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Background Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and is gradually spreading worldwide. We assessed the effect of thyroid-stimulating hormone (TSH) levels on PTMC enlargement in patients on AS. Methods We enrolled 2705 patients with cytologically diagnosed PTMC who had undergone AS between January 2005 and July 2019. Patients with Graves disease were excluded. The median AS period was 5.5 years (range 1.0–15.7 years). Tumor enlargement was defined as a size increase ≥3 mm. Chi-square test, Kaplan–Meier method, log-rank test, Cox proportional hazard, and logistic regression were used to compare variables. Results Ninety-two patients (3.4%) experienced tumor enlargement; the 5-, 10-, and 15-year enlargement rates were 3.0%, 5.5%, and 6.2%, respectively. Young age (<40 years, p  < 0.001), large tumor size (≥9 mm, p  = 0.017), and high detailed TSH score (≥3, higher than the lower normal limit, p  = 0.011) were significant factors relating to tumor enlargement in the multivariate analysis. In a subset of patients aged <40 years, a low detailed TSH score (<3) was an independent factor against tumor enlargement ( p  = 0.039). Only 22 patients (0.8%) experienced novel lymph node metastasis; the 5-, 10-, and 15-year node metastasis rates were very low, at 0.9%, 1.1%, and 1.1%, respectively. Conclusions Young patients with PTMC are more likely to experience tumor growth. Mild TSH suppression to achieve a low normal range may prevent carcinoma enlargement; however, prospective studies are needed to draw more reliable conclusions.

Background Acute suppurative thyroiditis through the congenital pyriform sinus fistula (PSF) often recurs if the fistula is not resected. Although endoscopic chemo-cauterization (ECC) to obliterate the orifice of the fistula is less invasive than open fistulectomy, it may require repeated treatments. We recently adopted an endoscopic diode laser-cauterization (ELC) system with the intention of improving treatment outcomes in PSF. Here, we describe ELC and compare the outcomes of these three modalities. Methods We evaluated 83 patients with PSF who underwent treatment between 2007 and 2018 at Kuma Hospital, a tertiary thyroid treatment hospital. ECC and ELC were implemented in 2007 and 2015, respectively. Patients who were ineligible for the endoscopic procedures underwent open fistulectomy. Barium swallow studies and computed tomography scan under a trumpet maneuver were performed after treatment to evaluate obliteration or removal of the fistula. Results In total, 70 of the 81 (86%) patients who underwent barium swallow studies after the first treatment achieved obliteration or removal of the fistula. The success rates for open fistulectomy, ECC, and ELC were 100% (9/9), 83% (49/59), and 100% (13/13), respectively. ECC and ELC had significantly shorter operative times and lower blood loss than open fistulectomy. Insufficient opening of the mouth was the major reason for converting endoscopic procedures to open fistulectomy. Conclusions ELC may yield superior outcomes and is therefore the optimal treatment modality for PSF. However, it is still associated with certain limitations. Thus, treatment selection remains dependent on the shape and size of the PSF and the mouth opening of the individual patient. Graphical Abstract

Children often experience impalement trauma when they fall while holding objects in their mouths. While most cases heal without complications, here we report a case of buccal abscess formation after toothbrush trauma. A two-year-old boy fell while running with a toothbrush in his mouth, which punctured his right buccal mucosa. The following day, he presented to a pediatrician with a fever and buccal swelling and was treated with oral antibiotics. However, the buccal swelling did not improve, and the patient was referred to our department. Four days after the visit, the buccal swelling and fever worsened, requiring hospitalization, intravenous antibiotics, and drainage. The inflammation quickly disappeared following treatment, with no recurrence. Prophylactic antibiotic administration for oral impalement trauma is controversial. Our results suggest that prophylactic antibiotics covering both anaerobic and aerobic bacteria are necessary in cases of toothbrush-related oral trauma, where multiple bacterial infections may occur.

The class 2 type V CRISPR effector Cas12 is thought to have evolved from the IS200/IS605 superfamily of transposon-associated TnpB proteins 1 . Recent studies have identified TnpB proteins as miniature RNA-guided DNA endonucleases 2 , 3 . TnpB associates with a single, long RNA (ωRNA) and cleaves double-stranded DNA targets complementary to the ωRNA guide. However, the RNA-guided DNA cleavage mechanism of TnpB and its evolutionary relationship with Cas12 enzymes remain unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of Deinococcus radiodurans ISDra2 TnpB in complex with its cognate ωRNA and target DNA. In the structure, the ωRNA adopts an unexpected architecture and forms a pseudoknot, which is conserved among all guide RNAs of Cas12 enzymes. Furthermore, the structure, along with our functional analysis, reveals how the compact TnpB recognizes the ωRNA and cleaves target DNA complementary to the guide. A structural comparison of TnpB with Cas12 enzymes suggests that CRISPR–Cas12 effectors acquired an ability to recognize the protospacer-adjacent motif-distal end of the guide RNA–target DNA heteroduplex, by either asymmetric dimer formation or diverse REC2 insertions, enabling engagement in CRISPR–Cas adaptive immunity. Collectively, our findings provide mechanistic insights into TnpB function and advance our understanding of the evolution from transposon-encoded TnpB proteins to CRISPR–Cas12 effectors. Cryo-electron microscopy analysis of the Deinococcus radiodurans ISDra2 TnpB in complex with its cognate ωRNA and target DNA provides insights into the mechanism of TnpB function and the evolution of CRISPR–Cas12 effectors.

Background The airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens. Methods BEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated. Results The amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin. Conclusions The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

Purpose Incorporation of patient-generated health data (PGHD) into clinical research requires an investigation of the validity of outcomes and feasibility of implementation. This single-arm pilot trial investigated the feasibility of using a commercially available activity tracking wearable device in cancer patients to assess adherence to the device and real-time PGHD collection in a clinical research setting. Methods From July to November 2017, enrolled adult patients were asked to wear a wristband-style device. Brief Fatigue Inventory (BFI) and MD Anderson Symptom Inventory (MDASI) were assessed at baseline and on day 29. Furthermore, 29-day Pittsburgh Sleep Quality Index, global impression of the devices, and NCI CTCAE v4 were evaluated. Results Of 30 patients (mean age, 58.6 years; male, 21 [70%]), 15 (50%) and 11 (36.7%) had gastrointestinal and lung cancer, respectively, and 27 (90%, 95% CI: 0.74–0.98) were well adhered (> 70%) to the device for 28 days. The mean adherence was 84.9% (range: 41.7–95.2%). More frequent PGHD synchronization tended to show better device adherence, with moderate correlation ( r  = 0.62, 95% CI: 0.33–0.80, p  < 000.1). Conclusions The feasibility of using a wearable activity tracker was confirmed in cancer patients receiving chemotherapy for a month. For future implementation in clinical trials, there is a need for further comprehensive assessment of the validity and reliability of wearable activity trackers. Trial registration This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN: UMIN000027575.

Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease. The physiological roles of supersulphides and the enzymes that trigger their production in various airway diseases are not fully understood. Here, the authors show in animal models of viral and chronic lung diseases that supersulphide production can mitigate lung pathology and lethal effects, highlighting their protective role and potential as a therapeutic target.

The Fukushima Daiichi Nuclear Power Plant (FNPP) accident released large amounts of radioactive substances into the environment. In order to provide basic information for biokinetics of radionuclides and for dose assessment of internal exposure brought by the FNPP accident, we determined the activity concentration of radionuclides in the organs of 79 cattle within a 20-km radius around the FNPP. In all the specimens examined, deposition of Cesium-134 ((134)Cs, half-life: 2.065 y) and (137)Cs (30.07 y) was observed. Furthermore, organ-specific deposition of radionuclides with relatively short half-lives was detected, such as silver-110m ((110m)Ag, 249.8 d) in the liver and tellurium-129m ((129m)Te, 33.6 d) in the kidney. Regression analysis showed a linear correlation between the radiocesium activity concentration in whole peripheral blood (PB) and that in each organ. The resulting slopes were organ dependent with the maximum value of 21.3 being obtained for skeletal muscles (R(2) = 0.83, standard error (SE) = 0.76). Thus, the activity concentration of (134) Cs and (137)Cs in an organ can be estimated from that in PB. The level of radioactive cesium in the organs of fetus and infants were 1.19-fold (R(2) = 0.62, SE = 0.12), and 1.51-fold (R(2) = 0.70, SE = 0.09) higher than that of the corresponding maternal organ, respectively. Furthermore, radiocesium activity concentration in organs was found to be dependent on the feeding conditions and the geographic location of the cattle. This study is the first to reveal the detailed systemic distribution of radionuclides in cattle attributed to the FNPP accident.

Increased lipid utilization after food odor perception is a recently identified Pavlovian cephalic phase response in fasted mice that serves to prevent diet-induced glucose intolerance. However, the impact of olfactory dysfunction on metabolic functions remains unclear. Since olfactory bulbectomized (OBX) rodents have been used as a model of irreversible complete anosmia, we investigated whether glucose, lipid, and energy metabolism change over time in OBX mice fed a normal chow diet (NCD) or high-fat diet (HFD). OBX caused constant hyperactivity and triphasic temporal changes in lipid and glucose metabolism. In the early stage, OBX disrupted the olfactory regulation of lipid utilization and reduced fasting serum fatty acid levels without affecting glucose tolerance. In the middle stage (10–40 weeks after OBX on NCD; 5–10 weeks after OBX on HFD), OBX mice showed a mild reduction in body weight gain and improved glucose tolerance. In the later stage, glucose tolerance did not improve in NCD-fed OBX mice, while glucose tolerance was impaired and the expression of hepatic genes related to lipid metabolism was abnormal in HFD-fed OBX mice. In the absence of orexin, which regulates the brain-liver network, HFD-fed OBX mice showed an improvement in, but not the subsequent impairment of glucose tolerance. These results suggest that OBX rapidly impairs lipid metabolism, which gradually exacerbates glucose metabolism, whereas the associated hyperactivity contributes to improvements in glucose metabolism. Therefore, the olfactory bulb plays an essential role in the maintenance of lipid and glucose homeostasis.