Association between pembrolizumab-related thyroid adverse events and outcomes in early-stage triple negative breast cancer patients.

Pembrolizumab-related thyroid dysfunction has been associated with better outcomes in metastatic cancer patients. This study aims to examine the outcomes [pathological Complete Response (pCR) and event-free survival (EFS)] in early-stage triple negative breast cancer (TNBC) patients receiving preoperative therapy who developed pembrolizumab-related thyroid dysfunction. Patients were divided into four groups based on the occurrence or not of pembrolizumab-related thyroid dysfunction (group A and D, respectively) and, in case of pre-existing thyroid disorder, based on the need of levothyroxine start/adjustment or not (group B and C, respectively). pCR and EFS in groups ABC were compared to the ones in group D. Sixty-four early-stage TNBC patients were included and the median follow-up was 16.5 months (IQR 12.0-23.8). Multiple patterns of thyroid irAEs were observed (overt hypothyroidism in 56.3%, subclinical thyrotoxicosis in 28.1%, overt thyrotoxicosis and subclinical hypothyroidism in 21.9%, and 21.9% of patients). No statistical difference was found in pCR (chi-square test, p=0.611) comparing groups ABC to group D. The median EFS in groups ABC and in group D were 16.5 (IQR 12.0-24.0) and 16.0 (IQR 12.0-22.3) months, respectively (log-rank test, p=0.671). The percentage of patients obtaining pCR was 85.7% in patients developing pembrolizumab-related overt thyrotoxicosis and 42.1% in remaining patients (Chi-square test, p=0.036). The EFS was 16.0 months (IQR 12.0-25.0) in patients developing pembrolizumab-related overt thyrotoxicosis and 16.0 months (IQR 12.0-23.5) in the remaining patients (log-rank test, p=0.494). In conclusion, multiple patterns of pembrolizumab-related thyroid dysfunction occurs in early-stage TNBC. Patients developing pembrolizumab-related overt thyrotoxicosis are more likely to achieve pCR.

The protein domains of vertebrate species in which selection is more effective have greater intrinsic structural disorder.

The nearly neutral theory of molecular evolution posits variation among species in the effectiveness of selection. In an idealized model, the census population size determines both this minimum magnitude of the selection coefficient required for deleterious variants to be reliably purged, and the amount of neutral diversity. Empirically, an 'effective population size' is often estimated from the amount of putatively neutral genetic diversity and is assumed to also capture a species' effectiveness of selection. A potentially more direct measure of the effectiveness of selection is the degree to which selection maintains preferred codons. However, past metrics that compare codon bias across species are confounded by among-species variation in %GC content and/or amino acid composition. Here, we propose a new Codon Adaptation Index of Species (CAIS), based on Kullback-Leibler divergence, that corrects for both confounders. We demonstrate the use of CAIS correlations, as well as the Effective Number of Codons, to show that the protein domains of more highly adapted vertebrate species evolve higher intrinsic structural disorder.

Evolution is the process through which populations change over time, starting with mutations in the genetic sequence of an organism. Many of these mutations harm the survival and reproduction of an organism, but only by a very small amount. Some species, especially those with large populations, can purge these slightly harmful mutations more effectively than other species. This fact has been used by the 'drift barrier theory' to explain various profound differences amongst species, including differences in biological complexity. In this theory, the effectiveness of eliminating slightly harmful mutations is specified by an 'effective' population size, which depends on factors beyond just the number of individuals in the population. Effective population size is normally calculated from the amount of time a 'neutral' mutation (one with no effect at all) stays in the population before becoming lost or taking over. Estimating this time requires both representative data for genetic diversity and knowledge of the mutation rate. A major limitation is that these data are unavailable for most species. A second limitation is that a brief, temporary reduction in the number of individuals has an oversized impact on the metric, relative to its impact on the number of slighly harmful mutations accumulated. Weibel, Wheeler et al. developed a new metric to more directly determine how effectively a species purges slightly harmful mutations. Their approach is based on the fact that the genetic code has 'synonymous' sequences. These sequences code for the same amino acid building block, with one of these sequences being only slightly preferred over others. The metric by Weibel, Wheeler et al. quantifies the proportion of the genome from which less preferred synonymous sequences have been effectively purged. It judges a population to have a higher effective population size when the usage of synonymous sequences departs further from the usage predicted from mutational processes. The researchers expected that natural selection would favour 'ordered' proteins with robust three-dimensional structures, i.e., that species with a higher effective population size would tend to have more ordered versions of a protein. Instead, they found the opposite: species with a higher effective population size tend to have more disordered versions of the same protein. This changes our view of how natural selection acts on proteins. Why species are so different remains a fundamental question in biology. Weibel, Wheeler et al. provide a useful tool for future applications of drift barrier theory to a broad range of ways that species differ.

Hyoid Position and Aging: A Comprehensive Analysis Using AI-assisted Segmentation of 282 Computed Tomography Scans.

Background: With neck, aging the cervicomental angle becomes obtuse and may be influenced by hyoid bone aging. An understanding of hyoid position changes with aging will further our understanding of its role in neck contour changes. Methods: A 3D volumetric reconstruction of 282 neck computed tomography scans was performed. The cohort was categorized into three groups based on age: 20 years or older and younger than 40 years, 40 years or older and younger than 60 years, and 60 years or older and younger than 80 years. The vertical and horizontal hyoid distances in relation to the mandible were calculated for each patient. Results: A total of 282 patients (153 women, 129 men) were included in the cohort. The age groups were evenly distributed in men and women. Mean hyoid vertical and horizontal distances differed between women and men in all age groups. There was a significant difference in the hyoid vertical distance between 20-39 years old to 40-59 years old in men (P < 0.01), and 20-39 years old to 60-79 years old in both genders (women P = 0.005, men P < 0.01). Hyoid horizontal distance was not affected by age and sex (age and sex: P > 0.05), but rather by body mass index (BMI). Every 5 BMI points corresponded to a forward movement of 2 mm. Conclusions: As individuals age, the hyoid bone descends in both sexes, and an increase in BMI is associated with forward movement. Additional studies are needed to assess the correlation of the hyoid position between upright and supine positions.

Standardized Data Elements for Patients With Acute Pulmonary Embolism: A Consensus Report from the Pulmonary Embolism Research Collaborative.

Recent advances in therapy and the promulgation of multidisciplinary pulmonary embolism teams show great promise to improve management and outcomes of acute pulmonary embolism (PE). However, the absence of randomized evidence and lack of consensus leads to tremendous variations in treatment and compromises the wide implementation of new innovations. Moreover, the changing landscape of health care, where quality, cost, and accountability are increasingly relevant, dictates that a broad spectrum of outcomes of care must be routinely monitored to fully capture the impact of modern PE treatment. We set out to standardize data collection in patients with PE undergoing evaluation and treatment, and thus establish the foundation for an expanding evidence base that will address gaps in evidence and inform future care for acute PE. To do so, >100 international PE thought leaders convened in Washington, DC, in April 2022 to form the Pulmonary Embolism Research Collaborative. Participants included physician experts, key members of the US Food and Drug Administration, patient representatives, and industry leaders. Recognizing the multidisciplinary nature of PE care, the Pulmonary Embolism Research Collaborative was created with representative experts from stakeholder medical subspecialties, including cardiology, pulmonology, vascular medicine, critical care, hematology, cardiac surgery, emergency medicine, hospital medicine, and pharmacology. A list of critical evidence gaps was composed with a matching comprehensive set of standardized data elements; these data points will provide a foundation for productive research, knowledge enhancement, and advancement of clinical care within the field of acute PE, and contribute to answering urgent unmet needs in PE management. Evidence produced through the Pulmonary Embolism Research Collaborative, as it is applied to data collection, promises to provide crucial knowledge that will ultimately produce a robust evidence base that will lead to standardization and harmonization of PE management and improved outcomes.

Heterogeneity of Residual Disease After Neoadjuvant Systemic Therapy in Breast Cancer: A Review.

Importance: Over the past 2 decades, systemic therapy for early-stage breast cancer has gradually moved from the adjuvant to the neoadjuvant setting. Administration of systemic therapy before surgery leads to potential improvements in surgical outcomes and allows for the assessment of the pathologic response to treatment. For patients with residual disease (RD), 3 adjuvant strategies have been shown to improve outcomes: (1) adjuvant trastuzumab emtansine for ERBB2-positive disease, (2) adjuvant capecitabine for triple-negative disease, and (3) adjuvant olaparib for patients with germline BRCA variants. Furthermore, studies are testing novel drugs in the postneoadjuvant setting. Given the potential to tailor adjuvant therapy based on the response to preoperative systemic therapy, recognizing the complexities of response to neoadjuvant therapy and moving beyond the binary paradigm of RD vs experiencing a pathologic complete response is becoming increasingly necessary. Observations: Novel antibody-drug conjugates, anti-ERBB2 tyrosine kinase inhibitors, and immune checkpoint inhibitors are being evaluated as additional rescue options in phase 3 trials for patients with RD after neoadjuvant treatment. Concomitantly, the prognostic role of RD has been refined by the introduction of the residual cancer burden. In addition, the genomic landscape of RD has been found to be associated with long-term prognosis, as has the immune background of the disease evaluated via the presence of tumor-infiltrating lymphocytes. Lastly, the dynamics of circulating tumor DNA may allow for further improvement in prognostication by understanding which patients harbor detectable minimal RD. Conclusions and Relevance: Escalating adjuvant treatment has led to meaningful survival improvements among patients with breast cancer and RD after neoadjuvant therapy. Uncovering the anatomic and biological intricacies of RD will allow for increased precision in postneoadjuvant treatments, moving beyond the binary paradigm of RD vs pathologic complete response, toward more tailored rescue strategies in the adjuvant setting.

Protective effect of rupatadine on testicular ischemia/reperfusion injury in rats: Modulation of IL-6/STAT3, Akt/ mTOR signaling pathways.

BACKGROUNDS & AIM: Spermatic cord rotation is a common problem in the field of urology, that finally results in necrosis of testicular tissue as well as male infertility. Rupatadine (RUP); a second-generation antihistaminic drug; demonstrated to have a possible protective effect in variable ischemia/reperfusion (I/R) rat models, but its role has not been studied yet in testicular I/R model. MATERIAL & METHODS: The present study investigated RUP ability to ameliorate testicular I/R injury. The study includes four groups (6 rats/group); sham group, sham group pretreated with RUP (6 mg/kg/day; orally) for 14 days, I/R group, and RUP-I/R pretreated group. KEY FINDINGS: The results demonstrated that I/R significantly lowered serum testosterone level and testicular tissue content of reduced glutathione. Besides, a significant elevation in malondialdehyde level, hypoxia-inducible factor-1, signal transducers and activators of transcription-3 (STAT-3), interleukin-6 (IL-6), histamine, and platelet activating factor levels along with an inhibition in testicular tissue level of vascular endothelial growth factor-A (VEGF-A) with an evident increase in caspase-3 immunoexpression in germ cells. Also, I/R significantly lowered p-AKT and mTOR testicular expression. While, RUP-I/R pretreated group showed a reversal in the testicular I/R damaging effects in a significant manner in the all the aforementioned parameters. CONCLUSION: Based on these findings; RUP was proved to have a possible protective effect in testicular I/R injury via its antioxidant effect and its ability to modulate IL-6/STAT3, Akt/ mTOR inflammatory signaling pathways with improvement in the testicular VEGF-A level.

Mapping high-risk areas for Mycobacterium tuberculosis complex bacteria transmission: Linking host space use and environmental contamination.

In many Mediterranean ecosystems, animal tuberculosis (TB), caused by Mycobacterium bovis, an ecovar of Mycobacterium tuberculosis complex (MTBC), is maintained by multi-host communities. It is hypothesised that interspecies transmission is mainly indirect via shared contaminated environments. Therefore, identifying spatial areas where MTBC bacteria occur and quantifying space use by susceptible hosts might help predict the spatial likelihood of transmission across the landscape. Here, we aimed to evaluate the transmission risk of MTBC in a multi-host system involving wildlife (ungulates and carnivores) and cattle (Bos taurus). We collected eighty-nine samples from natural substrates (water, soil, and mud) at 38 sampling sites in a TB endemic area within a Mediterranean agroforestry system in Portugal. These samples were analysed by real-time PCR to detect MTBC DNA. Additionally, host-specific space use intensity maps were obtained through camera-trapping covering the same sampling sites. Results evidenced that a significant proportion of samples were positive for MTBC DNA (49 %), suggesting that the contamination is widespread in the area. Moreover, they showed that the probability of MTBC occurrence in the environment was significantly influenced by topographic features (i.e., slope), although other non-significant predictor related with soil conditions (SMI: soil moisture index) incorporated the MTBC contamination model. The integration of host space use intensity maps with the spatial detection of MTBC showed that the red deer (Cervus elaphus) and wild boar (Sus scrofa) exhibited the highest percentages of high-risk areas for MTBC transmission. Furthermore, when considering the co-occurrence of multiple hosts, transmission risk analyses revealed that 26.5 % of the study area represented high-risk conditions for MTBC transmission, mainly in forest areas.

Mentorship of Junior Surgical Faculty Across Academic Programs in Surgery.

Importance: Because mentorship is critical for professional development and career advancement, it is essential to examine the status of mentorship and identify challenges that junior surgical faculty (assistant and associate professors) face obtaining effective mentorship. Objective: To evaluate the mentorship experience for junior surgical faculty and highlight areas for improvement. Design, Setting, and Participants: This qualitative study was an explanatory sequential mixed-methods study including an anonymous survey on mentorship followed by semistructured interviews to expand on survey findings. Junior surgical faculty from 18 US academic surgery programs were included in the anonymous survey and interviews. Survey responses between "formal" (assigned by the department) vs "informal" (sought out by the faculty) mentors and male vs female junior faculty were compared using χ2 tests. Interview responses were analyzed for themes until thematic saturation was achieved. Survey responses were collected from November 2022 to August 2023, and interviews conducted from July to December 2023. Exposure: Mentorship from formal and/or informal mentors. Main Outcomes and Measures: Survey gauged the availability and satisfaction with formal and informal mentorship; interviews assessed broad themes regarding mentorship. Results: Of 825 survey recipients, 333 (40.4%) responded; 155 (51.7%) were male and 134 (44.6%) female. Nearly all respondents (319 [95.8%]) agreed or strongly agreed that mentorship is important to their surgical career, especially for professional networking (309 respondents [92.8%]), career advancement (301 [90.4%]), and research (294 [88.3%]). However, only 58 respondents (18.3%) had a formal mentor. More female than male faculty had informal mentors (123 [91.8%] vs 123 [79.4%]; P = .003). Overall satisfaction was higher with informal mentorship than formal mentorship (221 [85.0%] vs 40 [69.0%]; P = .01). Most male and female faculty reported no preferences in gender or race and ethnicity for their mentors. When asked if they had good mentor options if they wanted to change mentors, 141 (47.8%) responded no. From the interviews (n = 20), 6 themes were identified, including absence of mentorship infrastructure, preferred mentor characteristics, and optimizing mentorship. Conclusions and Relevance: Academic junior surgical faculty agree mentorship is vital to their careers. However, this study found that few had formal mentors and almost half need more satisfactory options if they want to change mentors. Academic surgical programs should adopt a framework for facilitating mentorship and optimize mentor-mentee relationships through alignment of mentor-mentee goals and needs.

Comparative and phylogenetic analyses of plastid genomes of the medicinally important genus Alisma (Alismataceae).

Alisma L. is a medicinally important genus of aquatic and wetland plants consisting of c. 10 recognized species. However, largely due to polyploidy and limited taxon and gene sampling, the phylogenomic relationships of Alisma remain challenging. In this study, we sequenced 34 accessions of Alismataceae, including eight of the ten species of Alisma, one species of Echinodorus and one species of Luronium, to perform comparative analyses of plastid genomes and phylogenetic analyses. Comparative analysis of plastid genomes revealed high sequence similarity among species within the genus. Our study analyzed structural changes and variations in the plastomes of Alisma, including IR expansion or contraction, and gene duplication or loss. Phylogenetic results suggest that Alisma is monophyletic, and constitutes four groups: (1) A. lanceolatum and A. canaliculatum; (2) the North American clade of A. subcordatum and A. triviale; (3) A. wahlenbergii and A. gramineum; and (4) A. plantago-aquatica from Eurasia and northern Africa with the eastern Asian A. orientale nested within it. Hence the results challenge the recognition of A. orientale as a distinct species and raise the possibility of treating it as a synonym of the widespread A. plantago-aquatica. The well-known Alismatis Rhizoma (Zexie) in Chinese medicine was likely derived from the morphologically variable Alisma plantago-aquatica throughout its long history of cultivation in Asia. The plastome phylogenetic results also support the tetraploid A. lanceolatum as the likely maternal parent of the hexaploid eastern Asian A. canaliculatum.

Short-term HIIT impacts HDL function differently in lean, obese, and diabetic subjects.

Introduction: High density lipoproteins (HDL) exert cardiovascular protection in part through their antioxidant capacity and cholesterol efflux function. Effects of exercise training on HDL function are yet to be well established, while impact on triacylglycerol (TG)-lowering has been often reported. We previously showed that a short-term high-intensity interval training (HIIT) program improves insulin sensitivity but does not inhibit inflammatory pathways in immune cells in insulin-resistant subjects. The purpose of this study is to evaluate HDL function along with changes of lipoproteins after the short-term HIIT program in lean, obese nondiabetic, and obese type 2 diabetic (T2DM) subjects. Methods: All individuals underwent a supervised 15-day program of alternative HIIT for 40 minutes per day. VO2peak was determined before and after this training program. A pre-training fasting blood sample was collected, and the post-training fasting blood sample collection was performed 36 hours after the last exercise session. Results: Blood lipid profile and HDL function were analyzed before and after the HIIT program. Along with improved blood lipid profiles in obese and T2DM subjects, the HIIT program affected circulating apolipoprotein amounts differently. The HIIT program increased HDL-cholesterol levels and improved the cholesterol efflux capacity only in lean subjects. Furthermore, the HIIT program improved the antioxidant capacity of HDL in all subjects. Data from multiple logistic regression analysis showed that changes in HDL antioxidant capacity were inversely associated with changes in atherogenic lipids and changes in HDL-TG content. Discussion: We show that a short-term HIIT program improves aspects of HDL function depending on metabolic contexts, which correlates with improvements in blood lipid profile. Our results demonstrate that TG content in HDL particles may play a negative role in the anti-atherogenic function of HDL.

Identification of host endotypes using peripheral blood transcriptomics in a prospective cohort of patients with endocarditis.

BACKGROUND: Host responses to infection are a major determinant of outcome. However, the existence of different response profiles in patients with endocarditis has not been addressed. Our objective was to apply transcriptomics to identify endotypes in patients with infective endocarditis. METHODS: Thirty-two patients with infective endocarditis were studied. Clinical data and a blood sample were collected at diagnosis, and RNA sequenced. Gene expression was used to identify two clusters (endocarditis endotypes EE1 and EE2). RNA sequencing was repeated after surgery. Transcriptionally active cell populations were identified by deconvolution. Differences between endotypes in clinical data, survival, gene expression and molecular pathways involved were assessed. Identified endotypes were recapitulated in a cohort of COVID19 patients. RESULTS: 18 and 14 patients were assigned to EE1 and EE2 respectively, with no differences in clinical data. Patients assigned to EE2 showed an enrichment in genes related to T-cell maturation and a decrease in the activation of the STAT pathway, with higher counts of active T-cells and lower counts of neutrophils. Fourteen patients (9 in EE1 and 5 in EE2) were submitted to surgery. Surgery in EE2 patients shifted gene expression towards a EE1-like profile. In-hospital mortality was higher in EE1 (56% vs 14%, p=0.027) with adjusted hazard ratio of 12.987 (95% confidence interval 3.356 - 50]. Translation of these endotypes to COVID19 and non-COVID septic patients yielded similar results in cell populations and outcome. CONCLUSIONS: Gene expression reveals two endotypes in patients with acute endocarditis, with different underlying pathogenetic mechanisms, response to surgery and outcome.

Clinical outcomes and emergence of resistance of Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam.

Few studies compare outcomes of patients with difficult-to-treat resistance (DTR) Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam. A multicenter prospective study was conducted of unique patients with DTR P. aeruginosa infections from 2018 to 2023 receiving >72 h of ceftolozane-tazobactam or ceftazidime-avibactam, with confirmation that the P. aeruginosa isolate was susceptible to the agent administered by broth microdilution. Inverse probability weighting (IPW) incorporating propensity scores was utilized to ensure balanced baseline characteristics. Regression performed on the post-IPW group determined 30-day mortality and subsequent emergence of resistance (i.e., ≥4-fold increase in MIC) to the initial treatment (i.e., ceftolozane-tazobactam or ceftazidime-avibactam). Among 186 eligible patients, 102 (55%) received ceftolozane-tazobactam and 84 (45%) received ceftazidime-avibactam. In the post-IPW cohort, balance was achieved across all variables [e.g., demographics, severity of illness, severe immunocompromise, Charlson Comorbidity Index ≥5, continuous renal replacement therapy (CRRT), source of infection, combination therapy]. Thirty-day mortality was similar between the ceftolozane-tazobactam and ceftazidime-avibactam groups [21% vs 17%; adjusted odds ratio (aOR): 1.01 (95% confidence interval, CI: 0.90-1.14)]. Emergence of resistance was higher in the ceftolozane-tazobactam group [38% vs 25%; aOR: 1.89 (95% CI: 0.98-4.88)], but did not achieve statistical significance. Prolonged treatment durations and use of CRRT were associated with increased emergence of resistance (both P = 0.04). Although the survival of patients with DTR P. aeruginosa infections appears similar regardless of whether ceftolozane-tazobactam or ceftazidime-avibactam is prescribed, the emergence of resistance may be more concerning with the former. Plausible mechanistic explanations support these findings. Modifiable risk factors were identified that may mitigate this risk.

An Improved Chromosome-scale Genome Assembly and Population Genetics resource for Populus tremula.

Aspen (Populus tremula L.) is a keystone species and a model system for forest tree genomics. We present an updated resource comprising a chromosome-scale assembly, population genetics and genomics data. Using the resource, we explore the genetic basis of natural variation in leaf size and shape, traits with complex genetic architecture. We generated the genome assembly using long-read sequencing, optical and high-density genetic maps. We conducted whole-genome resequencing of the Umeå Aspen (UmAsp) collection. Using the assembly and re-sequencing data from the UmAsp, Swedish Aspen (SwAsp) and Scottish Aspen (ScotAsp) collections we performed genome-wide association analyses (GWAS) using Single Nucleotide Polymorphisms (SNPs) for 26 leaf physiognomy phenotypes. We conducted Assay of Transposase Accessible Chromatin sequencing (ATAC-Seq), identified genomic regions of accessible chromatin, and subset SNPs to these regions, improving the GWAS detection rate. We identified candidate long non-coding RNAs in leaf samples, quantified their expression in an updated co-expression network, and used this to explore the functions of candidate genes identified from the GWAS. A GWAS found SNP associations for seven traits. The associated SNPs were in or near genes annotated with developmental functions, which represent candidates for further study. Of particular interest was a ~177-kbp region harbouring associations with several leaf phenotypes in ScotAsp. We have incorporated the assembly, population genetics, genomics, and GWAS data into the PlantGenIE.org web resource, including updating existing genomics data to the new genome version, to enable easy exploration and visualisation. We provide all raw and processed data to facilitate reuse in future studies.

Colletotrichum species causing Glomerella leaf spot and apple bitter rot in the southeastern United States exhibit disparities in relative frequency, morphological phenotype, and QoI sensitivity.

Glomerella leaf spot (GLS), Glomerella fruit rot (GFR) and apple bitter rot (ABR), caused by Colletotrichum spp. are amongst the most devastating apple diseases in the southeastern United States. While several species have been identified as causal pathogens of GLS, GFR, and ABR, their relative frequency and fungicide sensitivity status in the southeastern U.S. is unknown. In total, 381 Colletotrichum isolates were obtained from symptomatic leaves and fruit from 18 conventionally managed apple orchards and two baseline populations in western North Carolina and Georgia in 2016 and 2017. Multilocus DNA sequence analysis revealed that C. chrysophilum was the predominant cause of GLS and GFR, and C. fioriniae was the causal agent of ABR. Baseline and commercial populations of Colletotrichum spp. were evaluated for sensitivity to pyraclostrobin and trifloxystrobin and no statistical differences in sensitivity between the two species were observed for conidial germination. However, EC50 values were significantly lower for C. fioriniae compared to C. chrysophilum for both fungicides regarding mycelial inhibition. Isolates recovered from commercial orchards revealed that 5 populations of C. chrysophilum and 1 population of C. fioriniae had reduced sensitivity to trifloxystrobin, and 1 C. fioriniae population had reduced sensitivity to pyraclostrobin via conidial germination assays. The cytb gene for 27 isolates of C. fioriniae, C. chrysophilum, and C. fructicola with different QoI sensitivities revealed the G143A mutation in a single isolate of C. chrysophilum with insensitivity to both fungicides. Results of these studies suggest that two Colletotrichum spp. predominantly cause GLS and ABR in the southeastern U.S. and that a reduction in sensitivity to some QoI fungicides may be responsible for control failures. This study also provides basis for monitoring shifts in QoI sensitivity in Colletotrichum spp. causing disease on apple in the southeastern U.S.

Parasiticide use and obesity in dogs with sudden acquired retinal degeneration syndrome.

OBJECTIVE: To investigate parasiticide use and describe signalment features in patients with sudden acquired retinal degeneration syndrome (SARDS). ANIMALS: Retrospective case-control study of dogs with (n = 71) and without (136) SARDS. METHODS: Parasiticide use, presentation season, weight, body condition, and signalment were compared between dogs diagnosed with SARDS and the reference population by use of descriptive statistics and logistic regression. RESULTS: Animals with SARDS were at a 5.99 times higher odds of having previously used imidacloprid (95% CI, 1.6 to 22.2; P = .003). However, time of last imidocloprid administration was > 6 years prior to diagnosis in 6 SARDS-affected individuals and 15, 26, or 42 months before diagnosis (n = 1 each). No other class of parasiticide had a significant association with SARDS. Seasonal variation was observed with a negative association identified between incidence of SARDS and tick season (October to January; P < .001). Overweight and obese dogs were 4.42 (95% CI, 1.9 to 10.4) and 4.96 (95% CI, 2.1 to 11.6) times more likely to have SARDS (P ≤ .001). History of polyphagia or weight gain was not associated with an increased likelihood of being overweight or obese within the SARDS-affected population (P > .108). CLINICAL RELEVANCE: While a statistically significant association was found between imidacloprid use and SARDS, this is unlikely to be clinically significant given the lack of a temporal association, sparse exposure numbers, and low point estimate of the OR. A positive association between being overweight or obese and a diagnosis of SARDS was found independent of polyphagia and weight gain, suggesting that it may be a risk factor for the development of SARDS.

Dual HER2 inhibition: mechanisms of synergy, patient selection, and resistance.

HER2-targeted therapies for patients with HER2+ breast cancer are rapidly evolving, offering a range of more complex and personalized treatment options. Currently, an array of anti-HER2 monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates are administered, sometimes alongside chemotherapy or endocrine therapy, both in curative and palliative contexts. However, the heterogeneous nature of HER2+ breast cancer demands a deeper understanding of disease biology and its role in responsiveness to novel HER2-targeted agents, as well as non-HER2-targeted therapies, in order to optimize patient outcomes. In this Review, we revisit the mechanisms of action of HER2-targeted agents, examine the evidence supporting the use of dual HER2 blockade in patients with HER2-amplified tumours, and explore the role of biomarkers in guiding future treatment strategies. We also discuss potential implications for the future treatment of patients with HER2+ breast cancer.

In the search for new gold metalloantibiotics: In vitro evaluation of Au(III) (C

A series of (C^S)-cyclometallated Au(III) cationic complexes of general formula [Au(dppta)(dtc)]+, [Au(dppta)(azmtd)]+ and [Au(dppta)(azc)Cl]+ (dppta = N,N-diisopropyl-P,P-diphenylphosphinothioic amide-κ2C,S; dtc = dithiocarbamate-κ2S,S'; azc = azolium-2-dithiocarboxylate-κ1S; azmdt = azol(in)ium-2-(methoxy)methanedithiol-κ2S,S') were synthetized and tested against a panel of bacterial strains belonging to different Gram-positive and Gram-negative species of the ESKAPE group of pathogens. Among the tested compounds, complex 4c had the higher Therapeutic Index (TI) against multidrug resistant strains of S. aureus, S. epidermidis and A. baumannii, showing a more favourable cytotoxicity profile than the reference gold metalloantibiotic Auranofin. © 2024 xxxxxxxx. Hosting by Elsevier B.V. All rights reserved.

Liposomal formulation of a gold(III) metalloantibiotic: a promising strategy against antimicrobial resistance.

A novel lipoformulation was developed by encapsulating cationic (S^C)-cyclometallated gold(III) complex [Au(dppta)(N2Py-PZ-dtc)]+ (AuPyPZ) in liposomes. The liposomal form of compound AuPyPZ has a bactericidal action similar to that of the free drug without any appreciable effect on the viability of mammalian cells. Furthermore, the nanoformulation reduces metalloantibiotic-induced inhibition of hERG and the inhibition of cytochromes, significantly decreasing the potential liabilities of the metallodrug. The obtained metalloantibiotic liposomal formulation shows high stability and suitable properties for drug delivery, representing an effective strategy to fight against drug-resistant bacteria.

Burnout and resilience among physical therapy students: a cross-sectional study.

BACKGROUND: This study aimed to examine the prevalence of burnout, determine burnout-related factors, investigate resilience levels, and assess the relationship between burnout and resilience among physical therapy (PT) students at King Saud University (KSU) in Saudi Arabia. MATERIAL AND METHODS: This cross-sectional study involved 153 PT students studying at KSU between January and March 2023. The participants completed an online questionnaire, a Maslach Burnout Inventory, and a Brief Resilience Scale. RESULTS: Low-to-moderate levels of Emotional Exhaustion (EE) were observed in 85% of the participants and high Depersonalization (DP) levels were reported by 34.2%. Female participants reported higher levels of EE and DP, whereas males had a greater prevalence of low Personal Achievement (PA) levels. Approximately 6.5% of the study participants reported high burnout levels (a combination of high DP, high EE, and low PA). Academic stress, followed by sleeping difficulties and changes in the academic year structure, were the most important factors contributing to higher levels of burnout (75.2%, 56.9%, and 43.8%, respectively). Most study participants around (66.0%) reported normal resilience levels. A significant correlation was detected between resilience and 2 domains of burnout (DP and PA), with the correlation being negative and weak for DP and positive and moderate for PA. CONCLUSIONS: Overall, low-to-moderate levels of burnout were observed among the PT students who took part. Related factors that contributed to burnout were academic stress, sleeping difficulties, and academic year structure. A normal level of resilience was found to be significantly related to DP and PA but not to EE on the burnout subscales. Higher levels of resilience can be considered to play a protective role against burnout among PT students. Med Pr Work Health Saf. 2024;75(4):343-354.

A "plus one" strategy impacts replication of felid alphaherpesvirus 1, Mycoplasma and Chlamydia, and the metabolism of coinfected feline cells.

Coinfections are known to play an important role in disease progression and severity. Coinfections are common in cats, but no coinfection studies have investigated the in vitro dynamics between feline viral and bacterial pathogens. In this study, we performed co-culture and invasion assays to investigate the ability of common feline bacterial respiratory pathogens, Chlamydia felis and Mycoplasma felis, to replicate in and invade into Crandell-Rees feline kidney cells. We subsequently investigated how coinfection of these feline cells with each bacterium (C. felis or M. felis) and the common feline viral pathogen, felid alphaherpesvirus 1 (FHV-1), affects replication of each agent in this cell culture system. We also investigated the metabolic impact of each co-pathogen using metabolomic analysis of infected and coinfected cells. C. felis was able to invade and replicate in CRFKs, while M. felis had little capacity to invade. During coinfection, FHV-1 replication was minimally affected by the presence of either bacterial pathogen, but bacterial replication kinetics were more affected, particularly in M. felis. Both C. felis and M. felis replicated to higher levels in the presence of a secondary pathogen. Coinfections resulted in reprogramming of the glycolysis pathway, the pentose phosphate pathway, and the tricarboxylic acid cycle. The distinct metabolic profiles of coinfected cells compared to those of cells infected with just one of these three pathogens, as well as the impact of coinfections on viral or bacterial load, suggest strong interactions between these three pathogens and possible synergistic mechanisms enhancing virulence that need further investigation.IMPORTANCEIn the natural world, respiratory pathogens coexist within their hosts, but their dynamics and interactions remain largely unexplored. Herpesviruses, mycoplasmas, and chlamydias are common and significant causes of acute and chronic respiratory and system disease in animals and people, and these diseases are increasingly found to be polymicrobial. This study investigates how coinfection of feline cells between three respiratory pathogens of cats impact each other as well as the host innate metabolic response to infection. Each of these pathogens have been implicated in the induction of feline upper respiratory tract disease in cats, which is the leading cause of euthanasia in shelters. Understanding how coinfection impacts co-pathogenesis and host responses is critical for improving disease management.