Nonsurgical Gluteal Volume Correction with Hyaluronic Acid: A Retrospective Study to Assess Long-term Safety and Efficacy.

Background: Augmentation and reshaping of body volume, particularly in the gluteal area, presents a significant challenge in aesthetic surgery. Hyaluronic acid (HA) fillers have emerged as an effective and safe tool for such indications, but literature examining nonsurgical gluteal reshaping with HA remains limited. This study aims to evaluate the long-term safety of using recommended volumes of HA body fillers for nonsurgical gluteal augmentation. Methods: A retrospective, observational study was carried out across multiple centers in Italy and the United Arab Emirates. The study involved participants between 22 and 53 years of age who underwent gluteal augmentation using HA body filler (HYAcorp MLF1/2) between 2017 and 2021, with up to 4 years and 7 months of follow-up. Participants and investigators independently evaluated the procedure's effectiveness by comparing pre- and posttreatment photographs. The Global Aesthetic Improvement Scale was used to assess posttreatment satisfaction by both participants and investigators. All adverse effects (AEs) were recorded. Results: The study included a diverse group of 91 participants. No serious adverse events were reported, with the majority of AE occurring shortly after treatment and resolving in 1 week. AEs were more frequently observed in participants with previous treatments using different substances in the treatment area. Conclusions: The real-world application of HA body filler (HYAcorp MLF1/2) for gluteal augmentation in the participants of this study showed the treatment's effectiveness, with no severe adverse events reported among the participants. High levels of satisfaction were reported among both participants and investigators.

Effects of urban-induced mutations on ecology, evolution and health.

Increasing evidence suggests that urbanization is associated with higher mutation rates, which can affect the health and evolution of organisms that inhabit cities. Elevated pollution levels in urban areas can induce DNA damage, leading to de novo mutations. Studies on mutations induced by urban pollution are most prevalent in humans and microorganisms, whereas studies of non-human eukaryotes are rare, even though increased mutation rates have the potential to affect organisms and their populations in contemporary time. Our Perspective explores how higher mutation rates in urban environments could impact the fitness, ecology and evolution of populations. Most mutations will be neutral or deleterious, and higher mutation rates associated with elevated pollution in urban populations can increase the risk of cancer in humans and potentially other species. We highlight the potential for urban-driven increased deleterious mutational loads in some organisms, which could lead to a decline in population growth of a wide diversity of organisms. Although beneficial mutations are expected to be rare, we argue that higher mutation rates in urban areas could influence adaptive evolution, especially in organisms with short generation times. Finally, we explore avenues for future research to better understand the effects of urban-induced mutations on the fitness, ecology and evolution of city-dwelling organisms.

SMEMO: Social Memory for Trajectory Forecasting.

Effective modeling of human interactions is of utmost importance when forecasting behaviors such as future trajectories. Each individual, with its motion, influences surrounding agents since everyone obeys to social non-written rules such as collision avoidance or group following. In this paper we model such interactions, which constantly evolve through time, by looking at the problem from an algorithmic point of view, i.e., as a data manipulation task. We present a neural network based on an end-to-end trainable working memory, which acts as an external storage where information about each agent can be continuously written, updated and recalled. We show that our method is capable of learning explainable cause-effect relationships between motions of different agents, obtaining state-of-the-art results on multiple trajectory forecasting datasets.

The functional mutational landscape of the lacZ gene.

The lacZ gene of Escherichia coli encodes ß-galactosidase (ß-gal), a lactose metabolism enzyme of the lactose operon. Previous chemical modification or site-directed mutagenesis experiments have identified 21 amino acids that are essential for ß-gal catalytic activity. We have assembled over 10,000 lacZ mutations from published studies that were collected using a positive selection assay to identify mutations in lacZ that disrupted ß-gal function. We analyzed 6,465 independent lacZ mutations that resulted in 2,732 missense mutations that impaired ß-gal function. Those mutations affected 492 of the 1,023 lacZ codons, including most of the 21 previously known residues critical for catalytic activity. Most missense mutations occurred near the catalytic site and in regions important for subunit tetramerization. Overall, our work provides a comprehensive and detailed map of the amino acid residues affecting the structure and catalytic activity of the ß-gal enzyme.

Error-corrected next generation sequencing - Promises and challenges for genotoxicity and cancer risk assessment.

Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools. Additionally, early data suggest that ecNGS can measure clonal expansion of mutations as a mechanism-agnostic early marker of carcinogenic potential and can evaluate mutational load directly in human biomonitoring studies. In this review, we discuss promising applications, challenges, limitations, and key data initiatives needed to enable regulatory testing and adoption of ecNGS - including for advancing safety assessment, augmenting weight-of-evidence for mutagenicity and carcinogenicity mechanisms, identifying early biomarkers of cancer risk, and managing human health risk from chemical exposures.

Error-corrected duplex sequencing enables direct detection and quantification of mutations in human TK6 cells with strong inter-laboratory consistency.

Error-corrected duplex sequencing (DS) enables direct quantification of low-frequency mutations and offers tremendous potential for chemical mutagenicity assessment. We investigated the utility of DS to quantify induced mutation frequency (MF) and spectrum in human lymphoblastoid TK6 cells exposed to a prototypical DNA alkylating agent, N-ethyl-N-nitrosourea (ENU). Furthermore, we explored appropriate experimental parameters for this application, and assessed inter-laboratory reproducibility. In two independent experiments in two laboratories, TK6 cells were exposed to ENU (25-200 µM) and DNA was sequenced 48, 72, and 96 h post-exposure. A DS mutagenicity panel targeting twenty 2.4-kb regions distributed across the genome was used to sample diverse, genome-representative sequence contexts. A significant increase in MF that was unaffected by time was observed in both laboratories. Concentration-response in the MF from the two laboratories was strongly positively correlated (r = 0.97). C:G>T:A, T:A>C:G, T:A>A:T, and T:A>G:C mutations increased in consistent, concentration-dependent manners in both laboratories, with high proportions of C:G>T:A at all time points. The consistent results across the three time points suggest that 48 h may be sufficient for mutation analysis post-exposure. The target sites responded similarly between the two laboratories and revealed a higher average MF in intergenic regions. These results, demonstrating remarkable reproducibility across time and laboratory for both MF and spectrum, support the high value of DS for characterizing chemical mutagenicity in both research and regulatory evaluation.

Inferior mesenteric artery ligation level in rectal cancer surgery: still no answer-a systematic review and meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis is to summarize the current scientific evidence regarding the impact of the level of inferior mesenteric artery (IMA) ligation on post-operative and oncological outcomes in rectal cancer surgery. METHODS: We conducted a systematic review of the literature up to 06 September 2022. Included were RCTs that compared patients who underwent high (HL) vs. anterior (LL) IMA ligation for resection of rectal cancer. The literature search was performed on Medline/PubMed, Scopus, and the Web of Science without any language restrictions. The primary endpoint was overall anastomotic leakage (AL). Secondary endpoints were oncological outcomes, intraoperative complications, urogenital functional outcomes, and length of hospital stay. RESULTS: Eleven RCTs (1331 patients) were included. The overall rate of AL was lower in the LL group, but the difference was not statistically significant (RR 1.43, 95% CI 0.95 to 2.96). The overall number of harvested lymph nodes was higher in the LL group, but the difference was not statistically significant (MD 0.93, 95% CI - 2.21 to 0.34). The number of lymph nodes harvested was assessed in 256 patients, and all had a laparoscopic procedure. The number of lymph nodes was higher when LL was associated with lymphadenectomy of the vascular root than when IMA was ligated at its origin, but there the difference was not statistically significant (MD - 0.37, 95% CI - 1.00 to 0.26). Overall survival at 5 years was slightly better in the LL group, but the difference was not statistically significant (RR 0.98, 95% CI 0.93 to 1.05). Disease-free survival at 5 years was higher in the LL group, but the difference was not statistically significant (RR 0.97, 95% CI 0.89 to 1.04). CONCLUSIONS: There is no evidence to support HL or LL according to results in terms of AL or oncologic outcome. Moreover, there is not enough evidence to determine the impact of the level of IMA ligation on functional outcomes. The level of IMA ligation should be chosen case by case based on expected functional and oncological outcomes.

Duplex sequencing provides detailed characterization of mutation frequencies and spectra in the bone marrow of MutaMouse males exposed to procarbazine hydrochloride.

Mutagenicity testing is an essential component of health safety assessment. Duplex Sequencing (DS), an emerging high-accuracy DNA sequencing technology, may provide substantial advantages over conventional mutagenicity assays. DS could be used to eliminate reliance on standalone reporter assays and provide mechanistic information alongside mutation frequency (MF) data. However, the performance of DS must be thoroughly assessed before it can be routinely implemented for standard testing. We used DS to study spontaneous and procarbazine (PRC)-induced mutations in the bone marrow (BM) of MutaMouse males across a panel of 20 diverse genomic targets. Mice were exposed to 0, 6.25, 12.5, or 25 mg/kg-bw/day for 28 days by oral gavage and BM sampled 42 days post-exposure. Results were compared with those obtained using the conventional lacZ viral plaque assay on the same samples. DS detected significant increases in mutation frequencies and changes to mutation spectra at all PRC doses. Low intra-group variability within DS samples allowed for detection of increases at lower doses than the lacZ assay. While the lacZ assay initially yielded a higher fold-change in mutant frequency than DS, inclusion of clonal mutations in DS mutation frequencies reduced this discrepancy. Power analyses suggested that three animals per dose group and 500 million duplex base pairs per sample is sufficient to detect a 1.5-fold increase in mutations with > 80% power. Overall, we demonstrate several advantages of DS over classical mutagenicity assays and provide data to support efforts to identify optimal study designs for the application of DS as a regulatory test.

Long term Implications in Surgical re-Assisting (L.I.S.A. study) during the Covid-19 outbreak. A retrospective observational cohort study on a rural population.

BACKGROUND: COVID-19 is having a worldwide impact on surgical treatment. Our aim was to investigate the impact of the pandemic in a rural hospital serving a low densely populated area. METHODS: We investigated the volume and type of surgical performed operations during both the pandemic (March 2020 - February 2021) and pre-pandemic periods (March 2019 - February 2020) as well as during the first and second pandemic waves compared to the pre-pandemic period. We compared the volume and timing of emergency appendectomy and cholecystectomy performed during the pandemic with those of the pre-pandemic period, doing the same with the volume, timing and stages of elective gastric and colorectal resections for cancer. RESULTS: In the pre-pandemic period a higher number of appendectomies (42 vs. 24) and urgent and elective cholecystectomies (174 vs. 126) was performed. The patients operated during the pandemic period (both for appendectomy and cholecystectomy) were on average older (58 vs. 52 years old, p=0.006), including for cholecystectomy (73 vs. 66 years old, p=0.01) and appendectomy (43 vs. 30 years old, p =0.04). The logistic regression analysis with regard to the cholecystectomies and appendectomies performed in emergency showed that male sex and age were associated with gangrenous type histology, both in the pandemic and pre-pandemic period. Finally, we found a reduction in the stage I and IIA colorectal cancers operated during the pandemic compared to those of the pre-pandemic period, with no increase of the advanced stages. CONCLUSIONS: The reduction in services imposed by governments during the first months of total lock down could not justify the whole decrease in surgical interventions in the year of the pandemic. Data suggest that greater "non-operative management" for appendicitis and acute cholecystitis does not lead to an increase of cases operated over time, nor to an increase in the "gangrenous" pattern, this seems to depend on age advanced and male population. KEY WORDS: COVID-19, Emergency Surgery, General Surgery, Pandemics.

Chronic Suppressive Antibiotic Treatment for Staphylococcal Bone and Joint Implant-Related Infections.

Prosthetic joint infection (PJI) and fracture-related infection (FRI) are difficult-to-treat conditions in patients with severe comorbidity or significant surgical risk. In cases not eligible for standard strategy, debridement procedures with the retention of prosthesis or internal fixation device, combined with long-term antibiotic treatment and subsequent indefinite chronic oral antimicrobial suppression (COAS), can be the only reasonable choice. The aim of this study was to investigate the role of COAS and its follow-up in the management of these cases. We retrospectively analyzed a cohort of 16 patients with a follow-up of at least 6 months (mean age 75 yo, 9F, 7M, 11 PJI, 5 FRI). All microbiological isolates were tetracycline-susceptible staphylococci and for this reason a minocycline-based COAS was adopted after debridement and 3 months of antibiogram-guided antibiotic treatment. Patient monitoring was carried out on a clinical basis, with bimonthly execution of the inflammation indices and serial radiolabeled leukocyte scintigraphy (LS). The overall median time of COAS follow-up was 15 months (min 6-max 30). Moreover, 62.5% of patients were still taking COAS with no relapse after cure at the last evaluation available. Clinical failure with a relapse of the infection was observed in 37.5% of patients; interestingly, 50% of them had previously stopped COAS due to side effects of the antibiotic used. In the COAS follow-up, a combination of clinical, laboratory and LS evaluation seems to monitor the infection properly. COAS can be considered as an interesting approach in patients not suitable for standard treatments of PJI or FRI but it requires careful monitoring.

Multiple Trajectory Prediction of Moving Agents With Memory Augmented Networks.

Pedestrians and drivers are expected to safely navigate complex urban environments along with several non cooperating agents. Autonomous vehicles will soon replicate this capability. Each agent acquires a representation of the world from an egocentric perspective and must make decisions ensuring safety for itself and others. This requires to predict motion patterns of observed agents for a far enough future. In this paper we propose MANTRA, a model that exploits memory augmented networks to effectively predict multiple trajectories of other agents, observed from an egocentric perspective. Our model stores observations in memory and uses trained controllers to write meaningful pattern encodings and read trajectories that are most likely to occur in future. We show that our method is able to natively perform multi-modal trajectory prediction obtaining state-of-the art results on four datasets. Moreover, thanks to the non-parametric nature of the memory module, we show how once trained our system can continuously improve by ingesting novel patterns.

Impact of sampling time on the detection of mutations in rapidly proliferating tissues using transgenic rodent gene mutation models: A review.

The OECD Test Guideline 488 (TG 488) for the Transgenic Rodent Gene Mutation Assay has undergone several revisions to update the recommended design for studying mutations in somatic tissues and male germ cells. The recently revised TG recommends a single sampling time of 28 days following 28 days of exposure (i.e., 28 + 28 days) for all tissues, irrespective of proliferation rates. An alternative design (i.e., 28 + 3 days) is appropriate when germ cell data is not required, nor considered. While the 28 + 28 days design is clearly preferable for slowly proliferating somatic tissues and germ cells, there is still uncertainty about the impact of extending the sampling time to 28 days for rapidly somatic tissues. Here, we searched the available literature for evidence supporting the applicability and utility of the 28 + 28 days design for rapidly proliferating tissues. A total of 79 tests were identified. When directly comparing results from both designs in the same study, there was no evidence that the 28 + 28 days regimen resulted in a qualitatively different outcome from the 28 + 3 days design. Studies with a diverse range of agents that employed only a 28 + 28 days protocol provide further evidence that this design is appropriate for rapidly proliferating tissues. Benchmark dose analyses demonstrate high quantitative concordance between the 28 + 3 and 28 + 28 days designs for rapidly proliferating tissues. Accordingly, our review confirms that the 28 + 28 days design is appropriate to assess mutagenicity in both slowly and rapidly proliferating somatic tissues, and germ cells, and provides further support for the recommended design in the recently adopted TG 488.

Duplex sequencing identifies genomic features that determine susceptibility to benzo(a)pyrene-induced in vivo mutations.

Exposure to environmental mutagens increases the risk of cancer and genetic disorders. We used Duplex Sequencing (DS), a high-accuracy error-corrected sequencing technology, to analyze mutation induction across twenty 2.4 kb intergenic and genic targets in the bone marrow of MutaMouse males exposed to benzo(a)pyrene (BaP), a widespread environmental pollutant. DS revealed a linear dose-related induction of mutations across all targets with low intra-group variability. Heterochromatic and intergenic regions exhibited the highest mutation frequencies (MF). C:G > A:T transversions at CCA, CCC and GCC trinucleotides were enriched in BaP-exposed mice consistent with the known etiology of BaP mutagenesis. However, GC-content had no effect on mutation susceptibility. A positive correlation was observed between DS and the "gold-standard" transgenic rodent gene mutation assay. Overall, we demonstrate that DS is a promising approach to study in vivo mutagenesis and yields critical insight into the genomic features governing mutation susceptibility, spectrum, and variability across the genome.

A Case Study on Integrating a New Key Event Into an Existing Adverse Outcome Pathway on Oxidative DNA Damage: Challenges and Approaches in a Data-Rich Area.

Adverse outcome pathways (AOPs) synthesize toxicological information to convey and weigh evidence in an accessible format. AOPs are constructed in modules that include key events (KEs) and key event relationships (KERs). This modular structure facilitates AOP expansion and network development. AOP development requires finding relevant information to evaluate the weight of evidence supporting each KER. To do this, the use of transparent/reproducible search methods, such as systematic review (SR), have been proposed. Applying SR to AOP development in a data-rich area is difficult as SR requires screening each article returned from a search. Here we describe a case study to integrate a single new KE into an existing AOP. We explored the use of SR concepts and software to conduct a transparent and documented literature search to identify empirical data supporting the incorporation of a new KE, increase in cellular reactive oxygen species (ROS), upstream of an existing AOP: "Oxidative DNA Damage Leading to Chromosomal Aberrations and Mutations". Connecting this KE to the AOP is supported by the development of five new KERs, the most important being the first adjacent KER (increase in ROS leading to oxidative DNA damage). We initially searched for evidence of all five KERs and screened 100 papers to develop a preliminary evidence map. After removing papers not containing relevant data based on our Population, Exposure, Comparator and Outcome statement, 39 articles supported one or more KERs; these primarily addressed temporal or dose concordance of the non-adjacent KERs with limited evidence supporting the first adjacent KER. We thus conducted a second focused set of searches using search terms for specific methodologies to measure these first two KEs. After screening, 12 articles were identified that contained quantitative evidence supporting the first adjacent KER. Given that integrating a new KE into an existing AOP requires the development of multiple KERs, this approach of building a preliminary evidence map, focusing evidence gathering on the first adjacent KER, and applying reproducible search strategies using specific methodologies for the first adjacent KER, enabled us to prioritize studies to support expansion of this data-rich AOP.

Comprehensive interpretation of in vitro micronucleus test results for 292 chemicals: from hazard identification to risk assessment application.

Risk assessments are increasingly reliant on information from in vitro assays. The in vitro micronucleus test (MNvit) is a genotoxicity test that detects chromosomal abnormalities, including chromosome breakage (clastogenicity) and/or whole chromosome loss (aneugenicity). In this study, MNvit datasets for 292 chemicals, generated by the US EPA's ToxCast program, were evaluated using a decision tree-based pipeline for hazard identification. Chemicals were tested with 19 concentrations (n = 1) up to 200 µM, in the presence and absence of Aroclor 1254-induced rat liver S9. To identify clastogenic chemicals, %MN values at each concentration were compared to a distribution of batch-specific solvent controls; this was followed by cytotoxicity assessment and benchmark concentration (BMC) analyses. The approach classified 157 substances as positives, 25 as negatives, and 110 as inconclusive. Using the approach described in Bryce et al. (Environ Mol Mutagen 52:280-286, 2011), we identified 15 (5%) aneugens. IVIVE (in vitro to in vivo extrapolation) was employed to convert BMCs into administered equivalent doses (AEDs). Where possible, AEDs were compared to points of departure (PODs) for traditional genotoxicity endpoints; AEDs were generally lower than PODs based on in vivo endpoints. To facilitate interpretation of in vitro MN assay concentration-response data for risk assessment, exposure estimates were utilized to calculate bioactivity exposure ratio (BER) values. BERs for 50 clastogens and two aneugens had AEDs that approached exposure estimates (i.e., BER < 100); these chemicals might be considered priorities for additional testing. This work provides a framework for the use of high-throughput in vitro genotoxicity testing for priority setting and chemical risk assessment.

AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations.

The Genetic Toxicology Technical Committee (GTTC) of the Health and Environmental Sciences Institute (HESI) is developing adverse outcome pathways (AOPs) that describe modes of action leading to potentially heritable genomic damage. The goal was to enhance the use of mechanistic information in genotoxicity assessment by building empirical support for the relationships between relevant molecular initiating events (MIEs) and regulatory endpoints in genetic toxicology. Herein, we present an AOP network that links oxidative DNA damage to two adverse outcomes (AOs): mutations and chromosomal aberrations. We collected empirical evidence from the literature to evaluate the key event relationships between the MIE and the AOs, and assessed the weight of evidence using the modified Bradford-Hill criteria for causality. Oxidative DNA damage is constantly induced and repaired in cells given the ubiquitous presence of reactive oxygen species and free radicals. However, xenobiotic exposures may increase damage above baseline levels through a variety of mechanisms and overwhelm DNA repair and endogenous antioxidant capacity. Unrepaired oxidative DNA base damage can lead to base substitutions during replication and, along with repair intermediates, can also cause DNA strand breaks that can lead to mutations and chromosomal aberrations if not repaired adequately. This AOP network identifies knowledge gaps that could be filled by targeted studies designed to better define the quantitative relationships between key events, which could be leveraged for quantitative chemical safety assessment. We anticipate that this AOP network will provide the building blocks for additional genotoxicity-associated AOPs and aid in designing novel integrated testing approaches for genotoxicity.

The challenging management of cardiac involvement in systemic sarcoidosis.

A 34 year-old young man came to our attention after an occasional finding of complete AV block. We made the diagnosis of systemic sarcoidosis with cardiac involvement through an FDG-PET even with a normal CMR. We started corticosteroid therapy and we decided to follow-up the patient through an implantable loop recorder (ILR). Beyond an initial regression of the AV block, after 8 months the ILR revealed AV block and pauses more than 3 s during the day; a new FDG-PET evidenced FDG uptake in new areas of left ventricle. Hence we started infliximab and implanted a dual chamber ICD.

Magnetic resonance imaging of pure ovarian dysgerminoma: a series of eight cases.

BACKGROUND: Imaging findings have a prominent role in early and correct identification of ovarian dysgerminoma, the most common ovarian malignant germ cell tumor (OMGCT). Despite Computed Tomography (CT) is widely used, Magnetic Resonance Imaging (MRI) has proved to be superior in adnexal masses characterization. Limited data and small series are available concerning MRI aspects of dysgerminoma. CASE PRESENTATION: From January 2012 to December 2018, a database of solid ovarian masses was retrospectively reviewed. Eight patients with histologically proven pure ovarian dysgerminoma and complete imaging available were identified and analyzed. Imaging findings were evaluated separately by two radiologists expert in female genito-urinary MRI. CONCLUSIONS: MRI findings of a lobulated, purely solid, encapsulated mass with hyper-intensity of lobules and hypo-intensity of septa on T2w images contribute to differentiate dysgerminomas from other ovarian neoplasms.