Jump Squats Performed with Both Light and Heavy Loads Have Similar Effects on the Physical Performance of Elite Rugby Players during the Initial Phase of the Competitive Period.

We examined the effectiveness of two different jump-squat (JS) loading ranges on the physical performance of rugby players. Twenty-eight elite male rugby players were divided into two JS training groups: a light-load JS group ("LJS"; JS at 40% of the one-repetition maximum [1RM] in the half-squat (HS) exercise) and a heavy-load JS group ("HJS"; JS at 80% HS-1RM). Players completed the distinct training programs over four weeks, three times per week, during the initial phase of the competitive period. Pre- and post-training tests were conducted in the following sequence: vertical jumps, a 30-m speed test, peak power in the JS and the HS, and maximum isometric force in the HS. Additionally, the rating of perceived exertion (RPE) was assessed at the end of all training sessions throughout the intervention. A two-way ANOVA with repeated measures, followed by the Tukey's post-hoc test, was employed to analyze differences between groups. The level of significance was set at p < 0.05. Effect sizes were used to assess the magnitude of differences between pre- and post-training data. Except for the RPE values (which were lower in the LJS group), no significant changes were detected for any other variable. In summary, using either a light- (40% HS-1RM) or a heavy-load (80% HS-1RM) JS during the initial phase of the competitive period is equally effective in maintaining physical performance levels attained during the preceding training period (pre-season), with the significant advantage of the light-load protocol resulting in lower levels of the RPE. This finding may have important implications for resistance training programming, especially in disciplines where acute and chronic fatigue is always a problematic issue.

Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Evaluation of novel compounds as anti-bacterial or anti-virulence agents.

Antimicrobial resistance is a global threat, leading to an alarming increase in the prevalence of bacterial infections that can no longer be treated with available antibiotics. The World Health Organization estimates that by 2050 up to 10 million deaths per year could be associated with antimicrobial resistance, which would equal the annual number of cancer deaths worldwide. To overcome this emerging crisis, novel anti-bacterial compounds are urgently needed. There are two possible approaches in the fight against bacterial infections: a) targeting structures within bacterial cells, similar to existing antibiotics; and/or b) targeting virulence factors rather than bacterial growth. Here, for the first time, we provide a comprehensive overview of the key steps in the evaluation of potential new anti-bacterial and/or anti-virulence compounds. The methods described in this review include: a) in silico methods for the evaluation of novel compounds; b) anti-bacterial assays (MIC, MBC, Time-kill); b) anti-virulence assays (anti-biofilm, anti-quorum sensing, anti-adhesion); and c) evaluation of safety aspects (cytotoxicity assay and Ames test). Overall, we provide a detailed description of the methods that are an essential tool for chemists, computational chemists, microbiologists, and toxicologists in the evaluation of potential novel antimicrobial compounds. These methods are cost-effective and have high predictive value. They are widely used in preclinical studies to identify new molecular candidates, for further investigation in animal and human trials.

Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas.

T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice.

Insight into the role of copper-based materials against the coronaviruses MHV-3, a model for SARS-CoV-2, during the COVID-19 pandemic.

Coating high-touch surfaces with inorganic agents, such as metals, appears to be a promising long-term disinfection strategy. However, there is a lack of studies exploring the effectiveness of copper-based products against viruses. In this study, we evaluated the cytotoxicity and virucidal effectiveness of products and materials containing copper against mouse hepatitis virus (MHV-3), a surrogate model for SARS-CoV-2. The results demonstrate that pure CuO and Cu possess activity against the enveloped virus at very low concentrations, ranging from 0.001 to 0.1% (w/v). A greater virucidal efficacy of CuO was found for nanoparticles, which showed activity even against viruses that are more resistant to disinfection such as feline calicivirus (FCV). Most of the evaluated products, with concentrations of Cu or CuO between 0.003 and 15% (w/v), were effective against MHV-3. Cryomicroscopy images of an MHV-3 sample exposed to a CuO-containing surface showed extensive damage to the viral capsid, presumably due to the direct or indirect action of copper ions.

Agreement between Handheld and Standard Echocardiography for Diagnosis of Latent Rheumatic Heart Disease in Brazilian Schoolchildren from High-Prevalence Settings (Agreement between Screening and Standard Echo for RHD).

Introduction: Handheld echocardiography (echo) is the tool of choice for rheumatic heart disease (RHD) screening. We aimed to assess the agreement between screening and standard echo for latent RHD diagnosis in schoolchildren from an endemic setting. Methods: Over 14 months, 3 nonphysicians used handheld machines and the 2012 WHF Criteria to determine RHD prevalence in consented schoolchildren from Brazilian low-income public schools. Studies were interpreted by telemedicine by 3 experts (Brazil, US). RHD-positive children (borderline/definite) and those with congenital heart disease (CHD) were referred for standard echo, acquired and interpreted by a cardiologist. Agreement between screening and standard echo, by WHF subgroups, was assessed. Results: 1390 students were screened in 6 schools, with 110 (7.9%, 95% CI 6.5-9.5) being screen positive (14 ± 2 years, 72% women). Among 16 cases initially diagnosed as definite RHD, 11 (69%) were confirmed, 4 (25%) reclassified to borderline, and 1 to normal. Among 79 cases flagged as borderline RHD, 19 (24%) were confirmed, 50 (63%) reclassified to normal, 8 (10%) reclassified as definite RHD, and 2 had mild CHD. Considering the 4 diagnostic categories, kappa was 0.18. In patients with borderline RHD reclassified to non-RHD, the most frequent WHF criterion was B (isolated mitral regurgitation, 64%), followed by A (2 mitral valve morphological features, 31%). In 1 patient with definite RHD reclassified to normal, the WHF criterion was D (borderline RHD in aortic and mitral valves). After standard echo, RHD prevalence was 3.2% (95% CI 2.3-4.2). Conclusions: Although practical, RHD screening with handheld devices tends to overestimate prevalence.

Renal angina index for early identification of risk of acute kidney injury in critically ill children.

BACKGROUND: The main objective was to test whether the Renal Angina Index (RAI), calculated on patient admission to the pediatric intensive care unit (PICU), is associated with the risk of acute kidney injury (AKI) based on the Kidney Disease: Improving Global Outcomes (KDIGO) (stage ≥ 2) in 72 h. The specific aim was to analyze the performance of the RAI at a specialized oncology PICU. METHODS: Retrospective cohort study involving two pediatric intensive care units located within a general hospital and an oncology hospital. Children aged ≥ 3 months to < 18 years admitted to the intensive care units in 2017 with a length of stay ≥ 72 h were included. RESULTS: The sample included 249 patients, of which 51% were male (127 patients), with median age of 77 months, and mean ICU stay of 5 days. Of the total admissions, 141 were clinical (57%) and 108 surgical. The rate of AKI was 15% and death rate within 30 days was 13%. Having a positive RAI on admission showed a statistically significant association with AKI at Day 3 (OR = 18.5, 95%CI = 4.3 - 78.9, p < 0.001) and with death (OR = 3.9, 95%CI = 1.6 - 9.9, p = 0.004). The accuracy of the RAI in the cancer population was 0.81 on the ROC curve (95%CI 0.74, 0.88). CONCLUSIONS: The RAI is a useful tool for predicting AKI and death in critically ill children, including in oncology units.

A Population-Based Family Case-Control Study of Sun Exposure and Follicular Lymphoma Risk.

BACKGROUND: Epidemiologic evidence suggests an inverse association between sun exposure and follicular lymphoma risk. METHODS: We conducted an Australian population-based family case-control study based on 666 cases and 459 controls (288 related, 171 unrelated). Participants completed a lifetime residence and work calendar and recalled outdoor hours on weekdays, weekends, and holidays in the warmer and cooler months at ages 10, 20, 30, and 40 years, and clothing types worn in the warmer months. We used a group-based trajectory modeling approach to identify outdoor hour trajectories over time and examined associations with follicular lymphoma risk using logistic regression. RESULTS: We observed an inverse association between follicular lymphoma risk and several measures of high lifetime sun exposure, particularly intermittent exposure (weekends, holidays). Associations included reduced risk with increasing time outdoors on holidays in the warmer months [highest category OR = 0.56; 95% confidence interval (CI), 0.42-0.76; Ptrend < 0.01], high outdoor hours on weekends in the warmer months (highest category OR = 0.71; 95% CI, 0.52-0.96), and increasing time outdoors in the warmer and cooler months combined (highest category OR = 0.66; 95% CI, 0.50-0.91; Ptrend 0.01). Risk was reduced for high outdoor hour maintainers in the warmer months across the decade years (OR = 0.71; 95% CI, 0.53-0.96). CONCLUSIONS: High total and intermittent sun exposure, particularly in the warmer months, may be protective against the development of follicular lymphoma. IMPACT: Although sun exposure is not recommended as a cancer control policy, confirming this association may provide insights regarding the future control of this intractable malignancy.

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Investigation of Structure-Activity Relationships for Benzoyl and Cinnamoyl Piperazine/Piperidine Amides as Tyrosinase Inhibitors.

Melanin is a substance that plays important roles in several organisms. Its function as an antioxidant and metal-complexing agent makes tyrosinase, the key enzyme that controls melanogenesis, an interesting target for designing inhibitors. In this article, we report a set of piperazine/piperidine amides of benzoic and cinnamic acid derivatives as tyrosinase inhibitors with improved potency and drug-likeness. The most potent compound 5b showed a pIC50 of 4.99 in the monophenolase assay, and only compound 3a showed reasonable potency in the diphenolase assay (pIC50, 4.18). These activities are not correlated to antiradical activity, suggesting that the activity is dependent on competition with the substrates. Molecular docking studies indicated that the benzyl substituent of 5b and other analogues perform important interactions in the enzyme that may explain the higher potency of these compounds. Moreover, the compounds present adequate lipophilicity and skin permeability and no relevant cytotoxicity (CC50 > 200 µM) to mammalian cells.

Evaluation of trans- and cis-4-[18F]Fluorogabapentin for Brain PET Imaging.

Gabapentin, a selective ligand for the α2δ subunit of voltage-dependent calcium channels, is an anticonvulsant medication used in the treatment of neuropathic pain, epilepsy, and other neurological conditions. We recently described two radiofluorinated derivatives of gabapentin (trans-4-[18F]fluorogabapentin, [18F]tGBP4F, and cis-4-[18F]fluorogabapentin, [18F]cGBP4F) and showed that these compounds accumulate in the injured nerves in a rodent model of neuropathic pain. Given the use of gabapentin in brain diseases, here we investigate whether these radiofluorinated derivatives of gabapentin can be used for imaging α2δ receptors in the brain. Specifically, we developed automated radiosynthesis methods for [18F]tGBP4F and [18F]cGBP4F and conducted dynamic PET imaging in adult rhesus macaques with and without preadministration of pharmacological doses of gabapentin. Both radiotracers showed very high metabolic stability, negligible plasma protein binding, and slow accumulation in the brain. [18F]tGBP4F, the isomer with higher binding affinity, showed low brain uptake and could not be displaced, whereas [18F]cGBP4F showed moderate brain uptake and could be partially displaced. Kinetic modeling of brain regional time-activity curves using a metabolite-corrected arterial input function shows that a one-tissue compartment model accurately fits the data. Graphical analysis using Logan or multilinear analysis 1 produced similar results as compartmental modeling, indicating robust quantification. This study advances our understanding of how gabapentinoids work and provides an important advancement toward imaging α2δ receptors in the brain.

Modifiable lifestyle risk factors and survival after diagnosis with multiple myeloma.

BACKGROUND: While remaining incurable, median overall survival for MM now exceeds 5 years. Yet few studies have investigated how modifiable lifestyle factors influence survival. We investigate whether adiposity, diet, alcohol, or smoking are associated with MM-related fatality. RESEARCH DESIGN AND METHODS: We recruited 760 incident cases of MM via cancer registries in two Australian states during 2010-2016. Participants returned questionnaires on health and lifestyle. Follow-up ended in 2020. Flexible parametric survival models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lifestyle exposures and risk of all-cause and MM-specific fatality. RESULTS: Higher pre-diagnosis Alternative Healthy Eating Index (AHEI) scores were associated with reduced MM-specific fatality (per 10-unit score, HR = 0.84, 95%CI = 0.70-0.99). Pre-diagnosis alcohol consumption was inversely associated with MM-specific fatality, compared with nondrinkers (0.1-20 g per day, HR = 0.59, 95%CI = 0.39-0.90; >20 g per day, HR = 0.67, 95%CI = 0.40-1.13). Tobacco smoking was associated with increased all-cause fatality compared with never smoking (former smokers: HR = 1.44, 95%CI = 1.10-1.88; current smokers: HR = 1.30, 95%CI = 0.80-2.10). There was no association between pre-enrollment body mass index (BMI) and MM-specific or all-cause fatality. CONCLUSIONS: Our findings support established recommendations for healthy diets and against smoking. Higher quality diet, as measured by the AHEI, may improve survival post diagnosis with MM.

Evaluation of trans- and cis-4-[18F]fluorogabapentin for brain PET imaging.

Gabapentin, a selective ligand for the α2δ subunit of voltage-dependent calcium channels, is an anticonvulsant medication used in the treatment of neuropathic pain, epilepsy and other neurological conditions. We recently described two radiofluorinated derivatives of gabapentin (trans-4-[18F]fluorogabapentin, [18F]tGBP4F, and cis-4-[18F]fluorogabapentin, [18F]cGBP4F) and showed that these compounds accumulate in the injured nerves in a rodent model of neuropathic pain. Given the use of gabapentin in brain diseases, here we investigate whether these radiofluorinated derivatives of gabapentin can be used for imaging α2δ receptors in the brain. Specifically, we developed automated radiosynthesis methods for [18F]tGBP4F and [18F]cGBP4F and conducted dynamic PET imaging in adult rhesus macaques with and without preadministration of pharmacological doses of gabapentin. Both radiotracers showed very high metabolic stability, negligible plasma protein binding and slow accumulation in the brain. [18F]tGBP4F, the isomer with higher binding affinity, showed low brain uptake and could not be displaced whereas [18F]cGBP4F showed moderate brain uptake and could be partially displaced. Kinetic modeling of brain regional time-activity curves using a metabolite-corrected arterial input function shows that a 1-tissue compartment model accurately fits the data. Graphical analysis using Logan or multilinear analysis 1 produced similar results as compartmental modeling indicating robust quantification. This study advances our understanding of how gabapentinoids work and provides an important advancement towards imaging α2δ receptors in the brain.

Occupational exposure to extremely low-frequency magnetic fields and follicular lymphoma risk: a family case-control study.

OBJECTIVES: We aimed to examine the relationship between occupational exposure to extremely low-frequency magnetic fields (ELF-MFs) and follicular lymphoma (FL) risk. METHODS: We conducted a family case-control study between 2011 and 2016 in Australia and included 681 cases. Controls were either a family member of cases (related (n=294), unrelated (n=179)) or were unrelated recruited for a similarly designed Australian multiple myeloma study (n=711). We obtained detailed job histories using lifetime work calendars. We assigned exposure to ELF-MFs using an enhanced job exposure matrix, with a lag period of 10 years. We examined associations with FL risk using logistic regression accounting for relatedness between cases and controls. We performed sensitivity analyses including by control type, by sex, complete case analyses, ELF-MF exposure percentiles in addition to quartiles, ELF-MF exposure in the maximum exposed job, a shorter lag period (1 year) and the cumulative exposure in the most recent time period (1-9 years). RESULTS: We observed no association with the average intensity, duration or lifetime cumulative exposure to occupational ELF-MF exposure in the primary or sensitivity analyses. CONCLUSIONS: Our findings do not support an association between occupational ELF-MF exposure and FL risk. Although the inclusion of family members as part of the larger control group may have biased our risk estimates towards the null, findings were similar in sensitivity analyses restricted to cases and unrelated controls. Further research incorporating enhanced exposure assessment to ELF-MF is warranted to inform occupational safety regulations and any potential role in lymphomagenesis.

Prevalence of Australians exposed to potentially cardiotoxic cancer medicines: a population-based cohort study.

Background: Cardiovascular disease (CVD) and cancer are leading causes of death and people with cancer are at higher risk of developing CVD than the general population. Many cancer medicines have cardiotoxic effects but the size of the population exposed to these potentially cardiotoxic medicines is not known. We aimed to determine the prevalence of exposure to potentially cardiotoxic cancer medicines in Australia. Methods: We identified potentially cardiotoxic systemic cancer medicines through searching the literature and registered product information documents. We conducted a retrospective cohort study of Australians dispensed potentially cardiotoxic cancer medicines between 2005 and 2021, calculating age-standardised annual prevalence rates of people alive with exposure to a potentially cardiotoxic medicine during or prior to each year of the study period. Findings: We identified 108,175 people dispensed at least one potentially cardiotoxic cancer medicine; median age, 64 (IQR: 52-74); 57% female. Overall prevalence increased from 49 (95%CI: 48.7-49.3)/10,000 to 232 (95%CI: 231.4-232.6)/10,000 over the study period; 61 (95%CI: 60.5-61.5)/10,000 to 293 (95%CI: 292.1-293.9)/10,000 for females; and 39 (95%CI: 38.6-39.4)/10,000 to 169 (95%CI: 168.3-169.7)/10,000 for males. People alive five years following first exposure increased from 29 (95%CI: 28.8-29.2)/10,000 to 134 (95%CI: 133.6-134.4)/10,000; and from 22 (95%CI: 21.8-22.2)/10,000 to 76 (95%CI: 75.7-76.3)/10,000 for those alive at least 10 years following first exposure. Most people were exposed to only one potentially cardiotoxic medicine, rates of which increased from 39 (95%CI: 38.7-39.3)/10,000 in 2005 to 131 (95%CI: 130.6-131.4)/10,000 in 2021. Interpretation: The number of people exposed to efficacious yet potentially cardiotoxic cancer medicines in Australia is growing. Our findings can support the development of service planning and create awareness about the magnitude of cancer treatment-related cardiotoxicities. Funding: NHMRC Centre for Research Excellence in Medicines Intelligence, Cancer Institute NSW Early Career Fellowship.

Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity.

The absence of effective chronic treatment, expansion to non-endemic countries and the significant burden in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by Trypanosoma cruzi. Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expansion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility. In this work, we report a new set of 13 compounds with modifications in both the arylpiperazine and the aromatic region linked by an amide group. Five analogues showed activity against intracellular amastigotes (IC50 17.8 to 35.9 µM) and no relevant cytotoxicity to mammalian cells (CC50 > 200 µM). Principal component analysis (PCA) was performed to identify structural features associated to improved activity. The data revealed that polarity, hydrogen bonding ability and flexibility were key properties that influenced the antiparasitic activity. In silico drug-likeness assessments indicated that compounds with the 4-methoxycinammyl (especially compound 2b) had the most prominent balance between properties and activity in the series, as confirmed by SAR analysis.

Carcinoma adrenocortical en mujeres en edad fértil / Adrenocortical carcinoma in women of reproductive age

Resumen Los carcinomas adrenocorticales son tumores infre cuentes, habitualmente hiperfuncionantes y con una supervivencia global pobre. La edad frecuente de pre sentación se describe en adultos entre 40 a 60 años, con predominio en sexo femenino. Se presentan dos casos inusuales de carcinoma adrenal diagnosticados en mujeres en edad fértil. El primero de ellos se descubrió en el segundo trimestre de gestación, con un cuadro de hipercortisolismo y lesión adrenal localizada, que resolvió con resección completa hacia la semana 20. En el segundo, la paciente debutó con manifestaciones clínicas de virilización rápidamente progresiva, sien do el hiperandrogenismo puro el patrón bioquímico hallado. En ambos casos, a pesar de haberse realizado la resección completa, el Ki67 elevado como principal factor pronóstico condujo a categorizarlas como de "alto riesgo de recurrencia". Asimismo, se ha asociado a la gestación y al patrón secretor de glucocorticoides como factores adicionales de mayor riesgo de recurrencia. Este es particularmente elevado dentro de los dos primeros años posteriores al diagnóstico. Existe aún controversia sobre el uso de mitotane adyuvante en estos pacientes, y su inicio está recomendado hasta los tres meses del postquirúrgico. Sin embargo, la evidencia disponible no permite suponer la falta de eficacia si se utiliza fuera de ese período. Los limitantes, como fueron el curso de la gestación y el puerperio inmediato, así como la difi cultad para el acceso a la medicación en nuestro medio, impidieron el inicio precoz del tratamiento adyuvante en ambos casos, aunque surge la inquietud de si aún sería oportuna su instauración.

Abstract Adrenocortical carcinomas are rare tumors, usually hyperfunctioning, with poor overall survival. Frequent age of presentation is described in adults between 40 and 60 years of age, predominantly female. Two unusual cases of adrenal carcinoma diagnosed in young women are presented. The first one was discovered in the sec ond trimester of gestation, with signs and symptoms of hypercortisolism and localized adrenal lesion, which was resolved with complete resection by week 20 of pregnancy. In the second case, the patient begined with clinical manifestations of rapidly progressive virilization, the biochemical pattern being pure hyperandrogenism. In both cases, despite complete resection, the high Ki67 as the main prognostic factor leaded to categorization as "high risk of recurrence". In addition, pregnancy and glucocorticoid secretory pattern have been associated as additional risk factors of recurrence. This is particularly high within the first two years after diagnosis. There is controversy about the use of adjuvant mitotane in these patients, and the general recommendation is to be started no longer than 3 months after surgery. However, the available evidence does not suggest that its use is ineffective beyond that period. Limitations, such as the course of pregnancy and the immediate puerperium, as well as the difficulty of accessing this medication in our environment, prevented the early initiation of adjuvant treatment with mitotane in both cases, although there is still concern whether its administration would still be appropriate.

Targeting outer membrane protein A (OmpA) - inhibitory effect of 2'-hydroxychalcone derivatives on Acinetobacter baumannii and Candida albicans dual-species biofilm formation.

Biofilm production facilitates microbial colonization of wounds and catheters. Acinetobacter baumannii produces high levels of biofilm and causes difficult-to-treat nosocomial infections. Candida albicans is another strong biofilm producer which may facilitate A. baumannii adhesion by providing hyphae-mediated OmpA-binding sites. Here we tested the potential of 2'-hydroxychalcones to inhibit dual-species biofilm production of A. baumannii and Candida spp., and further predicted the mechanism of structure-related difference in activity. The results suggest that 2'-hydroxychalcones exhibit potent activity against Candida spp./A. baumannii dual-species biofilm production. Particularly active was trifluoromethyl-substituted derivative (p-CF3), which decreased C. albicans/A. baumannii biomass produced on vein-indwelling parts of the central venous catheterization set by up to 99%. Further, higher OmpA-binding affinity was also calculated for p-CF3, which together with demonstrated significant ompA-downregulating activity, suggests that superior antibiofilm activity of this chalcone against the tested dual-species community of A. baumannii is mediated through the OmpA.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.