Primary Site Research Articles

Medical imaging for the diagnosis, recurrence and metastasis evaluation of clear cell sarcoma

Clear cell sarcoma (CCS) of soft tissue is extremely rare, accounting for approximately 1% of all soft tissue tumours. It is very difficult to diagnose CCS based on clinical manifestations. Magnetic resonance imaging (MRI) provides high-resolution images of soft tissues and pathological features such as mucus, necrosis, bleeding, and fat through high and low signals on T1 weighted image (T1WI) and T2 weighted image (T2WI). On the other hand, the paramagnetism of melanin in CCS shortens the relaxation time of T1 and T2, and high signal intensity on T1WI and low signal intensity on T2WI can be found. This is different from most other soft tissue sarcomas. At present, the treatment method for CCS is surgical resection. MRI can effectively display the tumour edge, extent of surrounding oedema, and extent of fat involvement, which is highly important for guiding surgical resection and predicting postoperative recurrence. As an invasive sarcoma, CCS has a high risk of metastasis. Regardless of the pathological condition of the resected tumour, MRI or computed tomography (CT) should be performed every 1-2 years to assess recurrence at the primary site and to screen for metastasis in the lungs, liver, and bones. If necessary, PET-CT can be performed to evaluate the overall condition of the patient.

Left atrial appendage orifice morphology in sickness and in health.

The left atrial appendage (LAA) is the primary site of embolism in individuals with atrial fibrillation (AF). We aimed to evaluate the morphological features of the LAA orifice in patients with sinus rhythm, paroxysmal AF, and persistent AF using three-dimensional (3D) transesophageal echocardiography (TOE). We also intended to identify morphometric parameters of the LAA orifice that may be potentially associated with an increased risk of ischemic stroke. We prospectively enrolled 106 patients undergoing TOE. Patients were divided into three groups: group1 (sinus rhythm), group2 (persistent AF), and group3 (paroxysmal AF). All patients underwent acomprehensive evaluation through transthoracic echocardiography (TTE) and TOE. Off-line analyses were performed of the recorded images. The LAA minor orifice area and minimal orifice diameter were greater in patients with persistent AF compared with individuals in sinus rhythm. Patients with persistent AF also had deeper LAAs compared with those in sinus rhythm. None of the LAA orifice morphometric measures were related to ischemic stroke risk. The only independent predictors of ischemic stroke were heart rhythm and the CHA2DS2VASc score. Persistent AF is associated with LAA dilation, increased depth, and larger orifice size. To our knowledge, this is the first study to demonstrate LAA orifice structural remodeling in patients with AF using 3D TOE.

The Role of Transoral Robotic Palatine and Lingual Tonsillectomy in the Diagnosis of Carcinoma of Unknown Primary in the Head and Neck Region.

The use of transoral robotic surgery (TORS) lingual tonsillectomy in the diagnostic algorithm for head and neck carcinoma of unknown primary (CUP) has gained recent popularity. The primary aim of our study was to determine the identification rate of primary tumors in our cohort undergoing lingual ± palatine tonsillectomy for the workup of head and neck CUP. This was a retrospective study of all patients undergoing diagnostic TORS for head and neck CUP over an eight-year period, across four centers in two countries. Fifty-six patients undergoing TORS to aid diagnosis of a primary site were included. Overall, TORS lingual ± palatine tonsillectomy identified a primary tumor in 41 (73.2%) patients. Over half were T1 tumors, with 25% measuring under 10 mm. Among those with human papilloma virus (HPV)+ nodal disease, the identification rate was 82.6%. TORS lingual tonsillectomy is an effective addition to the diagnostic workup of CUP, particularly in those with HPV+ nodal disease.

Community-acquired sepsis in the medical intensive care unit: An experience from a lower-middle-income country.

To determine microbiological pathogens and in-hospital mortality in patients admitted with communityacquired sepsis to the intensive care unit in a tertiary-care setting in a low- and middle-income country. The retrospective, observational study was conducted at the medical intensive care unit of a large tertiary care hospital in Karachi, and comprised data from January 1 to December 31, 2019 of patients with community-acquired sepsis who were assessed using the Sepsis-3 criteria. Data was compared between survivors and non-survivors, and independent factors associated with in-hospital mortality were identified. Data was analysed using SPSS 23. Of the 135 patients with mean age 49.8±18.0 years, 91(67.4%) were males and 44(32.6%) were females. The most common primary site of infection was the respiratory tract 63(46.7%). Multi-drug-resistant organisms were isolated in 39 (28.9%) patients. In-hospital mortality was noted in 52(38.5%) cases, while there were 83(61.5%) survivors. Serum levels of lactate and bicarbonate as well as urine output, fungal pathogens, septic shock and sequential organ failure assessment score were significantly associated with mortality (p<0.05). Clinical and microbiological spectrum of community-acquired sepsis in a low- and middle-income country was found to be different from other regions of the world. Clinicians should keep these differences in mind while managing these critically ill patients.

The Weight of Nutrition on Post-Resection Oncologic Morbidity and Mortality: A Systematic Review and Meta-Analysis of Nutritional Indices

Abstract Context Nutritional status is a critical factor in the selection of patients for solid tumor resection. A variety of indices have been developed to quantify nutritional status, and they have differing degrees of predictive power for various postoperative outcomes. Objective This study aimed to comprehensively evaluate the predictive ability of commonly used nutritional indices in relation to postoperative complications (POCs), recurrence-free survival (RFS), and OS. Data Sources We performed a systematic review of 14 established nutritional indices from January 2015 to July 2022: Data Extraction The primary end point was OS, while the secondary end points were POCs and RFS. A subsequent meta-analysis was performed to further assess the predictive ability of these indices for OS based on general index type, primary tumor site, and the patient’s index status. Data Analysis In this evaluation, 38 articles reporting data on 23 970 patients were analyzed, focusing on 14 nutritional indices. The indices were categorized into phenotypic, metabolic, immunologic, and combined types. Patients within the cut-off range of any index were predicted to have lower OS (hazard ratio [HR] 2.14, 95% CI 1.84–2.49, P &amp;lt; .01). Lower gastrointestinal (GI) and “other” sites were less predictive than upper GI primary tumors (HR 1.63, HR 1.82, and HR 2.54, respectively; all with P &amp;lt; .01). Phenotypic indices were less predictive than combined indices (HR 1.73 vs HR 2.47, P &amp;lt; .01). Within the combined category, there was no significant difference in the predictive ability of Prognostic Nutritional Index (PNI) vs Geriatric Nutritional Risk Index (GNRI) vs Controlling Nutritional Index (CONUT) (HR 2.63 vs HR 2.42 vs HR 2.07, P = .07). Conclusion The predictive efficacy of a nutritional index was found to be highly dependent on the index type, the primary tumor site, and the outcome of interest. In the context of upper GI resections, nutritional status appeared to be more of a significant predictor of OS, compared with cases involving lower GI and hepatic malignancies. Indices that integrate phenotypic, metabolic, and immunologic patient factors potentially offer greater clinical utility in forecasting OS.

Pediatric non-nasopharyngeal head and neck squamous cell carcinoma: Analysis of the Surveillance, Epidemiology, and End Results (SEER) program with review of the literature

BackgroundDespite its prevalence in adults, head and neck squamous cell carcinoma (HNSCC) is considered a rare entity in pediatrics where lymphomas, neural tumors, and soft tissue sarcomas predominate in the head and neck. Given the association of squamous cell carcinoma with the human papillomavirus, a risk factor that may be present from birth, and the difficulties in staging this disease for prognostication in children, it is important to revisit nationally collected data for prevalence and outcomes assessments. ObjectiveTo examine a publicly available national database to describe the incidence, pathology, treatment, and survival of pediatric HNSCC. To review the available literature regarding management, outcomes, and risk factors for this disease process. MethodsThe National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) tumor database was queried to identify pediatric subjects ages 0 to 19 diagnosed HNSCC between 1973 and 2019. ResultsTwo-hundred ninety-two cases were identified. Subjects were 62.7 % male (n = 183) and the average age was 15.4 years (range 2–19, median 16). Subjects were 65.8 % white (n = 192), 22.9 % black (n = 67), 8.9 % Asian/Pacific Islander (n = 26), 1 % American Indian (n = 3), and 1.4 % unknown (n = 4). The most common primary sites were nasopharynx (45.9 %), oral cavity (30.5 %), larynx (8.6 %), salivary gland (4.1 %), nasal cavity & paranasal sinus (3.4 %), and lip (2.7 %). There was no statistically significant difference between primary subsite and age, race, histologic grade, or extent of disease. The 5-year overall survival was 83.6 %. DiscussionHead and neck squamous cell carcinoma is more likely to present in older children and is more prevalent in White populations. The nasopharynx is the most common subsite involved, which differs from adult populations in which non-nasopharyngeal subsites including the larynx, oral cavity, and oropharynx are most frequently affected. ConclusionHead and neck squamous cell carcinoma is rare in pediatric patients but should not be overlooked by physicians in the differential diagnosis, particularly in teenagers. Further study is needed to determine whether this represents a unique entity or can be staged and treated according to adult guidelines.

Retinoid X Receptor Signaling Mediates Cancer Cell Lipid Metabolism in the Leptomeninges.

Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC-and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro . In vivo , while deletion of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby metastatic cancer cells awake locally-generated developmental cues for metabolically reprograming, suggesting novel therapeutic approaches.

Red Blood Cell Transfusions in Patients with Advanced Cancer Receiving Home Palliative Care.

Background: Red blood cell (RBC) transfusion is the standard treatment for anemia in advanced cancer. Nevertheless, guidelines for managing this condition are still not exhaustive. Objective: To investigate frequency, timing, and clinical characteristics associated with RBC transfusions in patients with advanced cancer assisted by at-home oncological care service and to evaluate the association between parameters at the entry and the possibility of receiving RBC transfusions during homecare. Design: Retrospective observational study without medication. Setting/Subjects: Patients with advanced cancer entered in homecare during 2021 living in Bologna (Italy). Measurements: Gender, tumor primary site, oncological therapy, and symptoms at the entry were considered as possible factors in a binary logistic regression for the possibility of receiving at least one RBC transfusion during assistance. Data about transfusions were analyzed, and the transfusion history for each patient from the entry to death was traced. Results: Among the 1108 patients admitted, 179 (16.2%) were given at least one RBC transfusion during homecare. Genitourinary, hematological malignancies, and being still in therapy for advanced cancer are associated with a higher probability of receiving RBC transfusion during assistance (p = 0.017, p < 0.001, and p = 0.032, respectively). Half of the patients (52%) underwent RBC transfusions less than a month before death. Duration of the assistance was correlated with the period from last transfusion to death (p < 0.001). Conclusion: Hematological and genitourinary cancer and being in simultaneous care at the entry were associated with transfusion. Although the appropriateness of this treatment remains to be defined in this population, transfused patients frequently received "late in life" transfusions.

Therapeutic and Diagnostic Tactics for Metastases to the Lymph Nodes of the Neck without an Identified Primary Focus

Introduction. Metastatic squamous cell carcinoma from an unknown primary focus accounts for less than 5 % of malignant tumors in the head and neck. Improving the methods of diagnosis can reduce the incidence of this pathology. Materials and methods. A retrospective analysis of the results of diagnosis and treatment of 59 patients with metastasis to the lymph nodes of the neck without an identified primary focus was performed. The proportion of male patients was 86 % (51/59), female — 14 % (8/59). The average age of patients is 61 years. Squamous cell carcinoma prevailed — 79 % (47/59). Results. Metastatically affected lymph nodes were localized in 92 % of cases at levels II and III. The proportion of patients with stages N2, N3 prevailed — 55 % (abs. 26), 32 % (abs. 15), respectively. Overexpression of the P­16 protein in metastatically affected lymph nodes was detected in 70 %, PD­L1 in 48 %, and Epstein­Barr virus (EBV) in 6 %. Ipsilateral diagnostic palatine tonsillectomy of an apparently unchanged tonsil was performed in 15 % (9/59) of cases, revealing the primary site in one instance. Of the special treatment methods, complex and combined treatment prevailed — 55 % (abs. 26). Radiation therapy in an independent version was performed by 48 % of patients, while 76 % received the full course (abs. 16). Combined treatment (a course of Radiation therapy followed by chemotherapy) — in 7 % (abs. 3) 20 % of patients received polychemotherapy. Palliative immunotherapy (pembrolizumab 200 mg IV — 5 courses) was given to 1 patient. The average life expectancy was higher with complex treatment — it was 60 months (95 % CI 43.5–76.4), the median survival is 60 months. Discussion. The main methods of treatment of patients with metastases of squamous cell carcinoma without were radiation therapy in an independent version, as well as complex treatment. Ipsilateral diagnostic palatine tonsillectomy of an apparently unchanged tonsil was performed in 15 % (abs. 9), and allowed to identify the primary focus in 1 case.Conclusion. Metastasis to the lymph nodes of the neck without remains an urgent interdisciplinary problem. Prospective multicenter studies are required to improve and optimize the algorithms for diagnosis and treatment of these patients.

Investigating the Dynamics of a Soft Crystalline Covalent Organic Framework during Benzene and Cyclohexane Adsorption by in situ Powder X‐ray Diffraction

Due to their similar boiling points, separation of benzene and cyclohexane mixtures is among the current challenging processes faced by the petrochemical industry. As recently assessed, the soft imine‐based covalent organic framework [(TAM)(BDA)2] (COF‐300; TAM = tetrakis(4‐aminophenyl)methane, BDA = terephthaldehyde) possesses higher affinity for benzene than cyclohexane in both static conditions at 298 K and dynamic conditions in the range of 298–348 K. As shown in this contribution, in situ powder X‐ray diffraction while dosing benzene and cyclohexane vapors in the range of 0.01–4.74 bar on the narrow‐pore form of COF‐300 confirmed the coherent switchability of its framework, unveiling the progressive formation of different intermediate‐ and large‐pore forms. In addition, a basket of otherwise inaccessible key crystallochemical details—“on/off” structural‐feature changes cooperating to adsorption, primary adsorption sites, and host–guest and guest–guest interactions—was successfully retrieved. Overall, these findings allowed to shed light on the framework dynamics underneath the previously observed selectivity toward benzene over cyclohexane, completing this case of study and providing relevant information for the design of new‐generation adsorbents for this applicative context.

High caregiver adverse childhood experiences are associated with increased pediatric infection-related healthcare utilization and antibiotic use

Abstract Background Higher caregiver adverse childhood experiences (ACEs) have been associated with a range of pediatric outcomes, including hospitalizations. We recently found that higher caregiver ACEs are associated with higher rates of influenza vaccine uptake. However, to our knowledge, no studies have examined links between caregiver ACEs and specific infections or infection-related outcomes, such as antibiotics prescribed. We sought to evaluate associations between caregiver ACEs and pediatric infection-related outcomes. Methods We conducted a retrospective cohort study of two pediatric primary care sites, each serving a predominantly non-Hispanic Black, publicly insured population. At one primary care site (Clinic A), routine screenings for caregiver ACEs began in 2019 at the 1-month well-child check and were retrieved from the electronic health record. For the other primary care site (Clinic B), a prior research study surveyed caregiver ACEs of 283 children. Focusing on children 0-4 years of age in both primary care sites, we retrieved data from the electronic health record, including patient infection-related outcomes, demographic characteristics, and social risk screen results for those who had caregiver ACEs systematically recorded. The number of reported caregiver ACEs was our exposure variable, dichotomized as high (≥4) or low (≤3). Patient demographic characteristics, results of the overall social risk and maternal depression screen, and area deprivation index scores linked to patients’ geocoded home addresses were also collected. Bivariate analyses were pursued using chi square test statistics. Results A total of 1,442 children 0-4 years of age were included in the study, and 50.0% were female, 74.7% Black, and 2.6% Hispanic. Fifteen percent of caregivers had high (≥4) ACEs. Differences in infection-related outcomes, and relevant covariates, based on high and low caregiver ACEs are depicted in Table 1. Children of caregivers with high ACEs had more outpatient infection-related visits (80% versus 72.6%, p = 0.03), including more diagnoses of streptococcal pharyngitis (10.1% versus 4.1%, p = 0.0004). They also had more prescriptions for any oral antibiotic (30.9% versus 23.2%, p = 0.02). In bivariate analyses, high caregiver ACEs (31.3% versus 23.7%, p = 0.03), lower area deprivation index score (mean (SD) of 0.47 (0.16) versus 0.50 (0.16), p &amp;lt; 0.01), older patient age (mean (SD) of 2.73 (1.10) versus 1.73 (1.00) years, p &amp;lt; 0.0001), and any outpatient (35.9% versus 2.2%, p &amp;lt; 0.0001), emergent (40.0% versus 10.9%, p &amp;lt; 0.0001), or inpatient visit (42.7% versus 23.0%, p &amp;lt; 0.0001) were each associated with the presence of antibiotic use. Race, ethnicity, a positive social risk screen, and positive depression screen were not associated with antibiotic use. Conclusion High caregiver ACEs appear to be associated with some types of pediatric infectious diagnoses, antibiotic use and increased infection-related outpatient healthcare utilization. Future adjusted analyses assessing for potential links between ACEs and infection-related outcomes, independent of variables like insurance status, social risk, and area-level deprivation, are warranted and planned.

Evaluation of a Faculty-Led Clinical Model to Meet Pediatric Preventive Care Competencies Through a Pediatric Mobile Clinic.

Limited pediatric primary care clinical placement sites and preceptors have made it difficult for family nurse practitioner (FNP) students to meet pediatric preventive clinical competencies. The purpose of this project was to evaluate a faculty-led clinical model to meet pediatric preventive care competencies through a pediatric mobile clinic. A pre-post evaluation design was used to evaluate student perceptions of their achievement of competencies. Students demonstrated improvement in all seven competencies. A faculty-led clinical model through a pediatric mobile clinic may be an effective way to improve pediatric clinical competencies for FNP students.

Comprehensive Review of Post-treatment Imaging in Head and Neck Cancers: From expected to unexpected and beyond.

Head and neck cancer management requires multidisciplinary approach in which radical surgery with or without flap reconstructions and neck dissection, along with radiotherapy (RT)/chemoradiotherapy (CRT) serve as the key components. Neoadjuvant chemotherapy (NACT) and immunotherapy are used in selected cases based on the institutional preference. Knowledge of expected posttreatment changes on imaging is essential to differentiate it from recurrence. In addition, awareness of various posttreatment complications is imperative for their early detection on imaging. Distorted anatomy after treatment poses diagnostic challenge, hence, proper choice of imaging modality and appropriate timing of scan is pertinent for accurate posttreatment evaluation. In this article, we have provided a comprehensive review on expected imaging appearances post RT/CRT and after major types of head and neck squamous cell carcinoma (HNSCC) surgeries. In addition, we have extensively reviewed the imaging appearances of various posttreatment complications, and recurrences at the primary and lymph nodal sites. We have also delved into the patterns of recurrence in human papillomavirus (HPV) positive HNSCC in this article. Furthermore, we have provided flowcharts and discussed recommendations on the site-specific and treatment related imaging modalities to be used along with their appropriate timing, for adequate evaluation of HNSCC after treatment. We have also reviewed posttreatment reporting of imaging findings using Neck Imaging Reporting and Data Systems (NIRADS) and Hopkins criteria. In addition, we have also touched upon the role of advanced imaging techniques for posttreatment HNSCC evaluation.

Neutrophil Hitchhiking Enhances Liposomal Dexamethasone Therapy of Sepsis.

Sepsis is characterized by a dysregulated immune response and is very difficult to treat. In the cecal ligation and puncture (CLP) mouse model, we show that nanomedicines can effectively alleviate systemic and local septic events by targeting neutrophils. Specifically, by decorating the surface of clinical-stage dexamethasone liposomes with cyclic arginine-glycine-aspartic acid (cRGD) peptides, we promote their engagement with neutrophils in the systemic circulation, leading to their prominent accumulation at primary and secondary sepsis sites. cRGD-targeted dexamethasone liposomes potently reduce immature circulating neutrophils and neutrophil extracellular traps in intestinal sepsis induction sites and the liver. Additionally, they mitigate inflammatory cytokines systemically and locally while preserving systemic IL-10 levels, contributing to lower IFN-γ/IL-10 ratios as compared to control liposomes and free dexamethasone. Our strategy addresses sepsis at the cellular level, illustrating the use of neutrophils both as a therapeutic target and as a chariot for drug delivery.

Insights into Retinal Metastasis from Systemic Carcinoma: A Systematic Review of Clinical and Multimodal Imaging Characteristics.

Background/Objectives: Retinal metastasis (RM) is an exceptionally rare clinical condition, comprising less than 1% of ocular metastasis cases. This study aims to investigate the clinical features of RM originating from systemic carcinoma. Methods: A systematic review (PROSPERO ID: CRD42022344724). Results: The systematic review revealed 58 cases involving 61 eyes. Most of the cases (82.8%) had a known primary malignancy before RM was diagnosed. The main primary sites were the lung (45.8%), gastrointestinal tract (23.7%), and breast (16.9%). The lung was the most common (80.0%) carcinoma in cases with unknown primary sites. The median survival after RM diagnosis was 11 months. The main clinical patterns were patchy retinal infiltrates (35.7%), an elevated retinal mass (63.8%), and punctate retinal infiltrates (7.1%). Subretinal fluid, vitreous seeding, and choroidal invasion were noted in 57.4%, 41.0%, and 6.6% of eyes, respectively. Key multimodal imaging features were early hypofluorescence with mid-to-late hyperfluorescence on fluorescein angiography (84.6%) and hyper-reflectiveness on optical coherence tomography (70.8%). A final best-corrected visual acuity of ≤20/200 was noted in 66.7% of the eyes. Conclusions: Patchy retinal infiltrates, an elevated retinal mass, and punctate retinal infiltrates are the major clinical patterns of RM from systemic carcinoma. The primary carcinoma sites are the lung, gastrointestinal tract, and breast. Systemic and visual prognoses were unfavorable.

P16 status or response to induction chemotherapy, which predicts survival outcomes in Chinese oropharyngeal cancer treated with definitive radiotherapy?

PurposeTo identify whether p16 status or response to induction chemotherapy (IC) predicts the radiotherapy (RT) response and survival outcomes in Chinese oropharyngeal squamous cell carcinoma (OPSCC). MethodsA total of 211 patients, including 128 p16-positive and 83 p16-negative were analyzed. All patients underwent IC followed by definitive RT or concurrent chemoradiotherapy (CCRT). Propensity score matching (PSM) was used to eliminate the baseline variations. ResultsAge, sex, smoking history, alcohol history, and primary site were unbalanced between different p16 status subgroups. Before PSM, the objective response rates to IC between p16-positive and p16-negative groups were 80.5 % and 85.5 % (p = 0.344). After RT, the complete response (CR) rates were 73.4 % and 66.3 %, respectively (p = 0.264). IC-sensitive (IC-s) subgroups had a higher percentage of RT-CR rate than the IC-resistant (IC-r) subgroups in both p16-positive and p16-negative patients. IC-s showed significant improvement in cancer-specific survival (CSS) (92.9 % vs. 53.6 %, p < 0.0001), progression-free survival (PFS) (p < 0.0001), locoregional relapse-free survival (LRFS) (p < 0.0001) and distant metastasis-free survival (DMFS) (p = 0.025). After PSM, the CR rates among different p16 groups remained comparable following RT (71.2 % vs. 65.8 %, p = 0.476). Before or after PSM, CSS, PFS, LRFS, and DMFS were similar between different p16 status either in IC-s or IC-r subgroups (p > 0.05). IC-r was independently associated with shorter PFS (HR = 2.661, p = 0.002) and LRFS (HR = 2.876, p = 0.002; HR = 2.78, p = 0.018). ConclusionsResponse to IC is an important predictor of prognosis in Chinese OPSCC treated with definitive RT. Poor response to IC is associated with unsatisfactory outcomes either in p16-positive or p16-negative OPSCC.

Synthesis and reactivity of a heteroleptic magnesium hydride on a dearomatized picolyl-based NNN-chelator.

Heteroleptic magnesium hydrides are important for their stoichiometric and catalytic reduction chemistry. Their primary nucleophilic site is typically the hydride, while the ancillary ligands commonly used are mostly spectators. Chemically non-innocent ligands in comparison are rarely applied on MgH as their reactivity can be complex. Milstein et al. have recently reported Mg-mediated alkyne hydrogenation by using their metal-ligand cooperation (MLC) concept on a dearomatized picolyl-based PNP pincer that is non-innocent with a nucleophilic nature. A '(PNP)MgH' is noted as the active catalyst in hydrogenation but without structural validation. Inspired by the same, we report herein a novel NNN-chelator (MesL) with a dearomatized picolyl moiety and its well-defined MgH. Having two prominent nucleophilic sites, the present MgH shows metal-ligand competition while reacting with certain electrophiles. It also distinguishes nonpolar alkynes and polar carbonyls by cleanly inserting itself into the former but not the latter. The nucleophilicities of the two sites are also probed by DFT methods and compared with Milstein's (PNP)MgH. Although the present system shows no MLC-type H2 activation, the addition of a CS2 molecule in that way is realized.

Identifying Gaps in the International Consensus Case Definitions for Invasive Aspergillosis: A Review of Clinical Cases Not Meeting These Definitions.

International consensus definitions for invasive aspergillosis (IA) in research are rigorous, yet clinically significant cases are often excluded from clinical studies for not meeting proven/probable IA case definitions. To better understand reasons for the failure to meet criteria for proven/probable infection, we herein review 47 such cases for their clinical and microbiological characteristics and outcomes. Data on 47 cases that did not meet consensus IA definitions but were deemed significant were derived from a retrospective, observational, multicenter survey of 382 presumed IA cases across Australasia, of which findings of 221 proven/probable infections were recently published. The clinical, microbiological, and radiologic characteristics of these cases were analyzed. Mortality outcomes were compared with those of 221 proven/probable cases. Of 47 cases studied, 15 lacked classical host factors; 22 exhibited only a single positive Aspergillus polymerase chain reaction result; 7 lacked typical IA radiologic findings on chest computed tomography; and 3 had borderline galactomannan optical density indices (<1.0 but ≥0.5) in bronchoalveolar lavage fluid. The median age of patients was 61 years (IQR, 52-68); 34 were male (72%). Seven patients (15%) required intensive care admission. All patients had lung as the primary site of infection. Antifungal treatment was initiated in 42 patients (89%). All-cause 90-day mortality was 33%, similar to the 30% mortality in the comparative cohort (n = 221). Our findings highlight the limitations of current consensus definitions for IA. Notably, the mortality of patients not meeting these definitions was similar to that of patients with proven/probable IA. Further studies, especially of patients with a single positive Aspergillus polymerase chain reaction result and those without host factors, are needed to determine if future consensus definitions may benefit from modifications.

Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction

Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9(K9me3) region, while a secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.

Depressive and Anxiety Symptoms in Community-Dwelling Women in Rural Areas of Greece in the Post-COVID-19 Pandemic Era

Background/Objectives: Depressive and anxiety syndromes are associated with elevated disability and are more prevalent in women. Data on the prevalence of depressive and anxiety disorders in the rural context are limited and contradictory. It is relevant to study common mental disorders in rural areas in the most vulnerable population of women, particularly in the post-COVID-19 pandemic era. Methods: This is a cross-sectional study that was conducted in two primary healthcare sites in the rural region of Farsala, Central Greece after the obviation of all restrictive measures that had been posed due to the COVID-19 pandemic. All consecutive female patients that attended the study sites for any non-emergent reason were asked to participate in the study. For the recording of symptoms of depression and anxiety, the self-reported Depression, Anxiety, Stress Scale-21 (DASS-21) was used. Results: The study sample consisted of 129 women. The majority of participants were &gt;50 years, with 27.9% being older adults. A small percentage (13.2%) suffered a chronic physical disease. A large proportion of the sample, slightly exceeding 40%, reported clinically relevant symptoms of anxiety, whereas a lower percentage of women with depressive symptoms was detected (17.1%). Symptoms of anxiety and depression were found to be interrelated, while a number of sociodemographic variables were associated with both, such as older age, education (primary), living status (alone, OR 123.5; 95% CI: 7.3–2098.8 for anxiety; OR 3.5; 95% CI: 1.3–9.8 for depression), employment (not working, (OR 0.157; 95% CI: 0.06–0.41 for anxiety; OR 0.08; 95% CI: 0.01–0.62 for depression) and the history of a chronic disease (OR 33.8; 95% CI: 4.3–264.7 for anxiety; OR 37.2; 95% CI: 10–138.1 for depression). Self-rated financial status was not related to symptoms of anxiety or depression. Conclusions: The study highlights the importance of inquiring for symptoms of depression and anxiety in women attending the rural primary care setting. The use of valid and reliable self-reported instruments that are easy to administrate may be helpful in this regard.