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Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8+ T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function is dependent on the cytokine IL15. Ablation of the IL15 signaling inhibitor CIS (Cish) enhances NK-cell antitumor immunity by increasing NK-cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK-cell fitness via the production of immunosuppressive transforming growth factor β (TGFβ), a suppression which occurs even in the presence of high IL15 signaling. Here, we identified an unexpected interaction between CIS and the TGFβ signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyperresponsive to IL15 and hyporesponsive to TGFβ, with dramatically enhanced antitumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anticancer immunity.

Supplementary Figure from TGFβ and CIS Inhibition Overcomes NK-cell Suppression to Restore Antitumor Immunity

Little evidence exists on neurological adverse events (movement disorders and seizures) that occur during adjuvant use of antipsychotics with antidepressants, especially in children and adolescents.To assess the association between neurological adverse events (movement disorders, including parkinsonism, dystonia, extrapyramidal symptoms, chorea, and tic, and seizures) and the adjuvant use of antipsychotics in children and adolescents with depression.A retrospective cohort study using the Health Insurance Review and Assessment claims database in Korea between 2008 and 2018. The study population was children and adolescents aged 2 to 18 years with depression who began treatment with antidepressants between January 1, 2010, and December 31, 2018. Data were analyzed between December 9, 2020, and December 10, 2021.Time-varying exposure to antidepressants, antipsychotics, and concomitant use of antidepressants and antipsychotics. Concomitant use was further subdivided according to the antipsychotic treatment status (dose and agent).The extended Cox proportional hazards regression model, with adjustment for sex, age, health insurance type, psychiatric comorbidities, psychiatric hospitalization, and comedication with other psychotropic drugs, was used to estimate adjusted hazard ratios (aHRs) and 95% CIs for the associations of movement disorders and seizures with use of antidepressants and antipsychotics.A total of 9890 patients were included in the study: 9541 (mean [SD] age, 14.8 [2.8] years; 4956 [51.9%] female) and 7731 (mean [SD] age, 14.9 [2.7] years; 4150 [53.7%] female) met the inclusion criteria for movement disorders and seizures, respectively. For movement disorders, associations were found between concomitant use (aHR, 3.68; 95% CI, 3.06-4.44) and antipsychotic-only use (aHR, 3.84; 95% CI, 3.03-4.87) compared with antidepressant-only use, but their CIs overlapped. The associations with seizure were similar (concomitant use: aHR, 2.06; 95% CI, 1.66-2.55; antipsychotic-only use: aHR, 2.05; 95% CI, 1.53-2.75). With concomitant use, the aHRs gradually increased with increasing doses of antipsychotics. Haloperidol had the highest aHR, 7.15 (95% CI, 3.89-10.00) for movement disorders. The highest aHR for seizure was observed with quetiapine (aHR, 2.36; 95% CI, 1.55-3.59), followed by aripiprazole (aHR, 2.05; 95% CI, 1.52-2.77).In this cohort study, adjunctive antipsychotics with antidepressants were associated with movement disorders and seizures compared with antidepressant monotherapy in children and adolescents with depression. These results suggest that careful consideration of the risk-benefit profile of the antipsychotic use as adjuvant therapy in this population is needed.

Significance Although the need for a universal influenza vaccine has long been recognized, only a handful of candidates have been identified so far, with even fewer advancing in the clinical pipeline. The 24–amino acid ectodomain of M2 protein (M2e) has been developed over the past two decades. However, M2e-based vaccine candidates have shortcomings, including the need for several administrations and the lack of sustained antibody titers over time. We report here a vaccine targeting strategy that has the potential to confer sustained and strong protection upon a single shot of a small amount of M2e antigen. The current COVID-19 pandemic has highlighted the importance of developing versatile, powerful platforms for the rapid deployment of vaccines against any incoming threat.

Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8+ T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function is dependent on the cytokine IL15. Ablation of the IL15 signaling inhibitor CIS (Cish) enhances NK-cell antitumor immunity by increasing NK-cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK-cell fitness via the production of immunosuppressive transforming growth factor β (TGFβ), a suppression which occurs even in the presence of high IL15 signaling. Here, we identified an unexpected interaction between CIS and the TGFβ signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyperresponsive to IL15 and hyporesponsive to TGFβ, with dramatically enhanced antitumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anticancer immunity.

This study aimed to evaluate the cost-effectiveness of bariatric surgery (BS) compared to non-surgical treatment (NST) in Korean people with morbid obesity according to comorbidities and body mass index (BMI) severity. The target cohort was people with morbid obesity, defined as BMI of ≥ 35 kg/m2, or obese people with BMI of 30–34.9 kg/m2 having obesity-related comorbidities. A decision-tree model for 1-year obesity treatment and Markov model for the rest of life were used. In the decision-tree model, the comorbidity remission rate and BMI change after 1-year treatment were decided based on a prospective clinical trial. In the Markov model, the transition probabilities were calculated considering the BMI level and age. The starting age of 20 years, a cycle length of 1 year, a time horizon of 80 years, and a 5% discount rate were applied for the base case from the healthcare system perspective. In the base case, BS improved quality-adjusted life years (QALYs) and was the cost-effective option in total cohort (incremental cost-effectiveness ratio of BS vs. NST was 674 USD/QALY). It was shown to be cost-effective in all subgroup analyses based on BMI level. In particular, BS was a dominant alternative for the subgroup with basal BMI of 35.0–37.4 kg/m2. Various sensitivity analyses showed the robustness of results indicating the cost-effectiveness of BS. BS at BMI of > 30 kg/m2 was more effective than NST for a reduction in BMI and remission of obesity-related comorbidities and was cost-effective in Korea.

Aim Subsequent cancers (SCs) after melanoma diagnosis further increases the risks of mortality and medical costs. This population-based analysis aimed to evaluate risk factors for SC, mortality, and medical costs of melanoma patients with SC. Methods A retrospective cohort analysis was conducted using a nationwide claims database during 2002-2017 in South Korea. SC was defined as having other types of cancer diagnoses other than subsequent melanoma during-up to 5 years after melanoma diagnosis. Melanoma patients were divided into patients with and without SC, and the overall and subgroup survival rates, the risk of developing SC, and the total medical costs were analyzed using a Kaplan-Meier method and regressions. Results A total of 3740 melanoma patients were included in the analysis (mean age, 62.3 ± 15.4 y; 47.2% men), and 2273 patients (1157 within 2 months, 756 after 2 months of melanoma diagnosis) had SC. Higher Charlson comorbidity index score and male sex significantly increased the risk of developing SC. Five-year survival rate and cumulative medical costs were 62.3% (95% confidence interval [CI], 60.8-63.9) and $21,413, respectively, in all patients. Patients with SC diagnosed after 2 months showed the lowest survival rate of 47.8% (95% CI, 44.3-51.4) and the highest costs of $27,081, showing a mortality hazard ratio of 1.65 (range, 1.46-1.86) and a cost ratio of 1.189 (range, 1.112-1.271) compared with those without SC. Conclusion This study presented survival outcomes and medical costs in melanoma patients and confirmed that SC after the first diagnosis of melanoma significantly increased disease burden in terms of mortality and medical costs.

Background: Tuberculosis (TB) has significant effects on patients’ health-related quality of life (HRQOL) and this study was conducted to evaluate the HRQOL based on EQ-5D utility score according to various health statuses of TB patients.Methods: A systematic literature review was conducted to select articles on HRQOLs outcomes of TB patients since 2000. A total of 1,710 articles were searched for primary screening and seven studies that directly assessed all types of TB patients using the EQ-5D were finally selected.Results: The EQ-5D scores of TB patients were in the ranges of 0.43–0.70. After the completion of TB treatment, the utility weights increased to the ranges of 0.88–0.98 and the EQ VAS values showed similar trend as the results of the EQ-5D. The EQ-5D score for multi-drug-resistant TB was very low at 0.51 during treatment but increased to 0.88 after the treatment was completed. The utility weights of latent TB were not significantly different from those of the general population.Conclusion: This study showed that the HRQOL based on the EQ-5D utility score of TB patients has significantly decreased, and the TB treatment has a significantly positive effect on the quality of life of patients.

The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective CD8+ T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligase RNF41 and define a new ubiquitin-mediated mechanism for regulation of Clec9A, reflecting the unique properties of Clec9A as a receptor specialized for delivery of antigens for cross-presentation. We reveal RNF41 is a negative regulator of Clec9A and the cross-presentation of dead cell-derived antigens by mouse dendritic cells. Intriguingly, RNF41 regulates the downstream fate of Clec9A by directly binding and ubiquitinating the extracellular domains of Clec9A. At steady-state, RNF41 ubiquitination of Clec9A facilitates interactions with ER-associated proteins and degradation machinery to control Clec9A levels. However, Clec9A interactions are altered following dead cell uptake to favor antigen presentation. These findings provide important insights into antigen cross-presentation and have implications for development of approaches to modulate immune responses.

Background It is essential to have information on the disease burden of lung cancer at an individual level throughout the life; however, few such results have been reported. Thus, this study aimed to assess the lifetime disease burden in patients with lung cancer by assessing various factors, such as survival, years of life lost (YLL) and medical expenditure in South Korea based on real-world data and extrapolation. Methods Newly diagnosed lung cancer patients (n = 2919) in 2004–2010 were selected and observed until the end of 2015 using nationwide reimbursement claim database. The patients were categorised into the Surgery group, Chemo and/or Radiotherapy group (CTx/RTx), and Surgery+CTx/RTx according to their treatment modality. Age- and sex-matched control subjects were selected from among general population using the life table. The survival and cost data after diagnosis were analysed by a semi-parametric method, the Kaplan–Meier analysis for the first 100 months and rolling extrapolation algorithm for 101–300 months. YLL were derived from the difference in survival between patients and controls. Results Lifetime estimates (standard error) were 4.5 (0.2) years for patients and 14.5 (0.1) years for controls and the derived YLL duration was 10.0 (0.2) years. Lifetime survival years showed the following trend: Surgery (14.2 years) > Surgery+CTx/RTx (8.5 years) > CTx/RTx group (3.0 years), and YLL were increased as lifetime survival years decreased (2.3, 8.7, 12.2 years, respectively). The mean lifetime medical cost was estimated at 30,857 USD/patient. Patients in the Surgery group paid higher treatment cost in first year after diagnosis, but the overall mean cost per year was lower at 4359 USD compared with 7075USD of Surgery+CTx/RTx or 7626USD of CTx/RTx group. Conclusions Lung cancer has resulted in about 10 years of life lost in overall patients. The losses were associated with treatment modality, and the results indicated that diagnosing lung cancer in patients with low stage disease eligible for surgery is beneficial for reducing disease burden in terms of survival and treatment cost per year throughout the life.

After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption results in secondary injury including apoptotic cell death of neurons and oligodendrocytes, thereby leads to permanent neurological deficits. Recently, we reported that the histone H3K27me3 demethylase Jmjd3 plays a role in regulating BSCB integrity after SCI. Here, we investigated whether gallic acid (GA), a natural phenolic compound that is known to be anti-inflammatory, regulates Jmjd3 expression and activation, thereby attenuates BSCB disruption following the inflammatory response and improves functional recovery after SCI. Rats were contused at T9 and treated with GA (50 mg/kg) via intraperitoneal injection immediately, 6 h and 12 h after SCI, and further treated for 7 d with the same dose once a day. To elucidate the underlying mechanism, we evaluated Jmjd3 activity and expression, and assessed BSCB permeability by Evans blue assay after SCI. GA significantly inhibited Jmjd3 expression and activation after injury both in vitro and in vivo. GA also attenuated the expression and activation of matrix metalloprotease-9, which is well known to disrupt the BSCB after SCI. Consistent with these findings, GA attenuated BSCB disruption and reduced the infiltration of neutrophils and macrophages compared with the vehicle control. Finally, GA significantly alleviated apoptotic cell death of neurons and oligodendrocytes and improved behavior functions. Based on these data, we propose that GA can exert a neuroprotective effect by inhibiting Jmjd3 activity and expression followed the downregulation of matrix metalloprotease-9, eventually attenuating BSCB disruption after SCI.

OBJECTIVES: To provide an overview and quantitatively demonstrate the reach of the Health Resources and Services Administration’s Maternal and Child Health Bureau autism research program. METHODS: We reviewed program reports and internal data from 59 autism research grantees. The US federal Interagency Autism Coordinating Committee’s strategic plan questions were used as a framework to highlight the contributions of the autism research program in advancing the field. RESULTS: The autism research program grantees advance research in several ways. Grantees have strengthened the evidence for autism interventions by conducting 89 studies at 79 distinct research sites. A total of 212 708 participants have enrolled in autism research program studies and 361 researchers have contributed to furthering autism research. The program addresses topics that align with the majority of the Interagency Autism Coordinating Committee’s priority topic areas, including advancements in treatments and interventions, services and supports, and identifying risk factors. Grantee products include 387 peer-reviewed publications, 19 tools, and 13 practice guidelines for improving care and intervention practices. CONCLUSIONS: The autism research program has contributed to medical advances in research, leveraged innovative training platforms to provide specialized training, and provided access to health services through research-based screening and diagnostic procedures. Autism research program studies have contributed to the development of evidence-based practice guidelines, informed policy guidelines, and quality improvement efforts to bolster advancements in the field. Although disparities still exist, the Health Resources and Services Administration’s Maternal and Child Health Bureau can reduce gaps in screening and diagnosis by targeting interventions to underserved populations including minority and rural communities.

Additional file 1: Figure A.1. Target subject selection scheme. Table A.1. Comparison of 10-year survival estimates between the semi-parametric extrapolation method (5-year follow-up and 5-year extrapolation) and the Kaplan–Meier method (10-year follow-up). Table A.2. Sensitivity analysis in the lifetime of 20 years. Table A.3. Sensitivity analysis in the lifetime of 30 years.

Targeting model antigens (Ags) to Clec9A on DC has been shown to induce, not only cytotoxic T cells, but also high levels of Ab. In fact, Ab responses against immunogenic Ag were effectively generated even in the absence of DC-activating adjuvants. Here we tested if targeting weakly immunogenic putative subunit vaccine Ags to Clec9A could enhance Ab responses to a level likely to be protective. The proposed “universal” influenza Ag, M2e and the enterovirus 71 Ag, SP70 were linked to anti-Clec9A Abs and injected into mice. Targeting these Ags to Clec9A greatly increased Ab titres. For optimal responses, a DC-activating adjuvant was required. For optimal responses, a boost injection was also needed, but the high Ab titres against the targeting construct blocked Clec9A-targeted boosting. Heterologous prime-boost strategies avoiding cross-reactivity between the priming and boosting targeting constructs overcame this limitation. In addition, targeting small amounts of Ag to Clec9A served as an efficient priming for a conventional boost with higher levels of untargeted Ag. Using this Clec9A-targeted priming, conventional boosting strategy, M2e immunisation protected mice from infection with lethal doses of influenza H1N1 virus., Vaccine technology: targeting the vaccine to the immune system Duration and intensity of vaccine response can be boosted using antibodies to target pathogen fragments to specific immune system cells. Dendritic cells exist to take fragments of infectious diseases and present them to the immune system, sparking host defenses. Now, researchers led by Monash University’s Mireille Lahoud, and Ken Shortman of the Walter and Eliza Hall Institute, have successfully used antibodies to target fragments of influenza and hand, foot and mouth disease directly to dendritic cell molecules, specifically chosen to elicit a prolonged immune response. Mice inoculated with the targeted vaccine were protected from lethal influenza exposure, whereas the hand, foot and mouth disease vaccine elicited promising, but less marked results. With further development, this technology could provide a vital boost to vaccines that offer poor immunity on their own.

Published studies on the association between polypharmacy and parkinsonism or Parkinson disease are very limited. The objective of this study was to investigate whether polypharmacy is associated with parkinsonism or Parkinson disease in elderly patients. From a South Korean national health insurance sample cohort database for 2002–2013, we matched parkinsonism cases (defined by diagnosis codes for parkinsonism/Parkinson disease) and Parkinson disease cases (patients who had records for both Parkinson disease diagnosis and anti-Parkinson disease drug prescriptions) with controls. Logistic regression analysis evaluated the associations of parkinsonism/Parkinson disease with polypharmacy (i.e., five or more prescribed daily drugs) during the year preceding parkinsonism/Parkinson disease diagnosis, medications potentially associated with parkinsonism, and comorbidity status (using the Charlson Comorbidity Index score and hospitalization records). The study population included 6209 cases and 24,836 controls for parkinsonism and 1331 cases and 5324 controls for Parkinson disease. In univariate logistic regression, odds ratios for parkinsonism/Parkinson disease increased significantly with increased polypharmacy, medications potentially associated with parkinsonism, Charlson Comorbidity Index score, or prior hospitalizations. In multiple logistic regression, odds ratios for parkinsonism/Parkinson disease (adjusted for medications potentially associated with parkinsonism and comorbidities) also increased with increased polypharmacy. Odds ratios (95% confidence interval) for Parkinson disease were higher than those for parkinsonism with stronger statistical significance: 1.41 (1.28–1.55) and 2.17 (1.84–2.57) for parkinsonism and 2.87 (2.30–3.58) and 4.75 (3.39–6.66) for Parkinson disease for between five and ten prescribed daily drugs and ten or more drugs, respectively. Polypharmacy in the year preceding diagnosis may be associated with an increased risk for parkinsonism/Parkinson disease. Medications potentially associated with parkinsonism were assumed to increase the risk for parkinsonism/Parkinson disease, but more studies are required to confirm this relationship.

// Jung Ku Jo 1, * , Jong Jin Oh 2, * , Yong Tae Kim 1 , Hong Sang Moon 3 , Hong Yong Choi 3 , Seunghyun Park 4 , Jin-Nyoung Ho 5 , Sungroh Yoon 4 , Hae Young Park 1 and Seok-Soo Byun 2 1 Department of Urology, Hanyang University Hospital, Seoul, Korea 2 Department of Urology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea 3 Department of Urology, Hanyang University Guri Hospital, Guri-si, Korea 4 Department of Electrical and Computer Engineering, Seoul National University, Seoul, Korea 5 Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea * These authors contributed equally to this work Correspondence to: Seok-Soo Byun, email: ssbyun@snubh.org Hae Young Park, email: nopcme@hanyang.ac.kr Keywords: metastasis, prostate cancer, castration, genetic variation Received: December 14, 2016 Accepted: May 01, 2017 Published: May 30, 2017 ABSTRACT Background: Genetic variation which related with progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT) has not been elucidated in patients with metastatic prostate cancer (mPCa). Therefore, we assessed the association between genetic variats in mPCa and progession to CRPC. Results: Analysis of exome genotypes revealed that 42 SNPs were significantly associated with mPCa. The top five polymorphisms were statistically significantly associated with metastatic disease. In addition, one of these SNPs, rs56350726, was significantly associated with time to CRPC in Kaplan-Meier analysis (Log-rank test, p = 0.011). In multivariable Cox regression, rs56350726 was strongly associated with progression to CRPC (HR = 4.172 95% CI = 1.223-14.239, p = 0.023). Materials and Methods: We assessed genetic variation among 1000 patients with PCa with or without metastasis, using 242,221 single nucleotide polymorphisms (SNPs) on the custom HumanExome BeadChip v1.0 (Illuminam Inc.). We analyzed the time to CRPC in 110 of the 1000 patients who were treated with ADT. Genetic data were analyzed using unconditional logistic regression and odds ratios calculated as estimates of relative risk of metastasis. We identified SNPs associated with metastasis and analyzed the relationship between these SNPs and time to CRPC in mPCa. Conclusions: Based on a genetic variation, the five top SNPs were observed to associate with mPCa. And one (SLC28A3, rs56350726) of five SNP was found the association with the progression to CRPC in patients with mPCa.

An optimized therapeutic regimen involving a non-ablative fractionated laser or radiofrequency therapy for acne scars has not yet been established. To evaluate whether the combination of a non-ablative fractional laser (NAF) and fractional micro-needling radiofrequency (FMR) has clinical advantages for the treatment of atrophic acne scars compared with NAF alone, a 16-week prospective, randomized split-face study was performed. Each facial side of a patient was treated with 3 sessions of either NAF with FMR or NAF alone, with a 4-week interval between each session. Although both sides demonstrated significant decreases in the échelle d’évaluation clinique des cicatrices d’acné (ECCA) score, the facial side treated using the combination regimen demonstrated greater improvement in ECCA score regarding degree and onset time than the NAF-treated side. Histopathological and immunohistochemical results confirmed the clinical findings. This study demonstrated that a combination regimen involving NAF and FMR could be a viable option with satisfactory efficacy.

BACKGROUND To assess the cost-effectiveness of drug therapy to prevent osteoporotic fractures in postmenopausal women with osteopenia in Korea. METHODS A Markov cohort simulation was conducted for lifetime with a hypothetical cohort of postmenopausal women with osteopenia and without prior fractures. They were assumed to receive calcium/vitamin D supplements only or drug therapy (i.e., raloxifene or risedronate) along with calcium/vitamin D for 5 years. The Markov model includes fracture-specific and non-fracture specific health states (i.e. breast cancer and venous thromboembolism), and all-cause death. Published literature was used to determine the model parameters. Local data were used to estimate the baseline incidence rates of fracture in those with osteopenia and the costs associated with each health state. RESULTS From a societal perspective, the estimated incremental cost-effectiveness ratios (ICERs) for the base cases that had T-scores between -2.0 and -2.4 and began drug therapy at the age of 55, 60, or 65 years were $16,472, $6,741, and -$13,982 per quality-adjusted life year (QALY) gained, respectively. Sensitivity analyses for medication compliance, risk of death following vertebral fracture, and relaxing definition of osteopenia resulted in ICERs reached to $24,227 per QALY gained. CONCLUSIONS ICERs for the base case and sensitivity analyses remained within the World Health Organization's willingness-to-pay threshold, which is less than per-capita gross domestic product in Korea (about $25,700). Thus, we conclude that drug therapy for osteopenia would be a cost-effective intervention, and we recommend that the Korean National Health Insurance expand its coverage to include drug therapy for osteopenia.

* Abbreviations: AIR-P — : Autism Intervention Research Network on Physical Health ASD — : autism spectrum disorder CAA — : Combating Autism Act DBPNet — : Developmental-Behavioral Pediatrics Research Network HRSA — : Health Resources and Services Administration MCHB — : Maternal and Child Health Bureau In the United States, it is estimated that 1 in 68 children have autism spectrum disorder (ASD) according to data from the Centers for Disease Control and Prevention’s Autism and Developmental Disabilities Monitoring Network.1 Based on data from the 2011–2012 National Survey of Children’s Health, a recent report suggests an even higher prevalence estimate of 1 in 50 children with ASD.2 These increasing prevalence data indicate that ASD continues to be a major public health concern in the United States requiring coordinated and collaborative efforts at the national, state, and community levels. Since 1995, the US Department of Health and Human Services has supported initiatives aimed at increasing our understanding of ASD, its causes, and potential treatments.3 These initiatives have paved the way to a more coordinated federal effort to address ASD and other developmental disabilities with the enactment of the Combating Autism Act of 2006 (CAA). This act authorized programs to address ASD and other developmental disabilities through research, screening, intervention, and education. Congressional appropriations included funding for the Health Resources and Services Administration (HRSA) to implement section 399BB of the CAA4 to address the following: 1. increase awareness of ASD and other developmental disabilities; 2. reduce barriers to screening and diagnosis; 3. support … Address correspondence to Hae Young Park, MPH, Maternal and Child Health Bureau, Health Resources and Services Administration, 5600 Fishers Ln, 18W51, Rockville, MD 20857. E-mail: hpark{at}hrsa.gov

Polypharmacy, regarded as an indicator of potentially inappropriate medications (PIMs), may lead to a higher risk of serious health consequences in elderly patients with osteoporosis. Thus, this study aimed to analyze the association between polypharmacy and hip fracture in patients with osteoporosis because only a limited number of studies have reported on this association, with inconsistent results to date. In this nested case–control study using a population-based sample cohort, the target cases were female patients with hip fracture diagnosed with osteoporosis and aged ≥ 50 years. Polypharmacy (prescription of an average of five or more daily drugs), PIMs for hip fracture (such as benzodiazepines and glucocorticoids), Charlson Comorbidity Index (CCI) score, and other comorbidities were analyzed during the year preceding the diagnosis of hip fracture. Adjusted odds ratios (ORs) for hip fracture for the variables were also analyzed. The cases (n = 1003) showed higher exposure rates to polypharmacy, glucocorticoids, and benzodiazepines, and had more severe comorbidity statuses compared with the controls. The ORs for hip fracture adjusted for confounders increased with polypharmacy level, with persistent statistical significance in most analyses. The ORs (95% confidence intervals), with reference to the 0 to

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding the α-galactosidase A (α-Gal A) lysosomal enzyme, which results in globotriaosylceramide (Gb3) storage in vascular endothelial cells and different cell types throughout the body. Involvement of the kidney and heart is life threatening, and fibrosis of these organs is considered to be involved in the pathogenesis of Fabry disease. An increased concentration of deacylated Gb3 (lyso‑Gb3) in the plasma of symptomatic patients has also been suggested as a causative molecular event. To elucidate the molecular mechanisms involved in renal fibrosis in Fabry disease, the present analyzed the changes in global gene expression prior to and following Gb3 or lyso‑Gb3 treatment in two types of kidney cell lines, human proximal renal tubular epithelial (HK‑2) and mouse renal glomerular mesangial (SV40 MES 13) cells. Gb3 and lyso‑Gb3 treatment regulated the expression of 199 and 328 genes in each cell type, demonstrating a >2.0‑fold change. The majority of the biological functions of the regulated genes were associated with fibrogenesis or epithelial‑mesenchymal transition (EMT). The gene expression patterns of sphingolipid‑treated HK‑2 cells were distinguishable from the patterns in the SV40 MES 13 cells. Several genes associated with the EMT were selected and evaluated further in kidney cells and in Fabry mouse kidney tissues. In the SV40 MES 13 cells, the DLL1, F8, and HOXA11 genes were downregulated, and FOXP2 was upregulated by treatment with Gb3 or lyso‑Gb3. In the HK‑2 cells, the ADAMTS6, BEST1, IL4, and MYH11 genes were upregulated. Upregulation of the FOXP2, COL15A1, IL4, and MYH11 genes was also observed in the Fabry mouse kidney tissues. The gene expression profiles in kidney cells following the addition of Gb3 or lyso‑Gb3 revealed substrate‑specific and cell‑specific patterns. These findings suggested that Gb3 and lyso‑Gb3 lead to renal fibrosis in Fabry disease through different biochemical modulations.