AlphaFold has transformed structure prediction by enabling highly accurate predictions on par with experimentally determined structures. Still, for difficult cases, in particular, multimers, there is still room for improvement. Important for the success of AlphaFold is its ability to assess its own predictions. The basic idea for the Wallner group in CASP15 was to exploit the excellent ranking score in AlphaFold by massive sampling. To this end, we ran AlphaFold using six different settings, with and without templates, and with an increased number of recycles using both multimer v1 and v2 weights. In all cases, the dropout layers were enabled at inference to sample the uncertainty and increase the diversity of the generated models. A median of 4,810 models per target was generated and almost all (35/38) received a ranking_confidence >0.7. Compared to other groups in CASP15, Wallner obtained the highest sum of Z-scores based on the DockQ score, 40.8 compared to 26.3 for the second highest, much higher than -0.2 achieved by the AlphaFold baseline method, NBIS-AF2-multimer. The improvement over the baseline is substantial with the mean DockQ increasing from 0.43 to 0.56, with several targets showing a DockQ score increase by +0.6 units. Remarkable, considering Wallner and NBIS-AF2-multimer were using identical input data. The reason for the success can be attributed to the diversified sampling using dropout with different settings and, in particular, the use of multimer v1, which seems to be much more susceptible to sampling compared to v2. The method is available here: http://wallnerlab.org/AFsample/.

Background. Attention to the healthcare workforce has increased, yet comprehensive information on migrant healthcare workers is missing. This study focuses on migrant healthcare workers’ experiences and mobility patterns in the middle of a global health crisis, aiming to explore the capacity for circular migration and support effective and equitable healthcare workforce policy. Material and methods. Romanian physicians working in Germany during the COVID-19 pandemic served as an empirical case study. We applied a qualitative explorative approach; interviews (n=21) were collected from mid of September to early November 2022 and content analysis was performed. Results and discussion. Migrant physicians showed strong resilience during the COVID-19 crisis and rarely complained. Commitment to high professional standards and career development were major pull factors towards Germany, while perceptions of limited career choices, nepotism and corruption in Romania caused strong push mechanisms. We identified two major mobility patterns that may support circular migration policies: well-integrated physicians with a wish to give something back to their home country, and mobile cosmopolitan physicians who flexibly balance career opportunities and personal/family interests. Health policy must establish systematic monitoring of the migrant healthcare workforce including actor-centred approaches, support integration in destination countries as well as health system development in sending countries, and invest in evidence-based circular migration policy.

Edwardsiella ictaluri is an emerging bacterial pathogen that affects farmed tilapia ( Oreochromis spp.). This study reports the arrival, establishment, and widespread findings of E. ictaluri in farmed tilapia in Vietnam. Among 26 disease outbreaks from 9 provinces in Northern Vietnam during 2019–2021, 19 outbreaks originated from imported seeds, while outbreaks in seven farms were from domestic sources. Clinically sick fish showed the appearance of numerous white spots in visceral organs, and accumulative mortality reached 30%–65%. Twenty-six representative bacterial isolates recovered from 26 disease outbreaks were identified as E. ictaluri based on a combination of phenotypic tests, genus- and species-specific polymerase chain reaction assays, 16S rRNA and gyrB sequencing, and phylogenetic analysis. All isolates harbored the same virulence gene profiles esrC +, evpC +, ureA-C +, eseI-, escD-, and virD4-. Antimicrobial susceptibility tests revealed that 80.8%–100% of isolates were multidrug resistant, with resistance to 4–8 antimicrobials in the groups of penicillin, macrolides, sulfonamides, amphenicols, and glycopeptides. The experimental challenge successfully induced disease that mimicked natural infection. The median lethal doses (LD 50) of the tested isolates (n = 4) were 42–61 colony forming units/fish, indicating their extremely high virulence. This emerging pathogen is established and has spread to various geographical locations, causing serious impacts on farmed tilapia in northern Vietnam. It is likely that this pathogen will continue to spread through contaminated stocks (both imported and domestic sources) and persist. Thus, increased awareness, combined with biosecurity measures and emergent vaccination programs is essential to mitigate the negative impact of this emerging disease on the tilapia farming industry.

Background: Uniformity and compliance with clinical practice guidelines (CPGs) for use of palivizumab in preventing severe RSV infection in Australian high-risk infants remain unclear. Methods: An online survey was conducted across the Australian and New Zealand Neonatal Network (ANZNN) to determine clinical practices around palivizumab. A literature search was also performed to identify and compare national and international guidelines. Results: Sixty-five of 422 ANZNN members completed the survey. Respondents included 61 senior medical staff of consultants/staff specialists (78%) and four nursing staff (6%). Infants most likely to be recommended palivizumab included preterm infants born <29 weeks gestational age (GA) (30%), children with chronic lung diseases (CLD) born <32 weeks GA (40%), and with hemodynamically significant heart disease (35%). Many respondents (53%) stated that CPGs for palivizumab were developed locally. Twenty guidelines (10 international and 10 domestic) were obtained in total; 16(80%) recommended palivizumab use in preterm infants, 16(80%) recommended use in infants with CLD, 17(85%) congenital heart disease (CHD) and six (30%) bronchopulmonary dysplasia (BPD). Eight (40%) guidelines provided specific recommendations for immunocompromised infants. Canada, Western Australia, and American Academy of Paediatrics provided recommendations for Indigenous children. Frequency and dosage of palivizumab was universal across all CPGs. None of the international guidelines obtained were from low- or middle-income countries. Conclusions: Standardisation of CPGs may improve clinical decision making around use of palivizumab in high-risk infants.

In this paper, a class of stochastic fractional differential equations (SFDEs) with impulses is considered. By virtue of the Monch’s fixed point theorem and Banach contraction principle, we explore the existence and uniqueness of solutions to the addressed system. Furthermore, with the aid of the Jensen’s inequality, Holder inequality, Burkholder-Davis-Gundy inequality, Gronwall-Bellman inequality and some novel assumptions, the averaging principle of our considered system is obtained. At the end of this paper, an example is provided to illustrate the theoretical results.

Background: Ibrutinib is associated with atrial fibrillation (AF), though echocardiographic predictors of AF have not been studied in this population. We sought to determine whether left atrial (LA) strain on transthoracic echocardiography could identify patients at risk for developing ibrutinib-related atrial fibrillation (IRAF). Methods: We performed a retrospective review of 66 patients who had an echocardiogram prior to ibrutinib treatment. LA strain was measured with TOMTEC Imaging Systems, obtaining peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) on 4-chamber and 2-chamber views. Statistical analysis was performed with Chi-square analysis, T-test, or binomial regression analysis, with a p-value < 0.05 considered statistically significant. Results: Twenty-two patients developed IRAF (33%). Age at initiation of ibrutinib was significantly associated with IRAF (65.1 years vs. 74.1 years, p = 0.002). Mean ibrutinib dose was lower among patients who developed IRAF (388.2 ± 121.7 vs. 448.6 ± 88.4, p = 0.025). E/e’ was significantly higher among patients who developed IRAF (11.5 vs. 9.3, p = 0.04). PALS was significantly lower in patients who developed AF (30.3% vs. 36.3%, p = 0.01). On multivariate regression analysis, age, PALS and PACS were significantly associated with IRAF. On multivariate regression analysis, only PACS remained significantly associated with IRAF while accounting for age. Conclusions: Age, ibrutinib dose, E/e’, and PALS on pre-treatment echocardiogram were significantly associated with development of IRAF. On multivariate regression analyses, age, PALS and PACS remained significantly associated with IRAF. Impaired LA mechanics add to the assessment of patients at risk for IRAF

Palaeolimnological records provide valuable information about how phytoplankton respond to long-term drivers of environmental change. Traditional palaeolimnological tools such as microfossils and pigments are restricted to taxa that leave sub-fossil remains, and a method that can be applied to the wider community is required. Sedimentary DNA (sedDNA), extracted from lake sediment cores, shows promise in palaeolimnology, but validation against data from long-term monitoring of lake water is necessary to enable its development as a reliable record of past phytoplankton communities. To address this need, 18S rRNA gene amplicon sequencing was carried out on lake sediments from a core collected from Esthwaite Water (English Lake District) spanning ~105 years. This sedDNA record was compared with concurrent long-term microscopy-based monitoring of phytoplankton in the surface water. Broadly comparable trends were observed between the datasets, with respect to the diversity and relative abundance and occurrence of chlorophytes, dinoflagellates, ochrophytes and bacillariophytes. Up to 20% of genera identified in the microscopy record were also detected using sedDNA, and sedDNA revealed a previously undetected community of phytoplankton. However, a substantial proportion of genera identified by microscopy were not detected using sedDNA, highlighting the current limitations of the technique that require further development such as reference database coverage. These results suggest that sedDNA can be used as an effective record of past phytoplankton communities, at least over timescales of less than 100 years, but the taphonomic processes which may affect its reliability, such as the extent and rate of deposition and DNA degradation, require further research.

Photopolymerization as an energy-saving and environment-friendly technology has been applied in many fields and developed continuously since the middle of the 20th century. Today, photopolymerization technology is ubiquitous in every aspect of our lives. This review starts from the principle of photopolymerization reaction, introduces the process of photopolymerization, initiation mechanism of photoinitiators and three kinds of polymerization methods according to the wavelength of irradiation source. Subsequently, review focuses on the application of photopolymerization technology in thiol-based click reaction, 3D printing, photoresist, hydrogels and other fields, so as to demonstrate its irreplaceable role in the present.

Machine learning-based code smell detection has been demonstrated to be a valuable approach for improving software quality and enabling developers to identify problematic patterns in code. However, previous researches have shown that the code smell datasets commonly used to train these models are heavily imbalanced. While some recent studies have explored the use of imbalanced learning techniques for code smell detection, they have only evaluated a limited number of techniques and thus their conclusions about the most effective methods may be biased and inconclusive. To thoroughly evaluate the effect of imbalanced learning techniques on machine learning-based code smell detection, we examine 31 imbalanced learning techniques with seven classifiers to build code smell detection models on four code smell data sets. We employ four evaluation metrics to assess the detection performance with the Wilcoxon signed-rank test and Cliff’s δ. The results show that (1) Not all imbalanced learning techniques significantly improve detection performance, but deep forest significantly outperforms the other techniques on all code smell data sets. (2) SMOTE (Synthetic Minority Over-sampling TEchnique) is not the most effective technique for resampling code smell data sets. (3) The best-performing imbalanced learning techniques and the top-3 data resampling techniques have little time cost for code smell detection. Therefore, we provide some practical guidelines. First, researchers and practitioners should select the appropriate imbalanced learning techniques (e.g., deep forest) to ameliorate the class imbalance problem. In contrast, the blind application of imbalanced learning techniques could be harmful. Then, better data resampling techniques than SMOTE should be selected to preprocess the code smell data sets.

Tobacco production and curing is the single most important contributor to soil degradation and deforestation. To minimise the environmental effects of tobacco production, the environmentally friendly, and energy-efficient rocket barns technology was developed. In spite of its energy saving and environmental benefits, the adoption of rocket barns remains low and understudied. This paper assessed farmers perception and factors affecting the adoption of rocket barn technology. Data was collected using in a cross-sectional survey using structured questionnaires were from 242 Flue Cured Virginia (FCV) tobacco farmers in Uganda. Analysed was done using SPSS and STATA software. Results show that the adoption of rocket barn technology was low, at 12%, with farmers. Farmers perceived adopting the rocket barns technology to be risky and costly. Experience, training, distance to wood fuel, access to extension information, and benefits and risk perceptions were the major determinants of adoption of rocket barns technology. Promotion and adoption of rocket barns technology will require concerted sensitization and training of farmers on the environmental benefits of rocket barn technology. Emphasis such efforts should target the relatively young and inexperienced FCV tobacco farmers.

Cell viability evaluation is significantly meaningful for cellular assays. Some cells with weak viability are easily killed in the detection of anti-cancer drugs, while others with strong viability survive and proliferate, ultimately leading to the treatment failure or the inaccuracy of biological assays. Accurately evaluating cell viability heterogeneity still remains difficult. This paper proposed a multi-physical property information fusion method for evaluating cell viability heterogeneity based on multiple linear regression (MLR) on a single-channel integrated microfluidic chip. In this method, adhesion strengths τN, that are defined as the magnitude of shear stress needed to detach (100-N) % of cell population, were extracted as the independent variables of MLR model by calculating the linear fitting of the impedance-response curves for shear stress (cell detachment assay). Besides, by calculating the non-linear fitting of the drug dose-response curves for cancer cells (IC50 assay), the half-maximal inhibitory concentration (IC50) was extracted as the dependent variables of MLR model. The results show that the mean relative error of our fusion method reduces by 17.87% and 59.66% compared with the single-parameter method and the cell counting method. Moreover, through the theoretical analysis of the drug resistance heterogeneity model, it proved that there is a qualitative relationship between the cell adhesion strength and cell viability heterogeneity, which provides a theoretical basis for our fusion method.

Attention maps, a popular heatmap-based explanation method for Visual Question Answering (VQA), are supposed to help users understand the model by highlighting portions of the image/question used by the model to infer answers. However, we see that users are often misled by current attention map visualizations that point to relevant regions despite the model producing an incorrect answer. Hence, we propose Error Maps that clarify the error by highlighting image regions where the model is prone to err. Error maps can indicate when a correctly attended region may be processed incorrectly leading to an incorrect answer, and hence, improve users’ understanding of those cases. To evaluate our new explanations, we further introduce a metric that simulates users’ interpretation of explanations to evaluate their potential helpfulness to understand model correctness. We finally conduct user studies to see that our new explanations help users understand model correctness better than baselines by an expected 30% and that our proxy helpfulness metrics correlate strongly (rho>0.97) with how well users can predict model correctness.

Aim: The risk-benefit profile of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (Covid-19) is still a matter of debate. With growing evidence on the protective effect of this group of commonly used antihypertensives in Covid-19, we aimed to thoroughly investigate the association between the use of major classes of antihypertensive medications and Covid-19 outcomes in comparison with the use of ACEIs and ARBs. Methods: We conducted a population-based study in patients with pre-existing hypertension in the UK Biobank. Multivariable logistic regression analysis was performed adjusting for a wide range of confounders. Results: The use of either beta-blockers (BBs), calcium-channel blockers (CCBs), or diuretics was associated with a higher risk of Covid-19 hospitalization compared to ACEI use (adjusted OR, 1.63; 95% CI, 1.40 to 1.90) and ARB use (adjusted OR, 1.50; 95% CI, 1.27 to 1.77). The risk of 28-day mortality among Covid-19 patients was also increased among users of BBs, CCBs or diuretics when compared to ACEI users (adjusted OR, 1.64; 95% CI, 1.23 to 2.19) but not when compared to ARB users (adjusted OR, 1.18; 95% CI, 0.87 to 1.59). However, no associations were observed when the same analysis was conducted among hospitalized Covid-19 patients only. Conclusion: Our results suggest protective effects of blocking of the renin-angiotensin-aldosterone system on Covid-19 hospitalization and mortality among patients with pharmaceutically treated hypertension, which should be addressed by randomized controlled trials. If confirmed, this finding could have high clinical relevance for treating hypertension during the SARS-CoV-2 pandemic.

The space debris management and alleviation in the microgravity environment is a dynamic research theme of contemporary interest. Herein, we provide a theoretical proof of the concept of a lucrative energy conversion system that is capable for changing the space debris into useful powders in the international space station (ISS) for various bids. A specially designed broom is adapted to collect the space debris of various sizes. An optical sorting method is proposed for the debris segregation in the ISS by creating an artificial gravitational field using frame-dragging or gravitomagnetism. An induction furnace is facilitated for converting the segregated metal-scrap into liquid metal. A fuel-cell aided water atomization method is proposed for transforming the liquid debris into metal powder. The high-energetic metal powders obtained from the space debris could be employed for producing propellants for useful aerospace applications, and the silicon powder obtained could be used for making soil for fostering the pharmaceutical-flora in the space lab in the future aiming for the scarce-drug discoveries for high-endurance health care management. The proposed energy conversion system is a possible alternative for the space debris extenuation, and its real applications in orbiting laboratories through the international collaboration for the benefits to humanity.

Aim: Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite is 4-methylaminoantipyrine (4-MAA), which can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. Our aim was to identify the CYPs involved. Methods: We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in healthy volunteers. Results: The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation. CYP2C19 and CYP2D6 contributed to N-demethylation but not to FAA formation. In the subsequent clinical study, we investigated the influence of ciprofloxacin (strong CYP1A2 inhibitor), fluconazole (strong CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of a single dose of metamizole in n=12 healthy volunteers in a randomized, placebo-controlled, double-blind study. Both ciprofloxacin and fluconazole inhibited the metabolism of 4-MAA, confirming the in vitro results. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the AUC0-12h of 4-MAA by 51%, 17% and 92%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole decreased the AUC0-12h of 4-AA by 27%, 12% and 24%, respectively, and of 4-FAA by 33%, 9% and 51%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the half-life of 4-MAA from 3.22 h (placebo) to 3.91, 3.69 and 6.07 h, respectively. Conclusion: CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. CYP1A2 inhibition increases the 4-MAA exposure by a factor of approximately 1.5, which could be relevant for dose-dependent adverse reactions.

Floodplain restoration can enhance capacity for carbon sequestration by facilitating higher water tables, deposition of fine sediment, and increased input and residence time of organic matter. We measured floodplain soil organic carbon stocks in nine stream restoration projects across the western United States and compared them to nearby degraded and reference condition floodplains. Degraded floodplains had the lowest soil mean carbon stocks in the majority of floodplains measured (range 161-894 Mg C/ha), and reference stocks had the highest stocks (range 391-904 Mg C/ha) of those with statistically significant differences between the three categories. Across all sites measured, stream restoration sites, referred to as treatment sites, had stocks (range 203-1028 Mg C/ha) similar to degraded condition floodplains but the largest range. When modeled under degraded conditions, four out of nine of the treatment sites had significantly higher OC stocks than predicted. Climate and geologic variables are most influential in predicting carbon stocks, and floodplains in the interior western USA have the highest carbon stocks. As the demand for carbon sequestration increases due to climate change, ecologically responsible floodplain restoration provides a significant opportunity for carbon storage. However, despite the statistically significant relationships we observed in this dataset, the variations within the data in relation to degraded/treatment/reference categories illustrate the uncertainties in quantifying the effects of restoration on floodplain carbon stocks.

Hypnotizability is a psychophysiological trait measured by scales and associated with several differences including interoceptive accuracy and the morpho-functional characteristics of interoception-related brain regions. The aim of the study was to assess whether the amplitude of the heartbeat evoked cortical potential (HEP), a correlate of interoceptive accuracy, differs in participants with low (lows) and high (highs) hypnotizability scores (assessed by the Stanford Hypnotic Susceptibility Scale, form A) before and after the induction of hypnosis. ECG and EEG were monitored in 16 highs and 15 lows during an experimental session including open eyes baseline (B), closed eyes relaxation (R), hypnotic induction (IND), neutral hypnosis (NH), post session baseline (Post). No significant difference was observed between groups and conditions in autonomic variables. The HEP amplitude was lower in highs than in lows at the right parietal site, likely due to hypnotizability-related differences in the functional connection between the right insula and parietal cortex. It increased in highs and decreased in lows across the session, possibly due to the highs’ preeminently internally directed attention and to the lows’ possible disengagement from the task. Since interoception is involved in several cognitive-emotional functions, its hypnotizability-related differences may contribute to the variability of experience and behavior in daily life.

A 46-year-old gentleman had a complicated course of COVID-19 pneumonia. Despite the recovery of the respiratory status, he developed corpus callosum hematoma and critical illness neuropathy/myopathy, the clinical situation became more complicated by developing pulmonary embolism that required anticoagulation. Fortunately, the patient made a good recovery.