U-KIM-1 as a predictor of treatment response in lupus nephritis.

OBJECTIVE: Biomarkers of disease activity in lupus nephritis (LN) are in demand. This is because they may be useful in patients who are unable to undergo invasive kidney biopsy, as predictors of renal function, and for early detection of LN recurrence. The focus is on the measurement of urinary chemokines and cytokines, especially in urinary biomarkers, which are non-invasive and simple. In our previous report, we reported that kidney injury molecule-1 (KIM-1) is expressed in injured tubules and that the number of tubular-KIM-expressing positive cells correlates with renal pathology findings and also with urinary (u)-KIM-1 levels. However, there have been no reports examining the effect of u-KIM-1 levels on response to therapy, correlation with renal pathology, and usefulness as a predictor of renal function. METHODS: U-KIM-1 levels were measured by ELISA in 61 SLE patients. In 38 active LN who underwent renal biopsy, we also examined whether u-KIM-1 levels affected LN disease activity, renal histological findings, and predictors of renal function. RESULTS: In SLE patients, proteinuria and u-KIM-1 levels were elevated in active LN compared to inactive LN. U-KIM-1 and proteinuria decreased with intensified treatment. U-KIM-1 levels also correlated with the percentage of glomerular crescent formation in renal pathology. In addition, patients with higher baseline u-KIM-1 levels had significantly higher eGFR and lower LN disease activity at 12 months after treatment intensification. CONCLUSIONS: These data suggest that u-KIM-1 levels correlate with LN disease activity and renal histopathology findings and may be used as a predictor of treatment response.

Iguratimod versus salazosulfapyridine in rheumatoid arthritis patients with an inadequate response to methotrexate: Adjusted with propensity score matching.

OBJECTIVES: Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). METHODS: We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group). RESULTS: The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group's 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group's good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group's good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. CONCLUSIONS: IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up.

Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation.

The cyclic GMP-AMP synthase (cGAS)-cGAMP-STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGASCD-DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGASCD-DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS-DNA interface. We also report the crystal structure of the h-cGASCD-DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGASCD, thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site-binding inhibitors.

Design and synthesis of a monocyclic derivative as a selective ACC1 inhibitor by chemical modification of biphenyl ACC1/2 dual inhibitors.

A structure-activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of the linker in biaryl derivative 1 g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover novel phenoxybenzyloxy derivative 1i as a potent ACC1-selective inhibitor. Further chemical modification of this scaffold to improve cellular potency as well as physicochemical and pharmacokinetic (PK) properties produced N-2-(pyridin-2-ylethyl)acetamide derivative 1n, which showed highly potent ACC1-selective inhibition as well as sufficient PK profile for further in vivo evaluations. Oral administration of 1n significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of 100 mg/kg. Accordingly, our novel series of potent ACC1-selective inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid-related diseases.

Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response.

General control nonderepressible 2 (GCN2) plays a major role in the cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, the contribution of GCN2 to cancer cell survival and proliferation is poorly understood. In this study, we generated GCN2 inhibitors and demonstrated that inhibition of GCN2 sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the antileukemic agent l-asparaginase (ASNase) in vitro and in vivo. We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of ASNS, resulting in reduced levels of de novo protein synthesis. Comprehensive gene-expression profiling revealed that combined treatment with ASNase and GCN2 inhibitors induced the stress-activated MAPK pathway, thereby triggering apoptosis. By using cell-panel analyses, we also showed that acute myelogenous leukemia and pancreatic cancer cells were highly sensitive to the combined treatment. Notably, basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer.

Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.

Cancer cells reprogram their metabolism to support growth and to mitigate cellular stressors. The serine synthesis pathway has been identified as a metabolic pathway frequently altered in cancers and there has been considerable interest in developing pharmacological agents to target this pathway. Here, we report a series of indole amides that inhibit human 3-phosphoglycerate dehydrogenase (PHGDH), the enzyme that catalyzes the first committed step of the serine synthesis pathway. Using X-ray crystallography, we show that the indole amides bind the NAD+ pocket of PHGDH. Through structure-based optimization we were able to develop compounds with low nanomolar affinities for PHGDH in an enzymatic IC50 assay. In cellular assays, the most potent compounds inhibited de novo serine synthesis with low micromolar to sub-micromolar activities and these compounds successfully abrogated the proliferation of cancer cells in serine free media. The indole amide series reported here represent an important improvement over previously published PHGDH inhibitors as they are markedly more potent and their mechanism of action is better defined.

Association between the FGFR1 rs13317 single nucleotide polymorphism and orbitale-nasion depth based on cephalometric images.

The fibroblast growth factor receptor 1 (FGFR1) gene plays an important role in craniofacial morphogenesis. In our previous study, an association between FGFR1 single nucleotide polymorphisms (SNPs) and craniofacial morphology was demonstrated in Japanese and Korean subjects. The present study aimed to evaluate the relationship between a common FGFR1 SNP (rs13317) with craniofacial morphology, increasing the number of measurements and examining Egyptian subjects (n = 191) in addition to the Japanese (n = 211) and Korean (n = 226) subjects. Genotyping for rs13317 was performed using the TaqMan assay, and its associations with 81 craniofacial measurements derived from lateral and posteroanterior cephalograms were analyzed by multiple regression analysis controlling sex and facial size. The results from each of the populations were then statistically combined. In the Egyptian subjects, rs13317 was significantly associated with the nasion-orbitale depth (P = 0.00040), and a suggestive association was also observed in the Japanese (P = 0.037) and Korean subjects (P = 0.045). The combined analysis revealed that only the nasion-orbitale depth showed a significant association (P = 0.000062) and that several measurements showed a suggestive association. Our results strongly indicate that rs13317 is associated with a smaller depth between the nasion and orbitale, representing a relative protrusion of the cheekbones and retrusion of the nasal root. A similar characteristic is also observed in individuals with Pfeiffer syndrome, which is caused by a dysfunctional FGFR1 mutation.

In vivo optical interferometric imaging of human skin utilizing monochromatic light source.

We have demonstrated tomographic imaging of in vivo human skin with an optical interferometric imaging technique using a monochromatic light source. The axial resolution of this method is determined by the center wavelength and the NA of the objective and is irrelevant to the bandwidth of the light source in contrast to optical coherence tomography. Our imaging system is constructed with low-priced and small-sized compact disk optical pickup components, a laser diode, a high NA objective, and a voice coil actuator. In spite of its low cost and small size, our imaging system can visualize the structure of human skin as clearly as a commercial reflectance confocal microscope.

A Case of Direct-Acting Oral Anticoagulant-Induced Intramural Colon Hematoma Successfully Treated by Laparoscopic Surgery.

Intramural intestinal hematoma is a rare disease, one of the triggering factors of which is the use of anticoagulants. In previous reports, most patients were on treatment with warfarin. Herein, we report a case of direct-acting oral anticoagulant (DOAC)-induced intramural hematoma of the ascending colon in a patient refractory to conservative treatment and required laparoscopic right hemicolectomy. An 80-year-old male patient with a history of atrial fibrillation and cerebral infarction, on treatment with apixaban, was brought to our hospital with the chief complaints of abdominal pain, vomiting, and melena. Imaging revealed the cause of symptoms to be intestinal obstruction caused by a mass lesion on the wall of the ascending colon. We initially opted for conservative treatment with discontinuation of apixaban and insertion of an ileus tube. Intestinal dilatation findings showed improvement; however, subsequent imaging examinations did not reveal the shrinkage of a lesion in the ascending colon. If the mass was not removed, recurrence of bowel obstruction symptoms was expected, so we decided to perform surgical intervention. A laparoscopic right hemicolectomy was performed, and an intramural hematoma of the ascending colon was diagnosed based on the excised specimen. He needed a blood transfusion for anemia but was discharged on postoperative day 14 with no other complications. DOACs are now widely used in patients with atrial fibrillation, and the risk of bleeding as a side effect is extremely low compared to conventional anticoagulants, including warfarin. However, when abdominal pain occurs, as in the present case, an intramural hematoma should be considered in the differential diagnosis. There is no established treatment plan for intestinal intramural hematoma. Although conservative treatment is effective in some cases, it is difficult to evaluate the risk of bleeding associated with DOACs using coagulation tests. Even if conservative treatment is selected, it is essential to determine surgical resection, if necessary, based on the clinical course and imaging and blood test findings.

Pancreatitis After Treatment With Encorafenib, Binimetinib, and Cetuximab for BRAF V600E Mutation-Positive Colorectal Cancer.

BRAF V600E mutation-positive advanced recurrent colorectal cancer has a poor prognosis. Encorafenib, binimetinib, and cetuximab were approved for use to treat this cancer in 2020 in Japan. Here, we present the case of a patient with BRAF V600E mutation-positive colorectal cancer, who was treated with encorafenib, binimetinib, and cetuximab, and developed grade 3 pancreatitis at our hospital. After pancreatitis treatment, the drug doses were reduced from 300 mg to 225 mg of encorafenib and from 90 mg to 60 mg of binimetinib, and the treatment was resumed. Since then, no grade 3 or higher adverse events were observed. Although pancreatitis has been reported to occur after the use of encorafenib and binimetinib, it is rare. With appropriate dose reduction and attention to side effects, this regimen is considered feasible for the long-term treatment of BRAF V600E mutation-positive advanced recurrent colorectal cancer in patients aged >70 years.

Internal Hernia Through a Mesenteric Defect Following Esophagectomy and Reconstruction With a Stomach-Preserved Ileocolic Interposition.

Esophagectomy is the standard treatment for esophageal cancer and often involves the stomach as a substitute organ for esophageal reconstruction. However, we actively perform stomach-preserved ileocolic interposition because of its advantages in gastrointestinal function and the prevention of reflux esophagitis. Despite its benefits, few facilities perform esophageal reconstruction with ileocolic interposition; hence, postoperative complications following this procedure have rarely been reported. We present the first case of internal hernia through a mesenteric defect following esophagectomy and reconstruction with a stomach-preserved ileocolic interposition. This type of internal hernia after esophageal cancer surgery is a rare complication following a common gastric pull-up reconstruction. A 66-year-old Japanese female underwent esophagectomy and reconstruction with stomach-preserved ileocolic interposition for stage I esophageal cancer. One month after surgery, the patient experienced abdominal pain and vomiting. CT showed a dilated small bowel and a suspected postoperative adhesive bowel obstruction. Despite conservative management, the patient experienced recurrent episodes that required hospitalization. Although an exact preoperative diagnosis was not made, we decided on a surgical exploration six months after the first symptoms appeared. Laparotomy revealed an internal herniation through a mesenteric defect between the transverse mesocolon and the ileum mesentery following ileocolic interposition. We then repositioned the fitted small intestine and closed the mesenteric defects. The patient recovered uneventfully without a hernia recurrence. Minimally invasive techniques for treating esophageal cancer are becoming more common. As survival rates improve, the number of internal hernia cases, such as those described in this report, will likely increase. Therefore, more cases are needed to determine whether closing mesenteric defects can effectively prevent herniation. However, immediate surgical treatment should be considered based on the symptoms, even when a preoperative diagnosis is difficult.

Laparoscopic Surgery for Sigmoid Colon Cancer in a Patient With a History of Two Renal Transplantations and Peritoneal Dialysis.

The development of transplantation technology has improved the prognosis of transplantation surgery; however, the negative impact of immunosuppressive drugs has increased the number of patients with cancer after transplantation. Recently, minimally invasive surgery has become more common for cancer treatment. We report our experience of performing laparoscopic sigmoid colon resection for a patient with a history of two renal transplantations and peritoneal dialysis. A 42-year-old male patient who developed purpura nephropathy underwent renal transplantation at ages eight and 34 years. He had been on peritoneal dialysis for five years before the second transplantation. The patient was referred to our department with the chief complaint of sudden abdominal pain. After an examination of imaging, we obtained a diagnosis of sigmoid colon cancer. Despite a history of peritoneal dialysis, laparoscopic sigmoid colon resection was successfully performed without complications after confirming that there were no adhesions in the abdominal cavity. The left lower port position had to be adjusted because the transplanted kidney protruded into the left iliac fossa. No postoperative complications and graft loss occurred. In this case, laparoscopic surgery was effective in lowering the risk of damage to the transplanted kidney and safely performing the procedure. The number of colorectal cancer cases in renal transplant patients is expected to increase, and some of these patients will have a history of peritoneal dialysis, which may make surgery more difficult. The successful outcome of this case highlights that laparoscopic surgery could be viable for patients with such a complex medical history.

Maxillary Protrusion with Severe Overjet Treated by Maxillary Anterior Alveolar Osteotomy.

In addition to affecting oral functions such as temporomandibular joint function, mastication, and speech, malocclusion caused by skeletal maxillary prognathism also entails sociopsychological implications. Surgical orthodontic treatment to improve occlusion and oral function and to correct esthetic disharmony is important to improve patients' quality of life. We report the case of a 32-year-old woman who visited our hospital with a chief complaint of proclined upper front teeth. Clinical examination revealed maxillary overgrowth and severe labial inclination of the maxillary incisors with palatal gingival recession. The incisal protrusion was corrected with a maxillary anterior alveolar osteotomy-a surgical orthodontic method that could improve the overbite without causing excessive lingual inclination, while also minimizing orthodontic movement of the maxillary anterior teeth. This treatment is generally indicated in cases of maxillary prognathism with a relatively stable occlusal relationship in the molar region. As a result of the treatment, the patient's chief complaint improved and a long-term functional occlusion was achieved. This paper outlines the pre- and posttreatment skeletal and occlusal changes.

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors.

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound 5). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound 21), a novel, highly potent, and peripherally active EZH2 inhibitor based on a 7 member ring structure.

Maxillary movement in distraction osteogenesis using internal devices in cleft palate patients.

OBJECTIVE: The purpose of this cephalometric study was to compare the actual movement with the planned movement of the maxilla by using internal maxillary distraction in cleft lip and palate patients. PATIENTS: Twelve patients, including eight with unilateral and four with bilateral cleft lip and palate, underwent maxillary advancement with internal maxillary distractors. MAIN OUTCOME MEASURES: Lateral cephalometric radiographs obtained preoperatively, predistraction, and postdistraction were used for analysis. The movement of the maxilla, angular change of the internal devices and rotation of the mandible were measured at each stage, and the planned vector of advancement predicted from the placement vector of the distractors was compared with the actual vector. RESULTS: Internal maxillary distractors were rotated in a clockwise direction during the distraction period. The angular change of the distractors was 7.7°. The amount of actual advancement at anterior nasal spine with distraction was 6.3 mm, which represented about 70% of the distance of activation of distraction. The actual advanced vector at anterior nasal spine was 9.7° smaller than the planned vector. The mandible underwent a clockwise rotation of 3.5°. CONCLUSION: In the internal distraction technique, the maxilla was advanced inferiorly to the planned vector and with a slight clockwise rotation. These results are useful for surgical planning when using internal distractors.

Intestinal intussusception and progressive anemia due to pyogenic granuloma of the ileum: a case report.

BACKGROUND: Pyogenic granuloma is a benign vascular tumor, usually occurring on the skin or in the oral cavity. Small intestinal pyogenic granuloma is extremely rare, but intestinal intussusception due to the tumor is even rarer. Only 3 cases have been reported in the English literature at this writing. CASE PRESENTATION: An 86-year-old woman presented with abdominal pain and vomiting. Laboratory data discovered anemia. Contrast-enhanced computed tomography revealed small bowel obstruction due to intestinal intussusception. After decompression by long tube for 1 week, the obstruction did not improve and the anemia got worse. Therefore, laparoscopic assisted small bowel resection was performed as a diagnostic therapy. Pathology confirmed the diagnosis of pyogenic granuloma. The postoperative course was uneventful and the patient was discharged 10 days after surgery. CONCLUSIONS: We experienced a case of intestinal intussusception and progressive anemia due to pyogenic granuloma of the ileum. Although the condition is extremely rare, surgeons must take into consideration the tumor in similar cases, and complete surgical resection is required.

[Observing the time course of early long pyramidal tract Wallerian degeneration after acute ischemic stroke: a case report].

A 75-year-old man was found lying prostrate in a hot room in the middle of summer. On admission, he had high fever, dehydration, and multiple decubitus, in addition to right hemiparesis and total aphasia. Brain CT showed subacute ischemic stroke in the territory of left middle cerebral artery. Brain MRI diffusion-weighted imaging (DWI) 4 days after admission detected high signal intensity lesions in the left pyramidal tract from the midbrain cerebral peduncle to the lower pons, indicating early Wallerian degeneration. The lesions were found to extend to the contralateral pyramidal decussation by MRI DWI day 12, but they had disappeared on day 28. On the other hand, brain MRI FLAIR images detected the lesions clearly day 44. Also, diffusion tensor tractography detects fewer left cerebral pyramidal tracts. No previous reports have documented the time course of such long Wallerian degeneration. This case suggests that dehydration may promote the onset of early and long Wallerian degeneration.

Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still's Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults.

Background: Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the 'cytokine storm' such as adult-onset Still's disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group). Patients and Methods: We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group. Results: Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and 'arthralgia or arthritis' are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83-1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data. Conclusions: IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

Real-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizumab Pegol With Rheumatoid Arthritis.

Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated-conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF. Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25-83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1- <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate. Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage. Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.

Three-dimensional assessment of the pharyngeal airway in Japanese preschoolers with orofacial clefts.

OBJECTIVES/HYPOTHESIS: Individuals with orofacial clefts often experience respiratory problems because of nasopharyngeal abnormalities. Pharyngeal airway morphology is thought to differ among the various cleft types. We measured three-dimensional (3D) airway volume using cone-beam computed tomography (CBCT) analysis to evaluate and compare pharyngeal airways in Japanese preschoolers with and without orofacial clefts. STUDY DESIGN: Retrospective case-control study. METHODS: We enrolled 83 subjects (37 boys, 46 girls; mean age = 4.66 ± 0.56 years) with nonsyndromic orofacial clefts and 16 noncleft healthy subjects (seven boys, nine girls; mean age = 5.30 ± 0.52 years) as controls. The subjects were divided into five groups. Four groups were based on the cleft type: isolated cleft palate, unilateral cleft lip and alveolus), unilateral cleft lip and palate, and bilateral cleft lip and palate. The fifth group included the noncleft controls. All subjects were examined with CBCT, and the 3D airway volume was measured. We analyzed group differences statistically using analysis of covariance with the Bonferroni post hoc pairwise comparison tests for the corrected means. RESULTS: Compared with the noncleft group, each cleft group exhibited significantly decreased total and nasal airway volumes and increased superior and inferior pharyngeal airway volumes. The differences were all statistically significant. CONCLUSIONS: Our findings suggest that anatomical differences exist in pharyngeal airway volumes among various cleft groups and in those without a cleft. LEVEL OF EVIDENCE: 3b Laryngoscope, 130:533-540, 2020.