Chronic disease management program applied to type 2 diabetes patients and prevention of diabetic complications: a retrospective cohort study using nationwide data.

BACKGROUND: The outcomes of education and counseling by medical professionals for patients with type 2 diabetes mellitus (T2DM) are unclear. This study examined the effects of the Chronic Disease Management Program (CDMP), a health insurance fee-for-service benefit, on the incidence of diabetic complications in patients newly diagnosed with T2DM using the National Health Insurance data. METHODS: Patients newly diagnosed with T2DM aged ≥ 20 years from 2010 to 2014 were followed up until 2015. Selection bias was minimized using propensity score matching. A stratified Cox proportional hazards model was used to analyze the association between the CDMP and the risk of incident diabetic complications. Subgroup analysis was performed for patients with high medication adherence, which was indicated by a medication possession ratio (MPR) ≥ 80. RESULTS: Among the 11,915 patients with T2DM in the cohort, 4,617 were assigned to the CDMP and non-CDMP group each. The CDMP helped reduce the overall and microvascular risks of complications compared to the non-CDMP group; however, the protective effect against macrovascular complications was only observed in those aged ≥ 40 years. Subgroup analysis of the group aged ≥ 40 years with high adherence (an MPR ≥ 80) showed that the CDMP effectively reduced the incidence of micro- and macrovascular complications. CONCLUSIONS: Effective management of T2DM is crucial in preventing complications in patients with the condition, and includes regular monitoring and adjustment of treatment by qualified physicians. Nevertheless, long-term prospective studies on the effects of CDMP are required to confirm this finding.

Comparative Interrupted Time Series Analysis of Long-term Direct Medical Costs in Patients With Hip Fractures and a Matched Cohort: A Large-database Study.

BACKGROUND: Previous studies on medical costs in patients with hip fractures have focused on medical costs incurred for a short period after the injury. However, patients often had comorbidities before their hip fractures that would have affected medical costs even had they not sustained a fracture. Consequently, these studies may have overestimated the costs associated with hip fractures and did not characterize the duration of increased medical costs adequately. Without knowing this crucial information, it is difficult to craft thoughtful health policy to support these patients' needs. QUESTIONS/PURPOSES: (1) To compare the direct medical costs for 5 years before fracture and up to 5 years after injury in a group of patients who underwent hip fracture surgery with a matched group of patients who did not experience a hip fracture, (2) to analyze the duration over which the increased direct medical costs associated with a hip fracture continues, and (3) to analyze whether there is a difference in direct medical costs according to age group using a nationwide claims database in South Korea. METHODS: The National Health Insurance Service Sample cohort in South Korea consisted of 1 million patients who were selected using a systematic, stratified, random sampling method from 48,222,537 individuals on December 31, 2006. Under a compulsory social insurance system established by the National Health Insurance Act, all patients were followed until 2015. Patients with hip fractures and matched controls were selected from the National Health Insurance Service sample of South Korea. Patients with hip fractures were defined as those who were hospitalized with a diagnosis of femoral neck fracture or intertrochanteric fracture and who underwent surgical treatment. We excluded patients with hip fractures before January 1, 2007 to ensure a minimum 5-year period that was free of hip fractures. Patients with hip fractures were matched with patients of the same age and gender at the date of admission to an acute care hospital for surgery (time zero). If patients with hip fractures died during the follow-up period, we performed matching among patients whose difference from the time of death was within 1 month. This method of risk-set matching was repeated sequentially for the next patient until the last patient with a hip fracture was matched. We then sequentially performed 1:5 random sampling for each risk set. A total of 3583 patients in the hip fracture cohort (patients with hip fractures) and 17,915 patients in the matched cohort (those without hip fractures) were included in this study. The mean age was 76 ± 9 years, and 70% were women in both groups. Based on the Charlson comorbidity index score, medication, and medical history, the patients with hip fractures had more comorbidities. Person-level direct medical costs per quarter were calculated for 5 years before time zero and up to 5 years after time zero. Direct medical costs were defined as the sum of that insurer's payments (that is, the National Health Insurance Service's payments), and that patient's copayments, excluding uncovered payments. We compared direct medical costs between patients with hip fractures and the patients in the matched cohort using a comparative interrupted time series analysis. The difference-in-difference estimate is the ratio of the differences in direct medical costs before and after time zero in the hip fracture cohort to the difference in direct medical costs before and after time zero in the matched cohort; the difference in difference estimates were calculated each year after injury. To identify changes in direct medical cost trends in patients with hip fractures and all subgroups, joinpoint regression was estimated using statistical software. RESULTS: The direct medical costs for the patients with hip fractures were higher than those for patients in the matched cohort at every year during the observation period. The difference in direct medical costs between the groups before time zero has increased every year. The direct medical costs in patients with hip fractures was the highest in the first quarter after time zero. Considering the differential changes in direct medical costs before and after time zero, hip fractures incurred additional direct medical costs of USD 2514 (95% CI 2423 to 2606; p < 0.01) per patient and USD 264 (95% CI 166 to 361; p < 0.01) per patient in the first and second years, respectively. The increase in direct medical costs attributable to hip fracture was observed for 1.5 to 2 years (difference-in-difference estimate at 1 year 3.0 [95% CI 2.8 to 3.2]; p < 0.01) (difference-in-difference estimate at 2 years 1.2 [95% CI 1.1 to 1.3]; p < 0.01; joinpoint 1.5 year). In the subgroups of patients younger than 65, patients between 65 and 85, and patients older than 85 years of age, the increase in direct medical costs attributable to hip fracture continued up to 1 year (difference-in-difference estimate ratio at 1 year 2.7 [95% CI 2.1 to 3.4]; p < 0.01; joinpoint 1 year), 1.5 to 2 years (difference-in-difference estimate ratio at 1 year 2.8 [95% CI 2.6 to 3.1]; p < 0.01; difference-in-difference estimate ratio at 2 years 1.2 [95% CI 1.1 to 1.3]; p < 0.01; joinpoint 1.5 years), and 39 months to 5 years (difference-in-difference estimate ratio at 1 year 5.2 [95% CI 4.4 to 6.2]; p < 0.01; difference-in-difference estimate ratio at 5 years 2.1 [95% CI 1.4 to 3.1]; p < 0.01; joinpoint 39 months) from time zero, respectively. CONCLUSION: The direct medical costs in patients with hip fractures were higher than those in the matched cohort every year during the 5 years before and after hip fracture. The increase in direct medical costs because of hip fractures was maintained for 1.5 to 2 years and was greater in older patients. Based on this, we suggest that health policies should focus on patients' financial and social needs, with particular emphasis on the first 2 years after hip fracture with stratification based on patients' ages. LEVEL OF EVIDENCE: Level II, economic analysis.

Nipple Reconstruction Using the Semilunar Flap and Omega-shaped Acellular Dermal Matrix Strut.

BACKGROUND: Various operative methods exist for nipple reconstruction. Selection of an appropriate skin flap and core strut material is imperative in achieving a satisfactory outcome in nipple reconstruction. Long-term maintenance of nipple projection requires further investigation by surgeons. We propose a new technique that uses a semilunar flap and omega-shaped acellular dermal matrix (ADM). METHODS: Total 53 nipples were reconstructed by this method. An omega-shaped ADM strut was inserted into the barrel made by a semilunar flap. The footplates of omega-shaped ADM struts were spread out under the subcutaneous tissue of the donor site of the semilunar flap to support the dome of the omega strut. RESULTS: The mean maintenance rate of nipple projection was 95.12 ± 6.30% at 3 weeks, 80.60 ± 8.93% at 3 months, and 71.70 ± 8.67% at 6 months postoperatively when compared to the projection observed in the immediate postoperative period. Thirty-five patients (66.0%) showed a maintenance rate over 70% at 6 months post operation, with most patients (94.3%) demonstrating a maintenance rate greater than 60%. CONCLUSIONS: Our study with the omega-shaped ADM strut showed superior maintenance rates of projection when compared to other studies on that used AlloDerm® as a core strut for nipple reconstruction. Omega-shaped struts, when made with cross-linked thick ADM, supported the skin flap quite well. We propose that our method combining the semilunar flap with an omega-shaped ADM may be a good option for nipple reconstruction. LEVEL OF EVIDENCE IV: "This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 ."

Effects of Stocking Density on Stress, Hematological Responses, and Growth of Black Rockfish Sebastes schlegelii.

The objective of the current study was to evaluate the effect of stocking density on juvenile Black Rockfish Sebastes schlegelii (average weight = 12 g) in terms of stress, hematological responses, and growth performance during a 4-month growth trial in a flow-through system. The initial stocking densities were 1.3 kg/m3 (low), 1.8 kg/m3 (medium), and 2.3 kg/m3 (high), and the final densities were 4.9 kg/m3 (low), 5.6 kg/m3 (medium), and 6.3 kg/m3 (high). At the end of the trial, the high stocking density significantly affected growth characteristics, levels of growth hormone and insulin-like growth factor 1, and hematological indices (hematocrit, red blood cell count, and hemoglobin level) compared to the medium and low stocking densities. The plasma cortisol and immunoglobulin-M levels were significantly higher at the high density than at the other two densities. Taken together, while the low and medium stocking densities (final densities of up to 5.6 kg/m3 ) did not affect stress and hematological indices or growth, the high stocking density (final density of 6.3 kg/m3 ) significantly impacted those variables, which suggests an allostatic load at that density. Thus, the use of a final stocking density less than 6.3 kg/m3 should be considered to avoid compromising the stress and health condition and growth of Black Rockfish at this size and temperature range.

SCF-Slimb is critical for Glycogen synthase kinase-3ß-mediated suppression of TAF15-induced neurotoxicity in Drosophila.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized pathologically by motor neuron degeneration and associated with aggregation of RNA-binding proteins. TATA-binding protein-associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, and clearance of these aggregates is considered a potential therapeutic strategy for ALS. However, the exact pathogenic mechanism of TAF15-induced neurotoxicity remains to be elucidated. Glycogen synthase kinase-3 (GSK-3) plays a critical role in the protection of ALS pathology. In the present study, we use a transgenic fly model over-expressing human TAF15 to study the protective effects of Shaggy/GSK3ß on TAF15-induced neuronal toxicity in Drosophila brain. Transgenic flies were examined for locomotor activity and lithium treatment. The expression level and solubility of TAF15 were assessed with western blotting, whereas immunohistochemistry was used to assess TAF15 aggregation in Drosophila brain. We have revealed that Shaggy/GSK3ß was abnormally activated in neurons of TAF15-expressing flies and its inhibition can suppress the defective phenotypes, thereby preventing retinal degeneration and locomotive activity caused by TAF15. We have also found that Shaggy/GSK3ß inhibition in neuronal cells leads to a reduction in TAF15 levels. Indeed, the F-box proteins Slimb and archipelago genetically interact with TAF15 and control TAF15 protein level in Drosophila. Importantly, SCFslimb is a critical regulator for Shaggy/GSK3ß-mediated suppression of TAF15-induced toxicity in Drosophila. The present study has provided an in vivo evidence supporting the molecular mechanism of GSK3ß inhibition for protection against TAF15-linked proteinopathies.

Inhibition of biofilm and virulence properties of Pseudomonas aeruginosa by sub-inhibitory concentrations of aminoglycosides.

Aminoglycosides are a commonly used class of antibiotics; however, their application has been discontinued due to the emergence of multi-drug resistance bacterial strains. In the present study, the subinhibitory concentrations (sub-MIC) of several aminoglycosides were determined and tested as an antibiofilm and for their anti-virulence properties against Pseudomonas aeruginosa PAO1, which is an opportunistic foodborne pathogen. P. aeruginosa PAO1 exhibits multiple mechanisms of resistance, including the formation of biofilm and production of several virulence factors, against aminoglycoside antibiotics. The sub-MIC of these antibiotics exhibited biofilm inhibition of P. aeruginosa in alkaline TSB (pH 7.9). Moreover, various concentrations of these aminoglycosides also eradicate the mature biofilm of P. aeruginosa. In the presence of sub-MIC of aminoglycosides, the morphological changes of P. aeruginosa were found to change from rod-shaped to the filamentous, elongated, and streptococcal forms. Similar growth conditions and sub-MIC of aminoglycosides were also found to attenuate several virulence properties of P. aeruginosa PAO1. Molecular docking studies demonstrate that these aminoglycosides possess strong binding properties with the LasR protein, which is a well-characterized quorum-sensing receptor of P. aeruginosa. The present study suggests a new approach to revitalize aminoglycosides as antibiofilm and antivirulence drugs to treat infections caused by pathogenic bacteria.

Streptomycin mediated biofilm inhibition and suppression of virulence properties in Pseudomonas aeruginosa PAO1.

Pseudomonas aeruginosa is known as an opportunistic pathogen whose one of the antibiotic resistance mechanisms includes biofilm formation and virulence factor production. The present study showed that the sub-minimum inhibitory concentration (sub-MIC) of streptomycin inhibited the formation of biofilm and eradicated the established mature biofilm. Streptomycin at sub-MIC was also capable of inhibiting biofilm formation on the urinary catheters. In addition, the sub-MIC of streptomycin attenuated the bacterial virulence properties as confirmed by both phenotypic and gene expression studies. The optimal conditions for streptomycin to perform anti-biofilm and anti-virulence activities were proposed as alkaline TSB media (pH 7.9) at 35 °C. However, sub-MIC of streptomycin also exhibited a comparative anti-biofilm efficacy in LB media at similar pH level and temperature. Furthermore, this condition also improved the biofilm inhibition and eradication properties of streptomycin, tobramycin and tetracycline towards the biofilm formed by a clinical isolate of P. aeruginosa. Findings from the present study provide an important insight for further studies on the mechanisms of biofilm inhibition and dispersion of pre-existing biofilm by streptomycin as well as tobramycin and tetracycline under a specific culture environment.

Synthesis and characterization of chitosan oligosaccharide-capped gold nanoparticles as an effective antibiofilm drug against the Pseudomonas aeruginosa PAO1.

The infection caused by Pseudomonas aeruginosa is a serious concern in human health. The bacterium is an opportunistic pathogen which has been reported to cause nosocomial and chronic infections through biofilm formation and synthesis of several toxins and virulence factors. Furthermore, the formation of biofilm by P. aeruginosa is known as one of the resistance mechanisms against conventional antibiotics. Natural compounds from marine resources have become one of the simple, cost-effective, biocompatible and non-toxicity for treating P. aeruginosa biofilm-related infections. Furthermore, hybrid formulation with nanomaterials such as nanoparticles becomes an effective alternative strategy to minimize the drug toxicity problem and cytotoxicity properties. For this reason, the present study has employed chitosan oligosaccharide for the synthesis of chitosan oligosaccharide-capped gold nanoparticles (COS-AuNPs). The synthesized COS-AuNPs were then characterized by using UV-Visible spectroscopy, Dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), Field emission transmission electron microscopy (FE-TEM), and Energy dispersive X-ray diffraction (EDX). The synthesized COS-AuNPs were applied for inhibiting P. aeruginosa biofilm formation. Results have shown that COS-AuNPs exhibited inhibition to biofilm as well as eradication to pre-existing mature biofilm. Simultaneously, COS-AuNPs were also able to reduce bacterial hemolysis and different virulence factors produced by P. aeruginosa. Overall, the present study concluded that the hybrid nanoformulation such as COS-AuNPs could act as a potential agent to exhibit inhibitory properties against the P. aeruginosa pathogenesis arisen from biofilm formation.

Fucoidan-Stabilized Gold Nanoparticle-Mediated Biofilm Inhibition, Attenuation of Virulence and Motility Properties in Pseudomonas aeruginosa PAO1.

The emergence of antibiotic resistance in Pseudomonas aeruginosa due to biofilm formation has transformed this opportunistic pathogen into a life-threatening one. Biosynthesized nanoparticles are increasingly being recognized as an effective anti-biofilm strategy to counter P. aeruginosa biofilms. In the present study, gold nanoparticles (AuNPs) were biologically synthesized and stabilized using fucoidan, which is an active compound sourced from brown seaweed. Biosynthesized fucoidan-stabilized AuNPs (F-AuNPs) were subjected to characterization using UV-visible spectroscopy, Fourier transform infrared spectroscopy (FTIR), field emission transmission electron microscopy (FE-TEM), dynamic light scattering (DLS), and energy dispersive X-ray diffraction (EDX). The biosynthesized F-AuNPs were then evaluated for their inhibitory effects on P. aeruginosa bacterial growth, biofilm formation, virulence factor production, and bacterial motility. Overall, the activities of F-AuNPs towards P. aeruginosa were varied depending on their concentration. At minimum inhibitory concentration (MIC) (512 µg/mL) and at concentrations above MIC, F-AuNPs exerted antibacterial activity. In contrast, the sub-inhibitory concentration (sub-MIC) levels of F-AuNPs inhibited biofilm formation without affecting bacterial growth, and eradicated matured biofilm. The minimum biofilm inhibition concentration (MBIC) and minimum biofilm eradication concentration (MBEC) were identified as 128 µg/mL. Furthermore, sub-MICs of F-AuNPs also attenuated the production of several important virulence factors and impaired bacterial swarming, swimming, and twitching motilities. Findings from the present study provide important insights into the potential of F-AuNPs as an effective new drug for controlling P. aeruginosa-biofilm-related infections.

Distribution of internal thoracic artery perforators: A clincal anatomy study.

There are various modifications of the transverse rectus abdominis musculocutaneous flap and deep inferior epigastric perforator flap to reduce the morbidity of the donor site or to augment the vascularity of the flap. For microanastomosis of multiple pedicles, multiple recipient vessels or an intervening vein graft should be provided. In addition, alternative perforator-based flaps used in breast reconstruction have small caliber pedicles. Therefore, small recipient vessels such as internal thoracic artery perforators are more suitable for appropriate microanastomosis. Therefore, it is important to acquaint the distribution and anatomical characteristics of internal thoracic artery perforators. We researched the perforators running in the intercostal spaces under the pectoralis major muscle to provide an overview of the anatomical distribution and characteristics of the perforators in patients who underwent immediate subpectoral implant-based breast reconstructions. In our study, the major perforators (diameter > 1.5 mm) were easily found 2-7 cm medially between the third and fourth intercostal space and were sparse in the lateral area from the midline of the breast (usually 8-9 cm lateral to the midsternal line) and above the third rib. In each side of the breast, the average number of perforators greater than 1.5 mm was 1.6, and the average number of perforators between 1 mm and 1.5 mm in diameter was 3.2. Our results provide information about perforators in the anterior chest wall related to the breast area. Clin. Anat. 32:471-475, 2019. © 2018 Wiley Periodicals, Inc.

Postoperative Changes in Isolated Medial Orbital Wall Fractures Based on Computed Tomography.

The treatment has been improved on the accurate reduction of blow-out fracture for many decades. But still, it has been limited to reduce completely when surgeons are approaching by conventional technique. The authors analyzed the postoperative results using computed tomography (CT) scans after conventional open reduction of isolated medial wall fracture. Thirty-seven patients with isolated medial wall fracture were reviewed. All patients underwent preoperative, immediate, and postoperative CT scans. Two surgeons have performed the surgery by conventional open reduction with transcaruncular approach and absorbable mesh insertion. The authors evaluated changing orbital volume and distance, comparing the immediate and 6 months postoperative outcomes with preoperative outcome. The differences between immediate postoperative and 6 months postoperatively data were statistically evaluated. The authors used the distant value to minimize bias of CT view selection. Significant differences from the 2 kinds of data were observed (P < 0.05 for volume, P < 0.01 for distance, Paired t test). Bone remodeling process after conventional open reduction of orbital wall has not been fully understood. Most popular technique is conventional open reduction and mesh insertion but it is not easy for surgeons to reduce fractured bones completely. The authors analyzed the bone remodeling after incomplete reduction. These results suggest that the decreased measurements might be caused from the scar contracture with fibrosis. This research is very limited to explain the change while bone remodeling is progressed. Further research should be continued to discover the understanding of the process.

Could -79 °C Spray-Type Cryotherapy Be an Effective Monotherapy for the Treatment of Keloid?

Cryotherapy has been regarded as an effective modality for the treatment of keloids, and the spray-type device is one of the novel cryotherapeutic units. However, the biological mechanisms and therapeutic effects of this technique are incompletely studied. We evaluated the clinical efficacy of our cryotherapy protocol with molecular and pathologic evidence for the treatment of keloids. We evenly split each of ten keloid lesions into a non-treated (C-) and treated (C+) area; the C+ area was subjected to two freeze-thaw cycles of spray-type cryotherapy using -79 °C spray-type CryoPen™. This treatment was repeated after an interval of two weeks. The proliferation and migration abilities of the fibroblasts isolated from the dermis under the cryotherapy-treated or untreated keloid tissues (at least 5 mm deep) were compared and pathologic findings of the full layer were evaluated. Molecular analysis revealed that the number of dermal fibroblasts was significantly higher in C+ group as compared with C- group. The dermal fibroblasts from C+ group showed more than two-fold increase in the migration ability as compared with the fibroblasts from C- group. The expression of matrix metallopeptidase 9 was increased by more than two-fold and a significant increase in transforming growth factor beta 1 expression and Smad2/3 phosphorylation level was observed in C+ group. C+ group showed more extensive lymphoplasmacytic infiltration with thicker fibrosis and occasional "proliferating core collagen" as compared with C- group. Thus, -79 °C spray-type cryotherapy is ineffective as a monotherapy and should be used in combination with intralesional corticosteroids or botulinum toxin A for favourable outcomes in the treatment of thick keloids.

Extracellular volume expansion and the preservation of residual renal function in Korean peritoneal dialysis patients: a long-term follow up study.

INTRODUCTION: In chronic peritoneal dialysis patients, preservation of residual renal function (RRF) is a major determinant of patient survival, and maintaining sufficient intravascular volume has been hypothesized to be beneficial for the preservation of RRF. The present study aimed to test this hypothesis using multifrequency bioimpedence analyzer (MFBIA), in Korean peritoneal dialysis patients. METHODS: A total of 129 patients were enrolled in this study. The baseline MFBIA was checked, and the patients were divided into the following two groups: group 1, extracellular water per total body water (ECW/TBW) < median, group 2, ECW/TBW > median. We followed up the patients, and then we analyzed the changes in the urine output (UO) and the solute clearance (weekly uKt/V) in each group. Data associated with patient and technical survivor were collected by medical chart review. The volume measurement was made using Inbody S20 equipment (Biospace, Seoul, Korea). We excluded the anuric patients at baseline. RESULT: The median value of ECW/TBW was 0.396. The mean patient age was 49.74 ± 10.01 years, and 62.1 % of the patients were male; most of the patients were on continuous ambulatory peritoneal dialysis (89.1 %). The mean dialysis vintage was 26.20 ± 28.71 months. All of the patients were prescribed hypertensive medication, and 48.5 % of the patients had diabetes. After 25.47 ± 6.86 months of follow up, ΔUO and Δweekly Kt/V were not significantly different in the two groups as follows: ΔUO (-236.07 ± 185.15 in group 1 vs -212.21 ± 381.14 in group 2, p = 0.756); Δ weekly Kt/v (-0.23 ± 0.43 in group 1 vs -0.29 ± 0.49 in group 2, p = 0.461). The patient and technical survivor rate was inferior in the group 2, and in the multivariable analysis, initial hypervolemia was an independent factor that predicts both of the patient mortality [HR 1.001 (1.001-1.086), p = 0.047] and the technical failure [HR 1.024 (1.001-1.048), p = 0.042]. CONCLUSIONS: Extracellular volume expansion, measured by MFBIA, does not help preserve residual renal function, and is harmful for the technical and patient survival in Korean peritoneal dialysis patients.

Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs.

α6ß2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6ß2* nAChRs (α6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6ß2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9'S NAc. Overall, these results show that enhanced α6ß2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels.

Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study.

BACKGRUOUND: Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients. METHODS: We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy. RESULTS: A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05-1.24 and 1.17- 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence. CONCLUSION: High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

The Trends and Outcomes of Initial Palliative Chemotherapy in Patients with Pancreatic Cancer in Korea Based on National Health Insurance Service Data.

Background/Objectives: The survival rate of patients with pancreatic cancer (PC) has improved gradually since the introduction of FOLFIRINOX (FFX) and gemcitabine + albumin-bound paclitaxel (GnP) regimens. However, the trends and outcomes of initial palliative chemotherapy before and after the advent of these regimens and their contribution to survival rates are not well understood. This study aimed to investigate this in patients with PC in Korea using claims data from the National Health Insurance Service (NHIS). Methods: Patients diagnosed with PC who underwent initial palliative chemotherapy between 2007 and 2019 were identified from the NHIS database. Patient demographics, comorbidities, chemotherapy regimens, and survival rates were analyzed using follow-up data up to 2020. Results: In total, 14,760 patients (mean age, 63.78 ± 10.18 years; men, 59.19%) were enrolled. As initial palliative chemotherapy, 3823 patients (25.90%) received gemcitabine alone; 2779 (18.83%) received gemcitabine + erlotinib; 1948 (13.20%) received FFX; and 1767 (11.97%) received GnP. The median survival values were 15.00 months for FFX; 11.04 months for GnP; 8.40 months for gemcitabine alone; and 8.51 months for gemcitabine + erlotinib. The adjusted hazard ratio (aHR) for GnP vs. FFX was 1.291 (95% CI, 1.206-1.383) in the multivariate Cox regression analysis of mortality. Radiation therapy (aHR, 0.667; 95% CI, 0.612-0.728) and second-line chemotherapy (aHR, 0.639; 95% CI, 0.597-0.684) were significantly associated with improved survival. Conclusions: Our study found that first-line chemotherapy with FFX was associated with significantly longer survival than the other regimens, although caution is needed in interpreting the results.

A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans.

Cryptococcosis, caused by the basidiomycetous fungus Cryptococcus neoformans, is responsible for more than 600,000 deaths annually in AIDS patients. Flucytosine is one of the most commonly used antifungal drugs for its treatment, but its resistance and regulatory mechanisms have never been investigated at the genome scale in C. neoformans. In the present study, we performed comparative transcriptome analysis by employing two-component system mutants (tco1Δ and tco2Δ) exhibiting opposing flucytosine susceptibility. As a result, a total of 177 flucytosine-responsive genes were identified, and many of them were found to be regulated by Tco1 or Tco2. Among these, we discovered an APSES-like transcription factor, Mbs1 (Mbp1- and Swi4-like protein 1). Expression analysis revealed that MBS1 was regulated in response to flucytosine in a Tco2/Hog1-dependent manner. Supporting this, C. neoformans with the deletion of MBS1 exhibited increased susceptibility to flucytosine. Intriguingly, Mbs1 played pleiotropic roles in diverse cellular processes of C. neoformans. Mbs1 positively regulated ergosterol biosynthesis and thereby affected polyene and azole drug susceptibility. Mbs1 was also involved in genotoxic and oxidative stress responses. Furthermore, Mbs1 promoted production of melanin and capsule and thereby was required for full virulence of C. neoformans. In conclusion, Mbs1 is considered to be a novel antifungal therapeutic target for treatment of cryptococcosis.

Impacts of Temperature on the Growth, Feed Utilization, Stress, and Hemato-Immune Responses of Cherry Salmon (Oncorhynchus masou).

Cherry salmon (Oncorhynchus masou) hold commercial value in aquaculture, and there is a need for controlled laboratory studies to isolate the specific effects of temperature on their growth, feeding, and well-being. We examined the effects of different temperatures (10 °C, 14 °C, 18 °C, and 22 °C) on juvenile cherry salmon (average mass 29.1 g) in triplicate tanks per treatment over eight weeks. The key parameters assessed included growth rate, feed efficiency, stress response, and hemato-immune responses. Our objectives were to determine the most and less favorable temperatures among the four designated temperatures and to assess the adverse effects associated with these less favorable temperatures. The results showed that body weight, growth rates, feed intake, and feed efficiency were significantly higher at 10 °C and 14 °C compared to 18 °C and 22 °C. Reduced appetite and feeding response were observed at 22 °C. Red blood cell parameters were significantly lower at 22 °C. At 10 °C, the results showed significantly increased plasma cortisol levels, gill Na+/K+-ATPase activity, body silvering, and decreased condition factors, suggesting potential smoltification. The potential smoltification decreased with increasing temperatures and disappeared at 22 °C. Furthermore, the plasma lysozyme concentrations significantly increased at 18 °C and 22 °C. In conclusion, our study identifies 10 °C and 14 °C as the temperatures most conducive to growth and feed performance in juvenile cherry salmon under these experimental conditions. However, temperatures of 22 °C or higher should be avoided to prevent compromised feeding, reduced health, disturbed immune responses, impaired growth, and feed performance.

Second Primary Malignancy After Radioiodine Therapy in Thyroid Cancer Patient: A Nationwide Study.

Objective: This study aimed to investigate the risk of second primary malignancy after radioiodine (RAI) therapy in patients with thyroid cancer, using the National Health Insurance Service (NHIS) database. Methods: We extracted data from the NHIS database of South Korea, which covers the entire population of the nation. Risk of second primary malignancy in the thyroid cancer patients who received RAI therapy were compared with the thyroid cancer patients who received surgery only. Results: Between January 1, 2004, and December 31, 2018, we identified 363,155 patients who underwent thyroid surgery due to thyroid cancer for analysis. The surgery only cohort was 215,481, and the RAI cohort was 147,674 patients. A total of 19,385 patients developed second primary malignancy (solid cancer, 18,285; hematologic cancer, 1,100). There was no significant increase in the risk of second primary malignancy in patients who received a total cumulative dose of 100 mCi or less (hazard ratio [HR], 1.013; 95% confidence interval [CI], 0.979-1.049). However, a statistically significant increase in the risk of second primary malignancy was observed in patients who received 101-200 mCi (HR, 1.214; 95% CI, 1.167-1.264), 201-300 mCi (HR, 1.422; 95% CI, 1.258-1.607), and > 300 mCi (HR, 1.693; 95% CI, 1.545-1.854). Conclusion: Total cumulative doses of 100 mCi or less of RAI can be safely administered without concerns about second primary malignancy. However, the risk of second primary malignancy increases in a dose-dependent manner, and the risk-benefit needs to be considered for doses over 100 mCi of RAI therapy.