This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, that induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100-times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, i.e., ribavirin, favipiravir, and 2 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (Duplex Sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.

Complete uniparental disomy of chromosome 1 (UPD1) is an uncommon genetic finding about which a specific phenotype has not yet been established. We present a boy who has complete paternal UPD1 and isolated developmental delay. We suggest that there is no clear phenotype of UPD1.

Urbanization is recognized as an important driver of the diversity and abundance of tree associated insect herbivores, but its consequences for insect herbivory are controversial. A likely source of variability among studies is the insufficient consideration of intra-urban variability in forest cover. With the help of citizen scientists, we investigated the independent and interactive effect of urbanization and local canopy cover on insect herbivory in the pedunculate oak (Quercus robur) throughout most of its geographic range in Europe. The damage caused by chewing insect herbivores as well as the incidence of leaf-mining and gall-inducing herbivores consistently decreased with increasing urbanization around focal oaks. Herbivory by chewing herbivores increased with increasing forest cover, regardless of urbanization. In contrast, an increase in local canopy cover buffered the negative effect of urbanization on leaf-miners and strengthened its effect on gall-inducers. These results show the complexity of plant-herbivore interactions in urbanized areas, highlighting that the presence of local canopy cover within cities has the potential to attenuate or modify the effect of urbanization on biotic interactions.

Abiotic and biotic factors structure species assembly in ecosystems both horizontally and vertically. However, the way community composition changes along comparable horizontal and vertical distances in complex three-dimensional habitats, and the factors driving these patterns, remain poorly understood. By sampling ant assemblages at comparable vertical and horizontal spatial scales in a tropical rain forest, we compared observed patterns with those predicted according to decreased resource availability in the upper canopy, environmental filtering by microclimate and microhabitat structure, presence of competition in the form of ant mosaics, and structural connectivity. We found although dissimilarity between ant assemblages increased with vertical distance, the dissimilarity was higher horizontally but was independent of distance in this dimension. Moreover, there was not a more rapid increase in horizontal distance-dissimilarity at greater heights in the canopy, as would be predicted if large competitive ant colonies drove these patterns. The pronounced horizontal and vertical structuring of ant assemblages across short distances is likely explained by a combination of microclimate and microhabitat connectivity. Our results demonstrate the importance of considering three-dimensional spatial variation in local assemblages and reveal how highly diverse communities can be supported by complex habitats.

Levetiracetam (LEV) is a second-generation antiepileptic drug (AED) that is well tolerated, has a broad spectrum of action, low protein binding, and minimal hepatic metabolism. The incidence of hypersensitivity to LEV in children and adults is 0.6%. This is the first reported fixed drug eruption (FDE) identified using a patch test in a pediatric case associated with LEV

The growing trend of agricultural abandonment necessitates understanding the development of regrowth forests on old fields in the context of forest restoration. However, the successional patterns of ecosystem functioning and functional diversity of afrotropical regrowth forests are rarely examined. We assessed whether aboveground biomass (AGB) and functional diversity (FD) vary with restoration age and proximity to old-growth forests, compared AGB and FD between regrowth and old-growth forests to measure restoration success and investigated the FD – AGB relationship. We sampled trees in 63 plots (2000 m2 each) in a regrowth forest and 5 plots in an old‐growth forest in 2011, 2014 and 2017. We calculated AGB using diameter, height and wood density. We collated species functional traits (dispersal modes, habitat types, fruit sizes and regeneration guilds) and computed FD measures (richness, evenness, dispersion, divergence and RaoQ’s entropy). AGB and FD measures (richness, dispersion and RaoQ) increased with restoration age. Functional divergence declined with increasing distance to the old-growth forest. Within 22 years, regrowth forests regained 22% of the AGB and recovered all FD measures of the old-growth forest. We found positive, negative and quadratic relationships between AGB and FD depending on the FD measure and forest type. We demonstrate that regrowth forests increase ecosystem production and functional diversity in abandoned areas, however they cannot substitute old-growth forests. Considering multiple measures of functional diversity in different habitats provides a better understanding of the influence of functional diversity on ecosystem functioning.

Trait-environment correlations can arise from local adaptation and can identify genetically and environmentally appropriate seeds for restoration projects. However, anthropogenic changes can disrupt the relationships between traits and fitness. Finding the best seed sources for restoration may rely on describing plant traits adaptive in disturbed and invaded environments, recognizing that while traits may differ among species and functional groups, there may be similarities in the strategies that increase seedling establishment. Focusing on three grass genera, two shrub species, and two forb genera, we collected seeds of all taxa from 16 common sites in the sagebrush steppe of the western United States. We measured seed and seedling characteristics, including seed size, emergence timing, and root and shoot traits, and compiled a suite of environmental variables for each collection site. We described trait-environment associations and asked how traits or environment of origin were associated with seedling survival in invaded gardens. Sampling seven taxa from the same sites allowed us to ask how trait-environment-performance associations differ among taxa and whether natural selection favors similar traits across multiple taxa and functional groups. All taxa showed trait-environment associations consistent with local adaptation, and both environment of origin and phenotypic traits predicted survival in competitive restoration settings, with some commonalities among taxa. Notably, rapid emergence and larger seeds increased survival for multiple taxa. Environmental factors at collection sites, including lower slopes (especially for grasses), greater mean annual temperatures (especially for shrubs and forbs), and greater precipitation seasonality were frequently associated with increased survival. We noted one collection site with high seedling survival across all seven taxa, suggesting that conditions within some sites may result in selection for traits that increase establishment for multiple species. Thus, choosing native plant sources with the most adaptive traits, along with matching climates, will likely improve the restoration of invaded communities.

A 53-year-old woman was admitted at our hospital for the treatment of acute myeloid leukaemia. Heterozygous c.566C>T mutation in the TP53 gene was found in leukaemia cells and germline cells. The number of germline mutation found incidentally will increase. Therefore, patients with such incidental findings must undergo adequate genetic counselling.

Uremic stomatitis is a rare manifestation associated with longstanding uremia in chronic renal failure patients. Its evolution is favorable with earlier institution of renal replacement therapy. This case shows that this condition should always be suspected by the dentist when the context of advanced renal disease is present.

Objective: To systematically investigate the clinical utility of noninvasive prenatal screening (NIPS) commercially used for the common fetal aneuploidies as a prenatal screening tool for rare chromosome abnormalities (RCAs). Design: Prospective study. Setting: Hospital-based. Population or Sample: 528 gravidas with positive NIPS results for RCAs. Methods: Gravidas with positive NIPS results for RCAs subsequently underwent amniocentesis for single nucleotide polymorphism array (SNP-array) were recruit. The degrees of concordance between NIPS and SNP-array were classified into full concordance, partial concordance, discordance related and discordance. Main Outcome Measures: The positive predictive values (PPVs) for rare aneuploidies and segmental imbalances, while incidental findings for regions of homozygosity/uniparental disomy (ROH/UPD), were used to evaluate the performance of NIPS. Results: Of the 528 gravidas with positive NIPS results, 29.2% were confirmed with positive prenatal SNP-array results (154/528). The PPVs for rare aneuploidies and segmental imbalances were 6.1% (7/115) and 21.1% (87/413), respectively. ROH/UPDs, as incidental findings, have been identified in 9.5% (50/528) of gravidas with positive NIPS results. The PPV for clinical significant findings was 8.9% (47/528), including 7 cases with mosaic rare aneuploidies, 35 with pathogenic/likely pathogenic copy number variants, and 5 with imprinting disorders. Conclusions: NIPS commercially used for the common fetal aneuploidies yielded low PPV for rare aneuploidies, moderate PPV for segmental imbalances, and incidental findings for ROH/UPD. For the low PPV for clinical significant findings, NIPS has limited clinical utility for RCAs. Prenatal SNP-array should be regarded as the first-tier test for positive NIPS, particularly for those involved imprinted chromosomes.

Aim: To examine the association between serum levels and effectiveness of omalizumab in patients with chronic spontaneous urticaria (CSU), and explore patient-specific factors associated with omalizumab pharmacokinetics. Methods: Patients with CSU, who were refractory to high-dose antihistamines and who initiated treatment with omalizumab (300 mg every four weeks) were eligible for the study. Treatment was evaluated every 4 th week during 12 weeks of treatment with urticaria activity score in the past week (UAS7) as primary outcome and urticaria control test (UCT), Chronic Urticaria Quality of Life Questionnaire (CU 2QoL) and dermatology life quality index (DLQI) as secondary outcomes. Serum drug level of omalizumab was measured before (trough level) and at day seven (peak level) after each injection. Results: A total of 23 patients were included. After 12 weeks of treatment with omalizumab, an improvement of 16.8 UAS7 points (95% CI 10.8-22.8), p<0.001 was seen. The omalizumab trough and peak levels were 7.0-33.1 µg/mL and 11.4-54.0 µg/mL and reached a plateau (steady state) after 8-12 weeks of treatment. Among the patient-specific factors measured at baseline (age, sex, body mass index (BMI), angioedema, basophil histamine release (HR) test, blood basophils and eosinophils, and serum total IgE), BMI was the only significant predictor of omalizumab peak concentrations during the study (difference -2.75, p<0.05), whereas omalizumab trough concentrations were significantly associated with UAS7 scores (difference -0.82, p<0.001). The same was observed for UCT, DLQI, and CU 2QoL. Conclusion: In patients with CSU initiating treatment with omalizumab, a higher BMI predicts lower peak concentrations of omalizumab during treatment, whereas lower trough concentrations of omalizumab are associated with a poorer response on UAS7 and other patient reported outcomes.

Background:  Manouguian aortic root enlargement (ARE) has been a standard root enlargement procedure to assist in patients with a small annular size. We describe a modification to the Manouguian ARE similar to Yang et al. This approach could serve as an alternate technique for performing ARE; to date only case reports have defined this approach and no studies have evaluated its efficacy or safety. Methods:  A retrospective case series was performed on patients who underwent ARE for surgical aortic valve replacement via the modified Manouguian procedure at a single institution. Thirteen patients were identified between 2015-2021, and all surgeries were performed by a single operator. Data were collected via the Society of Thoracic Surgeons database and chart review. The primary outcome was difference in valve size after the procedure.  Results:  The most common indication for surgery was aortic stenosis (12, 92%), with the most common etiology being degenerative calcification (7, 54%). Congenital bicuspid or uni-cuspid valves were identified in 5 (38%) patients. The majority (10, 77%) of patients received a mechanical valve. This procedure was successfully performed in all 13 of the patients. Additionally, 13 of the 13 patients (100%) were upsized to a satisfactory valve size based on pre-operative echocardiography sizing. Conclusions:  The modified Manouguian aortic enlargement technique can be safely and effectively used as an aortic enlargement procedure in a broad sample of patients.

A 49 year-old male with severe low back pain showed multilevel disc bulges with spinal stenosis. After 18 treatments of low-frequency vibro-percussion stimulation initial VAS pain score of 9.5 reduced to 2.5 and the Rolland-Morris score of 13 reduced to 3. The MRI showed some resolution of L3-L4 and L4-L5.

Objective: Report a novel technique of flexible endoscopy (FE) with noninvasive ventilation (NIV) and sustained pharyngeal inflation (FE-NIV-SPI) in assessing aeroesophageal tracts (AET) to facilitate early detect laryngeal clefts (LC). Methods: Medical charts and FE videos of the children who were diagnosed as LC in a tertiary care hospital between 2000 and 2020 were retrospectively reviewed and analyzed. FE-NIV-SPI technique was applied for all the reviewed children. Results: Of all the FE videos reviewed, twelve infants with laryngeal clefts were collected. This equates to a prevalence of 0.28% in all the children underwent FE at our institution. Their mean age was 5.0 ± 4.9 month-old and the mean body weight was 4.7 ± 2.3 kg. Nine (75%) infants were referred in without LC diagnosis, which was missed by 11 prior bronchoscopy and 5 computer tomography exams. With FE-NIV-SPI, the pharyngolaryngeal space could be pneumatically expanded and allowed detailed assessment. All LC types and coexisted AET lesions were visualized at the first FE-NIV-SPI examination with a mean time of 4.2 ± 0.9 minutes. They were eight type I, two type II and one type III. Ten (83.3%) infants coexisted airway malacia. Conclusion: Routinely using the FE-NIV-SPI technique can help detect the LC defect and associated AET lesions at the first assessment.

In the last decades fungal pathogens are causing devastating population declines across a broad range of taxa. A newly emerging fungal disease, sea turtle egg fusariosis, caused by members of the Fusarium solani species complex (FSSC), has been reported to be responsible for hatching failure in sea turtles around the world. However, this has not been reported in other non-marine turtle species. Herein we report high hatching failure from eggs symptomatic of fusariosis in the yellow-spotted Amazon river turtle ( Podocnemis unifilis), inhabiting a pristine environment in the Ecuadorian Amazon. We assessed hatching success from eggs symptomatic and asymptomatic of fusariosis ( n = 680 eggs), tested for Fusarium infection by PCR amplifying the TEF-1α gene (n= 68 turtle internal egg swab samples) and sequenced eight amplicons for screening of FSSC membership on an Illumina Miseq. Hatchability was 72% for asymptomatic eggs, whilst only 8% of symptomatic eggs hatched. Eight percent of asymptomatic and 58% of symptomatic eggs tested positive for Fusarium spp. and sequencing revealed that nine sequence variants from three asymptomatic and four symptomatic eggs corresponded to F. keratoplasticum, F. solani and F. falciforme, the three major FSSC pathogens already reported in sea turtle egg fusariosis. Our study therefore suggests that observed hatching failure of eggs showing symptoms of fusariosis is at least partially caused by Fusarium pathogens within FSSC in a freshwater turtle. This report highlights that fusariosis is more widespread among the Testudines order than previously reported and is not limited to sea environments, which is of particular conservation concern.

Toxoplasmosis is a zoonotic disease caused by the ubiquitous coccidia Toxoplasma gondii. Rodents play an important role in maintaining its life cycle, as they are one of the main diet sources for felids (wild and domestic), the unique definitive hosts. However, reports of toxoplasmosis in porcupines (Rodentia Order) are uncommon, with gaps concerning its pathophysiology. South America is the continent with the greatest genetic diversity of rodents and T. gondii. A free-ranging hairy dwarf porcupine was admitted to a wildlife rescue center with a history of trauma. During rehabilitation, the animal presented neurological symptoms (sporadic episodes of hind limbs paresis) and died five months later. The main findings during necropsy were brain congestion and severe incisor overgrowth associated with maxillary perforation. The histopathological exam showed moderate encephalitis, with variable-sized round cysts, positive for PAS stain and immunohistochemistry for T. gondii. Additionally, two cysts were observed in the medulla of the adrenal gland. Molecular techniques were performed to characterize the parasite load by qPCR (Cq=30) and the genotype by PCR-RFLP with 11 markers, which revealed a new genotype. This case adds to the body of knowledge in comparative pathology of Neotropical Rodentia and reports a new genotype circulating in South America.

Waterbird responses to habitat changes are of great concern in ecology. Dongting Lake is the second-largest freshwater lake in China, and its vast wetland area provides an important wintering habitat for migratory waterbirds of the East Asian–Australasian Flyway. However, lake reclamation and illegal human-made dykes have degraded the Dongting Lake wetland area at different degrees in the recent decades, seriously threatening the ecology of this area. In 2017, to restore the natural properties of Dongting Lake, the Chinese government completely demolished 459 dykes and preserved 14 dykes for various purposes (biodiversity conservation and flood control). However, the direct impact of dyke demolition on wintering waterbirds has not been comprehensively assessed. In this study, based on annual (2013/14–2020/21) waterbird census data, we compared the differences in species composition of waterbirds in the dyke-demolished and dyke-preserved areas. The results indicated that waterbird diversity, in terms of species number, abundance, the proportion of abundance, number of rare waterbirds species, and exclusive species, was higher in the dyke preserved areas than in the previously demolished areas. Species turnover and reordering further identified dynamic differences in the spatial and temporal distributions of waterbirds. Therefore, we used long-term habitat data to explore whether habitat changes were responsible for the changes in waterbirds; the results showed significantly decreased water and mudflat areas, but a significantly increased vegetation area in the dyke-demolished areas. The water area was significantly positively correlated with waterbirds in this habitat. Compared to the dyke-demolished areas, the stable and suitable habitat area in the dyke-preserved areas might be closely related to the higher waterbird diversity. Our study revealed habitat changes in the context of large-scale dyke demolition in Dongting Lake and demonstrated the dynamic response of waterbirds to habitat changes.

A woman complaining of dyspnea and chest pain since childhood, was referred to our hospital with an initial diagnosis of biventricular hypertrophic cardiomyopathy. Multimodality imaging evaluation revealed massive right ventricular (RV) hypertrophy and severe RV outflow tract obstruction, with a final diagnosis of double chambered RV associated with small ventricular septal defect with right-to-left shunt and right partial anomalous pulmonary vein return. This represents an uncommon combination of congenital abnormalities, extremely rarely diagnosed in adulthood.

More than 1.6 million Americans have at least moderate to severe tricuspid regurgitation, yet fewer than 8000 tricuspid valve operations are performed annually in the USA.The under-treatment for isolated tricuspid regurgitation might be related to the fact that in the past years no clear guidelines on how and when to treat tricuspid regurgitation were issued. Here, we discuss the meta-analysis by Sarris-Michopoulos et al, and we comment what is available in literature on diagnosis and decision making for tricuspid valve intervention.

Risk of permanent pacemaker implantation after transcatheter aortic valve replacement: How do we manage beyond risk assessment?

The authors present an excellent retrograde analysis of a rare condition of a phenomenal number of cases and their surgical outcomes. A majority of the studies in published literature are anecdotal case reports which are a rare and dreadful entity. A comprehensive countrywide view of the UK National Adult Cardiac Surgery Audit database is presented in this study. This study represents the changing trends in the risk factors, management strategies, and outcomes of ventricular septal rupture for over 23 years in a nutshell.

Objectives: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is increasingly being used in acutely deteriorating patients with end-stage lung disease as a bridge to transplantation (BTT). It can allow critically ill recipients to remain eligible for lung transplant (LTx) while reducing pretransplant deconditioning. We analyzed early and mid-term postoperative outcomes of patients on VV-ECMO as a BTT and the impact of preoperative VV-ECMO on posttransplant survival outcomes. Methods: All consecutive LTx performed at our institution between January 2012 and December 2018 were analyzed. After matching, BTT patients were compared with non-bridged LTx recipients. Results: Out of 297 transplanted patients, 21 (7.1%) were placed on VV-ECMO as a BTT. After matching, we observed a similar 30-day mortality between BTT and non-BTT patients (4.6% vs. 6.6%, p=0.083) despite a higher incidence of early postoperative complications (need for ECMO, delayed chest closure, acute kidney injury). Furthermore, preoperative VV-ECMO did not appear associated with 30-day or 1-year mortality in both frequentist and Bayesian analysis (OR 0.35, 95%CI 0.03-3.49, p=0.369; OR 0.27, 95%CrI 0.01-3.82, P=84.7%, respectively). In sensitivity analysis, both subgroups were similar in respect to 30-day (7.8% vs. 6.5%, p=0.048) and 1-year mortality (12.5% vs. 18%, p=0.154). Conclusions: Patients with acute refractory respiratory failure while waiting for LTx represent a high-risk cohort of patients. We observed that these patients can be successfully bridged to LTx with VV-ECMO with post-transplant mortality comparable to non-BTT patients.

Objectives —We sought to investigate the technical feasibility, fidelity and the potential applications of three-dimensional(3D) printed atrial septal defect (ASD) models based on three-dimensional transesophageal echocardiography (3D-TEE) images preliminarily. Methods—We retrospectively collected 40 ASD patients’ 3D-TEE images. The 3D-TEE data were imported into post-processing software to create printable 3D digital models, the patient-specific models were then printed by the 3D printer. Fidelity of the 3D printed models were quantitatively evaluated by comparing the measurements from 3D ASD models and echocardiographic data. Results —Ultrasound-derived 3D ASD models were acquired in all the forty cases successfully. There was good consistency and no significant differences in ASD size parameters among 3D printed models, 2D-TEE images and 3D-TEE images（all P>0.05）. Also, it showed small difference among 3D printed models, 2D-TEE images and 3D-TEE images in the absolute difference value of ASD size parameters. There’s a highly significant correlation between the ASD parameters including the maximal diameter, the minimal diameter and circumference measured by 3D ASD printed models and the corresponding parameters of ASD occluders applied in actual surgical procedure. Simulation exercises in the 3D ASD printed models had an impressive effect based on the comprehensive assessment of the ASD parameters. Conclusions—It is feasible to use 3D-TEE images as the data source of ASD 3D printed models. Ultrasound-derived ASD 3D printed models show highly fidelity, which contributes to provide evidence for the clinical application of 3D printing technology in decision of ASD occlusion.

This paper describes a mathematical model of solute transfer in fluid flow across a permeable channel with variable viscosity, with applications to glomerular capillary blood flow. Solute transfer through the glomerular capillary wall is controlled by the difference in transcapillary hydrostatic pressure and the analogous difference in colloid osmotic pressure (Starling’s law). Using appropriate analytical and numerical approaches, the solutions of coupled equations regulating fluid flow and solute transport are found. The current study’s hydrostatic and osmotic pressure curves are qualitatively in excellent agreement with the experimental data. The effects of variable viscosity on velocity profiles, concentration profiles, and total solute clearance are seen to be substantial, and the findings are graphically depicted.