Predictive role of FRAX© for postoperative proximal junctional kyphosis with vertebral fracture after adult spinal deformity surgery.

PURPOSE: To identify risk factors, including FRAX (a tool for assessing osteoporosis) scores, for development of proximal junctional kyphosis (PJK), defined as Type 2 in the Yagi-Boachie classification (bone failure), with vertebral fracture (VF) after surgery for symptomatic adult spinal deformity. METHODS: This was a retrospective, single institution study of 127 adults who had undergone corrective long spinal fusion of six or more spinal segments for spinal deformity and been followed up for at least 2 years. The main outcome was postoperative development of PJK with VF. Possible predictors of this outcome studied included age at surgery, BMI, selected radiographic measurements, bone mineral density, and 10-year probability of major osteoporotic fracture (MOF) as determined by FRAX. We also analyzed use of medications for osteoporosis. Associations between the selected variables and PJK with VF were assessed by the Mann-Whitney, Fishers exact, and Wilcoxon signed-rank tests, and Kaplan-Meier analysis, as indicated. RESULTS: Forty patients (31.5%) developed PJK with VF postoperatively,73% of them within 6 months of surgery. Statistical analysis of the selected variables found that only a preoperative estimate by FRAX of a > 15% risk of MOF within 10 years, pelvic tilt > 30° at first standing postoperatively and lower instrumented level (fusion terminating at the pelvis) were significantly associated with development of PJK with VF. CONCLUSION: Preoperative assessment of severity of osteoporosis using FRAX provides an accurate estimate of risk of postoperative PJK with VF after surgery for adult spinal deformity.

Efficacy and safety of Janus kinase inhibitors in patients with difficult-to-treat rheumatoid arthritis.

OBJECTIVES: This study evaluated the effectiveness of Janus kinase inhibitors (JAKi) in patients with difficult-to-treat rheumatoid arthritis (D2T RA). METHODS: This study included 220 patients with RA who were treated with JAKi. Sixty-two patients were naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs)/JAKi (1st group), 57 patients were failure to one bDMARDs/JAKi (2nd group), and 101 patients were failure to ≥ 2 bDMARDs/JAKi. Of these 101 patients, 25 did not meet the D2T RA criteria (non-D2T RA group) and 76 met the D2T RA criteria (D2T RA group). RESULTS: : DAS28-ESR was improved in all groups at 24 weeks (1st: p<0.01, 2nd: p<0.01, non-D2T RA: p=0.01, D2TRA: p=0.02), and improvement ratio of DAS28-ESR was not different between DT2RA group and 2nd (p=0.73) or non-D2T RA group (p=0.68). Glucocorticoid use (odds ratios: 8.67; 95% CI: 1.23-60.90; P=0.03) and number of past bDMARD/JAKi uses ≥ 3 (odds ratios: 10.55; 95% CI: 1.39-80.30; P=0.02) were risk factors for DAS28-ESR ≥ 3.2 at 24 weeks in the D2T RA group. CONCLUSIONS: Clinical efficacy of JAKi in D2T RA group did not differ from that in 2nd and non-D2T RA groups. Glucocorticoid use and multiple bDMARD/JAKi failure were poor prognostic factors for D2T RA.

The role of ROC75 as a daytime component of the circadian oscillator in Chlamydomonas reinhardtii.

The circadian clocks in chlorophyte algae have been studied in two model organisms, Chlamydomonas reinhardtii and Ostreococcus tauri. These studies revealed that the chlorophyte clocks include some genes that are homologous to those of the angiosperm circadian clock. However, the genetic network architectures of the chlorophyte clocks are largely unknown, especially in C. reinhardtii. In this study, using C. reinhardtii as a model, we characterized RHYTHM OF CHLOROPLAST (ROC) 75, a clock gene encoding a putative GARP DNA-binding transcription factor similar to the clock proteins LUX ARRHYTHMO (LUX, also called PHYTOCLOCK 1 [PCL1]) and BROTHER OF LUX ARRHYTHMO (BOA, also called NOX) of the angiosperm Arabidopsis thaliana. We observed that ROC75 is a day/subjective day-phase-expressed nuclear-localized protein that associates with some night-phased clock genes and represses their expression. This repression may be essential for the gating of reaccumulation of the other clock-related GARP protein, ROC15, after its light-dependent degradation. The restoration of ROC75 function in an arrhythmic roc75 mutant under constant darkness leads to the resumption of circadian oscillation from the subjective dawn, suggesting that the ROC75 restoration acts as a morning cue for the C. reinhardtii clock. Our study reveals a part of the genetic network of C. reinhardtii clock that could be considerably different from that of A. thaliana.

Rhythmic adenosine triphosphate release from the cyanobacterial circadian clock protein KaiC revealed by real-time monitoring of bioluminescence using firefly luciferase.

The cyanobacterial circadian clock is composed of three clock proteins, KaiA, KaiB and KaiC. This KaiABC clock system can be reconstituted in vitro in the presence of adenosine triphosphate (ATP) and Mg2+ , and shows circadian rhythms in the phosphorylation level and ATPase activity of KaiC. Previously, we found that ATP regulates a complex formation between KaiB and KaiC, and KaiC releases ATP from KaiC itself (PLoS One, 8, 2013, e80200). In this study, we examined whether the ATP release from KaiC shows any rhythms in vitro. We monitored the release of ATP from wild-type and ATPase motif mutants of KaiC as a bioluminescence in real time using a firefly luciferase assay in vitro and obtained the following results: (a) ATP release from KaiC oscillated even without KaiA and KaiB although period of the oscillation was not 24 hr; (b) ATP was mainly released from the N-terminal domain of KaiC; and (c) the ATP release was enhanced and suppressed by KaiB and KaiA, respectively. These results suggest that KaiC can generate basal oscillation as a core clock without KaiA and KaiB, whereas these two proteins contribute to adjusting and stabilizing the oscillation.

Pre-existing vertebral fracture is a risk factor for postoperative proximal junctional fracture after adult spinal deformity surgery: A propensity score-matched analysis.

BACKGROUND: Corrective surgery for adult spinal deformity has recently been increasingly performed because of aging populations and advances in minimally invasive surgery. Low bone mineral density is a major contributor to proximal junctional kyphosis after spinal long fusion. Assessment for low bone mineral density ideally involves both dual energy X-ray absorptiometry and identification of pre-existing vertebral fractures, the latter, requiring only standard equipment, being performed more frequently. We therefore aimed to examine the impact of pre-existing vertebral fractures on the incidence of type 2 proximal junctional kyphosis, including proximal junctional fracture and failure, after corrective surgery for adult spinal deformity. METHODS: We performed a retrospective, single institution study of 106 women aged over 50 years who had undergone corrective long spinal fusion for severely symptomatic spinal deformity from 2014 to 2017. We allocated them to three groups (with and without pre-existing vertebral fractures and with severe [Grades 2-3 according to Genant et al.'s classification] preexisting vertebral fractures) and used propensity score matching to minimize bias. The primary outcome was postoperative proximal junctional fracture and the secondary outcome proximal junctional kyphosis/failure. RESULTS: The primary and secondary endpoints were achieved significantly more often in the 28 patients with than in the 78 without preexisting vertebral fractures (total 41). The former group was also significantly older and had greater pelvic tilt and fewer fused segments than those without vertebral fractures. After propensity score matching, the incidences of the endpoints did not differ with pre-existing vertebral fracture status; however, patients with severe vertebral fractures more frequently had proximal junctional fractures postoperatively. Postoperative improvements in health-related quality of life scores did not differ with pre-existing vertebral fracture status. CONCLUSIONS: Severe pre-existing vertebral fractures are a risk factor for proximal junctional fracture after correction of adult spinal deformity.

Effect of long spinal fusion including the pelvis on activities of daily living related to lumbar spinal function in adults with spinal deformity.

BACKGROUND: Spinal sagittal malalignment is managed by long spinal fusion including the pelvis, which reduces lumbar spine range of motion and impairs the activities of daily living. This study aimed to evaluate the changes in activities of daily living after long spinal fusion in adults with spinal deformity, and clarify the improvement or deterioration in the specific activities of daily living postoperatively. METHODS: We retrospectively reviewed 40 adults who underwent long spinal fusion in a single institution between 2014 and 2016 (female/male, 39/1; mean age, 68.5 years; range, 52-79 years). Each patient undertook three self-assessed health-related quality of life measures preoperatively and again at 2-years postoperatively: Oswestry Disability Index (ODI), Scoliosis Research Society (SRS)-22 questionnaire, and Japanese Orthopaedic Association back pain evaluation questionnaire (JOABPEQ). Radiographic outcomes were measured preoperatively and at 2 years postoperatively. RESULTS: Total ODI and all SRS-22 domains were improved at 2 years postoperatively. The JOABPEQ scores were also improved in all domains, except lumbar function. The change in pelvic incidence minus lumbar lordosis correlated with improvements in total ODI, SRS-22 function, and self-image scores. At 2 years postoperatively, satisfaction was correlated with total ODI, all SRS-22 domains, and the JOABPEQ pain domain. Subclass analysis of the JOABPEQ lumbar function domain at 2 years postoperatively revealed that 65% of patients had difficulty 'putting on socks or stockings', 42% had great difficulty 'bending forward, kneeling, or stooping', 32% reported improvement in 'sit to stand', and 32% reported deterioration in 'putting on socks or stockings' after surgery compared with before surgery. The JOABPEQ lumbar function domain was not correlated with the SRS-22 satisfaction domain. CONCLUSIONS: Despite restricting lumbar function, spinopelvic fusion improves health-related quality of life. Surgeons and patients should discuss potential changes and limitations in the activities of daily living after long spinal fusion including the pelvis.

A Japanese nationwide multicenter survey on perioperative complications of corrective fusion for elderly patients with adult spinal deformity.

BACKGROUND: Recently, corrective fusion surgery for patients with adult spinal deformity (ASD) has become common in Japan. This study aimed to clarify the status of surgeries for ASD in Japan, focusing on perioperative complications. A nationwide multicenter survey gathering information on surgically treated ASD patients was conducted by the committee for Adult Spinal Deformity of the Japanese Scoliosis Society. METHODS: This study was a review of retrospectively collected data from 18 spine scoliosis centers belonging to the Japanese Scoliosis Society. Patients who underwent corrective fusion surgery for ASD between 2011 and 2013 were included. Demographics, comorbidities, surgical data, and complications were investigated. RESULTS: A total of 1192 patients (mean age, 57.7 years) were included in this study. Of these, 611 patients were aged less than 65 years and 581 patients were aged 65 years or greater. The age distribution had two peaks, in the third and eighth decades. Deformities caused by degeneration represented 67% of the pathology in patients aged over 65 years; however, non-degenerative disease such as adult idiopathic scoliosis and syndromic or congenital deformity represented over 60% of pathology in patients aged less than 65 years. The iatrogenic deformity and reoperation rates were both less than 3%. The mean operation time and estimated blood loss were 370 min and 1642 ml, respectively. Major perioperative complications occurred in 160 patients (14.5%). The incidence of complications was significantly higher in patients aged over 65 years, including neurological deficits, hemorrhagic shock, hematoma, heart failure, and surgical site infection (p < 0.05). CONCLUSIONS: Older (aged over 65 years) ASD patients showed greater rates of deformity due to the occurrence of degeneration and vertebral fractures, as well as a higher incidence of peri-and postoperative complications. Efforts to reduce perioperative complications are therefore imperative, especially for elderly ASD patients in our aging society.

Importance of the monomer-dimer-tetramer interconversion of the clock protein KaiB in the generation of circadian oscillations in cyanobacteria.

The molecular machinery of the cyanobacterial circadian clock oscillator consists of three proteins, KaiA, KaiB and KaiC, which interact with each other to generate circadian oscillations in the presence of ATP (the in vitro KaiABC clock oscillator). KaiB comprises four subunits organized as a dimer of dimers. Our previous study suggested that, on interaction with KaiC, the tetrameric KaiB molecule dissociates into two molecules of dimeric KaiB. It is uncertain whether KaiB also exists as a monomer and whether the KaiB monomer can drive normal circadian oscillation. To address these questions, we constructed a new KaiB oligomer mutant with an N-terminal deletion, KaiB10-108 . KaiB10-108 was a monomer at 4 °C but a dimer at 35 °C. KaiB10-108 was able to drive normal clock oscillation in an in vitro reconstituted KaiABC clock oscillator at 25 °C, but it was not able to drive normal circadian gene expression rhythms in cyanobacterial cells at 41 °C. Wild-type KaiB existed in equilibrium between a dimer and tetramer at lower KaiB concentrations or in the presence of 1 m NaCl. Our findings suggest that KaiB is in equilibrium between a monomer, dimer and tetramer in cyanobacterial cells.

The characteristics of scoliosis in Prader-Willi syndrome (PWS): analysis of 58 scoliosis patients with PWS.

BACKGROUND: The purpose of this study was to compare the characteristics of scoliosis in Prader-Willi syndrome (PWS) patients versus idiopathic scoliosis (IS). METHODS: We identified 193 PWS patients. Scoliosis was found in 58 PWS patients, 39 of whom were treated with GH. Fifty-five IS patients were consecutively selected from an outpatient clinic. We investigated 113 patients (58 PWS group, 55 IS group) followed for a minimum of 2 years. The mean age was 17.9 and 16.1 years, respectively. Deformity was measured using Lenke classification, Cobb angle, thoracic kyphosis at T2-5 and T5-12, lumbar lordosis at T12-S1, and sagittal alignment at the C7 plumb line. BMI was also recorded. RESULTS: According to the Lenke system, patients were classified as (PWS group/IS group): Type 1 (8/26), Type 2 (1/4), Type 3 (3/15), Type 4 (1/0), Type 5 (32/8), and Type 6 (13/2). The average Cobb angles were 32.6° in the PWS and 35.4° in the IS. No significant differences were found for the thoracic kyphosis (T2-5, T5-12), lumbar lordosis (T12-S1) or C7 plumb line between the two groups. BMI was increased in the PWS group not treated previously with GH as compared with the IS group and the PWS group with GH. CONCLUSIONS: Most PWS patients presented with lumbar or thoracolumbar curves (Type 5, 6), whereas IS patients typically had thoracic scoliosis (Type 1, 2, 3).

Climate change and Southern Ocean ecosystems I: how changes in physical habitats directly affect marine biota.

Antarctic and Southern Ocean (ASO) marine ecosystems have been changing for at least the last 30 years, including in response to increasing ocean temperatures and changes in the extent and seasonality of sea ice; the magnitude and direction of these changes differ between regions around Antarctica that could see populations of the same species changing differently in different regions. This article reviews current and expected changes in ASO physical habitats in response to climate change. It then reviews how these changes may impact the autecology of marine biota of this polar region: microbes, zooplankton, salps, Antarctic krill, fish, cephalopods, marine mammals, seabirds, and benthos. The general prognosis for ASO marine habitats is for an overall warming and freshening, strengthening of westerly winds, with a potential pole-ward movement of those winds and the frontal systems, and an increase in ocean eddy activity. Many habitat parameters will have regionally specific changes, particularly relating to sea ice characteristics and seasonal dynamics. Lower trophic levels are expected to move south as the ocean conditions in which they are currently found move pole-ward. For Antarctic krill and finfish, the latitudinal breadth of their range will depend on their tolerance of warming oceans and changes to productivity. Ocean acidification is a concern not only for calcifying organisms but also for crustaceans such as Antarctic krill; it is also likely to be the most important change in benthic habitats over the coming century. For marine mammals and birds, the expected changes primarily relate to their flexibility in moving to alternative locations for food and the energetic cost of longer or more complex foraging trips for those that are bound to breeding colonies. Few species are sufficiently well studied to make comprehensive species-specific vulnerability assessments possible. Priorities for future work are discussed.

Growth hormone treatment for osteoporosis in patients with scoliosis of Prader-Willi syndrome.

BACKGROUND: Patients with Prader-Willi syndrome (PWS) have fragile bones. Osteoporosis is a major concern in scoliosis surgery. Our aim was to investigate bone mineral density (BMD) in PWS patients and to verify the efficacy of and scoliosis deterioration with growth hormone (GH) administration for osteoporosis. METHODS: We followed 148 PWS patients who underwent lumbar spine (L2-4) BMD testing. Sixty-four patients had scoliosis, and 84 were non-scoliosis patients. Patients were treated with GH (0.245 mg/kg/week) until they reached a skeletal age of 17 years for males and 15 years for females. We also evaluated the effect of GH treatment on BMD in 101 patients (60 males, 41 females) undergoing BMD testing more than twice. The mean patient age was 5.4 years. The mean duration of GH administration was 54 months. RESULTS: Mean lumbar BMD was 0.567 g/cm(2). Fifty patients (33.8%) had osteoporosis and 41 (27.7%) had osteopenia. There was no significant difference in mean BMD between patients with scoliosis (0.598 g/cm(2)) and without scoliosis (0.548 g/cm(2)). GH treatment caused a significant increase in Z score (pre-GH: mean -2.28 vs. post-GH: mean -1.53, P < 0.001). There was no statistical difference in the prevalence of scoliosis between the GH treatment group (45/112, 40.1%) and non-treatment group (19/36, 52.8%). CONCLUSIONS: Among patients with PWS, 61.5% had low BMDs. GH administration significantly improved the lumbar BMD (Z score). There were no statistically significant differences in the prevalence of scoliosis among patients who received GH treatment compared to patients who did not.

Clinical analysis of progressive destroyed lung after lung cancer surgery.

Background: "Progressive destroyed lung (PDL)" refers to a state in which the normal structure and function of the lung are permanently disrupted owing to repeated inflammation. After lung cancer surgery, the remaining lung tissue can experience progressive destruction; however, the exact cause remains unclear. In this study, we retrospectively analyzed cases in which the remaining lung deteriorated after lung cancer surgery and investigated the associated risk factors. Methods: A case-control study was conducted on 31 cases of PDL and 247 cases of non-PDL among 1,234 patients who underwent surgery for primary lung cancer from 2006 to 2021. The following factors were analyzed: age, sex, medical history, smoking status, surgical procedure, lung cancer histology, surgical approach, postoperative complications, chemotherapy, radiation therapy, and lung cancer recurrence. Patients were matched 1:1 based on preoperative factors, and postoperative risk factors were evaluated using multivariate logistic regression analysis. Results: A higher proportion of men and higher prevalence of chronic lung diseases, smokers, squamous cell carcinoma (SCC), postoperative acute pneumonia, chronic pneumonia, air leak, and history of radiation therapy were noted in the PDL group than in the non-PDL group. In the analysis following propensity score matching, chronic pneumonia [odds ratio (OR): 10.1, 95% confidence interval (CI): 2.9 to 35.8] was identified as an independent risk factor for PDL. Conclusions: In this study, PDL after lung cancer surgery was associated with postoperative chronic pneumonia, including Aspergillus infection and aspiration pneumonia.

Fatty-marrow transformation following radiotherapy for pancreatic cancer detected using dual-energy computed tomography: A case report.

Bone damage, a late side effect of radiotherapy, occurs concurrently with the replacement of fat cells in the bone marrow, causing changes in bone composition. Changes in composition can affect bone quality and disease states, and reduced bone mass can reduce quality of life by increasing the risk of fractures. A 70-year-old woman presented to the orthopedic outpatient clinic with the chief complaint of lower-back pain. The patient reported no history of trauma but was in great pain and had difficulty walking. Since the patient had a history of pancreatic cancer, tumor-marker testing, bone scintigraphy, and dual-energy computed tomography were performed. Although the tumor-marker levels were normal, dual-energy computed tomography and bone scintigraphy revealed fresh compression fractures of the L1 and L3 vertebrae. In addition, dual-energy computed tomography material-discrimination analysis suggested high fat density in the L2 vertebral body. The patient had received approximately 30 Gy radiation to the L2 vertebral body for her pancreatic cancer, which resulted in fatty myelination in the bone. The diagnosis of fatty myelination is made on T1-weighted magnetic resonance images; however, diagnosis remains challenging because of the difficulty in assessing bone morphology on magnetic resonance images. Moreover, some patients are not candidates for magnetic resonance imaging. Dual-energy computed tomography-based material-discrimination analysis can visually depict changes in the bone marrow, and is a valuable diagnostic tool owing to its simplicity.

Factors associated with rod fracture following surgery for adult spinal deformity: a single-center retrospective study.

PURPOSE: Adult spinal deformity (ASD) has a significant impact on trunk balance and quality of life in the elderly. Postoperative rod fractures pose significant challenges, but the mechanisms of their occurrence are underexplored compared to other complications such as proximal junctional kyphosis. This study investigated factors associated with rod fracture in patients with ASD. METHODS: A retrospective single-center study analyzed 110 adult patients who underwent spinal deformity correction between 2012 and 2020. Comparative analysis and univariate and multivariate Cox regression analyses were employed to identify factors associated with rod fracture. RESULTS: In this study, rod fracture occurred in 14.5% of patients. The rod fracture group exhibited a larger change in lumbar lordosis (LL), a higher proportion of patients with pre-operatively existing (pre-existing) vertebral fractures, and a greater percentage of patients with a rod diameter of 6 mm or less compared to the non-rod fracture group. Univariate Cox regression analysis revealed that rod fracture was associated with pre-existing vertebral fracture, LL change, preoperative sagittal vertical axis, and preoperative pelvic tilt. Multivariate Cox regression analysis identified pre-existing vertebral fractures and the amount of LL change as independent factors associated with rod fractures. CONCLUSION: Pre-existing vertebral fractures and the magnitude of lumbar lordosis correction are independent risk factors for rod fracture following ASD surgery. Surgeons should consider these factors during preoperative planning to reduce the risk of postoperative rod fracture. LEVEL OF EVIDENCE: IV.

Independent Risk Factors of Proximal Junctional Kyphosis with Vertebral Fracture After Spinal Long Fusion: Survivorship Analysis of Adult Spinal Deformity Surgery Patients.

OBJECTIVE: This study aimed to identify risk factors for postoperative proximal junctional kyphosis (PJK) with vertebral fracture in adult spinal deformity (ASD) patients. We performed a survival analysis considering various factors, including osteoporosis. METHODS: This single-center retrospective study included 101 ASD patients (mean age: 67.2 years, mean follow-up: 8.1 years). We included patients aged ≥50 years with abnormal radiographic variables undergoing corrective long spinal fusion. The main outcome measure was PJK with vertebral fracture, analyzed based on patient data, radiographic measurements, sagittal parameters, bone mineral density, and osteoporosis medication. RESULTS: PJK occurred in 37.6% of patients, with vertebral fracture type 2 accounting for 65% of these cases. Kaplan-Meier analysis indicated a median PJK-free survival time of 60.7 months. Existing vertebral fracture (grade 1 or higher or grade 2 or higher) was a significant risk factor for PJK with vertebral fracture, with hazard ratios of 4.58 and 5.61, respectively. The onset time of PJK with vertebral fracture was 1.5 months postoperatively, with 44% of these cases occurring within 1 month and 64% within 2 months. CONCLUSIONS: PJK with vertebral fracture affected 25% of ASD patients, emphasizing the importance of osteoporosis evaluation. Existing vertebral fracture emerged as a significant independent risk factor, surpassing bone mineral density. This study provides valuable insights for spine surgeons, highlighting the need to provide osteoporosis treatment and emphasize potential postoperative complications during discussions with patients.

NECTIN2 is a prognostic biomarker and potential therapeutic target in lung adenocarcinoma.

INTRODUCTION: NECTINs are transmembrane proteins mediating cell-to-cell adhesion. NECTINs interact with integrins or other membrane receptors to trigger multiple cellular functions. Aberrant NECTIN expression is associated with cancer progression and poor outcomes. While NECTIN2 is overexpressed in various cancer types, its role in lung cancer is not well understood. MATERIAL AND METHODS: We investigated the function of NECTIN2 in lung adenocarcinoma (LUAD) using the Cancer Genome Atlas (TCGA) dataset and clinical samples of 105 LUAD patients who had undergone surgical resection. Cell proliferation, apoptosis, migration and invasion were investigated using human lung adenocarcinoma cell lines. RESULTS: We found that high NECTIN2 expression correlated with reduced overall survival in LUAD in TCGA database. In clinical samples, high NECTIN2 expression was associated with lower recurrence-free survival in all patients (P < 0.001) and in stage I patients (P = 0.001). Functional analyses demonstrated that NECTIN2 knockout promoted cell apoptosis and diminished cell proliferation and migration capacity. NECTIN2 overexpression did not significantly affect cellular functions. DISCUSSION: Our results suggest that NECTIN2 plays a significant role in cell apoptosis and cancer cell migration, leading to increased postoperative recurrence. Furthermore, NECTIN2 serves as a prognostic indicator and a potential therapeutic target in LUAD. CONCLUSIONS: High NECTIN2 expression in LUAD was found to be associated with postoperative recurrence, and was observed to play an important role in cell apoptosis and migration.

Biologic and targeted synthetic disease-modifying anti-rheumatic drugs improve body composition in rheumatoid arthritis patients more than conventional synthetic disease-modifying anti-rheumatic drugs: Results from the PRESENT study.

INTRODUCTION: The effects of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on body composition and muscle function in rheumatoid arthritis (RA) patients requiring treatment enhancement were compared. METHODS: This multicenter, prospective, observational study (PRESENT Study) divided RA patients non-randomly into a csDMARD group (n = 100) and a b/tsDMARD group (n = 100). Changes in body composition and muscle function were examined in 80 patients in each group followed for 52 weeks. The percentages of new-onset and improved sarcopenia over 1 year were investigated. Patients in the b/tsDMARD group were divided into three groups by drug type: TNF inhibitors (n = 30), non-TNF inhibitors (n = 23), and JAK inhibitors (n = 27). RESULTS: Baseline median age and disease duration were 70.0 and 4.0 years, respectively. Changes in weight (24 and 52 weeks) and muscle mass (52 weeks) were significantly higher in the b/tsDMARD group (p = .035, p < .001, and p = .002, respectively). On multivariate logistic regression analysis, b/tsDMARD treatment (OR 3.21, p = .002), DAS28-ESR (OR 0.65 p = .011), and muscle mass (OR 0.90, p = .023) were independently associated with increased muscle mass at 52 weeks. The percentages of new-onset and improved sarcopenia were almost equal. There were no significant differences in the time-dependent changes (52 weeks) of clinical status, body composition, muscle function, and status of sarcopenia among TNF inhibitors, non-TNF inhibitors, and JAK inhibitors. CONCLUSIONS: Weight and muscle mass increased significantly more with b/tsDMARD than with csDMARD treatment. There were no differences in body composition changes by mode of action with b/tsDMARDs.

Modified Ravitch procedure for pectus excavatum in Marfan syndrome with annuloaortic ectasia.

OBJECTIVES: This case series aimed to determine the feasibility of simultaneous modified Ravitch and David procedures for Marfan syndrome patients with pectus excavatum and annuloaortic ectasia. METHODS: Between March 2014 and December 2019, 7 consecutive patients underwent simultaneous surgery of modified Ravitch and David procedures for pectus excavatum and annuloaortic ectasia. The completion of cardiac surgery and sternal closure were followed by the modified Ravitch procedure. The bilateral fourth to seventh costal cartilages were resected, the sternal body partially wedge resected and the sternum raised anteriorly with re-suture. An oblique incision was performed on bilateral third costal cartilages, and they were fixed on top of each other, with the medial end superior and the lateral end inferior. The sternum was raised anteriorly, bypassing the fourth to seventh rib ends through the back of the sternum with threads. The feasibility and safety of the procedure were assessed through a retrospective review of the patients' clinical charts. RESULTS: The total sample had a median age of 28 years and comprised 5 males and 2 females. There was a significant difference in the preoperative and postoperative median Haller index, which were 6.8 and 3.9, respectively. All patients were discharged without serious complications, and there was no significant recurrence of pectus excavatum at 35-92 months postoperatively. CONCLUSIONS: The results of our case series suggest the feasibility of one-stage surgery for pectus excavatum combined with cardiac surgery using the modified Ravitch procedure. Future efforts should be tailored for more uneventful postoperative clinical courses.

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study.

Introduction: Adolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated. Material and methods: Mendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese. Results: Significant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI. Conclusions: Our Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS.

Identification of a Functional Susceptibility Variant for Adolescent Idiopathic Scoliosis that Upregulates Early Growth Response 1 (EGR1)-Mediated UNCX Expression.

Adolescent idiopathic scoliosis (AIS) is a serious health problem affecting 3% of live births all over the world. Many loci associated with AIS have been identified by previous genome wide association studies, but their biological implication remains mostly unclear. In this study, we evaluated the AIS-associated variants in the 7p22.3 locus by combining in silico, in vitro, and in vivo analyses. rs78148157 was located in an enhancer of UNCX, a homeobox gene and its risk allele upregulated the UNCX expression. A transcription factor, early growth response 1 (EGR1), transactivated the rs78148157-located enhancer and showed a higher binding affinity for the risk allele of rs78148157. Furthermore, zebrafish larvae with UNCX messenger RNA (mRNA) injection developed body curvature and defective neurogenesis in a dose-dependent manner. rs78148157 confers the genetic susceptibility to AIS by enhancing the EGR1-regulated UNCX expression. © 2022 American Society for Bone and Mineral Research (ASBMR).