HCN channel-dependent presynaptic potentiation at LA-BA synapses is required for fear memory formation.

Previously, we demonstrated that auditory fear conditioning produces presynaptic potentiation at lateral to basal amygdala (LA-BA) synapses, which occludes high-frequency stimulation (HFS)-induced ex-vivo LTP. We also found that the HFS-induced ex-vivo LTP requires presynaptic hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity. In this study, we investigated whether HCN channels are necessary for auditory fear conditioning in vivo. Our results show that ZD7288, an HCN channel blocker, reduced synaptic transmission and decreased the paired pulse ratio (PPR) only in slices from rats that underwent auditory fear conditioning, but not from naïve rats. This indicates that fear conditioning involves HCN channel-dependent presynaptic potentiation at LA-BA synapses. Importantly, injecting ZD7288 into the basal amygdala (BA) before auditory fear conditioning significantly impaired long-term fear memory formation. Since HCN channel activity is necessary for LTP at LA-BA synapses but not at cortico-BA, cortico-LA, or thalamo-LA synapses, HCN channel-dependent presynaptic potentiation at LA-BA synapses appears to be crucial for auditory fear conditioning.

Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors.

BACKGROUND: Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i). METHODS: Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium > 5.0 mmol/L), mild hyperkalemia (potassium > 5-≤5.5 mmol/L) and moderate to severe hyperkalemia (potassium > 5.5 mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs). RESULTS: 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. CONCLUSIONS: In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.

Is Colonoscopy Alone Adequate for Surveillance in Stage I Colorectal Cancer?

Purpose: While colonoscopy is the standard surveillance tool for stage I colorectal cancer according to NCCN guidelines, its effectiveness in detecting recurrence is debated. This study evaluates recurrence risk factors and patterns in stage I colorectal cancer to inform comprehensive surveillance strategies. Materials and Methods: A retrospective analysis of 2,248 stage I colorectal cancer patients who underwent radical surgery at Samsung Medical Center (2007-2018) was conducted. Exclusions were based on familial history, prior recurrences, preoperative treatments, and inadequate data. Surveillance included colonoscopy, laboratory tests, and CT scans. Results: Stage I colorectal cancer patients showed favorable 5-year disease-free survival (98.3% colon, 94.6% rectal). Among a total of 1,467 colon cancer patients, 26 (1.76%) experienced recurrence. Of the 781 rectal cancer patients, 47 (6.02%) experienced recurrence. Elevated preoperative CEA levels and perineural invasion were significant recurrence risk factors in colon cancer, while tumor budding was significant in rectal cancer. Distant metastasis was the main recurrence pattern in colon cancer (92.3%), while rectal cancer showed predominantly local recurrence (50%). Colonoscopy alone detected recurrences in a small fraction of cases (3.7% in colon cancer and 14.9% in rectal cancer). Conclusion: Although recurrence in stage I colorectal cancer is rare, relying solely on colonoscopy for surveillance may miss distant metastases or locoregional recurrence outside the colorectum. For high-risk patients, we recommend considering regular CT scans alongside colonoscopy. This targeted approach may enable earlier recurrence detection and improve outcomes in this subset while avoiding unnecessary scans for the low-risk majority.

Estimated GFR in the Korean and US Asian Populations Using the 2021 Creatinine-Based GFR Estimating Equation Without Race.

Rationale & Objective: In 2021, the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) updated the creatinine-based estimated glomerular filtration rate (eGFR) equation and removed the coefficient for race. The development and validation of this equation involved binarizing race into African American and non-African American, involving few Asian participants. This study aimed to examine the difference between the 2021 equation and the previous 2009 equation on CKD prevalence estimates in 2 Asian populations. Study Design: Observational study using 2 national surveys. Setting & Participants: Participants from the 2019 Korea National Health and Nutrition Survey and participants self-reported as Asian from the 2011-2020 US National Health and Nutrition Survey. Exposure: eGFR using 2009 and 2021 CKD-EPI creatinine equation. Outcomes: Prevalence of CKD (eGFR <60 mL/min/1.73 m2 or urine albumin-creatinine ratio ≥30 mg/g). Analytical Approach: Sampling-weighted prevalence estimated using the 2009 and 2021 equations as well as the percentage of individuals with CKD G3+ using the 2009 equation being reclassified as not having CKD G3+ using the 2021 equation. Results: The prevalence of CKD estimated using the 2021 equation was 9.75% (95% confidence intervals [CI], 8.80-10.80%) in Koreans and 11.60% (95% CI, 10.23-13.13%) in US Asians. The prevalence of CKD estimated using the 2021 equation was slightly lower than that using the 2009 equation in both Korean and US Asian populations by 0.63% (95% CI, 0.44-0.90%) and 0.84% (95% CI, 0.52-1.34%), respectively. Furthermore, 32.8% and 30.2% of Koreans and US Asians with CKD G3-5, respectively, estimated using the 2009 equation were reclassified as not having CKD G3-5 when the eGFR was calculated using the 2021 equation. Limitations: Measured GFR was not available. Conclusions: Use of the 2021 CKD-EPI creatinine equation leads to a small decrease in CKD prevalence in both Korean and US Asian populations, and of similar magnitude, resulting in significant reclassification among those originally classified as having CKD G3+.

The 2009 serum creatinine-based kidney function estimating equation used demographic information including race. Because race is a social construct, race was eliminated in the new equation developed in 2021. As race was categorized into African American and non-African American during its development, this study examined the impact of the 2021 equation in 2 distinct Asian populations (Koreans and US Asians) using 2 national datasets. We found that the prevalence of chronic kidney disease (CKD) estimated using the 2021 equation was slightly lower that estimated using the 2009 equation in both Koreans and US Asians. Approximately one-third of people with CKD estimated using the 2009 equation were reclassified as not having CKD estimated using the 2021 equation.

Clonal hematopoiesis with DNMT3A mutations is associated with multiple system atrophy.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with cardiovascular diseases and other disorders, possibly via inflammation. Recent research suggests a connection of CHIP with neurodegenerative disorders. OBJECTIVE: We aimed to investigate the association between multiple system atrophy (MSA) and CHIP. METHODS: We included 100 patients with MSA and 4457 controls. Targeted sequencing of peripheral blood DNA samples was performed, focusing on a panel of 25 genes commonly. LINKED TO CHIP: The prevalence of CHIP in patients with MSA was assessed against controls at variant allele frequency (VAF) thresholds of 1.5 % and 2.0 %. RESULTS: DNMT3A mutation rates were significantly higher in patients with MSA, with a VAF of 1.5 %, which remained significant after adjusting for age and sex (adjusted odds ratio, 1.848; 95 % CI, 1.024-3.335; p = 0.0416). CONCLUSION: Our results suggest an association between DNMT3A mutations and MSA.

Corrigendum: 2023 Korean Society of Menopause - Osteoporosis Guidelines Part I.

This corrects the article on p. 1 in vol. 30, PMID: 38714490.

Particulate Matter and Its Molecular Effects on Skin: Implications for Various Skin Diseases.

Particulate matter (PM) is a harmful air pollutant composed of chemicals and metals which affects human health by penetrating both the respiratory system and skin, causing oxidative stress and inflammation. This review investigates the association between PM and skin disease, focusing on the underlying molecular mechanisms and specific disease pathways involved. Studies have shown that PM exposure is positively associated with skin diseases such as atopic dermatitis, psoriasis, acne, and skin aging. PM-induced oxidative stress damages lipids, proteins, and DNA, impairing cellular functions and triggering inflammatory responses through pathways like aryl hydrocarbon receptor (AhR), NF-κB, and MAPK. This leads to increased production of inflammatory cytokines and exacerbates skin conditions. PM exposure exacerbates AD by triggering inflammation and barrier disruption. It disrupts keratinocyte differentiation and increases pro-inflammatory cytokines in psoriasis. In acne, it increases sebum production and inflammatory biomarkers. It accelerates skin aging by degrading ECM proteins and increasing MMP-1 and COX2. In conclusion, PM compromises skin health by penetrating skin barriers, inducing oxidative stress and inflammation through mechanisms like ROS generation and activation of key pathways, leading to cellular damage, apoptosis, and autophagy. This highlights the need for protective measures and targeted treatments to mitigate PM-induced skin damage.

Effectiveness of Machine Learning in Predicting Orthodontic Tooth Extractions: A Multi-Institutional Study.

The study aimed to evaluate the effectiveness of machine learning in predicting whether orthodontic patients would require extraction or non-extraction treatment using data from two university datasets. A total of 1135 patients, with 297 from University 1 and 838 from University 2, were included during consecutive enrollment periods. The study identified 20 inputs including 9 clinical features and 11 cephalometric measurements based on previous research. Random forest (RF) models were used to make predictions for both institutions. The performance of each model was assessed using sensitivity (SEN), specificity (SPE), accuracy (ACC), and feature ranking. The model trained on the combined data from two universities demonstrated the highest performance, achieving 50% sensitivity, 97% specificity, and 85% accuracy. When cross-predicting, where the University 1 (U1) model was applied to the University 2 (U2) data and vice versa, there was a slight decrease in performance metrics (ranging from 0% to 20%). Maxillary and mandibular crowding were identified as the most significant features influencing extraction decisions in both institutions. This study is among the first to utilize datasets from two United States institutions, marking progress toward developing an artificial intelligence model to support orthodontists in clinical practice.

Long-term Outcomes of Mitral Valve Repair for Atrial Functional Mitral Regurgitation.

BACKGROUND: Atrial functional mitral regurgitation (AFMR), defined by normal left ventricular function, enlarged left atrium, and a dilated mitral valve annulus, has been a concept discussed for >10 years. However, there are still no established guidelines for its treatment in the American College of Cardiology/American Heart Association recommendations. This study aimed to determine the long-term outcomes of mitral annuloplasty as a treatment for AFMR. METHODS: We analyzed 1435 patients who underwent mitral valve repair at our institution between 2005 and 2020, with 162 classified as having AFMR. Exclusion criteria for AFMR were established based on preoperative echocardiography and operative notes. The primary outcome was overall mortality, and the secondary outcome was MR recurrence, which was defined as moderate or greater mitral regurgitation observed on echocardiography during the follow-up period, analyzed using our hospital's medical records and data from the National Statistical Office. RESULTS: The median follow-up duration for the entire patient cohort was 6.1 years (interquartile range, 3.2-11.2 years). Patients had a 5-year survival rate of 86% and a 10-year survival rate of 73%, with freedom from MR recurrence rates of 89% and 80% at 5 and 10 years, respectively. Although all 162 patients had moderate or greater MR before surgery, most experienced trivial or mild MR after mitral valve repair throughout the follow-up period. CONCLUSIONS: In summary, mitral valve repair effectively treats patients with AFMR, addressing survival and mitigating MR recurrence.

Surveillance of pathogenic yeasts in hospital environments in Taiwan in 2020.

BACKGROUND: A predominate azole-resistant Candida tropicalis clade 4 genotype causing candidemia has been detected in not only Taiwan but also China, Singapore, and Australia. It can also be detected on fruit surfaces. In addition to determining distribution and drug susceptibilities of pathogenic yeasts in environments of intensive care units of 25 hospitals in Taiwan, we would also like to investigate whether the azole-resistant C. tropicalis exists in Taiwan's hospital environment. METHODS: The swabs of hospital environments were collected from August to November in 2020 and were cultured for yeasts. The yeasts were identified by rDNA sequence and the antifungal susceptibilities of those isolates were determined by the broth microdilution method. RESULTS: The average yeast-culture rate of hospitals was 9.4% (217/2299). Sinks had the highest yeast-positive culture rate (32.7%), followed by bedside tables (28.9%), floors (26.0%), water-dispenser buttons (23.8%), and TV controller/touch panels (19.0%). Of 262 identified isolates, Candida parapsilosis was the most common species, accounting for 22.1%, followed by Filobasidium uniguttulatum (18.3%), Candida albicans (9.5%), C. tropicalis (8.0%), Candida glabrata (Nakaseomyces glabratus) (6.9%), and 30 other species (35.1%). Of the 21 C. tropicalis isolates from 11 units in 9 hospitals, 15 diploid sequence types (DSTs) were identified. The two DST506 fluconazole-resistant ones belonged to clade 4. CONCLUSION: We detected not only various pathogenic yeast species but also the predominant clade 4 genotype of azole-resistant C. tropicalis. Our findings highlight and re-emphasize the importance of regular cleaning and disinfection practices.

Parkinson's disease is associated with clonal hematopoiesis with TET2 mutation.

Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson's disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11-2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

Association between Use of Combustible Cigarettes and Noncombustible Nicotine or Tobacco Products and Health-Related Quality of Life in Korean Men: A Nationwide Population-Based Study.

Background: Although the association between smoking and health-related quality of life (HRQoL) has been established, the effects of tobacco products, including combustible cigarettes (CCs) and non-combustible nicotine or tobacco products (NNTPs), on HRQoL remain unclear. This study examined the association between tobacco use and HRQoL in Korean men. Methods: Data from the Korea National Health and Nutrition Examination Survey conducted between 2013 and 2020 were analyzed. A total of 16,429 male participants aged ≥19 years completed the European Quality of Life-5 Dimensions (EQ-5D). Impaired HRQoL was defined as scoring in the lowest 20% of the EQ-5D index and having some or extreme problems in the following five domains of the EQ-5D: mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression. Multiple logistic regression was conducted to evaluate the risk of impaired HRQoL in current tobacco users. Results: Current tobacco users exhibited a significantly higher risk of impaired HRQoL compared with never users (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.05-1.92). Compared to never users, current tobacco users reported more problems with mobility and pain/discomfort (all P<0.05). Moreover, compared with former tobacco users, current tobacco users had a higher risk of impaired HRQoL (OR, 1.60; 95% CI, 1.18-2.17). Compared to former tobacco users, current tobacco users reported more problems with mobility and pain/discomfort (all P<0.05). Conclusion: Use of CCs and NNTPs is associated with impaired HRQoL in Korean men. Therefore, further interventions for lifestyle modification and smoking cessation treatments are required to reduce the risk of impaired HRQoL among current tobacco users.

The Evaluation of Hospitalist Care for Patients with Aspiration Pneumonia Using Risk-adjusted Performance Indicators Developed from a Nationwide Inpatient Database.

Background High-quality evidence proving the superiority of hospitalist services is lacking. We developed risk-adjusted performance indicators from a multilevel prediction model using a nationwide inpatient database to evaluate hospitalist medical care for patients with aspiration pneumonia. Methods We extracted cases diagnosed with aspiration pneumonia between 2014 and 2021 from the Diagnosis Procedure Combination (DPC) database. Hospital-level risk-adjusted performance indicators were the observed-to-expected ratio of the following outcomes using a multilevel prediction model containing both patient- and hospital-level variables: death or transfer in poor condition within 30 days (poor outcome), in-hospital death within 30 days, and discharges within the 25th and 50th percentiles for length of stay defined by the DPC system. Using the predicted numbers of each outcome without random intercept as denominators of both indicators, the numerators of Indicator 1 were observed numbers of each outcome, while those in Indicator 2 were "smoothed" predicted numbers of outcomes estimated by the fitted model with random intercept. The ratio of the number of outcomes for each hospital to the mean number of outcomes among participating hospitals was used as a reference. We applied these indicators to Takatsuki General Hospital (TGH) as a working example. Results A total of 526,245 patients were analyzed. Compared with indicator 1, indicator 2 showed greater stability in the mean ratio and bootstrapping confidence interval (CI). Indicator 2 of poor outcome and discharges within the 25th percentile in 2017 at TGH were 1.110 (95% CI 0.784-1.375) and 1.458 (95% CI 1.272-1.597), respectively. Conclusions Utilizing a nationwide inpatient database, we developed risk-adjusted performance indicators using a multilevel prediction model to evaluate hospitalist medical care for patients with aspiration pneumonia. Given the reliable results shown in the working example, these indicators have potential benefits for the accurate evaluation of the quality of medical care.

Involvement of posterior hypothalamic CaMKII-positive neurons in ADHD-like behaviors in mice.

This study explores the behavioral effects of modulating CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus (PH). Utilizing a chemogenetic approach in mice, we discovered that the activation of CaMKII + neurons within the PH is associated with heightened locomotor activity, reduced social interaction, and impulsive behavior unrelated to anxiety or avoidance. These observed behaviors share a significant resemblance with characteristics commonly found in attention deficit and hyperactivity disorder (ADHD). Notably, treatment with clonidine, which is frequently prescribed for ADHD, effectively reduced impulsive behaviors in our mouse model. Our findings uncover the role of the PH that has not been previously explored and suggest a possible involvement of the PH in the manifestation of ADHD-like behaviors.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

Monoaminergic degeneration, cognition, and autonomic symptom trajectory in early Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) encompasses a range of non-motor symptoms attributed to deficits in various neurotransmitter systems. This study aimed to investigate the associations between cognitive and autonomic symptoms and the degeneration of brainstem monoaminergic nuclei, particularly the serotonergic and noradrenergic nuclei, in a prospective cohort of early PD patients. METHODS: Twenty-eight early PD patients (with an average disease duration of approximately three years) underwent baseline [18F]FP-CIT positron emission tomography (PET) scans, Montreal Cognitive Assessment (MoCA), and Composite Autonomic Symptom Scale-31 (COMPASS-31) evaluations, followed by repeat MoCA and COMPASS-31 assessments three years later. Regression models were utilized to analyze both cross-sectional and longitudinal changes in non-motor symptoms relative to baseline degeneration of the noradrenergic locus coeruleus (LC) and serotonergic raphe, normalized by striatal dopaminergic terminal loss. RESULTS: Baseline LC and raphe degeneration in early PD was cross-sectionally associated with poorer MoCA performances. Over the three-year follow-up, gastrointestinal symptoms exhibited progression, while cognitive scores remained stable. Profound baseline degeneration of the LC and raphe, relative to nigrostriatal terminal loss, were predictive of subsequent accelerated deterioration in gastrointestinal symptoms. CONCLUSION: Brainstem non-dopaminergic dysfunction in early PD is linked to cognitive dysfunction and predicts progression in gastrointestinal symptoms, offering potential indicators for worsening non-motor trajectories.