Negative association of steroids with immunotherapy efficacy in a multi-tumor cohort: time and dose-dependent.

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism.

Urinary excretion of calcium, phosphate, magnesium, and uric acid in healthy infants and young children. Influence of feeding practices in early infancy.

BACKGROUND: Reference values for urinary calcium (Ca) and other solutes/creatinine (Cr) ratios in infants and young children are scarce. Its variation with type of lactation administered, breastfed (BF) or formula (F), is incompletely known. METHODS: A total of 511 spot urine samples from 136 children, aged 6 days to < 5 years, was collected. Urine was collected no fasting in infants < 18 months and first morning fasting in children aged 2.5-4 years. Urinary osmolality, Cr, urea, Ca, phosphate (P), magnesium (Mg), and uric acid (UA) were determined. Values are expressed as solute-to-Cr ratio. RESULTS: Urinary values were grouped according to the child's age: 6-17 days (G1), 1-5 months (G2), 6-12 months (G3), 13-18 months (G4), and 2.5-4 years (G5). G1 was excluded; Ca/Cr and UA/Cr (95th percentile) decreased with age (G2 vs. G5) from 1.64 to 0.39 and 2.33 to 0.83 mg/mg, respectively. The P/Cr median rises significantly with age from 0.31 (G2) to 1.66 mg/mg (G5). Mg/Cr was similar in all groups (median 0.20, 95th percentile 0.37 mg/mg). Ca/Cr (95th percentile) of BF infants was 1.80 mg/mg (< 3 months) and 1.63 mg/mg (3-5 months), much higher than F infants (0.93 and 0.90 mg/mg, respectively). P/Cr and P/Ca were lower in BF infants. CONCLUSIONS: Values for urinary Ca/Cr, P/Cr, Mg/Cr, and UA/Cr in infants and children < 5 years were updated. BF infants < 6 months showed higher Ca/Cr and lower P/Cr than F infants. New cutoff values to diagnose hypercalciuria in infants < 6 months, according to the type of lactation, are proposed.

Trace elements and heavy metal(loid)s triggering ecological risks in a heavily polluted river-reservoir system of central Mexico: Probabilistic approaches.

The contamination of trace elements and heavy metal(loid)s in water bodies has emerged as a global environmental concern due to their high toxicity at low concentrations to both biota and humans. This study aimed to evaluate the ecological risk associated with the occurrence and spatial distribution of Mn, Fe, Co, Cd, Ni, Zn, Sb, As, Tl, Cu, Pb, U, and V in the heavily polluted waters of an important river-reservoir system (Atoyac River Basin) in central Mexico, using two-level tired probabilistic approaches: Risk Quotient based on Species Sensitivity Distribution (RQSSD) and Joint Probability Curves (JPCs). The concentrations of these elements varied widely, ranging from 0.055 µg L-1 to 9200 µg L-1 and from 0.056 µg L-1 to 660 µg L-1, in both total and dissolved fractions, respectively. Although geogenic and anthropogenic sources contribute to the presence of these elements in waters, the discharge of untreated or poorly treated industrial wastewater is the main source of contamination. In this regard, the RQSSD results indicated high ecological risk for Mn, Fe, Co, Ni, Zn, and Sb, and medium or low ecological risk for As, Tl, U, and V at almost all sampling sites. The highest RQSSD values were found downstream of a large industrial corridor for Co, Zn, Tl, Pb, and V, with Tl, Pb, and V escalating to higher risk levels, highlighting the negative impact of industrial contamination on biota. The JPC results for these elements are consistent with the RQSSD approach, indicating an ecological risk to species from Mn, Fe, Co, Ni, Zn, and Sb in waters of the Atoyac River Basin. Therefore, the results of this study offer a thorough assessment of pollution risk, providing valuable insights for legislators on managing and mitigating exposure.

Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3.

BACKGROUND: EMPOWER-Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimab plus platinum-doublet chemotherapy versus placebo plus chemotherapy for first-line treatment of advanced non-small cell lung cancer. This study evaluated patient-reported outcomes (PROs). METHODS: PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) and Quality of Life-Lung Cancer Module (QLQ-LC13) questionnaires. Prespecified analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and proportional hazards model. RESULTS: A total of 312 patients were assigned to receive cemiplimab plus platinum-doublet chemotherapy and 154 to receive placebo plus chemotherapy; 391 (83.9%) were male and the median age was 63.0 years (range, 25-84). For pain symptoms (EORTC QLQ-C30), a statistically significant overall improvement from baseline (-4.98, 95% confidence interval [CI] -8.36 to -1.60, p = .004) and a statistically significant delay in TTD (hazard ratio, 0.39; 95% CI, 0.26-0.60, p < .0001) favoring cemiplimab plus chemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimab plus chemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimab plus chemotherapy compared with nonsignificant overall change from baseline for placebo plus chemotherapy (1.69, 95% CI, 0.20-3.19 vs. 1.08, 95% CI, -1.34 to 3.51; between arms, p = .673). No analyses yielded statistically significant PRO results favoring placebo plus chemotherapy for any QLQ-C30 or QLQ-LC13 scale. CONCLUSION: Cemiplimab plus chemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer-related and lung cancer-specific symptoms and functions.

Zoonoses in a changing world.

Animals are continuously exposed to pathogens but rarely get infected, because pathogens must overcome barriers to establish successful infections. Ongoing planetary changes affect factors relevant for such infections, such as pathogen pressure and pathogen exposure. The replacement of wildlife with domestic animals shrinks the original host reservoirs, whereas expanding agricultural frontiers lead to increased contact between natural and altered ecosystems, increasing pathogen exposure and reducing the area where the original hosts can live. Climate change alters species' distributions and phenology, pathogens included, resulting in exposure to pathogens that have colonized or recolonized new areas. Globalization leads to unwilling movement of and exposure to pathogens. Because people and domestic animals are overdominant planetwide, there is increased selective pressure for pathogens to infect them. Nature conservation measures can slow down but not fully prevent spillovers. Additional and enhanced surveillance methods in potential spillover hotspots should improve early detection and allow swifter responses to emerging outbreaks.

Occupational exposure to pesticides and symptoms of depression in agricultural workers. A systematic review.

BACKGROUND: The use of pesticides can result in harm to both the environment and human health. There is a growing concern in the field of occupational health about the impact on the mental health of agricultural workers. OBJECTIVES: The objective of this review was to systematize scientific evidence from the last ten years on the impact of occupational exposure to pesticides on the development of depression symptoms in agricultural workers. METHODS: We conducted a comprehensive search in the PubMed and Scopus databases from 2011 to September 2022. Our search included studies in English, Spanish, and Portuguese that examined the association between occupational exposure to pesticides and symptoms of depression in agricultural workers, following the guidelines recommended by the PRISMA statement and the PECO strategy (Population, Exposure, Comparison, and Outcomes). RESULTS: Among the 27 articles reviewed, 78% of them indicated a link between exposure to pesticides and the incidence of depression symptoms. The pesticides most frequently reported in the studies were organophosphates (17 studies), herbicides (12 studies), and pyrethroids (11 studies). The majority of the studies were rated as having intermediate to intermediate-high quality, with the use of standardized measures to assess both exposure and effect. CONCLUSION: The updated evidence presented in our review indicates a clear association between pesticide exposure and the development of depressive symptoms. However, more high-quality longitudinal studies are necessary to control for sociocultural variables and utilize pesticide-specific biomarkers and biomarkers of depression. Given the increased use of these chemicals and the health risks associated with depression, it is crucial to implement more stringent measures to monitor the mental health of agricultural workers regularly exposed to pesticides and to enhance surveillance of companies that apply these chemicals.

Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas.

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.

Complexity of Genomic Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae Isolates in Colombia Urges the Reinforcement of Whole Genome Sequencing-Based Surveillance Programs.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging public health problem. This study explores the specifics of CRKP epidemiology in Colombia based on whole genome sequencing (WGS) of the National Reference Laboratory at Instituto Nacional de Salud (INS)'s 2013-2017 sample collection. METHODS: A total of 425 CRKP isolates from 21 departments were analyzed by HiSeq-X10®Illumina high-throughput sequencing. Bioinformatic analysis was performed, primarily using the pipelines developed collaboratively by the National Institute for Health Research Global Health Research Unit (GHRU) on Genomic Surveillance of Antimicrobial Resistance (AMR), and AGROSAVIA. RESULTS: Of the 425 CRKP isolates, 91.5% were carbapenemase-producing strains. The data support a recent expansion and the endemicity of CRKP in Colombia with the circulation of 7 high-risk clones, the most frequent being CG258 (48.39% of isolates). We identified genes encoding carbapenemases blaKPC-3, blaKPC-2, blaNDM-1, blaNDM-9, blaVIM-2, blaVIM-4, and blaVIM-24, and various mobile genetic elements (MGE). The virulence of CRKP isolates was low, but colibactin (clb3) was present in 25.2% of isolates, and a hypervirulent CRKP clone (CG380) was reported for the first time in Colombia. ST258, ST512, and ST4851 were characterized by low levels of diversity in the core genome (ANI > 99.9%). CONCLUSIONS: The study outlines complex CRKP epidemiology in Colombia. CG258 expanded clonally and carries specific carbapenemases in specific MGEs, while the other high-risk clones (CG147, CG307, and CG152) present a more diverse complement of carbapenemases. The specifics of the Colombian situation stress the importance of WGS-based surveillance to monitor evolutionary trends of sequence types (STs), MGE, and resistance and virulence genes.

Genomic Diversity of Burkholderia pseudomallei Isolates, Colombia.

We report an analysis of the genomic diversity of isolates of Burkholderia pseudomallei, the cause of melioidosis, recovered in Colombia from routine surveillance during 2016-2017. B. pseudomallei appears genetically diverse, suggesting it is well established and has spread across the region.

Factors associated with the desire to undergo post-mastectomy breast reconstruction in a Mexican breast cancer center.

PURPOSE: To assess the proportion of breast cancer patients treated with total mastectomy who are interested in undergoing breast reconstruction, the factors associated with their desire to undergo this procedure, and the motives stated for their decision. METHODS: Women with stage I-III breast cancer, public health insurance, and history of total mastectomy treated at a center in Monterrey, Mexico, were invited to answer a series of questionnaires regarding their clinical and demographic characteristics, information received about breast reconstruction, body image, and relationship satisfaction. RESULTS: A total of 100 patients were interviewed, of which 68% desired to undergo breast reconstruction. Only 35% recalled talking about this procedure with a physician and 85% claimed not to have enough information to make an informed decision. Those who desired breast reconstruction were younger (p < 0.001), more likely to be in a relationship (p = 0.025), and had a higher probability of having talked to a physician about the procedure (p = 0.019). Furthermore, they felt less sexually attractive (p < 0.001), more deformed (p = 0.006), and less feminine (p = 0.005) since the mastectomy. The main motives to undergo this procedure were to have breast symmetry and greater freedom on which clothes to wear, while the main deterrent was the high economical cost. CONCLUSIONS: Insufficient information about the procedure and high economical cost were identified as potential barriers to undergo breast reconstruction. The findings of this study emphasize the pressing need to optimize patient care by providing information in a standardized manner and improving access to breast reconstruction within the Mexican public healthcare system.