Changes in dementia treatment patterns associated with changes in the National Policy in South Korea among patients with newly diagnosed Alzheimer's disease between 2011 and 2017: results from the multicenter, retrospective CAPTAIN study.

BACKGROUND: The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function training program and home nursing service. This study aimed to investigate changes in treatment patterns for Alzheimer's disease (AD) between July 2011 and June 2017 which spanned the 2014 revision. METHODS: This multicenter, retrospective, observational study of patients with newly diagnosed AD analyzed electronic medical records from 17 general hospitals across South Korea. Based on their time of AD diagnosis, subjects were categorized into Cohort 1 (1 July 2011 to 30 June 2014) and Cohort 2 (1 July 2014 to 30 June 2017). RESULTS: Subjects (N=3,997) divided into Cohorts 1 (n=1,998) and 2 (n=1,999), were mostly female (66.4%) with a mean age of 84.4 years. Cohort 1 subjects were significantly older (P<0.0001) and had a lower number of comorbidities (P=0.002) compared with Cohort 2. Mean Mini-Mental State Examination (MMSE) scores in Cohorts 1 and 2 at the time of AD diagnosis or start of initial treatment were 16.9 and 17.1, respectively (P=0.2790). At 1 year, mean MMSE scores in Cohorts 1 and 2 increased to 17.9 and 17.4, respectively (P=0.1524). Donepezil was the most frequently administered medication overall (75.0%), with comparable rates between cohorts. Rates of medication persistence were ≥98% for acetylcholinesterase inhibitor or memantine therapy. Discontinuation and switch treatment rates were significantly lower (49.7% vs. 58.0%; P<0.0001), and mean duration of initial treatment significantly longer, in Cohort 2 vs. 1 (349.3 vs. 300.2 days; P<0.0001). CONCLUSIONS: Comparison of cohorts before and after revision of the national LTCI system for dementia patients found no significant difference in mean MMSE scores at the time of AD diagnosis or start of initial treatment. The reduction in the proportion of patients who discontinued or changed their initial treatment, and the significant increase in mean duration of treatment, were observed following revision of the LTCI policy which enabled increased patient access to long-term care.

Serum exosomal miRNA-145 and miRNA-200c as promising biomarkers for preoperative diagnosis of ovarian carcinomas.

Background: Exosomes are extracellular microvesicles that are released by most cells and widely distributed in various body fluids. Malignant cells secrete large amounts of exosomes containing various molecular constituents reflecting the originating tumor. We investigated the difference in microRNA (miRNA) expression in serum exosomes from the patients with benign, borderline and malignant ovarian masses to assess the diagnostic relevance of serum exosomal miRNAs as biomarkers for preoperative diagnosis of ovarian carcinoma. Methods: A total of 68 cases of ovarian masses were enrolled, comprising benign ovarian cysts (benign; n=10), borderline ovarian tumors (BOT, n=10), high-grade serous ovarian carcinomas (HGSOC, n=39) and non-HGSOCs (n=9). Exosomal RNA was extracted from the serum, and expression levels of seven miRNAs (miRNA-21, -93, -141, -145, -200a, -200b and -200c), which were reportedly dysregulated in serous ovarian cancer in previous studies, were quantified by real-time PCR, and compared between the four groups. Results: MiR-93, -145, and -200c, showed significantly higher expression in serum exosomes of the cancer group (HGSOC and non-HGSOC) than of the non-cancer group (benign and BOT; all p<0.05). The remaining three miRs (miR-141, -200a, and -200b) were expressed at extremely low levels, and not appropriate as serological biomarkers. To test discrimination of cancer from non-cancer, the area under the receiver operating characteristic curves determined for cancer antigen 125 (CA125), miR-145, miR-200c, miR-21, and miR-93 were 0.801 (p<0.001), 0.910 (p<0.001), 0.802 (p<0.001), 0.585 (p=0.303), and 0.755 (p=0.002), respectively. MiR-145 showed superior sensitivity (91.6%), and miR-200c showed superior specificity (90.0%), compared with CA125. Conclusion: Expression of exosomal miR-93, miR-145 and miR-200c was significantly elevated in the serum of ovarian cancer patients. Serum exosomal miR-145 in particular appeared to be the most promising biomarker for preoperative diagnosis of ovarian cancer.

Effect of mammography screening on stage at breast cancer diagnosis: results from the Korea National Cancer Screening Program.

In Asian countries, breast densities and the proportion of younger women with breast cancer are higher than those in Western countries. This study was designed to determine differences in stage at diagnosis of breast cancer among Korean women according to screening history. The study population was derived from the Korea National Cancer Screening Program (KNCSP). The study cohort comprised 17,689 women who were newly diagnosed with breast cancer in 2011 and were invited to undergo breast cancer screening via the KNCSP between 2002 and 2011. Ductal carcinoma in situ (DCIS) and localized breast cancer were most frequent in both ever-screened and never-screened patients. Late stage cancer was significantly more frequent in never-screened patients, compared with ever-screened patients. Compared to never-screened women, the odds ratio (OR) for being diagnosed with early stage breast cancer among screened women was 1.41 (95% Confidence Interval [CI] = 1.28-1.55). The OR for being diagnosed with early stage breast cancer was highest among patients who underwent screening three times or more (aOR = 1.89, 95% CI = 1.57-2.29). Screening by mammography was associated with diagnosis of early stage breast cancer in Korean women. However, significant increases in the diagnosis of DCIS and localized breast cancers among ever-screened patients suggest the possibility of overdiagnosis due to screening.

Budget Impact of the Accreditation Program for Clinical Laboratories on Colorectal Cancer Screening via Fecal Immunochemical Testing: Results from the National Cancer Screening Program in Korea.

BACKGROUND: False-positive fecal immunochemical test (FIT) results in the National Cancer Screening Program (NCSP) for colorectal cancer may lead to unnecessary procedures, such as colonoscopies, increasing the medical costs. We estimated reductions in the cost of National Health Insurance according to the accreditation status of screening facilities participating in the NCSP for colorectal cancer. METHODS: We used data collected between 2007 and 2010 from NCSP and the Korea Central Cancer Registry to identify patients with colorectal cancer. We also ascertained the history of the accreditation of each facility by the Korean Laboratory Accreditation Program (KLAP). Budget impact was defined as a reduction in medical costs achieved when the false-positive rate of the non-accredited facilities decreased relative to that of the accredited facilities. RESULTS: A total of 3,285 screening facilities participated in the NCSP. Of these, 196 were accredited by the KLAP. The false-positive rate of the accredited facilities was 2.47%, and that of the non-accredited facilities was 6.83%. Medical costs were estimated to be reduced by approximately 19 million US dollars (USD), and the cost of detecting one case of colorectal cancer was estimated to decrease from 9,212 USD to 7,332 USD if the false-positive rate of non-accredited facilities were decreased to that of the accredited facilities. Clinics were estimated to have the largest associated cost reduction. CONCLUSIONS: Quality assurance in clinical laboratories could lower false-positive rates and prevent the use of unnecessary procedures, ensuring patient safety and increasing the cost-effectiveness of FIT screening in the NCSP for colorectal cancer.

Elevated blood viscosity is associated with cerebral small vessel disease in patients with acute ischemic stroke.

BACKGROUND: Increased level of blood viscosity, which is one of the major factors that determine blood rheology, has been reported as a risk factor or predictor for cerebrovascular events. We investigated how blood viscosity is associated with acute stroke and chronic radiological manifestations of cerebral small vessel disease, and how blood viscosity changes after stroke. METHODS: We prospectively enrolled consecutive patients with acute ischemic stroke. Whole blood viscosities at a low or high shear rate were measured using a scanning capillary tube viscometer, and were referred to as diastolic blood viscosity (DBV) and systolic blood viscosity (SBV), respectively. Correlations between blood viscosity and acute stroke etiology or chronic radiological manifestations of cerebral small vessel disease were investigated. The temporal profiles of blood viscosity at the onset of stroke and follow-up at 1 and 5 weeks were investigated. RESULTS: Of the 127 patients admitted with acute ischemic stroke, 63 patients were included in the final analyses. DBV at the onset of stroke was significantly higher in small artery occlusion (SAO) stroke than in other stroke subtypes (p = 0.037). DBV showed a significant positive correlation with the number of chronic lacunes (r = 0.274, p = 0.030). The temporal profiles of DBV in SAO stroke showed a transient decrease due to the hydration therapy after 1 week and recurrent elevation at 5 week follow-up (p = 0.009). CONCLUSIONS: Our study suggests that elevated DBV may play a role in the development of acute and chronic manifestations of cerebral small vessel disease. The recurring elevation of DBV in SAO stroke indicates that sufficient hydration and additional therapeutic interventions targeting blood viscosity may be needed in patients with SAO stroke.

Effectiveness of the Korean National Cancer Screening Program in Reducing Gastric Cancer Mortality.

BACKGROUND & AIMS: It is not clear whether screening for gastric cancer by upper endoscopy or upper gastrointestinal (UGI) series examinations (looking at the upper and middle sections of the gastrointestinal tract by imaging techniques) reduces mortality. Nevertheless, the Korean National Cancer Screening Program for gastric cancer was launched in 1999 to screen individuals 40 years and older for gastric cancer using these techniques. We evaluated the effectiveness of these techniques in gastric cancer detection and compared their effects on mortality in the Korean population. METHODS: We performed a nested case-control study using data from the Korean National Cancer Screening Program for gastric cancer since 2002. A total of 16,584,283 Korean men and women, aged 40 years and older, comprised the cancer-free cohort. Case subjects (n = 54,418) were defined as individuals newly diagnosed with gastric cancer from January 2004 through December 2009 and who died before December 2012. Cases were matched with controls (subjects who were alive on the date of death of the corresponding case subject, n = 217,672) for year of entry into the study cohort, age, sex, and socioeconomic status. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained via conditional logistic regression analysis. RESULTS: Compared with subjects who had never been screened, the overall OR for dying from gastric cancer among ever-screened subjects was 0.79 (95% CI, 0.77-0.81). According to screening modality, the ORs of death from gastric cancer were 0.53 (95% CI, 0.51-0.56) for upper endoscopy and 0.98 (95% CI, 0.95-1.01) for UGI series. As the number of endoscopic screening tests performed per subject increased, the ORs of death from gastric cancer decreased: 0.60 (95% CI, 0.57-0.63), 0.32 (95% CI, 0.28-0.37), and 0.19 (95% CI, 0.14-0.26) for once, twice, and 3 or more times, respectively. CONCLUSIONS: Within the Korean National Cancer Screening Program, patients who received an upper endoscopy were less likely to die from gastric cancer; no associations were found for UGI series.

Metabolic engineering of 3-hydroxypropionic acid biosynthesis in Escherichia coli.

3-Hydroxypropionic acid (3-HP) can be produced in microorganisms as a versatile platform chemical. However, owing to the toxicity of the intermediate product 3-hydroxypropionaldehyde (3-HPA), the minimization of 3-HPA accumulation is critical for enhancing the productivity of 3-HP. In this study, we identified a novel aldehyde dehydrogenase, GabD4 from Cupriavidus necator, and found that it possessed the highest enzyme activity toward 3-HPA reported to date. To augment the activity of GabD4, several variants were obtained by site-directed and saturation mutagenesis based on homology modeling. Escherichia coli transformed with the mutant GabD4_E209Q/E269Q showed the highest enzyme activity, which was 1.4-fold higher than that of wild type GabD4, and produced up to 71.9 g L(-1) of 3-HP with a productivity of 1.8 g L(-1) h(-1) . To the best of our knowledge, these are the highest 3-HP titer and productivity values among those reported in the literature. Additionally, our study demonstrates that GabD4 can be a key enzyme for the development of industrial 3-HP-producing microbial strains, and provides further insight into the mechanism of aldehyde dehydrogenase activity.

Recurrent posterior circulation infarction caused by anomalous occipital bony process in a young patient.

BACKGROUND: Structural anomaly of the cervical spine or craniocervical junction has been reported as one of the rare causes of ischemic stroke. We report a case of a young patient with recurrent posterior circulation infarction that may have been associated with an anomalous occipital bony process compressing the vertebral artery. CASE PRESENTATION: A 23-year-old man experienced recurrent posterior circulation infarction 5 times over a period of 5 years. He had no conventional vascular risk factors. Young age stroke work-up including thorough cardiac, intra- and extracranial vascular evaluation and laboratory tests for the hypercoagulable state or connective tissue disease yielded unremarkable results. An anomalous bony process from the occipital base compressing the left vertebral artery was observed on brain CT. All the recurrent strokes were explainable by the arterial thromboembolism originating from the compressed left vertebral artery. Therefore, the left vertebral artery compressed by the anomalous occipital bony process may have been the culprit behind the recurrent thromboembolic strokes in our patient. Intractable recurrent strokes even under optimal medical treatment led us to make a decision for the intervention. Instead of surgical removal of the anomalous occipital bony process, the left vertebral artery was occluded permanently by endovascular coiling after confirming that this would cause no neurological deficits or flow disturbance in the posterior circulation. There was no recurrence of stroke for 2 years after permanent occlusion of the left vertebral artery. CONCLUSION: Arterial thromboembolism originating from the left vertebral artery compressed by the anomalous occipital bony process is a rare but not to be overlooked cause of posterior circulation infarction. When intractable to medical treatment, endovascular occlusion of the vertebral artery without flow disturbance to the posterior circulation may be a useful treatment option when surgical removal is not feasible.

Recent advances in the biological production of mannitol.

Mannitol is a fructose-derived, 6-carbon sugar alcohol that is widely found in bacteria, yeasts, fungi, and plants. Because of its desirable properties, mannitol has many applications in pharmaceutical products, in the food industry, and in medicine. The current mannitol chemical manufacturing process yields crystalline mannitol in yields below 20 mol% from 50% glucose/50% fructose syrups. Thus, microbial and enzymatic mannitol manufacturing methods have been actively investigated, in particular in the last 10 years. This review summarizes the most recent advances in biological mannitol production, including the development of bacterial-, yeast-, and enzyme-based transformations.

Thermotoga maritima TM0298 is a highly thermostable mannitol dehydrogenase.

Thermotoga maritima TM0298 is annotated as an alcohol dehydrogenase, yet it shows high identity and similarity to mesophilic mannitol dehydrogenases. To investigate this enzyme further, its gene was cloned and expressed in Escherichia coli. The purified recombinant enzyme was most active on fructose and mannitol, making it the first known hyperthermophilic mannitol dehydrogenase. T. maritima mannitol dehydrogenase (TmMtDH) is optimally active between 90 and 100 degrees C and retains 63% of its activity at 120 degrees C but shows no detectable activity at room temperature. Its kinetic inactivation follows a first-order mechanism, with half-lives of 57 min at 80 degrees C and 6 min at 95 degrees C. Although TmMtDH has a higher V (max) with NADPH than with NADH, its catalytic efficiency is 2.2 times higher with NADH than with NADPH and 33 times higher with NAD(+) than with NADP(+). This cofactor specificity can be explained by the high density of negatively charged residues (Glu193, Asp195, and Glu196) downstream of the NAD(P) interaction site, the glycine motif. We demonstrate that TmMtDH contains a single catalytic zinc per subunit. Finally, we provide the first proof of concept that mannitol can be produced directly from glucose in a two-step enzymatic process, using a Thermotoga neapolitana xylose isomerase mutant and TmMtDH at 60 degrees C.