Clinical Course of TGA After Arterial Switch Operation in the Current Era.

Background: The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era. Objectives: The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events. Methods: A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined. Results: At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6%-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2). Conclusions: TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood.

Vanadium haloperoxidases as noncanonical terpene synthases.

Vanadium-dependent haloperoxidases (VHPOs) are a unique family of enzymes that utilize vanadate, an aqueous halide ion, and hydrogen peroxide to produce an electrophilic halogen species that can be incorporated into electron rich organic substrates. This halogen species can react with terpene substrates and trigger halonium-induced cyclization in a manner reminiscent of class II terpene synthases. While not all VHPOs act in this capacity, several notable examples from algal and actinobacterial species have been characterized to catalyze regio- and enantioselective reactions on terpene and meroterpenoid substrates, resulting in complex halogenated cyclic terpenes through the action of single enzyme. In this article, we describe the expression, purification, and chemical assays of NapH4, a difficult to express characterized VHPO that catalyzes the chloronium-induced cyclization of its meroterpenoid substrate.

Cognitive functioning associated with acute and subacute effects of classic psychedelics and MDMA - a systematic review and meta-analysis.

Classic psychedelics and MDMA have a colorful history of recreational use, and both have recently been re-evaluated as tools for the treatment of psychiatric disorders. Several studies have been carried out to assess potential long-term effects of a regular use on cognition, delivering distinct results for psychedelics and MDMA. However, to date knowledge is scarce on cognitive performance during acute effects of those substances. In this systematic review and meta-analysis, we investigate how cognitive functioning is affected by psychedelics and MDMA during the acute drug effects and the sub-acute ("afterglow") window. Our quantitative analyses suggest that acute cognitive performance is differentially affected by psychedelics when compared to MDMA: psychedelics impair attention and executive function, whereas MDMA primarily affects memory, leaving executive functions and attention unaffected. Our qualitative analyses reveal that executive functioning and creativity may be increased during a window of at least 24 h after the acute effects of psychedelics have subsided, whereas no such results have been observed for MDMA. Our findings may contribute to inform recommendations on harm reduction for recreational settings and to help fostering differential approaches for the use of psychedelics and MDMA within a therapeutic framework.

Facing the Next "Geriatric Giant"-A Systematic Literature Review and Meta-Analysis of Interventions Tackling Loneliness and Social Isolation Among Older Adults.

OBJECTIVES: Loneliness and social isolation are associated with adverse health outcomes, especially within the older adult population, underlining the need for effective interventions. This systematic review and meta-analysis aims to summarize all available evidence regarding the effectiveness of interventions for loneliness and social isolation, to map out their working mechanisms, and to give implications for policy and practice. DESIGN: Systematic literature review and meta-analysis. SETTING AND PARTICIPANTS: Older adults (≥65 years). METHODS: A systematic search was conducted in MEDLINE, PsycINFO, and CINAHL for studies quantitively or qualitatively assessing effects of interventions for loneliness and social isolation in older adults, following predefined selection criteria. Risk of bias as well as small study effects were assessed and, wherever appropriate, information about effect sizes of individual studies pooled using random-effects meta-analyses. Sources for between-study heterogeneity were explored using meta-regression. RESULTS: Of n = 2223 identified articles, n = 67 were eventually included for narrative synthesis. Significant intervention effects were reported for a proportion of studies (55.9% and 50.0% for loneliness and social isolation, respectively) and 57.6% of studies including a follow-up measure (n = 29) reported sustained intervention effects. Meta-analysis of n = 27 studies, representing n = 1756 participants, suggested a medium overall effect of loneliness interventions (d = -0.47; 95% CI, -0.62 to -0.32). Between-study heterogeneity was substantial and could not be explained by differences in study design, year of publication, outcome measures, intervention length, participant demographics, setting, baseline level of loneliness, or geographic location. However, non-technology-based interventions reported larger effect sizes on average (Δd = -0.35; 95% CI, -0.66 to -0.04; P = .029) and were more often significant. Qualitative assessment of potential intervention mechanisms resulted in 3 clusters of effective components: "promoting social contact," "transferring knowledge and skills," and "addressing social cognition". CONCLUSIONS AND IMPLICATIONS: Interventions for loneliness and social isolation can generally be effective, although some unexplained between-study heterogeneity remains. Further research is needed regarding the applicability of interventions across different settings and countries, also considering their cost-effectiveness.

Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes.

The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.

Neutrophil NLRP3 promotes cardiac injury following acute myocardial infarction through IL-1ß production, VWF release and NET deposition in the myocardium.

NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta (IL-1ß). Permanent ligation of the left anterior descending artery was used to induce MI in WT and NLRP3-/- mice as well as in NLRP3-/- recipient mice transfused with either WT or NLRP3-/- neutrophils. NLRP3 deficiency reduced infarct size to roughly a third of WT heart injury and preserved left ventricular (LV) function at 12 h after MI as assessed by echocardiography and triphenyltetrazolium chloride staining of live tissue. Transfusion of WT but not NLRP3-/- neutrophils after MI increased infarct size in NLRP3-/- mice and significantly reduced LV function. The key features of myocardial tissue in WT neutrophil transfused recipients were increased H3Cit-positive deposits with NET-like morphology and increased tissue levels of IL-1ß and plasma levels of von Willebrand Factor (VWF). Flow cytometry analysis also revealed that neutrophil NLRP3 increased the number of labeled and transfused neutrophils in the bone marrow of recipient mice following MI. Our data suggest a key role for neutrophil NLRP3 in the production of IL-1ß and deposition of NETs in cardiac tissue exacerbating injury following MI. We provide evidence for a link between neutrophil NLRP3 and VWF release likely enhancing thromboinflammation in the heart. Neutrophil NLRP3 deficiency conferred similar cardioprotective effects to general NLRP3 deletion in MI rendering anti-neutrophil NLRP3 therapy a promising target for early cardioprotective treatment.

Accuracy of Event Rate and Effect Size Estimation in Major Cardiovascular Trials: A Systematic Review.

Importance: For the design of a randomized clinical trial (RCT), estimation of the expected event rate and effect size of an intervention is needed to calculate the sample size. Overestimation may lead to an underpowered trial. Objective: To evaluate the accuracy of published estimates of event rate and effect size in contemporary cardiovascular RCTs. Evidence Review: A systematic search was conducted in MEDLINE for multicenter cardiovascular RCTs associated with MeSH (Medical Subject Headings) terms for cardiovascular diseases published in the New England Journal of Medicine, JAMA, or the Lancet between January 1, 2010, and December 31, 2019. Identified trials underwent abstract review; eligible trials then underwent full review, and those with insufficiently reported data were excluded. Data were extracted from the original publication or the study protocol, and a random-effects model was used for data pooling. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. The primary outcome was the accuracy of event rate and effect size estimation. Accuracy was determined by comparing the observed event rate in the control group and the effect size with their hypothesized values. Linear regression was used to determine the association between estimation accuracy and trial characteristics. Findings: Of the 873 RCTs identified, 374 underwent full review and 30 were subsequently excluded, resulting in 344 trials for analysis. The median observed event rate was 9.0% (IQR, 4.3% to 21.4%), which was significantly lower than the estimated event rate of 11.0% (IQR, 6.0% to 25.0%) with a median deviation of -12.3% (95% CI, -16.4% to -5.6%; P < .001). More than half of the trials (196 [61.1%]) overestimated the expected event rate. Accuracy of event rate estimation was associated with a higher likelihood of refuting the null hypothesis (0.13 [95% CI, 0.01 to 0.25]; P = .03). The median observed effect size in superiority trials was 0.91 (IQR, 0.74 to 0.99), which was significantly lower than the estimated effect size of 0.72 (IQR, 0.60 to 0.80), indicating a median overestimation of 23.1% (95% CI, 17.9% to 28.3%). A total of 216 trials (82.1%) overestimated the effect size. Conclusions and Relevance: In this systematic review of contemporary cardiovascular RCTs, event rates of the primary end point and effect sizes of an intervention were frequently overestimated. This overestimation may have contributed to the inability to adequately test the trial hypothesis.

Diazirine-Functionalized Polyurethane Crosslinkers for Isocyanate-Free Curing of Polyol-Based Coatings.

Polyurethane coatings have strong material properties due to the hydrogen bonding inherent to the urethane groups. However, installing this urethane moiety usually requires curing through difficult-to-handle isocyanates. In this work, we show the development of a polyurethane-based crosslinker that can be used to formulate a one-component polyurethane coating with material properties similar to those of isocyanate-based polyurethane coatings. To achieve this, we used diazirine functionalities that generate carbenes upon heating, which react with alcohol functionalities in a polyol to generate a crosslinked network with a high storage modulus.

Spatio-temporal modeling of high-throughput multispectral aerial images improves agronomic trait genomic prediction in hybrid maize.

Design randomizations and spatial corrections have increased understanding of genotypic, spatial, and residual effects in field experiments, but precisely measuring spatial heterogeneity in the field remains a challenge. To this end, our study evaluated approaches to improve spatial modeling using high-throughput phenotypes (HTP) via unoccupied aerial vehicle (UAV) imagery. The normalized difference vegetation index was measured by a multispectral MicaSense camera and processed using ImageBreed. Contrasting to baseline agronomic trait spatial correction and a baseline multitrait model, a two-stage approach was proposed. Using longitudinal normalized difference vegetation index data, plot level permanent environment effects estimated spatial patterns in the field throughout the growing season. Normalized difference vegetation index permanent environment were separated from additive genetic effects using 2D spline, separable autoregressive models, or random regression models. The Permanent environment were leveraged within agronomic trait genomic best linear unbiased prediction either modeling an empirical covariance for random effects, or by modeling fixed effects as an average of permanent environment across time or split among three growth phases. Modeling approaches were tested using simulation data and Genomes-to-Fields hybrid maize (Zea mays L.) field experiments in 2015, 2017, 2019, and 2020 for grain yield, grain moisture, and ear height. The two-stage approach improved heritability, model fit, and genotypic effect estimation compared to baseline models. Electrical conductance and elevation from a 2019 soil survey significantly improved model fit, while 2D spline permanent environment were most strongly correlated with the soil parameters. Simulation of field effects demonstrated improved specificity for random regression models. In summary, the use of longitudinal normalized difference vegetation index measurements increased experimental accuracy and understanding of field spatio-temporal heterogeneity.

P80 natural essence spray and lozenges provide respiratory protection against Influenza A, B, and SARS-CoV-2.

Seasonally circulating viruses, such as Influenza, as well as newly emerging viruses and variants thereof, and waning immunity urge the need for safe, easy-to-use and inexpensive drugs to protect from these challenges. To prevent transmission of these viruses and subsequent excessive inflammatory reactions on mucous membranes, we tested the efficacy of the natural essence P80 as spray and in form of lozenges against respiratory infections caused by SARS-CoV-2 variants of concern (VoCs), influenza A (H3N2) and influenza B (Victoria). P80 natural essence, a Dimocarpus longan extract, shielded highly differentiated human airway epithelia from SARS-CoV-2 wildtype and Omicron variant as well as Influenza A and B infection and dampened inflammation by down-modulating pro-inflammatory cytokine and anaphylatoxin secretion. A single application of P80 natural essence spray maintained tissue integrity long-term. This also significantly reduced the release of infectious viral particles and the secretion of IP10, MCP1, RANTES and C3a, all of which mediate the migration of immune cells to the sites of infection. Even P80 lozenges dissolved in distilled water or non-neutralizing saliva efficiently prevented SARS-CoV-2 and Influenza-induced tissue destruction. Consequently, our in vitro data suggest that P80 natural essence can act as antiviral prophylactic, both in form of nasal or oral spray and in form of lozenges, independent of circulating respiratory challenges.

Komagataella phaffii Erp41 is a protein disulfide isomerase with unprecedented disulfide bond catalyzing activity when coupled to glutathione.

In the methylotrophic yeast Komagataella phaffii, we identified an endoplasmic reticulum-resident protein disulfide isomerase (PDI) family member, Erp41, with a peculiar combination of active site motifs. Like fungal ERp38, it has two thioredoxin-like domains which contain active site motifs (a and a'), followed by an alpha-helical ERp29c C-terminal domain (c domain). However, while the a domain has a typical PDI-like active site motif (CGHC), the a' domain instead has CGYC, a glutaredoxin-like motif which confers to the protein an exceptional affinity for GSH/GSSG. This combination of active site motifs has so far been unreported in PDI-family members. Homology searches revealed ERp41 is present in the genome of some plants, fungal parasites, and a few nonconventional yeasts, among which are Komagataella spp. and Yarrowia lipolytica. These yeasts are both used for the production of secreted recombinant proteins. Here, we analyzed the activity of K. phaffii Erp41. We report that it is nonessential in K. phaffii, and that it can catalyze disulfide bond formation in partnership with the sulfhydryl oxidase Ero1 in vitro with higher turnover rates than the canonical PDI from K. phaffii, Pdi1, but slower activation times. We show how Erp41 has unusually fast glutathione-coupled oxidation activity and relate it to its unusual combination of active sites in its thioredoxin-like domains. We further describe how this determines its unusually efficient catalysis of dithiol oxidation in peptide and protein substrates.

Enhanced Photocurrent and Electrically Pumped Quantum Dot Emission from Single Plasmonic Nanoantennas.

Integrating cavity-enhanced colloidal quantum dots (QDs) into photonic chip devices would be transformative for advancing room-temperature optoelectronic and quantum photonic technologies. However, issues with efficiency, stability, and cost remain formidable challenges to reach the single antenna limit. Here, we present a bottom-up approach that delivers single QD-plasmonic nanoantennas with electrical addressability. These QD nanojunctions exhibit robust photoresponse characteristics, with plasmonically enhanced photocurrent spectra matching the QD solution absorption. We demonstrate electroluminescence from individual plasmonic nanoantennas, extending the device lifetime beyond 40 min by utilizing a 3 nm electron-blocking polymer layer. In addition, we reveal a giant voltage-dependent redshift of up to 62 meV due to the quantum-confined Stark effect and determine the exciton polarizability of the CdSe QD monolayer to be 4 × 10-5 meV/(kV/cm)2. These developments provide a foundation for accessing scalable quantum light sources and high-speed, tunable optoelectronic systems operating under ambient conditions.

Designing for passengers' information needs on fellow travelers: A comparison of day and night rides in shared automated vehicles.

Shared automated mobility-on-demand promises efficient, sustainable, and flexible transportation. Nevertheless, security concerns, resilience, and their mutual influence - especially at night - will likely be the most critical barriers to public adoption since passengers have to share rides with strangers without a human driver on board. Prior research points out that having information about fellow travelers could alleviate the concerns of passengers and we designed two user interface variants to investigate the role of this information in an exploratory within-subjects user study (N=24). Participants experienced four automated day and night rides with varying personal information about co-passengers in a simulated environment. The results of the mixed-method study indicate that having information about other passengers (e.g., photo, gender, and name) positively affects user experience at night. In contrast, it is less necessary during the day. Considering participants' simultaneously raised privacy concerns, balancing security and privacy demands poses a substantial challenge for resilient system design.

Application of bone cement directly to the implant in primary total knee arthroplasty. Short-term radiological and clinical follow-up of two different cementing techniques.

PURPOSE: This study aimed to optimize cement application techniques in fully cemented primary total knee arthroplasty (TKA) by comparing the effects of two different approaches: cement on bone surface (CoB) versus cement on bone surface and implant surface (CoBaI) on the short-term presence of radiolucent lines (RLL) as indicators of potential complications. METHODS: In this monocentric study, a total of 379 fully cemented primary TKAs (318 patients) were included. The two study groups were differentiated by the technique of cement application: CoB group (cement applied only on bone surface) and CoBaI group (cement applied on both bone surface and implant surface). The presence of RLL or osteolysis was evaluated using the updated Knee Society Radiographic Evaluation System. RESULTS: In the whole study population, RLL were present in 4.7% of cases, with a significantly higher incidence in the CoBaI group (10.5%) at the 4-week follow-up. At the 12-month follow-up, RLL were observed in 29.8% of TKAs in the CoBaI group, while the incidence was lower in the CoB group (24.0%) (not statistically significant). There were two revisions in each group, none of which were due to aseptic loosening. CONCLUSION: The findings of this study suggest that the application of bone cement on bone surface only (CoB) may be more beneficial than applying it on both bone surface and implant surface (CoBaI) in terms of short-term presence of RLL in fully cemented primary TKA. Long-term results, especially with regard to aseptic loosening, will be of interest and may provide valuable guidance for future directions in bone cement applications in TKA.

Sudden cardiac arrest in infants and children: proposal for a diagnostic workup to identify the etiology. An 18-year multicenter evaluation in the Netherlands.

Sudden cardiac arrest (SCA) studies are often population-based, limited to sudden cardiac death, and excluding infants. To guide prevention opportunities, it is essential to be informed of pediatric SCA etiologies. Unfortunately, etiologies frequently remain unresolved. The objectives of this study were to determine paediatric SCA etiology, and to evaluate the extent of post-SCA investigations and to assess the performance of previous cardiac evaluation in detecting conditions predisposing to SCA. In a retrospective cohort (2002-2019), all children 0-18 years with out-of-hospital cardiac arrest (OHCA) referred to Erasmus MC Sophia Children's Hospital or the Amsterdam UMC (tertiary-care university hospitals), with cardiac or unresolved etiologies were eligible for inclusion. SCA etiologies, cardiac and family history and etiologic investigations in unresolved cases were assessed. The etiology of arrest could be determined in 52% of 172 cases. Predominant etiologies in children ≥ 1 year (n = 99) were primary arrhythmogenic disorders (34%), cardiomyopathies (22%) and unresolved (32%). Events in children < 1 year (n = 73) were largely unresolved (70%) or caused by cardiomyopathy (8%), congenital heart anomaly (8%) or myocarditis (7%). Of 83 children with unresolved etiology a family history was performed in 51%, an autopsy in 51% and genetic testing in 15%. Pre-existing cardiac conditions presumably causative for SCA were diagnosed in 9%, and remained unrecognized despite prior evaluation in 13%. CONCLUSION: SCA etiology remained unresolved in 83 of 172 cases (48%) and essential diagnostic investigations were often not performed. Over one-fifth of SCA patients underwent prior cardiac evaluation, which did not lead to recognition of a cardiac condition predisposing to SCA in all of them. The diagnostic post-SCA approach should be improved and the proposed standardized pediatric post-SCA diagnostics protocol may ensure a consistent and systematic evaluation process increasing the diagnostic yield. WHAT IS KNOWN: • Arrests in infants remain unresolved in most cases. In children > 1 year, predominant etiologies are primary arrhythmia disorders, cardiomyopathy and myocarditis. • Studies investigating sudden cardiac arrest are often limited to sudden cardiac death (SCD) in 1 to 40 year old persons, excluding infants and successfully resuscitated children. WHAT IS NEW: • In patients with unresolved SCA events, the diagnostic work up was often incompletely performed. • Over one fifth of victims had prior cardiac evaluation before the arrest, with either a diagnosed cardiac condition (9%) or an unrecognized cardiac condition (13%).

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921.

PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.

Medialized Dome and Anatomic Onlay Patella Designs in the Modern Posterior Stabilized Rotating Platform Total Knee Arthroplasty Demonstrate No Clinical or Radiological Differences at One Year.

BACKGROUND: A successful outcome after total knee arthroplasty (TKA) includes the restoration of patellofemoral function. Modern patella component designs in TKA include a medialized dome and more recently, an anatomic design. There is a paucity of literature comparing these 2 implants. METHODS: This prospective nonrandomized study examined 544 consecutive TKAs with patella resurfacing using a posterior-stabilized, rotating platform knee prothesis performed by a single surgeon. A medialized dome patella design was used in the first 323 cases and an anatomic design in the subsequent 221 cases. Patients were assessed preoperatively, at 4 weeks and 1-year post-TKA for Oxford Knee Score (OKS) (total, pain, and kneeling components) and range of movement (ROM). Radiolucent lines (RLLs), patellar tilts and displacements, as well as reoperations were assessed at 1-year post-TKA. RESULTS: At 1-year post-TKA, both groups demonstrated similar improvements in ROM, OKS, pain, and kneeling scores, and had a similar incidence of fixed-flexion deformity (all P > .05). Radiographically, there was no clinically significant difference in the incidence of RLLs, patellar tilts, and displacements. The prevalence of reoperations (1.8 versus 3.2%, P = .526) was similar between the designs with no patella-related complications. CONCLUSION: Both medialized dome and anatomic patella designs result in improved ROM and OKS with no patella-related complications. However, our study showed no differences between the designs at 1 year.

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.

Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.

Catalyzing Singlet Fission by Transition Metals: Second versus Third Row Effects.

The synthesis and characterization of platinum(II) and palladium(II) complexes bearing two (dimers Pt(Lpc)2Cl2 and Pd(Lpc)2Cl2), one (monomers Pt(Lpc)(Lref)Cl2 and Pd(Lpc)(Lref)Cl2), or no (reference compounds Pt(Lref)2Cl2 and Pd(Lref)2Cl2) pentacene-based pyridyl ligands are presented. Photophysical properties of the dimers are probed by means of steady-state and time-resolved transient absorption measurements in comparison to the monomer and model compounds. Our results document that despite enhanced spin-orbit coupling from the presence of heavy atoms, intramolecular singlet fission (iSF) is not challenged by intersystem crossing. iSF thus yields correlated triplet pairs and even uncorrelated triplet excited states upon decoherence. Importantly, significant separation of the two pentacenyl groups facilitates decoupling of the two chromophores. Furthermore, the mechanism of iSF is altered depending on the respective metal center, that is, Pt(II) versus Pd(II). The dimer based on Pt(II), Pt(Lpc)2Cl2, exhibits a direct pathway for the iSF and forms a correlated triplet pair with singlet-quintet spin-mixing within 10 ns in variable solvents. On the other hand, the dimer based on Pd(II), Pd(Lpc)2Cl2, leads to charge transfer mixing during the population of the correlated triplet pair that is dependent on solvent polarity. Moreover, Pd(Lpc)2Cl2 gives rise to a stable equilibrium between singlet and quintet correlated triplet pairs with lifetimes of up to 170 ns. Inherent differences in the size and polarizability, when contrasting platinum(II) with palladium(II), are the most likely rationale for the underlying trends.

Omicron subvariants illustrate reduced respiratory tissue penetration, cell damage and inflammatory responses in human airway epithelia.

Introduction: To explore whether the reported lower pathogenicity in infected individuals of variant of concern (VoC) Omicron and its current subvariants compared to VoC Delta may be related to fundamental differences in the initial virus-tissue interaction, we assessed their ability to penetrate, replicate and cause damage in a human 3D respiratory model. Methods: For this, we used TEER measurements, real-time PCR, LDH, cytokine and complex confocal imaging analyses. Results and discussion: We observed that Delta readily penetrated deep into the respiratory epithelium and this was associated with major tissue destruction, high LDH activity, high viral loads and pronounced innate immune activation as observed by intrinsic C3 activation and IL-6 release at infection sites. In contrast, Omicron subvariants BA.5, BQ.1.1 and BF7 remained superficially in the mucosal layer resulting merely in outward-directed destruction of cells, maintenance of epithelial integrity, minimal LDH activity and low basolateral release of virus at infection sites, as well as significantly smaller areas of complement activation and lower IL-6 secretion. Interestingly, also within Omicron subvariants differences were observed with newer Omicron subvariants BQ.1.1 and BF.7 illustrating significantly reduced viral loads, IL-6 release and LDH activity compared to BA.5. Our data indicate that earliest interaction events after SARS-CoV-2 transmission may have a role in shaping disease severity.