Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Continuous glucose monitoring with structured education in adults with type 2 diabetes managed by multiple daily insulin injections: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to compare the effectiveness of stand-alone intermittently scanned continuous glucose monitoring (isCGM) with or without a structured education programme and blood glucose monitoring (BGM) in adults with type 2 diabetes on multiple daily insulin injections (MDI). METHODS: In this 24 week randomised open-label multicentre trial, adults with type 2 diabetes on intensive insulin therapy with HbA1c levels of 58-108 mmol/mol (7.5-12.0%) were randomly assigned in a 1:1:1 ratio to isCGM with a structured education programme on adjusting insulin dose and timing according to graphical patterns in CGM (intervention group), isCGM with conventional education (control group 1) or BGM with conventional education (control group 2). Block randomisation was conducted by an independent statistician. Due to the nature of the intervention, blinding of participants and investigators was not possible. The primary outcome was change in HbA1c from baseline at 24 weeks, assessed using ANCOVA with the baseline value as a covariate. RESULTS: A total of 159 individuals were randomised (n=53 for each group); 148 were included in the full analysis set, with 52 in the intervention group, 49 in control group 1 and 47 in control group 2. The mean (± SD) HbA1c level at baseline was 68.19±10.94 mmol/mol (8.39±1.00%). The least squares mean change (± SEM) from baseline HbA1c at 24 weeks was -10.96±1.35 mmol/mol (-1.00±0.12%) in the intervention group, -6.87±1.39 mmol/mol (-0.63±0.13%) in control group 1 (p=0.0367 vs intervention group) and -6.32±1.42 mmol/mol (-0.58±0.13%) in control group 2 (p=0.0193 vs intervention group). Adverse events occurred in 28.85% (15/52) of individuals in the intervention group, 26.42% (14/53) in control group 1 and 48.08% (25/52) in control group 2. CONCLUSIONS/INTERPRETATION: Stand-alone isCGM offers a greater reduction in HbA1c in adults with type 2 diabetes on MDI when education on the interpretation of graphical patterns in CGM is provided. TRIAL REGISTRATION: ClinicalTrials.gov NCT04926623. FUNDING: This study was supported by Daewoong Pharmaceutical Co., Ltd.

Findings from the KNOW-CKD Study indicate that higher systolic blood pressure time in target range is associated with a lower risk of chronic kidney disease progression.

Time-in-target range (TTR) of systolic blood pressure (SBP) is determined by the proportion of time during which SBP remains within a defined optimal range. TTR has emerged as a useful metric for assessing SBP control over time. However, it is uncertain if SBP-TTR can predict the progression of chronic kidney disease (CKD). Here, we investigated the association between SBP-TTR during the first year of enrollment and CKD progression among 1758 participants from the KNOW-CKD (KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease). Baseline median estimated glomerular filtration rate (eGFR) was 51.7 ml/min per 1.73 m2. Participants were categorized into four SBP-TTR groups (0%, 1-50%, 51-99%, and 100%). The primary outcome was CKD progression defined as 50% or more decline in eGFR from baseline measurement or the initiation of kidney replacement therapy. During the follow-up period (9212 person-years over a median 5.4 years), the composite outcome occurred in 710 participants. In the multivariate cause-specific hazard model, a one-standard deviation increase in SBP-TTR was associated with an 11% lower risk of the composite outcome with hazard ratio, 0.89 (95% confidence interval, 0.82-0.97). Additionally, compared to patients with SBP-TTR 0%, the respective hazard ratios for those with SBP-TTR 1-50%, 51-99%, and 100% were 0.85 (0.68-1.07), 0.76 (0.60-0.96), and 0.72 (0.55-0.94), and the respective corresponding slopes of eGFR decline were -3.17 (-3.66 to -2.69), -3.02 (-3.35 to -2.68), -2.62 (-2.89 to - 2.36), and -2.33 (-2.62 to -2.04) ml/min/1.73 m2. Thus, higher SBP-TTR was associated with a decreased risk of CKD progression in patients with CKD.

Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials.

BACKGROUND: We assessed the efficacy and safety of enavogliflozin (0.3 mg), a newly developed SGLT-2 inhibitor, in patients with type 2 diabetes mellitus based on kidney function via pooled analysis of two 24-week, randomized, double-blind phase III trials. METHODS: Data from 470 patients were included (enavogliflozin: 0.3 mg/day, n = 235; dapagliflozin: 10 mg/day, n = 235). The subjects were classified by mildly reduced (60 ≤ eGFR < 90 mL/min/1.73 m², n = 247) or normal eGFR (≥ 90 mL/min/1.73 m², n = 223). RESULTS: In the mildly reduced eGFR group, enavogliflozin significantly reduced the adjusted mean change of HbA1c and fasting plasma glucose levels at week 24 compared to dapagliflozin (- 0.94% vs. -0.77%, P = 0.0196). Enavogliflozin exhibited a more pronounced glucose-lowering effect by HbA1c when combined with dipeptidyl peptidase-4 inhibitors than that observed in their absence. Enavogliflozin showed potent blood glucose-lowering effects regardless of renal function. Conversely, dapagliflozin showed a significant decrease in the glucose-lowering efficacy as the renal function decreased. Enavogliflozin showed a higher urinary glucose excretion rate in both groups. The homeostatic model assessment showed that enavogliflozin markedly decreased the insulin resistance. The blood pressure, weight loss, or homeostasis model assessment of beta-cell function values did not differ significantly between enavogliflozin and dapagliflozin. Adverse events were similar between both drugs. CONCLUSIONS: The glucose-lowering efficacy of enavogliflozin is superior to that of dapagliflozin in patients with type 2 diabetes mellitus with mild renal function impairment; this is attributed to its potent urinary glucose excretion-promoting ability. The emergence of new and potent SGLT-2 inhibitors is considered an attractive option for patients with inadequate glycemic control and decreased renal function. TRIAL REGISTRATION: Not applicable (pooled analysis).

Nonlinear Hall Effect from Long-Lived Valley-Polarizing Relaxons.

The nonlinear Hall effect has attracted much attention due to the famous, widely adopted interpretation in terms of the Berry curvature dipole in momentum space. Using ab initio Boltzmann transport equations, we find a 60% enhancement in the nonlinear Hall effect of n-doped GeTe and its noticeable frequency dependence, qualitatively different from the predictions based on the Berry curvature dipole. The origin of these differences is long-lived valley polarization in the electron distribution arising from electron-phonon scattering. Our findings await immediate experimental confirmation.

Atypical post-infectious glomerulonephritis with c-ANCA positivity followed by endocarditis.

Post-infectious glomerulonephritis (PIGN), an uncommon variety of glomerulonephritis (GN), is characterized by emergence of nephritic syndrome within a few weeks following an infectious event. PIGN typically presents as a mild condition and tends to resolve by the time of diagnosis for GN. Aggregatibacter actinomycetemcomitans belongs to the HACEK group of bacteria, which constitutes less than 3% of bacteria responsible for community-acquired infective endocarditis. We present a case of 29-year-old man suspected of lymphoma with B-symptoms along with severe splenomegaly and nephromegaly. Shortly after, he developed an episode of nephritic syndrome accompanied by acute kidney injury (AKI) and high titers of cytoplasmic ANCA (c-ANCA)-positivity. Kidney biopsy revealed PIGN with tubulointerstitial nephritis. Despite treatment with antibiotics and corticosteroid, he visited the emergency room due to worsening dyspnea and multi-organ failure. An echocardiogram showed a bicuspid aortic valve with vegetation unseen on previous echocardiogram. He underwent aortic valve replacement immediately without adverse events. Four months after valve replacement, his renal function and cardiac performance have remained stable. We report a case of PIGN with AKI and high titers of c-ANCA appearing later as an infective endocarditis due to Aggregatibacter actinomycetemcomitans. With careful clinical observation and appropriate and timely management, satisfactory outcomes for patient health are possible.

Does obesity and varying body mass index affect the clinical outcomes and safety of biportal endoscopic lumbar decompression? A comparative cohort study.

BACKGROUND: Endoscopic spine surgery has recently grown in popularity due to the potential benefits of reduced pain and faster recovery time as compared to open surgery. Biportal spinal endoscopy has been successfully applied to lumbar disc herniations and lumbar spinal stenosis. Obesity is associated with increased risk of complications in spine surgery. Few prior studies have investigated the impact of obesity and associated medical comorbidities with biportal spinal endoscopy. METHODS: This study was a prospectively collected, retrospectively analyzed comparative cohort design. Patients were divided into cohorts of normal body weight (Bone Mass Index (BMI)18.0-24.9), overweight (BMI 25.0-29.9) and obese (BMI > 30.0) as defined by the World Health Organization (WHO). Patients underwent biportal spinal endoscopy by a single surgeon at a single institution for treatment of lumbar disc herniations and lumbar spinal stenosis. Demographic data, surgical complications, and patient-reported outcomes were analyzed. Statistics were calculated amongst treatment groups using analysis of variance and chi square where appropriate. Statistical significance was determined as p < 0.05. RESULTS: Eighty-four patients were followed. 26 (30.1%) were normal BMI, 35 (41.7%) were overweight and 23 (27.4%) were obese. Patients with increasing BMI had correspondingly greater American Society of Anesthesiologist (ASA) scores. There were no significant differences in VAS Back, VAS Leg, and ODI scores, or postoperative complications among the cohorts. There were no cases of surgical site infections in the cohort. All cohorts demonstrated significant improvement up to 1 year postoperatively. CONCLUSIONS: This study demonstrates that obesity is not a risk factor for increased perioperative complications with biportal spinal endoscopy and has similar clinical outcomes and safety profile as compared to patients with normal BMI. Biportal spinal endoscopy is a promising alternative to traditional techniques to treat common lumbar pathology.

A cohort study found a high risk of end-stage kidney disease associated with acromegaly.

Acromegaly is a chronic systemic disease caused by excess levels of growth hormone and insulin-like growth factor-1 and is associated with numerous complications. Significantly, there is a lack of longitudinal data on kidney complications in patients with acromegaly. As such, we investigated the risk of end-stage kidney disease (ESKD) (stage 5D, 5T) in these patients with nationwide data obtained from the National Health Information Database of the National Health Insurance Service in Republic of Korea. A retrospective cohort study was conducted of 2.187 patients with acromegaly and 10,935 age- and sex-matched (1:5) control subjects without acromegaly over a mean follow-up period of 6.51 years. The study outcomes were analyzed using Cox proportional hazards regression analysis controlling for age, sex, household income, residential area, type 2 diabetes, hypertension, dyslipidemia, urolithiasis, congestive heart failure, myocardial infarction, stroke, and atrial fibrillation. The incidence (per 1,000 person-years) ESKD was 2.00 among patients with acromegaly but only 0.46 among controls, (hazard ratio 4.35 (95% confidence interval 2.63-7.20)) implicating a significantly higher risk. After adjustment for covariates, the risk of ESKD (2.36 (1.36-4.12)) was still significantly higher in patients with acromegaly than that in controls. Among the covariates, diabetes and hypertension were significant facilitators between acromegaly and ESKD in mediation analysis. Pituitary surgery and somatostatin analogues did not significantly change these associations. Thus, acromegaly may be linked with a higher risk for ESKD both independently and through mediators such as diabetes and hypertension.

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

The 2021 KDIGO blood pressure target and the progression of chronic kidney disease: Findings from KNOW-CKD.

BACKGROUND: The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) recommends a target systolic BP of <120 mmHg as this target can provide cardiovascular benefits. However, it remains unclear whether implementing the new BP target could improve kidney outcomes. METHODS: The association between the 2021 KDIGO BP target and CKD progression was examined and compared with the 2012 KDIGO BP target among 1724 participants included in the KoreaN Cohort Study for Outcomes in Patients With CKD. The main exposure was the BP status categorized according to the 2012 or 2021 KDIGO guideline: (1) controlled within the 2021 target, (2) controlled within the 2012 target only, and (3) above both targets. The primary outcome was a composite kidney outcome of ≥50% decline in the estimated glomerular filtration rate from baseline or the initiation of kidney replacement therapy during the follow-up period. RESULTS: Composite kidney outcomes occurred in 650 (37.7%) participants during the 8078 person-years of follow-up (median, 4.9 years). The incidence rates of this outcome were 55, 66.5, and 116.4 per 1000 person-years in BP controlled within the 2021 and 2012 KDIGO targets, and BP above both targets, respectively. In the multivariable cause-specific hazard model, hazard ratios for the composite outcome were 0.76 (95% confidence interval (CI), 0.60-0.95) for BP controlled within the 2021 target and 1.36 (95% CI, 1.13-1.64) for BP above both targets, compared with BP controlled within 2012 target only. CONCLUSION: The newly lowered BP target by the 2021 KDIGO guideline was associated with improved kidney outcome compared with BP target by the 2012 KDIGO guideline.

Data-driven prediction models for forecasting multistep ahead profiles of mammalian cell culture toward bioprocess digital twins.

Recently, the advancement in process analytical technology and artificial intelligence (AI) has enabled the generation of enormous culture data sets from biomanufacturing processes that produce various recombinant therapeutic proteins (RTPs), such as monoclonal antibodies (mAbs). Thus, now it is very important to exploit them for the enhanced reliability, efficiency, and consistency of the RTP-producing culture processes and for the reduced incipient or abrupt faults. It is achievable by AI-based data-driven models (DDMs), which allow us to correlate biological and process conditions and cell culture states. In this work, we provide practical guidelines for choosing the best combination of model elements to design and implement successful DDMs for given hypothetical in-line data sets during mAb-producing Chinese hamster ovary cell culture, as such enabling us to forecast dynamic behaviors of culture performance such as viable cell density, mAb titer as well as glucose, lactate and ammonia concentrations. To do so, we created DDMs that balance computational load with model accuracy and reliability by identifying the best combination of multistep ahead forecasting strategies, input features, and AI algorithms, which is potentially applicable to implementation of interactive DDM within bioprocess digital twins. We believe this systematic study can help bioprocess engineers start developing predictive DDMs with their own data sets and learn how their cell cultures behave in near future, thereby rendering proactive decision possible.

Efficacy of intermittent short-term use of a real-time continuous glucose monitoring system in non-insulin-treated patients with type 2 diabetes: A randomized controlled trial.

AIM: To evaluate the efficacy of intermittent short-term use of a real-time continuous glucose monitoring (RT-CGM) system in non-insulin-treated patients with type 2 diabetes (T2D) uncontrolled with oral antidiabetic drugs (OADs). MATERIALS AND METHODS: In this multicentre, randomized prospective study, 61 participants were randomly assigned to treatment group 1 (one session of RT-CGM), treatment group 2 (two sessions of RT-CGM with a 3-month interval between sessions) and a control group. All participants used blinded continuous glucose monitoring for up to 6 days with education before randomization, and RT-CGM was additionally applied for 1 week in the intervention groups. The primary outcome was change in HbA1c at 6 months. RESULTS: Among 61 participants, 48 subjects completed the study (baseline HbA1c 8.2% ± 0.5%). At 3 months, a significant HbA1c reduction was observed in treatment group 1 (adjusted difference = -0.60%, P = .044) and treatment group 2 (adjusted difference = -0.64%, P = .014) compared with the control group. However, at 6 months, only treatment group 2 achieved a significant HbA1c reduction (adjusted difference = -0.68%, P = .018). Especially in the treatment groups, patients performing self-monitoring of blood glucose (SMBG) at least 1.5 times/day showed a significant HbA1c improvement, at both 3 and 6 months, but those performing SMBG less than 1.5 times/day showed no significant improvement. CONCLUSIONS: In non-insulin-treated patients with T2D uncontrolled with OADs, intermittent short-term use of RT-CGM was an effective method for glucose control, especially in those performing SMBG frequently.

Synthesis of dithioacetals via gold-catalysed hydrothiolation of vinyl sulfides.

The synthesis of unsymmetrical dithioacetals based on gold catalysis is described. Although many approaches to the preparation of symmetrical dithioacetals have been developed, the methods to access unsymmetrical ones remain limited. In this regard, we report a mild synthetic method with a broad substrate scope. Screening of various gold catalysts identified a catalyst, which allows the hydrothiolation of both activated and unactivated vinyl sulfides with high efficiency. Moreover, the reaction displays broad compatibility for both aryl and aliphatic thiols.

Clinical outcomes and complications after biportal endoscopic spine surgery: a comprehensive systematic review and meta-analysis of 3673 cases.

PURPOSE: Current literature suggests that biportal spinal endoscopy is safe and effective in treating lumbar spine pathology such as lumbar disc herniation, lumbar stenosis, and degenerative spondylolisthesis. No prior study has investigated the postoperative outcomes or complication profile of the technique as a whole. This study serves as the first comprehensive systematic review and meta-analysis of biportal spinal endoscopy in the lumbar spine. METHODS: A PubMed literature search provided over 100 studies. 42 papers were reviewed and 3673 cases were identified with average follow-up time of 12.5 months. Preoperative diagnoses consisted of acute disc herniation (1098), lumbar stenosis (2432), and degenerative spondylolisthesis (229). Demographics, operative details, complications, and perioperative outcome and satisfaction scores were analyzed. RESULTS: Average age was 61.32 years, 48% male. 2402 decompressions, 1056 discectomies, and 261 transforaminal lumbar Interbody fusions (TLIFs) were performed. Surgery was performed on 4376 lumbar levels, with L4-5 being most common(61.3%). 290 total complications occurred, 2.23% durotomies, 1.29% inadequate decompressions, 3.79% epidural hematomas, and < 1% transient nerve root injuries, infections, and iatrogenic instability. Significant improvement in VAS-Back, VAS-Leg, ODI, and Macnab Scores were seen across the cohort. CONCLUSION: Biportal spinal endoscopy is a novel method to address pathology in the lumbar spine with direct visualization through an endoscopic approach. Complications are comparable to previously published rates. Clinical outcomes demonstrate effectiveness. Prospective studies are required to assess the efficacy of the technique as compared to traditional techniques. This study demonstrates that the technique can be successful in the lumbar spine.

Anatomic femoral tunnel position in medial patellofemoral ligament reconstruction: anterior versus posterior.

BACKGROUND: This study aimed to compare the clinical and radiological outcomes of medial patellofemoral ligament reconstruction (MPFLR) between anatomic femoral tunnel positions at anterior and posterior footprints. METHODS: Fifty-seven patients who underwent MPFLR for patellofemoral instability with anterior or posterior femoral tunnels between 2014 and 2021 with at least 2 years of follow-up were retrospectively analyzed. Based on postoperative images, the femoral tunnel positions anterior to the line connecting the adductor tubercle and medial epicondyle were assigned to the anterior group, group A, and those posterior to the line to the posterior group, group P. Thirty-two patients were included in group A (mean age, 22.4 ± 8.8 years), and another 25 patients were included in group P (mean age, 21.1 ± 6.1 years). The International Knee Documentation Committee (IKDC) subjective score, Lysholm score, Tegner activity score, Kujala score, and complications were evaluated. Radiologically, the Caton-Deschamps index (CDI), patellar tilt angle, and patellofemoral osteoarthritis (PFOA) using the Kellgren-Lawrence (KL) scale were evaluated. The patellofemoral cartilage status according to the International Cartilage Repair Society (ICRS) grade, bone contusion, femoral tunnel enlargement, and MPFL graft signal intensity were also evaluated. RESULTS: All clinical scores significantly improved in both groups (p < 0.01). No differences were noted between the two groups in terms of their preoperative demographic data, postoperative clinical scores (IKDC, Lysholm, Tegner, and Kujala), complications, or radiological findings (CDI, patellar tilt angle, PFOA, bone contusion, femoral tunnel enlargement, and graft signal intensity). The ICRS grade for the medial facet of the patella progressed in group A (30%, p = 0.02) but not in group P (18%, p = n.s.). Additionally, no significant differences were observed in the other compartments of the patellofemoral joint. CONCLUSIONS: The clinical outcomes were significantly improved in both groups; however, MPFLR with anterior femoral tunnel position had worse cartilage status on the medial facet of the patella than the posterior femoral tunnel position. LEVEL OF EVIDENCE: Level III.

Acromegaly and cardiovascular outcomes: a cohort study.

AIMS: Cardiovascular disease is a common complication in acromegaly. We investigated the risk of cardiovascular disease and mortality in patients with acromegaly in a large-scale population using nationwide data in Korea. METHODS AND RESULTS: We performed a nationwide, retrospective, observational, cohort study of patients with acromegaly (n = 1874) and age- and sex-matched subjects without acromegaly (n = 9370) for a mean follow-up of 7.5 ± 3.2 years. The study outcomes were myocardial infarction, stroke, atrial fibrillation, congestive heart failure, and all-cause death. All outcomes were analysed by Cox proportional hazards regression analysis while controlling for age, sex, household income, place, Type 2 diabetes, hypertension, and dyslipidaemia. The incidence (per 1000 person-years) of atrial fibrillation (3.06 vs. 1.70; P = 0.001), congestive heart failure (3.11 vs. 1.63; P < 0.001), and all-cause mortality (6.31 vs. 4.03; P < 0.001) in patients with acromegaly was higher than in controls. However, the incidence of myocardial infarction and stroke did not differ between groups. After adjustment for covariates, the risk for atrial fibrillation [hazard ratio (HR): 1.59; 95% confidence interval (CI): 1.09-2.31], congestive heart failure (HR: 1.54; 95% CI: 1.06-2.25), and all-cause mortality (HR: 1.31; 95% CI: 1.01-1.69) was significantly higher in patients with acromegaly. In time lag sensitivity analysis, a higher risk for atrial fibrillation was observed only in the first 4 years after diagnosis in acromegaly patients compared with controls (HR: 3.05; 95% CI: 1.94-4.79). CONCLUSION: Patients with acromegaly were at higher risk for atrial fibrillation, congestive heart failure, and all-cause death. The risk of atrial fibrillation had a time-dependent association with acromegaly.

Mid-flexion laxity could be identified with continuous flexion-arc gap assessment in patients with a large preoperative convergence angle.

PURPOSE: To analyze the incidence of intraoperative mid-flexion laxity using continuous flexion-arc gap assessment, risk factors for mid-flexion laxity, and clinical results in navigation-assisted total knee arthroplasty (TKA). METHODS: Ninety posterior-stabilized TKAs were performed under navigation guidance for patients with degenerative arthritis and varus deformity. Intraoperatively, the gap between the trial femoral component and insert was evaluated in the navigation system with continuous flexion-arc gap assessment. Each medial and lateral gap at flexion (90°) and extension (0°) were made to be less than 3 mm. Mid-flexion laxity was determined when the gap in the flexion range between 15° and 60° was 3 mm or more. The proportion of knees with mid-flexion laxity was investigated. The factors affecting mid-flexion laxity were identified in terms of demographics, preoperative convergence angle, and change in joint line height and posterior femoral offset. The Knee Society Score and Western Ontario and McMaster Universities Osteoarthritis Index were evaluated. RESULTS: There were 31 cases (34.4%) of lateral mid-flexion laxity (average peak mid-flexion gap = 3.7 mm). The other 59 cases did not show mid-flexion laxity. The preoperative convergence angle was the only significant factor affecting lateral mid-flexion laxity (odds ratio = 1.466, p = 0.002). There were no significant differences in the clinical results between the groups with and without mid-flexion laxity. CONCLUSIONS: The continuous flexion-arc gap assessment was useful in evaluating mid-flexion laxity using navigation-assisted TKA. The preoperative convergence angle, reflecting soft-tissue laxity, can be a practical and simple radiographic finding for predicting lateral mid-flexion laxity. LEVEL OF EVIDENCE: IV.

Closed-wedge high tibial osteotomy is more advantageous to maintain the correction than open-wedge high tibial osteotomy in osteopenic patients.

PURPOSE: To compare the incidence of correction loss and survival rate between closed-wedge and open-wedge high tibial osteotomies (CWHTO and OWHTO, respectively) in patients with osteopenic and normal bone. METHODS: Retrospective review was conducted for 115 CWHTOs and 119 OWHTOs performed in osteopenic patients [- 2.5 < Bone mineral density (BMD) T scores ≤ - 1] and 136 CWHTOs and 138 OWHTOs performed in normal patients (BMD T score > - 1) from 2012 to 2019. Demographics were not different between CW- and OWHTOs in osteopenic and normal patients (n.s., respectively). Radiographically, the mechanical axis (MA), medial proximal tibial angle (MPTA), and posterior tibial slope (PTS) were evaluated pre- and postoperatively (2 weeks after HTO). The occurrence of hinge fractures was investigated using radiographs taken on the operation day. The correction change was calculated as the last follow-up value minus postoperative MPTA. Correction loss was defined when the correction change was ≥ 3°. The survival rate (failure: correction loss) was investigated. RESULTS: There were no significant differences in the pre and postoperative MA, MPTA, PTS, and value changes between CW- and OWHTOs in osteopenic and normal patients (n.s., respectively); the incidence of unstable hinge fractures also did not differ significantly (CWHTO vs. OWHTO = 7 vs. 7.6% in osteopenic patients; 2.9 vs. 3.6% in normal patients; n.s., respectively). The average correction change (CWHTO = - 0.6°, OWHTO = - 1.3°, p = 0.007), incidence of correction loss (CWHTO = 1.7%, OWHTO = 9.2%, p = 0.019), and 5-year survival rates (CWHTO = 98.3%, OWHTO = 90.8%, p = 0.013) differed significantly in osteopenic patients; there were no significant differences in these results in normal patients (n.s., respectively). CONCLUSION: CWHTO was more advantageous than OWHTO regarding the correction loss in osteopenic patients. Intra- and postoperative care that consider poor bone quality will be required when performing OWHTOs in osteopenic patients. LEVEL OF EVIDENCE: III.

Aseptic survival of the 1.5-stage exchange arthroplasty for periprosthetic joint infection was acceptable when using an autoclaved femoral component and a new polyethylene insert.

PURPOSE: To investigate the aseptic survival of 1.5-stage exchange arthroplasty for periprosthetic joint infection (PJI) after total knee arthroplasty (TKA). METHODS: Eighty-eight cases of 1.5-stage exchange arthroplasty for PJI without reinfection were retrospectively analysed. The autoclaved femoral component and new polyethylene insert (PE) were implanted using antibiotic mixed cement. The explanted tibial component was not reinserted. The Western Ontario and McMaster Universities Osteoarthritis Index and range of motion were clinically evaluated preoperatively and at the last follow-up (the last time for the implant in situ). Radiographically, hip-knee-ankle angle (HKA) and component positions were measured preoperatively, postoperatively (1 month after the 1.5-stage exchange arthroplasty), and at the last follow-up. The survival rate was analysed using the Kaplan-Meier method, in which failure was defined as reoperation due to aseptic failure. Mean period to failure and failure site were analysed. Factors affecting survival were investigated in terms of demographics and inappropriateness of the postoperative HKA (HKA > 0 ± 3°) and component positions (α angle > 95 ± 3°, ß angle > 90 ± 3°, γ angle > 3 ± 3°, and δ angle > 87 ± 3°). RESULTS: The spacer in-situ time was 3.7 years (0.2-6.4). The clinical results improved hip-knee-ankle significantly at the last follow-up. Radiographically, the average HKA was valgus 0.1° postoperatively. The average α, ß, γ, and δ angles of the postoperative component positions were 95.9°, 90.4°, 3.8°, and 86.7°, respectively. The 1-, 2-, and 5-year postoperative survival rates were 90.9%, 86.4%, and 80.6%, respectively. The mean period to failure was 2.0 years (0.2-5.3). There were 18 cases of aseptic loosening (20.8%), occurring on both the femur and tibial sides in 1 knee, and only on the tibial side in 17 knees. Inappropriate coronal position of the PE (ß angle > 90 ± 3°) was a significant factor affecting survival (odds ratio = 5.491; p = 0.011). CONCLUSION: The aseptic survival of the 1.5-stage exchange arthroplasty was acceptable when using an autoclaved femoral component and new PE. The appropriate coronal position of the PE helps ensure favourable survival of 1.5-stage exchange arthroplasty. LEVEL OF EVIDENCE: IV.

Costal chondrocyte-derived pellet-type scaffold-free autologous chondrocyte implantation provided acceptable mid-term outcomes in osteochondral defects with up to 10-mm depth.

PURPOSE: To evaluate clinical, radiographic, and magnetic resonance (MR) results of costal chondrocyte-derived pellet-type scaffold-free autologous chondrocyte implantation (CCP-ACI) in osteochondral defects (ODs) up to 10-mm depth during 5 years of follow-up. METHODS: Ten patients with CCP-ACI performed in ODs with depth up to 10 mm were retrospectively analyzed. The minimum follow-up period was 5 years. The median age was 36.5 (range 20-55) years. The median size and the depth of the OD lesion were 4.25 cm2 (range 2-6) and 7.0 mm (6-9), respectively. Clinically, the International Knee Documentation Committee, Lysholm, and visual analog scale pain scores were evaluated. Radiographically, the hip‒knee‒ankle (HKA) angle and the Kellgren‒Lawrence (K‒L) grade were assessed. On MR imaging, the magnetic resonance observation of cartilage repair tissue (MOCART) 2.0 score and the defect depth were evaluated. RESULTS: All average clinical scores improved significantly by 1, 2, and 5 years postoperatively. The average HKA angle and the proportion of K‒L grade did not change significantly within 5 years. The median total MOCART scores were 50 (range 45-65), 50 (35-90), 57.5 (40-90), and 65 (50-85) at 6 months, 1 year, 2 years, and 5 years postoperatively, respectively (p = 0.001), with significant improvement at 2 years compared to that at 6 months postoperatively. The signal intensity of the repair tissue and subchondral change significantly improved from 10 (range 10-10) to 12.5 (10-15) (p = 0.036), and from 10 (10-10) to 17.5 (0-20) (p = 0.017), respectively. Significant improvements were seen at 5 years postoperatively for the former and at 2 years postoperatively for the latter. The average depths on MR imaging were 6.7, 6.7, 6.8, 6.6, and 6.6 mm preoperatively and at 6 months, 1 year, 2 years, and 5 years postoperatively with no significant changes (n.s). CONCLUSION: CCP-ACI provided acceptable mid-term outcomes in ODs up to 10-mm in depth without bone grafting despite of no scaffold. The procedure can be one of minimally invasive treatment options for ODs without scaffold-related problems. LEVEL OF EVIDENCE: IV.