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A rockfall dataset for Germany is analysed with the objective of identifying the meteorological and hydrological (pre-)conditions that change the probability for such events in central Europe. The factors investigated in the analysis are precipitation amount and intensity, freeze–thaw cycles, and subsurface moisture. As there is no suitable observational dataset for all relevant subsurface moisture types (e.g. water in rock pores and cleft water) available, simulated soil moisture and a proxy for pore water are tested as substitutes. The potential triggering factors were analysed both for the day of the event and for the days leading up to it. A logistic regression model was built, which considers individual potential triggering factors and their interactions. It is found that the most important factor influencing rockfall probability in the research area is the precipitation amount at the day of the event, but the water content of the ground on that day and freeze–thaw cycles in the days prior to the event also influence the hazard probability. Comparing simulated soil moisture and the pore-water proxy as predictors for rockfall reveals that the proxy, calculated as accumulated precipitation minus potential evaporation, performs slightly better in the statistical model. Using the statistical model, the effects of meteorological conditions on rockfall probability in German low mountain ranges can be quantified. The model suggests that precipitation is most efficient when the pore-water content of the ground is high. An increase in daily precipitation from its local 50th percentile to its 90th percentile approximately doubles the probability for a rockfall event under median pore-water conditions. When the pore-water proxy is at its 95th percentile, the same increase in precipitation leads to a 4-fold increase in rockfall probability. The occurrence of a freeze–thaw cycle in the preceding days increases the rockfall hazard by about 50 %. The most critical combination can therefore be expected in winter and at the beginning of spring after a freeze–thaw transition, which is followed by a day with high precipitation amounts and takes place in a region preconditioned by a high level of subsurface moisture.

The characterization of the physical and chemical properties of coal on a standard provides an understanding of its characteristics towards spontaneous combustion. The trend of linear relationships between coal recording standards (% air-dried (ad), % dry (db) and % dry ash free (daf) basis) of 30 selected coal samples from the Witbank coalfields and spontaneous combustion liability indices were evaluated. The spontaneous combustion liability indices of these samples were evaluated by crossing point temperature (XPT), Stage II Slope, FCC (Feng, Chakravorty, Cochrane) and the Wits-Ehac tests, while the coal properties were determined from the proximate and ultimate analyses. The results obtained from these coal properties were related to different liability indices to develop trends of linear relationships using regression analysis. The ad basis indicated higher correlation coefficients than the db and daf basis for the XPT and FCC index, while the daf showed higher correlation coefficients than the ad and db basis for the Wits-Ehac index. It was found that the trend of linear relationships of these coal properties differs from one liability index to the next. The XPTs showed a better trend followed by the Stage II Slope on the coal properties among the spontaneous combustion liability indices evaluated.

Topographic shading, including both shaded relief and cast shadowing, plays a fundamental role in determining direct solar radiation on glacier ice. However, shading has been oversimplified or incorrectly incorporated in surface energy balance models in some past studies. In addition, no systematic studies have been conducted to evaluate relationships between shading and other topographic characteristics. Here we develop a topographic solar radiation model to examine the variability in irradiance throughout the glacier melt season due to topographic shading and combined slope and aspect. We apply the model to multiple glaciers in high-mountain Asia (HMA) and test the sensitivity of shading to valley aspect and latitude. Our results show that topographic shading significantly alters the potential direct clear-sky solar radiation received at the surface for valley glaciers in HMA, particularly for north- and south-facing glaciers. Additionally, we find that shading can be extremely impactful in the ablation zone. Cast shadowing is the dominant mechanism in determining total shading for valley glaciers in parts of HMA, especially at lower elevations. Although shading can be predictable, it is overall extremely variable between glacial valleys. Our results suggest that topographic shading not only is an important factor contributing to surface energy balance but could also influence glacier response and mass balance estimates throughout HMA.

Examines the utility of liquid chromatography/tandem mass spectrometry for the extraction, cleanup, determination and confirmation of chloramphenicol (CAP) in cooked crab meat. Pulverization of cooked crab meat with dry ice; Extraction of the CAP into ethyl acetate; Average absolute recoveries of the drug.

Copyright of Der Orthopäde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Orthopäde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Orthopäde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

El polen recolectado por las abejas es un producto apícola usado en la dieta humana por su alto valor nutricional y por ser un alimento balanceado. El polen comercializado consiste en una mezcla de pólenes de distinto origen botánico, néctar y secreciones de las abejas. Este producto de la colmena, rico en azúcares, lípidos y compuestos polifenólicos, principalmente flavonoides, presenta, además, propiedades bioactivas tanto farmacológicas como antioxidantes. El objetivo de este trabajo fue determinar la composición nutricional y la actividad antioxidante del polen apícola proveniente de las zonas melíferas más importantes de la provincia del Chubut: la región cordillerana y la región del valle inferior del río Chubut (VIRCH). Para determinar el contenido proteico se empleó el método de Bradford y los valores fueron expresados en % (g proteínas/100 g polen seco). Las cantidades de polifenoles totales y flavonoides fueron determinadas mediante los métodos de Folin-Ciocalteu y la técnica espectrofotométrica de nitrato de aluminio [Al(NO 3 ) 3 ] respectivamente. La capacidad antioxidante fue evaluada empleando la técnica del radical libre 1,1-difenil-2 picrilhidracilo (DPPH*). El contenido de proteínas presentó un valor medio de 20,2%. Los contenidos de polifenoles totales y flavonoides para las dos regiones melíferas oscilaron entre 50,5 mg y 163,9 mg de ácido gálico (GAE)/ g de polen seco y 10,3 mg y 65,6 mg de rutina (RE)/ g de polen seco. La actividad antirradicalaria en los extractos polínicos de ambas zonas fue alto y el EC 50 varió entre 0,34 mg/ml y 5,82 mg/ml. La mayor capacidad antioxidante correspondió al polen apícola de la región del VIRCH, la cual también presentó un alto contenido de compuestos fenólicos.

Nitrogen-fixing and phosphate-mobilizing bateria, as well as mycorrhizal fungi, can influence plant nutrition beneficially and thus be used as biofertilizers in agriculture. This paper briefly reviews the role of wheat genotypes in the interaction of wheat with soil microorganisms like phosphate solubilizing and nitrogen fixing bacteria, specifically Azotobacter sp., and with mycorrhizal fungi for the development of sustainable wheat crop production. The role of rhizosphere microorganisms and the mechanisms, factors affecting response of bioinoculants and the possibilities of breeding wheat genotypes responsive to these bioinoculants for sustainable wheat production in semi-arid tropics are discussed.

A produção de formas jovens em laboratório é uma etapa fundamental para a implantação e desenvolvimento da aquicultura de pepinos-do-mar. No Brasil, poucos estudos nesse sentido foram realizados, sendo Holothuria grisea considerado o holoturoide com maior potencial para cultivo. Esta tem ocorrência no litoral brasileiro, até Santa Catarina, seu limite sul de distribuição. O objetivo deste trabalho foi avaliar o uso de técnicas para indução à desova e cultivo de larvas de H. grisea, registrando-se seu crescimento, sobrevivência e desenvolvimento. Adultos foram coletados em substrato areno-rochoso na zona entremarés, na Armação do Itapocoroy, Penha, SC, Brasil em fevereiro de 2021. Após determinação do índice gonádico dos reprodutores, foram realizadas indução à desova e fertilização dos ovócitos. As larviculturas foram realizadas em sistema estático, com trocas de água diárias, e foram testados dois métodos: um com troca de água completa e outro com renovação parcial (80%), onde as larvas eram mantidas nas unidades de cultivo. O índice gonádico dos reprodutores apresentou-se baixo (0,85%). Dois exemplares responderam aos estímulos de indução, sendo uma fêmea, que liberou 150.000 ovócitos (135,8µm). Após 48 horas, verificou-se 23,3% de recuperação de larvas auriculárias iniciais (375,5µm). Decorridos 20 dias de experimento, foram observadas larvas auriculárias finais com comprimento médio de 876,8µm (±65,5) e a sobrevivência final foi de 0,51% (±0,04) no tratamento com troca total de água. Já no outro tratamento não houve larvas sobreviventes ao final do experimento. Com este primeiro ensaio de reprodução e larvicultura de H. grisea em seu limite sul de distribuição conclui-se que há possibilidade de induzir a desova e cultivar larvas de H. grisea utilizando técnicas empregadas para outros holoturoides, mesmo com baixo índice gonádico dos reprodutores. Torna-se necessário o prosseguimento de estudos para melhor compreensão do ciclo reprodutivo de H. grisea e determinar protocolos de cultivo adequados para esta espécie.

N-acetylaspartate (NAA) and choline (Cho) are two brain metabolites implicated in several key neuronal functions. Abnormalities in these metabolites have been reported in both early course and chronic patients with schizophrenia (SCZ). It is, however, unclear whether NAA and Cho’s alterations occur even before the onset of the disorder. Clinical high risk (CHR) individuals are a population uniquely enriched for psychosis and SCZ. In this exploratory study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to examine differences in total NAA (tNAA; NAA + N-acetylaspartylglutamate [NAAG]) and major choline-containing compounds, including glycerophosphorylcholine and phosphorylcholine [tCho], over the creatine (Cre) levels between 26 CHR and 32 healthy control (HC) subjects in the subcortical and cortical regions. While no tCho/Cre differences were found between groups in any of the regions of interest (ROIs), we found that CHR had significantly reduced tNAA/Cre in the right dorsal lateral prefrontal cortex (DLPFC) compared to HC, and that the right DLPFC tNAA/Cre reduction in CHR was negatively associated with their positive symptoms scores. No tNAA/Cre differences were found between CHR and HC in other ROIs. In conclusion, reduced tNAA/Cre in CHR vs. HC may represent a putative molecular biomarker for risk of psychosis and SCZ that is associated with symptom severity.

There is an emerging need for regional applications of sea ice projections to provide more accuracy and greater detail to scientists, national, state and local planners, and other stakeholders. The present study offers a prototype for a comprehensive, interdisciplinary study to bridge observational data, climate model simulations, and user needs. The study's first component is an observationally based evaluation of Arctic sea ice trends during 1980–2008, with an emphasis on seasonal and regional differences relative to the overall pan-Arctic trend. Regional sea ice loss has varied, with a significantly larger decline of winter maximum (January–March) extent in the Atlantic region than in other sectors. A lead–lag regression analysis of Atlantic sea ice extent and ocean temperatures indicates that reduced sea ice extent is associated with increased Atlantic Ocean temperatures. Correlations between the two variables are greater when ocean temperatures lag rather than lead sea ice. The performance of 13 global climate models is evaluated using three metrics to compare sea ice simulations with the observed record. We rank models over the pan-Arctic domain and regional quadrants and synthesize model performance across several different studies. The best performing models project reduced ice cover across key access routes in the Arctic through 2100, with a lengthening of seasons for marine operations by 1–3 months. This assessment suggests that the Northwest and Northeast Passages hold potential for enhanced marine access to the Arctic in the future, including shipping and resource development opportunities.

There is a substantial amount of carbon stored in the permafrost soils of boreal forest ecosystems, where it is currently protected from decomposition. The surface organic horizons insulate the deeper soil from variations in atmospheric temperature. The removal of these insulating horizons through consumption by fire increases the vulnerability of permafrost to thaw, and the carbon stored in permafrost to decomposition. In this study we ask how warming and fire regime may influence spatial and temporal changes in active layer and carbon dynamics across a boreal forest landscape in interior Alaska. To address this question, we (1) developed and tested a predictive model of the effect of fire severity on soil organic horizons that depends on landscape-level conditions and (2) used this model to evaluate the long-term consequences of warming and changes in fire regime on active layer and soil carbon dynamics of black spruce forests across interior Alaska. The predictive model of fire severity, designed from the analysis of field observations, reproduces the effect of local topography (landform category, the slope angle and aspect and flow accumulation), weather conditions (drought index, soil moisture) and fire characteristics (day of year and size of the fire) on the reduction of the organic layer caused by fire. The integration of the fire severity model into an ecosystem process-based model allowed us to document the relative importance and interactions among local topography, fire regime and climate warming on active layer and soil carbon dynamics. Lowlands were more resistant to severe fires and climate warming, showing smaller increases in active layer thickness and soil carbon loss compared to drier flat uplands and slopes. In simulations that included the effects of both warming and fire at the regional scale, fire was primarily responsible for a reduction in organic layer thickness of 0.06 m on average by 2100 that led to an increase in active layer thickness of 1.1 m on average by 2100. The combination of warming and fire led to a simulated cumulative loss of 9.6 kgC m ^−2 on average by 2100. Our analysis suggests that ecosystem carbon storage in boreal forests in interior Alaska is particularly vulnerable, primarily due to the combustion of organic layer thickness in fire and the related increase in active layer thickness that exposes previously protected permafrost soil carbon to decomposition.

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Accurate measurement of transcutaneous oxygen saturation is important for the assessment of cyanosis in CHD. Aim of this study was the evaluation of a supplementary transcutaneous oxygen saturation measurement with an Apple watch® in children with cyanotic heart disease., Material and Methods: During a six-minute walk test, measurement of transcutaneous oxygen saturation was performed simultaneously with an Oximeter (Nellcor, Medtronic, USA) and an Apple watch® Series 7 (Apple inc, USA) in 36 children with cyanotic heart disease., Results: Median age was 9.2 (IQR 5.7-13.8) years. Transcutaneous oxygen saturation measurement with the Apple watch® was possible in 35/36 and 34/36 subjects before and after six-minute walk test. Children, in whom Apple watch® measurement was not possible, had a transcutaneous oxygen saturation < 85% on oximeter. Before six-minute walk test, median transcutaneous oxygen saturation was 93 (IQR 91-97) % measured by oximeter and 95 (IQR 93-96) % by the Apple watch®. After a median walking distance of 437 (IQR 360-487) m, transcutaneous oxygen saturation dropped to 92 (IQR 88-95, p < 0.001) % by oximeter and to 94 (IQR 90-96, p = 0.013) % measured with the Apple watch®., Conclusion: In children with mild cyanosis measurement of transcutaneous oxygen saturation with an Apple watch® showed only valid results if transcutaneous oxygen saturation was > 85%, with higher values being measured with the smart watch. In children with moderate or severe cyanosis transcutaneous oxygen saturation , measurement with the Apple watch® was not reliable and cannot be recommended to monitor oxygen saturation at home.

Background/objectives: Weight loss outcomes vary individually. Magnetic resonance imaging (MRI)-based evaluation of adipose tissue (AT) might help to identify AT characteristics that predict AT loss. This study aimed to assess the impact of an 8-week low-calorie diet (LCD) on different AT depots and to identify predictors of short-term AT loss using MRI in adults with obesity., Methods: Eighty-one adults with obesity (mean BMI 34.08 ± 2.75 kg/m², mean age 46.3 ± 10.97 years, 49 females) prospectively underwent baseline MRI (liver dome to femoral head) and anthropometric measurements (BMI, waist-to-hip-ratio, body fat), followed by a post-LCD-examination. Visceral and subcutaneous AT (VAT and SAT) volumes and AT fat fraction were extracted from the MRI data. Apparent lipid volumes based on MRI were calculated as approximation for the lipid contained in the AT. SAT and VAT volumes were subdivided into equidistant thirds along the craniocaudal axis and normalized by length of the segmentation. T-tests compared baseline and follow-up measurements and sex differences. Effect sizes on subdivided AT volumes were compared. Spearman Rank correlation explored associations between baseline parameters and AT loss. Multiple regression analysis identified baseline predictors for AT loss., Results: Following the LCD, participants exhibited significant weight loss (11.61 ± 3.07 kg, p < 0.01) and reductions in all MRI-based AT parameters (p < 0.01). Absolute SAT loss exceeded VAT loss, while relative apparent lipid loss was higher in VAT (both p < 0.01). The lower abdominopelvic third showed the most significant SAT and VAT reduction. The predictor of most AT and apparent lipid losses was the normalized baseline SAT volume in the lower abdominopelvic third, with smaller volumes favoring greater AT loss (p < 0.01 for SAT and VAT loss and SAT apparent lipid volume loss)., Conclusions: The LCD primarily reduces lower abdominopelvic SAT and VAT. Furthermore, lower abdominopelvic SAT volume was detected as a potential predictor for short-term AT loss in persons with obesity., (© 2024. The Author(s).)

The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3-deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3-deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5, restores normal concentrations of soluble cardiac proteins in juvenile Bag3-deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3-deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Next-generation sequencing (NGS) is becoming more relevant for medical diagnostics, especially for using cell-free DNA to monitor response to therapy in cancer management, as high sensitivity of NGS enables detection of rare events. Sequencing Library preparation is a time-consuming and complex process, and large-scale liquid handlers are often used for automation. However, for smaller labs and low-to-medium throughput samples, these liquid handlers are expensive and need experts for handling. This work presents a proof-of-concept for library preparation on a commercially available and open lab-on-a-chip platform, which provides an alternative automation for low-to-medium throughput requirements. It covers common library preparation steps optimized to a microfluidic environment that include customizable PCR for target enrichment, end-repair, adapter ligation, nucleic acid purification via magnetic beads, and an integrated quantification step. The functionality of the cartridge is demonstrated with reference cfDNA containing different allelic frequencies of seven known mutations. Processing the samples in the cartridge reveals highly comparable results to manual processing (Pearson r = 0.94) based on amplicon sequencing. Summarized, the proposed automated lab-on-a-chip workflow for customizable library preparation could further pave the way for NGS to evolve from a technology used for research purposes to one that is applied in routine cancer management., (© 2024. The Author(s).)

Sex-specific abdominal organ volume and proton density fat fraction (PDFF) in people with obesity during a weight loss intervention was assessed with automated multiorgan segmentation of quantitative water-fat MRI. An nnU-Net architecture was employed for automatic segmentation of abdominal organs, including visceral and subcutaneous adipose tissue, liver, and psoas and erector spinae muscle, based on quantitative chemical shift-encoded MRI and using ground truth labels generated from participants of the Lifestyle Intervention (LION) study. Each organ's volume and fat content were examined in 127 participants (73 female and 54 male participants; body mass index, 30-39.9 kg/m 2 ) and in 81 (54 female and 32 male participants) of these participants after an 8-week formula-based low-calorie diet. Dice scores ranging from 0.91 to 0.97 were achieved for the automatic segmentation. PDFF was found to be lower in visceral adipose tissue compared with subcutaneous adipose tissue in both male and female participants. Before intervention, female participants exhibited higher PDFF in subcutaneous adipose tissue (90.6% vs 89.7%; P < .001) and lower PDFF in liver (8.6% vs 13.3%; P < .001) and visceral adipose tissue (76.4% vs 81.3%; P < .001) compared with male participants. This relation persisted after intervention. As a response to caloric restriction, male participants lost significantly more visceral adipose tissue volume (1.76 L vs 0.91 L; P < .001) and showed a higher decrease in subcutaneous adipose tissue PDFF (2.7% vs 1.5%; P < .001) than female participants. Automated body composition analysis on quantitative water-fat MRI data provides new insights for understanding sex-specific metabolic response to caloric restriction and weight loss in people with obesity. Keywords: Obesity, Chemical Shift-encoded MRI, Abdominal Fat Volume, Proton Density Fat Fraction, nnU-Net ClinicalTrials.gov registration no. NCT04023942 Supplemental material is available for this article. Published under a CC BY 4.0 license.

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system. Pedigrees indicated autosomal recessive inheritance. We mapped the suspected genetic defect to a 15 Mb critical interval by combined linkage and autozygosity analysis. Whole genome sequencing revealed a private homozygous missense variant, PCYT2:c.4A>G, predicted to change the second amino acid of the encoded ethanolamine-phosphate cytidylyltransferase 2, XP&#95;038402224.1:(p.Ile2Val). Genotyping of additional Saarlooswolfdogs confirmed the homozygous genotype in all eleven affected dogs and demonstrated an allele frequency of 9.9% in the population. This experiment also identified three additional homozygous mutant young dogs without overt clinical signs. Subsequent examination of one of these dogs revealed early-stage progressive retinal atrophy (PRA) and expansion of subarachnoid CSF spaces in MRI. Dogs homozygous for the pathogenic variant showed ether lipid accumulation, confirming a functional PCYT2 deficiency. The clinical and metabolic phenotype in affected dogs shows some parallels with human patients, in whom PCYT2 variants lead to a rare form of spastic paraplegia or axonal motor and sensory polyneuropathy. Our results demonstrate that PCYT2:c.4A>G in dogs cause PCYT2 deficiency. This canine model with histopathologically documented retinal, central, and peripheral neurodegeneration further deepens the knowledge of PCYT2 deficiency., Competing Interests: Declaration of competing interest A.K. is an employee of Laboklin, a veterinary diagnostic laboratory that offers genetic testing for animals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We aimed to evaluate retrospectively associated anomalies and outcome in prenatal aortic arch anomalies (AAAs). We included ninety patients with aberrant right subclavian artery (ARSA), right aortic arch (RAA) with mirror image branching (RAA-mirror) or aberrant left subclavian artery (RAA-ALSA) and double aortic arch (DAA) between 2011 and 2020. In total, 19/90 (21.1%) had chromosomal anomalies, the highest rate being within the ARSA subgroup (17/46, 37%). All (13/13) of the RAA-mirror subgroup, 10/27 (37.0%) of RAA-ALSA, 13/46 (28.3%) of ARSA and 0/4 within the DAA subgroup had additional intracardiac anomaly. The rate of extracardiac anomalies was 30.7% in RAA-mirror, 28.3% in ARSA, 25.0% in DAA and 22.2% in the RAA-ALSA subgroup. A total of 42/90 (46.7%) had isolated AAAs: three (7.1%) with chromosomal anomalies, all trisomy 21 (3/26, 11.5%) within the ARSA subgroup. Out of 90, 19 (21.1%) were lost to follow-up (FU). Two (2.2%) intrauterine deaths occurred, and six (6.7%) with chromosomal anomalies terminated their pregnancy. In total, 63 (70.0%) were liveborn, 3/63 (4.8%) with severe comorbidity had compassionate care and 3/60 (5.0%) were lost to FU. The survival rate in the intention-to-treat cohort was 53/57 (93%). Forty-one (77.4%) presented with vascular ring/sling, two (4.9%) with RAA-ALSA developed symptoms and one (2.4%) needed an operation. We conclude that intervention due to vascular ring is rarely necessary. NIPT could be useful in isolated ARSA cases without higher a priori risk for trisomy 21 and after exclusion of other anomalies.

Despite tremendous global efforts since the beginning of the COVID-19 pandemic, still only a limited number of prophylactic and therapeutic options are available. Although vaccination is the most effective measure in preventing morbidity and mortality, there is a need for safe and effective post-infection treatment medication. In this study, we explored a pipeline of 21 potential candidates, examined in the Calu-3 cell line for their antiviral efficacy, for drug repurposing. Ralimetinib and nafamostat, clinically used drugs, have emerged as attractive candidates. Due to the inherent limitations of the selected drugs, we formulated targeted liposomes suitable for both systemic and intranasal administration. Non-targeted and targeted nafamostat liposomes (LipNaf) decorated with an Apolipoprotein B peptide (ApoB-P) as a specific lung-targeting ligand were successfully developed. The developed liposomal formulations of nafamostat were found to possess favorable physicochemical properties including nano size (119-147 nm), long-term stability of the normally rapidly degrading compound in aqueous solution, negligible leakage from the liposomes upon storage, and a neutral surface charge with low polydispersity index (PDI). Both nafamostat and ralimetinib liposomes showed good cellular uptake and lack of cytotoxicity, and non-targeted LipNaf demonstrated enhanced accumulation in the lungs following intranasal (IN) administration in non-infected mice. LipNaf retained its anti-SARS-CoV 2 activity in Calu 3 cells with only a modest decrease, exhibiting complete inhibition at concentrations >100 nM. IN, but not intraperitoneal (IP) treatment with targeted LipNaf resulted in a trend to reduced viral load in the lungs of K18-hACE2 mice compared to targeted empty Lip. Nevertheless, upon removal of outlier data, a statistically significant 1.9-fold reduction in viral load was achieved. This observation further highlights the importance of a targeted delivery into the respiratory tract. In summary, we were able to demonstrate a proof-of-concept of drug repurposing by liposomal formulations with anti-SARS-CoV-2 activity. The biodistribution and bioactivity studies with LipNaf suggest an IN or inhalation route of administration for optimal therapeutic efficacy., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic subdural hematoma (cSDH) is one of the most common types of intracranial hemorrhages, particularly in the elderly. Despite extensive research regarding cSDH diagnosis and treatment, there is conflicting data on predictors of postoperative mortality (POM). We conducted a large retrospective review of patients who underwent a cSDH evacuation at a single urban institution between 2015 and 2022. Data were collected from the electronic medical record on prior comorbidities, anticoagulation use, mental status on presentation, preoperative labs, and preoperative/postoperative imaging parameters. Univariate and multivariate analyses were conducted to analyze predictors of mortality. Mortality during admission for this cohort was 6.1%. Univariate analysis showed the mortality rate was higher in those presenting with a history of dialysis. In addition, those who presented with altered mental status, were intubated, and lower GCS scores had higher rates of POM. Usage of Coumadin was correlated with higher rates of POM. Examination of preoperative labs showed that patients who presented with anemia or thrombocytopenia had higher POM. Imaging data showed that cSDH volume and greatest dimension were correlated with higher rates of POM. Finally, patients that were not extubated postoperatively had higher rates of POM. Multivariate analysis showed that only altered mental status and being not being extubated postoperatively were correlated with a higher risk of mortality. In summation, we demonstrated that altered mental status and failure to extubate were independent predictors or mortality in cSDH evacuation. Interestingly, patient age was not a significant predictor of mortality., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We sought to develop and validate an Anticipated Surveillance Requirement Prediction Instrument (ASRI) for prediction of prolonged postanesthesia care unit length of stay (PACU-LOS, more than four hours) after ambulatory surgery., Methods: We analyzed hospital registry data from patients who received anesthesia care in ambulatory surgery centres (ASCs) of university-affiliated hospital networks in New York, USA (development and internal validation cohort [n = 183,711]) and Massachusetts, USA (validation cohort [n = 148,105]). We used stepwise backwards elimination to create ASRI., Results: The model showed discriminatory ability in the development, internal, and external validation cohorts with areas under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI], 0.82 to 0.83), 0.82 (95% CI, 0.81 to 0.83), and 0.80 (95% CI, 0.79 to 0.80), respectively. In cases started in the afternoon, ASRI scores ≥ 43 had a total predicted risk for PACU stay past 8 p.m. of 32% (95% CI, 31.1 to 33.3) vs 8% (95% CI, 7.9 to 8.5) compared with low score values (P-for-interaction < 0.001), which translated to a higher direct PACU cost of care of USD 207 (95% CI, 194 to 2,019; model estimate, 1.68; 95% CI, 1.64 to 1.73; P < 0.001) The effects of using the ASRI score on PACU use efficiency were greater in a free-standing ASC with no limitations on PACU bed availability., Conclusion: We developed and validated a preoperative prediction tool for prolonged PACU-LOS after ambulatory surgery that can be used to guide scheduling in ambulatory surgery to optimize PACU use during normal work hours, particularly in settings without limitation of PACU bed availability., (© 2023. Canadian Anesthesiologists' Society.)

Candida albicans, the primary etiology of human mycoses, is well-adapted to catabolize proline to obtain energy to initiate morphological switching (yeast to hyphal) and for growth. We report that put1-/- and put2-/- strains, carrying defective Proline UTilization genes, display remarkable proline sensitivity with put2-/- mutants being hypersensitive due to the accumulation of the toxic intermediate pyrroline-5-carboxylate (P5C), which inhibits mitochondrial respiration. The put1-/- and put2-/- mutations attenuate virulence in Drosophila and murine candidemia models and decrease survival in human neutrophils and whole blood. Using intravital 2-photon microscopy and label-free non-linear imaging, we visualized the initial stages of C. albicans cells infecting a kidney in real-time, directly deep in the tissue of a living mouse, and observed morphological switching of wildtype but not of put2-/- cells. Multiple members of the Candida species complex, including C. auris, are capable of using proline as a sole energy source. Our results indicate that a tailored proline metabolic network tuned to the mammalian host environment is a key feature of opportunistic fungal pathogens., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Silao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Peripheral nerve sheath tumors (PNSTs) are a group of neoplasms originating from Schwann cells or pluripotent cell of the neural crest. Therapeutic options and prognosis are influenced by their degree of malignancy and location., Hypothesis/objectives: Identify magnetic resonance imaging (MRI) features predictive of PNST histologic grade., Animals: Forty-four dogs with histopathological diagnosis of spinal PNSTs and previous MRI investigation., Methods: A multicenter retrospective study including cases with (a) histopathologic diagnosis of PNST and (b) MRI studies available for review. Histologic slides were reviewed and graded by a board-certified pathologist according to a modified French system (FNCLCC) for grading soft tissue sarcomas. The MRI studies were reviewed by 2 board-certified radiologists blinded to the grade of the tumor and the final decision on the imaging characteristics was reached by consensus. Relationships between tumor grade and histological and MRI findings were assessed using statistical analysis., Results: Forty-four cases met inclusion criteria; 16 patients were PNSTs Grade 1 (low-grade), 19 were PNSTs Grade 2 (medium-grade), and 9 were PNSTs Grade 3 (high-grade). Large volume (P = .03) and severe peripheral contrast enhancement (P = .04) were significantly associated with high tumor grade. Degree of muscle atrophy, heterogeneous signal and tumor growth into the vertebral canal were not associated with grade., Conclusions and Clinical Importance: Grade of malignancy was difficult to identify based on diagnostic imaging alone. However, some MRI features were predictive of high-grade PNSTs including tumor size and peripheral contrast enhancement., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Cardiac motion causes unpredictable signal loss in respiratory-triggered diffusion-weighted magnetic resonance imaging (DWI) of the liver, especially inside the left lobe. The left liver lobe may thus be frequently neglected in the clinical evaluation of liver DWI. In this work, a data-driven algorithm that relies on the statistics of the signal in the left liver lobe to mitigate the motion-induced signal loss is presented. The proposed data-driven algorithm utilizes the exclusion of severely corrupted images with subsequent spatially dependent image scaling based on a signal-loss model to correctly combine the multi-average diffusion-weighted images. The signal in the left liver lobe is restored and the liver signal is more homogeneous after applying the proposed algorithm. Furthermore, overestimation of the apparent diffusion coefficient (ADC) in the left liver lobe is reduced. The proposed algorithm can therefore contribute to reduce the motion-induced bias in DWI of the liver and help to increase the diagnostic value of DWI in the left liver lobe.

The planula larvae of the sea anemone Aiptasia have so far not been reported to complete their life cycle by undergoing metamorphosis into adult forms. This has been a major obstacle in their use as a model for coral-dinoflagellate endosymbiosis. Here, we show that Aiptasia larvae actively feed on crustacean nauplii, displaying a preference for live prey. This feeding behavior relies on functional stinging cells, indicative of complex neuronal control. Regular feeding leads to significant size increase, morphological changes, and efficient settlement around 14 d postfertilization. Surprisingly, the presence of dinoflagellate endosymbionts does not affect larval growth or settlement dynamics but is crucial for sexual reproduction. Our findings finally close Aiptasia's life cycle and highlight the functional nature of its larvae, as in Haeckel's Gastrea postulate, yet reveal its active carnivory, thus contributing to our understanding of early metazoan evolution.

To survive in the nutrient-poor waters of the tropics, reef-building corals rely on intracellular, photosynthetic dinoflagellate symbionts. Photosynthates produced by the symbiont are translocated to the host, and this enables corals to form the structural foundation of the most biodiverse of all marine ecosystems. Although the regulation of nutrient exchange between partners is critical for ecosystem stability and health, the mechanisms governing how nutrients are sensed, transferred, and integrated into host cell processes are largely unknown. Ubiquitous among eukaryotes, the mechanistic target of the rapamycin (mTOR) signaling pathway integrates intracellular and extracellular stimuli to influence cell growth and cell-cycle progression and to balance metabolic processes. A functional role of mTOR in the integration of host and symbiont was demonstrated in various nutritional symbioses, and a similar role of mTOR was proposed for coral-algal symbioses. Using the endosymbiosis model Aiptasia, we examined the role of mTOR signaling in both larvae and adult polyps across various stages of symbiosis. We found that symbiosis enhances cell proliferation, and using an Aiptasia-specific antibody, we localized mTOR to symbiosome membranes. We found that mTOR signaling is activated by symbiosis, while inhibition of mTOR signaling disrupts intracellular niche establishment and symbiosis altogether. Additionally, we observed that dysbiosis was a conserved response to mTOR inhibition in the larvae of a reef-building coral species. Our data confim that mTOR signaling plays a pivotal role in integrating symbiont-derived nutrients into host metabolism and symbiosis stability, ultimately allowing symbiotic cnidarians to thrive in challenging environments., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Human-animal pathogenic transmissions threaten both human and animal health, and the processes catalyzing zoonotic spillover and spillback are complex. Prior field studies offer partial insight into these processes but overlook animal ecologies and human perceptions and practices facilitating human-animal contact. Conducted in Cameroon and a European zoo, this integrative study elucidates these processes, incorporating metagenomic, historical, anthropological and great ape ecological analyses, and real-time evaluation of human-great ape contact types and frequencies. We find more enteric eukaryotic virome sharing between Cameroonian humans and great apes than in the zoo, virome convergence between Cameroonian humans and gorillas, and adenovirus and enterovirus taxa as most frequently shared between Cameroonian humans and great apes. Together with physical contact from hunting, meat handling and fecal exposure, overlapping human cultivation and gorilla pillaging in forest gardens help explain these findings. Our multidisciplinary study identifies environmental co-use as a complementary mechanism for viral sharing., (© 2023. The Author(s).)

Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart., Methods and Results: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4-10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected., Conclusion: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy)., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cardiomyopathies (CMs) are a heterogeneous and severe group of diseases that shows a highly variable cardiac phenotype and an incidence of app. 1/100.000. Genetic screening of family members is not yet performed routinely., Patients and Methods: Three families with dilated cardiomyopathy (DCM) and pathogenic variants in the troponin T2, Cardiac Type ( TNNT2 ) gene were included. Pedigrees and clinical data of the patients were collected. The reported variants in the TNNT2 gene showed a high penetrance and a poor outcome, with 8 of 16 patients dying or receiving heart transplantation. The age of onset varied from the neonatal period to the age of 52. Acute heart failure and severe decompensation developed within a short period in some patients., Conclusion: Family screening of patients with DCM improves risk assessment, especially for individuals who are currently asymptomatic. Screening contributes to improved treatment by enabling practitioners to set appropriate control intervals and quickly begin interventional measures, such as heart failure medication or, in selected cases, pulmonary artery banding.

Reversing neuromuscular blockade with sugammadex can eliminate residual paralysis, which has been associated with postoperative respiratory complications. There are equivocal data on whether sugammadex reduces these when compared with neostigmine. We investigated the association of the choice of reversal drug with postoperative respiratory complications and advanced healthcare utilisation. We included adult patients who underwent surgery and received general anaesthesia with sugammadex or neostigmine reversal at two academic healthcare networks between January 2016 and June 2021. The primary outcome was postoperative respiratory complications, defined as post-extubation oxygen saturation < 90%, respiratory failure requiring non-invasive ventilation, or tracheal re-intubation within 7 days. Our main secondary outcome was advanced healthcare utilisation, a composite outcome including: 7-day unplanned intensive care unit admission; 30-day hospital readmission; or non-home discharge. In total, 5746 (6.9%) of 83,250 included patients experienced postoperative respiratory complications. This was not associated with the reversal drug (adjusted OR (95%CI) 1.01 (0.94-1.08); p = 0.76). After excluding patients admitted from skilled nursing facilities, 8372 (10.5%) patients required advanced healthcare utilisation, which was not associated with the choice of reversal (adjusted OR (95%CI) 0.95 (0.89-1.01); p = 0.11). Equivalence testing supported an equivalent effect size of sugammadex and neostigmine on both outcomes, and neostigmine was non-inferior to sugammadex with regard to postoperative respiratory complications or advanced healthcare utilisation. Finally, there was no association between the reversal drug and major adverse cardiovascular events (adjusted OR 1.07 (0.94-1.21); p = 0.32). Compared with neostigmine, reversal of neuromuscular blockade with sugammadex was not associated with a reduction in postoperative respiratory complications or post-procedural advanced healthcare utilisation., (© 2022 Association of Anaesthetists.)

Background: Encapsulation of rocuronium or vecuronium with sugammadex can reverse neuromuscular block faster than neostigmine reversal. This pharmacodynamic profile might facilitate patient discharge after ambulatory surgery., Methods: We included patients who underwent ambulatory surgery with general anaesthesia and neuromuscular block between 2016 and 2021 from hospital registries at two large academic healthcare networks in the USA. The primary outcome was postoperative length of stay in the ambulatory care facility (PLOS-ACF). We examined post hoc whether the type of reversal affects postoperative nausea and vomiting and direct hospital costs., Results: Among the 29 316 patients included, 8945 (30.5%) received sugammadex and 20 371 (69.5%) received neostigmine for reversal. PLOS-ACF and costs were lower in patients who received sugammadex vs neostigmine (adjusted difference in PLOS-ACF: -9.5 min; 95% confidence interval [95% CI], -10.5 to -8.5 min; adjusted difference in direct hospital costs: -US$77; 95% CI, -$88 to -$66; respectively; P<0.001). The association was magnified in patients over age 65 yr, with ASA physical status >2 undergoing short procedures (<2 h) (adjusted difference in PLOS-ACF: -18.2 min; 95% CI, -23.8 to -12.4 min; adjusted difference in direct hospital costs: -$176; 95% CI, -$220 to -$128; P<0.001). Sugammadex use was associated with reduced postoperative nausea and vomiting (17.2% vs 19.6%, P<0.001), which mediated its effects on length of stay., Conclusions: Reversal with sugammadex compared with neostigmine was associated with a small decrease in postoperative length of stay in the ambulatory care unit. The effect was magnified in older and high-risk patients, and can be explained by reduced postoperative nausea and vomiting. Sugammadex reversal in ambulatory surgery may also help reduce cost of care., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: Avoidable case cancellations within 24 h reduce operating room (OR) efficiency, add unnecessary costs, and may have physical and emotional consequences for patients and their families. We developed and validated a prediction tool that can be used to guide same day case cancellation reduction initiatives., Design: Retrospective hospital registry study., Setting: University-affiliated hospitals network (NY, USA)., Patients: 246,612 (1/2016-6/2021) and 58,662 (7/2021-6/2022) scheduled elective procedures were included in the development and validation cohort., Measurements: Case cancellation within 24 h was defined as cancelling a surgical procedure within 24 h of the scheduled date and time. Our candidate predictors were defined a priori and included patient-, procedural-, and appointment-related factors. We created a prediction tool using backward stepwise logistic regression to predict case cancellation within 24 h. The model was subsequently recalibrated and validated in a cohort of patients who were recently scheduled for surgery., Main Results: 8.6% and 8.7% scheduled procedures were cancelled within 24 h of the intended procedure in the development and validation cohort, respectively. The final weighted score contains 29 predictors. A cutoff value of 15 score points predicted a 10.3% case cancellation rate with a negative predictive value of 0.96, and a positive predictive value of 0.21. The prediction model showed good discrimination in the development and validation cohort with an area under the receiver operating characteristic curve (AUC) of 0.79 (95% confidence interval 0.79-0. 80) and an AUC of 0.73 (95% confidence interval 0.72-0.73), respectively., Conclusions: We present a validated preoperative prediction tool for case cancellation within 24 h of surgery. We utilize the instrument in our institution to identify patients with high risk of case cancellation. We describe a process for recalibration such that other institutions can also use the score to guide same day case cancellation reduction initiatives., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Inc.)

Nitride complexes are key species in homogeneous nitrogen fixation to NH 3 via stepwise proton-coupled electron transfer (PCET). In contrast, direct generation of nitrogenous organic products from N 2 -derived nitrides requires new strategies to enable efficient reductive nitride transfer in the presence of organic electrophiles. We here present a 2-step protocol for the conversion of dinitrogen to benzonitrile. Photoelectrochemical, reductive N 2 splitting produces a rhenium(V) nitride with unfavorable PCET thermochemistry towards ammonia generation. However, N-benzoylation stabilizes subsequent reduction as a basis for selective nitrogen transfer in the presence of the organic electrophile and Brønsted acid at mild reduction potentials. This work offers a new strategy for photoelectrosynthetic nitrogen fixation beyond ammonia-to yield nitrogenous organic products., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background and Objectives: Individuals who experience early life adversity are at an increased risk for chronic disease later in life. Less is known about how early life factors are associated with cancer susceptibility. Here, we use a life history framework to test whether early life adversity increases the risk of breast cancer. We predict that early life adversity can shift investment in somatic maintenance and accelerate the timing of reproduction, which may mediate or interact with the risk of breast cancer., Methodology: We use population-wide data from the Utah Population Database (UPDB) and Utah Cancer Registry, leading to 24 957 cases of women diagnosed with breast cancer spanning 20 years (1990-2010) and 124 785 age-matched controls. We generated a cumulative early life adversity summation score to evaluate the interaction (moderation) and mediation between early life adversity, reproductive history and their association with breast cancer risk., Results: Our analyses led to three key findings: (i) more early life adversity, when considered as a main effect, accelerates the time to first birth and death, (ii) early age at first birth and high parity decreases the risk of breast cancer and (iii) we find no association between early adversity and breast cancer risk either as a main effect or in its interaction with reproductive history., Conclusion and Implications: Early adversity elevates the risk of overall mortality through mechanisms other than breast cancer risk. This suggests early life factors can generate different effects on health. Future work should incorporate more complex view of life history patterns, including multiple life stages, when making predictions about cancer susceptibility., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

We investigated two litters of distantly related Nova Scotia Duck Tolling Retrievers (NSDTR), of which four puppies were affected by cerebellar signs with or without neuromuscular weakness. The phenotype was termed cerebellar degeneration—myositis complex (CDMC). We suspected a heritable condition and initiated a genetic analysis. The genome of one affected dog was sequenced and compared to 565 control genomes. This search yielded a private protein-changing SLC25A12 variant in the affected dog, XM&#95;038584842.1:c.1337C>T, predicted to result in the amino acid change XP&#95;038440770.1:(p.Pro446Leu). The genotypes at the variant co-segregated with the phenotype as expected for a monogenic autosomal recessive mode of inheritance in both litters. Genotyping of 533 additional NSDTR revealed variant allele frequencies of 3.6% and 1.3% in a European and a North American cohort, respectively. The available clinical and biochemical data, together with current knowledge about SLC25A12 variants and their functional impact in humans, mice, and dogs, suggest the p.Pro446Leu variant is a candidate causative defect for the observed phenotype in the affected dogs.

Helicobacter pylori ( H. pylori ) is a causative agent of peptic ulcer disease and plays an important role in the development of various other upper and lower gastrointestinal tract and systemic diseases; in addition to carcinogenesis and the development of mucosa-associated lymphoid tissue lymphoma, extragastric manifestations of H. pylori are increasingly being unraveled. Therefore, prompt and accurate diagnosis is essential. Within this narrative review we present an overview of the current trend in the diagnosis of H. pylori infection and its potential oncogenic sequelae, including gastric mucosa atrophy, intestinal metaplasia, dysplasia and gastric cancer. Signs of H. pylori -related gastric cancer risk can be assessed by endoscopy using the Kyoto classification score. New technology, such as optical or digital chromoendoscopy, improves diagnostic accuracy and provides information regarding H. pylori -related gastric preneoplastic and malignant lesions. In addition, a rapid urease test or histological examination should be performed, as these offer a high diagnostic sensitivity; both are also useful for the diagnosis of sequelae including gastric and colon neoplasms. Culture is necessary for resistance testing and detecting H. pylori -related gastric dysbiosis involved in gastric oncogenesis. Likewise, molecular methods can be utilized for resistance testing and detecting H. pylori -related gastric cancer development and progression. Noninvasive tests, such as the urea breath and stool antigen tests, can also be implemented; these are also suitable for monitoring eradication success and possibly for detecting H. pylori -related gastric malignancy. Serological tests may help to exclude infection in specific populations and detect gastric and colon cancers. Finally, there are emerging potential diagnostic biomarkers for H. pylori -related gastric cancer., Competing Interests: Conflict of Interest: S. Rupp has received a travel grant from Takeda. M. Doulberis and T. Kuntzen have received a travel grant from Gilead Sciences Switzerland Sàrl. S. Rupp and T. Kuntzen have also received a travel grant from Vifor. The rest of the authors declare no conflict of interest., (Copyright: © Hellenic Society of Gastroenterology.)

Inflammatory polyradiculoneuropathy (IMPN) is one of the causes of sudden onset of neuromuscular signs such as para-/tetraparesis in young cats. Even though most cases have a favorable outcome, persistent deficits, relapses, and progressive courses are occasionally seen. As clinical presentation does not always appear to predict outcome and risk of recurrence, this study was initiated to screen for prognostic biopsy findings in a large cohort of histologically confirmed IMPN cases with clinical follow-up. In total, nerve and muscle specimens of 107 cats with biopsy diagnosis of presumed autoreactive inflammatory polyneuropathy and 22 control cases were reviewed by two blinded raters for a set of 36 histological parameters. To identify patterns and subtypes of IMPN, hierarchical k-means clustering of 33 histologic variables was performed. Then, the impact of histological parameters on IMPN outcome was evaluated via an univariate analysis to identify variables for the final multivariate model. The data on immediate outcome and follow-up were collected from submitting neurologists using a purpose-designed questionnaire. Hierarchical k-means clustering sorted the tissues into 4 main categories: cluster 1 (44/129) represents a purely inflammatory IMPN picture, whereas cluster 2 (47/129) was accompanied by demyelinating features and cluster 3 (16/129) by Wallerian degeneration. Cluster 4 (22/129) reflects normal tissues from non-neuropathic control cats. Returned questionnaires provided detailed information on outcome in 63 animals. They were categorized into recovered and non-recovered. Thereby, fiber-invasive infiltrates by mononuclear cells and mild fiber loss in intramuscular nerve branches correlated with higher probabilities of recovery. Remyelination in semithin sections, on the other hand, is correlated with a less favorable outcome. Animals grouping in cluster 1 had a tendency to a higher probability of recovery compared to other clusters. In conclusion, diagnosis of feline IMPN from nerve and muscle biopsies allowed for the identification of histologic features that were positively or negatively correlated with outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kolb, Matiasek, van Renen, Fischer, Zablotski, Wieländer, Nessler, Tipold, Cappello, Flegel, Loderstedt, Dietzel, Gnirs, Rentmeister, Rupp, von Klopmann, Steffen, Jurina, Del Vecchio, Deutschland, König, Gandini, Harcourt-Brown, Kornberg, Bianchi, Gagliardo, Menchetti, Schenk, Tabanez and Rosati.)

Cellobiose lipids (CL) are glycolipids synthesized by Ustilaginaceae species with potential application as detergents or in cosmetics. This study identified process optimisation potential for CL fermentation based on process modelling and techno-economic analysis. Using a stoichiometric equation based on laboratory data, we calculated the maximum possible CL yield Y P/S of 0.45 g CL ·g glucose -1 at the biomass yield of 0.10 g Biomass ·g glucose -1 with an Ustilago maydis strain. Due to substrate inhibition that may occur at high glucose concentrations, a fed-batch process to increase biomass and CL concentrations was considered in our model. Simulation of different process scenarios showed that the choice of aeration units with high oxygen transfer rates and adaptation of power input to oxygen uptake can significantly decrease electricity consumption. We further assessed scenarios with different fermentation media and CL purification methods, suggesting additional process optimisation potential. Here the omission of vitamins from the fermentation medium proved to be a possible mean to enhance process economy, without compromising CL productivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oraby, Rupp and Zibek.)

Mannosylerythritol lipids are glycolipid biosurfactants with many interesting properties. Despite the general interest in those molecules and the need for a robust process, studies on their production in bioreactors are still scarce. In the current study, the fermentative production of MEL in a bioreactor with Moesziomyces aphidis was performed using a defined mineral salt medium. Several kinetic process parameters like substrate consumption rates and product formation rates were evaluated and subsequently enhanced by increasing the biomass concentration through an exponential fed-batch strategy. The fed-batch approaches resulted in two to three fold increased dry biomass concentrations of 10.9-15.5 g/L at the end of the growth phase, compared with 4.2 g/L in the batch process. Consequently, MEL formation rates were increased from 0.1 g/Lh up to around 0.4 g/Lh during the MEL production phase. Thus, a maximum concentration of up to 50.5 g/L MEL was obtained when oil was added in excess, but high concentrations of residual fatty acids were also present in the broth. By adjusting the oil feeding to biomass-specific hydrolysis and MEL production rates, a slightly lower MEL concentration of 34.3 g/L was obtained after 170 h, but at the same time a very pure crude lipid extract with more than 90% MEL and a much lower concentration of remaining fatty acids. With rapeseed oil as substrate, the ideal oil-to-biomass ratio for full substrate conversion was found to be around 10 g oil /g biomass . In addition, off-gas analysis and pH trends could be used to assess biomass growth and MEL production. Finally, kinetic models were developed and compared to the experimental data, allowing for a detailed prediction of the process behavior in future experiments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beck, Vogt, Hägele, Rupp and Zibek.)

There is a paucity of information on the clinical course and outcome of young cats with polyneuropathy. The aim of the study was to describe the clinical features, diagnostic investigations, and outcome of a large cohort of cats with inflammatory polyneuropathy from several European countries. Seventy cats with inflammatory infiltrates in intramuscular nerves and/or peripheral nerve biopsies were retrospectively included. Information from medical records and follow up were acquired via questionnaires filled by veterinary neurologists who had submitted muscle and nerve biopsies (2011-2019). Median age at onset was 10 months (range: 4-120 months). The most common breed was British short hair (25.7%), followed by Domestic short hair (24.3%), Bengal cat (11.4%), Maine Coon (8.6%) and Persian cat (5.7%), and 14 other breeds. Male cats were predominantly affected (64.3%). Clinical signs were weakness (98.6%) and tetraparesis (75.7%) in association with decreased withdrawal reflexes (83.6%) and, less commonly, cranial nerve signs (17.1%), spinal pain/hyperesthesia (12.9%), and micturition/defecation problems (14.3%). Onset was sudden (30.1%) or insidious (69.1%), and an initial progressive phase was reported in 74.3%. Characteristic findings on electrodiagnostic examination were presence of generalized spontaneous electric muscle activity (89.6%), decreased motor nerve conduction velocity (52.3%), abnormal F-wave studies (72.4%), pattern of temporal dispersion (26.1%) and unremarkable sensory tests. The clinical course was mainly described as remittent (49.2%) or remittent-relapsing (34.9%), while stagnation, progressive course or waxing and waning were less frequently reported. Relapses were common and occurred in 35.7% of the cats' population. An overall favorable outcome was reported in 79.4% of patients. In conclusion, young age at the time of diagnosis and sudden onset of clinical signs were significantly associated with recovery ( p < 0.05). Clinical and electrodiagnostic features and the remittent-relapsing clinical course resembles juvenile chronic inflammatory demyelinating polyneuropathy (CIDP), as seen in human (children/adolescents), in many aspects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van Renen, Fischer, Kolb, Wielaender, Zablotski, Nessler, Tipold, Cappello, Flegel, Loderstedt, Gnirs, Rentmeister, Rupp, von Klopmann, Steffen, Jurina, Del Vecchio, Deutschland, König, Gandini, Harcourt-Brown, Kornberg, Bianchi, Gagliardo, Menchetti, Schenk, Tabanez, Matiasek and Rosati.)

Herpes simplex virus-1 (HSV-1) is highly contagious, and there is a need for a therapeutic means to eradicate it. We have identified an siRNA (siHSV) that knocks down gene expression of the infected cell protein 0 (ICP0), which is important in the regulation of HSV infection. The selected siHSV was encapsulated in liposomes to overcome its poor stability, increase cell permeability, and prolonging siRNA circulation time. Several siRNAs against ICP0 have been designed and identified. We examined the role of various parameters, including formulation technique, lipids composition, and ratio. An optimal liposomal siHSV formulation (LipDOPE-siHSV) was characterized with desirable physiochemical properties, in terms of nano-size, low polydispersity index (PDI), neutral surface charge, high siHSV loading, spherical shape, high stability in physiologic conditions in vitro, and long-term shelf-life stability (>1 year, 4 °C). The liposomes exhibited profound internalization by human keratinocytes, no cytotoxicity in cell cultures, no detrimental effect on mice liver enzymes, and a gradual endo-lysosomal escape. Mice biodistribution studies in intact mice revealed accumulation, mainly in visceral organs but also in the trigeminal ganglion. The therapeutic potential of siHSV liposomes was demonstrated by significant antiviral activity both in the plaque reduction assay and in the 3D epidermis model, and the mechanism of action was validated by the reduction of ICP0 expression levels.