Clinical indications and protocol considerations for selecting initial body weight support levels in gait rehabilitation: a systematic review.

BACKGROUND: Body weight support (BWS) training devices are frequently used to improve gait in individuals with neurological impairments, but guidance in selecting an appropriate level of BWS is limited. Here, we aim to describe the initial BWS levels used during gait training, the rationale for this selection and the clinical goals aligned with BWS training for different diagnoses. METHOD: A systematic literature search was conducted in PubMed, Embase and Web of Science, including terms related to the population (individuals with neurological disorders), intervention (BWS training) and outcome (gait). Information on patient characteristics, type of BWS device, BWS level and training goals was extracted from the included articles. RESULTS: Thirty-three articles were included, which described outcomes using frame-based (stationary or mobile) and unidirectional ceiling-mounted devices on four diagnoses (multiple sclerosis (MS), spinal cord injury (SCI), stroke, traumatic brain injury (TBI)). The BWS levels were highest for individuals with MS (median: 75%, IQR: 6%), followed by SCI (median: 40%, IQR: 35%), stroke (median: 30%, IQR: 4.75%) and TBI (median: 15%, IQR: 0%). The included studies reported eleven different training goals. Reported BWS levels ranged between 30 and 75% for most of the training goals, without a clear relationship between BWS level, diagnosis, training goal and rationale for BWS selection. Training goals were achieved in all included studies. CONCLUSION: Initial BWS levels differ considerably between studies included in this review. The underlying rationale for these differences was not clearly motivated in the included studies. Variation in study designs and populations does not allow to draw a conclusion on the effectiveness of BWS levels. Hence, it remains difficult to formulate guidelines on optimal BWS settings for different diagnoses, BWS devices and training goals. Further efforts are required to establish clinical guidelines and to experimentally investigate which initial BWS levels are optimal for specific diagnoses and training goals.

Biomechanical Performance of Transtibial Pull-Out Posterior Horn Medial Meniscus Root Repair Is Improved With Knotless Adjustable Suture Anchor-Based Fixation.

Background: While posterior medial meniscus root (PMMR) techniques have evolved, there remains a need to both optimize repair strength and improve resistance to cyclic loading. Hypothesis: Adjustable tensioning would lead to higher initial repair strength and reduce displacement with cyclic loading compared with previously described transtibial pull-out repair (TPOR) fixation techniques. Study Design: Controlled laboratory study. Methods: A total of 56 porcine medial menisci were used. Eight intact specimens served as a control for the native meniscus. For the others, PMMR tears were created and repaired with 6 different TPOR techniques (8 in each group). Fixed PMMR repairs were executed using 4 different suture techniques (two No. 2 cinch sutures, two cinch tapes, two No. 2 simple sutures, and two No. 2 sutures in a Mason-Allen configuration) all tied over a cortical button. Adjustable PMMR repairs using Mason-Allen sutures were fixed with an adjustable soft tissue anchor fixation tensioned at either 80 N or 120 N. The initial force, stiffness, and relief displacement of the repairs were measured after fixation. Repair constructs were then cyclically loaded, with cyclic displacement and stiffness measured after 1000 cycles. Finally, the specimens were pulled to failure. Results: The PMMR repaired with the 2 cinch sutures fixed technique afforded the lowest (P < .001) initial repair load, stiffness, and relief displacement. The adjustable PMMR repairs achieved a higher initial repair load (P < .001) and relief displacement (P < .001) than all fixed repairs. The 2 cinch sutures fixed technique showed an overall higher cyclic displacement (P < .028) and was completely loose compared with the native meniscus functional zone. Repairs with adjustable intratunnel fixation showed displacement with cyclic loading similar to the native meniscus. With cyclic loading, the Mason-Allen adjustable repair with 120 N of tension showed less displacement (P < .016) than all fixed repairs and a stiffness comparable to the fixed Mason-Allen repair. The fixed Mason-Allen technique demonstrated a higher ultimate load (P < .007) than the adjustable Mason-Allen techniques. All repairs were less stiff, with lower ultimate failure loads, than the native meniscus root attachment (P < .0001). Conclusion: Adjustable TPOR led to considerably higher initial repair load and relief displacement than other conventional fixed repairs and restricted cyclic displacement to match the native meniscus function. However, the ultimate failure load of the adjustable devices was lower than that of a Mason-Allen construct tied over a cortical button. All repair techniques had a significantly lower load to failure than the native meniscus root. Clinical Relevance: Knotless adjustable PMMR repair based on soft anchor fixation results in higher tissue compression and less displacement, but the overall clinical significance on healing rates remains unclear.

Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease.

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast (TNNI2) and TnI-slow (TNNI1), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca2+] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca2+], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.

Quadriceps Tendon Autograft ACL Reconstruction With Suture Tape Augmentation: Safe Results Based on Minimum 2-Year Follow-up MRI.

Background: The potential intra-articular effects of ≥1 year after anterior cruciate ligament reconstruction (ACLR) with independent suture tape augmentation (STA) are not fully understood. Purpose: To investigate whether incorporating suture tape in an all-soft tissue quadriceps tendon autograft (QTA) ACLR leads to satisfactory patient outcomes while having no intra-articular side effects as determined by magnetic resonance imaging (MRI). Study Design: Case series; Level of evidence, 4. Methods: Included were 25 patients with a mean age of 19.9 years (95% CI, 17.3-22.5 years) who underwent QTA ACLR with STA between 2016 and 2019. All patients underwent MRI at ≥1 year postoperatively and had at least a 2-year follow-up (mean, 28 months [95% CI, 26.5-29.5 months]) that included physical examination with anterior laxity testing with KT-1000 arthrometer, radiographs, and patient-reported outcome measures (PROMs). At the final follow-up, the minimal clinically important difference (MCID) and the Patient Acceptable Symptom State (PASS) for applicable PROMs were applied to each patient. Postoperative graft and joint integrity were assessed using the Howell classification and the MRI Osteoarthritis Knee Score (MOAKS) joint effusion/synovitis grade. The Mann-Whitney U test for continuous variables and the chi-square or the Fisher exact test for categorical variables were used for statistical analyses. Results: The MRI assessment of the grafts demonstrated intact grafts in all patients. Overall, 96% of patients demonstrated grades 0 or 1 MOAKS for joint effusion/synovitis. All patient outcomes significantly improved from preoperatively to the final follow-up (P < .001), except for the Marx score, which decreased significantly (14.2 [95% CI, 12.7-15.8] vs 9.72 [95% CI, 7.3-12.2]; P = .0014). At least 68% of the patients achieved the MCID threshold, and 92% achieved the PASS threshold for all applicable PROMs. Conclusion: QTA ACLR with STA did not demonstrate adverse intra-articular changes on MRI at ≥1 year postoperatively. In addition, STA did not appear to negatively affect PROMs.

Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy.

Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.

Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.

Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.

Preoperative 3-dimensional computed tomography bone density measures provide objective bone quality classifications for stemless anatomic total shoulder arthroplasty.

BACKGROUND: Reproducible methods for determining adequate bone densities for stemless anatomic total shoulder arthroplasty (aTSA) are currently lacking. The purpose of this study was to evaluate the utility of preoperative computed tomography (CT) imaging for assessing the bone density of the proximal humerus for supportive differentiation in the decision making for stemless humeral component implantation. It was hypothesized that preoperative 3-dimensional (3-D) CT bone density measures provide objective classifications of the bone quality for stemless aTSA. METHODS: A 3-part study was performed that included the analysis of cadaveric humerus CT scans followed by retrospective application to a clinical cohort and classification with a machine learning model. Thirty cadaveric humeri were evaluated with clinical CT and micro-CT (µCT) imaging. Phantom-calibrated CT data were used to extract 3-D regions of interest and defined radiographic scores. The final image processing script was applied retrospectively to a clinical cohort (n = 150) that had a preoperative CT and intraoperative bone density assessment using the "thumb test," followed by placement of an anatomic stemmed or stemless humeral component. Postscan patient-specific calibration was used to improve the functionality and accuracy of the density analysis. A machine learning model (Support vector machine [SVM]) was utilized to improve the classification of bone densities for a stemless humeral component. RESULTS: The image processing of clinical CT images demonstrated good to excellent accuracy for cylindrical cancellous bone densities (metaphysis [ICC = 0.986] and epiphysis [ICC = 0.883]). Patient-specific internal calibration significantly reduced biases and unwanted variance compared with standard HU CT scans (P < .0001). The SVM showed optimized prediction accuracy compared with conventional statistics with an accuracy of 73.9% and an AUC of 0.83 based on the intraoperative decision of the surgeon. The SVM model based on density clusters increased the accuracy of the bone quality classification to 87.3% with an AUC of 0.93. CONCLUSIONS: Preoperative CT imaging allows accurate evaluation of the bone densities in the proximal humerus. Three-dimensional regions of interest, rescaling using patient-specific calibration, and a machine learning model resulted in good to excellent prediction for objective bone quality classification. This approach may provide an objective tool extending preoperative selection criteria for stemless humeral component implantation.

Tape-Reinforced Graft Suturing and Retensioning of Adjustable-Loop Cortical Buttons Improve Quadriceps Tendon Autograft Biomechanics in Anterior Cruciate Ligament Reconstruction: A Cadaveric Study.

PURPOSE: To investigate the biomechanical effects of tape-reinforced graft suturing and graft retensioning for all-soft tissue quadriceps tendon (ASTQT) anterior cruciate ligament reconstruction (ACLR) in a full-construct human cadaveric model. METHODS: Harvested cadaveric ASTQT grafts were assigned to either (1) double-suspensory adjustable-loop cortical button device (ALD) fixation in which both graft ends were fixed with a suspensory fixation device with (n = 5) or without (n = 5) tape-reinforced suturing or (2) single-suspensory distal tendon fixation in which only the patellar end was fixed with an ALD (n = 5) or fixed-loop cortical button device (FLD) (n = 5). All specimens were prepared using a No. 2 whipstitch technique, and tape-reinforced specimens had an integrated braided tape implant. Graft preparation time was recorded for double-suspensory constructs. Samples were tested on an electromechanical testing machine using a previously published protocol simulating rehabilitative kinematics and loading. RESULTS: Tape-reinforced graft suturing resulted in greater graft load retention after cycling (11.9% difference, P = .021), less total elongation (mean [95% confidence interval (CI)], 5.57 mm [3.50-7.65 mm] vs 32.14 mm [25.38-38.90 mm]; P < .001), greater ultimate failure stiffness (mean [95% CI], 171.9 N/mm [158.8-185.0 N/mm] vs 119.4 N/mm [108.7-130.0 N/mm]; P < .001), and less graft preparation time (36.4% difference, P < .001) when compared with unreinforced specimens. Retensioned ALD constructs had less cyclic elongation compared with FLD constructs (mean total elongation [95% CI], 7.04 mm [5.47-8.61 mm] vs 12.96 mm [8.67-17.26 mm]; P = .004). CONCLUSIONS: Tape-reinforced graft suturing improves time-zero ASTQT ACLR construct biomechanics in a cadaveric model with 83% less total elongation, 44% greater stiffness, and reduced preparation time compared with a whipstitched graft without tape reinforcement. ALD fixation improves construct mechanics when compared with FLD fixation as evidenced by 46% less total elongation. CLINICAL RELEVANCE: Tape-reinforced implants and graft retensioning using ALDs improve time-zero ACLR graft construct biomechanics in a time-zero biomechanical model. Clinical studies will be necessary to determine whether these implants improve clinical outcomes including knee laxity and the incidence of graft rupture.

Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with granulomatosis with polyangiitis.

OBJECTIVES: Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory, as it relies on strong immunosuppressive regimens, with either CYC or rituximab, which reduce the immunogenicity of several vaccines and are risk factors for a severe form of COVID-19. This emphasizes the need to identify new drug targets and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. METHODS: Peripheral blood samples from 27 patients with GPA in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with phorbol myristate acetate, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+ T helper (CD4+TH) cells were assessed using flow cytometry. RESULTS: ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17 and IL-21 in CD4+TH cells from patients with GPA in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. CONCLUSIONS: Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis.

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27+ memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-ß (IKKß, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement.

Stroke survivors' long-term participation in paid employment.

BACKGROUND: Knowledge on long-term participation is scarce for patients with paid employment at the time of stroke. OBJECTIVE: Describe the characteristics and the course of participation (paid employment and overall participation) in patients who did and did not remain in paid employment. METHODS: Patients with paid employment at the time of stroke completed questions on work up to 30 months after starting rehabilitation, and the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P, Frequency, Restrictions and Satisfaction scales) up to 24 months. Baseline characteristics of patients with and without paid employment at 30 months were compared using Fisher's Exact Tests and Mann-Whitney U Tests. USER-P scores over time were analysed using Linear Mixed Models. RESULTS: Of the 170 included patients (median age 54.2 interquartile range 11.2 years; 40% women) 50.6% reported paid employment at 30 months. Those returning to work reported at baseline more working hours, better quality of life and communication, were more often self-employed and in an office job. The USER-P scores did not change statistically significantly over time. CONCLUSION: About half of the stroke patients remained in paid employment. Optimizing interventions for returning to work and achieving meaningful participation outside of employment seem desirable.

Clinical Work-Integrating Care in Current Practice: A Scoping Review.

PURPOSE: Clinical work-integrating care (CWIC) refers to paying attention to work participation in a clinical setting. Working patients may benefit from CWIC. The purpose of this study is to explore the extent and nature to which medical specialists provide CWIC and what policies and guidelines oblige or recommend specialists to do. METHODS: A scoping review was conducted. The databases MEDLINE, EMBASE, Psychinfo, CINAHL, and Web of Science were searched for studies on the extent and nature of CWIC and supplemented by gray literature on policies and guidelines. Six main categories were defined a priori. Applying a meta-aggregative approach, subcategories were subsequently defined using qualitative data. Next, quantitative findings were integrated into these subcategories. A separate narrative of policies and guidelines using the same main categories was constructed. RESULTS: In total, 70 studies and 55 gray literature documents were included. The main findings per category were as follows: (1) collecting data on the occupation of patients varied widely; (2) most specialists did not routinely discuss work, but recent studies showed an increasing tendency to do so, which corresponds to recent policies and guidelines; (3) work-related advice ranged from general advice to patient-physician collaboration about work-related decisions; (4) CWIC was driven by legislation in many countries; (5) specialists sometimes collaborated in multidisciplinary teams to provide CWIC; and (6) medical guidelines regarding CWIC were generally not available. CONCLUSION: Medical specialists provide a wide variety of CWIC ranging from assessing a patient's occupation to extensive collaboration with patients and other professionals to support work participation. Lack of medical guidelines could explain the variety of these practices.

Geranylgeranylacetone reduces cardiomyocyte stiffness and attenuates diastolic dysfunction in a rat model of cardiometabolic syndrome.

Titin-dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure-overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty-one-week-old male lean (n = 10) and obese (n = 20) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200 mg/kg/day) or vehicle by oral gavage for 4 weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25 weeks of age. Titin-based stiffness (Fpassive ) was determined by force measurements in relaxing solution with 100 nM [Ca2+ ] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4 µm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament-bound HSPB5 and HSPB1 expression. Vehicle-treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0 µm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament-bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome.

The elevation of the anion gap in steady state chronic kidney disease may be less prominent than generally accepted.

Background: A presumed cause of metabolic acidosis in chronic kidney disease (CKD) is accumulation of unmeasured anions, leading to a high anion gap (AG). In patients with CKD with a high AG, only minor increases are expected. The aim of this study is to evaluate the magnitude of the AG in documented steady state CKD to examine the effect of CKD on a high-AG metabolic acidosis (HAGMA). Methods: In this cross-sectional study the AG, bicarbonate, and chloride were evaluated in 1045 blood and urine samples of 501 patients with steady state CKD in the outpatient clinic. The influence of phosphate, albumin and potassium on the AG were evaluated. Results: The mean AG increased from 8.8 mEq/l (±1.57) in CKD stage 1 to 11.2 mEq/l (±2.22) in CKD stage 5 (P < 0.001). Correction for albumin or phosphate did not influence the magnitude of the AG. Correction for potassium did alter the prevalence of HAGMA, but not the severity. [HCO3-] decreased between CKD stages 1 and 5 by 5.1 mEq/l. The [Cl-] increased by 2.6 mEq/l between CKD stages 1 and 5. Conclusions: The elevation of the AG in patients with steady state CKD is limited and less pronounced than the decrease in [HCO3-]. Normal AG metabolic acidosis seems to be more important in CKD than HAGMA. The CKD stage and the magnitude of the AG should be taken into account when evaluating a patient with HAGMA. This study suggests that an AG >15 mEq/l is rarely due to renal failure alone.

Stabilization and Gap Formation of Adjustable Versus Fixed Primary ACL Repair With Internal Brace: An in Vitro Full-Construct Biomechanical Cadaveric Study.

Background: A knotless, tensionable primary anterior cruciate ligament (ACL) repair system preloaded with an internal brace has been released. Currently, there is no biomechanical data on the stabilization and gap formation behavior of the adjustable system when compared with fixed repairs in human ACL tissue. Hypothesis: That knotless adjustable suture repair with an internal brace would provide overall higher construct stability and greater load share on the ACL with less gap formation compared with fixed repair. Study Design: Controlled laboratory study. Methods: Human cadaveric knees were utilized for internal braced ACL repair constructs (each group n = 16). Two fixed groups consisting of a single-cinch loop (SCL), cortical button (SCL group), and knotless suture-anchor (anchor group) were compared with an SCL-adjustable loop device (SCL-ALD) group. Testing was performed at 4 different peak loads (50, 150, 250, 350 N) over 4000 cycles at 0.75 Hz including suture repair preconditioning (10 cycles at 0.5 Hz) for SCL-ALD. Specimens were ultimately pulled to failure with a cut internal brace. The final loading situation of the construct and ACL repair with gap formation and ultimate strength were evaluated. Results: Peak elongation at various peak loads showed a significantly higher (P < .001) stabilization of SCL-ALD when compared with both fixed groups. There was a significantly higher (P < .001) load share of SCL-ALD, especially at lower loads (48% of 50 N), and the gap formation remained restricted up to 250 N. With only a little load share on the fixed constructs (<6%) at lower loads (50, 150 N), gap formation in these groups started at a load of 150 N, leading to significantly higher gaps (P < .001). The ultimate failure load for SCL-ALD and anchor groups was significantly increased (P < .001) as compared with SCL. The stiffness of SCL-ALD (62.9 ± 10.6 N/mm) was significantly increased (P < .001). Conclusion: Internal braced knotless adjustable fixation for ACL repair with preconditioning of the suture repaired ligament increased the overall stabilization with higher load share on the ACL and restricted gap formation (<0.5 mm up to 350 N) compared with fixed suture repair. All internal braced repairs restored stability according to native ACL function. Clinical Relevance: Adjustable ACL repair improved the mechanical characteristics and reduced gap formation, but the overall clinical significance on healing remains unclear.

Biomechanical Comparison of 3 Adjustable-Loop Suspensory Devices for All-Inside ACL Reconstruction: A Time-Zero Full-Construct Model.

Background: Little is known about the stability of adjustable-loop devices (ALDs) for anterior cruciate ligament (ACL) reconstruction (ACLR). Purpose: To evaluate the stabilization behavior of 3 different types of ALDs for all-inside ACLR in a full-construct surgical technique-based manner. Study Design: Controlled laboratory study. Methods: The femoral and tibial devices of Ultrabutton (Smith & Nephew), Infinity (Conmed), and TightRope II (Arthrex) were applied to quadrupled bovine tendon grafts (n = 8 each) with tibial-sided traction applied (350 N) for graft tensioning in a simulated fully extended knee. Knotless femoral graft fixation was based on either a suture-locking device (SLD; Ultrabutton), button-locking device (BLD; Infinity), or dual-locking device (DLD; TightRope II). All constructs were progressively loaded (50 N/500 cycles) from 50 to 300 N for 3000 cycles (0.75 Hz), including complete unloading situations and pull to failure (50 mm/min). Construct elongation, stiffness, and ultimate load were analyzed. Results: BLD showed significantly greater initial elongation (-2.69 ± 0.15 mm) than DLD (-3.19 ± 0.21 mm; P < .001) but behaved similarly to SLD (-2.93 ± 0.23 mm). While DLD and SLD had the smallest initial elongation at the same significance level, they behaved opposite to each other with gradually increasing peak loading. At the end of testing, DLD had the lowest (-0.64 ± 0.32 mm) and SLD the highest (3.41 ± 1.01 mm) total elongation (P < .003 for both). SLD displayed significantly higher dynamic elongation (6.34 ± 0.23 mm) than BLD (3.21 ± 0.61 mm) and DLD (2.56 ± 0.31 mm) (P < .001 for both). The failure load of BLD (865.0 ± 183.8 N) was significantly lower (P < .026) compared with SLD and DLD (>1000 N). The predominant failure mode was suture rupture and tibial bone breakage with button subsidence (SLD, n = 4). No significant difference in stiffness between constructs was found. Conclusion: While DLD successfully restricted critical construct elongation, BLD partially and SLD completely exceeded the clinical failure threshold (>3 mm) of plastic elongation with loop lengthening during increasing cyclic peak loading with complete unloading. Higher failure loads of SLD and DLD implants (>1000 N) were achieved at similar construct stiffness to BLD. Clinical Relevance: A detailed biomechanical understanding of the stabilization potential is pertinent to the continued evolution of ALDs to improve clinical outcomes.

Specific IgG glycosylation differences precede relapse in PR3-ANCA associated vasculitis patients with and without ANCA rise.

Introduction: Immunoglobulin G (IgG) contains a conserved N-glycan in the fragment crystallizable (Fc), modulating its structure and effector functions. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) alterations of IgG Fc-glycosylation have been observed to correlate with the disease course. Here, we examined longitudinal changes in N-linked Fc glycans of IgG in an AAV patient cohort and their relationship with disease flares. Methods: Using liquid chromatography coupled with mass spectrometry, we analysed IgG Fc-glycosylation in 410 longitudinal samples from 96 individuals with AAV. Results: Analysis of the cross-sectional differences as well as longitudinal changes demonstrated that IgGs of relapsing PR3-ANCA patients have higher ΔFc-bisection at diagnosis (P = 0.004) and exhibit a decrease in Fc-sialylation prior to the relapse (P = 0.0004), discriminating them from non-relapsing patients. Most importantly, PR3-ANCA patients who experienced an ANCA rise and relapsed shortly thereafter, exhibit lower IgG Fc-fucosylation levels compared to non-relapsing patients already 9 months before relapse (P = 0.02). Discussion: Our data indicate that IgG Fc-bisection correlates with long-term treatment outcome, while lower IgG Fc-fucosylation and sialylation associate with impending relapse. Overall, our study replicated the previously published reduction in total IgG Fc-sialylation at the time of relapse, but showed additionally that its onset precedes relapse. Furthermore, our findings on IgG fucosylation and bisection are entirely new. All these IgG Fc-glycosylation features may have the potential to predict a relapse either independently or in combination with known risk factors, such as a rise in ANCA titre.

External ureteric stent versus internal double J stent in kidney transplantation: a retrospective analysis on the incidence of urological complications and urinary tract infections.

Introduction: Urologic complications (UCs) and urinary tract infections (UTIs) are common after kidney transplantation. Intraoperative stent placement at the vesicoureteric anastomosis reduces UC risk, but increases UTI risk. Methods: In 2014 our stenting protocol changed from external ureteric stent (ES) to internal double J stent (DJ). We retrospectively studied the occurrence of UCs and UTIs in relation to ES or DJ in 697 kidney recipients. Methods: An ES was used in 403 patients (57.8%), in 294 (42.2%) a DJ. ES was removed 7-12 days and DJ 3-4 weeks post-operative. Induction immunosuppression was the same in both groups. Primary outcomes at 6 months follow-up were UC (urinary leakage/ureter stenosis) and UTI; they were related to stenting procedure and clinical and transplant characteristics. The incidence of UCs was similar for ES (8.4%) and DJ (6.8%), p=0.389. ES use was a significant risk factor for UTI (OR 1.69 (1.15-2.50), p=0.008). Post-transplant hospitalization was significantly shorter in the DJ group. Despite more acute rejection episodes with ES (ES/DJ: 16.4%/6.1%, p<0.001), no clinical relevant differences in graft outcomes existed. Discussion: A DJ is, compared to ES, associated with a lower incidence of UTIs and comparable occurrence of UCs and is therefore the preferred technique for stenting the vesicoureteric anastomosis.

Primary Stability and Bone Contact Loading Evaluation of Suture and Screw based Coracoid Graft Fixation for Anterior Glenoid Bone Loss.

BACKGROUND: Reconstruction techniques for anterior glenoid bone loss have seen a trend from screws to suture-based fixations. However, comparative biomechanical data, including primary fixation and glenoid-graft contact pressure mapping, are limited. HYPOTHESIS: Suture-based bone block cerclage (BBC) and suspensory suture button (SB) techniques provide similar primary fixation and cyclic stability to double-screw fixation but with higher contact loading at the bony interface. STUDY DESIGN: Controlled laboratory study. METHODS: In total, 60 cadaveric scapulae were prepared to simulate anterior glenoid bone loss with coracoid autograft reconstruction. Graft fixation was performed with 3 different techniques: (1) an interconnected all-suture BBC, (2) 2 SB suspensions, and (3) 2 screws. Initial compression was analyzed during primary fixation. Cyclic peak loading with 50 N and 100 N over 250 cycles at 1 Hz was performed with a constant valley load of 25 N. Optical recording and pressure foils allowed for spatial bone block tracking and contact pressure mapping at the glenoid-graft interface. Load-to-failure testing was performed at a rate of 1.5 mm/s with ultimate load and stiffness measured. RESULTS: Initial graft compression was higher with screw fixation (141 ± 5 N) compared with suture-based fixations (P < .001), with BBC fixation providing significantly higher compression than SB fixation (116 ± 7 N vs. 91 ± 5 N; P < .001). Spatial bone block migration and ultimate failure load were similar between the BBC and screw groups. The SB group showed significantly increased bone block translation (3.1 ± 1.0 mm; P≤ .014) and rotation (2.5°± 1.4°; P≤ .025) and significantly lower ultimate failure load (180 ± 53 N) compared with the BBC (P = .046) and screw (P = .002) groups. Both suture-based fixations provided significantly increased graft-glenoid contact loading with higher pressure amplitudes (P≤ .032) and contact pressure after cyclic loading (+13%; SB: P = .007; BBC: P = .004) compared with screw fixation. CONCLUSION: Both SB and interconnected cerclage fixation improved dynamic contact loading compared with screw fixation in a biomechanical glenoid bone loss model. Cerclage fixation was biomechanically comparable with screw fixation but with a greater variability. SB fixation showed significantly lower primary fixation strength and greater bone block rotation and migration. CLINICAL RELEVANCE: Suture-based bone block fixations improved graft-glenoid contact loading, but the overall clinical consequence on healing remains unclear.