Search

Background and Purpose Methods Results Conclusion Early and reliable prediction of hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) is crucial for treatment decisions and early intervention. The purpose of this study was to conduct a systematic review and meta‐analysis on the performance of artificial intelligence (AI) and machine learning (ML) models that utilize neuroimaging to predict HT.A systematic search of PubMed, EMBASE, and Web of Science was conducted until February 19, 2024. Inclusion criteria were as follows: patients with AIS who received reperfusion therapy; AI/ML algorithm using imaging to predict HT; or presence of sufficient data on the predictive performance. Exclusion criteria were as follows: articles with less than 20 patients; articles lacking algorithms that operate solely on images; or articles not detailing the algorithm used. The quality of eligible studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies‐2 and Checklist for Artificial Intelligence in Medical Imaging. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated using a random‐effects model, and a summary receiver operating characteristic curve was constructed using the Reitsma method.We identified six eligible studies, which included 1640 patients. Aside from an unclear risk of bias regarding flow and timing identified in two of the studies, all studies showed low risk of bias and applicability concerns in all categories. Pooled sensitivity, specificity, and DOR were .849, .878, and 45.598, respectively.AI/ML models can reliably predict the occurrence of HT in AIS patients. More prospective studies are needed for subgroup analyses and higher clinical certainty and usefulness. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Inferior vena cava atresia is a rare condition with highly variable anatomy due to the complexity of caval embryology. When endovascular venovenous reconstruction is considered for severe persistent sequelae, multimodality imaging with CT and invasive venography is used to determine the appropriateness of intervention and for procedural planning. [ABSTRACT FROM AUTHOR]

Cutaneous fungal infections affect millions around the world. However, severe, multi‐resistant fungal infections are increasingly being reported over the past years. As a result of the high rate of resistance which urged for drug repurposing, statins were studied and found to have multiple pleiotropic effects, especially when combined with other already‐existing drugs. An example of this is the synergism found between several typical antifungals and statins, such as antifungals Imidazole and Triazole with a wide range of statins shown in this review. The main mechanisms in which they exert an antifungal effect are ergosterol inhibition, protein prenylation, mitochondrial disruption, and morphogenesis/mating inhibition. This article discusses multiple in vitro studies that have proven the antifungal effect of systemic statins against many fungal species, whether used alone or in combination with other typical antifungals. However, as a result of the high rate of drug–drug interactions and the well‐known side effects of systemic statins, topical statins have become of increasing interest. Furthermore, patients with dyslipidemia treated with systemic statins who have a new topical fungal infection could benefit from the antifungal effect of their statin. However, it is still not indicated to initiate systemic statins in patients with topical mycotic infections if they do not have another indication for statin use, which raises the interest in using topical statins for fungal infections. This article also tackles the different formulations that have been studied to enhance topical statins' efficacy, as well as the effect of different topical statins on distinct dermatologic fungal diseases. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. Methods: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty‐five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale‐Revised (ALSFRS‐R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS‐R. Results: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel‐treated participants (baseline NfL, baseline latency‐associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin‐1, all p <.01), with baseline NfL and LAP/TGFβ1 remaining (p <.05) when disease characteristics (p <.005) were incorporated. Change from baseline to the last measurement showed debamestrocel‐driven reductions in NfL were associated with less decline in ALSFRS‐R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p =.037). Discussion: Following debamestrocel treatment, many biomarkers showed increases (anti‐inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed. [ABSTRACT FROM AUTHOR]

Background and Purpose: We aimed to predict the functional outcome of acute ischemic stroke patients with anterior circulation large vessel occlusions (LVOs), irrespective of how they were treated or the severity of the stroke at admission, by only using imaging parameters in machine learning models. Methods: Consecutive adult patients with anterior circulation LVOs who were scanned with CT angiography (CTA) and CT perfusion were queried in this single‐center, retrospective study. The favorable outcome was defined as a modified Rankin score (mRS) of 0‐2 at 90 days. Predictor variables included only imaging parameters. CatBoost, XGBoost, and Random Forest were employed. Algorithms were evaluated using the area under the receiver operating characteristic curve (AUROC), the area under the precision‐recall curve (AUPRC), accuracy, Brier score, recall, and precision. SHapley Additive exPlanations were implemented. Results: A total of 180 patients (102 female) were included, with a median age of 69.5. Ninety‐two patients had an mRS between 0 and 2. The best algorithm in terms of AUROC was XGBoost (0.91). Furthermore, the XGBoost model exhibited a precision of 0.72, a recall of 0.81, an AUPRC of 0.83, an accuracy of 0.78, and a Brier score of 0.17. Multiphase CTA collateral score was the most significant feature in predicting the outcome. Conclusions: Using only imaging parameters, our model had an AUROC of 0.91 which was superior to most previous studies, indicating that imaging parameters may be as accurate as conventional predictors. The multiphase CTA collateral score was the most predictive variable, highlighting the importance of collaterals. [ABSTRACT FROM AUTHOR]

One of William Lane Craig's key arguments for the finitude of the past is the Successive Addition Argument (SAA). Malpass (2021) has recently developed a novel challenge to the SAA, utilising a thought experiment from the work of Fred Dretske, which is meant to show that it is possible to count to infinity, to argue that there is a counterexample to the SAA's second premise. In this paper, I contend that the Malpass‐Dretske counterexample should not worry advocates of the SAA. First, I argue that one objection Malpass considers—the Potential Infinite Objection—reveals an interesting fact: the SAA's second premise is unnecessarily strong and can be weakened whilst still yielding the same conclusion. Second, I show how another one of the objections considered by Malpass—the Accumulation Objection—is successful, provided some clarification to the SAA's premises. The upshot of both analyses is that we generate two 'new' Successive Addition arguments that not only move the dialectic forward, but shed light on deeper assumptions and motivating intuitions concerning the Kalām. [ABSTRACT FROM AUTHOR]

This is a study of Norway's sustainable environment development amidst the interactions of natural resources, external investment (FDI) and economic development. Much has been done with respect to the study of Norway's economic performance in relation to the link between the natural resources and FDI with little emphasis on the environmental performance of the resource‐based economy. Also, Norway is classified as among the top countries in Europe with a greater percentage of adopting renewable energy, and no study has done a critical review of the impact of natural resources and FDI which are part of drivers of carbon emission that can counter the positive impact of renewable energy towards the Norway's sustainable environment. On this basis, this study adopts a time series data of Norway, 1970 to 2018 to study its environmental performance. Approaches such as structural break analysis, Autoregressive Distributed Lag (ARDL)‐bound testing and Granger causality estimations are utilised in this study for in‐depth analysis of the subject. Findings from ARDL confirmed a positive association between fuels and carbon emission, other indicators (economic growth and natural resources) are improving the quality of the country's environment. FDI even though shows positive sign remains insignificant in impacting the environmental performance in the short run reverted to a significant negative relationship with carbon emissions. This confirms the pollution halo hypothesis and rejects the pollution haven hypothesis (PHH) for Norway, and this trend can be sustained with the constant implementation of environmental rules in the country. Granger test confirms, a one‐way transition from fossil fuels to carbon emission, from carbon emission to growth, and from economic growth to fossil fuels. Also, a two‐way transmission is found between fossil fuels and FDI. These findings from Granger causality are consistent with the findings from ARDL, hence, two ways interactions between FDI and fossil fuel energy source consumption from Granger causality and the two variables (fossil fuels and FDI) are seen impacting on Norway's environmental performance. Findings from the estimates suggest that natural resources and FDI are mitigating pollution, hence, Norway's policy is expected to be resources and FDI driven in sustainable environment development. [ABSTRACT FROM AUTHOR]

Schottky barrier diodes on GaN on GaN substrates are fabricated for the purpose of material and technology characterization. The epitaxial layers are grown by MOCVD. I–V measurements as a function of the temperature in the range 80–480 K show ideality factor (n) and barrier height (ϕB) variations not following a thermionic (TE) model. Consequently, barrier height fluctuations are considered. In the temperature range 280–480 K, an average barrier height of 1.31 eV with a relatively large standard deviation (σ) of 0.15 eV is extracted using this model. The n(T) variation is also analyzed in order to extract the field sensibility of 1) the mean barrier height variation (ρ2 = −0.1) and 2) the barrier height standard deviation (ρ3 = −15 mV). The corrected Richardson plot using ϕB and σ values is linear and gives a Richardson constant of 31.5 A cm−2 K−2 close to the theoretical value of 26.4 A cm−2 K−2. For a deeper understanding of ϕB fluctuation origins, micro‐Raman mapping of the epitaxial layers and deep‐level transient spectroscopy (DLTS) are used. μ‐RS mappings show compressive strain for diodes having suffered electrical breakdown. DLTS analysis shows the presence of nine levels whose signatures are extracted and nature discussed. [ABSTRACT FROM AUTHOR]

Background: Brain natriuretic peptide (BNP) is a marker of myocardial stretch and may have prognostic significance in patients with atrial fibrillation (AF) without heart failure (HF). We investigated the association between baseline BNP levels and arrhythmia recurrence following pulmonary vein isolation (PVI) among patients with persistent AF without HF. Methods: We analyzed 125 patients with persistent AF without HF who had baseline BNP measured from the DECAAF II trial. The primary outcome was arrhythmia recurrence following ablation. The baseline characteristics across the two groups were compared using Chi‐square test and Wilcoxon rank test accordingly. Cox regression analysis was used to analyze the association between baseline BNP levels and the primary outcome. Results: Across the entire cohort, 64 (51%) patients experienced arrhythmia recurrence. When comparing patients who experienced arrythmia recurrence to patients who did not, patients with recurrent arrhythmia had higher levels of pre‐ablation BNP, as evidenced by differences in means (330.05 pg/mL) compared to patients without recurrent arrhythmia (182.39 pg/mL) (p <.05). A cut‐off BNP value of 300 pg/mL provided the largest area under curve (AUC) of receiver‐operating characteristic (ROC) curve on univariate logistic regression. On unadjusted Cox analysis, for every 100 unit increase in BNP, the hazard ratio for the primary outcome increased 1.09 (1.026–1.158) times (p =.004). After adjusting for sex, hypertension, and stroke, the results remained significant (HR = 1.8516, CI 95% [1.0139 – 3.381], p =.045). Conclusion: In the non‐heart failure population, BNP levels predict AF recurrence following PVI in persistent AF patients. [ABSTRACT FROM AUTHOR]

Novel, selective, facile, and precise spectroscopic approaches were validated to determine nilotinib hydrochloride, a tyrosine kinase inhibitor used to treat patients with chronic myeloid leukemia. These approaches depend on the reaction of the tertiary amine group of nilotinib with erythrosine B in the Britton–Robinson buffer at pH 4. Method I, depends on measuring the absorbance of the formed complex at 551 nm. The absorbance concentration plot showed linearity over the concentration range of 1.0 to 9.0 μg/ml. Method II, involved the measurement of the quenching of the native fluorescence of erythrosine B by adding nilotinib in an acidic medium. The fluorescence quenching of erythrosine B was measured at 549 nm after excitation at 528 nm. This approach showed excellent linearity in the concentration range of 0.04 to 0.7 μg/ml. The limit of detection values for Method I and Method II were 0.225 and 0.008 μg/ml, respectively, while the limit of quantitation values for Method I and Method II were 0.68 and 0.026 μg/ml, respectively. To get the optimal conditions, factors that may affect the formation of the ion‐pairing complex were thoroughly examined. The two approaches were carefully validated following the International Conference of Harmonization (ICH Q2R1) guidelines. Statistical assessment of the results achieved using the suggested and previously published comparison approaches showed no significant difference. The approaches were successful in determining nilotinib in a pharmaceutical dosage form as well as spiked human plasma samples. The eco‐friendly properties of the methods were evaluated by three different tools. [ABSTRACT FROM AUTHOR]

Background: Outcomes from Gram‐negative bacteremia (GNB) in solid organ transplant (SOT) recipients are poorly understood. Methods: This is a single center prospective cohort study comparing the clinical characteristics and outcomes of SOT recipients with GNB to immunocompetent non‐SOT patients with GNB between 1/1/2002 through 12/31/2018. Outcomes of interest included incidence of septic shock, respiratory failure, and time to death. A multivariable logistic regression model was used to determine factors associated with incidence of septic shock and respiratory failure. Time to death was evaluated using Cox proportional hazard models. Results: A total of 297 SOT and 1245 immunocompetent non‐SOT patients were included. Incidence of septic shock did not significantly differ between the groups (SOT 25.3% vs. non‐SOT 24.6%, p =.8225). Overall survival did not significantly differ by transplant status (30‐day survival: SOT 76%, 95% confidence interval [CI] 70, 92, non‐SOT 74%, 95% CI 71, 77: log rank: p =.76). SOT recipients taking three immunosuppressive medications had significantly lower odds of developing septic shock or respiratory failure requiring intubation and mechanical ventilation than those taking ≤1 agent (shock: adjusted odds ratio [aOR] 0.29, 95% CI 0.09, 0.90, p =.0316; respiratory failure: aOR 0.14, 95% CI: 0.04, 0.49, p =.0020). Conclusions: SOT recipients with GNB do not experience higher rates of septic shock, respiratory failure, or mortality than immnon‐SOT recipients with GNB. Among SOT recipients, a greater number of immunosuppressive medications may be associated with improved outcomes during GNB. Future studies are needed to understand the potential relationship between levels of immunosuppression and clinical outcome in SOT recipients with GNB. [ABSTRACT FROM AUTHOR]

ENGLISH SUMMARY: Corneal blindness is a leading cause of visual impairment worldwide. The most common treatment is to replace the diseased cornea by standard corneal transplantation. In eyes at high risk of graft failure, the Boston keratoprosthesis type 1 (KPro) can be used to restore vision and is currently the most frequently used artificial cornea in the world. However, glaucoma is a well‐known complication of KPro surgery and is the most important threat to vision in KPro‐implanted eyes (paper I). This chronic disease is influenced by elevated intraocular pressure (IOP) and damages the optic nerve, leading to progressive vision loss. In KPro patients, glaucoma is highly prevalent and extremely challenging to manage, yet its exact cause remains unknown. The overall purpose of this PhD Thesis (Geoffrion, 2021) was to better understand the mechanisms and how to improve management of glaucoma after KPro implantation. The approaches used in this thesis included investigating one of the largest KPro patient cohorts in North America, with a total of 157 operated patients at that time, as well as studying KPro surgery and outcomes in mice. The first objective was to identify risk factors for glaucoma development and progression after KPro implantation (paper II). Multivariate logistic regression revealed that high preoperative IOP signals a higher risk for both glaucoma development and progression. Stromal and endothelial corneal disorders were less associated with glaucoma progression, while autoimmune and ocular surface diseases precipitated glaucoma development. Second, there is no objective evidence that indicates the best order for glaucoma surgeries and KPro implantation. By comparing medical and surgical management in KPro eyes with either preexisting or de novo glaucoma (paper III), we showed that glaucoma surgery may be performed before or at the time of KPro in eyes with preexisting glaucoma to limit progression without increasing complications. In eyes with de novo glaucoma, glaucoma surgery did not increase complications compared with medications. Third, among glaucoma surgery interventions, the two most frequently implanted glaucoma drainage devices were compared in KPro patients (paper IV). Compared with the Ahmed glaucoma valve, the Baerveldt glaucoma implant was associated with lower failure rates, without increased postoperative complications. Fourth, even with aggressive management, many KPro patients suffer from progressive optic nerve damage, sometimes despite normal IOP. Inflammatory cytokines play an important role in glaucomatous optic neuropathy, but their role in KPro‐associated glaucoma is still unknown. By analysing tear fluid of KPro patients by multiplex bead immunoassay (paper V), we identified that cytokines TNF‐a, IL‐1b, FGF‐basic and IFN‐g were elevated in KPro patients with glaucoma compared to those without. These cytokines correlated with optic nerve excavation and IOP. For the first time in humans, these results concorded with the elevations of TNF‐a and IL‐1b documented in the mouse KPro model. Ocular surface inflammation may thus reflect the inflammatory processes that perpetuate glaucoma damage years after KPro surgery. Fifth, we determined that miniaturized mouse KPro implantation requires extensive practice to be used as a reproducible model of glaucoma post‐KPro (paper VI). KPro animal models with larger eyes and a full‐thickness, 360‐degree corneal excision should be prioritized to best validate human outcomes. In conclusion, glaucoma in KPro eyes is a long‐lasting and multifactorial process. Most probable mechanisms combine IOP‐independent inflammation mediated by TNF‐a and IL‐1b that prolong glaucoma damage, together with post‐surgical angle closure elevating the IOP. Altogether, our results inform glaucoma risk profiling of transplant recipients, improvement of surgical management of KPro patients with glaucoma and development of targeted treatments to minimize glaucomatous damage after KPro. Ultimately, this work has the potential to preserve the vision of thousands of patients who undergo KPro surgery every year worldwide and to provide insight for the role of inflammation in other diseases involving neuronal damage. RÉSUMÉ (FRENCH SUMMARY) La cécité cornéenne est l'une des causes les plus importantes de déficience visuelle dans le monde. Le traitement usuel est de remplacer la cornée malade par une greffe de cornée traditionnelle. Dans les yeux à haut risque d'échec de greffe, la kératoprothèse de Boston de type 1 (KPro) peut rétablir la vision et est la cornée artificielle la plus utilisée au monde. Cependant, le glaucome est une complication importante de la KPro (papier I). Cette maladie chronique est influencée par une pression intraoculaire (PIO) élevée et endommage le nerf optique, menant à une perte de vision. Chez les patients avec KPro, le glaucome est fréquent et difficile à contrôler, mais sa cause exacte demeure inconnue. L'objectif principal de cette thèse est de découvrir les mécanismes et d'optimiser la prise en charge du glaucome après l'implantation de la KPro. Pour ce faire, nous avons investigué l'une des plus grandes cohortes de patients KPro en Amérique du Nord avec un total de 157 patients, ainsi qu'un groupe de souris ayant reçu une implantation de kératoprothèse. Le premier but était d'identifier les facteurs de risque pour le développement et la progression du glaucome après la KPro (papier II). Par régression logistique multivariée, nous avons démontré qu'une PIO préopératoire élevée mène à un plus grand risque de développement et de progression du glaucome. Les maladies cornéennes stromales ou endothéliales sont moins associées à une progression, alors que les maladies autoimmunes ou de la surface oculaire précipitent le développement du glaucome. Deuxièmement, il n'existe aucune donnée objective pour indiquer le meilleur ordre des chirurgies de glaucome et de KPro. En comparant les traitements médicaux et chirurgicaux des yeux KPro avec glaucome (papier III), nous avons démontré que les chirurgies de glaucome peuvent limiter la progression en étant effectuées avant ou pendant l'implantation de KPro dans les yeux avec glaucome préexistant, sans augmenter les complications. Dans le glaucome de novo, les chirurgies de glaucome n'augmentent pas les complications en comparaison aux médicaments. Troisièmement, les deux implants de glaucome les plus communs ont été étudiés chez les patients KPro (papier IV). Comparé à la valve Ahmed, l'implant Baerveldt est associé à des taux d'échec plus bas, sans augmentation des complications. Quatrièmement, même avec une prise en charge agressive, plusieurs patients KPro souffrent de glaucome qui progresse, parfois sans PIO élevée. Les cytokines inflammatoires jouent un rôle dans la pathophysiologie du glaucome, mais leur rôle dans le glaucome associé à la KPro est inconnu. En analysant les larmes de patients KPro (papier V), nous avons identifié que les cytokines TNF‐a, IL‐1b, FGF‐basic et IFN‐g sont élevées chez les patients KPro avec glaucome comparé à ceux sans glaucome. Ces cytokines corrèlent avec l'excavation du nerf optique et la PIO. Pour la première fois chez les humains, ces résultats concordent avec les niveaux élevés de TNF‐a et IL‐1b documentés dans le modèle murin de KPro. L'inflammation de la surface oculaire pourrait donc refléter les processus inflammatoires qui perpétuent le dommage glaucomateux. Cinquièmement, nous avons déterminé que l'implantation de la KPro miniature chez la souris requiert beaucoup de pratique pour être utilisé comme modèle de glaucome post‐KPro (papier VI). Des modèles animaux avec des yeux plus larges et une excision cornéenne de pleine épaisseur sur 360 degrés devraient être priorisés pour valider les résultats chez l'humain. En conclusion, le glaucome associé à la KPro est un processus multifactoriel qui persiste à long terme. Les mécanismes probables combinent l'inflammation médiée par TNF‐a et IL‐1b et une fermeture de l'angle qui augmente la PIO. Nos résultats contribuent à établir les facteurs de risque de glaucome pour les receveurs de KPro, à améliorer leur prise en charge et à développer des thérapies ciblées. Ce travail a le potentiel de préserver la vision de milliers de patients recevant une KPro chaque année dans le monde et d'aider à mieux comprendre le rôle de l'inflammation dans d'autres maladies avec atteinte neuronale. [ABSTRACT FROM AUTHOR]

CdWO4 as one of the metal tungstate family has recently been identified as a strong photocatalyst for the degradation of organic pollutants. Several methods for the synthesis of different CdWO4 forms have been introduced. All these techniques, however, are either costly or environmentally harmful and create tremendous toxic waste. CdWO4 nanorods (NRs) are synthesized using a simple eco‐friendly method, in which for the first time hyphaene thebaica fruit extract is utilized as a reaction stabilizer, as well as the compounds of the extract serve in functionalizing the CdWO4 NRs surface, water is used as a solvent without elevated temperatures involved. The synthesized NRs' size, structure, morphology, and optical properties are characterized using TEM, XRD, UV‐visible absorption, and Raman spectroscopy techniques. The results demonstrate the successful synthesis of CdWO4 NRs with an average diameter of 40 nm and length of 100 nm. The CdWO4 NRs have high crystallinity, and exhibit absorption in the UV light region. As well, the photocatalytic activities of the as‐synthesized CdWO4 NRs are investigated under UV irradiation, in which Methylene Blue (MB) is used as a model for an organic pollutant. The degradation efficiency of CdWO4 NRs is shown to be 99 % after 90 minutes. The CdWO4 NRs significantly enhance the absorption of light and increase the rate of degradation of MB and the generation and separation of photoinduced charges (i. e. the exciton lifetime). The CdWO4 NRs showed a high‐level degradation rate of MB, as it is fitted with the first‐order kinetic model, this proves that the CdWO4 NRs can have a great potential for the elimination of organic contaminants, and for the treatment of wastewater as a photocatalyst. Moreover, the as‐synthesized CdWO4 NRs can be used in different environmental applications. [ABSTRACT FROM AUTHOR]

Intense research efforts over the last two decades have renewed our understanding of plant phylogeography and domestication in the Mediterranean basin. Here we aim to investigate the evolutionary history and the origin of domestication of the carob tree (Ceratonia siliqua), which has been cultivated for millennia for food and fodder. We used >1000 microsatellite genotypes to delimit seven carob evolutionary units (CEUs). We investigated genome‐wide diversity and evolutionary patterns of the CEUs with 3557 single nucleotide polymorphisms generated by restriction‐site associated DNA sequencing (RADseq). To address the complex wild vs. cultivated status of sampled trees, we classified 56 sampled populations across the Mediterranean basin as wild, seminatural or cultivated. Nuclear and cytoplasmic loci were identified from RADseq data and separated for analyses. Phylogenetic analyses of these genomic‐wide data allowed us to resolve west‐to‐east expansions from a single long‐term refugium probably located in the foothills of the High Atlas Mountains near the Atlantic coast. Our findings support multiple origins of domestication with a low impact on the genetic diversity at range‐wide level. The carob was mostly domesticated from locally selected wild genotypes and scattered long‐distance westward dispersals of domesticated varieties by humans, concomitant with major historical migrations by Romans, Greeks and Arabs. Ex situ efforts to preserve carob genetic resources should prioritize accessions from both western and eastern populations, with emphasis on the most differentiated CEUs situated in southwest Morocco, south Spain and eastern Mediterranean. Our study highlights the relevance of wild and seminatural habitats in the conservation of genetic resources for cultivated trees. [ABSTRACT FROM AUTHOR]

Aims: Cryoballoon‐guided pulmonary vein isolation (CB‐PVI) for symptomatic atrial fibrillation (AF) has become an established treatment option with encouraging results in terms of safety and efficacy. Data reporting on long‐term data beyond a follow‐up (FU) period of 5 years is scarce. This prospective study aimed to evaluate very long‐term outcome after CB‐PVI for AF. Methods: Data from consecutive patients treated with CB‐PVI for symptomatic and drug refractory AF between 2005 and 2012 were analyzed. Patients with a FU of ≥9 years after index CB‐PVI were included. All patients were continuously followed‐up in our outpatient clinic. Arrhythmia recurrence was defined as AF or atrial tachycardia (AT) lasting >30 s beyond a 3‐month blanking period. Results: A total of 385 patients (71% male) were included. Mean age was 58 ± 10 years and paroxysmal AF was present in 93% of patients. Mean FU duration was 124 ± 24 months. At the end of the observational period, 73% of all patients were in stable sinus rhythm after a mean of 2 ± 0.8 ablation procedures. Patients with AF/AT recurrence were older (60 ± 8 vs. 57 ± 10 years; p =.019), had a higher CHA2DS2‐Vasc Score (2.47 ± 1.46 vs. 1.98 ± 1.50; p =.01) and presented with a larger left atrium (LA)‐diameter (43 ± 5.6 vs. 40 ± 5.1 mm; p =.002). The LA‐diameter was also a significant predictor for AF/AT recurrence after CB‐PVI (odds ratio: 0.939, 95% confidence interval: [0.886, 0.992], p =.03). Conclusions: CB‐PVI as index procedure for AF ablation resulted in favorable long‐term outcome in symptomatic AF. CB‐PVI might be recommended as interventional therapy in patients with lower LA remodeling. HIGHLIGHTS: The follow‐up duration of 10 years is the longest present until to dateLong‐term arrhythmia free survival after a single cryoballoon PVI was highQuality of life is improved even 10 years after a single cryoballoon PVIRepeat cryoballoon PVI showed similiar outcome compared to RF‐based repeat PVI [ABSTRACT FROM AUTHOR]

Gasoline exposure has been widely reported in the literature as being toxic to human health. However, the exact underlying molecular mechanisms triggered by its inhalation have not been thoroughly investigated. We herein present a model of sub‐chronic, static gasoline vapor inhalation in adult female C57BL/6 mice. Animals were exposed daily to either gasoline vapors (0.86 g/animal/90 min) or ambient air for 5 days/week over 7 consecutive weeks. At the end of the study period, toxic and molecular mechanisms underlying the inflammatory, oxidative, and apoptotic effects triggered by gasoline vapors, were examined in the lungs and liver of gasoline‐exposed (GE) mice. Static gasoline exposure induced a significant increase (+21%) in lungs/body weight (BW) ratio in GE versus control (CON) mice along with a pulmonary inflammation attested by histological staining. The latter was consistent with increases in the transcript levels of proinflammatory cytokines [Interleukins (ILs) 4 and 6], respectively by ~ 6‐ and 4‐fold in the lungs of GE mice compared to CON. Interestingly, IL‐10 expression was also increased by ~ 10‐fold in the lungs of GE mice suggesting an attempt to counterbalance the established inflammation. Moreover, the pulmonary expression of IL‐12 and TNF‐α was downregulated by 2‐ and 4‐fold, respectively, suggesting the skewing toward Th2 phenotype. Additionally, GE mice showed a significant upregulation in Bax/Bcl‐2 ratio, caspases 3, 8, and 9 with no change in JNK expression in the lungs, suggesting the activation of both intrinsic and extrinsic apoptotic pathways. Static gasoline exposure over seven consecutive weeks had a minor hepatic portal inflammation attested by H&E staining along with an increase in the hepatic expression of the mitochondrial complexes in GE mice. Therefore, tissue damage biomarkers highlight the health risks associated with vapor exposure and may present potential therapeutic targets for recovery from gasoline intoxication. Gasoline exposure triggers pulmonary and hepatic inflammation in gasoline‐exposed versus control mice. Gasoline inhalation leads to an increase in interleukins 4, 6, and 10 mRNA levels and a decrease in IL‐12 and TNF‐α, suggesting the skewing toward Th2 phenotype. Gasoline exposure leads to the activation of both intrinsic and extrinsic apoptotic pathways. [ABSTRACT FROM AUTHOR]

Summary: Reactive oxygen species (ROS) release seed dormancy through an unknown mechanism. We used different seed dormancy‐breaking treatments to decipher the dynamics and localization of ROS production during seed germination.We studied the involvement of ROS in the breaking of Arabidopsis seed dormancy by cold stratification, gibberellic acid (GA3) and light. We characterized the effects of these treatments on abscisic acid and gibberellins biosynthesis and signalling pathways. ROS, mitochondrial redox status and peroxisomes were visualized and/or quantified during seed imbibition. Finally, we performed a cytogenetic characterization of the nuclei from the embryonic axes during seed germination.We show that mitochondria participate in the early ROS production during seed imbibition and that a possible involvement of peroxisomes in later stages should still be analysed. At the time of radicle protrusion, ROS accumulated within the nucleus, which correlated with nuclear expansion and chromatin decompaction.Taken together, our results provide evidence of the role of ROS trafficking between organelles and of the nuclear redox status in the regulation of seed germination by dormancy. [ABSTRACT FROM AUTHOR]

Microbes have developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme‐containing tetramer expressed in a broad range of aerobic fungi, shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal survival and host invasion. Here, it is demonstrated that catalase inactivation by blue light renders fungal cells highly susceptible to ROS attack. To confirm catalase as a major molecular target of blue light, wild type Candida albicans are systematically compared with a catalase‐deficient mutant strain regarding their susceptibility to ROS through 410 nm treatment. Upon testing a wide range of fungal species, it is found that intracellular catalase can be effectively and universally inactivated by 410 nm blue light. It is also found that photoinactivation of catalase in combination with ROS‐generating agents is highly effective in total eradication of various fungal species, including multiple Candida auris strains, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a C. albicans‐induced mouse model of skin abrasion. Taken together, the findings offer a novel catalase‐photoinactivation approach to address multidrug‐resistant Candida infections. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to translate, adapt and validate in French the Ankle Ligament Reconstruction - Return to Sport after Injury (ALR-RSI), a 12-item English language scale assessing the psychological impact of returning to sports after ACL reconstruction. Our hypothesis was that the French version of the ALR-RSI scale would be valid and adaptable to the French population. Methods: The procedure followed the guidelines for the intercultural adaptation of the self-administered questionnaires. A version of the ALR-RSI-Fr questionnaire was validated according to the international guidelines of COSMIN (COnsensus-based Standards for the selection of health status Measurement INstruments). A prospective study was conducted between March 2020 and June 2021. The study included two population groups, the first one being that of adult athletes of all levels who underwent arthroscopic ankle ligament reconstruction and the second being that of adult athletes who did not suffer from any ankle problems. After consent, patients completed three questionnaires, the ALR-RSI-Fr, the AOFAS and the Karlsson score. Results: The study included 30 patients and 30 controls who were all athletes. The mean age of the patients was 34.6 with 60% male and 40% female. The average time for patients to return to sport was 5.6 months. Twenty-nine patients (96.6%) underwent arthroscopic ankle reconstruction while only one was eligible for ligament reinsertion. The control group with demographic data matched to the patient group was included in this study. Correlations between ALRSI, the total Karlsson score and its different sub items and the AOFAS were estimated using Spearman coefficients. Discriminant validity was tested between the "patient" and "control" groups and sub-groups using the Wilcoxon tests. Reliability was evaluated on the ρ intraclass correlation coefficient (ICCC). A strong correlation was noted between the ALR-RSI-Fr , Karlsson and AOFAS with a Spearman score of 0.90 [0.76-0.96].A highly significant difference was found between the "patient" and "control" groups. The internal consistency of the questionnaire was excellent with a Cronbach's alfa of 0.94. Reproducibility was "excellent" with an interclass correlation coefficient of q = 0.97 [0.94-0.99]. Conclusion: This study showed that the cross-cultural adaptation of the English version of the ALR-RSI was successful and validated for the French-speaking population. The discriminant capacity of the scale between patients who underwent reconstruction and healthy subjects was also confirmed. This questionnaire will allow surgeons to better evaluate the psychological impact of returning to sports after ankle ligament reconstruction in French speaking patients Level of evidence: LEVEL II: Prospective cohort study (patients enrolled at different points in their disease) Control arm of randomized trial. [ABSTRACT FROM AUTHOR]

Stimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine‐related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d‐amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue‐induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue‐induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS‐11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d‐amphetamine did not augment the cue‐induced activations, but, in cocaine users, drug cue‐induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems. [ABSTRACT FROM AUTHOR]

Background: Connections among brain regions allow pathological perturbations to spread from a single source node to multiple nodes. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the network architecture (Seeley et al., 2009, Neuron), but how bvFTD‐related atrophy patterns relate to the network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture, such that connected regions display similar atrophy patterns. Method: Deformation‐based morphometry (DBM) was used to estimate regional changes in tissue volume density from T1‐weighted magnetic resonance images of 75 genetic bvFTD patients and 247 healthy controls (GENFI, http://genfi.org.uk/). We used linear mixed effects model to obtain a bvFTD‐related atrophy map, controlling for age, sex and aquision site. Structural and functional connectivity (SC and FC), derived from an independent sample of 70 healthy participants (Griffa et al., 2019, Zenodo), were used to estimate mean neighbor atrophy values of each region. Relationship between node and neighbor atrophy was examined by correlating neighbor atrophy with nodal atrophy. Statistical significance of the analyses was assessed using a spatial autocorrelation‐preserving null model. Analyses were replicated in an independent dataset (FTLDNI, AG032306) with 70 sporadic bvFTD patients and 123 healthy controls. Result: Distributed atrophy patterns were observed in bvFTD, mainly targeting areas associated with limbic intrinsic network and insular cytoarchitectonic class (Fig 1a). A node’s atrophy was significantly correlated with atrophy of its connected neighbors (e.g. high resolution: r=0.58, p=0.006 and r=0.54, p=0.0006, for SC‐ and FC‐ defined neighbors respectively) (Fig 2c). Relationship between node and neighbor atrophy was consistent across resolutions and greater in empirical networks compared to null networks. While a number of frontotemporal regions were identified as potential disease epicenters, anterior insula was the most likely one. Results were consistent in the sporadic cohort (Fig 1b&2d). Conclusion: Using connectivity models and rigorous statistical analyses that account for spatial autocorrelation, we demonstrate that bvFTD‐related neurodegeneration is conditioned by connectome architecture, accounting for 30‐40% of variance in atrophy. Atrophy is most profound in regions associated with insular cortex. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) recurrence after catheter ablation is associated with worse outcomes and quality of life. Left atrial (LA) structural remodeling provides the essential substrate for AF perpetuation. Baseline extent and the progression of LA fibrosis after ablation are strong predictors of postprocedural AF recurrence. Dronedarone is an antiarrhythmic drug proven to efficiently maintain sinus rhythm. Objective: We sought to investigate the effect of the antiarrhythmic drug Dronedarone in decreasing LA fibrosis progression and AF recurrence after ablation of AF patients. Methods: EDORA (NCT04704050) is a multicenter, prospective, randomized controlled clinical trial. Patients with persistent or paroxysmal AF undergoing AF ablation will be randomized into Dronedarone versus placebo/standard of care. The co‐primary outcomes are the recurrence of atrial arrhythmias (AA) within 13 months of follow‐up after ablation and the progression of left atrial fibrosis postablation. All patients will receive a late‐gadolinium enhancement magnetic resonance imaging at baseline, 3‐ and 12‐month follow‐up for the quantification of LA fibrosis and ablation‐related scarring. AA recurrence and burden will be assessed using a 30‐day ECG patch every 3 months with daily ECG recordings in between. Quality of life improvement is assessed using the AFEQT and AFSS questionnaires. Conclusion: EDORA will be the first trial to assess the progression of LA structural remodeling after ablation and its association with Dronedarone treatment and ablation success in a randomized controlled fashion. The trial will provide insight into the pathophysiology of AF recurrence after ablation and may provide potential therapeutic targets to optimize procedural outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Outcomes from Staphylococcus aureus bacteremia (SAB) in solid organ transplant (SOT) recipients are poorly understood. Methods: This is a prospective cohort study comparing the bacterial genotype and clinical outcomes of SAB among SOT and non‐transplant (non‐SOT) recipients from 2005 to 2019. Each subject's initial S. aureus bloodstream isolate was genotyped using spa typing and assigned to a clonal complex. Results: A total of 103 SOT and 1783 non‐SOT recipients with SAB were included. Bacterial genotype did not differ significantly between SOT and non‐SOT recipients (p =.4673), including the proportion of SAB caused by USA300 (13.2% vs. 16.0%, p =.2680). Transplant status was not significantly associated with 90‐day mortality (18.4% vs. 29.5%; adjusted odds ratio [aOR] 0.74; 95% confidence interval [CI]: 0.44, 1.25), but was associated with increased risk for septic shock (50.0% vs. 21.8%; aOR 2.31; 95% CI: 1.48, 3.61) and acute respiratory distress syndrome (21.4% vs. 13.7%; aOR 2.03; 95% CI: 1.22, 3.37), and a significantly lower risk of metastatic complications (33.0% vs. 45.5%; aOR 0.49; 95% CI: 0.32, 0.76). No association was found between bacterial genotype and 90‐day mortality (p =.6222) or septic shock (p =.5080) in SOT recipients with SAB. Conclusions: SOT recipients with SAB do not experience greater mortality than non‐SOT recipients. The genotype of S. aureus bloodstream isolates in SOT recipients is similar to that of non‐SOT recipients, and does not appear to be an important determinant of outcome in SOT recipients with SAB. [ABSTRACT FROM AUTHOR]

Background: The Multinational Association for Supportive Care in Cancer (MASCC) risk index has been utilized to determine the risk for poor clinical outcomes in patients with febrile neutropenia (FN) in an emergency center (EC). However, this index comprises subjective elements and elaborated metrics limiting its use in ECs. We sought to determine whether procalcitonin (PCT) level (biomarker of bacterial infection) with or without lactate level (marker of inadequate tissue perfusion) offers a potential alternative to MASSC score in predicting the outcomes of patients with FN presenting to an EC. Methods: We retrospectively identified 550 cancer patients with FN who presented to our EC between April 2018, and April 2019, and had serum PCT and lactate levels measured. Results: Compared with patients with PCT levels <0.25 ng/ml, those with levels ≥0.25 ng/ml had a significantly higher 14‐day mortality rate (5.2% vs. 0.7%; p = 0.002), a higher bloodstream infection (BSI) rate, and a longer hospital length of stay (LOS). Logistic regression analysis showed that patients with PCT levels ≥0.25 ng/ml and lactate levels >2.2 mmol/L were more likely to be admitted and have an LOS >7 days, BSI, and 14‐day mortality than patients with lower levels. PCT level was a significantly better predictor of BSI than MASSC score (p = 0.003) or lactate level (p < 0.0001). Conclusions: Procalcitonin level is superior to MASCC index in predicting BSI. The combination of PCT and lactate levels is a good predictor of BSI, hospital admission, and 14‐day mortality and could be useful in identifying high‐risk FN patients who require hospital admission. [ABSTRACT FROM AUTHOR]

Self‐reported maternal prenatal stress (MPS) has been associated with earlier febrile seizure (FS) age of onset in offspring. Studies are needed to understand how the biological systems associated with exposure to psychological MPS are linked to seizure disorders in children. The present study aimed to investigate whether placental markers of MPS are linked to FS incidence and age at first occurrence. A subsample of children with FS (n = 28) and matched controls (n = 84), were drawn from the longitudinal 3D pregnancy cohort (N = 2366 mother–child dyads). Expression of placental genes associated with glucocorticoids, serotonin and fetal/placental growth were analysed from placental tissues, compared between groups and associated with age at first FS. Overall placental normalized gene expression was statistically different (p <.001). Children with FS showed overexpression of the serotonin transporter (mean difference = 0.61, 95% confidence interval [CI] = 0.9–1.13), connexin 43 (mean difference = 0.69, 95% CI = 0.30–1.09), zonula occludens‐1 (mean difference = 0.84, 95% CI = 0.42–1.26) and underexpression of glucocorticoid receptor β (mean difference = 0.84, 95% CI = −1.49 to 0.19) and serotonin receptor 2B (mean difference = 1.57, 95% CI = −2.35 to 0.78) compared to controls. Increased expression of the serotonin transporter predicted 37.2% in variation of age at first FS. The correlation matrix showed pregnancy‐specific anxiety during the second trimester was moderately associated with age at first FS (r = −0.38) but was not a significant predictor in the regression model. Although our current results do not display a significant effect of self‐reported MPS on FS, the present study is the first to show that placental gene biomarkers usually known to be associated with MPS display different expressions in children with FS. Specifically, our results suggest that placental genes associated with the glucocorticoid, serotonergic and fetal/placental growth systems may be candidate mechanisms leading to increased vulnerability offspring in FS. Because self‐reported MPS was not found as a significant predictor in our statistical models, future studies are needed to investigate the mechanisms causing the observed changes in placental genes and their association with seizure disorders. [ABSTRACT FROM AUTHOR]

The Fracture Risk Assessment Tool (FRAX) is the most widely used tool for fracture prediction. It provides 10‐year probabilities for hip and major osteoporotic fracture (MOF). It uses country‐specific hip fracture incidence and life expectancy data, and for most countries, MOF/hip fracture incidence rate ratios (IRRs) from Malmo Sweden. However, the risk of MOF varies by age, sex, and geography. The objective is to compare the MOF/hip IRRs across countries, by sex and age. This systematic review targeted observational studies of MOF and hip fractures in individuals >50 years (PROSPERO 2019 CRD42019129259). One reviewer screened potential articles. Two reviewers completed duplicate and independent data abstraction, and assessed study quality based on population representativeness, study design and duration, definition of ethnicity, and fracture characteristics. We calculated the MOF/hip IRRs (95% confidence interval) and Z‐values to compare IRRs in various countries to those for Sweden. We included 27 studies, of fair to good quality in the majority, from Europe (15), US and Canada (7), Asia (3), and Australia (2). The IRRs were twofold to 10‐fold higher in younger compared to older age categories, and in women compared to men, with few exceptions. Within Europe, and using Sweden as a reference, MOF/Hip IRRs in women 50–54 years from Finland, Italy, Netherlands, Denmark, and UK were significantly lower by 38% to 60%. Findings were similar in men. At older ages, MOF/Hip IRRs were consistently lower in women from European countries compared to Sweden, by 10%–40% and 11%–51%, at 75–79 years and 85–89 years, respectively. Findings were heterogenous in men and in non‐European countries. In conclusion, the MOF/hip fracture IRR may vary between countries. The variability at older ages may affect FRAX prediction when country‐specific fracture IRRs are not used. Further research is needed to elucidate the implication of our findings to FRAX‐derived MOF estimates in various countries. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Brain asymmetry reflects left‐right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega‐analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance‐general and substance‐specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence. [ABSTRACT FROM AUTHOR]

Background: Unexpected high levels of atrial fibrosis are found in individuals with no history of atrial fibrillation (AF). The temporal behavior of atrial fibrosis in this population is still unknown. We sought to investigate the progression and predictors of atrial fibrosis in non‐AF individuals. Methods: Non‐AF individuals at baseline who underwent late gadolinium enhancement magnetic resonance imaging (LGE‐MRI) for assessment of left atrial (LA) fibrosis at least twice were retrospectively included in this study. The incidence of AF was assessed using review of medical records. Results: In 42 non‐AF patients (15 females, 65.9 ± 8.6 years old), all patients had a detectable level of LA fibrosis at baseline, ranging from 4.5% to 28.8%, with a mean of 12.9 ± 5.9%. LA fibrosis in the second LGE‐MRI was significantly higher in all patients compared to the first measurement (mean value of 12.9 ± 5.9% vs. 17.34 ± 6.8%; p <.05). Congestive heart failure was a significant clinical predictor of atrial fibrosis progression. The seven patients (16.6%) who developed new‐onset AF during follow‐up showed a significantly higher degree of LA fibrosis on their second MRI, compared to individuals who stayed in sinus rhythm (20.5 ± 6.9% vs. 16.7 ± 6.7%, p <.05). Conclusion: Atrial fibrotic remodeling is a dynamic process that is progressively increasing in non‐AF patients, accentuated by congestive heart failure. The higher extent of LA remodeling observed in patients who developed AF could highlight either the fact that AF is an expression of a highly dynamic left atrial substrate, or that remodeling processes are accelerated by AF. [ABSTRACT FROM AUTHOR]

Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). Objectives: We aimed to conduct an exome‐wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole‐exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. Results: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24–6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49–13.07, P = 0.005). Similar results were obtained after including only genetically‐undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05–365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7‐interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Conclusions: Our results provide evidence for complex inheritance in SPG7‐associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Specific details about cardiovascular complications, especially arrhythmias, related to the coronavirus disease of 2019 (COVID‐19) are not well described. Objective: We sought to evaluate the incidence and predictive factors of cardiovascular complications and new‐onset arrhythmias in Black and White hospitalized COVID‐19 patients and determine the impact of new‐onset arrhythmia on outcomes. Methods: We collected and analyzed baseline demographic and clinical data from COVID‐19 patients hospitalized at the Tulane Medical Center in New Orleans, Louisiana, between March 1 and May 1, 2020. Results: Among 310 hospitalized COVID‐19 patients, the mean age was 61.4 ± 16.5 years, with 58,7% females, and 67% Black patients. Black patients were more likely to be younger, have diabetes and obesity. The incidence of cardiac complications was 20%, with 9% of patients having new‐onset arrhythmia. There was no significant difference in cardiovascular outcomes between Black and White patients. A multivariate analysis determined age ≥60 years to be a predictor of new‐onset arrhythmia (OR = 7.36, 95% CI [1.95;27.76], p =.003). D‐dimer levels positively correlated with cardiac and new‐onset arrhythmic event. New onset atrial arrhythmias predicted in‐hospital mortality (OR = 2.99 95% CI [1.35;6.63], p =.007), a longer intensive care unit length of stay (mean of 6.14 days, 95% CI [2.51;9.77], p =.001) and mechanical ventilation duration(mean of 9.08 days, 95% CI [3.75;14.40], p =.001). Conclusion: Our results indicate that new onset atrial arrhythmias are commonly encountered in COVID‐19 patients and can predict in‐hospital mortality. Early elevation in D‐dimer in COVID‐19 patients is a significant predictor of new onset arrhythmias. Our finding suggest continuous rhythm monitoring should be adopted in this patient population during hospitalization to better risk stratify hospitalized patients and prompt earlier intervention. [ABSTRACT FROM AUTHOR]

Introduction: Success rates of catheter ablation in persistent atrial fibrillation (AF) remain suboptimal. A better and more targeted ablation strategy is urgently needed to optimize outcomes of AF treatment. We sought to assess the safety and efficacy of targeting atrial fibrosis during ablation of persistent AF patients in improving procedural outcomes. Methods: The DECAAF II trial (ClinicalTrials. gov identifier number NCT02529319) is a prospective, randomized, multicenter trial of patients with persistent AF. Patients with persistent AF undergoing a first‐time ablation procedure were randomized in a 1:1 fashion to receive conventional pulmonary vein isolation (PVI) ablation (Group 1) or PVI + fibrosis‐guided ablation (Group 2). Left atrial fibrosis and ablation induced scarring were defined by late gadolinium enhancement magnetic resonance imaging at baseline and at 3–12 months postablation, respectively. The primary endpoint is the recurrence of atrial arrhythmia postablation, including atrial fibrillation, atrial flutter, or atrial tachycardia after the 90‐day postablation blanking period. Patients were followed for a period of 12–18 months with a smartphone ECG Device (ECG Check Device, Cardiac Designs Inc.). With an anticipated enrollment of 900 patients, this study has an 80% power to detect a 26% reduction in the hazard ratio of the primary endpoint. Results and Conclusion: The DECAAF II trial is the first prospective, randomized, multicenter trial of patients with persistent AF using imaging defined atrial fibrosis as a treatment target. The trial will help define an optimal approach to catheter ablation of persistent AF, further our understanding of influencers of ablation lesion formation, and refine selection criteria for ablation based on atrial myopathy burden. [ABSTRACT FROM AUTHOR]

The recent financial and economic meltdown in Lebanon is the result of 30 years of social, economic, financial, and fiscal mismanagement, amplified by the Covid‐19 pandemic and further exacerbated by the Beirut port explosion. Lebanese citizens' trust, as well as the international community's trust in the government, have unfortunately been destroyed. Consequently, Lebanon's sole option is to rebuild confidence in the government and public institutions by implementing economic reforms and to seek an IMF program to pave the way for additional financing from other international sources. The most important confidence‐building step is a clear financial and economic plan that has the support of all key stakeholders. This article presents a road map for a reforms‐driven, export‐led growth strategy for Lebanon. Ultimately, the goal is to jump‐start the economy and put it on a path of sustainable, inclusive, and equitable economic growth. Such growth should be grounded in a small, open‐economy model and driven by low tariffs, a flexible exchange rate regime, and a dynamic export sector built on competitive and comparative advantages. This plan partially builds on proposals and recommendations provided by previous economic plans and policy notes. [ABSTRACT FROM AUTHOR]

Numerous studies have described the prognostic factors of canine and feline mammary carcinomas (MCs), that is, variables that predict patient survival after diagnosis. But how does survival estimation evolve in patients that escaped early death from their cancer? In human oncology, conditional survival (CS), the probability of surviving X further years when cancer patients have already survived Y years, is used to analyse cancer outcomes in a long‐term perspective. In this cohort of 344 dogs and 342 cats with surgically removed stage I to III invasive MCs, with a minimal follow‐up of 2 years, we calculated the 1‐year CS, that is, the probability for patients that have survived 1 year, to survive or to die from cancer during the subsequent year. The 1‐year conditional specific survival probabilities were 59% and 48% at diagnosis of invasive MC respectively in dogs and cats, and 80% and 52% in 1‐year surviving dogs and cats respectively, suggesting that 1‐year surviving dogs were relatively protected from cancer‐related death, whereas feline MCs remained life‐threatening cancers for longer periods of time. Among the most significant parameters associated with CS in surviving dogs and cats were the nodal stage and lymphovascular invasion, as well as patient age, cancer stage and margin status in surviving dogs. By comparison, tumour size and the histological grade did not significantly alter CS probabilities in surviving dogs and cats. Conditional survival may be considered a very interesting tool for veterinary practitioners to estimate the likely outcome of cancer survivors. [ABSTRACT FROM AUTHOR]

Objective: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD.Methods: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD.Results: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD.Interpretation: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357. [ABSTRACT FROM AUTHOR]

Motivation theories of obesity suggest that one of the brain mechanisms underlying pathological eating and weight gain is the dysregulation of dopaminergic circuits. Although these dysregulations likely occur at the microscopic level, studies on grey matter volume report macroscopic differences associated with obesity. One region suggested to play a key role in the pathophysiology of obesity is the nucleus accumbens (NAcc). We performed a meta‐analysis of findings regarding NAcc volume and overweight/obesity. We additionally examined whether grey matter volume in the NAcc and other mesolimbic areas depends on the longitudinal trajectory of obesity, using the UK Biobank dataset. To this end, we analysed the data using a latent growth model, which identifies whether a certain variable of interest (eg, NAcc volume) is related to another variable's (body mass index [BMI]) initial values or longitudinal trajectories. Our meta‐analysis showed that, overall, NAcc volume is positively related to BMI. However, further analyses revealed that the relationship between NAcc volume and BMI is dependent on age. For younger individuals, such a relationship is positive, whereas, for older adults, it is negative. This was corroborated by our analysis in the UK Biobank dataset, which includes older adults, where we found that a higher BMI was associated with a lower NAcc and thalamus volume. Overall, the present study suggests that increased NAcc volume at a young age might be a vulnerability factor for obesity, whereas, at an older age, decreased NAcc volume with increased BMI might be an effect of prolonged influences of neuroinflammation on the brain. [ABSTRACT FROM AUTHOR]

Dysregulated neural mechanisms in reward and somatosensory circuits result in an increased appetitive drive for and reduced inhibitory control of eating, which in turn causes obesity. Despite many studies investigating the brain mechanisms of obesity, the role of macroscale whole‐brain functional connectivity remains poorly understood. Here, we identified a neuroimaging‐based functional connectivity pattern associated with obesity phenotypes by using functional connectivity analysis combined with machine learning in a large‐scale (n ~ 2,400) dataset spanning four independent cohorts. We found that brain regions containing the reward circuit positively associated with obesity phenotypes, while brain regions for sensory processing showed negative associations. Our study introduces a novel perspective for understanding how the whole‐brain functional connectivity correlates with obesity phenotypes. Furthermore, we demonstrated the generalizability of our findings by correlating the functional connectivity pattern with obesity phenotypes in three independent datasets containing subjects of multiple ages and ethnicities. Our findings suggest that obesity phenotypes can be understood in terms of macroscale whole‐brain functional connectivity and have important implications for the obesity neuroimaging community. [ABSTRACT FROM AUTHOR]

Introduction: Cryoballoon (CB)‐guided ablation of atrial fibrillation (AF) is established in symptomatic AF patients. This study sought to determine the safety and efficacy of CB pulmonary vein isolation (PVI) in young adults. Methods and Results: A total of 93 consecutive patients aged <45 years referred to our center for AF ablation were included in this observational study. All patients received CB‐guided PVI according to a standardized institutional protocol. Follow‐up was performed in our outpatient clinic using 72‐h Holter monitoring and periodic telephone interview. Recurrence was defined as any AF/atrial tachycardia (AT) episode >30 s following a 3‐month blanking period. A propensity matched control group consisting of patients older than 45 years were used for further evaluation. Mean age was 35 ± 7 years, 22% suffered from persistent AF, 85% were male. Mean follow‐up was 2.6 ± 2 years. At the end of the observational period, 83% of patients were free of any AF/AT episodes. There was an excellent overall 12‐month success rate of 92%. In comparison to a matched group the overall recurrence rate was noticeably lower in the young group (15% vs. 27%). Increasing age was associated with a hazard ratio of 1.16 for recurrence. In a multivariate analysis model, left atrial diameter remained as significant predictor of AF/AT recurrence. The complication rate was low, no permanent phrenic nerve palsy was observed. Conclusion: CB‐guided PVI in young adults is safe and effective with favorable long‐term results. It may be considered as first‐line therapy in this relatively healthy population. [ABSTRACT FROM AUTHOR]

Seawater desalination is used to satisfy water needs in many countries worldwide. Disinfection is used during desalination process to avoid microbiological regrowth and biofouling. The disinfectant reacts with natural organic matter and inorganic compounds (e.g. Fe2+, Mn2+, S2−, bromide, iodide, etc.) leading to the formation of disinfection by‐products (DBPs) in desalinated water. The DBPs represent a great threat to human health due to their possible cancer and non‐cancer risks. In this work, the occurrence of DBPs in desalinated water and total organic carbon (TOC), and total organic halogen (TOX) levels were monitored. Since the water characteristics play a key role in determining the type and quantity of generated DBPs, the inorganic parameters were measured as well. The measured values of selected regulated DBPs compounds, trihalomethanes (THMs) and haloacetic acids (HAAs) were found far below the regulatory limits of Egypt, USEPA and WHO. [ABSTRACT FROM AUTHOR]

Mycophenolic acid (MPA) is an immunosuppressant commonly used to prevent renal transplant rejection and treat glomerulonephritis. MPA inhibits IMPDH2 within stimulated lymphocytes, reducing guanosine synthesis. Despite the widespread use of MPA, interindividual variability in response remains with rates of allograft rejection up to 15% and approximately half of individuals fail to achieve complete remission to lupus nephritis. We sought to identify contributors to interindividual variability in MPA response, hypothesizing that the HPRT1 salvage guanosine synthesis contributes to variability. MPA sensitivity was measured in 40 healthy individuals using an ex vivo lymphocyte viability assay. Measurement of candidate gene expression (n ± 40) and single‐cell RNA‐sequencing (n ± 6) in lymphocytes was performed at baseline, poststimulation, and post‐MPA treatment. After stimulation, HPRT1 expression was 2.1‐fold higher in resistant individuals compared with sensitive individuals (P ± 0.049). Knockdown of HPRT1 increased MPA sensitivity (12%; P ± 0.003), consistent with higher expression levels in resistant individuals. Sensitive individuals had higher IMPDH2 expression and 132% greater stimulation. In lymphocyte subpopulations, differentially expressed genes between sensitive and resistant individuals included KLF2 and LTB. Knockdown of KLF2 and LTB aligned with the predicted direction of effect on proliferation. In sensitive individuals, more frequent receptor‐ligand interactions were observed after stimulation (P ± 0.0004), but fewer interactions remained after MPA treatment (P ± 0.0014). These data identify a polygenic transcriptomic signature in lymphocyte subpopulations predictive of MPA response. The degree of lymphocyte stimulation, HPRT1, KLF2, and LTB expression may serve as markers of MPA efficacy. [ABSTRACT FROM AUTHOR]

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures. [ABSTRACT FROM AUTHOR]

In cats, assessment of the testicular function is mainly based on sperm evaluation. Whatever the technique used, the volume of collected sperm is often small, which may lead to technical difficulties to achieve the semen evaluation in routine practice. Fine‐needle aspiration (FNA) biopsy of the testicular parenchyma is one of the other methods used to assess testicular function. The aim of this study was to explore the relevance of FNA in the assessment of testicular cells in sexually mature cats. Eighteen cats over one year of age were recruited among animals presented for surgical neutering. Semen was collected by electroejaculation before it was evaluated. FNA biopsies of the testicles were taken using a 21‐gauge needle. After castration, histological analysis of the testes was performed. Semen evaluation and histological analysis showed no anomalies, which confirmed normal spermatogenesis in all the cats and allowed a proper interpretation of the cytological findings. The cells identified through cytological examination were spermatogonia (1.99 ± 0.17%), primary spermatocytes (10.49 ± 0.74%), round spermatids (34.80 ± 1.57%), elongated spermatids (23.59 ± 2.02%), spermatozoa (21.56 ± 1.86%), Sertoli cells (7.53 ± 1.23%) and Leydig cells (0.04 ± 0.03%). However, spermatocytes II were not identified. This is due to the low proportions of these cells, related to their very short lifespan. Likewise, the very low number of Leydig cells observed is probably due to the damage caused during the aspiration stage. This study showed that fine‐needle aspiration is an efficient method to describe cytologically normal testicular populations, a cornerstone for future research aimed to study abnormal spermatogenesis and to correlate it to cytological proportion of germ cells. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease (PD) present with a broad spectrum of nonmotor features including autonomic disorders. More severe autonomic dysfunction in PD is associated with increased cognitive deficits. The presence of cerebral small‐vessel disease, measured by T2‐weighted magnetic resonance imaging white matter hyperintensity (WMH) burden, is also observed in patients with PD with faster cognitive decline. Objective: To investigate whether baseline orthostatic hypotension and autonomic dysfunction in early‐stage PD affect later cognitive decline via mediation through cerebral small‐vessel disease. Methods: De novo PD patients (N = 365) and age‐matched controls (N = 174) with baseline T2‐weighted/ fluid‐attenuated inversion recovery scans were selected from the Parkinson's Progression Markers Initiative. WMHs were automatically segmented. Mediation analysis was used to assess whether WMH load mediates the effect of orthostatic hypotension and autonomic dysfunction (measured by Scales for Outcomes in Parkinson's Disease–Autonomic) on future cognitive decline (measured by Montreal Cognitive Assessment) in an average of 4 years of follow‐up. Results: Mediation analysis supported the existence of a full mediation of WMHs on the effect of diastolic orthostatic hypotension in patients with PD and future cognitive decline (average causal mediation effect: ab = −0.032, 95% confidence interval = −0.064 to −0.01, P = 0.01). There was also a partial mediation for overall autonomic dysfunction (ab = −0.027, 95% confidence interval = −0.054 to 0.00, P = 0.02). Conclusions: WMHs fully mediate the effect of diastolic orthostatic hypotension and partially mediate the effect of autonomic dysregulation on future cognitive decline in patients with PD. Our findings support the hypothesis that autonomic dysfunction in early clinical stages predisposes the brain to WMHs through dysregulation of the blood flow in the small vessels. This in turn increases the risk of future cognitive impairment in early PD. [ABSTRACT FROM AUTHOR]

Efforts to reduce postoperative venous thromboembolism are challenging due to heterogeneity in thromboprophylaxis practice. As a result, a 'one-size-fits-all' approach that accounts for surgery-specific risk, but fails to account for patient-level variation, is often adopted by healthcare networks. Updated clinical practice guidelines have advocated an individualised risk-stratified approach that balances the risk:benefit ratio associated with thromboprophylaxis; however, there are limited data confirming effectiveness of these recommendations on the incidence of postoperative venous thromboembolism and bleeding. We developed the surgical-thrombo-embolism-prevention protocol, a novel risk-stratified algorithm that classified patients into low-, intermediate-, and high-risk profiles according to surgical procedure and patient baseline medical risk. Expert-endorsed risk-specific thromboprophylaxis strategies were then applied. A staged quality improvement program was developed to implement the protocol. We postulated that compliance with the protocol would reduce postoperative venous thromboembolism rates without increasing the incidence of postoperative bleeding. Between June 2013 and March 2018, we evaluated the efficacy, safety and sustainability of this risk-stratified approach in 24,953 surgical admissions at a dedicated cancer centre. By final implementation, program compliance was 91%. Postoperative venous thromboembolism rates reduced from 3.1 per 1000 surgical admissions to 0.6 per 1000 surgical admissions (relative risk reduction 79%; p < 0.005). Postoperative bleeding rates also declined from 10.0 per 1000 surgical admissions to 6.3 per 1000 surgical admissions (relative risk reduction 37%; p = 0.02). Sustained improvement was evident more than 3 years after implementation. Implementation of the surgical-thrombo-embolism-prevention protocol significantly reduced the incidence of postoperative venous thromboembolism supporting its validation at other institutions. [ABSTRACT FROM AUTHOR]