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Abstract Macular degeneration (MD) embodies a collection of disorders causing a progressive loss of central vision. Cross-sectional MRI studies have revealed structural changes in the grey and white matter in the posterior visual pathway in MD but there remains a need to understand how such changes progress over time. To that end we assessed the posterior pathway, characterising the visual cortex and optic radiations over a ~ 2-year period in MD patients and controls. We performed cross-sectional and longitudinal analysis of the former. Reduced cortical thickness and white matter integrity were observed in patients compared to controls, replicating previous findings. While faster, neither the rate of thinning in visual cortex nor the reduction in white matter integrity during the ~ 2-year period reached significance. We also measured cortical myelin density; cross-sectional data showed this was higher in patients than controls, likely as a result of greater thinning of non-myelinated tissue in patients. However, we also found evidence of a greater rate of loss of myelin density in the occipital pole in the patient group indicating that the posterior visual pathway is at risk in established MD. Taken together, our results revealed a broad decline in grey and white matter in the posterior visual pathway in bilateral MD; cortical thickness and fractional anisotropy show hints of an accelerated rate of loss also, with larger effects emerging in the occipital pole.

Abstract Predictive modelling of cancer outcomes using radiomics faces dimensionality problems and data limitations, as radiomics features often number in the hundreds, and multi-institutional data sharing is ()often unfeasible. Federated learning (FL) and feature selection (FS) techniques combined can help overcome these issues, as one provides the means of training models without exchanging sensitive data, while the other identifies the most informative features, reduces overfitting, and improves model interpretability. Our proposed FS pipeline based on FL principles targets data-driven radiomics FS in a multivariate survival study of non-small cell lung cancer patients. The pipeline was run across datasets from three institutions without patient-level data exchange. It includes two FS techniques, Correlation-based Feature Selection and LASSO regularization, and Cox Proportional-Hazard regression with Overall Survival as endpoint. Trained and validated on 828 patients overall, our pipeline yielded a radiomic signature comprising "intensity-based energy" and "mean discretised intensity". Validation resulted in a mean Harrell C-index of 0.59, showcasing fair efficacy in risk stratification. In conclusion, we suggest a distributed radiomics approach that incorporates preliminary feature selection to systematically decrease the feature set based on data-driven considerations. This aims to address dimensionality challenges beyond those associated with data constraints and interpretability concerns.

Abstract Although bariatric surgery is an effective treatment for type 2 diabetes by inducing weight loss and augmenting gut hormone secretion, the immediate effect on beta-cell function itself remains to be elucidated in type 2 diabetes. Therefore, a prospective, randomized trial was performed in 30 patients with insulin-treated type 2 diabetes and a body mass index ≥ 35 kg/m2. Patients were randomly assigned (1:1:1) to Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in combination with protein-sparing modified fast (PSMF), or to PSMF alone. Eu- and hyperglycemic clamps were performed before and 3 weeks after surgery and/or PSMF initiation. The primary outcome was the evolution of insulin sensitivity and beta-cell function after surgery, calculated using the composite measures of glucose disposal rate, insulin secretion rate, and disposition index (DI). Results revealed that markers of insulin sensitivity increased similarly in all arms (p = 0.43). A higher marker for maximal beta-cell function was observed when comparing SG to PSMF (p = 0.007). The DI showed a clear positive evolution after RYGB and SG, but not after PSMF alone. Altogether, these findings indicate that bariatric surgery results in an immediate beta-cell function recovery in insulin-treated type 2 diabetes.

Abstract The effectiveness of the “Slash and Clear” method in reducing blackfly populations in low transmission areas is established, but its impact in high transmission settings with large rivers and dense vectors is yet to be proven. A community-based intervention study was conducted in the Mbam Valley, Centre Cameroon, involving two sites: Bayomen (control) and Biatsota (intervention). In each arm, baseline blackfly densities were collected over one year using the human landing method. The intervention consisted of destroying the trailing vegetation where blackflies breed. Blackfly densities were collected post-intervention to assess the impact of the intervention. Post-intervention data showed a 50.8% reduction in blackfly density in Biatsota (mean number of collected blackflies from 1936 to 953), while a reduction of 26.7% was observed in Bayomen (mean number of collected blackflies from 2418 to 1774). The reduction rate attributable to the intervention was 32.9%. Statistical analysis confirmed that the reduction in blackfly density was significantly greater in the intervention site. This study demonstrates the feasibility and significant impact of the “Slash and Clear” method in high transmission areas. However, further research is required to assess its long-term effects and determine how this strategy can be scaled up and sustained until onchocerciasis elimination is achieved.

Abstract Simultaneous intracellular depolymerization of xylo-oligosaccharides (XOS) and acetate fermentation by engineered Saccharomyces cerevisiae offers significant potential for more cost-effective second-generation (2G) ethanol production. In the present work, the previously engineered S. cerevisiae strain, SR8A6S3, expressing enzymes for xylose assimilation along with an optimized route for acetate reduction, was used as the host for expressing two β-xylosidases, GH43-2 and GH43-7, and a xylodextrin transporter, CDT-2, from Neurospora crassa, yielding the engineered SR8A6S3-CDT-2-GH34-2/7 strain. Both β-xylosidases and the transporter were introduced by replacing two endogenous genes, GRE3 and SOR1, that encode aldose reductase and sorbitol (xylitol) dehydrogenase, respectively, and catalyse steps in xylitol production. The engineered strain, SR8A6S3-CDT-2-GH34-2/7 (sor1Δ gre3Δ), produced ethanol through simultaneous XOS, xylose, and acetate co-utilization. The mutant strain produced 60% more ethanol and 12% less xylitol than the control strain when a hemicellulosic hydrolysate was used as a mono- and oligosaccharide source. Similarly, the ethanol yield was 84% higher for the engineered strain using hydrolysed xylan, compared with the parental strain. Xylan, a common polysaccharide in lignocellulosic residues, enables recombinant strains to outcompete contaminants in fermentation tanks, as XOS transport and breakdown occur intracellularly. Furthermore, acetic acid is a ubiquitous toxic component in lignocellulosic hydrolysates, deriving from hemicellulose and lignin breakdown. Therefore, the consumption of XOS, xylose, and acetate expands the capabilities of S. cerevisiae for utilization of all of the carbohydrate in lignocellulose, potentially increasing the efficiency of 2G biofuel production.

Abstract In the past decade, there has been a sharp increase in publications describing applications of convolutional neural networks (CNNs) in medical image analysis. However, recent reviews have warned of the lack of reproducibility of most such studies, which has impeded closer examination of the models and, in turn, their implementation in healthcare. On the other hand, the performance of these models is highly dependent on decisions on architecture and image pre-processing. In this work, we assess the reproducibility of three studies that use CNNs for head and neck cancer outcome prediction by attempting to reproduce the published results. In addition, we propose a new network structure and assess the impact of image pre-processing and model selection criteria on performance. We used two publicly available datasets: one with 298 patients for training and validation and another with 137 patients from a different institute for testing. All three studies failed to report elements required to reproduce their results thoroughly, mainly the image pre-processing steps and the random seed. Our model either outperforms or achieves similar performance to the existing models with considerably fewer parameters. We also observed that the pre-processing efforts significantly impact the model’s performance and that some model selection criteria may lead to suboptimal models. Although there have been improvements in the reproducibility of deep learning models, our work suggests that wider implementation of reporting standards is required to avoid a reproducibility crisis.

Abstract Until January 2023, Brazil recorded 37 million COVID-19 cases despite the decrease in mortality due to mass vaccination efforts against COVID-19. The infection continues to challenge researchers and health professionals with the persistent symptoms and onset manifestations after the acute phase of the disease, namely Post-Covid Condition (PCC). Being one of the countries with the highest infection rate, Brazil must prepare for a growing number of patients with chronic health consequences of COVID-19. Longitudinal studies that follow patients over extended periods are crucial in understanding the long-term impacts of COVID-19, including potential health consequences and the effects on quality of life. We describe the clinical profile of a cohort of COVID-19 patients infected during the first year of the pandemic in Brazil and a follow-up after two years to investigate the health impacts of SARS-CoV-2 infection. The first wave of SARS-CoV-2 infection in Brazil featured extensive drug misuse, notably the ineffective COVID kit comprised of ivermectin, antimalarials and azithromycin, and elevated in-hospital mortality. In the second phase of the study, Post-Covid Condition was reported by symptomatic COVID-19 subjects across different severity levels two years after infection. Long haulers are more likely to be women, previously hospitalized, and reported a range of symptoms from muscle pain to cognitive deficit. Our longitudinal study is essential to inform public health authorities to develop strategies and policies to control the spread of the virus and mitigate its impacts on society.

Abstract Realistic haptic feedback is a key for virtual reality applications in order to transition from solely procedural training to motor-skill training. Currently, haptic feedback is mostly used in low-force medical procedures in dentistry, laparoscopy, arthroscopy and alike. However, joint replacement procedures at hip, knee or shoulder, require the simulation of high-forces in order to enable motor-skill training. In this work a prototype of a haptic device capable of delivering double the force (35 N to 70 N) of state-of-the-art devices is used to examine the four most common haptic rendering methods (penalty-, impulse-, constraint-, rigid body-based haptic rendering) in three bimanual tasks (contact, rotation, uniaxial transition with increasing forces from 30 to 60 N) regarding their capabilities to provide a realistic haptic feedback. In order to provide baseline data, a worst-case scenario of a steel/steel interaction was chosen. The participants needed to compare a real steel/steel interaction with a simulated one. In order to substantiate our results, we replicated the study using the same study protocol and experimental setup at another laboratory. The results of the original study and the replication study deliver almost identical results. We found that certain investigated haptic rendering method are likely able to deliver a realistic sensation for bone-cartilage/steel contact but not for steel/steel contact. Whilst no clear best haptic rendering method emerged, penalty-based haptic rendering performed worst. For simulating high force bimanual tasks, we recommend a mixed implementation approach of using impulse-based haptic rendering for simulating contacts and combine it with constraint or rigid body-based haptic rendering for rotational and translational movements.

Abstract Distraction disrupts Working Memory (WM) performance, but how the brain filters distraction is not known. One possibility is that neural activity associated with distractions is suppressed relative to a baseline/passive task (biased competition). Alternatively, distraction may be denied access to WM, with no suppression. Furthermore, behavioural work indicates separate mechanisms for ignoring distractions which occur (1) while we put information into WM (Encoding Distraction, ED) and (2) while we maintain already encoded information during the WM delay period (Delay Distraction, DD). Here we used fMRI in humans to measure category-sensitive cortical activity and probe the extent to which ED/DD mechanisms involve enhancement/suppression during a WM task. We observed significant enhancement of task-relevant activity, relative to a passive view task, which did not differ according to whether or when distractors appeared. For both ED and DD we found no evidence of suppression, but instead a robust increase in stimulus specific activity in response to additional stimuli presented during the passive view task, which was not seen for the WM task, when those additional stimuli were to be ignored. The results indicate that ED/DD resistance does not necessarily involve suppression of distractor-related activity. Rather, a rise in distractor-associated activity is prevented when distractors are presented, supporting models of input gating, and providing a potential mechanism by which input-gating might be achieved.

Abstract The rapid spread of the SARS-CoV-2 Variant of Concern (VOC) Gamma in Amazonas during early 2021 fueled a second large COVID-19 epidemic wave and raised concern about the potential role of reinfections. Very few cases of reinfection associated with the VOC Gamma have been reported to date, and their potential impact on clinical, immunological, and virological parameters remains largely unexplored. Here we describe 25 cases of SARS-CoV-2 reinfection in Brazil. SARS-CoV-2 genomic analysis confirmed that individuals were primo-infected with distinct viral lineages between March and December 2020 (B.1.1, B.1.1.28, B.1.1.33, B.1.195, and P.2) and reinfected with the VOC Gamma between 3 to 12 months after primo-infection. We found a similar mean cycle threshold (Ct) value and limited intra-host viral diversity in both primo-infection and reinfection samples. Sera of 14 patients tested 10–75 days after reinfection displayed detectable neutralizing antibodies (NAb) titers against SARS-CoV-2 variants that circulated before (B.1.*), during (Gamma), and after (Delta and Omicron) the second epidemic wave in Brazil. All individuals had milder or no symptoms after reinfection, and none required hospitalization. These findings demonstrate that individuals reinfected with the VOC Gamma may display relatively high RNA viral loads at the upper respiratory tract after reinfection, thus contributing to onward viral transmissions. Despite this, our study points to a low overall risk of severe Gamma reinfections, supporting that the abrupt increase in hospital admissions and deaths observed in Amazonas and other Brazilian states during the Gamma wave was mostly driven by primary infections. Our findings also indicate that most individuals analyzed developed a high anti-SARS-CoV-2 NAb response after reinfection that may provide some protection against reinfection or disease by different SARS-CoV-2 variants.

Abstract TREML4 and other members of the triggering receptor expressed in the myeloid cell family are associated with a risk of atherosclerosis and progression in coronary artery disease, acute coronary syndrome, and coronary artery calcification. Herein, the relationship between TREML4 expression and its polymorphisms (rs2803495 and rs280396) was evaluated in patients with subclinical atherosclerosis (n = 340) and heart failure post-acute myocardial infarction (MI) (n = 68) for the first time. TREML4 variants rs2803495 (A > G) and rs2803496 (T > C) and leukocyte mRNA expression was analyzed by qRT–PCR. The rs2803495 G allele was associated with TREML4 expression (OR 8.01, CI 3.78–16.99, p

Abstract Severe COVID-19-related acute respiratory distress syndrome (C-ARDS) requires mechanical ventilation. While this intervention is often performed in the prone position to improve oxygenation, the underlying mechanisms responsible for the improvement in respiratory function during invasive ventilation and awake prone positioning in C-ARDS have not yet been elucidated. In this prospective observational trial, we evaluated the respiratory function of C-ARDS patients while in the supine and prone positions during invasive (n = 13) or non-invasive ventilation (n = 15). The primary endpoint was the positional change in lung regional aeration, assessed with electrical impedance tomography. Secondary endpoints included parameters of ventilation and oxygenation, volumetric capnography, respiratory system mechanics and intrapulmonary shunt fraction. In comparison to the supine position, the prone position significantly increased ventilation distribution in dorsal lung zones for patients under invasive ventilation (53.3 ± 18.3% vs. 43.8 ± 12.3%, percentage of dorsal lung aeration ± standard deviation in prone and supine positions, respectively; p = 0.014); whereas, regional aeration in both positions did not change during non-invasive ventilation (36.4 ± 11.4% vs. 33.7 ± 10.1%; p = 0.43). Prone positioning significantly improved the oxygenation both during invasive and non-invasive ventilation. For invasively ventilated patients reduced intrapulmonary shunt fraction, ventilation dead space and respiratory resistance were observed in the prone position. Oxygenation is improved during non-invasive and invasive ventilation with prone positioning in patients with C-ARDS. Different mechanisms may underly this benefit during these two ventilation modalities, driven by improved distribution of lung regional aeration, intrapulmonary shunt fraction and ventilation-perfusion matching. However, the differences in the severity of C-ARDS may have biased the sensitivity of electrical impedance tomography when comparing positional changes between the protocol groups. Trial registration: ClinicalTrials.gov (NCT04359407) and Registered 24 April 2020, https://clinicaltrials.gov/ct2/show/NCT04359407 .

Abstract Consuming wildmeat may protect against iron-deficiency anemia, a serious public health problem globally. Contributing to debates on the linkages between wildmeat and the health of forest-proximate people, we investigate whether wildmeat consumption is associated with hemoglobin concentration in rural and urban children (

Abstract The anatomical location and extent of primary lung tumors have shown prognostic value for overall survival (OS). However, its manual assessment is prone to interobserver variability. This study aims to use data driven identification of image characteristics for OS in locally advanced non-small cell lung cancer (NSCLC) patients. Five stage IIIA/IIIB NSCLC patient cohorts were retrospectively collected. Patients were treated either with radiochemotherapy (RCT): RCT1* (n = 107), RCT2 (n = 95), RCT3 (n = 37) or with surgery combined with radiotherapy or chemotherapy: S1* (n = 135), S2 (n = 55). Based on a deformable image registration (MIM Vista, 6.9.2.), an in-house developed software transferred each primary tumor to the CT scan of a reference patient while maintaining the original tumor shape. A frequency-weighted cumulative status map was created for both exploratory cohorts (indicated with an asterisk), where the spatial extent of the tumor was uni-labeled with 2 years OS. For the exploratory cohorts, a permutation test with random assignment of patient status was performed to identify regions with statistically significant worse OS, referred to as decreased survival areas (DSA). The minimal Euclidean distance between primary tumor to DSA was extracted from the independent cohorts (negative distance in case of overlap). To account for the tumor volume, the distance was scaled with the radius of the volume-equivalent sphere. For the S1 cohort, DSA were located at the right main bronchus whereas for the RCT1 cohort they further extended in cranio-caudal direction. In the independent cohorts, the model based on distance to DSA achieved performance: AUCRCT2 [95% CI] = 0.67 [0.55–0.78] and AUCRCT3 = 0.59 [0.39–0.79] for RCT patients, but showed bad performance for surgery cohort (AUCS2 = 0.52 [0.30–0.74]). Shorter distance to DSA was associated with worse outcome (p = 0.0074). In conclusion, this explanatory analysis quantifies the value of primary tumor location for OS prediction based on cumulative status maps. Shorter distance of primary tumor to a high-risk region was associated with worse prognosis in the RCT cohort.

Abstract This study investigated the acute and subacute toxicity of the ethanolic extract (EE) and alkaloid fraction (FA) from A. nitidum. The EE was obtained from trunk bark with ethanol, FA was obtained from the fractionation of EE. To test the acute toxicity, mice were divided into four groups, and the negative controls received water or aqueous solution of dimethyl sulfoxide, whereas the others received EE or FA (2000 mg/kg, orally, single dose). The same controls were used in the subacute trial. However, the animals were treated for 28 days, and the dose used was 1000 mg/kg per day of EE and FA. Daily clinical evaluations of the animals were performed. At the end of the experiment, hematological, biochemical, and histopathological assessments (liver, lung, heart, and kidney) were performed. In the acute and subacute toxicity studies, mice treated with EE and FA did not show any clinical changes, there were no changes in weight gain, hematological and biochemical parameters compared to the control groups (p > 0.05). In the histopathological examination, there was no abnormality in the organs of the treated animals. Therefore, EE and FA did not produce toxic effects in mice after acute and subacute treatment.

Abstract In the agricultural industry, advances in optical imaging technologies based on rapid and non-destructive approaches have contributed to increase food production for the growing population. The present study employed autofluorescence-spectral imaging and machine learning algorithms to develop distinct models for classification of soybean seeds differing in physiological quality after artificial aging. Autofluorescence signals from the 365/400 nm excitation-emission combination (that exhibited a perfect correlation with the total phenols in the embryo) were efficiently able to segregate treatments. Furthermore, it was also possible to demonstrate a strong correlation between autofluorescence-spectral data and several quality indicators, such as early germination and seed tolerance to stressful conditions. The machine learning models developed based on artificial neural network, support vector machine or linear discriminant analysis showed high performance (0.99 accuracy) for classifying seeds with different quality levels. Taken together, our study shows that the physiological potential of soybean seeds is reduced accompanied by changes in the concentration and, probably in the structure of autofluorescent compounds. In addition, altering the autofluorescent properties in seeds impact the photosynthesis apparatus in seedlings. From the practical point of view, autofluorescence-based imaging can be used to check modifications in the optical properties of soybean seed tissues and to consistently discriminate high-and low-vigor seeds.

Abstract The difference in incidence of oral cavity cancer (OCC) between Taiwan and the Netherlands is striking. Different risk factors and treatment expertise may result in survival differences between the two countries. However due to regulatory restrictions, patient-level analyses of combined data from the Netherlands and Taiwan are infeasible. We implemented a software infrastructure for federated analyses on data from multiple organisations. We included 41,633‬ patients with single-tumour OCC between 2004 and 2016, undergoing surgery, from the Taiwan Cancer Registry and Netherlands Cancer Registry. Federated Cox Proportional Hazard was used to analyse associations between patient and tumour characteristics, country, treatment and hospital volume with survival. Five factors showed differential effects on survival of OCC patients in the Netherlands and Taiwan: age at diagnosis, stage, grade, treatment and hospital volume. The risk of death for OCC patients younger than 60 years, with advanced stage, higher grade or receiving adjuvant therapy after surgery was lower in the Netherlands than in Taiwan; but patients older than 70 years, with early stage, lower grade and receiving surgery alone in the Netherlands were at higher risk of death than those in Taiwan. The mortality risk of OCC in Taiwanese patients treated in hospitals with higher hospital volume (≥ 50 surgeries per year) was lower than in Dutch patients. We conducted analyses without exchanging patient-level information, overcoming barriers for sharing privacy sensitive information. The outcomes of patients treated in the Netherlands and Taiwan were slightly different after controlling for other prognostic factors.

Abstract Bovine mastitis remains the main cause of economic losses for dairy farmers. Mammary pathogenic Escherichia coli (MPEC) is related to an acute mastitis and its treatment is still based on the use of antibiotics. In the era of antimicrobial resistance (AMR), bacterial viruses (bacteriophages) present as an efficient treatment or prophylactic option. However, this makes it essential that its genetic structure, stability and interaction with the host immune system be thoroughly characterized. The present study analyzed a novel, broad host-range anti-mastitis agent, the T4virus vB_EcoM-UFV13 in genomic terms, and its activity against a MPEC strain in an experimental E. coli-induced mastitis mouse model. 4,975 Single Nucleotide Polymorphisms (SNPs) were assigned between vB_EcoM-UFV13 and E. coli phage T4 genomes with high impact on coding sequences (CDS) (37.60%) for virion proteins. Phylogenetic trees and genome analysis supported a recent infection mix between vB_EcoM-UFV13 and Shigella phage Shfl2. After a viral stability evaluation (e.g pH and temperature), intramammary administration (MOI 10) resulted in a 10-fold reduction in bacterial load. Furthermore, pro-inflammatory cytokines, such as IL-6 and TNF-α, were observed after viral treatment. This work brings the whole characterization and immune response to vB_EcoM-UFV13, a biocontrol candidate for bovine mastitis.

Abstract High-level regions of the ventral visual pathway respond more to intact objects compared to scrambled objects. The aim of this study was to determine if this selectivity for objects emerges at an earlier stage of processing. Visual areas (V1–V3) were defined for each participant using retinotopic mapping. Participants then viewed intact and scrambled images from different object categories (bottle, chair, face, house, shoe) while neural responses were measured using fMRI. Our rationale for using scrambled images is that they contain the same low-level properties as the intact objects, but lack the higher-order combinations of features that are characteristic of natural images. Neural responses were higher for scrambled than intact images in all regions. However, the difference between intact and scrambled images was smaller in V3 compared to V1 and V2. Next, we measured the spatial patterns of response to intact and scrambled images from different object categories. We found higher within-category compared to between category correlations for both intact and scrambled images demonstrating distinct patterns of response. Spatial patterns of response were more distinct for intact compared to scrambled images in V3, but not in V1 or V2. These findings demonstrate the emergence of selectivity to natural images in V3.