Nonlinear mechanics of human mitotic chromosomes.

In preparation for mitotic cell division, the nuclear DNA of human cells is compacted into individualized, X-shaped chromosomes1. This metamorphosis is driven mainly by the combined action of condensins and topoisomerase IIα (TOP2A)2,3, and has been observed using microscopy for over a century. Nevertheless, very little is known about the structural organization of a mitotic chromosome. Here we introduce a workflow to interrogate the organization of human chromosomes based on optical trapping and manipulation. This allows high-resolution force measurements and fluorescence visualization of native metaphase chromosomes to be conducted under tightly controlled experimental conditions. We have used this method to extensively characterize chromosome mechanics and structure. Notably, we find that under increasing mechanical load, chromosomes exhibit nonlinear stiffening behaviour, distinct from that predicted by classical polymer models4. To explain this anomalous stiffening, we introduce a hierarchical worm-like chain model that describes the chromosome as a heterogeneous assembly of nonlinear worm-like chains. Moreover, through inducible degradation of TOP2A5 specifically in mitosis, we provide evidence that TOP2A has a role in the preservation of chromosome compaction. The methods described here open the door to a wide array of investigations into the structure and dynamics of both normal and disease-associated chromosomes.

Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations.

How spatial chromosome organization influences genome integrity is still poorly understood. Here, we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CCCTC-binding factor (CTCF) and cohesin-bound sites at the bases of chromatin loops, and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hotspots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability and are key contributors to the occurrence of genome rearrangements that drive cancer.

Sustainability considerations for organic electronic products.

The development of organic electronic applications has reached a critical point. While markets, including the Internet of Things, transparent solar and flexible displays, gain momentum, organic light-emitting diode displays lead the way, with a current market size of over $25 billion, helping to create the infrastructure and ecosystem for other applications to follow. It is imperative to design built-in sustainability into the materials selection, processing and device architectures of all of these emerging applications, and to close the loop for a circular approach. In this Perspective, we evaluate the status of embedded carbon in organic electronics, as well as options for more sustainable materials and manufacturing, including engineered recycling solutions that can be applied within the product architecture and at the end of life. This emerging industry has a responsibility to ensure a 'cradle-to-cradle' approach. We highlight that ease of dismantling and recycling needs to closely relate to the product lifetime, and that regeneration should be facilitated in product design. Materials choices should consider the environmental effects of synthesis, processing and end-product recycling as well as performance.

Mixed Ionic and Electronic Conduction in Small-Molecule Semiconductors.

Small-molecule organic semiconductors have displayed remarkable electronic properties with a multitude of π-conjugated structures developed and fine-tuned over recent years to afford highly efficient hole- and electron-transporting materials. Already making a significant impact on organic electronic applications including organic field-effect transistors and solar cells, this class of materials is also now naturally being considered for the emerging field of organic bioelectronics. In efforts aimed at identifying and developing (semi)conducting materials for bioelectronic applications, particular attention has been placed on materials displaying mixed ionic and electronic conduction to interface efficiently with the inherently ionic biological world. Such mixed conductors are conveniently evaluated using an organic electrochemical transistor, which further presents itself as an ideal bioelectronic device for transducing biological signals into electrical signals. Here, we review recent literature relevant for the design of small-molecule mixed ionic and electronic conductors. We assess important classes of p- and n-type small-molecule semiconductors, consider structural modifications relevant for mixed conduction and for specific interactions with ionic species, and discuss the outlook of small-molecule semiconductors in the context of organic bioelectronics.

Glucose evaluation and management in the ICU (GEM-ICU): Protocol for a bi-centre cohort study.

INTRODUCTION: Hyperglycaemia is common in intensive care unit (ICU) patients. Glycaemic monitoring and effective glycaemic control with insulin are crucial in the ICU to improve patient outcomes. However, glycaemic control and insulin use vary between ICU patients and hypo- and hyperglycaemia occurs. Therefore, we aim to provide contemporary data on glycaemic control and management, and associated outcomes, in adult ICU patients. We hypothesise that the occurrence of hypoglycaemia in acutely admitted ICU patients is lower than that of hyperglycaemia. METHODS: We will conduct a bi-centre cohort study of 300 acutely admitted adult ICU patients. Routine data will be collected retrospectively at baseline (ICU admission) and daily during ICU stay up to a maximum of 30 days. The primary outcome will be the number of patients with hypoglycaemia during their ICU stay. Secondary outcomes will be occurrence of severe hypoglycaemia, occurrence of hyperglycaemia, time below blood glucose target range, time above target range, all-cause mortality at Day 30, number of days alive without life support at Day 30 and number of days alive and out of hospital at Day 30. Process outcomes include the number of in-ICU days, glucose measurements (number of measurements and method) and use of insulin (including route of administration and dosage). All statistical analyses will be descriptive. CONCLUSIONS: This cohort study will provide a contemporary overview of glucose evaluation and management practices in adult ICU patients and, thus, highlight potential areas for improvement through future clinical trials in this area.

Poor usability of computer-assisted navigation for hip fracture surgery.

INTRODUCTION: The STRYKER ADAPT computer-assisted navigation system provides intraoperative feedback to the surgeon regarding implant placement of the Gamma3 nail. The usability of the ADAPT system has not been evaluated. The aim of the study was to investigate the perceived usability of the ADAPT system. MATERIALS AND METHODS: This was a descriptive study with prospectively collected data. ADAPT was introduced at Aarhus University Hospital in February 2021. Prior to introduction, surgeons at the department attended a general introduction to the system. ADAPT was introduced to the surgical nurses and was on display at the surgical ward at more than one occasion, where personal introduction to the system was possible. After introduction, it was mandatory to use ADAPT when using the Gamma3 nail to treat intertrochanteric femur fractures. After each procedure, primary and an eventual supervisor answered a questionnaire, which encompassed the System Usability Scale (SUS) questionnaire. The SUS is a ten-item questionnaire regarding the perceived usability of a system. SUS scores were translated to adjectives, describing user experience on a 7-point adjective scale (worst imaginable, awful, poor, ok, good, excellent, best imaginable). User acceptability, defined as "not acceptable", "marginal" or "acceptable", was also used to interpret the SUS scores. RESULTS: ADAPT was used in 50 procedures by 29 different surgeons, with varying skill-level. Median SUS-score after first-time use of ADAPT for all 29 surgeons was 43 (range: 5-60), which translated to "poor" or "not acceptable". For surgeons who performed ≥ 3 ADAPT-assisted procedures, there were no statistically significant difference in their first to latest SUS-score (median difference: 4.3, p = 0.5). In free text comments ADAPT was positively described as helpful in placement of K-wire and providing educational opportunities for inexperienced surgeons and negatively as inconsistent, slow, time consuming, and causing excessive fluoroscopy. CONCLUSIONS: Usability and acceptability of ADAPT was rated as "poor" or "not acceptable" by the majority of operating surgeons. ADAPT has not been used at our institution based on these findings. The System Usability Scale may be used in further research exploring usability and acceptability of novel computer-assisted navigation systems for orthopaedic surgery.

Half of all hip and knee arthroplasty patients may be potential day-case candidates: a nationwide register study of 166,730 procedures.

BACKGROUND AND PURPOSE: The overall potential pool of day-case candidates on a national level in hip and knee arthroplasty is unknown. We aimed to estimate the proportion of hip and knee arthroplasty patients eligible for day-case surgery based on contemporary widely used criteria and determine whether there has been a change in the proportion of eligible patients over time and, secondarily, to investigate the proportion of eligible patients discharged on the day of surgery. METHODS: Based on data from the Danish National Patient Register, we identified all patients undergoing primary unilateral hip or knee arthroplasty from January 2010 to March 2020. Using a modification of day-case eligibility criteria proposed by a national multicenter collaboration, we sorted patients into either day-case eligible or ineligible. A day-case procedure was defined as discharge on the day of surgery. RESULTS: We included patients comprising a total of 166,730 primary total hip (THA), total knee (TKA), and unicompartmental knee arthroplasty (UKA). 48% (95% confidence interval [CI] 48-49) were eligible for day-case surgery, with a decline from 50% (CI 49-51) in 2010 to 46% (CI 46-47) eligible in 2019. More UKA patients were day-case eligible (55%, CI 54-56) than THA (47%, CI 47-48) and TKA patients (49%, CI 48-49). A maximum of 8.0% (CI 7.4-8.5) of eligible patients were discharged on the day of surgery in 2019. CONCLUSION: 48% of the Danish hip and knee arthroplasty patients were potential day-case candidates, with a small decline in eligibility from 50% in 2010 to 46% in 2019. Day of surgery discharge among day-case eligible patients peaked at 8% in 2019. Thus, the potential for more day-case surgery seems large.

A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity.

Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.

Precision Measurement of Trident Production in Strong Electromagnetic Fields.

We demonstrate experimentally that the trident process e^{-}→e^{-}e^{+}e^{-} in a strong external field, with a spatial extension comparable to the effective radiation length, is well understood theoretically. The experiment, conducted at CERN, probes values for the strong field parameter χ up to 2.4. Experimental data and theoretical expectations using the local constant field approximation show remarkable agreement over almost 3 orders of magnitude in yield.

Low protection from breakthrough SARS-CoV-2 infection and mild disease course in ocrelizumab-treated patients with multiple sclerosis after three mRNA vaccine doses.

BACKGROUND: Our study investigated the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of multiple sclerosis (MS) patients who were treated with the anti-CD20 monoclonal antibody (Ab), ocrelizumab, before first, second and third BNT162b2 mRNA vaccinations. To correlate clinical outcomes with the humoral and cellular response. METHODS: The study was a prospective non-randomised controlled multicentre trial observational study. Participants with a diagnosis of MS who were treated for at least 12 months with ocrelizumab prior to the first BNT162b2 mRNA vaccination were prospectively followed up from January 2021 to June 2022. RESULTS: Out of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infection was observed in all infected participants. After the third vaccination, the non-infected participants had higher mean Ab levels compared to the infected participants (54.3 binding antibody unit (BAU)/mL vs 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4+ and CD8+ T lymphocytes in the two groups was not significant. CONCLUSION AND RELEVANCE: The study results demonstrate rates of 59% in breakthrough infections after the third SARS-CoV-2 mRNA vaccination in ocrelizumab-treated patients with MS, without resulting in critical disease courses. These findings suggest the need for continuous development of prophylactic treatments when proved important in the protection of severe breakthrough infection.

Topoisomerase IIα is essential for maintenance of mitotic chromosome structure.

Topoisomerase IIα (TOP2A) is a core component of mitotic chromosomes and important for establishing mitotic chromosome condensation. The primary roles of TOP2A in mitosis have been difficult to decipher due to its multiple functions across the cell cycle. To more precisely understand the role of TOP2A in mitosis, we used the auxin-inducible degron (AID) system to rapidly degrade the protein at different stages of the human cell cycle. Removal of TOP2A prior to mitosis does not affect prophase timing or the initiation of chromosome condensation. Instead, it prevents chromatin condensation in prometaphase, extends the length of prometaphase, and ultimately causes cells to exit mitosis without chromosome segregation occurring. Surprisingly, we find that removal of TOP2A from cells arrested in prometaphase or metaphase cause dramatic loss of compacted mitotic chromosome structure and conclude that TOP2A is crucial for maintenance of mitotic chromosomes. Treatments with drugs used to poison/inhibit TOP2A function, such as etoposide and ICRF-193, do not phenocopy the effects on chromosome structure of TOP2A degradation by AID. Our data point to a role for TOP2A as a structural chromosome maintenance enzyme locking in condensation states once sufficient compaction is achieved.

Obese Patients Achieve Good Improvements in Patient-Reported Outcome Measures After Medial Unicompartmental Knee Arthroplasty Despite a Lower Preoperative Score.

BACKGROUND: In this study, we examined the association between obesity and patient-reported outcome measures after medial unicompartmental knee arthroplasty (MUKA), assessed through score changes, Patient Acceptable Symptom State (PASS), and minimal important change (MIC). Second, the association between obesity and early readmissions was examined. METHODS: A total of 450 MUKAs (mean body mass index [BMI] 30.3, range, 19.6-53.1), performed from February 2016 to December 2020, were grouped using BMI: <30, 30-34.9, and >34.9. Oxford Knee Score (OKS), Forgotten Joint Score (FJS), and Activity and Participation Questionnaire (APQ) were assessed preoperatively and at 3, 12, and 24 months, postoperatively. The 12-month PASS and MIC were also assessed, defining PASS as OKS = 30, MIC-OKS as change in OKS = 8, and MIC-FJS as change in FJS = 14. RESULTS: No significant differences in OKS change were found between BMI groups. After 12 months, patients who had a BMI of 30-34.9 had lower change in FJS (estimate -8.1, 95% CI -14.9 to -1.4) and were less likely to reach PASS (odds ratio 0.4, 95% CI 0.2-0.7) as well as MIC-FJS (odds ratio 0.5, 95% CI 0.2-0.9). Both obese groups had lower change in APQ after 12 months. Differences in 90-day readmission rates were nonsignificant between groups. CONCLUSION: Our findings of no differences in OKS improvement between BMI groups and achieving MIC for BMI > 34.9 suggest good improvements in obese patients despite lower preoperative scores, supporting contemporary indications for MUKA. Lower APQ development and achievement of 12-month PASS may be used when addressing expectations of recovery.

10-year evolution of day-case hip and knee arthroplasty: a Danish nationwide register study of 166,833 procedures from 2010 to 2020.

BACKGROUND AND PURPOSE: No previous studies have investigated the use of day-case arthroplasty in Denmark on a national scale. We investigated the frequency of day-case surgery in total hip (THA), total knee (TKA), and unicompartmental knee arthroplasty (UKA) from 2010 to 2020 in Denmark. PATIENTS AND METHODS: Primary unilateral THAs, TKAs, and UKAs performed for osteoarthritis were identified in the Danish National Patient Register using procedural and diagnosis codes. Day-case surgery was defined as discharge on the day of surgery. 90-day readmissions were defined as any overnight admissions following discharge. RESULTS: From 2010 to 2020 Danish surgical centers performed 86,070 THAs, 70,323 TKAs, and 10,440 UKAs. From 2010 to 2014, less than 0.5% of THAs and TKAs were day-case procedures. They increased to 5.4% (95% confidence interval [CI] 4.9-5.8) of THAs and 2.8% (CI 2.4-3.2) of TKAs in 2019. From 2010 to 2014, 11% of UKAs were day-case procedures, but they increased to 20% (CI 18-22) in 2019. This increase was driven by a few surgical centers (3-7 centers). In 2010, readmission rates within 90 days of surgery were 10% after THAs and 11% after TKAs, and 9.4% for both THAs and TKAs in 2019. Readmission rates after UKA fluctuated between 4% and 7%. CONCLUSION: From 2010 to 2020 the use of day-case surgery in THA, TKA, and UKA increased in Denmark, driven by only a few centers. During the same period readmissions did not increase.

No difference in short-term readmissions following day-case vs. one overnight stay in patients having hip and knee arthroplasty: a nationwide register study of 51,042 procedures from 2010-2020.

BACKGROUND AND PURPOSE: Day-case hip and knee arthroplasty has gained in popularity, but there are conflicting results regarding readmissions. We aimed to investigate differences in 30- and 90-day readmission rates between day-case patients and patients with a single overnight stay following primary total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA). PATIENTS AND METHODS: We identified day-case (DC) and overnight (ON) THA, TKA, and UKA patients, operated on between 2010 and 2020, from the Danish National Patient Register. Day-case surgery was defined as discharge on the day of surgery. Overnight readmissions within 30 or 90 days of surgery were considered readmissions. We compared readmission rates between DC and ON patients within arthroplasty types using logistic regression adjusted for patient characteristics and year of surgery. We included 29,486 THAs (1,353 DC and 28,133 ON), 15,116 TKAs (617 DC and 14,499 ON), and 6,440 UKAs (1,528 DC and 4,914 ON). RESULTS: The 30-day readmission rates were: DC-THA 4.4% vs. ON-THA 4.4% (adjusted odds-ratio [aOR] 1.2, 95% confidence interval [CI] 0.91-1.6), DC-TKA 4.7% vs. ON-TKA 4.4% (aOR 1.1, CI 0.69-1.5), and DC-UKA 3.0% vs. ON-UKA 3.0% (aOR 1.1, CI 0.78-1.5). Similarly, no significant differences were present between DC and ON THA, TKA, and UKA regarding 90-day readmissions or time to readmission. CONCLUSION: We found no differences in readmission rates between day-case THA, TKA, and UKA patients and patients with a single overnight stay.

The Influence of Regiochemistry on the Performance of Organic Mixed Ionic and Electronic Conductors.

Thiophenes functionalised in the 3-position are ubiquitous building blocks for the design and synthesis of organic semiconductors. Their non-centrosymmetric nature has long been used as a powerful synthetic design tool exemplified by the vastly different properties of regiorandom and regioregular poly(3-hexylthiophene) owing to the repulsive head-to-head interactions between neighbouring side chains in the regiorandom polymer. The renewed interest in highly electron-rich 3-alkoxythiophene based polymers for bioelectronic applications opens up new considerations around the regiochemistry of these systems as both the head-to-tail and head-to-head couplings adopt near-planar conformations due to attractive intramolecular S-O interactions. To understand how this increased flexibility in the molecular design can be used advantageously, we explore in detail the geometrical and electronic effects that influence the optical, electrochemical, structural, and electrical properties of a series of six polythiophene derivatives with varying regiochemistry and comonomer composition. We show how the interplay between conformational disorder, backbone coplanarity and polaron distribution affects the mixed ionic-electronic conduction. Ultimately, we use these findings to identify a new conformationally restricted polythiophene derivative for p-type accumulation-mode organic electrochemical transistor applications with performance on par with state-of-the-art mixed conductors evidenced by a µC* product of 267 F V-1 cm-1 s-1 .

Quinoxaline derivatives as attractive electron-transporting materials.

This review article provides a comprehensive overview of recent advancements in electron transport materials derived from quinoxaline, along with their applications in various electronic devices. We focus on their utilization in organic solar cells (OSCs), dye-sensitized solar cells (DSSCs), organic field-effect transistors (OFETs), organic-light emitting diodes (OLEDs) and other organic electronic technologies. Notably, the potential of quinoxaline derivatives as non-fullerene acceptors in OSCs, auxiliary acceptors and bridging materials in DSSCs, and n-type semiconductors in transistor devices is discussed in detail. Additionally, their significance as thermally activated delayed fluorescence emitters and chromophores for OLEDs, sensors and electrochromic devices is explored. The review emphasizes the remarkable characteristics and versatility of quinoxaline derivatives in electron transport applications. Furthermore, ongoing research efforts aimed at enhancing their performance and addressing key challenges in various applications are presented.

Access to Cyclic N-Trifluoromethyl Ureas through Photocatalytic Activation of Carbamoyl Azides.

We report the mild activation of carbamoyl azides to the corresponding nitrenes using a blue light/[Ir]-catalyzed strategy, which enables stereospecific access to N-trifluoromethyl imidazolidinones and benzimidazolones. These novel structural motifs proved to be highly robust, allowing their downstream diversification. On the basis of our combined computational and experimental studies, we propose that an electron rebound with the excited metal catalyst is undergone, involving a reduction-triggered nitrogen loss, followed by oxidation to the corresponding carbamoyl nitrene and subsequent C-H insertion.

Recent progress in asymmetric synergistic catalysis - the judicious combination of selected chiral aminocatalysts with achiral metal catalysts.

In this review we survey recent synergistic applications of a chiral organocatalyst with an achiral metal to perform stereoselective transformations of synthetic utility (since 2016). The transformations are classified by the modes of reactivity deployed, focussing on organocatalytic activation of carbonyl substrates as chiral nucleophiles via the α-position (e.g., as enamines) and as chiral electrophiles via the ß-position (e.g., as iminium ions) combined with complementary activation of their reaction partners by an achiral metal co-catalyst (e.g., Pd or Cu-based). Corresponding radical reactions are also presented in which photocatalysis mediated by achiral metal complexes replaces the metal co-catalyst. Certain privileged structures are revealed and opportunities to develop this exciting field are highlighted.

Access to N-CF3 Formamides by Reduction of N-CF3 Carbamoyl Fluorides.

The departure into unknown chemical space is essential for the discovery of new properties and function. We herein report the first synthetic access to N-trifluoromethylated formamides. The method involves the reduction of bench-stable NCF3 carbamoyl fluorides and is characterized by operational simplicity and mildness, tolerating a broad range of functional groups as well as stereocenters. The newly made N-CF3 formamide motif proved to be highly robust and compatible with diverse chemical transformations, underscoring its potential as building block in complex functional molecules.