The thymus road to a T cell: migration, selection, and atrophy.

The thymus plays a pivotal role in generating a highly-diverse repertoire of T lymphocytes while preventing autoimmunity. Thymus seeding progenitors (TSPs) are a heterogeneous group of multipotent progenitors that migrate to the thymus via CCR7 and CCR9 receptors. While NOTCH guides thymus progenitors toward T cell fate, the absence or disruption of NOTCH signaling renders the thymus microenvironment permissive to other cell fates. Following T cell commitment, developing T cells undergo multiple selection checkpoints by engaging with the extracellular matrix, and interacting with thymic epithelial cells (TECs) and other immune subsets across the different compartments of the thymus. The different selection checkpoints assess the T cell receptor (TCR) performance, with failure resulting in either repurposing (agonist selection), or cell death. Additionally, environmental cues such as inflammation and endocrine signaling induce acute thymus atrophy, contributing to the demise of most developing T cells during thymic selection. We discuss the occurrence of acute thymus atrophy in response to systemic inflammation. The thymus demonstrates high plasticity, shaping inflammation by abrogating T cell development and undergoing profound structural changes, and facilitating regeneration and restoration of T cell development once inflammation is resolved. Despite the challenges, thymic selection ensures a highly diverse T cell repertoire capable of discerning between self and non-self antigens, ultimately egressing to secondary lymphoid organs where they complete their maturation and exert their functions.

Strategies Used by Puerto Rican Children in the Cognitive Assessment System and Their Relationship with Planning Performance.

Studies involving the Cognitive Assessment System (CAS) planning scale typically use only the subtest and scale scores without assessing the strategies employed by the participants. This study addressed this gap and examined the planning strategies used by children in the CAS2: Spanish version and their relationship with planning performance. We conducted an exploratory cross-sectional study with 26 Puerto Rican children aged 8 to 11. Results showed that no strategies were consistently used by participants according to examinees' reports (f = 0-46%), but examiners observed consistent use of some strategies such as "coded left to right, top to bottom", f = 92%; "scanned the page for the next number or letter", f = 100%. Welch's t-tests did not show relationships between participants' performance and the strategies observed by examiners, | mean differences | = 0.05-0.81, ps ≥ 0.05, nor with the strategies reported by participants, | mean differences | = 0.05-1.69, ps ≥ 0.05. These findings suggest that although the examiners may observe the use of strategies, the examinees are unaware of the strategies they use, and the strategies used are not associated with their performance. Future studies are needed to confirm these findings.

The Validation of the Greulich and Pyle Atlas for Radiological Bone Age Assessments in a Pediatric Population from the Canary Islands.

Bone age assessments measure the growth and development of children and adolescents by evaluating their skeletal maturity, which is influenced by various factors like heredity, ethnicity, culture, and nutrition. The clinical standards for this assessment should be up to date and appropriate for the specific population being studied. This study validates the GP-Canary Atlas for accurately predicting bone age by analyzing posteroanterior left hand and wrist radiographs of healthy children (80 females and 134 males) from the Canary Islands across various developmental stages and genders. We found strong intra-rater reliability among all three raters, with Raters 1 and 2 indicating very high consistency (intra-class coefficients = 0.990 to 0.996) and Rater 3 displaying slightly lower but still strong reliability (intra-class coefficients = 0.921 to 0.976). The inter-rater agreement was excellent between Raters 1 and 2 but significantly lower between Rater 3 and the other two raters, with intra-class coefficients of 0.408 and 0.463 for Rater 1 and 0.327 and 0.509 for Rater 2. The accuracy analysis revealed a substantial underestimation of bone age compared to chronological age for preschool- (mean difference = 17.036 months; p < 0.001) and school-age males (mean difference = 13.298 months; p < 0.001). However, this was not observed in females, where the mean difference was minimal (3.949 months; p < 0.239). In contrast, the Atlas showed greater accuracy for teenagers, showing only a slight overestimation (mean difference = 3.159 months; p = 0.823). In conclusion, the GP-Canary Atlas demonstrates overall precision but requires caution as it underestimates the BA in preschool children and overestimates it in school-age girls and adolescents.

Genomic Analysis of Antimicrobial Resistance in Pseudomonas aeruginosa from a "One Health" Perspective.

The "One Health" approach provides a comprehensive framework for understanding antimicrobial resistance. This perspective is of particular importance in the study of Pseudomonas aeruginosa, as it is not only a pathogen that affects humans but also persists in environmental reservoirs. To assess evolutionary selection for niche-specific traits, a genomic comparison of 749 P. aeruginosa strains from three environments (clinical, aquatic, and soil) was performed. The results showed that the environment does indeed exert selective pressure on specific traits. The high percentage of persistent genome, the lack of correlation between phylogeny and origin of the isolate, and the high intrinsic resistance indicate that the species has a high potential for pathogenicity and resistance, regardless of the reservoir. The flexible genome showed an enrichment of metal resistance genes, which could act as a co-selection of antibiotic resistance genes. In the plasmids, resistance genes were found in multigenic clusters, with the presence of a mobile integron being prominent. This integron was identified in several pathogenic strains belonging to distantly related taxa with a worldwide distribution, showing the risk of rapid evolution of resistance. These results provide a more complete understanding of the evolution of P. aeruginosa, which could help develop new prevention strategies.

[Neuroendocrine expression markers in triple-negative, luminal-A, luminal-B and HER2neu breast cancer]. / Expresión de marcadores neuroendócrinos en cáncer de mama triple-negativo, luminal-A, luminal-B y HER2neu.

Background: Primary breast tumors with neuroendocrine (NE) differentiation are a heterogeneous tumor group with diversity of biological behavior, with poorly defined prevalence and prognosis. Objective: To evaluate the chromogranin, synaptophysin, CD56, INSM1 markers expression prevalence and the association between NE differentiation and tumor molecular type. Material and methods: Observational, cross-sectional study which included 110 breast tissue samples with primary invasive carcinoma. Immunohistochemistry was performed for chromogranin, synaptophysin, CD56 and INMS1 markers. NE differentiation was considered with 10-90% positive cells, and NE tumor with > 90% positive cells. Results: 26.3% showed neuroendocrine differentiation. Out of these, 48.2% were luminal-A type, 24.1% luminal-B, 11.5% HER2neu, 17.2% triple-negative; 1.8% were NE tumors. Tumors were marker positive, and out of these to chromogranin in 24.5%, synaptophysin in 28.2%, CD56 in 2.7%, INSM1 in 16.4%. Synaptophysin was expressed in 17.3% luminal-A type, 6.4% luminal-B, 0.9% HER2neu, 3.6% triple-negative. NE differentiation showed association with synaptophysin expression (r = 0.586, p = 0.0001). Conclusion: The NE differentiation prevalence was 26.3% in primary invasive breast cancers, with luminal-A molecular type predominance.

Introducción: los tumores primarios de mama con diferenciación neuroendócrina (NEBC por sus siglas en inglés) son un grupo heterogéneo de tumores con diversidad de comportamiento biológico, con prevalencia y pronóstico poco definido. Objetivo: evaluar la prevalencia de la expresión los marcadores cromogranina, sinaptofisina, CD56, INSM1 y la asociación entre la diferenciación neuroendócrina y el tipo molecular del tumor. Material y métodos: estudio observacional, transversal que incluyó 110 muestras de tejido mamario con carcinoma invasor primario. Se realizó inmunohistoquímica para los marcadores cromogranina, sinaptofisina, CD56 y INMS1. La presencia 10-90% de células positivas se consideró diferenciación neuroendócrina y tumor neuroendócrino con > 90% de células positivas. Resultados: el 26.3% mostró diferenciación neuroendócrina. De estos, 48.2% fueron tipo luminal-A, 24.1% luminal-B, 11.5% HER2neu y 17.2% triple-negativo; 1.8% resultaron tumores neuroendócrinos. Los tumores presentaron marcadores positivos y de estos, 24.5% fueron a cromogranina, 28.2% a sinaptofisina, 2.7% a CD56 y 16.4% a INSM1. La sinaptofisina se expresó en 17.3% del tipo luminal-A, 6.4% luminal-B, 0.9% HER2neu, 3.6% triple-negativo. La diferenciación neuroendócrina mostró asociación con la expresión de sinaptofisina (r = 0.586, p = 0.0001). Conclusión: la prevalencia de la diferenciación neuroendócrina fue del 26.3% en los cánceres invasores primarios de mama, con predominio en el tipo molecular luminal-A.

Development of a new definition of maternal near miss based on organ dysfunction in Latin America and the Caribbean: A prospective multicenter cohort study.

BACKGROUND: There has been debate over whether the existing World Health Organization (WHO) criteria accurately represent the severity of maternal near misses. OBJECTIVE: This study assessed the diagnostic accuracy of two WHO clinical and laboratory organ dysfunction markers for determining the best cutoff values in a Latin American setting. METHODS: A prospective multicenter cohort study was conducted in five Latin American countries. Patients with severe maternal complications were followed up from admission to discharge. Organ dysfunction was determined using clinical and laboratory data, and participants were classified according to severe maternal outcomes. This study compares the diagnostic criteria of Latin American Centre for Perinatology, Network for Adverse Maternal Outcomes (CLAP/NAMO) to WHO standards. RESULTS: Of the 698 women studied, 15.2% had severe maternal outcomes. Most measured variables showed significant differences between individuals with and without severe outcomes (all P-values <0.05). Alternative cutoff values suggested by CLAP/NAMOs include pH ≤7.40, lactate ≥2.3 mmol/L, respiratory rate ≥ 24 bpm, oxygen saturation ≤ 96%, PaO2/FiO2 ≤ 342 mmHg, platelet count ≤189 × 109 × mm3, serum creatinine ≥0.8 mg/dL, and total bilirubin ≥0.67 mg/dL. No significant differences were found when comparing the diagnostic performance of the CLAP/NAMO criteria to that of the WHO standards. CONCLUSION: The CLAP/NAMO values were comparable to the WHO maternal near-miss criteria, indicating that the WHO standards might not be superior in this population. These findings suggest that maternal near-miss thresholds can be adapted regionally, improving the identification and management of severe maternal complications in Latin America.

PATHOPHYSIOLOGY OF POSTTRAUMATIC ANKLE OSTEOARTHRITIS: A MULTICENTER PERSPECTIVE.

Besides the acute injury and trauma-induced macroscopic alterations, the evolution to posttraumatic ankle osteoarthritis (PTOA) is a complex process progressing at the tissue and molecular level. Furthermore, changes in the molecular pathways affect chondrocyte viability. Treatment modalities for PTOA focal or confined disease include innovative techniques. OBJECTIVE: Our purpose is to increase medical awareness based on scientific evidence of pathophysiology, molecular biology, and treatment of post-traumatic ankle osteoarthritis. METHODS: To support the perspectives of the experts, evidence from the scientific literature respected the PRISMA guidelines and the PICOS search strategy was used. We included case-control, cohort, experimental studies and case reports, written in English. RESULTS: The authors were homogeneously exposed to 282 selected abstracts and 114 full articles directly related to post-traumatic osteoarthritis after malleolar fractures. CONCLUSION: The pathophysiological factors involved in posttraumatic ankle osteoarthritis, such as biological, structural, mechanical, and molecular changes must be studied together, as the interaction between these factors determines the risk of progression of PTOA. Inhibition of a single catabolic molecule or cascade probably is not sufficient to alter the natural progression of the pathological process. Evidence level V, expert opinion.

A evolução para a osteoartrite pós-traumática do tornozelo (PTOA) a partir da lesão aguda e das alterações macroscópicas induzidas pelo trauma é um processo complexo, que progride em nível tecidual e molecular. Além disso, as alterações nas vias moleculares afetam a viabilidade dos condrócitos. As modalidades focais ou confinadas de tratamento para PTOA incluem técnicas inovadoras. Objetivo: Nosso objetivo é aumentar a conscientização médica, com base em evidências científicas de fisiopatologia, biologia molecular e tratamento da osteoartrite pós-traumática do tornozelo. Métodos: Para o embasamento das perspectivas dos autores experts, as evidências da literatura científica respeitaram as diretrizes Prisma e a estratégia de busca Picos foi empregada. Incluímos estudos de caso-controle, de coorte, experimentais e relatos de caso, escritos em inglês. Resultados: Os autores foram expostos de forma homogênea a 282 resumos e 114 artigos completos, diretamente relacionados à osteoartrite pós-traumática após fraturas maleolares. Conclusão: Os fatores fisiopatológicos envolvidos na osteoartrite pós-traumática do tornozelo, como alterações biológicas, estruturais, mecânicas e moleculares, devem ser estudados em conjunto, pois a interação entre esses fatores determina o risco de progressão da PTOA. A inibição de uma única molécula catabólica ou cascata provavelmente não é suficiente para alterar a progressão natural do processo patológico. Nível de evidência V, opinião do especialista.

Effectiveness of mass trapping interventions using autocidal gravid ovitraps (AGO) for the control of the dengue vector, Aedes (Stegomyia) aegypti, in Northern Mexico.

BACKGROUND: Mosquito-borne diseases, such as malaria, dengue, Zika and chikungunya, pose significant public health threats in tropical and subtropical regions worldwide. To mitigate the impact of these diseases on human health, effective vector surveillance and control strategies are necessary. Traditional vector control methods, which rely on chemical agents such as insecticides and larvicides, face challenges such as resistance and environmental concerns. Consequently, there has been a push to explore novel surveillance and control tools. Mass trapping interventions have emerged as a promising and environmentally friendly approach to reducing the burden of mosquito-borne diseases. This study assessed mass-trapping interventions using autocidal gravid ovitraps (AGOs) on Aedes aegypti populations in Reynosa, Tamaulipas, Mexico. METHODS: Four neighborhoods were selected to evaluate the effects of three treatments: AGO mass-trapping, integrated vector control (IVC), which included source reduction and the application of chemical larvicide and adulticide, and AGO + IVC on Ae. aegypti populations. A control area with no interventions was also included. The effectiveness of the interventions was evaluated by comparing Ae. aegypti abundance between the pre-treatment period (9 weeks) and the post-treatment period (11 weeks) for each treatment. RESULTS: Only treatment using AGO mass trapping with an 84% coverage significantly reduced Ae. aegypti female populations by 47%, from 3.75 ± 0.32 to 1.96 ± 0.15 females/trap/week. As expected, the abundance of Ae. aegypti in the control area did not differ from the pre- and post-treatment period (range of 4.97 ± 0.59 to 5.78 ± 0.53); Ae. aegypti abundance in the IVC treatment was 3.47 ± 0.30 before and 4.13 ± 0.35 after, which was not significantly different. However, Ae. aegypti abundance in the AGO + IVC treatment increased from 1.43 ± 0.21 before to 2.11 ± 0.20 after interventions; this increase may be explained in part by the low AGO (56%) coverage. CONCLUSIONS: This is the first report to our knowledge on the effectiveness of mass-trapping interventions with AGOs in Mexico, establishing AGOs as a potential tool for controlling Ae. aegypti in Northeastern Mexico when deployed with sufficient coverage.

FIRST RECORDS OF AEDES TORMENTOR AND CULEX PANOCOSSA AS A RESULT OF VECTOR SURVEILLANCE ACTIVITIES CONDUCTED DURING THE CHARACTERIZATION OF FOCI OF EASTERN EQUINE ENCEPHALITIS IN TAMAULIPAS, MEXICO.

We report the 1st records of Aedes tormentor and Culex panocossa throughout vector surveillance events carried out in putative foci of eastern equine encephalitis in Tamaulipas, Mexico. Formerly, Ae. tormentor had been reported in, at least, 2 Central American countries and Mexico. In Mexico, reports were from the states of Campeche, Chiapas, Quintana Roo, and Veracruz. Records of Ae. tormentor in these 4 Neotropical states were recently reviewed and eliminated; thus, the southernmost geographic distribution for this species is considered to be the state of Tamaulipas Mexico in its neotropical zone. Further, Cx. panocossa had been collected in Guerrero, Tabasco, and Veracruz. In Tamaulipas, there are 82 species of mosquitoes, being the 4th state accounting for the highest mosquito species diversity of 11 states in which comprehensive studies have been conducted on the subject of mosquito distribution.

Association of hTERT expression, Her2Neu, estrogen receptors, progesterone receptors, with telomere length before and at the end of treatment in breast cancer patients.

Background: Breast cancer shows significant clinical, morphologic, and molecular variation. Telomeres are nucleoprotein complexes composed of hexanucleotide repeat DNA sequence, TTAGGG, and numerous telomere-associated proteins. The maintenance of telomere length is carried out by a ribonucleoprotein called telomerase, which consists of two main components: a catalytic subunit called hTERT (human telomerase reverse transcriptase) and an RNA template called hTR (human telomerase RNA). The importance of evaluating hTERT expression lies in its potential therapeutic application, being an attractive target due to its almost non-existent expression in normal somatic cells. It is also expected that the anti-neoplastic effect would appear earlier in neoplastic cells with shorter telomeres. Additionally, a significant relationship has been observed between Her2-Neu overexpression and Her2-Neu positivity, which could suggest new combined therapies.The aim of this study was to detect the expression of hTERT, estrogen receptor (ER), progesterone receptor (PR), and HER2-Neu in neoplastic breast tissue embedded in paraffin before treatment and to investigate the relationship between them and with baseline and post-treatment telomere length, as well as with various clinicopathological parameters. Materials and methods: A cross-sectional-correlational, 21 women diagnosed with breast cancer at the Oncology Service of the High Specialty Medical Unit No. 1 of Bajio of the Mexican Institute of Social Security. The study complies with the Helsinki Declaration and was approved by the Institutional Ethical Committee of the Mexican Institute of Social Security (R-2019-1001-127). A peripheral blood sample was obtained before oncological treatment and at the end of oncological treatment for the measurement of telomere length by extracting DNA from leukocytes, was performed by the quantitative polymerase chain reaction (PCR) method described by Cawthon. Tumor samples were collected from each patient at the oncology department for immunohistochemical determination of biomarker expression (ER, PR, Her2/neu) and hTERT. Results: Of the 21 cases included in the study, the median age was 57.57 years. Eighteen cases were classified as invasive ductal carcinoma NOS (85.71%), 10 were histologic grade 2 (47.61%), 16 cases were hormone receptor positive (76.19%), 7 were Her2Neu positive (33.33%), and only 2 cases were triple negative (9.52%). Positive hTERT expression was detected in 11 cases (52.38%) and was negative in the remaining cases. A significant association was identified between hTERT-positive cases and Her2-Neu positive cases (p = 0.04). Baseline and post-treatment telomere lengths showed a significant difference using the non-parametric Wilcoxon t-test (p = 0.002). In hTERT-positive cases, there was significant telomere shortening at the end of oncological treatment (6.14 ± 1.54 vs. 4.75 ± 1.96 Kb, p = 0.007). Conclusion: Positive hTERT immunostaining cases were associated with poor prognostic factors, such as Her2-Neu overexpression and post-treatment telomere shortening. In the future, hTERT immunostaining could be used to select patients for therapies with antagonistic effects on hTERT, as well as in the selection of more appropriate chemotherapy regimens for patients who express it.

Ethanolic Extract of Salvia officinalis Leaves Affects Viability, Survival, Migration, and the Formation and Growth of 3D Cultures of the Tumourigenic Murine HPV-16+-Related Cancer Cell Line.

Salvia officinalis (SO) is one of the most widely used plants in traditional medicine worldwide. In the present study, the effect of an ethanolic extract of S. officinalis leaves on hallmarks of cancer of HPV-16-positive cancer tumorigenic cells, TC-1, was analyzed in vitro. Phytochemical and spectroscopic analysis were performed. Additionally, the extract's flavonoid content, reducing iron, and antioxidant capacity were determined. In regard to the in vitro tests, the cytotoxic activity and its effect on the replicative capacity and on the cell migration of TC-1 cells were analyzed by viability and clonogenic, survival, and wound healing assays. The effect of a pre-treatment or treatment on 3D culture formation, growth, and reversion capacity was also examined. The results of the phytochemical analysis allowed the detection of tannins, saponins, steroids, and flavonoids. The flavonoids content was found to be 153.40 ± 10.68 µg/mg of extract. Additionally, the extract exhibited an antioxidant capacity and a ferric-reducing capacity of around 40% compared to the ascorbic acid. Thin layer chromatographic (TLC) analysis and spectroscopic tests showed the presence of compounds similar to quercetin and catechin flavonoids in the extract. In the in vitro assays, the SO extract induced in a concentration-dependent way changes in cell morphology, the decrease of cell viability, survival, and migration. At a concentration of 125 µg/mL, the extract inhibited spheroid formation, reduced their growth, and affected their reversion to 2D. Ethanolic extract of S. officinalis leaves had inhibitory effects on hallmarks of the cancer line HPV-16+. This suggests that the phytochemicals present in it may be a source of chemotherapeutics against cervical cancer.

Domestic Dog Infection with Trypanosoma cruzi from Northern and Southern Regions of Mexico.

Background: Chagas disease or American trypanosomiasis, caused by Trypanosoma cruzi and vectored by triatomines, affects millions of people worldwide. In endemic countries including Mexico, infections in domestic animals, such as dogs, may affect the risk of human disease when they serve as a source of infection to vectors that subsequently infect humans. Materials and Methods: We conducted a cross-sectional study of 296 dogs from two cities near the northern and southern borders of Mexico: Reynosa, Tamaulipas, and Tuxtla Gutierrez, Chiapas. Infection was measured based on testing of blood using T. cruzi quantitative PCR (qPCR) and up to three antibody detection assays. The StatPak immunochromatographic assay was used to screen samples and the indirect fluorescent antibody (IFA) and multiplex microsphere immunoassay (MIA) tests were used as secondary tests on all samples that screened positive and a subset of negatives. Serologic positivity was defined based on reactivity on at least two independent tests. Results: Of the 280 samples tested for parasite DNA, two (0.7%) were positive, one of which (0.4%) was confirmed as T. cruzi discrete typing unit TcIV. Overall, 72 (24.3%) samples were reactive for T. cruzi antibodies via StatPak of which 8 were also positive using MIA and 2 were also positive using IFA (including one of the PCR-positive dogs). Overall, nine dogs (3.4%) met study criteria of positivity based on either/both serology or PCR tests. Positive dogs were found in both regions of Mexico; five (2.7%) from Reynosa and four (3.6%) from Tuxtla Gutierrez. We found no association between infection status and state of origin, sex, age group, breed group, neighborhood, and whether other pets lived in the home. Conclusion: Our results re-emphasize dogs' utility as sentinels for T. cruzi in Mexico and underscore the need for improved veterinary diagnostic tests and parasite surveillance at the household level in endemic countries.

TL1A and IL-18 synergy promotes GM-CSF-dependent thymic granulopoiesis in mice.

Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced acute thymic atrophy, while thymic neutrophils expanded. Fate mapping with Ms4a3-Cre mice demonstrated that thymic neutrophils emerge from thymic granulocyte-monocyte progenitors (GMPs), while Rag1-Cre fate mapping revealed a common developmental path with lymphocytes. These effects could be modeled ex vivo using neonatal thymic organ cultures (NTOCs), where TL1A and IL-18 synergistically enhanced neutrophil production and egress. NOTCH blockade by the LY411575 inhibitor increased the number of neutrophils in the culture, indicating that NOTCH restricted steady-state thymic granulopoiesis. To promote myelopoiesis, TL1A, and IL-18 synergistically increased GM-CSF levels in the NTOC, which was mainly produced by thymic ILC1s. In support, TL1A- and IL-18-induced granulopoiesis was completely prevented in NTOCs derived from Csf2rb-/- mice and by GM-CSFR antibody blockade, revealing that GM-CSF is the essential factor driving thymic granulopoiesis. Taken together, our findings reveal that TL1A and IL-18 synergism induce acute thymus atrophy while  promoting extramedullary thymic granulopoiesis in a NOTCH and GM-CSF-controlled manner.

Modified Oblique Lobenhoffer (MOL) approach for posterolateral and posteromedial column access in tibial plateau fractures: a detailed cadaveric anatomical study.

BACKGROUND: Tibial plateau fractures involving posteromedial (PM) and posterolateral (PL) columns are complex injuries that require an appropriate approach. The management of the PL column in these cases can be controversial, and limitations using deep posteromedial interval approaches have been referenced. In this paper, a modification of the Lobenhoffer approach, designed to optimize the access to the PL column, is described in detail. The aim of this study was to assess the feasibility of this approach in a cadaveric anatomical study. MATERIALS AND METHODS: In total, five fresh-frozen cadaveric specimens were used for detailed anatomical study surrounding the approach. Relationships with cutaneous and deep neurovascular structures were evaluated. The exposure area of the PL and PM columns using this approach was assessed. RESULTS: The cadaveric study showed safe and adequate exposure. Oblique skin and fascia incision just medial to the posterior midline was safe to protect the medial sural cutaneous nerve and the small saphenous vein. Elevation of the popliteus and tibialis posterior muscles offered safe protection of the anterior tibial artery and popliteal neurovascular bundle during retractor placement. Adequate full proximal exposure of the PM and PL columns, including the posterolateral lateral (PLL) and posterolateral central (PLC) segments, was obtained in all specimens. CONCLUSIONS: The Modified Oblique Lobenhoffer (MOL) approach can be a feasible option to access PL and PM columns in tibial plateau fractures. LEVEL OF EVIDENCE: IV.

RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis.

The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1ΔCD4) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4+, naive CD8+, and FoxP3+ regulatory T cells. Interestingly, peripheral naive CD8+ T cells in Ripk1ΔCD4 mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4+ T cells. Ripk1K45A mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1ΔCD4 naive T cells expressed the proliferation marker Ki-67+ despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1ΔCD4Casp8 ΔCD4 and Ripk1ΔCD4Tnfr1-/- double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4+ and CD8+ cells and FoxP3+ regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis.

Navigating HER2-Low Testing in Invasive Breast Cancer: Update Recommendations for Pathologists.

The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.

Effectiveness of JYNNEOS vaccine against symptomatic mpox disease in adult men in Los Angeles County, August 29, 2022 to January 1, 2023.

We describe real-world estimates of JYNNEOS vaccine effectiveness (VE) against symptomatic mpox in Los Angeles County (LAC). We conducted a retrospective cohort study of men aged ≥18 years residing in LAC who were at risk for mpox and eligible for the JYNNEOS vaccine from 5/19/2022 to 1/1/2023. Case demographics and route of JYNNEOS administration were obtained through vaccine administration data systems. HIV and sexually transmitted infection (STI) status was obtained through disease reporting systems for HIV and STI diagnoses in LAC. To estimate VE, we calculated weekly incidence of confirmed mpox for unvaccinated, partially vaccinated (episode date ≥14 days after first dose), and fully vaccinated (episode date ≥14 days after second dose) cohorts starting on 8/29/2022, when fully vaccinated coverage exceeded 3 %, and ending on 1/1/2023. Overall, 2,171 men had confirmed mpox, and 1,002 (46 %) of those were persons living with diagnosed HIV (PLWDH). 2,019 (93 %) mpox cases were unvaccinated, 114 (5 %) were partially vaccinated and 38 (2 %) were fully vaccinated. VE was 69 % (95 % CI 59-77) for partially vaccinated and 84 % (95 % CI 80-87) for fully vaccinated individuals. Among PLWDH, VE was 72 % (95 % CI 57-82) for fully vaccinated and 28 % (95 % CI -96 to 73) VE for partially vaccinated individuals. Among persons not living with diagnosed HIV, VE was 88 % (95 % CI 86-90) for fully vaccinated and 80 % (95 % CI 76-83) for partially vaccinated individuals. Of 111 individuals hospitalized with mpox, one was partially vaccinated, and the remaining were unvaccinated. Our results align with other published studies that reported that two doses of the JYNNEOS vaccine provided significant protection against symptomatic mpox.

Grass Infusions in Autocidal Gravid Ovitraps to Lure Aedes Albopictus.

Aedes albopictus is a vector of several pathogens of significant public health concern. In this situation, gravid traps have become a common surveillance tool for Aedes spp., which commonly use hay infusions as an attractant. Diverse grass infusions have been assessed to enhance the attraction to this vector mosquito. However, these studies have focused on the oviposition effect, and the attraction potential to gravid Ae. albopictus females has not been evaluated yet. Here we report the attractiveness of infusions of 4 different botanical species (Cenchrus purpureus, Cyanodon dactylon, Megathyrus maximus, Pennisetum ciliare) as baits in sticky ovitraps and autocidal gravid ovitraps (AGOs) under laboratory, semifield, and field conditions. In the laboratory, Cynodon dactylon showed attractiveness, whereas in semifield conditions, both C. dactylon and Megathyrsus maximus were similarly attractive for gravid Ae. albopictus. None of the infusions conducted with AGOs were able to lure Ae. albopictus and other species of mosquitoes in a 14-wk field experiment. Our results demonstrate the feasibility of finding more attractive infusions for Ae. albopictus females to improve the efficacy of AGO traps, but further testing of infusions in AGOs in field settings is needed.

Flexible genomic island conservation across freshwater and marine Methylophilaceae.

The evolutionary trajectory of Methylophilaceae includes habitat transitions from freshwater sediments to freshwater and marine pelagial that resulted in genome reduction (genome-streamlining) of the pelagic taxa. However, the extent of genetic similarities in the genomic structure and microdiversity of the two genome-streamlined pelagic lineages (freshwater "Ca. Methylopumilus" and the marine OM43 lineage) has so far never been compared. Here, we analyzed complete genomes of 91 "Ca. Methylopumilus" strains isolated from 14 lakes in Central Europe and 12 coastal marine OM43 strains. The two lineages showed a remarkable niche differentiation with clear species-specific differences in habitat preference and seasonal distribution. On the other hand, we observed a synteny preservation in their genomes by having similar locations and types of flexible genomic islands (fGIs). Three main fGIs were identified: a replacement fGI acting as phage defense, an additive fGI harboring metabolic and resistance-related functions, and a tycheposon containing nitrogen-, thiamine-, and heme-related functions. The fGIs differed in relative abundances in metagenomic datasets suggesting different levels of variability ranging from strain-specific to population-level adaptations. Moreover, variations in one gene seemed to be responsible for different growth at low substrate concentrations and a potential biogeographic separation within one species. Our study provides a first insight into genomic microdiversity of closely related taxa within the family Methylophilaceae and revealed remarkably similar dynamics involving mobile genetic elements and recombination between freshwater and marine family members.

Type 1 immunity enables neonatal thymic ILC1 production.

Acute thymic atrophy occurs following type 1 inflammatory conditions such as viral infection and sepsis, resulting in cell death and disruption of T cell development. However, the impact type 1 immunity has on thymic-resident innate lymphoid cells (ILCs) remains unclear. Single-cell RNA sequencing revealed neonatal thymic-resident type 1 ILCs (ILC1s) as a unique and immature subset compared to ILC1s in other primary lymphoid organs. Culturing murine neonatal thymic lobes with the type 1 cytokines interleukin-12 (IL-12) and IL-18 resulted in a rapid expansion and thymic egress of KLRG1+CXCR6+ cytotoxic ILC1s. Live imaging showed the subcapsular thymic localization and exit of ILC1s following IL-12 + IL-18 stimulation. Similarly, murine cytomegalovirus infection in neonates resulted in thymic atrophy and subcapsular localization of thymic-resident ILC1s. Neonatal thymic grafting revealed that type 1 inflammation enhances the homing of cytokine-producing thymus-derived ILC1s to the liver and peritoneal cavity. Together, we show that type 1 immunity promotes the expansion and peripheral homing of thymic-derived ILC1s.