Octyl gallate has potent anti-inflammasome activity by directly binding to NLRP3 LRR domain.

The NOD-, LRR-, and Pyrin domain-containing protein 3 (NLRP3) inflammasome plays key roles in regulating inflammation. Numerous studies show that the abnormal activation of NLRP3 associates with the initiation and progression of various diseases. Hence, the NLRP3 inflammasome may be a promising therapeutic target for these diseases. Octyl gallate (OG) is a small molecule with antioxidant, antimicrobial, antifungal, and anti-inflammatory activities; however, the mechanism underlying its anti-inflammatory activity is still unclear. Here, we developed a screening system for NLRP3-inflammasome inhibitors. A total of 3287 small molecules were screened for inhibitors of nigericin-induced NLRP3 oligomerization. OG was identified as a novel inhibitor. We show that OG directly targets the LRR domain of NLRP3 and thereby blocks the inflammatory cascade of the NLRP3 inflammasome. This contrasts with the mode-of-action of other direct NLRP3 inhibitors, which all bind to the NACHT domain of NLRP3. Interestingly, OG also inhibits the priming step by downregulating the Raf-MEK1/2-ERK1/2 axis. Thus, OG inhibits the NLRP3 inflammasome by two distinct mechanisms. Importantly, OG injection ameliorated the inflammation in mouse models of foot gout and sepsis. Our study identifies OG as a potential therapeutic agent for NLRP3-associated diseases.

Nuclear envelope assembly defects link mitotic errors to chromothripsis.

Defects in the architecture or integrity of the nuclear envelope are associated with a variety of human diseases1. Micronuclei, one common nuclear aberration, are an origin for chromothripsis2, a catastrophic mutational process that is commonly observed in cancer3-5. Chromothripsis occurs after micronuclei spontaneously lose nuclear envelope integrity, which generates chromosome fragmentation6. Disruption of the nuclear envelope exposes DNA to the cytoplasm and initiates innate immune proinflammatory signalling7. Despite its importance, the basis of the fragility of the micronucleus nuclear envelope  is not known. Here we show that micronuclei undergo defective nuclear envelope assembly. Only 'core' nuclear envelope proteins8,9 assemble efficiently on lagging chromosomes, whereas 'non-core' nuclear envelope proteins8,9, including nuclear pore complexes (NPCs), do not. Consequently, micronuclei fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and genome. We show that spindle microtubules block assembly of NPCs and other non-core nuclear envelope proteins on lagging chromosomes, causing an irreversible defect in nuclear envelope assembly. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective nuclear envelope assembly, prevent spontaneous nuclear envelope disruption, and suppress DNA damage in micronuclei. Thus, during mitotic exit in metazoan cells, chromosome segregation and nuclear envelope assembly are only loosely coordinated by the timing of mitotic spindle disassembly. The absence of precise checkpoint controls may explain why errors during mitotic exit are frequent and often trigger catastrophic genome rearrangements4,5.

Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks.

Excluding 53BP1 from chromatin is required to attenuate the DNA damage response during mitosis, yet the functional relevance and regulation of this exclusion are unclear. Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif. Phosphorylating these sites blocks the interaction of the UDR motif with mononuclesomes containing ubiquitinated histone H2A and impedes binding of 53BP1 to mitotic chromatin. Ectopic recruitment of 53BP1-T1609A/S1618A to mitotic DNA lesions was associated with significant mitotic defects that could be reversed by inhibiting nonhomologous end-joining. We also reveal that protein phosphatase complex PP4C/R3ß dephosphorylates T1609 and S1618 to allow the recruitment of 53BP1 to chromatin in G1 phase. Our results identify key sites of 53BP1 phosphorylation during mitosis, identify the counteracting phosphatase complex that restores the potential for DDR during interphase, and establish the physiological importance of this regulation.

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans.

The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo- and heterodimers and oligomers that transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intramolecular interactions of syndecan-2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe-169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe-169 in syndecan TMDs. Replacement of SDC2-Phe-169 by tyrosine (S2F169Y) did not affect SDS-resistant homodimer formation but significantly reduced SDS-resistant heterodimer formation between syndecan-2 and -4, suggesting that SDC2-Phe-169 is involved in the heterodimerization/oligomerization of syndecans. Similarly, in an in vitro binding assay, a syndecan-2 mutant (S2(F169Y)) showed a significantly reduced interaction with syndecan-4. FRET assays showed that heteromolecular interactions between syndecan-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the heterodimerization of syndecan-2 and -4, including Rac activity, cell migration, membrane localization of PKCα, and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed heterodimeric interaction with syndecan-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans.

Trans-regulation of Syndecan Functions by Hetero-oligomerization.

Syndecans, a family of transmembrane heparansulfate proteoglycans, are known to interact through their transmembrane domains to form non-covalently linked homodimers, a process essential for their individual functions. Because all syndecan transmembrane domains are highly conserved and thus might mediate interactions between different members of the syndecan family, we investigated syndecan interactions in detail. All recombinant syndecan-2 and -4 protein variants containing the transmembrane domain formed not only sodium dodecyl sulfate (SDS)-resistant homodimers but also SDS-resistant heterodimers. Biochemical and structural data revealed that recombinant syndecan-2 and -4 formed intermolecular interactions in vitro, and the GXXXG motif in transmembrane domain mediated this interaction. When exogenously expressed in rat embryonic fibroblasts, syndecan-2 interacted with syndecan-4 and vice versa. Furthermore, bimolecular fluorescence complementation-based assay demonstrated specific hetero-molecular interactions between syndecan-2 and -4, supporting hetero-oligomer formation of syndecans in vivo. Interestingly, hetero-oligomerization significantly reduced syndecan-4-mediated cellular processes such as protein kinase Cα activation and protein kinase Cα-mediated cell adhesion as well as syndecan-2-mediated tumorigenic activities in colon cancer cells such as migration and anchorage-independent growth. Taken together, these data provide evidence that hetero-oligomerization produces distinct syndecan functions and offer insights into the underlying signaling mechanisms of syndecans.

A unique phenylalanine in the transmembrane domain strengthens homodimerization of the syndecan-2 transmembrane domain and functionally regulates syndecan-2.

The syndecans are a type of cell surface adhesion receptor that initiates intracellular signaling events through receptor clustering mediated by their highly conserved transmembrane domains (TMDs). However, the exact function of the syndecan TMD is not yet fully understood. Here, we investigated the specific regulatory role of the syndecan-2 TMD. We found that syndecan-2 mutants in which the TMD had been replaced with that of syndecan-4 were defective in syndecan-2-mediated functions, suggesting that the TMD of syndecan-2 plays one or more specific roles. Interestingly, syndecan-2 has a stronger tendency to form sodium dodecyl sulfate (SDS)-resistant homodimers than syndecan-4. Our structural studies showed that a unique phenylalanine residue (Phe(167)) enables an additional molecular interaction between the TMDs of the syndecan-2 homodimer. The presence of Phe(167) was correlated with a higher tendency toward oligomerization, and its replacement with isoleucine significantly reduced the SDS-resistant dimer formation and cellular functions of syndecan-2 (e.g. cell migration). Conversely, replacement of isoleucine with phenylalanine at this position in the syndecan-4 TMD rescued the defects observed in a mutant syndecan-2 harboring the syndecan-4 TMD. Taken together, these data suggest that Phe(167) in the TMD of syndecan-2 endows the protein with specific functions. Our work offers new insights into the signaling mediated by the TMD of syndecan family members.

Filamin A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress cancer cell invasion and metastasis.

Identifying key mediators of cancer invasion and metastasis is crucial to the development of new and more effective therapies. We previously identified FILamin A Interacting Protein 1-Like (FILIP1L) as an important inhibitor of cell migration and invasion. FILIP1L expression was inversely correlated with the invasive potential of ovarian tumors. In our study, we established an orthotopic ovarian cancer model, wherein FILIP1L expression can be regulated in vivo. Using this model, we observed that expression of FILIP1L in ovarian cancer cells inhibited spontaneous lung metastasis. Experimental lung metastases (established via tail vein injection of cancer cells) as well as the extravasation step of metastasis were not inhibited by FILIP1L, suggesting that FILIP1L inhibits the earlier steps of metastasis such as invasion and intravasation. FILIP1L inhibited matrix metalloproteinase (MMP)-dependent invasion in vivo. MMP3, -7 and -9 were transcriptionally downregulated, and MMP9 protein expression and activity were inhibited in FILIP1L-expressing tumors. Importantly, overexpression of MMP9 compensated for the anti-invasive activity of FILIP1L. Furthermore, our studies suggest that FILIP1L regulates invasion and metastasis by inhibiting components of the WNT signaling pathway. FILIP1L expression reduced the induction of WNT target genes such as MMP3, -7 and -9, and ß-catenin-directed transcriptional activity, suggesting inhibition of the canonical WNT pathway. Nuclear ß-catenin, an indicator of an active canonical WNT pathway, was reduced in FILIP1L-expressing tumors. Overall, these findings suggest that FILIP1L reduces ß-catenin levels, which may lead to the transcriptional downregulation of WNT target genes such as MMPs, resulting in inhibition of metastasis. Modulation of FILIP1L expression has the potential to be a target for cancer therapy.

Interleukin-1α promotes extracellular shedding of syndecan-2 via induction of matrix metalloproteinase-7 expression.

The cell surface heparan sulfate proteoglycan, syndecan-2, is known to play an important role in the tumorigenic activity of colon cancer cells. In addition, the extracellular domain of syndecan-2 is cleaved by matrix metalloproteinase-7 (MMP-7) in various colon cancer cells, but factors involved in regulating this process remain unknown. Here, we demonstrate a role for interleukin-1α (IL-1α) in syndecan-2 shedding in colon cancer cells. Treatment of low metastatic (HT-29) and highly metastatic (HCT-116) colon cancer cells with various soluble growth factors and cytokines revealed that IL-1α specifically increased extracellular shedding of syndecan-2 in a concentration- and time-dependent manner. IL-1α did not affect the expression of syndecan-2, but did significantly reduce its cell surface levels. Notably, IL-1α increased the mRNA expression and subsequent secreted levels of MMP-7 protein and enhanced the phosphorylation of p38 and ERK mitogen-activated protein kinases. Furthermore, increased syndecan-2 shedding was dependent on the mitogen-activated protein kinase-mediated MMP-7 expression. Taken together, these data suggest that IL-1α regulates extracellular domain shedding of syndecan-2 through regulation of the MAP kinase-mediated MMP-7 expression in colon cancer cells.

The extracellular domain of syndecan-2 regulates the interaction of HCT116 human colon carcinoma cells with fibronectin.

The cell surface heparan sulfate proteoglycan, syndecan-2, is known to play an important role in the tumorigenic activity of colon cancer cells, but the function of its extracellular domain is not yet clear. Cell spreading assays showed that HCT116 human colon cancer cells attached and spread better on fibronectin compared to the other tested extracellular matrixes (ECMs). Notably, syndecan-2 overexpression enhanced the spreading of HCT116 cells on fibronectin, and the opposite effects were observed when syndecan-2 expression was reduced. In addition, an oligomerization-defective syndecan-2 mutant failed to increase cell-ECM interactions and adhesion-related syndecan-2 functions, including migration. Furthermore, analyses using a microfabricated post array detector system revealed that syndecan-2, but not the oligomerization-defective mutant, enhanced the interaction affinity of HCT116 cells on fibronectin. Taken together, these results suggest that the extracellular domain of syndecan-2 regulates the interaction of HCT116 human colon carcinoma cells with fibronectin.

Expanding roles of centrosome abnormalities in cancers.

Centrosome abnormalities are hallmarks of human cancers. Structural and numerical centrosome abnormalities correlate with tumor aggressiveness and poor prognosis, implicating that centrosome abnormalities could be a cause of tumorigenesis. Since Boveri made his pioneering recognition of the potential causal link between centrosome abnormalities and cancer more than a century ago, there has been significant progress in the field. Here, we review recent advances in the understanding of the causes and consequences of centrosome abnormalities and their connection to cancers. Centrosome abnormalities can drive the initiation and progression of cancers in multiple ways. For example, they can generate chromosome instability through abnormal mitosis, accelerating cancer genome evolution. Remarkably, it is becoming clear that the mechanisms by which centrosome abnormalities promote several steps of tumorigenesis are far beyond what Boveri had initially envisioned. We highlight various cancer-promoting mechanisms exerted by cells with centrosome abnormalities and how these cells possessing oncogenic potential can be monitored. [BMB Reports 2023; 56(4): 216-224].

European Committee on Antimicrobial Susceptibility Testing-Recommended Rapid Antimicrobial Susceptibility Testing of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus From Positive Blood Culture Bottles.

Background: Early diagnosis and treatment are important for a good prognosis of bloodstream infections. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommends rapid antimicrobial susceptibility testing (RAST) based on the disk diffusion methodology for 4, 6, and 8 hours of incubation. We evaluated EUCAST-RAST of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus from positive blood culture bottles. Methods: Twenty strains of E. coli, K. pneumoniae, and S. aureus were tested using EUCAST-RAST. Ten antimicrobial agents against E. coli and K. pneumoniae and four agents against S. aureus were tested. The diameter of the inhibition zone (mm) was compared with the minimal inhibitory concentration (µg/mL) obtained using the Sensititre AST system (TREK Diagnostic Systems, East Grinstead, UK). Results: For E. coli, the percentage of total categorical agreement (CA) was 69.5% at 4 hours, and 87% at 8 hours. For K. pneumoniae, the total CA was 89% at 4 hours, and 95.5% at 6 hours. For S. aureus, the total CA was 100% after 4 hours. Discrepancies were observed mainly for E. coli with ß-lactam antimicrobial agents, and the numbers of errors decreased over time. Conclusions: EUCAST-RAST for K. pneumoniae and S. aureus met the United States Food and Drug Administration criteria at 6 and 4 hours, respectively, whereas that for E. coli did not meet the criteria for up to 8 hours. RAST can shorten the turn-around testing time by more than one day; therefore, if applied accurately according to laboratory conditions, antimicrobial agent results can be reported faster.

Phylogenetic analysis of swine influenza A (H1N2) viruses isolated in Jinju City, Republic of Korea.

Genomic sequences of the swine influenza A (H1N2) viruses "A/Swine/South Korea/GN-1/2018" and "A/Swine/South Korea/GNJJ/2020" sampled from Jinju City, Republic of Korea, are reported here. The sequences of these viruses were 99% similar. These included eight genes from each of the H3N2pM, A(H1N1)2009pdm, and North American swine lineages.

Assessment of Equine Influenza Virus Status in the Republic of Korea from 2020 to 2022.

Equine influenza virus (EIV) causes acute respiratory disease in horses and belongs to the influenza A virus family Orthomyxoviridae, genus Orthomyxovirus. This virus may have severe financial implications for the horse industry owing to its highly contagious nature and rapid transmission. In the Republic of Korea, vaccination against EIV has been practiced with the active involvement of the Korea Racing Authority since 1974. In this study, we monitored the viral RNA for EIV using PCR, as well as the antibody levels against 'A/equine/South Africa/4/03 (H3N8, clade 1)', from 2020 to 2022. EIV was not detected using RT-PCR. The seropositivity rates detected using a hemagglutination inhibition assay were 90.3% in 2020, 96.7% in 2021, and 91.8% in 2022. The geometric mean of antibody titer (GMT) was 83.4 in 2020, 135.7 in 2021, and 95.6 in 2022. Yearlings and two-year-olds in training exhibited lower positive rates (59.1% in 2020, 38.9% in 2021, and 44.1% in 2022) than the average. These younger horses may require more attention for vaccination and vaccine responses against EIV. Continuous surveillance of EIV should be performed to monitor the prevalence and spread of this disease.

First Detection of Influenza D Virus Infection in Cattle and Pigs in the Republic of Korea.

Influenza D virus (IDV) belongs to the Orthomyxoviridae family, which also include the influenza A, B and C virus genera. IDV was first detected and isolated in 2011 in the United States from pigs with respiratory illness. IDV circulates in mammals, including pigs, cattle, camelids, horses and small ruminants. Despite the broad host range, cattle are thought to be the natural reservoir of IDV. This virus plays a role as a causative agent of the bovine respiratory disease complex (BRDC). IDV has been identified in North America, Europe, Asia and Africa. However, there has been no information on the presence of IDV in the Republic of Korea (ROK). In this study, we investigated the presence of viral RNA and seroprevalence to IDV among cattle and pigs in the ROK in 2022. Viral RNA was surveyed by the collection and testing of 999 cattle and 2391 pig nasal swabs and lung tissues using a real-time RT-PCR assay. IDV seroprevalence was investigated by testing 742 cattle and 1627 pig sera using a hemagglutination inhibition (HI) assay. The viral RNA positive rate was 1.4% in cattle, but no viral RNA was detected in pigs. Phylogenetic analysis of the hemagglutinin-esterase-fusion (HEF) gene was further conducted for a selection of samples. All sequences belonged to the D/Yamagata/2019 lineage. The seropositivity rates were 54.7% in cattle and 1.4% in pigs. The geometric mean of the antibody titer (GMT) was 68.3 in cattle and 48.5 in pigs. This is the first report on the detection of viral RNA and antibodies to IDV in the ROK.

A mitotic kinesin-6, Pav-KLP, mediates interdependent cortical reorganization and spindle dynamics in Drosophila embryos.

We investigated the role of Pav-KLP, a kinesin-6, in the coordination of spindle and cortical dynamics during mitosis in Drosophila embryos. In vitro, Pav-KLP behaves as a dimer. In vivo, it localizes to mitotic spindles and furrows. Inhibition of Pav-KLP causes defects in both spindle dynamics and furrow ingression, as well as causing changes in the distribution of actin and vesicles. Thus, Pav-KLP stabilizes the spindle by crosslinking interpolar microtubule bundles and contributes to actin furrow formation possibly by transporting membrane vesicles, actin and/or actin regulatory molecules along astral microtubules. Modeling suggests that furrow ingression during cellularization depends on: (1) a Pav-KLP-dependent force driving an initial slow stage of ingression; and (2) the subsequent Pav-KLP-driven transport of actin- and membrane-containing vesicles to the furrow during a fast stage of ingression. We hypothesize that Pav-KLP is a multifunctional mitotic motor that contributes both to bundling of interpolar microtubules, thus stabilizing the spindle, and to a biphasic mechanism of furrow ingression by pulling down the furrow and transporting vesicles that deliver new material to the descending furrow.

Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function.

Mps1, a dual-specificity kinase, is required for the proper functioning of the spindle assembly checkpoint and for the maintenance of chromosomal stability. As Mps1 function has been implicated in numerous phases of the cell cycle, the development of a potent, selective small-molecule inhibitor of Mps1 should facilitate dissection of Mps1-related biology. We describe the cellular effects and Mps1 cocrystal structures of new, selective small-molecule inhibitors of Mps1. Consistent with RNAi studies, chemical inhibition of Mps1 leads to defects in Mad1 and Mad2 establishment at unattached kinetochores, decreased Aurora B kinase activity, premature mitotic exit and gross aneuploidy, without any evidence of centrosome duplication defects. However, in U2OS cells having extra centrosomes (an abnormality found in some cancers), Mps1 inhibition increases the frequency of multipolar mitoses. Lastly, Mps1 inhibitor treatment resulted in a decrease in cancer cell viability.

Physical Activity, Sunshine Duration, and Osteoporotic Fractures: A Nested Case-Control Study.

This study examined the associations between the occurrence of osteoporotic fractures in detailed sites and combined physical activity (PA) and sunshine duration (SD). Data from the Korean National Health Insurance Service-National Health Screening Cohort for 7-year periods and from the Korea Meteorological Administration were used. Osteoporotic fractures (n = 12,103), including vertebral fractures, hip fractures, and distal radius fractures, and matched controls (n = 24,206) were selected in 1:2 ratios by age, sex, income, and region of residence. PA was classified as moderate- to high-intensity PA (High PA) and low-intensity PA (Low PA). SD was classified as Short SD (<6.1 h) and Long SD (≥6.1 h). Conditional logistic regression was used to calculate the odds ratios (ORs) with 95%-confidence intervals (CIs) of the combined PA and SD groups for the occurrence of each osteoporotic fracture. Compared to 'Low PA + Short SD', the adjusted ORs (95% CIs) for vertebral fracture in 'High PA + Short SD' and 'High PA + Long SD' were 0.83 (0.76-0.91) and 0.84 (0.77-0.92), respectively. Hip/distal radius fractures were not associated with the combined PA and SD group. We suggest that a higher intensity of PA is inversely associated with the risk of vertebral fracture.

Changes in the Mean of and Variance in Psychological Disease Incidences before and during the COVID-19 Pandemic in the Korean Adult Population.

The coronavirus disease 2019 (COVID-19) pandemic has been suggested to increase the risk of depression and anxiety disorders. This study expanded upon previous findings by estimating the changes in medical visits for various psychological disorders during the COVID-19 pandemic compared to before COVID-19. The entire Korean population ≥ 20 years old (~42.3 million) was included. The first COVID-19 case in Korea was reported on 20 January 2020. Thus, the period from January 2018 through to February 2020 was classified as "before COVID-19", and the period from March 2020 through to May 2021 was classified as "during COVID-19". Monthly medical visits due to the following 13 psychological disorders were evaluated: depressive disorder, bipolar disorder, primary insomnia, schizophrenia, panic disorder, hypochondriasis, posttraumatic stress disorder (PTSD), anxiety disorder, anorexia nervosa, addephagia, alcoholism, nicotine dependency, and gambling addiction were evaluated. The differences in the number of medical visits and the variance of diseases before and during the COVID-19 pandemic were analyzed using the Mann−Whitney U test and Levene's test. Subgroup analyses were conducted according to age and sex. The frequencies of medical visits for depressive disorder, bipolar disorder, primary insomnia, panic disorder, hypochondriasis, PTSD, anxiety disorder, anorexia nervosa, addephagia, and gambling addiction were higher during COVID-19 than before COVID-19 (all p < 0.001). However, the frequencies of medical visits for schizophrenia, alcoholism, and nicotine dependency were lower during the COVID-19 pandemic than before the COVID-19 pandemic (all p < 0.001). The psychological disorders with a higher frequency of medical visits during COVID-19 were consistent in all age and sex subgroups. In the old age group, the number of medical visits due to schizophrenia was also higher during COVID-19 than before COVID-19 (p < 0.001). Many psychological disorders, including depressive disorder, bipolar disorder, primary insomnia, panic disorder, hypochondriasis, PTSD, anxiety disorder, anorexia nervosa, addephagia, and gambling addiction, had a higher number of related medical visits, while disorders such as schizophrenia, alcoholism, and nicotine dependency had a lower number of related medical visits during COVID-19 among Korean adults.

Association between Proton Pump Inhibitor Use and Parkinson's Disease in a Korean Population.

Few studies have shown an increased risk of Parkinson's disease (PD) with the use of proton pump inhibitors (PPIs), and the pathophysiological mechanism for this association has not been unveiled. This study examined the relationship between PPI use and PD in a Korean population. We investigated 3026 PD patients and 12,104 controls who were matched by age, sex, income, and region of residence at a ratio of 1:4 in the Korean National Health Insurance Service, National Sample Cohort between 2002 and 2015. We estimated the associations between current and past use of PPIs and PD using odds ratios (ORs) and 95% confidence intervals (CIs) in a conditional/unconditional logistic regression after adjusting for probable confounders. Compared with PPI nonusers, both current users and past users had significantly greater odds of having PD, with ORs of 1.63 (95% CI = 1.44−1.84) and 1.12 (95% CI = 1.01−1.25), respectively. A significant association with PD was observed in individuals who used PPIs for 30−90 days and ≥90 days (OR = 1.26 and 1.64, 95% CI = 1.12−1.43 and 1.43−1.89) but not among those who used PPIs for <30 days. Both current and past use of PPIs associated with a higher probability of PD in the Korean population. Our study provides evidence regarding the association between PPI exposure and PD, but further investigation and possible explanations are warranted.

Physical Activity Is Associated with a Lower Risk of Osteoporotic Fractures in Osteoporosis: A Longitudinal Study.

The purpose of our study was to examine the occurrence of osteoporotic fractures (fxs) according to the level of physical activity (PA) among osteoporosis using the Korean National Health Insurance Service (NHIS) customized database. From NHIS data from 2009 to 2017, osteoporosis was selected as requested. PA was classified into 'high PA' (n = 58,620), 'moderate PA' (n = 58,620), and 'low PA' (n = 58,620) and were matched in a 1:1:1 ratio by gender, age, income within the household unit, and region of residence. A stratified Cox proportional hazard model was used to calculate hazard ratios (HRs) for each type of fx comparing PA groups. The 'low PA' group was the reference group. For vertebral fx, the adjusted HR (95% confidence intervals (CIs)) was 0.27 (0.26-0.28) for the 'high PA' group and 0.43 (0.42-0.44) for the 'moderate PA' group. For hip fx, the adjusted HR (95% CIs) was 0.37 (0.34-0.40) for the 'high PA' group and 0.51 (0.47-0.55) for the 'moderate PA' group. For distal radius fx, the adjusted HR (95% CIs) was 0.32 (0.30-0.33) for the 'high PA' group and 0.46 (0.45-0.48) for the 'moderate PA' group. The results of this study suggest that a higher intensity of PA is associated with a lower risk of osteoporotic fxs, including vertebral fx, hip fx, and distal radius fx.