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The aerodynamic behaviour and wake flow of a cluster of two-dimensional sharp-edged bluff bodies exhibits extremely complex unsteady phenomena in both near and far fields. Due to the high cost of wind-tunnel experiments and numerical simulations, a complete understanding of wake flows and a description of their characteristics are lacking. This paper presents large-eddy simulations (LES) in different flow/wind directions for a cluster of $$2 \times 2$$ 2 × 2 aligned square cylinders, at a separation distance in streamwise and cross-wind directions equal to cylinder side length, and at Reynolds number $${Re}=22,000$$ Re = 22 , 000 based on the single cylinder side length D. The case at $$0^\circ$$ 0 ∘ incidence shows an evident channel-type flow in the along-wind street/gap, and at its exit an irregularly pulsing jet with an intense shedding of large vortices. The wavelet analyses of the side force/lift coefficient and instantaneous velocities in the wake show that the characteristic length and time scales of the large vortical structures in the far-field wake are close to the cluster size 2D; this is the so called ‘cluster effect’. The cluster effect increases monotonically as the flow incidence angle increases. At a large incidence angle in the near-field wake, the cylinder-scale flow structures are much weaker compared to the cluster-scale structures. At the incidence angle of $$45^\circ$$ 45 ∘ , the overall wake flow and the aerodynamic characteristics are well scaled by the scale approximately equal to 2D. Nevertheless, the interaction between cylinders significantly affects the aerodynamics performance of the individual cylinders. The drag and lift coefficients of the individual cylinders differ substantially from each other in the cluster, and are significantly different from observations on a single isolated cylinder too.

Group B streptococcus (GBS) is a leading cause of neonatal morbidity and mortality worldwide. Development of a maternal vaccine to protect newborns through placentally transferred antibody is considered feasible based on the well-established relationship between anti-GBS capsular polysaccharide (CPS) IgG levels at birth and reduced risk of neonatal invasive GBS. An accurately calibrated serum reference standard that can be used to measure anti-CPS concentrations is critical for estimation of protective antibody levels across serotypes and potential vaccine performance. For this, precise weight-based measurement of anti-CPS IgG in sera is required. Here, we report an improved approach for determining serum anti-CPS IgG levels using surface plasmon resonance with monoclonal antibody standards, coupled with a direct Luminex-based immunoassay. This technique was used to quantify serotype-specific anti-CPS IgG levels in a human serum reference pool derived from subjects immunized with an investigational six-valent GBS glycoconjugate vaccine.

Siderophores belonging to the ferrichrome family are essential for the viability of fungal species and play a key role for virulence of numerous pathogenic fungi. Despite their biological significance, our understanding of how these iron-chelating cyclic hexapeptides are assembled by non-ribosomal peptide synthetase (NRPS) assembly lines remains poorly understood, primarily due to the nonlinearity exhibited by the domain architecture. Herein, we report the biochemical characterization of the SidC NRPS, responsible for construction of the intracellular siderophore ferricrocin.In vitroreconstitution of purified SidC revealed its ability to produce ferricrocin and its structural variant, ferrichrome. Application of intact protein mass spectrometry uncovered several non-canonical events during peptidyl siderophore biosynthesis, including inter-modular loading of amino acid substrates and an adenylation domain capable of poly-amide bond formation. This work expands the scope of NRPS programming, allows biosynthetic assignment of ferrichrome NRPSs, and sets the stage for reprogramming towards novel hydroxamate scaffolds.

Bacteroidota is a group of marine polysaccharide degraders, which play a crucial role in the carbon cycle in the marine ecosystems. In this study, three novel gliding strains, designated as SS9-22T, W9P-11T, and SW1-E11T, isolated from algae and decaying wood were proposed to represent three novel species of the genus Fulvivirga. We identified a large number of genes encoding for carbohydrate-active enzymes, which potentially participate in polysaccharide degradation, based on whole genome sequencing. The 16S rRNA sequence similarities among them were 94.4–97.2%, and against existing species in the genus Fulvivirga 93.1–99.8%. The complete genomes of strains SS9-22T, W9P-11T, and SW1-E11T comprised one circular chromosome with size of 6.98, 6.52, and 6.39 Mb, respectively; the GC contents were 41.9%, 39.0%, and 38.1%, respectively. The average nucleotide identity and the digital DNA-DNA hybridization values with members in the genus Fulvivirga including the isolates were in a range of 68.9–85.4% and 17.1–29.7%, respectively, which are low for the proposal of novel species. Genomic mining in three genomes identified hundreds of carbohydrate-active enzymes (CAZymes) covering up to 93 CAZyme families and 58–70 CAZyme gene clusters, exceeding the numbers of genes present in the other species of the genus Fulvivirga. Polysaccharides of alginate, chitin, laminarin, starch, and xylan were degraded in vitro, highlighting that the three strains are rich sources of CAZymes of polysaccharide degraders for biotechnological applications. The phenotypic, biochemical, chemotaxonomic, and genomic characteristics supported the proposal of three novel species in the genus Fulvivirga, for which the names Fulvivirga ulvae sp. nov. (SS9-22T = KCTC 82072T = GDMCC 1.2804T), Fulvivirga ligni sp. nov. (W9P-11T = KCTC 72992T = GDMCC 1.2803T), and Fulvivirga maritima sp. nov. (SW1-E11T = KCTC 72832T = GDMCC 1.2802T) are proposed.

Biologics, pharmaceuticals containing or derived from living organisms, such as vaccines, antibodies, stem cells, blood, and blood products are a cornerstone of modern medicine. However, nearly all biologics have a major deficiency: they are inherently unstable, requiring storage under constant cold conditions. The so-called ‘cold-chain’, while effective, represents a serious economic and logistical hurdle for deploying biologics in remote, underdeveloped, or austere settings where access to cold-chain infrastructure ranging from refrigerators and freezers to stable electricity is limited. To address this issue, we explore the possibility of using anhydrobiosis, the ability of organisms such as tardigrades to enter a reversible state of suspended animation brought on by extreme drying, as a jumping off point in the development of dry storage technology that would allow biologics to be kept in a desiccated state under not only ambient but elevated temperatures. Here we examine the ability of different protein and sugar-based mediators of anhydrobiosis derived from tardigrades and other anhydrobiotic organisms to stabilize Human Blood Clotting Factor VIII under repeated dehydration/rehydration cycles, thermal stress, and long-term dry storage conditions. We find that while both protein and sugar-based protectants can stabilize the biologic pharmaceutical Human Blood Clotting Factor VIII under all these conditions, protein-based mediators offer more accessible avenues for engineering and thus tuning of protective function. Using classic protein engineering approaches, we fine tune the biophysical properties of a protein-based mediator of anhydrobiosis derived from a tardigrade, CAHS D. Modulating the ability of CAHS D to form hydrogels make the protein better or worse at providing protection to Human Blood Clotting Factor VIII under different conditions. This study demonstrates the effectiveness of tardigrade CAHS proteins and other mediators of desiccation tolerance at preserving the function of a biologic without the need for the cold-chain. In addition, our study demonstrates that engineering approaches can tune natural products to serve specific protective functions, such as coping with desiccation cycling versus thermal stress. Ultimately, these findings provide a proof of principle that our reliance on the cold-chain to stabilize life-saving pharmaceuticals can be broken using natural and engineered mediators of desiccation tolerance.

There is a lack of effective programmed cell death protein 1 (PD-1)‐targeted immunotherapy with good tolerability in patients with advanced hepatocellular carcinoma (HCC) and severely compromised liver function. We assessed patient outcomes after combined camrelizumab and molecular targeted therapy in a multicenter cohort study in China. The study included 99 patients with advanced HCC (58 Child-Pugh A and 41 Child-Pugh B), 84 of them received camrelizumab combined with molecular targeted therapy from January 10, 2019, to March 31, 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. The median follow-up was 12.1 months. For patients with Child-Pugh B, the OS probability at 12-months, ORR and DCR were 49.7%, 31.7% and 65.9%, respectively, and the median PFS was 5.1 months [95% confidence interval (CI) 3.0–7.1], which were comparable with Child-Pugh A patients, although median OS was shorter in Child‐Pugh B patients (20.5 vs.13.4 months, P = 0.12). In multivariate analysis, macrovascular infiltration (MVI), but not sex, age, hepatitis B virus etiology, extrahepatic metastasis, Child-Pugh B, or AFP > 400 ng/ml, was associated with 12-months OS [hazard ratio (HR) 2.970, 95% CI 1.276–6.917, P = 0.012] and ORR (HR 2.906, 95% CI 1.18–7.16, P = 0.020). Grade 3/4 immune-related AEs occurred in 26.8% of Child-Pugh B patients, including one potentially treatment-related death. In both groups, the most common AEs were immune thrombocytopenia and hepatotoxicity. Camrelizumab combined with targeted therapy showed favorable effectiveness and tolerability with manageable toxicities in Chinese HCC patients, regardless of Child-Pugh A/B liver function. MVI was associated with suboptimal immunotherapy response and poor prognosis. Graphical abstract

Evidence of the impact of the COVID-19 pandemic on health behaviours in the general population is limited. In this retrospective longitudinal study including UK and US participants, we collected diet and lifestyle data pre-pandemic (896,286) and peri-pandemic (291,871) using a mobile health app, and we computed a bidirectional health behaviour disruption index. Disruption of health behaviour was higher in younger, female and socio-economically deprived participants. Loss in body weight was greater in highly disrupted individuals than in those with low disruption. There were large inter-individual changes observed in 46 health and diet behaviours measured peri-pandemic compared with pre-pandemic, but no mean change in the total population. Individuals most adherent to less healthy pre-pandemic health behaviours improved their diet quality and weight compared with those reporting healthier pre-pandemic behaviours, irrespective of relative deprivation; therefore, for a proportion of the population, the pandemic may have provided an impetus to improve health behaviours. Public policies to tackle health inequalities widened by the pandemic should continue to prioritize diet and physical activity for all, as well as more targeted approaches to support younger females and those living in economically deprived areas.

We aimed to compare the longitudinal changes in estimated glomerular filtration rate (eGFR) in chronic hepatitis B (CHB) patients treated with entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF). This is a retrospective study of 6189 adult treatment-naive CHB patients initiated therapy with TDF (n = 2482) or ETV (n = 3707) at 25 international centers using multivariable generalized linear modeling (GLM) to determine mean eGFR (mL/min/1.73 m2) and Kaplan–Meier method to estimate incidence of renal impairment (≥ 1 chronic kidney disease [CKD] stage worsening). We also examined above renal changes in matched ETV and TDF patients (via propensity score matching [PSM] on age, sex, diabetes mellitus [DM], hypertension [HTN], cirrhosis, baseline eGFR, and follow-up duration). In the overall cohort (mean age 49.7 years, 66.2% male), the baseline eGFR was higher for TDF vs. ETV group (75.9 vs. 74.0, p = 0.009). PSM yielded 1871 pairs of ETV or TDF patients with baseline eGFR ≥ 60 and 520 pairs for the eGFR

With the increase of cosmetic injectable hyaluronic acid (HA), there have been more cases with serious complications, including skin necrosis, blindness, and cerebral embolism. Patients who have recovered from HA filler-induced total vision loss are extremely rare. We report a case of a 27-year-old female who developed severe ocular pain on the right side and total vision loss following a 1.0 ml HA filler injection in the nasal dorsum. She arrived at our hospital 4 hours later. Her visual acuity was no light perception (NLP), and she exhibited eyelid ptosis, ophthalmoplegia, and frontal and nasal ecchymosis. She was promptly treated with subcutaneous and retrobulbar hyaluronidase injections, as well as intra-arterial 1500 IU hyaluronidase injections into the right ophthalmic artery with DSA assistance. Her vision improved from NLP to counting fingers at 1.0 meters. Unfortunately, 13 hours later, she felt an intense headache, and her vision again decreased to NLP. We immediately performed an injection of 1500 IU hyaluronidase combined with 8 mg alteplase for intra-arterial thrombolysis (IAT) into the right ophthalmic artery. Her vision improved immediately afterward. After 3 months, her visual acuity had significantly recovered from NLP (admission vision status) to 20/50 (Snellen chart with glasses). Similarly, skin, conjunctival, eye movement, and ptosis symptoms completely recovered. This case demonstrates that reversal of complete blindness due to embolism of the ophthalmic and central retinal arteries could be accomplished through multidisciplinary therapies, especially IAT using fibrinolytic agents combined with hyaluronidase followed by an anticoagulant regimen. Level of evidence VThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266 .

Orthoferrite Nd1−xSrxFeO3 nanocrystals with the size 30–50 nm have been successfully synthesized via a simple co-precipitation method through the hydrolysis of Nd(III), Sr(II), and Fe(III) cations in boiling water with 5% Na2CO3 solution as a precipitating agent and subsequent annealing at various temperatures (700, 850, and 950 °C) for 60 min. Introduction of Sr2+ cations to the nominal value x = 0.2 into the NdFeO3 lattice led to an increase in the average crystal size for all annealing temperatures. Synthesized Nd1−xSrxFeO3 (x = 0, 0.1) samples are soft magnetic materials with low coercivity (Hc) and remanent magnetization (Mr), and Nd1−xSrxFeO3 (x = 0.2, 0.3) are hard magnetic materials with very high values of the Hc and Mr. The Hc and Mr of the Nd0.76Sr0.18FeO3.52 sample were higher than those of NdFe1.11O3.36 by 33.3 and 70.9 times, respectively. Synthesized Nd1−xSrxFeO3 nanopowders with x = 0 and 0.1 can be applied in the production of the cores of transformers, electromagnets, and conductors; and those with x = 0.2 and 0.3 can be used for permanent magnets or magnetic recording on hard disks and tapes.

How well a surgery is performed impacts a patient’s outcomes; however, objective quantification of performance remains an unsolved challenge. Deconstructing a procedure into discrete instrument-tissue “gestures” is a emerging way to understand surgery. To establish this paradigm in a procedure where performance is the most important factor for patient outcomes, we identify 34,323 individual gestures performed in 80 nerve-sparing robot-assisted radical prostatectomies from two international medical centers. Gestures are classified into nine distinct dissection gestures (e.g., hot cut) and four supporting gestures (e.g., retraction). Our primary outcome is to identify factors impacting a patient’s 1-year erectile function (EF) recovery after radical prostatectomy. We find that less use of hot cut and more use of peel/push are statistically associated with better chance of 1-year EF recovery. Our results also show interactions between surgeon experience and gesture types—similar gesture selection resulted in different EF recovery rates dependent on surgeon experience. To further validate this framework, two teams independently constructe distinct machine learning models using gesture sequences vs. traditional clinical features to predict 1-year EF. In both models, gesture sequences are able to better predict 1-year EF (Team 1: AUC 0.77, 95% CI 0.73–0.81; Team 2: AUC 0.68, 95% CI 0.66–0.70) than traditional clinical features (Team 1: AUC 0.69, 95% CI 0.65–0.73; Team 2: AUC 0.65, 95% CI 0.62–0.68). Our results suggest that gestures provide a granular method to objectively indicate surgical performance and outcomes. Application of this methodology to other surgeries may lead to discoveries on methods to improve surgery.

Bone strength is important to prevent osteoporotic fractures and determined by bone mass and microarchitecture. This study suggests that having higher lean mass and lower fat mass, avoiding western dietary patterns, and improving steps per day may all be important for maintaining bone mass and microarchitecture in aging.To describe associations between exposures of lean mass and fat mass, dietary patterns, serum 25-hydroxyvitamin D (25(OH)D), physical activity and grip strength, and bone outcome measures including bone mineral density and microarchitecture in older adults.Data on 201 older adults (mean age 72 years, female 46% at 10.7-year follow-up (phase 4) from a population-based cohort study collected at baseline and follow-up at 2.6 (phase 2), 5.1 (phase 3), and 10.7 years (phase 4) were analyzed. Exposures were lean and fat mass, dietary patterns, physical activity (steps per day), serum 25(OH)D concentrations, and grip strength during follow-ups. Bone measures at phase 4 including areal bone mineral density (aBMD) at the spine, hip, and whole body by dual-energy X-ray absorptiometry, and radial cortical and trabecular bone microarchitecture by high-resolution peripheral computed tomography (HRpQCT). The cumulative average values of exposures were calculated. Multivariable linear regression was used to analyze associations between exposures and bone measures.Lean mass was beneficially associated with the hip, spine, and total body aBMD, radial cortical and trabecular bone area, and trabecular number and separation (β ranged from - 0.39/standard deviation (SD) to 0.73/SD). Fat mass was detrimentally associated with radial compact cortical and inner transitional zone bone area, vBMD, and porosity (β ranged from - 0.21 to 0.22/SD). Western dietary pattern scores were detrimentally associated with radial total and cortical bone vBMD and porosity (β ranged from - 0.20 to 0.20/SD). Steps per day were beneficially associated with inner transitional zone area and thickness (β = 0.12/SD and 0.19/SD), but no other measures. Grip strength and serum 25(OH)D were not associated with any radial bone measures.Lean mass was beneficially associated with aBMD, radial bone area, and trabecular bone microarchitecture. Fat mass had detrimental associations with radial bone area, vBMD, and porosity. A western dietary pattern was detrimental for radial bone microarchitecture while more steps per day (but not grip strength or 25(OH)D) appeared beneficial.

Objectives: Manually-collected suturing technical skill scores are strong predictors of continence recovery after robotic radical prostatectomy. Herein, we automate suturing technical skill scoring through computer vision (CV) methods as a scalable method to provide feedback. Methods: Twenty-two surgeons completed a suturing exercise three times on the Mimic™ Flex VR simulator. Instrument kinematic data (XYZ coordinates of each instrument and pose) were captured at 30 Hz. After standardized training, three human raters manually video segmented suturing task into four sub-stitch phases (Needle handling, Needle targeting, Needle driving, Needle withdrawal) and labeled the corresponding technical skill domains (Needle positioning, Needle entry, Needle driving, and Needle withdrawal). The CV framework extracted RGB features and optical flow frames using a pre-trained AlexNet. Additional CV strategies including auxiliary supervision (using kinematic data during training only) and attention mechanisms were implemented to improve performance. Results: This study included data from 15 expert surgeons (median caseload 300 [IQR 165–750]) and 7 training surgeons (0 [IQR 0–8]). In all, 226 virtual sutures were captured. Automated assessments for Needle positioning performed best with the simplest approach (1 s video; AUC 0.749). Remaining skill domains exhibited improvements with the implementation of auxiliary supervision and attention mechanisms when deployed separately (AUC 0.604–0.794). All techniques combined produced the best performance, particularly for Needle driving and Needle withdrawal (AUC 0.959 and 0.879, respectively). Conclusions: This study demonstrated the best performance of automated suturing technical skills assessment to date using advanced CV techniques. Future work will determine if a “human in the loop” is necessary to verify surgeon evaluations.

We previously reported that professional forms of address in speaker introductions were inconsistently used at the Society of Surgical Oncology (SSO) 2018 and 2019 annual meetings, suggesting unconscious bias in speaker introductions. We sought to better understand how speakers would like to be introduced, and if guidelines could improve consistency in speaker introductions. SSO 2021 abstract submitters received a survey regarding demographics and preferred form of address at the meeting. Respectful discourse guidelines were developed and distributed to meeting moderators. Speaker introductions were reviewed for the 2021 SSO annual meeting and were compared with the 2018 and 2019 meetings. The survey response rate was 183/347 (53%) abstract submitters, most of whom (143/183, 78%) indicated preference for a professional form of address (Doctor/Professor) during speaker introductions, which was significantly greater than those who were introduced with a professional form of address during the 2018 and 2019 meetings (351/499, 70%; Chi-square = 4.08, p = 0.043). There was no difference in speaker introduction preference based on gender or race/ethnic identification. Respectful discourse guidelines were developed and distributed to meeting moderators. During the 2021 SSO annual meeting, professional forms of address were used for 104 (84%) speakers, significantly greater than during the 2018 and 2019 meetings (Chi-square = 9.23, p = 0.002). More survey respondents preferred speaker introductions with a professional form of address than were used in prior meetings. This preference was similar across all demographic groups evaluated. Professional addresses during speaker introductions increased significantly after the distribution of guidelines encouraging consistency to decrease unconscious bias and promote an inclusive environment.

In this paper, we develop a subsampling Newton’s method to efficiently approximate the maximum likelihood estimate in logistic regression, which is especially useful for large-sample problems. One distinct feature of our algorithm is that matrix inversion is not explicitly performed. We propose two algorithms which are used to construct iteratively a sequence of matrices which converge to the Hessian of the maximum likelihood function on the subsample. We provide numerical examples to show that the proposed method is efficient and robust.

Compound and simple droplets have been studied and appeared in many life applications, e.g., drug processing and microfluidic systems. Many studies have been conducted on the thermocapillary effects on simple droplets, but similar studies on compound droplets are quite rare. Filling this missing gap, this paper presents the front-tracking-based simulation results of the thermocapillary effects on compound droplets in a certain limited domain. The compound droplet consists of a single inner core that is initially concentric with the outer one. Various dimensionless parameters including Reynolds number from 1 to 50, Marangoni number from 1 to 100, droplet radius ratio from 0.3 to 0.8, and viscosity ratios from 0.1 to 6.4 are varied to reveal their influences on the migration of a compound droplet from cold to hot regions. Initially, the inner droplet moves faster than the outer one, and when the leading surface of the inner droplet touches the outer one, the inner and outer droplets migrate at the same speed. The effects of these parameters on the compound droplet eccentricity are also considered.

The most common surgical approaches for breast augmentation in Asia have traditionally been peri-areolar and transaxillary. In recent years, transaxillary approach has become increasingly popular with the use of endoscopic methods, which result in safer and better outcomes. In the literature, there are no comparison studies of endoscopic transaxillary and peri-areolar approaches. This prospective study compared the outcomes of 275 women undergoing primary breast augmentation (endoscopic transaxillary n=205, peri-areolar n=70). All procedures were performed by a single surgeon using smooth round silicone implants and dual-plane pockets from April 2013 to March 2016. Every patient was monitored for a minimum of 4 years for minor and major complications. Types and percentage of patients experiencing minor complications among transaxillary and peri-areolar patients were localized fluid collection in the wound (1% transaxillary, 7.1% peri-areolar), hypertrophic scarring or keloids (1% transaxillary, 8.6% peri-areolar), and areolar and nipple deformity (0% transaxillary, 8.6% peri-areolar). Major complications were postoperative bleeding (0% transaxillary, 2.9% peri-areolar) and capsular contracture, Baker Group III or IV (1% transaxillary, 5.7% peri-areolar). Endoscopic transaxillary breast augmentation had better outcomes, with lower rates of complications than the peri-areolar approach. Reviewing the literature, our study is the first direct comparison of peri-areolar and endoscopic transaxillary incisions using smooth implants. With the risk of anaplastic large cell lymphoma associated with certain macrotexture implants, endoscopic transaxillary approach using smooth implants is the safer technique and very good alternative choice for Asian women who do not want any scarring on their breasts. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266