Cysteinylprolyl ester-mediated drug release from a lipid-drug conjugate.

For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid-gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.

Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

Enhanced tumor specific drug release by hypoxia sensitive dual-prodrugs based on 2-nitroimidazole.

Hypoxia in cancer is important in the development of cancer-selective medicines. Here, a novel hypoxia-responsible dual-prodrug is described. We designed and synthesized 2-nitroimidazole derivatives which spontaneously release both a PYG inhibitor and gemcitabine under hypoxic conditions. One such derivative, a prodrug 9 was found to be stable against chemical and enzymatic hydrolysis, and upon chemical reduction of the nitro group on imidazole, successfully releases both drugs. In an in vitro proliferation assay using human pancreatic cells, compound 9 exhibited significant anti-proliferative effects in hypoxia but fewer effects in normoxia. Consequently, prodrug 9 should be useful for cancer treatment due to its improved cancer selectivity and potential to overcome drug resistance.

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of lumbar spinal stenosis, 2021 - Secondary publication.

BACKGROUND: The Japanese Orthopaedic Association (JOA) guideline for the management of lumbar spinal stenosis (LSS) was first published in 2011. Since then, the medical care system for LSS has changed and many new articles regarding the epidemiology and diagnostics of LSS, conservative treatments such as new pharmacotherapy and physical therapy, and surgical treatments including minimally invasive surgery have been published. In addition, various issues need to be examined, such as verification of patient-reported outcome measures, and the economic effect of revised medical management of patients with lumbar spinal disorders. Accordingly, in 2019 the JOA clinical guidelines committee decided to update the guideline and consequently established a formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline, incorporating the recent advances of evidence-based medicine. METHODS: The JOA LSS guideline formulation committee revised the previous guideline based on the method for preparing clinical guidelines in Japan proposed by the Medical Information Network Distribution Service in 2017. Background and clinical questions were determined followed by a literature search related to each question. Appropriate articles based on keywords were selected from all the searched literature. Using prepared structured abstracts, systematic reviews and meta-analyses were performed. The strength of evidence and recommendations for each clinical question was decided by the committee members. RESULTS: Eight background and 15 clinical questions were determined. Answers and explanations were described for the background questions. For each clinical question, the strength of evidence and the recommendation were both decided, and an explanation was provided. CONCLUSIONS: The 2021 clinical practice guideline for the management of LSS was completed according to the latest evidence-based medicine. We expect that this guideline will be useful for all medical providers as an index in daily medical care, as well as for patients with LSS.

Formulation of Japanese Orthopaedic Association (JOA) clinical practice guideline for the management of low back pain- the revised 2019 edition.

BACKGROUND: The latest clinical guidelines are mandatory for physicians to follow when practicing evidence-based medicine in the treatment of low back pain. Those guidelines should target not only Japanese board-certified orthopaedic surgeons, but also primary physicians, and they should be prepared based entirely on evidence-based medicine. The Japanese Orthopaedic Association Low Back Pain guideline committee decided to update the guideline and launched the formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline with the latest data of evidence-based medicine. METHODS: The Japanese Orthopaedic Association Low Back Pain guideline formulation committee revised the previous guideline based on a method for preparing clinical guidelines in Japan proposed by Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Two key phrases, "body of evidence" and "benefit and harm balance" were focused on in the revised version. Background and clinical questions were determined, followed by literature search related to each question. Appropriate articles were selected from all the searched literature. Structured abstracts were prepared, and then meta-analyses were performed. The strength of both the body of evidence and the recommendation was decided by the committee members. RESULTS: Nine background and nine clinical qvuestions were determined. For each clinical question, outcomes from the literature were collected and meta-analysis was performed. Answers and explanations were described for each clinical question, and the strength of the recommendation was decided. For background questions, the recommendations were described based on previous literature. CONCLUSIONS: The 2019 clinical practice guideline for the management of low back pain was completed according to the latest evidence-based medicine. We strongly hope that this guideline serves as a benchmark for all physicians, as well as patients, in the management of low back pain.

The impact of diabetes mellitus on spinal fracture with diffuse idiopathic skeletal hyperostosis: A multicenter retrospective study.

BACKGROUND: Patients with diffuse idiopathic skeletal hyperostosis (DISH) are susceptible to spinal column injuries with neurological deterioration. Previous studies indicated that the prevalence of diabetes mellitus (DM) in patients with DISH was higher than that in patients without DISH. This study investigates the impact of DM on surgical outcomes for spinal fractures in patients with DISH. METHODS: We retrospectively evaluated 177 spinal fractures in patients with DISH (132 men and 45 women; mean age, 75 ± 10 years) who underwent surgery from a multicenter database. The subjects were classified into two groups according to the presence of DM. Perioperative complications, neurological status by Frankel grade, mortality rate, and status of surgical site infection (SSI) were compared between the two groups. RESULTS: DM was present in 28.2% (50/177) of the patients. The proportion of men was significantly higher in the DM group (DM group: 86.0% vs. non-DM group: 70.1%) (p = 0.03). The overall complication rate was 22.0% in the DM group and 19.7% in the non-DM group (p = 0.60). Poisson regression model revealed that SSI was significantly associated with DM (DM group: 10.0% vs. non-DM group: 2.4%, Relative risk: 4.5) (p = 0.048). Change in neurological status, mortality rate, instrumentation failure, and nonunion were similar between both groups. HbA1c and fasting blood glucose level (SSI group: 7.2% ± 1.2%, 201 ± 67 mg/dL vs. non-SSI group: 6.6% ± 1.1%, 167 ± 47 mg/dL) tended to be higher in patients with SSI; however, there was no significant difference. CONCLUSIONS: In spinal fracture in patients with DISH, although DM was an associated factor for SSI with a relative risk of 4.5, DM did not negatively impact neurological recovery. Perioperative glycemic control may be useful for preventing SSI because fasting blood glucose level was high in patients with SSI.

OPN4 belongs to the photosensitive system of the human skin.

The human skin has previously been described to be affected by light; however, the underlying mechanism remains unknown. OPN4 (melanopsin) expression was first identified in the skin of amphibians; however, whether it is also expressed and functioned in the human skin has not yet been identified. Here, we show that OPN4 was expressed in the human skin tissue and cultures of isolated keratinocytes, melanocytes and fibroblasts. Additionally, Ca2+ influx in vitro and ex vivo and phosphorylation of extracellular signal-regulated kinases 1/2 in human fibroblasts were observed by stimulation of blue light irradiation. Notably, our findings showed that this Ca2+ influx and phosphorylation of extracellular signal-regulated kinases 1/2 are promoted in an intensity-dependent manner, indicating that the light signal is converted to an intracellular signal via OPN4 in the human skin. Overall, in this study we showed that the human skin functions as a photoreceptor by demonstrating that in human skin, the photoreceptive protein was expressed, and photoreception was conducted via photoreceptive protein.

Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD+ salvage pathway. Since NAD+ plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators. Early optimization of HTS hits afforded compound 12, with a triazolopyridine core, as a lead compound. CYP direct inhibition (DI) was identified as an issue of concern, and was resolved through modulation of lipophilicity to culminate in 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea (21), which showed potent NAMPT activity accompanied with attenuated CYP DI towards multiple CYP isoforms.

Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators.

NAD+ is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD+ have been linked to numerous diseases including metabolic disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD+ is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD+ salvage pathway. We previously showed that NAMPT activators increase NAD+ levels in vitro and in vivo. Herein we describe the optimization of our NAMPT activator prototype (SBI-0797812) leading to the identification of 1-(4-((4-chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea (34) that showed far more potent NAMPT activation and improved oral bioavailability.

Predictors for quality of life improvement after acute osteoporotic vertebral fracture: results of post hoc analysis of a prospective randomized study.

PURPOSE: No study has investigated the clinical and radiographic risk factors for the deterioration of quality of life (QOL) beyond 6 months after osteoporotic vertebral fractures (OVF). The purpose of this study was to identify the predictors associated with poor QOL improvement after OVF. METHODS: This post hoc analysis included 166 women aged 65-85 years with acute 1-level OVFs. For the patient-reported outcome measures, scores on the European Quality of Life-5 Dimensions (EQ-5D) scale, and visual analogue scale (VAS) for low back pain were used. Lateral radiography at 0, 12, and 48 weeks and magnetic resonance imaging (MRI) at enrollment and at 48 weeks were performed. The associations between baseline variables with change scores for EQ-5D were investigated using a multiple linear regression model. RESULTS: Univariate analysis showed that time since fracture, EQ-5D score, and VAS for low back pain at 0 week showed significant association with increased EQ-5D score from 0 to 48 weeks. According to the multiple regression analysis, the following equation was obtained: increased EQ-5D score from 0 to 48 weeks = 1.305 - 0.978 × EQ-5D at 0 week - 0.021 × VAS for low back pain at 0 week - 0.006 × age + (fluid-intensity T2-weighted MR image patterns: - 0.037, except for fluid-intensity T2-weighted MR image patterns: + 0.037). CONCLUSION: In conclusion, older patients with severe low back pain and fluid-intensity T2-weighted MR image patterns were more likely to have lower QOL improvements after OVFs and may therefore need extra support to improve QOL.

Risk factors for subsequent vertebral fracture after acute osteoporotic vertebral fractures.

PURPOSE: To investigate the incidence and characteristics of subsequent vertebral fracture after osteoporotic vertebral fractures (OVFs) and identify risk factors for subsequent vertebral fractures. METHODS: This post-hoc analysis from a prospective randomized multicenter trial included 225 patients with a 48-week follow-up period. Differences between the subsequent and non-subsequent fracture groups were analyzed. RESULTS: Of the 225 patients, 15 (6.7%) had a subsequent fracture during the 48-week follow-up. The annual incidence of subsequent vertebral fracture after fresh OVFs in women aged 65-85 years was 68.8 per 1000 person-years. Most patients (73.3%) experienced subsequent vertebral fractures within 6 months. At 48 weeks, European Quality of Life-5 Dimensions, the Japanese Orthopedic Association Back Pain Evaluation Questionnaire pain-related disorder, walking ability, social life function, and lumbar function scores were significantly lower, while the visual analog scale (VAS) for low back pain was higher in patients with subsequent fracture. Cox proportional hazards analysis showed that a VAS score ≥ 70 at 0 weeks was an independent predictor of subsequent vertebral fracture. After adjustment for history of previous fracture, there was a ~ 67% reduction in the risk of subsequent vertebral fracture at the rigid-brace treatment. CONCLUSION: Women with a fresh OVF were at higher risk for subsequent vertebral fracture within the next year. Severe low back pain and use of soft braces were associated with higher risk of subsequent vertebral fractures. Therefore, when treating patients after OVFs with these risk factors, more attention may be needed for the occurrence of subsequent vertebral fractures. LEVEL OF EVIDENCE: III.

Baseline severity of myelopathy predicts neurological outcomes after posterior decompression surgery for cervical spondylotic myelopathy: a retrospective study.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVES: To identify the usefulness of the baseline severity of myelopathy for predicting surgical outcomes for cervical spondylotic myelopathy (CSM). SETTING: Seventeen institutions in Japan. METHODS: This study included 675 persons with CSM who underwent posterior decompression. According to baseline severity, the individuals were divided into the mild (Japanese Orthopaedic Association [JOA] score ≥ 14.5), moderate (JOA score = 10.5-14), and severe (JOA score ≤ 10) groups. Surgical outcomes and clinical variables were compared between the groups. Logistic regression analysis was used to develop a prediction model for unsatisfactory symptom state (postoperative JOA score ≤ 14, residual moderate or severe myelopathy). RESULTS: The mean (±standard deviation) age was 67 ± 12 years. The participants in the severe group were older than those in the mild group. Postoperative JOA scores were higher in the mild group than in the severe group. According to multivariate logistic regression analysis, the prediction model included preoperative JOA scores (odds ratio [OR] 0.60; 95% confidence interval [CI] 0.55-0.67) and age (OR 1.06, 95% CI 1.04-1.08). On the basis of the model, a representative combination of the thresholds to maximize the value of "sensitivity - (1 - specificity)" demonstrated a preoperative JOA score of 11.5 as a predictor of postoperative unsatisfactory symptom state in people around the mean age of the study cohort (67 years). CONCLUSIONS: The combination of the baseline severity of myelopathy and age can predict postoperative symptom states after posterior decompression surgery for CSM.

Discovery of DS68702229 as a Potent, Orally Available NAMPT (Nicotinamide Phosphoribosyltransferase) Activator.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the nicotinamide adenine dinucleotide (NAD+) salvage pathway. Because NAD+ plays a pivotal role in energy metabolism and boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Herein we report the discovery of 1-(2-phenyl-1,3-benzoxazol-6-yl)-3-(pyridin-4-ylmethyl)urea 12c (DS68702229), which was identified as a potent NAMPT activator. Compound 12c activated NAMPT, increased cellular NAD+ levels, and exhibited an excellent pharmacokinetic profile in mice after oral administration. Oral administration of compound 12c to high-fat diet-induced obese mice decreased body weight. These observations indicate that compound 12c is a promising anti-obesity drug candidate.

Collagen profiling of ligamentum flavum in patients with lumbar spinal canal stenosis.

BACKGROUND: Although several causes of ligamentum flavum (LF) hypertrophy have been identified, the pathomechanisms underlying LF hypertrophy are not fully understood. Because collagen fibers are essential for the maintenance of LF tissues, characterization of the collagen composition of hypertrophied LF may help to elucidate the pathology of lumbar spinal canal stenosis (LCS). This study aimed to determine the association between the collagen composition and LF hypertrophy. METHODS: LF tissues were collected from 23 patients who underwent spinal decompression surgery for lumbar disorders. The cross-sectional area of LF was measured using the axial images of lumbar MRI. The expression of each collagen in human surgical samples was evaluated by real-time RT-PCR and immunohistochemical analysis. To investigate the impact of inflammatory cytokines on the expression of each collagen, we treated primary human LF cells with TNF-α or IL-1ß. RESULTS: Real-time RT-PCR analysis and immunohistochemistry showed that of the 28 types of collagen, collagen type I, III, V, VI, VIII were highly expressed regardless of LF hypertrophy. In addition, we found the moderate correlation between the cross-sectional area of LF and the mRNA expression level of collagen type I, III, and VI. In vitro analysis showed that the mRNA expression of collagen type I, III, V, VI, and VIII was up-regulated by treatment with TNF-α and with IL-1ß. CONCLUSION: Our results suggested that collagen type I, III, V, VI, and VIII were the main components of the LF extracellular matrix and that collagen type I, III, and VI may serve as useful markers of LF hypertrophy. These findings may contribute to the future development of diagnostic and treatment modalities for LF hypertrophy and even LCS.

Predictors of residual low back pain after acute osteoporotic compression fracture.

BACKGROUND: Studies on the clinical and radiographic risk factors for the residual low back pain beyond 6 months after osteoporotic vertebral fractures (OVFs) are lacking. Hence, this study aimed to characterize a patient population with residual low back pain 48 weeks after acute OVFs and to identify the risk factors associated with residual low back pain. METHODS: This prospective multicenter study included 166 female patients aged 65-85 years with acute one-level OVFs. We defined the residual low back pain as visual analog scale (VAS) for low back pain ≥3.5 at 48 weeks in this study, as VAS score ≥3.5 is used to describe moderate or severe pain. Thus, outcome and risk factor analyses were performed by comparing patients with VAS scores <3.5 and ≥ 3.5. In the radiographic analysis, the anterior vertebral body compression percentage was measured at 0, 12, and 48 weeks. Magnetic resonance imaging (MRI) was performed at enrollment and 48 weeks. RESULTS: Of the 166 patients analyzed, 58 complained of residual low back pain at 48 weeks after OVFs. At 0 weeks, the VAS score was significantly higher, and the JOABPEQ mental health score and anterior vertebral body compression percentage were significantly lower in patients with persistent pain 48 weeks after OVFs. The independent risk factors in the acute phase for persistent pain 48 weeks after OVFs were a high VAS score, MRI T2 fluid-intensity image pattern, and a lower anterior vertebral body compression percentage. CONCLUSIONS: Severe low back pain, MRI T2 fluid-intensity image pattern, and severe vertebral body collapse in the acute phase were significant risk factors for residual low back pain 48 weeks after OVFs. Patients with acute OVFs who have these risk factors should be carefully monitored for the possible development of residual chronic low back pain.

Risk factors for delayed diagnosis of spinal fracture associated with diffuse idiopathic skeletal hyperostosis: A nationwide multiinstitution survey.

BACKGROUND: Patients with DISH are susceptible to spinal fractures and subsequent neurological impairment, including after minor trauma. However, DISH is often asymptomatic and fractures may have minimal symptoms, which may lead to delayed diagnosis. The purpose of this study was to identify risk factors for delayed diagnosis of spinal fractures in patients with diffuse idiopathic skeletal hyperostosis (DISH). METHODS: The subjects were 285 patients with DISH surgically treated at 18 medical centers from 2005 to 2015. Cause of injury, imaging findings, neurological status at the times of injury and first hospital examination, and the time from injury to diagnosis were recorded. A delayed diagnosis was defined as that made >24 h after injury. RESULTS: Main causes of injury were minor trauma due to a fall from a standing or sitting position (51%) and high-energy trauma due to a fall from a high place (29%) or a traffic accident (12%). Delayed diagnosis occurred in 115 patients (40%; 35 females, 80 males; mean age 76.0 ± 10.4 years), while 170 (60%; 29 females, 141 males; mean age 74.6 ± 12.8 years) had early diagnosis. Delayed group had a significantly higher rate of minor trauma (n = 73, 63% vs. n = 73, 43%), significantly more Frankel grade E (intact neurological status) cases at the time of injury (n = 79, 69% vs. n = 73, 43%), and greater deterioration of Frankel grade from injury to diagnosis (34% vs. 8%, p < 0.01). In multivariate analysis, a minor trauma fall (OR 2.08; P < 0.05) and Frankel grade E at the time of injury (OR 2.29; P < 0.01) were significantly associated with delayed diagnosis. CONCLUSION: In patients with DISH, it is important to keep in mind the possibility of spinal fracture, even in a situation in which patient sustained only minor trauma and shows no neurological deficit. This is because delayed diagnosis of spinal fracture can cause subsequent neurological deterioration.

Mechanical and Immunological Regulation in Wound Healing and Skin Reconstruction.

In the past decade, a new frontier in scarless wound healing has arisen because of significant advances in the field of wound healing realised by incorporating emerging concepts from mechanobiology and immunology. The complete integumentary organ system (IOS) regeneration and scarless wound healing mechanism, which occurs in specific species, body sites and developmental stages, clearly shows that mechanical stress signals and immune responses play important roles in determining the wound healing mode. Advances in tissue engineering technology have led to the production of novel human skin equivalents and organoids that reproduce cell-cell interactions with tissue-scale tensional homeostasis, and enable us to evaluate skin tissue morphology, functionality, drug response and wound healing. This breakthrough in tissue engineering has the potential to accelerate the understanding of wound healing control mechanisms through complex mechanobiological and immunological interactions. In this review, we present an overview of recent studies of biomechanical and immunological wound healing and tissue remodelling mechanisms through comparisons of species- and developmental stage-dependent wound healing mechanisms. We also discuss the possibility of elucidating the control mechanism of wound healing involving mechanobiological and immunological interaction by using next-generation human skin equivalents.

Stereospecific Epitaxial Growth of Bilayered Porous Molecular Networks.

Stereocontrolled multilayer growth of supramolecular porous networks at the interface between graphite and a solution was investigated. For this study, we designed a chiral dehydrobenzo[12]annulene (DBA) building block bearing alkoxy chains substituted at the 2 position with hydroxy groups, which enable van der Waals stabilization in a layer and potential hydrogen-bonding interactions between the layers. Bias voltage-dependent scanning tunneling microscopy (STM) experiments revealed the diastereospecificity of the bilayer with respect to both the intrinsic chirality of the building blocks and the supramolecular chirality of the self-assembled networks. Top and bottom layers within the same crystalline domain were composed of the same enantiomers but displayed opposite supramolecular chiralities.

Requirement of zinc transporter ZIP10 for epidermal development: Implication of the ZIP10-p63 axis in epithelial homeostasis.

Skin tissues, in particular the epidermis, are severely affected by zinc deficiency. However, the zinc-mediated mechanisms that maintain the cells that form the epidermis have not been established. Here, we report that the zinc transporter ZIP10 is highly expressed in the outer root sheath of hair follicles and plays critical roles in epidermal development. We found that ZIP10 marked epidermal progenitor cell subsets and that ablating Zip10 caused significant epidermal hypoplasia accompanied by down-regulation of the transactivation of p63, a master regulator of epidermal progenitor cell proliferation and differentiation. Both ZIP10 and p63 are significantly increased during epidermal development, in which ZIP10-mediated zinc influx promotes p63 transactivation. Collectively, these results indicate that ZIP10 plays important roles in epidermal development via, at least in part, the ZIP10-zinc-p63 signaling axis, thereby highlighting the physiological significance of zinc regulation in the maintenance of skin epidermis.

Risk Factors for Postoperative Distal Adding-on in Lenke Type 1B and 1C and its Influence on Residual Lumbar Curve.

BACKGROUND: Distal adding-on (DA) in adolescent idiopathic scoliosis is a radiographic complication that can negatively affect clinical results. However, the risk factors for DA and the influences of DA on the residual lumbar curves have not been fully elucidated in Lenke type 1B and 1C curves. The objective of this study was to investigate risk factors for postoperative DA in Lenke type 1B and 1C curves, and the influence of DA on residual lumbar curves. METHODS: We retrospectively evaluated 46 adolescent idiopathic scoliosis patients with Lenke type 1B or 1C curves who underwent posterior correction and fusion surgery with selective thoracic fusion. Patients were grouped according to the presence or absence of DA on radiographs at the 2-year follow-up. We compared coronal radiographic parameters between the 2 groups, including the Cobb angle, L4 tilt angle, apical translation, and relative positions of the end vertebra (EV), stable vertebra (SV), neutral vertebra (NV), and last touching vertebra (LTV) to the lower instrumented vertebra (LIV). RESULTS: DA was present in 11 patients (24%) at the 2-year follow-up, and the mean LIV-EV, LIV-NV, LIV-SV, and LIV-LTV relative positions were significantly smaller in the DA than in the non-DA group. Preoperative radiographic parameters were similar between the 2 groups, including the mean L4 tilt angle (non-DA, -8±4 degrees; DA, -7±4 degrees). At the 2-year follow-up, the mean apical translation of the lumbar curve was smaller in the DA group (non-DA, -16±8 mm; DA, -7±11 mm) and the mean L4 tilt angle was significantly more horizontalized (non-DA, -8±4 degrees; DA, -1±5 degrees). Multivariate analysis showed that the number of levels between the LIV and LTV (LIV-LTV) was significantly associated with DA. CONCLUSIONS: A LIV at or cranial to the LTV was a significant risk factor for postoperative DA in Lenke type 1B and 1C curves. Spontaneous correction of the residual lumbar curve was superior in patients with DA. LEVEL OF EVIDENCE: Level III.