existing large-sample-based model selection approaches may not fit in a meta-analysis of diagnostic studies, typically having a rather small sample size. Researchers need to effectively determine the final model for further inference, which motivates this article to investigate existing methods and to suggest a more robust method for this need. We considered models covering several widely-used methods for bivariate summary of sensitivity and specificity. Simulation studies were conducted based on different number of studies and different population sensitivity and specificity. Then final models were selected using several existing criteria, and we compared the summary receiver operating characteristic (sROC) curves to the theoretical ROC curve given the generating model. Even though parametric likelihood-based criteria are often applied in practice for their asymptotic property, they fail to consistently choose appropriate models under the limited number of studies. When the number of studies is as small as 10 or 5, our suggestion is best in different scenarios. An example for summary ROC curves for chemiluminescence immunoassay (CLIA) used in COVID-19 diagnosis is also illustrated.

Sirolimus treatment for tuberous sclerosis complex prior to epilepsy: Evidence from a registry-based real-world study.

OBJECTIVE: To evaluate whether sirolimus treatment could relieve the later burden of new-onset seizures in patients with tuberous sclerosis complex (TSC) prior to epilepsy. METHODS: A real-world matched case-control study was nested in another registry cohort study. Infants with TSC (<12 months old) without seizures whose parents agreed on sirolimus treatment for other symptoms were eligible for inclusion to the early sirolimus (ES) group. These patients were enrolled from 2015 to 2018. Controls in the late sirolimus (LS) group were matched from the registry cohort database for 2015-2018. Age and genotype were used as the initial stratifying criteria and other symptoms as the greedy matching criteria at a matching ratio of 1:4. None of the preventive drugs were introduced before seizure onset or before 2 years of age in the LS group. Both groups were followed up until June 2020. The primary objective was a comparison of the characteristics of the first seizure between the two groups. The secondary objective was the assessment of the final seizure status at the endpoint. RESULTS: There were 42 and 168 patients with TSC in the ES and LS groups, respectively. Early sirolimus treatment significantly reduced the seizure onset, especially in the patients aged <6 months. The mean onset-age was significantly delayed by sirolimus treatment (11.34±7.93 months vs. 6.94±6.03 months, P<0.001). The subtype of seizures that benefited the most was spastic (onset) seizures (all were infantile spasms) [5/42 (11.90%) vs. 73/168 (43.45%), P<0.001]; these seizures were either eliminated or alleviated. The sirolimus treatment addition prior to seizures was more effective than its addition after seizures in reducing drug-resistant epilepsy [10/42 (23.81%) vs. 70/147 (47.62%), P=0.004]. CONCLUSION: Early sirolimus treatment for TSC effectively modified the disease by preventing infantile spasms, delaying seizure onset, and relieving its severity. The anti-epileptogenic effect of sirolimus may be time- and dose-dependent.

Sirolimus Can Increase the Disappearance Rate of Cardiac Rhabdomyomas Associated with Tuberous Sclerosis: A Prospective Cohort and Self-Controlled Case Series Study.

OBJECTIVES: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. STUDY DESIGN: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. RESULTS: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. CONCLUSIONS: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

Retrospectively investigating the 12-year experience of prenatal diagnosis of small supernumerary marker chromosomes through array comparative genomic hybridization.

OBJECTIVE: This study retrospectively evaluated the incidences of small supernumerary marker chromosomes (sSMCs) in prenatal diagnoses and detected with gain of pathogenic copy number variation through array comparative genomic hybridization (CGH) in a laboratory in Taiwan. MATERIALS AND METHODS: We retrospectively searched and reviewed the sSMC cases detected during prenatal diagnoses in the Youthgene medical laboratory, between 2004 and 2015 and used array CGH to successfully analyze 45 of 47,XN,+mar or 47,XN + mar/46,XN. RESULTS: A total of 68,087 cases of amniocentesis were analyzed, of which 59 were identified as sSMCs. The overall frequency of sSMCs was 0.087%, and 7 of 45 sSMCs were identified with gain of pathogenic copy number variation (CNV). CONCLUSION: Array CGH offers useful tools that can be used to detect small fragments of chromosomal abnormalities and sSMC origins in prenatal diagnosis. In this study, we successfully used array CGH to detect 7 out of 45 sSMCs, which were identified with gain in pathogenic CNV.

A pilot study of limb stimulation for the treatment of neonatal apnea.

This study explored the feasibility effect and safety of the limb stimulation (LS) for the treatment of neonatal apnea (NAP).The cases of 30 eligible premature infants with NAP were included in this retrospective study. These cases were equally divided into an intervention group (n = 15) and a control group (n = 15). The infants in both groups received caffeine treatment. Moreover, cases in the intervention group also received LS for a total 30 hours, while the subjects in the control group did not receive LS during this period. The primary outcome included apnea frequency (number of episodes per 24 hours), and apnea rate. The secondary outcomes consisted of desaturation (number of episodes per 24 hours), and heart rate (beats per minute). Additionally, adverse events were also documented during the treatment period.After treatment, LS did not show better outcomes in apnea frequency (P = .48), apnea rate (P = .33), desaturation (P = .55), and heart rate (P = .41). Furthermore, no significant differences of all adverse events were found between 2 groups.The results of this pilot study demonstrated that LS might be not efficacious for premature infants with NAP.

Prevalence of primate and interdental spaces for primary dentition in 3- to 6-year-old children in Taiwan.

BACKGROUND/PURPOSE: Spaced primary dentition plays a critical role in the eruption of permanent teeth and the establishment of ideal occlusion. A lack of these spaces in deciduous dentition may result in disproportionate jaw and tooth sizes. Additionally, spaced primary dentition is significantly affected by ethnic factors. However, few of these studies have been conducted in Asia. The purpose of this study was to investigate the prevalence of spaced primary dentition in Taiwan. METHODS: One hundred and forty-seven 3- to 6-year-old Taiwanese children (58 girls and 89 boys) were recruited for a cross-sectional study. Primate and interdental spaces were recorded by intraoral photos. The prevalence of spaced dentition was evaluated. The interpersonal agreement of spaced dentition between the upper and lower arches was also assessed. RESULTS: Most of the subjects had spaced primary dentition. The prevalence of primate space was 83.7% in the upper arch and 61.2% in the lower arch, whereas the prevalence of interdental space was 44.2% in the upper arch and 53.1% in the lower arch. The prevalence rates of interdental space and upper primate space were significantly higher in boys than in girls. Interdental spaces of the lower arch increased with age. CONCLUSION: Ethnic factors can affect the ratio of spaced dentition. Most of the 3- to 6-year-old Taiwanese children have spaced dentition. The boys have higher incidence of spaced dentition than the girls. Furthermore, primate space is more frequently found in the upper arch than in the lower arch, whereas interdental space is reversed.

Trajectories of fasting plasma glucose variability and mortality in type 2 diabetes.

AIM: To investigate the effect of changes in fasting plasma glucose (FPG) variability, as assessed by 2-year trajectories of FPG variability, on mortality risk in patients with type 2 diabetes (T2D). METHODS: From 2009 to 2012, outpatients with T2D, aged>18 years, were enrolled from a medical centre. FPG was measured every 3 months for 2 years in 3569 people. For each of the eight 3-month intervals, FPG variability and means were calculated, with variability defined as the coefficient of variation of FPG. Also, trajectories of FPG variability and means were determined separately, using group-based trajectory analysis with latent class growth models. These models were fitted using the SAS Proc Traj procedure. The primary outcome was all-cause mortality, which was followed-up to the end of 2014. RESULTS: Five distinct trajectories of FPG variability (low, increasing, fluctuating, decreasing and high) and means (well controlled, stable control, worsening control, improving control and poor control) were established. The five trajectories of mean FPG were all associated with the same mortality risk. In contrast, in comparison to the low FPG variability trajectory, the fluctuating, decreasing and high variability trajectories all had significantly higher risks of mortality, with respective hazards ratios of 2.63 (95% CI: 1.40-4.93; P=0.003), 2.78 (95% CI: 1.33-5.80; P=0.007) and 4.44 (95% CI: 1.78-11.06; P=0.001) after multivariable adjustment. CONCLUSION: Changes in FPG variability were independently associated with increased mortality risk in patients with T2D.

Dissimilarity for functional data clustering based on smoothing parameter commutation.

Many studies measure the same type of information longitudinally on the same subject at multiple time points, and clustering of such functional data has many important applications. We propose a novel and easy method to implement dissimilarity measure for functional data clustering based on smoothing splines and smoothing parameter commutation. This method handles data observed at regular or irregular time points in the same way. We measure the dissimilarity between subjects based on varying curve estimates with pairwise commutation of smoothing parameters. The intuition is that smoothing parameters of smoothing splines reflect the inverse of the signal-to-noise ratios and that when applying an identical smoothing parameter the smoothed curves for two similar subjects are expected to be close. Our method takes into account the estimation uncertainty using smoothing parameter commutation and is not strongly affected by outliers. It can also be used for outlier detection. The effectiveness of our proposal is shown by simulations comparing it to other dissimilarity measures and by a real application to methadone dosage maintenance levels.

Transcatheter Closure of Congenital Coronary Artery Fistulas with a Giant Coronary Artery Aneurysm in Children: Experiences from a Single Center.

BACKGROUND: Transcatheter closure of congenital coronary artery fistulas (CCAFs) is an alternative therapy to surgery; however, data regarding transcatheter closure for CCAF with a giant coronary artery aneurysm (CAA) in pediatric patients are still limited due to the rarity of the disease. We aimed to evaluate the efficacy and safety of transcatheter closure for CCAF with a giant CAA in a pediatric population at a single center. METHODS: Medical records of pediatric patients (<18 years old) who underwent transcatheter closure of CCAF with a giant CAA between April 2007 and September 2016 at Guangdong Cardiovascular Institute (Guangdong, China) were reviewed. RESULTS: Twelve patients (median age, 6.1 years; range, 1.9-11.0 years) underwent successful transcatheter closure procedures. One patient underwent closure at both the entry and exit points of the CAA, three patients underwent closure at the exit point of the CAA, and eight patients underwent closure at the entry point of the CAA. After a mean follow-up of 7.2 years (range, 0.5-9.8 years), one patient (with closure at the exit point of the CAA) underwent transcatheter re-intervention because of a significant residual shunt. She eventually underwent a surgical procedure due to aneurysm dilation after the second intervention. One patient experienced thrombus formation within the CAA after the procedure. Among those with closure at the entry point of the CAA, a mild-to-moderate residual shunt was detected in three patients. CONCLUSIONS: Transcatheter closure appears to be a safe and effective alternative therapy for CCAF with a giant CAA in the pediatric population. Closure at the entry point of the CAA, and closure at both the entry and exit points when feasible, may reduce the risk of postinterventional complications.

Increased risk of Eustachian tube disorders in patients with sleep-disordered breathing.

Sleep-disordered breathing (SDB) and Eustachian tube disorders (ETDs) share the same risk factors. The specific aim of this study was to determine the correlation between these 2 conditions and to determine whether treatments for SDB reduce the risk of ETD.This is a retrospective and large population-based cohort study. According to Taiwan's National Health Insurance Research Database, out of 1,000,000 insured patients, 24,251 patients were newly diagnosed with SDB from year 2000 through 2009. The control group for this study comprised 96,827 patients without SDB who were randomly selected from the same database at a ratio of 1:4, frequency matched for sex, age, and index year of SDB. The incidence of developing ETD was compared between these 2 groups; the main covariates were demographic data, interventions, and medical comorbidities.There was an increased risk of developing ETD among the SDB cohort compared with the control group (hazard ratio = 1.51, 95% confidence interval = 1.41-1.63). Compared with SDB patients who did not receive treatment, those who received the treatment, that is, pharyngeal or nasal surgery, CPAP, or multiple modalities (both surgery and CPAP), had a significantly reduced risk of developing ETD.This study showed that patients with SDB are at an increased risk of developing ETD and other comorbidities. The risk of developing ETD can be reduced by implementing prompt treatment for SDB. Multidisciplinary evaluation including ETD should be conducted in the management of patients presenting with SDB.

Role of SDF-1α/CXCR4 signaling pathway in clinicopathological features and prognosis of patients with nasopharyngeal carcinoma.

The present study aims to explore the role of stromal cell-derived factor-1α (SDF-1α)/stromal cell-derived factor receptor-4 (CXCR4) signaling pathway to the clinicopathological features and prognosis of patients with nasopharyngeal carcinoma (NPC). From January 2009 to December 2010, 102 patients with NPC and 80 patients with chronic nasopharyngitis were enrolled for the study. Immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting were employed to determine the expressions of SDF-1α and CXCR4 proteins in NPC tissues and chronic nasopharyngitis tissues. Chi-square test was conducted to analyze the associations of the expressions of SDF-1α and CXCR4 proteins with the clinicopathological features of NPC patients. Spearman rank correlation analysis was used to analyze the correlation between the SDF-1α protein expression and CXCR4 protein expression. The mRNA and protein expressions of SDF-1α and CXCR4 in NPC tissues were significantly higher than those in chronic nasopharyngitis tissues. The expressions of SDF-1α and CXCR4 proteins showed associations with T staging, N staging, tumor node metastasis (TNM) staging, skull base invasion, and cervical lymph node metastasis of NPC patients. Compared with NPC patients showing negative expressions of SDF-1α and CXCR4 proteins, those with positive expressions of SDF-1α and CXCR4 proteins had a significantly shorter survival time. SDF-1α protein, CXCR4 protein, EBV-IgG status, T staging, N staging, TNM staging, skull base invasion, and cervical lymph node metastasis were independent risk factors for the prognosis of NPC. The findings indicated that SDF-1α/CXCR4 signaling pathway might be associated with the clinicopathological features and prognosis of patients with NPC.

Intermittent parathyroid hormone improve bone microarchitecture of the mandible and femoral head in ovariectomized rats.

BACKGROUND: Intermittent parathyroid hormone (PTH) can be used to treat osteoporosis of the spine and hip. However, whether it can be used to treat osteoporosis of the mandible is unclear. The purpose of this study was to explore the influence of applying intermittent PTH to ovariectomized rats on the trabecular bone microarchitecture of the mandible and femoral head. METHODS: Eighteen female rats were divided into three groups: the healthy group, ovariectomized (OVX) group, and OVX + PTH group. The OVX group and OVX + PTH group had an OVX at 8 weeks of age. The OVX + PTH group received intermittent PTH therapy for 12 weeks. The mandibles and femurs of all rats were removed at 20 weeks and were then scanned using microcomputed tomography (micro-CT). RESULTS: From the micro-CT analysis, the trabecular bone microarchitecture of the mandible and femoral head are offered as follows: (1) The bone volume fraction and trabecular thickness in the OVX group were lower than those in the healthy group. (2) The bone volume fraction and trabecular thickness in the OVX + PTH group approximated those in the healthy group. CONCLUSION: The conclusions of this study regarding the trabecular bone microarchitecture of the mandible and femoral head are offered as follows: (1) The BV/TV and TbTh in the OVX group were lower than those in the healthy group. (2) The BV/TV and TbTh in the OVX + PTH group approximated those in the healthy group, therefore, intermittent PTH displayed high efficacy for treating femoral or mandibular deterioration of bone microstructure resulting from loss of ovarian function. Osteoporosis of the femur or mandible in the rats was ameliorated by intermittent PTH therapy.

Treatment success with titratable thermoplastic mandibular advancement devices for obstructive sleep apnea: A comparison of patient characteristics.

A titratable thermoplastic mandibular advancement device (MAD) is clearly an effective treatment option in some patients with obstructive sleep apnea (OSA). Determining which patients may be more likely to respond to treatment with thermoplastic MADs and to adhere to treatment would be of obvious clinical relevance. This was an experimental descriptive study (N = 60). Patients with OSA were instructed to wear a titratable thermoplastic MAD for 3 months. Treatment success was defined as a ≥50% reduction from baseline in the apnea-hypopnea index (AHI) or AHI <10 when wearing MAD. Adherence was defined as MAD use ≥5 nights/week. Treatment was successful in 66.7% of patients and 60.0% were adherent. All polysomnographic parameters and visual analogue scale scores (sleep quality, snoring, waking refreshed) were significantly improved after treatment. The patients in whom treatment failed had significantly higher neck circumferences (39.3 cm vs. 37.5 cm, p = 0.014), higher baseline AHI values (26.6 vs. 18.0, p = 0.016), and smaller AHI reduction (-31.8 vs -53.1, p < 0.001) than those in the group in whom treatment succeeded. There were no significant differences in polysomnographic, cephalometric, or visual analogue scale measures between patients for whom treatment was and was not successful, regardless of baseline values or the change rates after the MAD was placed. Titratable thermoplastic MADs can improve indicators of sleep quality, even in patients in whom treatment is considered to have failed.

[Intermittent convulsions for 1.5 years and psychomotor retardation in a girl].

The study reports a girl with pyridoxine-dependent epilepsy. The girl was admitted at the age of 2 years because of intermittent convulsions for 1.5 years and psychomotor retardation. She had a history of "hypoxia" in the neonatal period. At the age of 5 months recurrent epileptic seizures occurred. The child was resistant to antiepileptic drugs, and had many more seizures when she got cold or fever. She also had a lot of convulsive status epilepticus. No discharges were found during several video-EEG monitorings. Cerebral MRI examinations showed normal results. So Dravet syndrome was clinically suspected. ALDH7N1 gene mutation analysis revealed two heterozygote mutations, and pyridoxine-dependent epilepsy was thus confirmed. Seizures were generally controlled after pyridoxine supplementation.

Hemoglobin level trajectories in the early treatment period are related with survival outcomes in patients with breast cancer.

Hemoglobin (Hb) levels are reportedly related with treatment outcomes and survival in patients of breast cancer. However, the long-term change in Hb levels after treatment and the effects of Hb on survival remain unknown. This retrospective cohort study enrolled 1931 breast cancer patients with pathological stage I-IV between 1/1/2003 and 12/31/2013. Latent class modeling was used to identify trajectories in monthly Hb levels over time. The primary endpoint was 10-year cancer-related death. We identified 5 distinct Hb trajectories: persistent anemia (5.6 %; n = 109), improved anemia (4.8 %, n = 93), mild anemia (21.0%; n = 406), low normal Hb (46.6 %; n = 899), and normal Hb (21.9%; n = 424). Compared with the normal-Hb group, trajectories with low Hb levels had worst 10-year survival. The adjusted hazard ratios were 1.79(95% CI, 0.91-3.53) for the improved anemia group, 1.09(95% CI, 0.68-1.74) for the mild anemia group, 1.06 (95% CI, 0.71-1.60) for the low normal Hb group, and 2.19(95% CI 1.28-3.75) for the persistent anemia group. Our findings show there are five Hb level trajectories during breast cancer treatment. The anemia Hb level trajectory during the first 12 months after treatment reflect the worst cancer-related 10-year survival in breast cancer patients.

Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2.

Oral cancer is the eighth most common type of cancer among men worldwide, with an age-standardized rate of 6.3 per 100,000, and is the fourth leading cause of cancer-associated mortality among men in Taiwan. Cisplatin and 5-fluorouracil (5-FU) are two of the most frequently utilized chemotherapy drugs for the treatment of oral cancer. Although oral cancer patients initially benefit from chemotherapy with these drugs, they may develop resistance to them, which worsens their prognosis and reduces survival rates. It has been reported that increased levels of epidermal growth factor receptor (EGFR) and multidrug resistance-associated protein 2 (MRP2) induce drug resistance in numerous types of human cancer. Therefore, the present study employed lentivirus vector-mediated RNA interference (RNAi) in order to target the genes encoding EGFR and MRP2 in the oral squamous cell carcinoma cell line OC2. It was observed that RNAi-mediated downregulation of EGFR or MRP2 increased the sensitivity to 5-FU and cisplatin in OC2 cells. Downregulation of EGFR resulted in significant suppression of OC2 tumor growth following 5-FU administration. However, simultaneous downregulation of the two genes did not further suppress the tumor growth, indicating that MRP2 does not have a significant role in the chemosensitivity of EGFR-downregulated cells to 5-FU. In contrast, downregulation of MRP2 was demonstrated to significantly enhance the therapeutic effects of cisplatin in EGFR-downregulated OC2 tumors. The observation that the expression of MRP2 was positively correlated with the level of cisplatin resistance in cells suggests that RNAi-mediated downregulation of MRP2 may be applicable as a therapeutic approach toward reversing MRP2-dependent cisplatin resistance in oral cancer.

Physical activity and albuminuria were associated with painful diabetic polyneuropathy in type 2 diabetes in an ethnic Chinese population.

BACKGROUND: Diabetic neuropathy is a common complication in patients with type 2 diabetes. However, the prevalence of painful diabetic polyneuropathy (PDPN) have been less studied. We examined the prevalence and risk factors of PDPN in outpatients with type 2 diabetes in an ethnic Chinese population. METHODS: This retrospective study enrolled 2358 outpatients with type 2 diabetes who had completed the Douleur Neuropathique en 4 Questions (DN4) questionnaire from January 2013 to October 2013. Patients with a total score ≥4 were defined as having PDPN. RESULTS: In all, 179 patients were diagnosed as having PDPN with a score of 4.49 on the DN4 questionnaire, compared with 0.66 for patients without PDPN. After adjusting the possible confounding factors, the risk of painful neuropathy was increased in the group without physical activity (Odds ratio 3.38, 95% CI 1.54-9.79), and in the group with macroalbuminuria (Odds ratio 2.31, 95% CI 1.44-3.73). Besides, there was a joint effect of macroalbuminuria and no physical activity habit on PDPN risk. CONCLUSIONS: The prevalence of PDPN was 7.6% among our outpatients with type 2 diabetes. Less physical activity and albuminuria, respectively, increased the risk of PDPN and had a joint effect.

Functional polymorphisms in the IL-10 gene with susceptibility to esophageal, nasopharyngeal, and oral cancers.

Emerging evidence showed that functional polymorphisms in the IL-10 gene may have effects on individuals' susceptibility to nasopharyngeal, oral and esophageal cancers, yet individually published findings are inconsistent. We therefore designed the meta-analysis to investigate the correlations of IL-10 genetic polymorphisms with susceptibility to nasopharyngeal, oral and esophageal cancers. The EMBASE, MEDLINE, CINAHL, Web of Science and the Chinese Biomedical Database (CBM) databases were searched with no language restrictions. We use Comprehensive Meta-analysis 2.0 software to carry out statistical analysis. Ten case-control studies with a number of 1,883 patients and 2,857 healthy subjects were enrolled. Our results revealed that IL-10 rs1800872 T>G and rs1800896 A>G polymorphisms has a significantly association with the increased risk of esophageal cancer under the allele and dominant models; rs1800871 T>G, rs1800872 T>G and rs1800896 A>G under allele and dominant models could increase the risk of nasopharyngeal cancer; rs1800871T>G, rs1800872T>G and rs1800896 A>G SNPs under allele model were closely related to the susceptibility to oral cancer. Our findings support the point that IL-10 genetic polymorphisms may play essential role in identifying esophageal cancer, nasopharyngeal cancer and oral cancer at early stage.