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Aims: The aim of this study was to perform a systematic review and bias evaluation of the current literature to create an overview of risk factors for re-revision following revision total knee arthroplasty (rTKA). Methods: A systematic search of MEDLINE and Embase was completed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The studies were required to include a population of index rTKAs. Primary or secondary outcomes had to be re-revision. The association between preoperative factors and the effect on the risk for re-revision was also required to be reported by the studies. Results: The search yielded 4,847 studies, of which 15 were included. A majority of the studies were retrospective cohorts or registry studies. In total, 26 significant risk factors for re-revision were identified. Of these, the following risk factors were consistent across multiple studies: age at the time of index revision, male sex, index revision being partial revision, and index revision due to infection. Modifiable risk factors were opioid use, BMI > 40 kg/m2, and anaemia. History of one-stage revision due to infection was associated with the highest risk of re-revision. Conclusion: Overall, 26 risk factors have been associated with an increased risk of re-revision following rTKA. However, various levels of methodological bias were found in the studies. Future studies should ensure valid comparisons by including patients with identical indications and using clear definitions for accurate assessments. Cite this article: Bone Jt Open 2024;5(8):644–651.

Background/Objectives: Genicular artery embolization (GAE) has demonstrated potential as a treatment for knee osteoarthritis by targeting inflammation and pain, although current evidence remains limited. This study used imaging biomarkers to objectively assess synovitis and possible ischemic complications following GAE. Methods: This was a prospective, single-center trial including participants with mild-to-moderate knee osteoarthritis. Ultrasound, contrast-enhanced (CE), and non-CE-MRI were performed two days before and one and six months after GAE. Ultrasound biomarkers included synovial hypertrophy, effusion, and Doppler activity. A combined effusion-synovitis score was assessed on non-CE-MRI, while CE-MRI allowed differentiation between synovium and effusion and was used to calculate whole-joint and local synovitis scores. The post-GAE MRIs were reviewed for ischemic complications. Results: Seventeen participants (aged 43–71) were treated. Significant reductions were observed in ultrasound-assessed synovial hypertrophy and Doppler activity, as well as in CE-MRI local and whole-joint synovitis scores. While reductions in effusion were noted in both ultrasound and MRI, these changes did not reach statistical significance. At one month, MRI revealed three cases of nonspecific osteonecrosis-like areas, which resolved completely by six months. Conclusions: This study demonstrated a reduction in synovitis and no permanent ischemic complication following GAE in knee osteoarthritis. Larger studies with longer follow-up are needed to confirm the long-term efficacy and safety of the procedure.

Knee osteoarthritis (OA) affects millions worldwide, leading to pain and reduced quality of life. Conventional treatments often fail to provide adequate relief, necessitating new therapeutic approaches. This study evaluated the efficacy and safety of genicular artery embolization (GAE) using permanent microspheres in patients with mild-to-moderate knee OA. In this prospective, single-center study, 17 participants underwent GAE. KOOS (Knee injury and Osteoarthritis Outcome Score), WOMAC (The Western Ontario and McMaster Universities Arthritis Index), and IPAQ (International Physical Activity Questionnaire) scores, along with physical performance tests, medication use, and dual-energy X-ray absorptiometry (DEXA) scans, were assessed at baseline and at multiple follow-up points over six months. The primary endpoint, VAS at six months, showed significant improvement (median reduction from 66 mm to 40 mm, p = 0.0004). All pain and function scores, as well as physical performance tests, improved significantly. No clinically relevant changes in medication use or DEXA parameters were observed after six months. Only minor, self-limiting adverse events occurred. This study indicates that GAE is a promising minimally invasive treatment for knee OA, providing significant pain relief and functional improvement. However, further long-term, randomized trials are needed to confirm these findings and establish optimal patient selection criteria.

Abstract Background Inferior scapular notching is a complication unique to reverse shoulder arthroplasty. The most efficient technique to avoid inferior scapular notching has been reported to be lateralization of the glenoid offset. This study aims to compare radiological and functional outcomes of the DELTA Xtend® Reverse Shoulder System Lateralized Glenosphere Line Extension (intervention group) with the Standard DELTA Xtend® Reverse Shoulder System (control group). We hypothesize that the lateralization improves the patient outcome by decreasing the risk of inferior scapular notching without increasing the risk of migration and loosening of glenoid component. Methods In this randomized controlled trial, all Danish citizens with rotator cuff arthropathy or degeneration of the glenohumeral joint with severe posterior wear and allocated for a reverse total shoulder arthroplasty at the department of orthopaedic surgery at Herlev and Gentofte Hospital, Copenhagen University Hospital, will be considered for participation. The exclusion criteria are as follows: below 50 years of age, cognitive or linguistic impairment, insufficient glenoid bone stock, previous fracture in the upper extremity and autoimmune-mediated inflammatory arthritis. There will be included a total of 122 patients of which 56 will participate in the radiostereometric analysis. This number of patients allows 20% to drop out. The co-primary outcomes are the pattern and magnitude of the migration of the glenoid component assessed by radiostereometric analysis and the Western Ontario Osteoarthritis of the Shoulder index. The secondary outcomes are inferior scapular notching, patient-reported and functional outcomes (Oxford shoulder score, Constant-Murley score and pain), side effects and complications, changes in bone mineral density and economy. The included patients will be examined before the surgery, within 1 week and 3, 6, 12 and 24 months after. Discussion No previous studies have compared the conventional reverse shoulder arthroplasty with the lateralized reverse shoulder arthroplasty in a randomized controlled trial regarding migration and functional outcome. Furthermore, radiostereometric analysis has not been used to evaluate the migration of reverse shoulder arthroplasty in a randomized controlled trial. This study intends to determine which treatment has the most optimal outcome for the benefit of future patients with an indication for reverse shoulder arthroplasty. Trial registration The study has been notified to Pactius and has approval number P-2021-231. Furthermore, the study will be registered on Clinicaltrials.gov before starting the inclusion.

BackgroundPain is a common complication for patients with metastatic bone disease. Animal models suggest that the pain, in part, is driven by pathological sprouting and reorganization of the nerve fibers innervating the bone. Here, we investigate how these findings translate to humans.MethodsBone biopsies were collected from healthy volunteers (n = 7) and patients with breast cancer and metastatic bone disease (permissions H-15000679, S-20180057 and S-20110112). Cancer-infiltrated biopsies were from patients without recent anticancer treatment (n = 10), patients with recent anticancer treatment (n = 10), and patients with joint replacement surgery (n = 9). Adjacent bone sections were stained for (1) protein gene product 9.5 and CD34, and (2) cytokeratin 7 and 19. Histomorphometry was used to estimate the area of bone marrow and tumor burden. Nerve profiles were counted, and the nerve profile density calculated. The location of each nerve profile within 25 μm of a vascular structure and/or cancer cells was determined.ResultsCancer-infiltrated bone tissue demonstrated a significantly higher nerve profile density compared to healthy bone tissue. The percentage of nerve profiles found close to vascular structures was significantly lower in cancer-infiltrated bone tissue. No difference was found in the percentage of nerve profiles located close to cancer between the subgroups of cancer-infiltrated bone tissue. Interestingly, no correlation was found between nerve profile density and tumor burden.ConclusionsTogether, the increased nerve profile density and the decreased association of nerve profiles to vasculature strongly suggests that neuronal sprouting and reorganization occurs in human cancer-infiltrated bone tissue.

Abstract Background Glenohumeral osteoarthritis can, in the most severe cases, require surgery with insertion of a shoulder arthroplasty. A design with a stem in the humeral bone canal is currently regarded as the standard treatment option in patients who have an intact rotator cuff function, but complications related to the stem including humeral fractures can have devastating consequences. By using a stemless humeral component, stem-related complications can be reduced. The aim of this study is to compare the Comprehensive Nano stemless total shoulder arthroplasty (intervention group) with the Comprehensive stemmed total shoulder arthroplasty (control group). Materials and methods This is a randomized controlled trial comparing the stemless and the stemmed total shoulder arthroplasty. All Danish citizens with glenohumeral osteoarthritis indicating a total shoulder arthroplasty referred to the orthopedic department at Copenhagen University Hospital in Herlev/Gentofte will be offered participation. The following exclude from participation: below 18 years of age, cognitive or linguistic impairment, insufficient function of the rotator cuff, poor bone quality, and ASA groups 4–5. A total of 122 patients will be included of which 56 will be part of a radiostereometric analysis (RSA) study of humeral component migration. The primary outcomes are magnitude of migration of the humeral component assessed by RSA and patient-reported outcome by Western Ontario Osteoarthritis of the Shoulder index (WOOS). The secondary outcomes are additional patient-reported outcomes, functional outcome, readmission, complications, revisions, and changes in bone mineral density (BMD) of the proximal humerus assessed by duel energy x-ray absorptiometry (DXA) and economy (cost-utility analysis). The patients are examined before the operation and 3, 6, 12, and 24 months postoperative. Discussion To our knowledge, RSA has never been used to access migration of a stemmed or a stemless humeral component nor has the stemmed and the stemless humeral component been compared with regard to pain relief and shoulder function in a randomized clinical trial. Today, the two designs are considered equal in the treatment of osteoarthritis. The study will provide surgeons and patients with information about shoulder arthroplasty for osteoarthritis and assist them in decision-making. Trial registration ClinicalTrials.gov NCT04105478 . Registered on 25 September 2019

Background. Sarcoma is a rare type of cancer with nonspecific symptoms and uncertain aetiology. Thus, timely diagnosis of sarcomas is a clinical challenge. The aim of this study was to investigate the use of healthcare services 24 months preceding a sarcoma diagnosis compared to a matched cohort. Materials and Methods. The study was a retrospective, population-based, matched cohort registry-study. Patients with sarcoma in Denmark in 2000–2013 were identified in the Danish Sarcoma Registry (n = 2167) and matched 1 : 10 on gender, age, and listed general practice. Using a binomial regression model, incidence rate ratios were calculated for face-to-face contacts in general practice, inpatient and outpatient visits, surgery, paraclinical examinations, and diagnostic imaging. Analyses were stratified for sarcoma subtypes, grade, stage, gender, and presence of comorbidity. Results. The sarcoma patients had significantly increased incidence rate ratios in use of healthcare services compared to the matched cohort a year before their diagnoses. An increase in consultation rates was seen 11 months before diagnosis for inpatient visits, 9 months before diagnosis in general practice and outpatient visits, 8 months before diagnosis for paraclinical examinations, and 4 and 3 months before diagnosis for diagnostic imaging and surgery, respectively. There were no clinical significant differences in length of increased consultation rates between sarcoma type, stage, and grade. Sarcoma patients with comorbidity had persistently higher consultation rates compared to patients without comorbidity. Conclusions. The use of healthcare services among sarcoma patients increased several months before diagnosis in all healthcare sectors. The results reveal a diagnostic time window and a potential to refer, diagnose, and treat sarcoma patients in a timelier manner.

Background. Compared to conventional hip arthroplasty, endoprosthetic reconstruction after tumor resection is associated with a substantially increased risk of periprosthetic joint infection (PJI), with reported rates of around 10% in a recent systematic review. The optimal duration of antibiotic prophylaxis for this patient population remains unknown. Material and Methods. To establish the infection rate associated with prolonged antibiotic prophylaxis in our department, we performed a retrospective review of all adult patients who underwent endoprosthetic reconstruction of the proximal femur after tumor resection for metastatic bone disease during a 4-year period from 2010 to 2013 (n=105 patients). Results. Intravenous antibiotic prophylaxis was administrated for an extended duration of a mean of 7.4 days. The overall infection rate was 3.6% (4/111 implants), infection free survival was 96% at 2 years, and the risk of amputation associated with infection was 25% (1/4 patients). Discussion. Preemptive eradication of bacterial contamination may be of value in certain clinical situations, where the risk level and consequences of implant-associated infection are unacceptable. Our findings suggest that extended postoperative antibiotic prophylaxis may reduce the risk of PJI in patients undergoing tumor resection and endoprosthetic replacement for metastatic bone disease associated impending or de facto pathologic fractures of the proximal femur.

Purpose. To assess the metastatic pattern of the histological subtype myxoid liposarcoma (MLS) with no or few round cells. Methods. Forty-five patients (F/M = 27/18, mean age 49 (range 17–85) years) were diagnosed with MLS at two Danish sarcoma centres in the period 1995–2004. A retrospective review of patients' files combined with an extraction of survival data from the Danish Centralised Civil Register was performed. Results. Seven patients had distant metastases during the observation period. Two patients had metastases at the time of diagnosis, while metastases occurred within 2.5 years in four patients, and in one patient 11.9 years after primary diagnosis. All metastases occurred at extrapulmonary sites. The first local relapse occurred within 3 years after surgery in six patients, in one patient after 4.0 years, and in one patient 7.7 years after surgery. The 5- and 10-year overall survival was 80% and 69%, respectively. Both the 5- and 10-year distant metastases-free survival was, respectively, 86%. The 5- and 10-year local relapse-free survival was, respectively, 83% and 80%. Conclusions. Patients with MLS had only extra-pulmonary metastases, and no lung metastases were found. Most local relapses and distant metastases occurred within the first 2-3 years after surgery.

Purpose: The primary aim of our study was to identify the absolute incidence and implant survival of multiply revised knee arthroplasties based on nationwide register data. The secondary aim was to determine the change in the absolute incidence and implant survival of multiply revised knee arthroplasties Methods: We performed a retrospective observational study of primary knee arthroplasties using several nationwide Danish registers. All primary knee arthroplasties performed in Denmark from 1998 to 2021 were identified. From these primary arthroplasties, revision procedures were identified. Kaplan–Meier plots were used in survival analysis to estimate the likelihood of implant survival. Results: 161,384 primary knee arthroplasties and their revisions performed between 1998 and 2021 were identified; of 13,786 (8.5%) revisions there were 10,638 1st revisions, 2,148 2nd revisions, 624 3rd revisions, 223 4th revisions, and 153 procedures that had been revised more than 4 times. The 10-year revision-free survival of primary arthroplasties was 92.3% (95% confidence interval [CI] 92.2–92.5). First-time revisions had a 10-year revision-free survival of 75.9% (CI 74.9–76.9). The 10-year survival of second- and third-time revisions was 65.1% (CI 62.6–67.6) and 57.8% (CI 53.4–62.5), respectively. The 10-year implant survival probabilities of primary knee arthroplasties were 91.4% in 1998–2009 and 93.3% in 2010–2021 (difference 2.2%). The 10-year implant survival probabilities of 1st revisions were 77% in 1998–2009 and 75% in 2010–2021 (difference –2.4%). Conclusion: We found that 0.3% of all primary knee arthroplasties resulted in 3 or more revisions. The implant survival decreased for each consecutive revision, with almost half of the 3rd revisions being re-revised within 10 years. The 10-survival of the primary implant was higher in 2010–2021, and the 10-year survival of the 1st revision was higher in 1998–2009.

Conclusion: In complex cases of revision THA, using a modular revision femoral system yielded promising results. The 5-year implant survival estimated by Kaplan–Meier survival analysis was 95% (95%-CI: 91%–99%), with all hips demonstrating radiographic evidence of osseointegration and no one with subsidence greater than 5 mm. Notably 80% showed radiographic evidence of restoration of proximal femoral bone.

Purpose Polymethyl-methacrylate cement (PMMA) is often used as bone defect reconstruction material after surgical removal of giant cell tumors. The purpose of this study was to investigate if the application of PMMA improves the local recurrence rates for giant cell tumors (GCT) of appendicular bone treated with intralesional curettage. Methods A retrospective analysis of all appendicular GTCs treated at two major Danish sarcoma centres between the 1 st of January 1998 and December 31 st 2013; minimum follow-up of 3.0 years (median: 8.9; 1.3–18.7 years). Kaplan-Meier survival model, log-rank and multivariate Cox regression were used to calculate and compare local recurrence rates. p -values

Background and purpose: Surgery for bone metastases in the appendicular skeleton (aBM) is a trade-off between limb function and survival. A previous study from a highly specialized center found that extended surgery is not a risk for 30-day mortality and hypothesized that wide resection and reconstruction might reduce postoperative mortality. The study aimed to investigate whether parameters describing the surgical trauma (blood loss, duration of surgery, and degree of bone resection) pose a risk for 30-day mortality in patients treated with endoprostheses (EPR) or internal fixation (IF) in a population-based cohort. Patients and methods: A population-based cohort having EPR/IF for aBM in the Capital Region of Denmark 2014–2019 was retrospectively assessed. Intraoperative variables and patient demographics were evaluated for association with 30-day mortality by logistic regression analysis. Kaplan–Meier estimate was used to evaluate survival with no loss to follow-up. Results: 437 patients had aBM surgery with EPR/IF. No parameters describing the magnitude of the surgical trauma (blood loss/duration of surgery/degree of bone resection) were associated with mortality. Overall 30-day survival was 85% (95% confidence interval [CI] 81–88). Univariate analysis identified ASA group 3+4, Karnofsky score < 70, fast-growth primary cancer, and visceral and multiple bone metastases as risk factors for 30-day mortality. Male sex (OR 2.8, CI 1.3–6.3), Karnofsky score < 70 (OR 4.2, CI 2.1–8.6), and multiple bone metastases (OR 3.4, CI 1.2–9.9) were independent prognostic factors for 30-day-mortality in multivariate analysis. Conclusion: The parameters describing the surgical trauma were not associated with 30-day mortality but, instead, general health status and extent of primary cancer influenced survival post-surgery.

Background and purpose — It is believed that in uncemented primary total hip arthroplasty (THA) the anchorage of the stem is dependent on the level of bone mineral density (BMD) of the femoral bone. This is one of the reasons for the widely accepted agreement that a cemented solution should be selected for people with osteoporosis or age > 75 years. We evaluated whether preoperative BMD of the femur bone is related to femoral stem migration in uncemented THA. Patients and methods — We enrolled 62 patients (mean age 64 years (range 49–74), 34 males) scheduled for an uncemented THA. Before surgery we undertook DEXA scans of the proximal femur including calculation of the T- and Z-scores for the femoral neck. Evaluation of stem migration by radiostereometric analysis (RSA) was performed with 24 months of follow-up. In 56 patients both preoperative DEXA data and RSA data were available with 24 months of follow-up. Results — None of the patients had a T-score below –2.5. We found no statistically significant relationship between preoperative BMD and femoral stem subsidence after 3 or 24 months. When comparing the average femoral stem subsidence between 2 groups with T-score > –1 and T-score ≤ –1, respectively, we found no statistically significant difference after either 3 or 24 months when measured with RSA. Interpretation — In a cohort of people ≤ 75 years of age and with local femur T-score > –2.5 we found no relationship between preoperative BMD and postoperative femoral stem subsidence of a cementless THA.

Background and purpose — Despite the good results after total hip arthroplasty (THA), new implants are continuously being developed to improve durability. The Echo Bi-Metric (EBM) THA stem is the successor to the Bi-Metric (BM) THA stem. The EBM stem includes many of the features of the BM stem, but minor changes in the design might improve the clinical performance. We compared the migration behavior with radiostereometric analysis (RSA) of the EBM stem and the BM stem at 24 months and evaluated the clinical outcome. Patients and methods — We randomized 62 patients with osteoarthritis (mean age 64 years, female/male 28/34) scheduled for an uncemented THA to receive either an EBM or a BM THA stem. We performed RSA within 1 week after surgery and at 3, 6, 12, and 24 months. The clinical outcome was evaluated using Harris Hip Score (HHS) and Oxford Hip Score (OHS). Results — At 24 months, we found no statistically significant differences in migration between the two implants. During the first 3 months both the EBM and the BM stems showed visible subsidence (2.5 mm and 2.2 mm respectively), and retroversion (2.5° and 2.2° respectively), but after 3 months this stabilized. The expected increase in HHS and OHS was similar between the groups. Interpretation — The EBM stem showed a migration at 24 months not different from the BM stem, and both stems display satisfying clinical results.

Purpose: The management of bone defects following simple curettage of bone tumors is controversial and in light of the numerous emerging substitutes for bone grafts, we wished to review and report our experience with the use of cancellous allograft bone in the treatment of benign and borderline bone tumors. Methods: We reviewed the medical records of 164 consecutive patients with benign or borderline bone tumors treated with simple curettage at our orthopedic oncology center between 2009 and 2013. Postoperative radiological changes were evaluated by a modified Neer’s classification in defects that were subsequently reconstructed with allograft bone ( n = 133). Results: Simple curettage with subsequent defect filling using allograft bone was the surgical procedure performed in the majority of our patients (81%) and was associated with a low overall 2.5-year local recurrence (LR; 9.8%) and complication rate (7.5%). The radiological appearance of the grafted defects was deemed satisfactory in 85% of cases, with signs of either complete or partial healing present 6–12 months postoperatively. With respect to pathology, we found high rates of LR in giant cell tumors (GCTs) of bone, simple cysts (SCs) in children, and preexisting local recurrent disease. We did not observe any allograft-related complications. Conclusions: Simple curettage and bone defect reconstruction with bone allograft is a sufficient treatment for most benign bone lesions and is associated with a low complication rate. For high-risk entities, such as GCTs of bone, SCs in children, and recurrent disease, additional adjuvant treatment could be considered to avoid LR.

Objective: To examine the effect of an alternative wound closure method after tumor arthroplasty of the hip compared to routine wound closure with skin staples. Method: Single center, frequency matched cohort study. We reviewed all patients who underwent tumor resection and endoprosthetic reconstruction of the proximal femur for pathologic fracture due to metastatic bone disease or malignant hematologic bone disease at our center between 2010 and 2014. All patients treated with occlusive wound closure (OWC), a combination of intradermal suture, Steri-Strips™, and an occlusive skin adhesive, during this period ( n = 35), were compared to an equally sized frequency matched group of patients having undergone routine wound closure with conventional skin staples. Results: Patients with OWC were significantly faster to achieve dry wound status and consequently had significantly shorter administration of antibiotics and hospital stay. Compared to the patients with conventional wound closure with staples, their wounds were already dry after a mean 3.4 days (vs. 6.7 days [95%CI: 3–3.8 vs. 5.5–7.9], p < 0.0001), they received antibiotics for a mean 4.2 days (vs. 6.8 days [95%CI: 3.7–4.8 vs. 5.5–8.0], p < 0.0003) and their mean hospital stay was 6.3 days (vs. 8.0 days [95%CI: 5.5–7 vs. 6.8–9.3], p < 0.015). Prolonged wound discharge (PWD) for 7 days or more was observed in 34% of patients ( n = 12) in the conventional group, whereas this complication was completely absent ( n = 0) in the investigational group. For every three patients treated with OWC, one complication of PWD over 7 days is avoided (number needed to treat = 3). Conclusion: Compared to conventional staples, OWC appears to significantly reduce wound complications, use of antibiotics, and hospital stay in patients undergoing tumor arthroplasty procedures of the hip. As such, it may also contribute to a reduction of the substantially increased risk for prosthetic joint infection in this patient population.

Aims: Pelvic discontinuity is a rare but increasingly common complication of total hip arthroplasty (THA). This single-centre study evaluated the performance of custom-made triflange acetabular components in acetabular reconstruction with pelvic discontinuity by determining: 1) revision and overall implant survival rates; 2) discontinuity healing rate; and 3) Harris Hip Score (HHS)., Methods: Retrospectively collected data of 38 patients (39 hips) with pelvic discontinuity treated with revision THA using a custom-made triflange acetabular component were analyzed. Minimum follow-up was two years (mean 5.1 years (2 to 11))., Results: There were eight subsequent surgical interventions. Two failures (5%) of the triflange acetabular components were both revised because of deep infection. There were seven (18%) patients with dislocation, and five (13%) of these were treated with a constraint liner. One patient had a debridement, antibiotics, and implant retention (DAIR) procedure. In 34 (92%) hips the custom-made triflange component was considered stable, with a healed pelvic discontinuity with no aseptic loosening at midterm follow-up. Mean HHS was 80.5 (48 to 96)., Conclusion: The performance of the custom triflange implant in this study is encouraging, with high rates of discontinuity healing and osteointegration of the acetabular implant with no aseptic loosening at midterm follow-up. However, complications are not uncommon, particularly instability which we successfully addressed with constrained liners.Cite this article: Bone Jt Open  2022;3(11):867-876.

We investigate the application of Ramsey spectroscopy for the development of a microcell atomic clock based on coherent population trapping (CPT). The dependence of the central Ramsey-CPT fringe properties on key experimental parameters is first studied for optimization of the clock's short-term frequency stability. The sensitivity of the clock frequency to light-shift effects is then studied. In comparison with the continuous-wave (CW) regime case, the sensitivity of the clock frequency to laser power variations is reduced by a factor up to 14 and 40.3 for dark times of 150 and [Formula: see text], respectively, at the expense of intensity 3.75 times higher for short-term stability optimization. The dependence of the clock frequency on the microwave power is also reduced in the Ramsey case. We demonstrate that the Ramsey-CPT interrogation improves the clock Allan deviation for averaging times higher than 100 s. With a dark time of [Formula: see text], a clock fractional frequency stability of 3.8 ×10 -12 at 10 4 s is obtained, in comparison with the level of 8×10 -11 obtained in the standard CW case, in similar environmental conditions. These results demonstrate that Ramsey-based interrogation protocols might be an attractive approach for the development of chip-scale atomic clocks (CSACs) with enhanced mid- and long-term stability.

Nucleotides that contain two nucleobases (double-headed nucleotides) have the potential to condense the information of two separate nucleotides into one. This presupposes that both bases must successfully pair with a cognate strand. Here, double-headed nucleotides that feature cytosine, guanine, thymine, adenine, hypoxanthine, and diaminopurine linked to the C2'-position of an arabinose scaffold were developed and examined in full detail. These monomeric units were efficiently prepared by convergent synthesis and incorporated into DNA oligonucleotides by means of the automated phosphoramidite method. Their pairing efficiency was assessed by UV-based melting-temperature analysis in several contexts and extensive molecular dynamics studies. Altogether, the results show that these double-headed nucleotides have a well-defined structure and invariably behave as functional dinucleotide mimics in DNA duplexes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: The present study aimed to test the hypothesis that cerebral oxygen saturation (ScO 2 ) measurements with the INVOS-5100-C and the ForeSight-Elite cerebral oximeters vary in their correlation with mixed venous oxygen saturation (SvO 2 ) upon changes in systemic oxygenation in extubated cardiac surgical patients. Additionally, we aimed to elucidate whether the ScO 2 measurements of both devices can be used interchangeably to detect reduced SvO 2 ., Methods: Forty-eight spontaneously breathing patients extubated after cardiac surgery were included in this prospective observational study. The patients were exposed to both high (10 oxygen L·min -1 via face mask) and low (room air) inspiratory oxygen concentrations. Bi-hemispherical ScO 2 was determined with the INVOS and ForeSight Elite cerebral oximeters. The SvO 2 was measured with a pulmonary artery catheter., Results: Significant changes in oxygen delivery, ScO 2 (by both cerebral oximeters), and SvO 2 were observed upon variation of oxygenation. The minimum mean (standard deviation) ScO 2 (ScO 2min ) using the INVOS and ForeSight did not differ significantly during high oxygen delivery [63.1 (8.6) % vs 65.8 (4.7) %, respectively; P = 0.07], but during low oxygen delivery, the INVOS value was significantly lower than that of the ForeSight oximeter [56.7 (8.9) % vs 61.3 (4.4) %, respectively; P = 0.003]. Both devices differed in the correlation between ScO 2min and SvO 2 for the combined oxygenation data (0.59, INVOS vs 0.28, ForeSight; correlation difference, 0.31; Bonferroni-adjusted 95% confidence interval [CI], 0.08 to 0.54; P = 0.008). The receiver-operating curve analysis revealed an area under the curve of 0.83 (95% CI, 0.74 to 0.9; P = 0.005) for detecting an SvO 2 below 50% by ScO 2min with the INVOS and 0.51 (95% CI, 0.41 to 0.62; P = 0.92), respectively, with the ForeSight., Conclusions: These findings suggest that the cerebral oximeters tested react differently to variations in systemic oxygenation and in their relationship with SvO 2 and thus give different information on cardiopulmonary function. These findings raise doubt about whether these devices should be used interchangeably.

Objective: To define the function of the "Ross valves" and its clinical meaning in a practical valve performance classification as part of the outcome analysis., Methods: From 1994 to 2017, 630 consecutive patients underwent the subcoronary Ross procedure at our institution. The valve performance classification combines hemodynamics, symptoms, and management criteria. Median follow-up was 12.5 years (maximum 22.3 years, 7404 patient-years, 99.4% completeness)., Results: The mean age of the patients was 44.7 ± 11.9 years. Hospital deaths was 0.3% (n = 2). Twenty years after the operation survival was 73.1% (95% confidence interval [CI], 65.4%-81.6%) and statistically not different from the age- and gender-matched general population; freedom from reoperation was 85.9% (95% CI, 80.2%-92.0%; 0.6% per patient-year), 89.8% (95% CI, 84.3%-95.7%) for autograft, and 91.0% (95% CI, 86.3%-96.0%) for homograft. Preoperative annulus diameter, aortic regurgitation, annulus reinforcement, sinotubular junction reinforcement, and bicuspid aortic valve type were no significant risk factors for reoperation. At 20 years the probability of a patient being in valve performance class I to IV was 5%, 74%, 19%, and 1%, respectively. Time to reoperation was not different in bicuspid and tricuspid aortic valves; preoperative aortic stenosis tended to have better outcome of autograft function., Conclusions: These up to 22 years data show that the subcoronary Ross procedure continues to provide an excellent tissue aortic valve replacement. The suggested valve performance classification emerged as a practical concept for outcome analysis with the probability of 79% being in the favorable class I or II at 20 years., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Remodeling or reimplantation are established operative techniques of aortic valve-sparing root replacement. Long-term follow-up is necessary comparing tricuspid and bicuspid aortic valves., Methods: A total of 315 patients (tricuspid, n = 225, bicuspid, n = 89, quadricuspid, n = 1; remodeling, n = 101, reimplantation, n = 214) were evaluated. Mean follow-up was 10.1 ± 5.6 and 6.4 ± 4.2 years for the remodeling and reimplantation group, respectively. Longest follow-up was 21.9 years with 99.2% completeness. Mean age of the patients was 55.9 ± 14.3 for the remodeling group and 48.9 ± 14.5 years for the reimplantation group., Results: There was no significant difference in survival between the remodeling and reimplantation group (P = .11). Survival was comparable with the normal population in the reimplantation group (P = .33). Risk factors for late death were age, diabetes, and a greater New York Heart Association classification. Cumulative incidence of reoperation at 10 years was 5.8% for the reimplantation and 11.7% for the remodeling group (P = .65). Overall, there was no difference in the cumulative incidence of reoperation between tricuspid and bicuspid aortic valve patients (P = .13); however, a landmark analysis showed that in the second decade, the cumulative incidence of reoperation was greater in bicuspid aortic valve patients (P < .001). A total of 10 of 11 reoperated bicuspid aortic valves were degenerated., Conclusions: The remodeling and reimplantation aortic valve-sparing root replacement techniques provided excellent long-term survival. Although the number of patients was relatively small, we provide some hints that in the second decade after the operation, especially in bicuspid aortic valve patients, the risk of reoperation may be increased, needing further evaluation., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To clarify whether reactivated cytomegalovirus (CMV) infections in critically ill patients lead to worse outcome or just identify more severely ill patients. If CMV has a pathogenic role, latently infected (CMV-seropositive) patients should have worse outcome than seronegative patients because only seropositive patients can experience a CMV reactivation., Design: Post-hoc analysis of a prospective observational study., Setting: Single university hospital., Participants: The study comprised 983 consecutive patients scheduled for on-pump surgery., Interventions: None., Measurements and Main Results: CMV antibodies were analyzed in preoperative plasma samples. Postoperative adverse events (reintubation, low cardiac output or reinfarction, dialysis, stroke) and 30-day and 1-year mortality were evaluated prospectively. The plasma of reintubated patients and matched control patients was tested for CMV deoxyribonucleic acid, and 618 patients were found to be seropositive for CMV (63%). Among these, the risk for reintubation was increased (10% v 4%, p = 0.001). This increase remained significant after correction for confounding factors (odds ratio 2.70, p = 0.003) and was detectable from the third postoperative day throughout the whole postoperative period. Other outcome parameters were not different. Reintubated seropositive patients were more frequently CMV deoxyribonucleic acid-positive than were matched control patients (40% v 8%, p<0.001)., Conclusions: CMV-seropositive patients had an increased risk of reintubation after cardiac surgery, which was associated with reactivations of their CMV infections. Additional studies should determine whether this complication may be prevented by monitoring of latently infected patients and administering antiviral treatment for reactivated CMV infections., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A normal duplex holds as many Watson-Crick base pairs as the number of nucleotides in its constituent strands. Here we establish that single nucleotides can be designed to functionally imitate dinucleotides without compromising binding affinity. This effectively allows sequence information to be more compact and concentrated to fewer phosphates.

Both function and dysfunction of serine protease inhibitors (serpins) involve massive conformational change in their tertiary structure but the dynamics facilitating these events remain poorly understood. We have studied the dynamic preludes to conformational change in the serpin plasminogen activator inhibitor 1 (PAI-1). We report the first multi-microsecond atomistic molecular dynamics simulations of PAI-1 and compare the data with experimental hydrogen/deuterium-exchange data (HDXMS). The simulations reveal notable conformational flexibility of helices D, E and F and major fluctuations are observed in the W86-loop which occasionally leads to progressive detachment of β-strand 2 A from β-strand 3 A. An interesting correlation between C α -RMSD values from simulations and experimental HDXMS data is observed. Helices D, E and F are known to be important for the overall stability of active PAI-1 as ligand binding in this region can accelerate or decelerate the conformational inactivation. Plasticity in this region may thus be mechanistically linked to the conformational change, possibly through facilitation of further unfolding of the hydrophobic core, as previously reported. This study provides a promising example of how computer simulations can help tether out mechanisms of serpin function and dysfunction at a spatial and temporal resolution that is far beyond the reach of any experiment.

A set of average atom-centered charges and polarizabilities has been developed for three types of phospholipids for use in polarizable embedding calculations. The lipids investigated are 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, and 1-palmitoyl-2-oleoyl-sn-glycerol-3-phospho-L-serine given their common use both in experimental and computational studies. The charges, and to a lesser extent the polarizabilities, are found to depend strongly on the molecular conformation of the lipids. Furthermore, the importance of explicit polarization is underlined for the description of larger assemblies of lipids, that is, membranes. In conclusion, we find that specially developed polarizable parameters are needed for embedding calculations in membranes, while common non-polarizable point-charge force fields usually perform well enough for structural and dynamical studies. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Dilatation of the ascending aorta is a common occurrence in patients with bicuspid aortic valve (BAV). The aim of the current study was to characterize collagen content in advanced glycation end products (AGEs) of dilated aortic tissue from two distinct areas, concave and convex aortic sites in patients with BAV and TAV. Collagen contents extracted from 100 mg tissue was isolated by enzymatic digestion using pepsin and the nondigested material was further digested using cyanogen bromide, insoluble collagen fraction (ICF) was extracted by hydrochloric acid hydrolysis. BAV tissue showed diminished fluorescence of the pepsin extracted fraction (PEF) compared with TAV tissue (12.4 ± 1.0% vs 32.9 ± 7.6%, p = 0.05). Patients with BAV had PEF of collagens significantly diminished in the dilated ascending aorta, especially in its convex portion, in course of aging and increment of dilated diameters. It is suggestible that BAV patients present more highly AGE-modified collagens in their ascending aorta.

Background: The purpose of this study was to evaluate the single-center experience in initial femoral versus central cannulation of the extracorporeal circulation for acute aortic dissection type A (AADA)., Methods: Between January 2003 and December 2015, 235 patients underwent repair of AADA. All patients were evaluated for the type of arterial cannulation (femoral vs. central) for initial bypass. Demographic data and outcome parameters were accessed., Results: One hundred and twenty seven (54.0%) were initially cannulated in the central aortic vessels (ascending aorta or subclavian/axillary artery) and 108 (46.0%) in the femoral artery. Patients were comparable between age (62.4±14.4 vs. 62.9±14.4 years, P=0.805), gender (male, 62.2 vs. 69.4%, P=0.152) and previous sternotomy (15.7 vs. 16.7%, P=0.861) between both cannulation groups; while EuroSCORE I (11.5±4.0 vs. 12.7±4.2, P=0.031) and ASA Score (3.5±0.81 vs. 3.8±0.57, P=0.011) were significantly higher in the femoral artery cannulation group. Bypass (249±102 vs. 240±81 min, P=0.474), X-clamp (166±85 vs. 157±67 min, P=0.418) and circulatory arrest time (51.6±28.7 vs. 48.3±21.7 min, P=0.365) were similar between the groups as were lowest temperature (18.1±2.0 vs. 18.1±2.2, P=0.775). Postoperative neurologic deficit and 30-day mortality were comparable between both cannulation groups (11.7 vs. 7.2%, P=0.449 and 20.2 vs. 16.9%, P=0.699, central vs. peripheral cannulation). Multivariate analysis revealed only EuroScore I above 13 as single preoperative predictor for mortality., Conclusions: AADA can be operated with both femoral and central cannulation with similar results. Risk for early mortality was driven by the preoperative clinical and hemodynamic status before operation rather than the cannulation technique.

Lipid II is critical for peptidoglycan synthesis, which is the main component of the bacterial cell wall. Lipid II is a relatively conserved and important part of the cell wall biosynthesis pathway and is targeted by antibiotics such as the lantibiotics, which achieve their function by disrupting the biosynthesis of the cell wall. Given the urgent need for development of novel antibiotics to counter the growing threat of bacterial infection resistance, it is imperative that a thorough molecular-level characterization of the molecules targeted by antibiotics be achieved. To this end, we present a molecular dynamics simulation study of the conformational dynamics of Lipid II within a detailed model of the Staphylococcus aureus cell membrane. We show that Lipid II is able to adopt a range of conformations, even within the packed lipidic environment of the membrane. Our simulations also reveal dimerization of Lipid II mediated by cations. In the presence of the defensin peptide plectasin, the conformational lability of Lipid II allows it to form loose complexes with the protein, via a number of different binding modes.

Purpose: Regenerex is a novel porous titanium construct with a three-dimensional porous structure and biomechanical characteristics close to that of normal trabecular bone. The aim of this study was to evaluate the adaptive bone remodeling of the proximal tibia after uncemented total knee arthroplasty (TKA) using a tibial tray with this novel coating compared to a well-proven standard porous coated (PPS) tibial tray., Materials: Sixty patients scheduled for TKA were randomized to receive either a Regenerex (n = 31) or a PPS tibial component (n = 29). Changes in bone mineral density (BMD) of the proximal tibia were measured at three, six, 12 and 24 months by dual-energy X-ray absorptiometry (DEXA)., Results: In the lateral region (ROI 3), a significant increase in BMD was seen in both groups at three, six, and 12 months after surgery. The relative increase at 12 months was 8.1 % (P = 0.007) for the PPS group and 6.5 % (P = 0.002) for the Regenerex group. Positive values were retained at 24 months in both groups. At 24 months BMD in the distal region below the central stem (ROI 1) had decreased in the PPS group by 3.4 % (P = 0.005) and in the Regenerex group by 2.4 % (P = 0.17). In the medial region (ROI 2) BMD remained unchanged at all follow-up evaluations in both groups. There were no significant differences between the two groups (P = 0.45) in any ROI at any follow-up evaluation., Conclusion: The significant increase in BMD of the lateral proximal tibia plateau with very limited changes medially and distally seen in both implants suggests that the novel porous titanium construct Regenerex and the PPS implant have a pronounced beneficial effect with regard to maintaining periprosthetic BMD in all regions of interest investigated.

In this study, we investigated the efficacy of an LNA (locked nucleic acid)-modified DNA aptamer named RNV66 targeting VEGF against various breast cancer cell lines. Our results demonstrate that RNV66 efficiently inhibits breast cancer cell proliferation both in vitro and in vivo. Introduction of LNA nucleotides were crucial for higher efficacy. Furthermore, the binding interaction of RNV66 with VEGF was investigated using molecular dynamic simulations leading to the first computational model of the LNA aptamer-VEGF complex blocking its interaction with VEGF-receptor.

Objectives: Acute aortic dissection type A (AADA) is still an emergency operation with high morbidity and mortality. In this acute situation quick cannulation to the heart-lung machine and systemic cooling is often life-saving. However, the often easy access to the femoral vessels for cannulation leads to an arterial backflow in the descending aorta with the likelihood of plaque rupture and cerebral embolism. We analysed the outcome after initial femoral versus central cannulation for AADA., Methods: All patients with acute aortic dissection type A operated between January 2003 and December 2012 were evaluated for the type of arterial cannulation (femoral vs central) for initial bypass. Demographic data and outcome parameters were accessed. No patient was excluded., Results: One hundred and seventy-seven patients were operated on with acute type A dissection in the last 10 years; 94 (53.1%) were initially cannulated in the central aortic vessels and 83 (46.9%) in the femoral artery. The patients were comparable with regard to age (61.1 ± 14.9 vs 62.2 ± 15.0 years, P = 0.607), gender (male, 62 vs 69%, P = 0.348), EuroSCORE (11.5 ± 4.0 vs 12.8 ± 4.3, P = 0.057) and previous sternotomy (17% in both groups). Bypass (243 ± 105 vs 233 ± 83 min, P = 0.471), cross-clamp (160 ± 86 vs 150 ± 66 min, P = 0.381) and circulatory arrest times (47.8 ± 24.7 vs 42.5 ± 21.7 min, P = 0.130) were similar as were lowest temperatures (17.7 ± 1.8 vs 17.6 ± 1.3, P = 0.652). Postoperative cerebral infarction and 30-day mortality were comparable between the cannulation groups (13 vs 9%, P = 0.449 and 20 vs 17%, P = 0.699, central vs peripheral cannulation). Only postoperative need for dialysis was borderline significantly higher in the femoral cannulation group (28 vs 40%, P = 0.073)., Conclusions: This single-centre study with 177 patients could show that an acute aortic dissection type A can be operated on with central and peripheral cannulation with similar results. Risk for early mortality was driven by the preoperative clinical and haemodynamic status before operation rather than the cannulation technique., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

A series of double-headed nucleosides were synthesized using the Sonogashira cross-coupling reaction. In the reactions, additional nucleobases (thymine, cytosine, adenine, or guanine) were attached to the 5-position of 2'-deoxyuridine or 2'-deoxycytidine through a propyne linker. The modified nucleosides were incorporated into oligonucleotides, and these were combined in different duplexes that were analyzed by thermal denaturation studies. All of the monomers were well tolerated in the DNA duplexes and induced only small changes in the thermal stability. Consecutive incorporations of the monomers led to increases in duplex stability owing to increased stacking interactions. The modified nucleotide monomers maintained the Watson-Crick base pair fidelity. Stable duplexes were observed with heavily modified oligonucleotides featuring 14 consecutive incorporations of different double-headed nucleotide monomers. Thus, modified duplexes with an array of nucleobases on the exterior of the duplex were designed. Molecular dynamics simulations demonstrated that the additional nucleobases could expose their Watson-Crick and/or Hoogsteen faces for recognition in the major groove. This presentation of nucleobases may find applications in providing molecular information without unwinding the duplex.

Objectives: The fate of the aortic dimensions in patients with a bicuspid aortic valve (BAV) after aortic valve replacement (AVR) is unclear. We investigated the evolution of aortic root and ascending aorta dimensions in patients with a BAV after AVR. To neutralize the effect of pathological transvalvular haemodynamics on aortic dimensions, we evaluated our hypotheses in patients with normal transvalvular haemodynamics after a subcoronary autograft procedure, which preserves intact the native aortic wall., Methods: We excluded patients operated on for endocarditis; who developed autograft insufficiency > trivial and who required autograft reoperation during the follow-up. We included 448 patients (361 with BAV; 340 males; 44.6 ± 11.4 years; mean follow-up: 7.5 ± 3.9 years). Valve phenotype was determined during surgery. Annual echocardiographic examinations (n = 3336) were performed (follow-up completeness: 98%). To allow for somatometric, gender and age influences, z-values of measurements were calculated from the general population (GP) and analysed using longitudinal methods., Results: The increase in ascending aorta did not differ from that expected in the GP (0.04 z-values/year; P = 0.06). No difference could be observed in diameter increase rates between BAV and tricuspid aortic valve patients (TAV) (0.04 vs 0.06 z-values/year; P = 0.3), as well as between BAV phenotypes. The sinus increase did not differ from that expected in the GP (0.03 z-values/year; P = 0.1), and no significant differences could be observed between BAV phenotypes. In patients undergoing aortoplasty (n = 70), no significant difference in the rates of ascending aorta and sinus increase could be observed, compared with the GP., Conclusion: For the time period of this study and in patients with normal aortic root haemodynamics after AVR, ascending aorta dimensions over time are similar to that of the matched GP. Patients with a BAV did not exhibit higher rates of ascending aorta dilatation after AVR than patients with TAV. At least for the first postoperative decade, transvalvular haemodynamics appear to exhibit a greater influence than the genetic component of BAV on the development of the BAV aortopathy.

Additional base pair: The DNA duplex can be extended with an additional Watson-Crick base pair on the same backbone by the use of double-headed nucleotides. These also work as compressed dinucleotides and form two base pairs with cognate nucleobases on the opposite strand., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: Sinuses of Valsalva are important in assuring the physiological function of the aortic valve. This study evaluates short-term clinical results of the reimplantation technique for aortic valve-sparing root replacement using a new prosthesis with three separate sinuses of Valsalva (sinus prosthesis)., Methods: Between February 2009 and February 2011, a total of 23 patients (20 m/3 f; mean age 52 ± 14.8 years; range 24-70 years) with aortic root aneurysm underwent aortic valve-sparing procedures according to the David reimplantation technique using the new sinus prosthesis. Eighteen patients had tricuspid and five patients bicuspid aortic valves. All patients received clinical as well as echocardiographic examinations postoperatively (mean 13 ± 9.3 months; 0.3-28 months)., Results: There was no death and no reoperation of the aortic valve. At latest follow-up, most patients were in New York Heart Association class I (n = 22; 95.7%). In 95.7% aortic valve regurgitation (AR) was 0 or 1+; one patient had AR 2+. Pressure gradients were between the normal range (mean pressure gradient 4.7 ± 1.9 mmHg). Echocardiographic images demonstrate physiological aortic root dimensions and configuration with three separate sinuses of Valsalva without systolic contact of leaflets to the wall., Conclusions: The new sinus prosthesis provides near normal root geometry and hemodynamics in valve-sparing aortic root replacement using the reimplantation technique, applicable for tricuspid and also bicuspid aortic valves.

Objectives: This study sought to determine the usefulness of plasma growth differentiation factor 15 (GDF-15) for risk stratification in patients undergoing cardiac surgery in comparison with the additive European System of Cardiac Operative Risk Evaluation (EuroSCORE), N-terminal pro-B-type natriuretic peptide (NTproBNP), and high-sensitive troponin T (hsTNT)., Background: GDF-15 is emerging as a humoral marker for risk stratification in cardiovascular disease. No data are available if this marker may also be used for risk stratification in cardiac surgery., Methods: In total, 1,458 consecutive patients were prospectively studied. Pre-operative plasma GDF-15, NTproBNP, hsTNT, clinical outcomes, and 30-day and 1-year mortality were recorded. GDF-15 was determined with a pre-commercial electrochemiluminescence immunoassay., Results: Median additive EuroSCORE (addES) was 5 (interquartile range: 3 to 8); 30-day and 1-year mortality were 3.4% and 7.6%, respectively. Median GDF-15 levels were 1.04 ng/ml (95% confidence interval [CI]: 1.0 to 1.07 ng/ml) in 30-day survivors and 2.62 ng/ml (95% CI: 1.88 to 3.88) in 30-day nonsurvivors (p < 0.0001). C-statistics showed that the area under the curve of a combined model of GDF-15 and addES for 30-day mortality was significantly greater (0.85 vs. 0.81; p = 0.0091) than of the addES alone. For the EuroSCORE categories (0 to 2, 3 to 5, 6 to 10, >10) the presence of GDF-15 ≥1.8 ng/ml resulted in a significant 41.4% (95% CI: 19.2 to 63.7%; p < 0.001) net reclassification improvement and an integrated discrimination improvement of 0.038 (95% CI: 0.022 to 0.0547; p < 0.0001) compared to the model including only the addES, whereas the presence of NTproBNP (cutoff ≥2,000 pg/ml) or hsTNT (cutoff 14 pg/ml) did not result in significant reclassification., Conclusions: The pre-operative plasma GDF-15 level is an independent predictor of post-operative mortality and morbidity in cardiac surgery patients, can further stratify beyond established risk scores and cardiovascular markers, and thus adds important additional information for risk stratification in these patients. (The Usefulness of Growth Differentiation Factor 15 [GDF-15] for Risk Stratification in Cardiac Surgery; NCT01166360)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Human telomeric DNA has the ability to fold into a 4-stranded G-quadruplex structure. Several G-quadruplex ligands are known to stabilize the structure and thereby inhibit telomerase activity. Such ligands have demonstrated efficient telomerase inhibition in dilute conditions, but under molecular crowding conditions mimicking physiological milieu, stabilization of the telomeric G-quadruplex is often lost. We attempted to demonstrate the enhanced G-quadruplex stabilizing ability under molecular conditions by using twisted intercalating nucleic acids (TINA)-modified oligonucleotides. We have shown using circular dichroism and ultraviolet spectroscopic methods that these TINA-modified short oligonucleotides function as G-quadruplex, inducing agents and participate in the formation of stabilized 3:1 G-quadruplex with the human telomeric oligonucleotide. Using enzyme-linked immunosorbent assay-based telomerase repeat amplification assay (TRAP) assay as well as nondenaturing polyacrylamide gel electrophoresis-based TRAP, we demonstrate remarkable enhancement in their anti-telomerase activity even under molecular crowding conditions. This is the first time in which a G-quadruplex stabilizing agent has demonstrated enhanced activity even under molecular crowding conditions.

Waardenburg syndrome (WS) is a rare (1/40,000) autosomal dominant disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four clinical subtypes (WS1-S4). Six genes have been identified to be associated with the different subtypes of WS, among which SOX10, which is localized within the region 22q13.1. Lately it has been suggested that whole SOX10 gene deletions can be encountered when testing for WS. In this study we report a case of a 13-year-old boy with a unique de novo 725 kb deletion within the 22q13.1 chromosomal region, including the SOX10 gene and presenting clinical features of a neurologic variant of WS2., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

We have designed and synthesised a double-headed nucleotide that presents two nucleobases in the interior of a dsDNA duplex. This nucleotide recognises and forms Watson-Crick base pairs with two complementary adenosines in a Watson-Crick framework. Furthermore, with judicious positioning in complementary strands, the nucleotide recognises itself through the formation of a T:T base pair. Thus, two novel nucleic acid motifs can be defined by using our double-headed nucleotide. Both motifs were characterised by UV melting experiments, CD and NMR spectroscopy and molecular dynamics simulations. Both motifs leave the thermostability of the native dsDNA duplex largely unaltered. Molecular dynamics calculations showed that the double-headed nucleotides are accommodated in the dsDNA by entirely local perturbations and that the modified duplexes retain an overall B-type geometry with the dsDNA unwound by around 25 or 60°, respectively, in each of the modified motifs. Both motifs can be accommodated twice in a dsDNA duplex without incurring any loss of stability and extrapolating from this observation and the results of modelling, it is conceivable that both can be multiplied several times within a dsDNA duplex. These new motifs extend the DNA recognition repertoire and may form the basis for a complete series of double-headed nucleotides based on all 16 base combinations of the four natural nucleobases. In addition, both motifs can be used in the design of nanoscale DNA structures in which a specific duplex twist is required., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)