Extensive Phylogenomic Discordance and the Complex Evolutionary History of the Neotropical Cat Genus Leopardus.

Even in the genomics era, the phylogeny of Neotropical small felids comprised in the genus Leopardus remains contentious. We used whole-genome resequencing data to construct a time-calibrated consensus phylogeny of this group, quantify phylogenomic discordance, test for interspecies introgression, and assess patterns of genetic diversity and demographic history. We infer that the Leopardus radiation started in the Early Pliocene as an initial speciation burst, followed by another in its subgenus Oncifelis during the Early Pleistocene. Our findings challenge the long-held notion that ocelot (Leopardus pardalis) and margay (L. wiedii) are sister species and instead indicate that margay is most closely related to the enigmatic Andean cat (L. jacobita), whose whole-genome data are reported here for the first time. In addition, we found that the newly sampled Andean tiger cat (L. tigrinus pardinoides) population from Colombia associates closely with Central American tiger cats (L. tigrinus oncilla). Genealogical discordance was largely attributable to incomplete lineage sorting, yet was augmented by strong gene flow between ocelot and the ancestral branch of Oncifelis, as well as between Geoffroy's cat (L. geoffroyi) and southern tiger cat (L. guttulus). Contrasting demographic trajectories have led to disparate levels of current genomic diversity, with a nearly tenfold difference in heterozygosity between Andean cat and ocelot, spanning the entire range of variability found in extant felids. Our analyses improved our understanding of the speciation history and diversity patterns in this felid radiation, and highlight the benefits to phylogenomic inference of embracing the many heterogeneous signals scattered across the genome.

Successful management of pulmonary edema secondary to accidental electrocution in a young dog.

BACKGROUND: Human records describe pulmonary edema as a life-threatening complication of electric shock. Successful management requires prompt recognition and intensive care. However, in companion animals, electrocutions are rarely reported, even though domestic environments are full of electrical devices and there is always the possibility of accidental injury. Therefore, it is important for veterinarians to know more about this condition in order to achieve successful patient outcomes. CASE PRESENTATION: A 3-month-old male Labrador Retriever was presented with a history of transient loss of consciousness after chewing on a household electrical cord. On admission, the puppy showed an orthopneic position with moderate respiratory distress. Supplemental oxygen via nasal catheter was provided, but the patient showed marked worsening of respiratory status. Point-of-care ultrasound exams suggested neurogenic pulmonary edema due to electrical shock close to the central nervous system and increased B-lines without evidence of cardiac abnormalities. Mechanical ventilation of the patient was initiated using volume-controlled mode with a tidal volume of 9 to 15 ml/kg until reaching an end-tidal carbon dioxide ≤ 40 mm Hg, followed by a stepwise lung-recruitment maneuver in pressure-controlled mode with increases of the peak inspiratory pressure (15 to 20 cm H2O) and positive end-expiratory pressure (3 to 10 cm H2O) for 30 min, and return to volume-controlled mode with a tidal volume of 15 ml/kg until reaching a peripheral oxygen saturation ≥ 96%. Weaning from the ventilator was achieved in six hours, and the patient was discharged two days after admission without neurological or respiratory deficits. CONCLUSIONS: We present a rather unusual case of a neurogenic pulmonary edema subsequent to accidental electrocution in a dog. Timely diagnosis by ultrasound and mechanical ventilation settings are described. Our case highlights that pulmonary edema should be considered a potentially life-threatening complication of electrical shock in small animal emergency and critical care medicine.

Native American ancestry and breast cancer risk in Colombian and Mexican women: ruling out potential confounding through ancestry-informative markers.

BACKGROUND: Latin American and Hispanic women are less likely to develop breast cancer (BC) than women of European descent. Observational studies have found an inverse relationship between the individual proportion of Native American ancestry and BC risk. Here, we use ancestry-informative markers to rule out potential confounding of this relationship, estimating the confounder-free effect of Native American ancestry on BC risk. METHODS AND STUDY POPULATION: We used the informativeness for assignment measure to select robust instrumental variables for the individual proportion of Native American ancestry. We then conducted separate Mendelian randomization (MR) analyses based on 1401 Colombian women, most of them from the central Andean regions of Cundinamarca and Huila, and 1366 Mexican women from Mexico City, Monterrey and Veracruz, supplemented by sensitivity and stratified analyses. RESULTS: The proportion of Colombian Native American ancestry showed a putatively causal protective effect on BC risk (inverse variance-weighted odds ratio [OR] = 0.974 per 1% increase in ancestry proportion, 95% confidence interval [CI] 0.970-0.978, p = 3.1 × 10-40). The corresponding OR for Mexican Native American ancestry was 0.988 (95% CI 0.987-0.990, p = 1.4 × 10-44). Stratified analyses revealed a stronger association between Native American ancestry and familial BC (Colombian women: OR = 0.958, 95% CI 0.952-0.964; Mexican women: OR = 0.973, 95% CI 0.969-0.978), and stronger protective effects on oestrogen receptor (ER)-positive BC than on ER-negative and triple-negative BC. CONCLUSIONS: The present results point to an unconfounded protective effect of Native American ancestry on BC risk in both Colombian and Mexican women which appears to be stronger for familial and ER-positive BC. These findings provide a rationale for personalised prevention programmes that take genetic ancestry into account, as well as for future admixture mapping studies.

Fasciola hepatica primoinfections and reinfections in sheep drive distinct Th1/Th2/Treg immune responses in liver and hepatic lymph node at early and late stages.

The expression of proinflammatory (IL-1ß, IFN-γ, TNF-α) and regulatory (IL-10, TGF-ß, IL-4) cytokines, as well as the transcription factor FoxP3, was quantified in the liver and hepatic lymph node (HLN) of sheep primoinfected and reinfected with Fasciola hepatica at early (4, 8 and 16 days post-infection [dpi]) and late (100 dpi) stages. The liver exerted a Th2 immune response at very early stages after the primoinfection with F. hepatica that induced the downregulation of IFN-γ, followed by a Th1/Th2/Treg response although the late stages were characterised by the expression of Th1/Th2 immune mediators. Contrarily, in reinfected sheep a robust mixed Th1/Th2/Treg immune response was found at very early stages meanwhile at late stages we observed a Th2/Treg immune response overcoming the expression of Th1 immune mediators. However, the HLN displayed a completely different Th1/Th2/Treg expression profile compared to the liver. Primoinfections with F. hepatica in HLN induced a mixed Th1/Th2/Treg environment from early stages, establishing a Th2 immune response at a late stage. However, the reinfected sheep exerted a Th2 immune response at early stages led by the IL-4 expression in opposition to the Th1/Th2/Treg found in the liver, meanwhile at late stages the HLN of reinfected sheep exerted a mixed Th1/Th2/Treg immune response. This is the first work publishing the expression of immune mediators in the liver and HLN from reinfected sheep with F. hepatica. The study of the immune responses exerted by the natural host in the target organs directly implied in the development of F. hepatica are crucial to better understand the immunopathogenesis of the fasciolosis being a key factor to develop effective vaccines.

Prevalence of BRCA1 and BRCA2 Germline Mutations in Patients of African Descent with Early-Onset and Familial Colombian Breast Cancer.

BACKGROUND: Pathogenic germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes contribute to hereditary breast/ovarian cancer (OC) in White/mestizo Colombian women. As there is virtually no genetic data on breast cancer (BC) in Colombians of African descent, we conducted a comprehensive BRCA1/2 mutational analysis of 60 Afro-Colombian families affected by breast/OC. MATERIALS AND METHODS: Mutation screening of the complete BRCA1/2 genes for small-scale mutations and large genomic alterations was performed in these families using next-generation sequencing and multiplex ligation-dependent probe amplification analysis. RESULTS: Four pathogenic germline mutations, including one novel mutation, were identified, comprising 3 in BRCA1 and one in BRCA2. The prevalence of BRCA1/2 mutations, including one BRCA1 founder mutation (c.5123C>A) previously identified in this sample set, was 3.9% (2/51) in female BC-affected families and 33.3% (3/9) in those affected by both breast and OC. Haplotype analysis of 2 BRCA2_c.2701delC carriers (one Afro-Colombian and one previously identified White/mestizo Colombian patient with BC) suggested that the mutation arose in a common ancestor. CONCLUSION: Our data showed that 2/5 (40%) mutations (including the one previously identified in this sample set) are shared by White/mestizo Colombian and Afro-Colombian populations. This suggests that these 2 populations are closely related. Nevertheless, variations in the BRCA1/2 mutational spectrum among Afro-Colombian subgroups from different regions of the country were observed, suggesting that specific genetic risk assessment strategies need to be developed.

Epidemiology, Outcomes, and Associated Factors of Coronavirus Disease 2019 (COVID-19) Reverse Transcriptase Polymerase Chain Reaction-Confirmed Cases in the San Pedro Sula Metropolitan Area, Honduras.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused substantial morbidity and mortality worldwide. Few reports exist in Latin America, a current epicenter of transmission. Here, we aim to describe the epidemiology and outcomes associated with coronavirus disease 2019 (COVID-19) in Honduras. METHODS: Baseline clinical and epidemiological information of SARS-CoV-2 reverse transcriptase polymerase chain reaction-confirmed cases detected between 17 March-4 May in the San Pedro Sula Metropolitan area was collected; for hospitalized cases, clinical data were abstracted. Logistic regression models were fit to determine the factors associated with hospitalization. RESULTS: We identified 877 COVID-19 cases, of which 25% (n = 220) were hospitalized. The 19-44-year age group (57.8%) and males (61.3%) were predominant in overall COVID-19 cases. Of the cases, 34% (n = 299) had at least 1 preexisting medical condition. Individuals aged 45-69 years (adjusted odds ratio [aOR] = 4.05; 95% confidence interval [CI], 2.85-5.76) or ≥70 years (aOR = 9.12; 95% CI, 5.24-15.86), of male sex (aOR = 1.72; 95% CI, 1.21-2.44), and those with a preexisting condition (aOR = 2.12; 95% CI, 1.43-3.14) had higher odds of hospitalization. Of inpatients, 50% were hospitalized more than 7 days. The median length of hospitalization was 13 days (interquartile range [IQR], 8-29) among individuals aged 19-44 years, and 17 days (IQR, 11-24.6) among those aged 45-69. Of the fatal cases, 42% occurred among adults under 60 years old. CONCLUSIONS: Our findings show that a high proportion of COVID-19 cases in Honduras occurred among younger adults, who also constituted a significant proportion of severe and fatal cases. Preexisting conditions were associated with severe outcomes independently from age and were highly prevalent in Honduran COVID-19 cases.

Colistin resistance in Gram-negative bacteria analysed by five phenotypic assays and inference of the underlying genomic mechanisms.

BACKGROUND: Colistin is used against multi-drug resistant pathogens, yet resistance emerges through dissemination of plasmid-mediated genes (mcr) or chromosomal mutation of genes involved in lipopolysaccharide synthesis (i.e. mgrB, phoPQ, pmrCAB). Phenotypic susceptibility testing is challenging due to poor diffusion of colistin in agar media, leading to an underestimation of resistance. Performance of five phenotypic approaches was compared in the context of different molecular mechanisms of resistance. We evaluated Vitek 2® (bioMérieux, AST N242), Colistin MIC Test Strip (Liofilchem Diagnostici), UMIC (Biocentric), and Rapid Polymyxin™ NP test (ELITechGroup) against the standard broth microdilution (BMD) method. We used whole genome sequencing (WGS) to infer molecular resistance mechanisms. We analysed 97 Enterobacterales and non-fermenting bacterial isolates, largely clinical isolates collected up to 2018. Data was analysed by comparing susceptibility categories (susceptible or resistant) and minimal inhibitory concentrations (MIC). Susceptibility category concordance is the percentage of test results sharing the same category to BMD. MIC concordance was calculated similarly but considering ±1 MIC titre error range. We determined genomic diversity by core genome multi locus sequencing typing (cgMLST) and identified putative antimicrobial resistance genes using NCBI and CARD databases, and manual annotation. RESULTS: Of 97 isolates, 54 (56%) were resistant with standard BMD. Highest susceptibility category concordance was achieved by Rapid Polymyxin™ NP (98.8%) followed by UMIC (97.9%), Colistin E-test MIC strip (96.9%) and Vitek 2® (95.6%). Highest MIC concordance was achieved by UMIC (80.4%), followed by Vitek 2® (72.5%) and Colistin E-test MIC strip (62.9%). Among resistant isolates, 23/54 (43%) were intrinsically resistant to colistin, whereas 31/54 (57%) isolates had acquired colistin resistance. Of these, mcr-1 was detected in four isolates and mcr-2 in one isolate. Non-synonymous mutations in mgrB, phoQ, pmrA, pmrB, and pmrC genes were encountered in Klebsiella pneumoniae, Escherichia coli, and Acinetobacter bereziniae resistant isolates. Mutations found in mgrB and pmrB were only identified in isolates exhibiting MICs of ≥16 mg/L. CONCLUSIONS: The Rapid Polymyxin™ NP test showed highest categorical concordance and the UMIC test provided MIC values with high concordance to BMD. We found colistin resistance in diverse species occurred predominantly through spontaneous chromosomal mutation rather than plasmid-mediated resistance.

Cognitive Impairments in Spinocerebellar Ataxia Type 10 and Their Relation to Cortical Thickness.

BACKGROUND: Spinocerebellar ataxia type 10 is a neurodegenerative disorder caused by the expansion of an ATTCT pentanucleotide repeat. Its clinical features include ataxia and, in some cases, epileptic seizures. There is, however, a dearth of information about its cognitive deficits and the neural bases underpinning them. OBJECTIVES: The objectives of this study were to characterize the performance of spinocerebellar ataxia type 10 patients in 2 cognitive domains typically affected in spinocerebellar ataxias, memory and executive function, and to correlate the identified cognitive impairments with ataxia severity and cerebral/cerebellar cortical thickness, as quantified by MRI. METHODS: Memory and executive function tests were administered to 17 genetically confirmed Mexican spinocerebellar ataxia type 10 patients, and their results were compared with 17 healthy matched volunteers. MRI was performed in 16 patients. RESULTS: Patients showed deficits in visual and visuospatial short-term memory, reduced storage capacity for verbal memory, and impaired monitoring, planning, and cognitive flexibility, which were ataxia independent. Patients with seizures (n = 9) and without seizures (n = 8) did not differ significantly in cognitive performance. There were significant correlations between short-term visuospatial memory impairment and posterior cerebellar lobe cortical thickness (bilateral lobule VI, IX, and right X). Cognitive flexibility deficiencies correlated with cerebral cortical thickness in the left middle frontal, cingulate, opercular, and temporal gyri. Cerebellar cortical thickness in several bilateral regions was correlated with motor impairment. CONCLUSIONS: Patients with spinocerebellar ataxia type 10 show significant memory and executive dysfunction that can be correlated with deterioration in the posterior lobe of the cerebellum and prefrontal, cingulate, and middle temporal cortices. © 2021 International Parkinson and Movement Disorder Society.

Design and Development of a Risk Classification Instrument for Virological Failure in HIV, Using Psychosocial Determinants of Health: Preliminary Evidence from a South American Country.

Predictive approaches in HIV to estimate a patient's risk to present with relevant health outcomes, such as hospitalizations and AIDS-related death, long before they happen, could be highly useful. We aimed to develop a risk classification instrument for virological failure through a scoring system that identifies patients with a low, medium, and high risk after six months of ART treatment. A case-control design was implemented through 355 HIV-positive Colombian adults who were assessed using the designed instrument. The variables with independent predictive values were selected using logistic regression analysis, and the diagnostic performance of the prediction score was evaluated using the area under the curve. The prediction score included relevant psychosocial and biological risk factors, some of them modifiable variables like substance use and low health literacy. The area under the curve value for the total prediction score was 0.85 (CI 0.80-0.90). Therefore, this instrument could be a valuable tool to identify at-risk patients of virological failure. In low and middle-income countries, the associated risk factors of virological failure are little known. Assessing such risk would lead to make individualized decisions regarding the patient's management and minimize the chance of non-desirable outcomes.

Interaction between genetic ancestry and common breast cancer susceptibility variants in Colombian women.

Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1022 Colombian BC cases and 1023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC) = 0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC = 0.58) or the combined effect of all 13 associated risk variants (AUC = 0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants.

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

[Prolonged initial empirical antibiotic treatment and the risk of morbidity and mortality in very low birthweight infants]. / Tratamiento antibiótico empírico inicial prolongado y riesgo de morbimortalidad en recién nacidos de muy bajo peso al nacer.

INTRODUCTION: The objective of this study is to evaluate the association between the duration of ini tial empirical antibiotic treatment and the subsequent development of late-onset sepsis, necrotizing enterocolitis (NEC) and death in very low birth weight (VLBW) infants. PATIENTS AND METHODS: Quantitative, cross-sectional, analytical study of VLBW infants admitted to the neonatal ICU were included over a period of five years. Initial empirical antibiotic therapy was that which started immediately after birth, without knowing the results of blood cultures. It was considered prolonged antibiotic therapy when the treatment duration was > 5 days. Perinatal variables, as well as the inci dence of late-onset sepsis, confirmed NEC and mortality were analyzed. RESULTS: 266 VLBW infants were studied, with an average gestational age and birth weight of 28.8 ± 2.5 weeks and 1.127 ± 264 g respectively. 213 infants received initial empiric antibiotic therapy (80.0%), which was prolonged in 67.6% of cases. All infants received two different antibiotics. 136 episodes of late-onset sepsis were described. The most common pathogens were coagulase-negative Staphylococcus and Staphylococcus aureus. Among the newborns with prolonged antibiotic therapy, there were 20 cases of confirmed NEC and 15 of the studied infants died (10.4%). When comparing the use of antibiotic therapy during > 5 days versus treatment less than 5 days duration, a statistically significant association was observed between prolonged antibiotic therapy and late-onset sepsis (p = 0.03) and confirmed NEC (p = 0.03), but not of mortality (p = 0.12). CONCLUSION: The use of empirical antibiotic therapy for five days or more was associated with an increased risk of late-onset sepsis and NEC, but not of mortality in VLBW infants.

Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review.

BACKGROUND: Numerous epidemiological factors affect the probability of developing breast or ovarian cancer, but no predictor is as determinant as inheriting a mutation in BRCA1 or BRCA2. The concept of the founder effect explains the reduced genetic variability in some populations, according to the theory that new populations can be formed from a reduced number of individuals, so the new population would carry only a small fraction of the genetic variability of the original population. The main purpose of this review is to provide an update on the state of the art in founder mutations and some recurrent mutations that have recently been described in Latin America. METHODS: A literature search was performed in the electronic databases of PUBMED, EMBASE, LILACS, and BIREME using the terms BRCA1, BRCA2, founder mutation, Latin American population, and Hispanic. Sixty-two papers were identified, of which 38 were considered relevant for this review. Each result is shown per country. RESULTS: In Latin America, clear founder effects have been reported in Mexico (BRCA1 del exons 9-12), Brazil (BRCA1 5382insC and BRCA2 c.156_157insAlu), and Colombia (BRCA1 3450del4, A1708E, and BRCA2 3034del4) and in Latinas residing in Southern California (BRCA1 185delAG, IVS5+1G>A, S955x, and R1443x). Of these, mutation BRCA1 3450del4 has also been reported in Brazil and Chile, whereas mutation BRCA2 3034del4 has been reported in Argentina and Peru. These data support the idea that although most Hispanic populations are the result of a mixture between Europeans, Africans, and Amerindians, the relative proportion of each genetic component varies throughout the Hispanic populations, making it necessary to identify the mutations characteristic of each population to generate mutation profiles adjusted to each one of them. CONCLUSION: In Latin American countries, and even among regions of the same country, there is great heterogeneity of ancestors. Therefore, Latinas should not be analyzed like other population groups without taking into account their genetic ancestry. The presence of founder mutations in specific population groups represents a cost-effective analysis. The importance of determining the founder mutations lies mainly in the decrease in costs. If we manage to decrease costs, screenings could be offered more widely and cover a larger number of women. IMPLICATIONS FOR PRACTICE: Hispanic and African-American populations are four to five times less likely than other populations worldwide to receive screening for BRCA mutations, a main reason being the high costs of these tools. The present study seeks to identify the prevalent mutations and the founder effect in the BRCA gene in the Hispanic population to address specific panels for this population group in the future and develop strategies for population screening.

A common coding variant in CASP8 is associated with breast cancer risk.

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy.

INTRODUCTION: Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). METHODS: We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. RESULTS: Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10⁻³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10⁻4) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10⁻4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10⁻4). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻5) without study heterogeneity. CONCLUSIONS: TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.

BACKGROUND: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. METHODS: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. RESULTS: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95% 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95% 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95% CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. CONCLUSIONS: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.

S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis.

RATIONALE: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. OBJECTIVES: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. METHODS: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. MEASUREMENTS AND MAIN RESULTS: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. CONCLUSIONS: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.

Discovery of dual-action phenolic 4-arylidene-isoquinolinones with antioxidant and α-glucosidase inhibition activities.

A multicomponent-derived synthesis of arylidene isoquinolinones decorated with phenolic moieties is described. The series demonstrated good DPPH trapping and, in the case of sinapic acid-containing analogs, excellent activity against lipoperoxidation; EPR also demonstrated that one derivative scavenged hydroxyl radicals. In addition, some compounds showed excellent inhibition of α-glucosidase activity and, according to both Lineweaver-Burk plots and molecular docking, they act as non-competitive or mixed inhibitors. In vitro assay also demonstrated that two compounds significantly reduced the plasma glucose levels after sucrose administration. In summary, the studied isoquinolinones become novel compounds with dual action (antioxidant and α-glucosidase inhibition) against diabetes and related metabolic diseases, whose optimization would lead to more potent candidates.

Exploring Pediatric Vision Care: Insights from Five Years of Referral Cases in the UCI Eye Mobile and Implications of COVID-19.

PURPOSE: To analyze referral rates, patient demographics, referral indications, and the impact of socioeconomic factors on ocular health from the University of California Irvine (UCI) Eye Mobile for Children, particularly during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A retrospective chart review was performed on de-identified records of children examined on the UCI Eye Mobile. GraphPad Prism 10.0.0 and Python software were used for statistical analyses. RESULTS: In the academic years from 2018 to 2022, 3,619 children received comprehensive eye examinations on the UCI Eye Mobile. Among them, 76 were referred to a pediatric ophthalmologist. The majority of these children were Hispanic (72.6%, 54 of 74), followed by Asian (10.9%, 8 of 74). A significant proportion (82.9%, 63 of 76) attended school districts with median incomes below that of Orange County. Statistically significant differences were found in age (P = .001; pre-COVID: 3.98 ± 1.08 years vs COVID: 5.75 ± 2.92 years) and gender (P = .023; pre-COVID female: 31 of 41 vs COVID female: 15 of 32) between the pre-COVID and COVID years. Additionally, there were significant differences in the proportion of children with hyperopia with astigmatism between the pre-COVID and COVID years (P = .044; pre-COVID: 23 of 40 vs COVID: 12 of 35). The most common indications for ophthalmologist referrals were for strabismus evaluation/treatment (28.9%, 22 of 76), followed by abnormal cup-to-disc ratio (21.1%, 16 of 76). CONCLUSIONS: The study highlights the pivotal role of the UCI Eye Mobile for children in identifying ocular conditions needing referrals to subspecialty care. The majority of children needing these referrals attended schools in lower economic communities. Additionally, the COVID-19 pandemic appears to have influenced the demographic and clinical characteristics. [J Pediatr Ophthalmol Strabismus. 20XX:X(X):XXX-XXX.].

UCI EyeMobile Exam Findings from School Children Following on-Site Screening.

Purpose: Uncorrected refractive errors (REs) and amblyopia can lead to visual impairment with deleterious effects on quality of life and academic performance. Early detection and treatment by community vision care programs, such as the UCI EyeMobile for Children, can aid in addressing preventable vision loss. Methods: A total of 5074 children between the ages of 3 and 10 years were screened at 153 locations, including preschools, head start programs, and elementary schools within Orange County (OC), California (CA). Subsequently, 1024 children presented for comprehensive eye examinations. A retrospective analysis of all examined children was conducted, determining the frequency and severity of REs and amblyopia and the spectacle prescription rate by age. Propensity score matching analysis evaluated the effect of median household income on RE and amblyopia frequency. Results: Among those who failed initial screening and were subsequently examined, significant rates of REs and amblyopia were detected: myopia (24.4%), hyperopia (35.4%), astigmatism (71.8%), anisometropia (8.9%), amblyopia (7.0%), and amblyopia risk (14.4%). A majority (65.0%) of those examined received prescription spectacles from UCI EyeMobile, with around a third requiring a new or updated prescription. The frequency of REs and amblyopia and the spectacle prescription rate were uniform across OC congressional districts. Myopia and amblyopia risk was positively and negatively associated with household income, respectively. Conclusion: The UCI EyeMobile for Children serves as a vital vision care program, providing free vision screening, comprehensive eye examinations, and spectacles. A significant number of children required examination, and a high frequency of REs and amblyopia were detected in examined children, with subsequent provision of prescription spectacles to most children.