Toward Self-Healing Concrete Infrastructure: Review of Experiments and Simulations across Scales.

Cement and concrete are vital materials used to construct durable habitats and infrastructure that withstand natural and human-caused disasters. Still, concrete cracking imposes enormous repair costs on societies, and excessive cement consumption for repairs contributes to climate change. Therefore, the need for more durable cementitious materials, such as those with self-healing capabilities, has become more urgent. In this review, we present the functioning mechanisms of five different strategies for implementing self-healing capability into cement based materials: (1) autogenous self-healing from ordinary portland cement and supplementary cementitious materials and geopolymers in which defects and cracks are repaired through intrinsic carbonation and crystallization; (2) autonomous self-healing by (a) biomineralization wherein bacteria within the cement produce carbonates, silicates, or phosphates to heal damage, (b) polymer-cement composites in which autonomous self-healing occurs both within the polymer and at the polymer-cement interface, and (c) fibers that inhibit crack propagation, thus allowing autogenous healing mechanisms to be more effective. In all cases, we discuss the self-healing agent and synthesize the state of knowledge on the self-healing mechanism(s). In this review article, the state of computational modeling across nano- to macroscales developed based on experimental data is presented for each self-healing approach. We conclude the review by noting that, although autogenous reactions help repair small cracks, the most fruitful opportunities lay within design strategies for additional components that can migrate into cracks and initiate chemistries that retard crack propagation and generate repair of the cement matrix.

Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

A comprehensive coding and microRNA transcriptome of vertebral bone in postlarvae and juveniles of Senegalese sole (Solea senegalensis).

Understanding vertebral bone development is essential to prevent skeletal malformations in farmed fish related to genetic and environmental factors. This is an important issue in Solea senegalensis, with special impact of spinal anomalies in postlarval and juvenile stages. Vertebral bone transcriptomics in farmed fish mainly comes from coding genes, and barely on miRNA expression. Here, we used RNA-seq of spinal samples to obtain the first comprehensive coding and miRNA transcriptomic repertoire for postlarval and juvenile vertebral bone, covering different vertebral phenotypes and egg-incubation temperatures related to skeleton health in S. senegalensis. Coding genes, miRNA and pathways regulating bone development and growth were identified. Differential transcriptomic profiles and suggestive mRNA-miRNA interactions were found between postlarvae and juveniles. Bone-related genes and functions were associated with the extracellular matrix, development and regulatory processes, calcium binding, retinol and lipid metabolism or response to stimulus, including those revealed by the miRNA targets related to signaling, cellular and metabolic processes, growth, cell proliferation and biological adhesion. Pathway enrichment associated with fish skeleton were identified when comparing postlarvae and juveniles: growth and bone development functions in postlarvae, while actin cytoskeleton, focal adhesion and proteasome related to bone remodeling in juveniles. The transcriptome data disclosed candidate coding and miRNA gene markers related to bone cell processes, references for functional studies of the anosteocytic bone of S. senegalensis. This study establishes a broad transcriptomic foundation to study healthy and anomalous spines under early thermal conditions across life-stages in S. senegalensis, and for comparative analysis of skeleton homeostasis and pathology in fish and vertebrates.

Nitrogen-Anchored Boridene Enables Mg-CO2 Batteries with High Reversibility.

Nanoscale defect engineering plays a crucial role in incorporating extraordinary catalytic properties in two-dimensional materials by varying the surface groups or site interactions. Herein, we synthesized high-loaded nitrogen-doped Boridene (N-Boridene (Mo4/3(BnN1-n)2-mTz), N-doped concentration up to 26.78 at %) nanosheets by chemical exfoliation followed by cyanamide intercalation. Three different nitrogen sites are observed in N-Boridene, wherein the site of boron vacancy substitution mainly accounts for its high chemical activity. Attractively, as a cathode for Mg-CO2 batteries, it delivers a long-term lifetime (305 cycles), high-energy efficiency (93.6%), and ultralow overpotential (∼0.09 V) at a high current of 200 mA g-1, which overwhelms all Mg-CO2 batteries reported so far. Experimental and computational studies suggest that N-Boridene can remarkably change the adsorption energy of the reaction products and lower the energy barrier of the rate-determining step (*MgCO2 → *MgCO3·xH2O), resulting in the rapid reversible formation/decomposition of new MgCO3·5H2O products. The surging Boridene materials with defects provide substantial opportunities to develop other heterogeneous catalysts for efficient capture and converting of CO2.

N-Decorated Main-Group MgAl2 O4 Spinel: Unlocking Exceptional Oxygen Reduction Activity for Zn-Air Batteries.

The development of economical and efficient oxygen reduction reaction (ORR) catalysts is crucial to accelerate the widespread application rhythm of aqueous rechargeable zinc-air batteries (ZABs). Here, a strategy is reported that the modification of the binding energy for reaction intermediates by the axial N-group converts the inactive spinel MgAl2 O4 into the active motif of MgAl2 O4 -N. It is found that the introduction of N species can effectively optimize the electronic configuration of MgAl2 O4 , thereby significantly reducing the adsorption strength of *OH and boosting the reaction process. This main-group MgAl2 O4 -N catalyst exhibits a high ORR activity in a broad pH range from acidic and alkaline environments. The aqueous ZABs assembled with MgAl2 O4 -N shows a peak power density of 158.5 mW cm-2 , the long-term cyclability over 2000 h and the high stability in the temperature range from -10 to 50 °C, outperforming the commercial Pt/C in terms of activity and stability. This work not only serves as a significant candidate for the robust ORR electrocatalysts of aqueous ZABs, but also paves a new route for the effective reutilization of waste Mg alloys.

Adverse effects of therapeutic phlebotomies: Prospective study of 587 procedures.

BACKGROUND: Therapeutic phlebotomy (TP), a widely used medical procedure, can be performed on diverse patients with iron overload or polyglobulia. However, its adverse events are not well known as most of the information on phlebotomy is derived from healthy blood donors (0.1%-5.3%). In contrast, TP is applicable to a broader, more complex population with comorbidities and old age. To ascertain the incidence of adverse events in phlebotomies, we conducted a prospective study on patients who attended our Unit. STUDY DESIGN AND METHODS: We prospectively gathered data from patients referred to our Unit for TP. Data regarding demographics, health status, and adverse events within at least 24 h of phlebotomy were gathered via a structured questionnaire during each visit. RESULTS: Between August 2021 and September 2022, 189 patients underwent 587 procedures. Most patients were men, over 60 (57.3%) had comorbidities, and 93% underwent at least two procedures during the study period. Twenty patients (10.8%) presented 25 adverse events (4.3% of phlebotomies), usually vasovagal reactions, none of which were clinically relevant, and all were managed by nursing staff on site, with full patient recovery. DISCUSSION: The rate of adverse events (<5%) in patients undergoing TP was low and comparable to that seen in healthy blood donors. Consequently, even old patients and those with some comorbidities can safely undergo TP when the process is carefully managed.

Beryllium as a base: complexes of Be(CO)3 with HX (X = F, Cl, Br, CN, NC, CCH, OH).

Beryllium chemistry is typically governed by its electron deficient character, but in some compounds it can act as a base. In order to understand better the unusual basicity of Be, we have systematically explored the complexes of one such compound, Be(CO)3, towards several hydrogen bond donors HX (X = F, Cl, Br, CN, NC, CCH, OH). For all complexes we find three different minima, two hydrogen bonded minima (to the Be or O atoms), and one weak beryllium bonded minimum. Further characterization of the interactions using a topological analysis of the electron density and Symmetry Adapted Perturbation Theory (SAPT) provide insight into the nature of these interactions. Overall these results highlight the capability of certain beryllium compounds to act as either a weak Lewis acid or, unconventionally, a Lewis base whose basicity towards hydrogen bonding is comparable to that of π systems.

Achieving Decentralized, Electrified, and Decarbonized Ammonia Production.

The rapid reduction in the cost of renewable energy has motivated the transition from carbon-intensive chemical manufacturing to renewable, electrified, and decarbonized technologies. Although electrified chemical manufacturing technologies differ greatly, the feasibility of each electrified approach is largely related to the energy efficiency and capital cost of the system. Here, we examine the feasibility of ammonia production systems driven by wind and photovoltaic energy. We identify the optimal regions where wind and photovoltaic electricity production may be able to meet the local demand for ammonia-based fertilizers and set technology targets for electrified ammonia production. To compete with the methane-fed Haber-Bosch process, electrified ammonia production must reach energy efficiencies of above 20% for high natural gas prices and 70% for low natural gas prices. To account for growing concerns regarding access to water, geospatial optimization considers water stress caused by new ammonia facilities, and recommendations ensure that the identified regions do not experience an increase in water stress. Reducing water stress by 99% increases costs by only 1.4%. Furthermore, a movement toward a more decentralized ammonia supply chain driven by wind and photovoltaic electricity can reduce the transportation distance for ammonia by up to 76% while increasing production costs by 18%.

Giant fronto-spheno-orbitary juvenile psammomatoid ossifying fibroma: Case report and literature review.

Juvenile psammomatoid ossifying fibroma (JPOF) is an osteofibrous neoplasm that originates in the craniofacial skeleton typically during the first three decades of life. JPOFs usually involve the orbit, paranasal sinuses or the jaws. Extensive involvement of the anterior cranial base with compromised visual function is a rare phenomenon. In such clinical context, a definite diagnosis can only be made on the basis of histopathological findings, given the absence of pathognomonic radiological features. Despite being considered a benign entity, JPOFs present a locally aggressive behavior. Therefore, these neoplasms must be included in the differential diagnosis in every patient harboring a skull base osteofibrous lesion, and, once diagnosed, gross total surgical removal should be attempted. In this study, we present our experience in the diagnosis and treatment of a patient diagnosed with a giant JPOF involving the cranial base.

Sensitization to textile dyes in Spain: Epidemiological situation (2019-2022).

BACKGROUND: Current frequency and features for positivity to textile dye mix (TDM) in Spain are unknown. OBJECTIVES: To study the frequency, clinical features and simultaneous positivity between TDM, para-phenylenediamine (PPD) and specific disperse dyes. MATERIALS AND METHODS: We analysed all consecutive patients patch-tested with TDM from the Spanish Contact Dermatitis Registry (REIDAC), from 1 January 2019 to 31 December 2022. Within this group, we studied all selected patients patch-tested with a textile dye series. RESULTS: Out of 6128 patients analysed, 3.3% were positive to the TDM and in 34% of them, the sensitization was considered currently relevant. TDM positivity was associated with working as a hairdresser/beautician and scalp, neck/trunk and arm/forearm dermatitis. From TDM-positive patients, 57% were positive to PPD. One hundred and sixty-four patients were patch-tested with the textile dye series. Disperse Orange 3 was the most frequent positive dye (16%). One of every six cases positive to any dye from the textile dye series would have been missed if patch-tested with the TDM alone. CONCLUSIONS: Positivity to TDM is common in Spain and often associated with PPD sensitization. TDM is a valuable marker of disperse dyes allergy that should be part of the Spanish and European standard series.

The Sex or Race of Program Directors May Not Play a Significant Role in Impacting Diversity Among Orthopaedic Surgery Residents.

PURPOSE: To identify the influence of residency program characteristics, including the presence of under-represented minorities in medicine (URiM) and/or female program directors (PDs), on the race and sex distribution of orthopaedic surgery residency trainees. METHODS: All active and Accreditation Council for Graduate Medical Education-accredited orthopaedic surgery residency programs from 2017-2021 that reported usable information in the Residency Explorer Tool were included. Data collected included program characteristics, as well as faculty and resident sex distribution, ethnicity, race, and demographic characteristics. The PDs' specific sex, ethnicity, race, and demographic characteristics were collected using residency program websites. The prevalence of factors in programs with the top quartile of female and URiM residents was compared with that in programs with the bottom 3 quartiles. RESULTS: Data were obtained from 148 of 200 Accreditation Council for Graduate Medical Education-accredited programs (3,694 residents). The 52 excluded programs had no usable information in the Residency Explorer Tool or on an identifiable program website. Overall, 15.9% of residents in orthopaedic surgery residency programs were women and 14% were under-represented minorities. The rates of female PDs and chairs were 12.4% and 6.9%, respectively, whereas those of URiM PDs and chairs were 8.3% and 4.6%, respectively. Programs with more female residents were not associated with female PDs (P = .79) or URiM PDs (P = .48). Programs with a greater percentage of URiM residents were not associated with URiM PDs (P = .16). Larger programs (P = .021) and university-based programs (P = .048) had a greater percentage of female residents. Orthopaedic residency programs with visa sponsorship had a greater percentage of URiM residents (P = .017). CONCLUSIONS: Programs with a higher percentage of female or URiM residents did not show a significant association with having female or URiM PDs. Larger programs and university-affiliated programs were more likely to have a larger percentage of female residents, whereas programs that offered visa sponsorship had a higher percentage of URiM residents. CLINICAL RELEVANCE: This study highlights factors influencing diversity among orthopaedic surgery residents. Although the presence of female or URiM PDs does not influence the percentage of female or URiM residents, other program characteristics such as size, affiliation, and visa sponsorship offer potentially actionable insights for promoting greater diversity in orthopaedic training. Doing so may increase under-represented groups within the field and could ultimately impact patient care and improve health care equity.

Reliability and Validity of the Strain Gauge "GSTRENGTH" for Measuring Peak Force in the Isometric Belt Squat at Different Joint Angles.

Since isometric training is gaining popularity, some devices are being developed to test isometric force as an alternative to the more expensive force plates (FPs); thus, the aim of this study was to test the reliability and validity of "GSTRENGTH" for measuring PF in the isometric belt squat exercise. Five subjects performed 24 contractions at three different knee angles (90°, 105° and 120°) on two occasions (120 total cases). Peak force data were measured using FPs and a strain gauge (SG) and analyzed by Pearson's product-moment correlation coefficient, ICCs, Cronbach's alpha, a paired sample t-test and Bland-Altman plots. Perfect or almost perfect relationships (r: 0.999-1) were found with an almost perfect or perfect level of agreement (ICCs: 0.992-1; α: 0.998-1). The t-test showed significant differences for the raw data but not for the predictions by the equations obtained with the SG values. The Bland-Altman plots, when significant, showed trivial to moderate values for systematic bias in general. In conclusion, "GSTRENGTH" was shown to be a valid alternative to FPs for measuring PF.

The important factors nurses consider when choosing shift patterns: A cross-sectional study.

AIM: To gain a deeper understanding of what is important to nurses when thinking about shift patterns and the organisation of working time. DESIGN: A cross-sectional survey of nursing staff working across the UK and Ireland collected quantitative and qualitative responses. METHODS: We recruited from two National Health Service Trusts and through an open call via trade union membership, online/print nursing profession magazines and social media. Worked versus preferred shift length/pattern, satisfaction and choice over shift patterns and nurses' views on aspects related to work and life (when working short, long, rotating shifts) were analysed with comparisons of proportions of agreement and crosstabulation. Qualitative responses on important factors related to shift preferences were analysed with inductive thematic analysis. RESULTS: Eight hundred and seventy-three survey responses were collected. When nurses worked long shifts and rotating shifts, lower proportions reported being satisfied with their shifts and working their preferred shift length and pattern. Limited advantages were realised when comparing different shift types; however, respondents more frequently associated 'low travel costs' and 'better ability to do paid overtime' with long shifts and 'healthy diet/exercise' with short shifts; aspects related to rotating shifts often had the lowest proportions of agreement. In the qualitative analysis, three themes were developed: 'When I want to work', 'Impacts to my life outside work' and 'Improving my work environment'. Reasons for nurses' shift preferences were frequently related to nurses' priorities outside of work, highlighting the importance of organising schedules that support a good work-life balance. RELEVANCE TO CLINICAL PRACTICE: General scheduling practices like adhering to existing shift work guidelines, using consistent and predictable shift patterns and facilitating flexibility over working time were identified by nurses as enablers for their preferences and priorities. These practices warrant meaningful consideration when establishing safe and efficient nurse rosters. PATIENT OR PUBLIC CONTRIBUTION: This survey was developed and tested with a diverse group of stakeholders, including nursing staff, patients, union leads and ward managers. REPORTING METHOD: The Strengthening the Reporting of Observational Studies (STROBE) checklist for cross-sectional studies was used to guide reporting.

Telemedicine in orthopaedics during the COVID-19 pandemic: a comparative landscape.

PURPOSE: The purpose of this study was to provide a comprehensive analysis on observed trends regarding the impact of the COVID-19 pandemic on telemedicine application in orthopaedics compared to other procedural, non-emergent specialties. METHODS: This was a retrospective review of all telemedicine and in-person visits at a large single institution from January to December 2020. The number of patient visits, visit type, location, and provider specifics were collected. Comparisons were made between subspecialties (orthopaedic surgery, oncology, family medicine, rheumatology) for analyses. RESULTS: All specialties included were not conducting virtual visits at the beginning of 2020. By April 2020, orthopaedic virtual visits spiked to an all-time high of 33.5% of all patient visits as compared to oncology at 25.5%, rheumatology at 92.9%, and family medicine at 94%. By the end of the study period, orthopaedic virtual visits decreased back down to 6.5% of patient visits compared to oncology at 7.0%, and family medicine (17.4%) and rheumatology (26.2%). Orthopaedic providers practicing greater than 20 years had the highest average virtual visit rates. CONCLUSION: Although the COVID-19 pandemic has posed unique challenges for healthcare providers, there was a great advancement in the rollout and application of telemedicine. To mitigate the spread of infection from coronavirus and given the recent adjustments to reimbursement policies and HIPAA regulations, orthopaedics saw a dramatic expansion of telemedicine since April 2020. The pandemic may have served as a catalyst to adopt telehealth into clinical practice. However, telehealth saw a downtrend trend by December 2020, particularly in procedure-based fields like orthopaedics and oncology.

Neuropathy of the suprascapular and axillary nerves in rotator cuff arthropathy: a prospective electrodiagnostic study.

PURPOSE: Prevalence of axillary (AN) and/or suprascapular (SSN) neuropathy in rotator cuff tear arthropathy (RCTA) is unknown. We aimed to prospectively evaluate for preoperative neurodiagnostic abnormalities in order to determine their prevalence, location, and influence on reverse shoulder arthroplasty (RSA) outcomes. METHODS: Patients who underwent RSA for RCTA were prospectively included. An electromyography and nerve conduction study were performed pre and post-surgery. Clinical situation: VAS, Relative Constant-Murley Score (rCMS) and ROM over a minimum of two years follow-up. RESULTS: Forty patients met the inclusion criteria; mean follow-up was 28.4 months (SD 4.4). Injuries in RCTA were present in 83.9% (77.4% in AN and 45.2% in SSN). There were no differences on preoperative VAS, ROM, and rCMS between patients with and without preoperative nerve injuries. Four acute postoperative neurological injuries were registered under chronic preoperative injuries. Six months after RSA, 69% of preoperative neuropathies had improved (82.14% chronic injuries and 77.7% disuse injuries). No differences in improvement between disuse and chronic injuries were found, but patients with preoperative neuropathy that had not improved at the postoperative electromyographic study at six months, scored worse on the VAS (1.44 vs 2.66; p .14) and rCMS (91.6 vs 89.04; p .27). CONCLUSIONS: The frequency of axillary and suprascapular neuropathies in RCTA is much higher than expected. Most of these injuries improve after surgery, with almost complete neurophysiological recovery and little functional impact on RSA. However, those patients with preoperative neuropathies and absence of neurophysiological improvement six months after surgery have lower functional results.

Functional results of Circumferential Capsular Release in adhesive shoulder capsulitis. Comparative study of patients over and under fifty years of age.

INTRODUCTION: The aim of our study is to evaluate the functional and mobility outcomes in patients who have undergone arthroscopic circumferential arthrolysis of the shoulder and to find out if there are differences in the results in relation to the patient's age. MATERIALS AND METHODS: This is a retrospective case series of patients with idiopathic adhesive capsulitis treated by arthroscopic 360º circumferential capsulotomy in lateral position and followed for a minimum of 2 years. Range of motion (ROM), functional outcomes using the Constant Score (CS), health-related quality of life outcomes with the EuroQol Five Dimensions tool (EQ-5D), pain using the Visual Analogue Scale (VAS). RESULTS: A total of 26 shoulders were included, 10 men (41.7%) and 14 women (58.3%), with 2 patients being bilateral. The mean age was 48.64 ± 7.5 years, and the mean follow-up was 50.2 months. Postoperative ROM improved significantly compared to preoperative ROM (p < 0.05). Shoulder forward flexion improved by 38.6° (95%CI 22.3-54.9, p < 0.01), abduction by 35.2° (95%CI 17.6-52.8, p < 0.01) and external rotation by 21.9° (95%CI 12.8-30.9, p < 0.01 p < 0.01). Median internal rotation improved from buttock to T12 (p < 0.01). The mean improvement in CS was 54.3 ± 24.4 points (p < 0.01). The EQ-5D and VAS scores at the end of follow-up were 0.73 ± 0.23 and 2.73 ± 2.55, respectively. There were no statistical differences between young patients and patients aged 50 years or older in ROM or functional results. CONCLUSIONS: Patient age did not affect outcomes significantly, with patients older than 50 years showing similar results to younger patients.

Do the humeral radiographic changes at 5-year follow-up affect the clinical outcomes of press-fit humeral stems in primary reverse shoulder arthroplasties?

INTRODUCTION: The purposes of this study were to analyze and compare the functional outcomes and radiological changes around the press-fit humeral components in two contemporary medialized reverse total shoulder arthroplasty (RTSA) systems at a minimum of 5-year follow-up. MATERIALS AND METHODS: Between December 2003 and December 2015, 249 consecutive RTSAs were performed at our hospital. Of these, 68 primary uncemented RTSA met our inclusion criteria. The Constant-Murley score (CMS), the modified Constant score, a visual analog scale (VAS) and active shoulder range of motion (ROM) were measured pre- and postoperatively. Radiological assessment was performed by plain radiographs at a minimum of 5 years postoperatively. RESULTS: At a mean follow-up of 80.2 months, there was no significant difference (p = .59) between the postoperative functional scores and range of motion of the two groups (Delta Xtend and Lima SMR). Radiological data of stress-shielding were observed in 38 patients (55.9%) being slightly more frequent in the Lima SMR group (21 patients) than in the Delta Xtend group (17 patients) (p = .62). CONCLUSIONS: Our study shows that the good functional results are similar between the two uncemented RTSA systems used and that they do not depend on the presence of radiological changes (stress-shielding) in the humeral stem at a minimum 5-year follow-up.

The metabolic effects of APOL1 in humans.

Harboring apolipoprotein L1 (APOL1) variants coded by the G1 or G2 alleles of the APOL1 gene increases the risk for collapsing glomerulopathy, focal segmental glomerulosclerosis, albuminuria, chronic kidney disease, and accelerated kidney function decline towards end-stage kidney disease. However, most subjects carrying APOL1 variants do not develop the kidney phenotype unless a second clinical condition adds to the genotype, indicating that modifying factors modulate the genotype-phenotype correlation. Subjects with an APOL1 high-risk genotype are more likely to develop essential hypertension or obesity, suggesting that carriers of APOL1 risk variants experience more pronounced insulin resistance compared to noncarriers. Likewise, arterionephrosclerosis (the pathological correlate of hypertension-associated nephropathy) and glomerulomegaly take place among carriers of APOL1 risk variants, and these pathological changes are also present in conditions associated with insulin resistance, such as essential hypertension, aging, and diabetes. Insulin resistance may contribute to the clinical features associated with the APOL1 high-risk genotype. Unlike carriers of wild-type APOL1, bearers of APOL1 variants show impaired formation of lipid droplets, which may contribute to inducing insulin resistance. Nascent lipid droplets normally detach from the endoplasmic reticulum into the cytoplasm, although the proteins that enable this process remain to be fully defined. Wild-type APOL1 is located in the lipid droplet, whereas mutated APOL1 remains sited at the endoplasmic reticulum, suggesting that normal APOL1 may participate in lipid droplet biogenesis. The defective formation of lipid droplets is associated with insulin resistance, which in turn may modulate the clinical phenotype present in carriers of APOL1 risk variants.

Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.

BACKGROUND: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. METHODS: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. RESULTS: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. CONCLUSIONS: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).

Dielectric Environment Sensitivity of Carbon Centers in Hexagonal Boron Nitride.

A key advantage of utilizing van-der-Waals (vdW) materials as defect-hosting platforms for quantum applications is the controllable proximity of the defect to the surface or the substrate allowing for improved light extraction, enhanced coupling with photonic elements, or more sensitive metrology. However, this aspect results in a significant challenge for defect identification and characterization, as the defect's properties depend on the the atomic environment. This study explores how the environment can influence the properties of carbon impurity centers in hexagonal boron nitride (hBN). It compares the optical and electronic properties of such defects between bulk-like and few-layer films, showing alteration of the zero-phonon line energies and their phonon sidebands, and enhancements of inhomogeneous broadenings. To disentangle the mechanisms responsible for these changes, including the atomic structure, electronic wavefunctions, and dielectric screening, it combines ab initio calculations with a quantum-embedding approach. By studying various carbon-based defects embedded in monolayer and bulk hBN, it demonstrates that the dominant effect of the change in the environment is the screening of density-density Coulomb interactions between the defect orbitals. The comparative analysis of experimental and theoretical findings paves the way for improved identification of defects in low-dimensional materials and the development of atomic scale sensors for dielectric environments.