Case Report and Review of Literature: Autosomal Recessive Hypophosphatemic Rickets Type 2 Caused by a Pathogenic Variant in ENPP1 Gene.

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare form of hereditary rickets, which is characterized by defective bone mineralization and renal phosphate wasting due to a loss-of-function variant in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene. Although pathogenic variant of ENPP1 has been known to manifest other phenotypes including arterial calcification, hearing loss, ossification of posterior longitudinal ligament, or pseudoxanthoma elasticum, there have been few reports including systematic examination in individuals diagnosed with ARHR2 to date. Herein, we report a case of ARHR2 with a bi-allelic pathogenic variant of ENPP1, in which the patient presented with gait abnormalities with severe genu varum at 26 months of age. Targeted gene panel sequencing was performed to investigate the genetic cause of rickets, and a homozygous nonsense variant in ENPP1, c.783C>G (p.Tyr261*), was identified. The patient was treated with oral phosphate and active vitamin D supplements and underwent corrective osteotomy for varus deformity. His phenotype was limited to rickets. A periodic systematic evaluation is needed to identify any comorbidities in ARHR2 patients since ENPP1 variants may present phenotypes other than rickets and symptoms may evolve or change over time.

Trends in Pediatric Thyroid Cancer Incidence, Treatment, and Clinical Course in Korea During 2004-2016: A Nationwide Population-Based Study.

Background: The incidence of thyroid cancer has increased worldwide. We investigated nationwide trends in the incidence and treatment course of pediatric thyroid cancer in South Korea. Methods: Using the National Health Information Database, we analyzed 1580 patients (324 males) <20 years of age diagnosed with thyroid cancer during 2004-2016 in South Korea. The annual percentage change (APC) in the age-standardized incidence rate (ASR) was calculated by joinpoint regression analysis. The initial treatment modality was categorized as either surgery only or surgery with radioactive-iodine treatment (surgery+RAIT), and we defined new treatment events as reoperations or additional RAITs among 1464 patients followed up for ≥12 months. Results: During 2004-2016, the mean ASR per 100,000 person-years increased from 0.6 [confidence interval; CI 0.5-0.8] to 0.9 [CI 0.8-1.1], with a mean APC of 4.0% [CI 1.8-6.2]. The ASRs (APCs) among 0-9-, 10-14-, 15-17-, and 18-19-year olds were 0.07 (9.9% [CI 0.08-20.7]), 0.6 (4.6% [CI 0.2-9.2]), 2.2 (3.9 [CI 1.7-6.0]), and 4.2 (3.5% [CI 0.9-6.2]), respectively. The lobectomy and lymph-node-dissection rates increased (from 18.5% to 33.6%, p = 0.0014; and from 29.6% to 84.5%, p < 0.001; respectively), but the RAIT rate decreased (67.9-39.7%, p < 0.001) during the study period. During a median 6.3-year follow-up, two patients died. New treatment events occurred in 56 (10.7%) of patients in the initial surgery-only group (n = 523). In the initial surgery+RAIT group (n = 941), 316 patients received two or more RAITs within 2 years, and 80 (12.8%) of the remaining 625 patients underwent new treatment events. In the surgery+RAIT subgroup, the event-free survival rate was lower in 0-14-year olds than in 18-19-year olds (hazard ratio 2.5 [CI 1.4-4.4]). Conclusions: The pediatric thyroid cancer incidence increased from 2004 to 2012 in South Korea. The lobectomy and lymph-node-dissection rates increased, but the RAIT rate decreased. The higher risk for new treatment events in patients younger than 15 years requiring initial RAIT may be linked to advanced stage at diagnosis, and it needs to be further evaluated.

Heparin-Coated Albumin Nanoparticles for Drug Combination in Targeting Inflamed Intestine.

Targeting areas of inflammation offers potential therapeutic and diagnostic benefits by maximizing drug and imaging marker on-target effects while minimizing systemic exposure that can be associated with adverse side effects. This strategy is particularly beneficial in the management of inflammatory bowel disease (IBD). Here an inflammation-targeting (IT) approach based on heparin-coated human serum albumin nanoparticles (HEP-HSA NPs) that utilize the increased intestinal permeability and changes in electrostatic interaction at the site of intestinal inflammation is described. Using small-molecule and biologic drugs as a model for drug combination, the HEP-HSA NPs demonstrate the capacity to load both drugs simultaneously; the dual-drug loaded HEP-HSA NPs exhibit a higher anti-inflammatory effect than both of the single-drug loaded NPs in vitro and selectively bind to inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future IT-NP formulation development.

Robotically handled whole-tissue culture system for the screening of oral drug formulations.

Monolayers of cancer-derived cell lines are widely used in the modelling of the gastrointestinal (GI) absorption of drugs and in oral drug development. However, they do not generally predict drug absorption in vivo. Here, we report a robotically handled system that uses large porcine GI tissue explants that are functionally maintained for an extended period in culture for the high-throughput interrogation (several thousand samples per day) of whole segments of the GI tract. The automated culture system provided higher predictability of drug absorption in the human GI tract than a Caco-2 Transwell system (Spearman's correlation coefficients of 0.906 and 0.302, respectively). By using the culture system to analyse the intestinal absorption of 2,930 formulations of the peptide drug oxytocin, we discovered an absorption enhancer that resulted in a 11.3-fold increase in the oral bioavailability of oxytocin in pigs in the absence of cellular disruption of the intestinal tissue. The robotically handled whole-tissue culture system should help advance the development of oral drug formulations and might also be useful for drug screening applications.

Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy.

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

Risk factors for low vitamin D status in Korean adolescents: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2009.

OBJECTIVE: To evaluate the prevalence of vitamin D deficiency and predictors for low vitamin D status in Korean adolescents living between latitudes 33° and 39° N. DESIGN: A descriptive cross-sectional study. SETTING: Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2009. SUBJECTS: A total of 1510 healthy adolescents aged 12-18 years (806 male, mean age 14.7 years) participated. Possible predictors for low vitamin D status (log-transformed 25-hydroxyvitamin D (25(OH)D) concentrations) were evaluated. RESULTS: The prevalence of vitamin D deficiency (25(OH)D<20 ng/ml) was 89.1% in spring, 53.7% in summer, 63.9% in autumn and 90.5% in winter. Winter season, older age, higher education level reached, being female, being obese, a lack of vitamin D supplementation, lower milk consumption (0-<200 ml/d) and a lack of physical activity were unadjusted predictors (all P < 0.05). Multiple linear regression analysis showed that winter season (P < 0.001), higher education level (P < 0.001) and a lack of vitamin D supplementation (P = 0.012) were independent predictors for low vitamin D status. The modifying effect of season on the association between vitamin D supplement use and vitamin D status was significant (P < 0.001). CONCLUSIONS: Vitamin D deficiency was highly prevalent in Korean adolescents, especially those in higher school grades. Vitamin D supplementation may contribute to maintain a better vitamin D status with lower seasonal variation. Further studies are required to determine optimal vitamin D intakes to maintain sufficient vitamin D status for Korean adolescents.