100 ancient genomes show repeated population turnovers in Neolithic Denmark.

Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Stable fixation of an ultra-short femoral neck-preserving hip prosthesis: a 5-year RSA, DXA, and clinical prospective outcome study of 48 patients.

BACKGROUND AND PURPOSE: We previously showed promising primary stability and preservation of bone stock with the ultra-short neck-loading hip implant in total hip arthroplasty (THA). The aim of this study was to evaluate clinical outcome, implant stability, and bone mineral density (BMD). METHODS: 50 patients were treated with the ultra-short neck Primoris hip implant at baseline and 48 were available for evaluation at 5-year follow-up. 5 different patient-reported outcome measures (PROMs) including hip-specific scores, disease-specific and generic quality of life outcome measures, and an activity score were used. Furthermore, implant stability using radiostereometric analysis (RSA) and assessment of periprosthetic BMD using dual-energy X-ray absorptiometry (DXA) were applied. RESULTS: By 1-year follow-up, all PROMs showed improvements and remained high at 5-year follow-up. After initial distal translation (subsidence) and negative rotation around the z-axis (varus tilt) the implant showed stable fixation at 5-year follow-up with no further migration beyond 12 months. In the regions of interest (ROI) 3 and 4, BMD remained stable. In ROI 2, further bone loss of 12% was found at 5-year follow-up. CONCLUSION: Clinical outcome including PROMs was satisfying throughout the 5-year follow-up period. The hip implant remains stable with both bone preservation and loss 5 years after surgery.

Double-Headed 2'-Deoxynucleotides That Hybridize to DNA and RNA Targets via Normal and Reverse Watson-Crick Base Pairs.

Through the use of modified nucleotides, synthetic nucleic acids have found several fields of application within biotechnology and in the pharmaceutical industry. We have previously introduced nucleotides with an additional functional nucleobase linked to C2' of arabinonucleotides (BX). These double-headed nucleotides fit neatly into DNA·DNA duplexes, where they can replace the corresponding natural dinucleotides and thus condense the molecular information. Here, we introduce a 2'-deoxy version of the BX design with inversion of the C2' stereochemistry (dSBX) with the aim of obtaining improved RNA recognition. Specifically, dSBX analogues with cytosine or isocytosine attached to C2' of 2'-deoxyuridine (dSUC and dSUiC) were synthesized and evaluated in duplexes. Whereas the dSBX design did not outperform the BX design in terms of mimicking dinucleotides in nucleic acid duplexes, it was able to engage in reverse Watson-Crick pairing using its 2'-base. This was evident from the ability of the dSUC cytosine to form stable mis-matching base pairs with opposite cytosines identified as hemiprotonated C·C+ pairs. Furthermore, specific base-pairing with guanine was only observed for the isocytosine-bearing dSUiC monomer. Very stable duplexes were obtained with dSUC/iC monomers in each strand indicating that fully modified double-headed nucleic acid sequences could be based on the dSBX design.

Projection of primary and revision hip arthroplasty surgery in Denmark from 2020 to 2050.

BACKGROUND AND PURPOSE: The incidence of primary and revision total hip arthroplasty (THA) has increased over the last decades. Previous forecasts from different healthcare systems have predicted a continuous increase. We present a forecast of both primary and revision surgery from 2020 to 2050 based on 25 years data from the healthcare system in Denmark. PATIENTS AND METHODS: We retrieved data from the Danish Hip Arthroplasty Register on 198,835 primary and 29,456 revision surgeries. Historical censuses and population forecasts were retrieved from Statistics Denmark. Logistic and Gompertz regression analysis was used to forecast incidence rates (IR) and total numbers in the next 30 years. RESULTS: Our forecast predicts an increase in IR of 3-9% and an increase in total numbers of primary THA of between 12% and 19% in 2050. For revision THA the IRs have reached a plateau but total numbers are predicted to increase by 19% in 2050. CONCLUSION: Our forecast shows that both primary and revision THA will increase in total numbers in the next decades, but the IR for primary THA is near its plateau and for revision THA the plateau has already been reached. The forecast may aid in healthcare resource planning for the decades to come.

Substituted 9-Diethylaminobenzo[a]phenoxazin-5-ones (Nile Red Analogues): Synthesis and Photophysical Properties.

Nile Red is a benzo[a]phenoxazone dye containing a diethylamino substituent at the 9-position. In recent years, it has become a popular histological stain for cellular membranes and lipid droplets due to its unrivaled fluorescent properties in lipophilic environments. This makes it an attractive lead for chemical decoration to tweak its attributes and optimize it for more specialized microscopy techniques, e.g., fluorescence lifetime imaging or two-photon excited fluorescence microscopy, to which Nile Red has never been optimized. Herein, we present synthesis approaches to a series of monosubstituted Nile Red derivatives (9-diethylbenzo[a]phenoxazin-5-ones) starting from 1-naphthols or 1,3-naphthalenediols. The solvatochromic responsiveness of these fluorophores is reported with focus on how the substituents affect the absorption and emission spectra, luminosity, fluorescence lifetimes, and two-photon absorptivity. Several of the analogues emerge as strong candidates for reporting the polarity of their local environment. Specifically, the one- and two-photon excited fluorescence of Nile Red turns out to be very responsive to substitution, and the spectroscopic features can be finely tuned by judiciously introducing substituents of distinct electronic character at specific positions. This new toolkit of 9-diethylbenzo[a]phenoxazine-5-ones constitutes a step toward the next generation of optical molecular probes for advancing the understanding of lipid structures and cellular processes.

Oligonucleotides containing 2'-O-methyl-5-(1-phenyl-1,2,3-triazol-4-yl)uridines demonstrate increased affinity for RNA and induce exon-skipping in vitro.

The nucleotide monomer containing the 1-phenyl-1,2,3-triazole group attached to the 5-position of 2'-O-methyluridine is hereby presented together with a derivative further substituted with a p-sulfonamide group on the phenyl ring. Both were conveniently synthesised, and synergistic effect of the modifications were demonstrated when introduced into oligonucleotides and hybridised to complementary RNA. The combination of stacking of the phenyltriazoles and the conformational steering from the 2'-OMe group gave thermally very stable duplexes. Exon skipping in the distrophin transcript using 20-mer 2'-OMePS sequences with two phenyltriazoles introduced in different positions with and without the sulfonamide demonstrated efficient exon skipping but at the same level as the 2'-OMePS reference ASO.

Using codesign to develop a mobile application for pelvic floor muscle training with an intravaginal device (femfit®).

AIMS: The aim of this project was to use codesign to develop a mobile application (app) for pelvic floor muscle training, with an intravaginal device (femfit®). The objective was to obtain user feedback to guide the design and development of a mobile app, consistent with the Mobile Application Rating Scale (MARS) framework. METHODS: Twenty-six women (22-62 years) provided mobile app feedback using a Design Thinking framework and grounded theory approach. Four focus groups (2 h each) and two sets of one-to-one interviews (1 h each) were held from May 2018 to October 2019. The researchers debriefed the focus groups and interviews, and undertook analysis based on project objectives and key questions. RESULTS: Recurring themes throughout the study aligned with sections of the MARS: (A) engagement (e.g., progress tracking), (B) functionality (e.g., intuitive interface), (C) aesthetics (e.g., smart graphics and colors), (D) information (e.g., clear, concise information). An internal preliminary assessment determined a MARS Quality Mean Score of 4.1 of 5 (engagement: 3.6 of 5; functionality: 4 of 5; aesthetics: 4.3 of 5: information: 4.4 of 5). CONCLUSIONS: The development of the mobile app is on track to meet MARS requirements, and to be a fun, motivating app for women. Future work is required to investigate its efficacy.

Assessing vaginal pressure profiles before and after prolapse surgery using an intravaginal pressure sensor (femfit®).

INTRODUCTION AND HYPOTHESIS: The impact of surgery on pelvic floor muscle (PFM) function remains uncertain. There is a pressure differential along the length of the vagina, influenced by surrounding active and passive tissue structures, giving rise to a pressure profile. The aim of this study is to determine if an intravaginal pressure sensor, femfit®, can measure differences in pressure profiles before and after surgery for pelvic organ prolapse (POP). METHODS: This pilot study includes 22 women undergoing POP surgery. Intravaginal pressure profiles were measured with femfit® pre- and post-surgery and differences tested using paired Student's t-tests. Patients completed validated questionnaires for vaginal, bowel, and urinary incontinence symptoms pre- and post-POP surgery and a femfit® usability questionnaire. RESULTS: Sixteen sets of vaginal pressure data were analysed. The highest pressure generated was identified as the peak PFM pressure, whilst all sensor measurements provided a pressure profile. Intra-abdominal pressure (IAP) was measured by the most distal sensor, 8. On average, the difference between peak PFM pressure and IAP was significantly greater post-surgery (p < 0.01). Urinary and vaginal symptom questionnaire scores were significantly improved after POP surgery. Femfit® usability questionnaires demonstrated high levels of patient acceptability. CONCLUSIONS: Women generate higher peak PFM pressures compared to IAP post-POP surgery, with pressure profiles that are comparable to women without POP. This metric might be useful to assess the outcome of POP surgery and encourage women to maintain this profile via PFM training, potentially reducing POP recurrence risk.

The role of diffusion tensor imaging in characterizing injury patterns on athletes with concussion and subconcussive injury: a systematic review.

Traumatic brain injury (TBI) is a major public health problem. The majority of TBIs are in the form of mild TBI (also known as concussion) with sports-related concussion (SRC) receiving public attention in recent years.Here we have performed a systematic review of the literature on the use of Diffusion Tensor Imaging (DTI) on sports-related concussion and subconcussive injuries. Our review found different patterns of change in DTI parameters between concussed and subconcussed groups. The Fractional Anisotropy (FA) was either unchanged or increased for the concussion group, while the subconcussed group generally experienced a decrease in FA. A reverse pattern was observed for Mean Diffusivity (MD) - where the concussed group experienced a decrease in MD while the subconcussed group showed an increase in MD. However, in general, discrepancies were observed in the results reported in the literature - likely due to the huge variations in DTI acquisition parameters, and image processing and analysis methods used in these studies. This calls for more comprehensive and well-controlled studies in this field, including those that combine the advanced brain imaging with biomechancial modeling and kinematic sensors - to shed light on the underlying mechanisms behind the structural changes observed from the imaging studies.

A projection of primary knee replacement in Denmark from 2020 to 2050.

Background and purpose - The incidence of knee replacements (KRs) has increased in the past decades. Previous studies have forecast a continuous and almost exponential rise in the use of KRs, but this rise must cease at some point. We estimated when and at what incidence the use of KRs will plateau in Denmark.Patients and methods - We retrieved 138,223 primary KRs conducted from 1997 to 2019 from the Danish Knee Arthroplasty Registry. Censuses from 1997 to 2019 as well as population projections from 2020 through 2050 were collected from Statistics Denmark. We applied logistic and Gompertz regression analysis to the data to estimate the future incidence until 2050 with root mean squared error (RMSE) as a quantitative measurement of the models' fit.Results - The Danish incidence of KRs from 1997 to 2009 increased by more than 300%, but has stalled since 2009. Logistic and Gompertz regression had an RMSE of 14 and 15 indicating that these models fitted the data well. Logistic and Gompertz regressions estimated that the maximum incidence will be reached in 2030 at 250 (95% prediction interval [PI]) 159-316) KRs per 105 or in 2035 at 260 (PI 182-336) KRs per 105, respectively.Interpretation - The Danish incidence of KRs seems set to plateau within the coming decades. Countries experiencing a current exponential rise at a lower incidence may benefit from this study's projection when forecasting their future demand for KRs.

One- and two-photon solvatochromism of the fluorescent dye Nile Red and its CF3, F and Br-substituted analogues.

The solvatochromic fluorophore Nile Red, 9-diethylamino-5H-benzo[a]phenoxazine-5-one, is one of the most commonly used stains to enhance contrast of lipid-rich areas of microscopic biosamples. Quite surprisingly, relatively little is known about the spectrally-resolved two-photon absorption (2PA) properties of this dye despite its promising features for two-photon microscopy of biological matter. For this reason, the two-photon solvatochromism of Nile Red still remains an uncharted territory as well. Also, no study has yet reported on how electron-withdrawing substituents attached to the Nile Red backbone affect its solvatochromic properties and two-photon brightness. In this paper, we demonstrate how solvent polarity influences the one- and two-photon absorption spectra of Nile Red as well as its fluorescence parameters, and we present new analogues that contain -CF3, -F and -Br substituents on its eastern side. Two-photon excited fluorescence experiments in a broad spectral range (780-1240 nm) and electronic structure calculations show that both the nature and location of the substituent have particular influence on the strength of 2PA, peaking in all cases at approx. 860 and 1050 nm. 2PA cross sections are higher at 1050 nm than at 860 nm, which suggests that Nile Red and its analogues are best suited for two-photon imaging employing excitation in the NIR-II optical transparency window of biological tissues.

Double-headed nucleotides as xeno nucleic acids: information storage and polymerase recognition.

Xeno nucleic acids (XNAs) are artificial genetic systems based on sugar-modified nucleotides. Herein, we investigate double-headed nucleotides as a new XNA. A new monomer, AT, is presented, and together with previous double-headed nucleotide monomers, new nucleic acid motifs consisting of up to five consecutive A·T base pairs have been obtained. Sections composed entirely of double-headed nucleotides are well-tolerated within a DNA duplex and can condense the genetic information. For instance, a 13-mer duplex is condensed to an 11-mer modified duplex containing four double-headed nucleotides while simultaneously improving duplex thermal stability with +14.0 °C. Also, the transfer of information from double-headed to natural nucleotides by DNA polymerases has been examined. The first double-headed nucleoside triphosphate was prepared but could not be recognized and incorporated by the tested DNA polymerases. On the other hand, it proved possible for Therminator DNA polymerase to transfer the information of a double-headed nucleotide in a template sequence to natural DNA under controlled conditions.

Is it time to rethink using digital palpation for assessment of muscle stiffness?

AIM: Physiotherapists typically use digital palpation to determine residual tension in a muscle, referred to as muscle stiffness or tone. These assessments are subjective, and little is known about their accuracy or repeatability. Despite this, it is standard practice to base clinical treatment on these findings. The aim of this study was to assess physiotherapists' ability to assign a seven-point palpation scale to quantitative stiffness values generated by a novel device. METHODS: Prospective observational study involving 125 musculoskeletal and pelvic floor physiotherapists. A novel device was developed that replicates the haptic feedback that clinicians assess as muscle stiffness. Measurements of displacement, force, and stiffness were recorded. RESULTS: There was wide overlap between each scale category assigned to the stiffness values, from low stiffness at -3 (119 [106, 132] N/m) to moderate stiffness at 0 (462 [435,489] N/m); to high stiffness at +3 (897 [881,913] N/m). Consistency in applying the scale was poor, and the probability of a similar value of stiffness being assigned to the same scale category by different participants was low. CONCLUSIONS: While palpation is used globally by physiotherapists as a readily available and low-cost method of assessing muscle stiffness, these results indicate that it should be used with caution in diagnosing and defining patient care. Clinical assessment of muscle stiffness requires a validated and reliable palpation scale if this metric is to be used to diagnose pathology and develop treatment protocols. Training in this scale should then be recommended to improve reliability in patient assessment.

Change in levator ani muscle stiffness and active force during pregnancy and post-partum.

INTRODUCTION AND HYPOTHESIS: It is assumed changes occur to the biomechanics and viscoelastic response of the levator ani muscle during pregnancy; however, there is limited evidence of this. This study used instrumentation and clinical measures to determine the stiffness and active force capacity of levator ani muscle during pregnancy and post-partum, investigated any associations with delivery outcomes, and explored the biomechanical properties associated with symptoms of pelvic floor dysfunction. METHODS: This was a prospective observational study, with nulliparous women with a singleton low-risk pregnancy. Data were collected at two stages during pregnancy and post-partum. Measurements included the Australian Pelvic Floor Questionnaire, palpation of active force, and elastometry measurements. Post-partum, 3D/4D ultrasound measurements were included. Repeated measures ANOVAs, pairwise comparisons, Pearson correlation coefficients, and Student's t-tests were used as appropriate. RESULTS: Fifty-nine women took part in the study. Active force was significantly different over the pregnancy and post-partum, measured with instrumentation (p = 0.002) and palpation (p = 0.006 right, p = 0.029 left). There was no significant change in muscle stiffness during pregnancy. Post-partum muscle stiffness was significantly different between women who gave birth vaginally vs. caesarean section (p = 0.002). Post-partum there were differences in levator hiatal area, symptoms of bladder dysfunction, prolapse symptoms, and sexual dysfunction symptoms. CONCLUSIONS: Active force of the levator ani muscle was significantly reduced during pregnancy and in the post-partum period, while muscle stiffness reduced only in those who had vaginal deliveries.

Postnatal pelvic floor muscle stiffness measured by vaginal elastometry in women with obstetric anal sphincter injury: a pilot study.

INTRODUCTION AND HYPOTHESIS: Vaginal childbirth is associated with pelvic floor muscle (PFM) damage in a third of women. The biomechanics prediction, detection and management of PFM damage remain poorly understood. We sought in this pilot study to determine whether quantifying PFM stiffness postnatally by vaginal elastometry, in women attending a perineal trauma clinic (PTC) within 6 months of obstetric anal sphincter injury, correlates with their antecedent labour characteristics, pelvic floor muscle damage, or urinary/bowel/sexual symptoms, to inform future definitive prospective studies. METHODS: In this pilot study, we measured postnatal PFM stiffness by vaginal elastometry in 54 women. A subset of participants (n = 14) underwent magnetic resonance imaging (MRI) to define any levator ani (LA) muscle defects from vaginal childbirth. We investigated the association of PFM stiffness with demographics, labour and delivery characteristics, clinical features and MRI evidence of LA damage. RESULTS: Raised maternal BMI was associated with reduced pelvic floor stiffness (r = -0.4; p < 0.01). Higher stiffness values were associated with forceps delivery for delayed second stage of labour (n = 14) vs non-forceps vaginal delivery (n = 40; 630 ± 40 N/m vs 500 ± 30 N/m; p < 0.05), and a non-significant trend towards longer duration of the second stage of labour. Women with urinary, bowel or sexual symptoms (n = 37) demonstrated higher pelvic floor stiffness values than those without (570 ± 30 N/m vs 450 ± 40 N/m; p < 0.05). CONCLUSIONS: A history of delayed second stage of labour and forceps delivery was associated with higher PFM stiffness values in the postnatal period. Whether high pelvic muscle stiffness antenatally is a risk factor for instrumental vaginal delivery and LA avulsion is unknown.

Can Machine-learning Algorithms Predict Early Revision TKA in the Danish Knee Arthroplasty Registry?

BACKGROUND: Revision TKA is a serious adverse event with substantial consequences for the patient. As the demand for TKA rises, reducing the risk of revision TKA is becoming increasingly important. Predictive tools based on machine-learning algorithms could reform clinical practice. Few attempts have been made to combine machine-learning algorithms with data from nationwide arthroplasty registries and, to the authors' knowledge, none have tried to predict the likelihood of early revision TKA. QUESTION/PURPOSES: We used the Danish Knee Arthroplasty Registry to build models to predict the likelihood of revision TKA within 2 years of primary TKA and asked: (1) Which preoperative factors were the most important features behind these models' predictions of revision? (2) Can a clinically meaningful model be built on the preoperative factors included in the Danish Knee Arthroplasty Registry? METHODS: The Danish Knee Arthroplasty Registry collects patients' characteristics and surgical information from all arthroplasties conducted in Denmark and thus provides a large nationwide cohort of patients undergoing TKA. As training dataset, we retrieved all preoperative variables of 25,104 primary TKAs from 2012 to 2015. The same variables were retrieved from 6170 TKAs conducted in 2016, which were used as a hold-out year for temporal external validation. If a patient received bilateral TKA, only the first knee to receive surgery was included. All patients were followed for 2 years, with removal, exchange, or addition of an implant defined as TKA revision. We created four different predictive models to find the best performing model, including a regression-based model using logistic regression with least shrinkage and selection operator (LASSO), two classification tree models (random forest and gradient boosting model) and a supervised neural network. For comparison, we created a noninformative model predicting that all observations were unrevised. The four machine learning models were trained using 10-fold cross-validation on the training dataset after adjusting for the low percentage of revisions by over-sampling revised observations and undersampling unrevised observations. In the validation dataset, the models' performance was evaluated and compared by density plot, calibration plot, accuracy, Brier score, receiver operator characteristic (ROC) curve and area under the curve (AUC). The density plot depicts the distribution of probabilities and the calibration plot graphically depicts whether the predicted probability resembled the observed probability. The accuracy indicates how often the models' predictions were correct and the Brier score is the mean distance from the predicted probability to the observed outcome. The ROC curve is a graphical output of the models' sensitivity and specificity from which the AUC is calculated. The AUC can be interpreted as the likelihood that a model correctly classified an observation and thus, a priori, an AUC of 0.7 was chosen as threshold for a clinically meaningful model. RESULTS: Based the model training, age, postfracture osteoarthritis and weight were deemed as important preoperative factors within the machine learning models. During validation, the models' performance was not different from the noninformative models, and with AUCs ranging from 0.57 to 0.60, no models reached the predetermined AUC threshold for a clinical useful discriminative capacity. CONCLUSION: Although several well-known presurgical risk factors for revision were coupled with four different machine learning methods, we could not develop a clinically useful model capable of predicting early TKA revisions in the Danish Knee Arthroplasty Registry based on preoperative data. CLINICAL RELEVANCE: The inability to predict early TKA revision highlights that predicting revision based on preoperative information alone is difficult. Future models might benefit from including medical comorbidities and an anonymous surgeon identifier variable or may attempt to build a postoperative predictive model including intra- and postoperative factors as these may have a stronger association with early TKA revisions.

Reduced survival of total knee arthroplasty after previous unicompartmental knee arthroplasty compared with previous high tibial osteotomy: a propensity-score weighted mid-term cohort study based on 2,133 observations from the Danish Knee Arthroplasty Registry.

Background and purpose - Both medial unicompartmental knee arthroplasties (UKA) and high tibial osteotomies (HTO) are reliable treatments for isolated medial knee osteoarthritis. However, both may with time need conversion to a total knee arthroplasty (TKA). We conducted the largest nationwide registry comparison of the survival of TKA following UKA with TKA following HTO.Patients and methods - From the Danish Knee Arthroplasty Registry, aseptic conversions to TKA from UKA and TKA converted from HTO within the period of 1997-2018 were retrieved. The Kaplan-Meier method and the Cox proportional hazards regression were used to estimate the survival and hazard ratio (HR) for revision, considering confounding by indication utilizing propensity-score based inverse probability of treatment weighting (PS-IPTW).Results - PS-IPTW yielded a well-balanced pseudo-cohort (standard mean difference (SMD) < 0.1 for all covariates, except implant supplementation) of 963.8 TKAs following UKA and 1139.1 TKAs following HTO. The survival of TKA following UKA was significantly less than that of TKA following HTO with a 5-year estimated survival of 0.88 (95% confidence interval (CI) 0.85-0.90) and 0.94 (CI 0.93-0.96), respectively. The differences in survival corresponded to an implant-supplementation adjusted HR of 2.7 (CI 2.4-3.1) for TKA following UKA compared with TKA following HTO.Interpretation - Previous UKA more than doubled the revision risk of a subsequent TKA compared with previous HTO. This potential risk should be considered in the shared treatment decision of patients who are candidates for both UKA and HTO.

Base-Pairing Properties of Double-Headed Nucleotides.

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.