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1.
Palliat Support Care ; : 1-9, 2024 Oct 03.
Article in English | MEDLINE | ID: mdl-39360707

ABSTRACT

OBJECTIVES: This paper reviews the existing literature to identify specific challenges that may arise in the context of providing palliative and end-of-life (EOL) care for Hindu patients in the physical, psychological, and spiritual domains. We offer practical strategies where appropriate to mitigate some of these challenges. We review how the Hindu faith impacts EOL decision-making, including the role of the family in decision-making, completion of advance directives, pain management, and decisions around artificial nutrition and hydration (ANH) and cardiopulmonary resuscitation (CPR). METHODS: The PubMed, MEDLINE Complete, Cochrane, and Embase databases were searched for articles using the search strings combinations of keywords such as Palliative care, Hindu, Hinduism, End of Life Care, India, Spirituality, and South Asian. Once inclusion criteria were applied, 40 manuscripts were eligible for review. RESULTS: Our results are organized into the following 4 sections - how Hindu religious or spiritual beliefs intersect with the physical, psychological, and spiritual domains: and decision-making at the EOL. SIGNIFICANCE OF RESULTS: Hindu beliefs, in particular the role of karma, were shown to impact decision-making regarding pain management, ANH and CPR, and advance directive completion. The complexity of Hindu thought leaves a significant role for interpretation and flexibility for individual factors in decision-making at the EOL.

2.
Phys Rev Lett ; 133(13): 131901, 2024 Sep 27.
Article in English | MEDLINE | ID: mdl-39392996

ABSTRACT

A symmetry-preserving approach to the calculation of baryon properties in relativistic quantum field theory is used to predict all form factors associated with nucleon-to-Δ axial and pseudoscalar transition currents, thereby unifying them with many additional properties of these and other baryons. The new parameter-free predictions can serve as credible benchmarks for use in analyzing existing and anticipated data from worldwide efforts focused on elucidation of ν properties.

3.
Article in English | MEDLINE | ID: mdl-39394332

ABSTRACT

PURPOSE: Answer the following PICO question: Are patients diagnosed with systemic sclerosis (SSc) (Population) who are evaluated clinically and audiometrically (Intervention), have a higher prevalence of audiovestibular pathology when compared with non-SSc patients (Comparison), and how do they present symptomatically and on testing audiovestibular symptomatology and testing modalities (Outcome)? METHODS: A systematic review and meta-analysis was performed. PubMed, Scopus, CINAHL, and Cochrane Library databases were searched from inception to November 27, 2023. Studies of patients diagnosed with SSc and audiologic and vestibular symptoms were selected for review. Studies of non-SSc pathologies, studies without audiovestibular outcomes, and case reports (fewer than four patients) were excluded. A meta-analysis of proportions and comparison of weighted proportions was performed in MedCalc 20.217. RESULTS: Thirteen studies with 414 SSc patients and 390 control patients were included. The mean ± SD symptom duration was 108.5 ± 71.8 (range: 6-600) months for SSc patients. Comparison of proportions showed patients with SSc were significantly more burdened with symptoms of tinnitus (Δ34.1% [95% CI, 27.6-40.5]; p < 0.0001), vertigo (Δ32.4% [95% CI, 24.8-40.3]; p < 0.0001), and subjective hearing loss (Δ26.0% [95% CI, 20.8-31.3]; p < 0.0001) compared to control patients. Findings regarding vestibular testing were not meta-analyzable because of incomplete data and lack of standard reporting. CONCLUSION: SSc patients showed statistically significant, yet not clinically significant, worse hearing than controls. These differences, along with increased reports of subjective audiological and vestibular symptoms in patients with SSc, emphasize interdisciplinary collaboration and assessment of SSc for audiovestibular pathologies in the appropriate clinical context.

4.
Forensic Sci Int Genet ; 74: 103155, 2024 Oct 08.
Article in English | MEDLINE | ID: mdl-39383603

ABSTRACT

Human environmental DNA (eDNA) application have not been fully applied or adequately considered in the fields of eDNA and forensics. Nonetheless, this technique holds great potential as a complementary tool for detecting human DNA in aquatic environments, particularly in cases involving crimes connect to such environments. However, the detectability or stability of eDNA can vary depending on several factors. Therefore, this preliminary study investigates the detection and degradation rates of human eDNA, as well as the recovery of nuclear short tandem repeat (STR) profiles and mitochondrial DNA (mtDNA) sequencing, using water samples from both saltwater and freshwater sources. To conduct the experiment, whole human blood was spiked into the water samples. Water samples were then filtered using a 5 µm pore size filter, and samples were collected at various time intervals up to 23 days. A human specific qPCR assay targeting HV1 region of human mtDNA was used to detect human eDNA. Results demonstrated that human eDNA remains detectable for up to 36 hours in freshwater samples and up 84 hours in saltwater samples. The limit of detection (LOD) of human eDNA, (205 copies/µl), was achieved after 60 hours in freshwater and 180 hours in saltwater samples. Partial STR profiles could be recovered up to 24 hours for freshwater and saltwater. Results from mtDNA sequencing indicate that full mtDNA profiles could be recovered from freshwater samples up to 48 hours and remained detectable up to 72 hours in saltwater. Overall, the findings of this study underscore the importance of considering and incorporating human eDNA analysis as a valuable tool in forensic practice. By harnessing the power of eDNA, law enforcement agencies can enhance their investigation capabilities, improve the accuracy of forensic reconstructions, and ultimately contribute to the resolution of cases involving aquatic environments. Further research and validation are needed to optimize and expand the utilization of eDNA techniques in forensic investigations.

5.
Health Aff (Millwood) ; 43(10): 1370-1378, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39374456

ABSTRACT

The quality of emergency department (ED) care for children in the US is highly variable. The National Pediatric Readiness Project aims to improve survival for children receiving emergency services. We conducted a cost-effectiveness analysis of increasing ED pediatric readiness, using a decision-analytic simulation model. Previously published primary analyses of a nationally representative, population-based cohort of children receiving emergency services at 747 EDs in eleven states provided clinical and cost parameters. From a health care sector perspective, we used a 3 percent annual discount rate and quantified lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We performed probabilistic, one-way, and subgroup sensitivity analyses. Increasing ED pediatric readiness yields 69,100 QALYs for the eleven-state cohort, costing $9,300 per QALY gained. Achieving high readiness nationally yields 179,000 QALYs at the same ICER (with implementation costs of approximately $260 million). Implementing high ED pediatric readiness for all EDs in the US is highly cost-effective.


Subject(s)
Cost-Benefit Analysis , Emergency Service, Hospital , Quality-Adjusted Life Years , Humans , Emergency Service, Hospital/economics , Emergency Service, Hospital/statistics & numerical data , United States , Child , Child, Preschool , Pediatrics/economics , Infant
6.
Microorganisms ; 12(9)2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39338504

ABSTRACT

The incidence of breast implant illness (BII) and BII-related explant procedures has not decreased with current surgical and treatment techniques. It is speculated the main underlying cause of BII complications is the result of chronic, sub-clinical infections residing on and around the implant. The infection, and subsequent biofilm, produce antagonistic compounds that drive chronic inflammation and immune responses. In this study, the microbial communities in over 600 consecutive samples of infected explant capsules and tissues were identified via next-generation sequencing to identify any commonality between samples. The majority of the bacteria identified were Gram-positive, with Cutibacterium acnes and Staphylococcus epidermidis being the dominant organisms. No correlation between sample richness and implant filling was found. However, there was a significant correlation between sample richness and patient age. Due to the complex nature, breast augmentation failures may be better addressed from a holistic approach than one of limited scope.

7.
BJC Rep ; 2(1): 71, 2024 Dec.
Article in English | MEDLINE | ID: mdl-39301277

ABSTRACT

Background: Increasing incidence of head and neck cancers (HNCs), driven by rising rates of oropharynx cancer (OPC), has been recorded around the world. This study examined trends in HNC and subsites (oral cavity, oropharynx, and larynx cancers) in Scotland focusing on assessing whether the sociodemographic profile has changed over the past 20 years. Methods: Scottish Cancer Registry data (2001-2020) including European Age Standardised Rates of HNC and subsites were analysed in multivariate Poisson regression by age, sex, area-based socioeconomic status, and year of diagnosis (with interaction tests). Results: Overall HNC and oral cavity cancer (OCC) incidence remained relatively stable. OPC incidence rates increased by 78%, while larynx cancer incidence declined by 27%. Over time, there were marginal shifts to a slightly older age profile for HNC (p = 0.001) and OCC (p = 0.001), but no changes in OPC (p = 0.86) and larynx cancer (p = 0.29). No shift in the sex profile of HNC was observed except for minor increases in female OCC rates (p = 0.001), and the socioeconomic distribution remained unchanged across all HNC subsites. Conclusions: There have been no significant changes in the sociodemographic profile of HNC in Scotland over the last 20 years, despite the changing trends in HNCs with dramatically increasing incidence rates in OPC and reducing larynx cancer. This information can be used to target or stratify HNC prevention and control.

8.
Cancer ; 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39301750

ABSTRACT

BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive neuroendocrine lung cancer, with a dismal 5-year survival rate. No reliable biomarkers or imaging are available for early SCLC detection. In a search for a specific marker of SCLC, this study identified that hepatocyte cell adhesion molecule 2 (HEPACAM2), a member of the immunoglobulin-like superfamily, is highly and specifically expressed in SCLC. METHODS: This study investigated HEPACAM2 expression in patients with SCLC via RNA sequencing and evaluated its relationship to progression-free survival (PFS) and overall survival (OS). Immunofluorescence microscopy was used to assess the cellular location of HEPACAM2 and to conduct in vitro and in vivo studies to understand its expression and functional significance. These findings were integrated with databases of patients with SCLC. RESULTS: HEPACAM2 is highly expressed and specific to SCLC. HEPACAM2 levels are inversely correlated with PFS and OS in patients with SCLC and are expressed at all stages. Moreover, HEPACAM2 messenger RNA and its peptides can be detected in the secretomes in cell lines. Positively correlated with ASCL1 expression in SCLC tumors, HEPACAM2 is localized primarily to the plasma membrane and linked to extracellular matrix signaling and cellular migration. A loss of HEPACAM2 in SCLC cells attenuated ASCL1 and MYC expression. Consistent with clinical data, in vitro and in vivo studies suggested that HEPACAM2 promotes cancer cell growth. CONCLUSIONS: With its remarkable specificity, high expression, presence in early disease, and extracellular secretion, HEPACAM2 could be a potential diagnostic cell surface biomarker for early SCLC detection. These findings warrant further investigation into its role in the pathobiology of SCLC.

9.
JCO Oncol Pract ; : OP2400575, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-39226488

ABSTRACT

To break the cycle of "rehabbed to death" in oncology, we must focus on improving communication and care coordination.

10.
Ann Plast Surg ; 2024 Sep 11.
Article in English | MEDLINE | ID: mdl-39293064

ABSTRACT

BACKGROUND: In the Military Health System (MHS), women with breast cancer may undergo surgical treatment in military hospitals (direct care) or in the civilian setting via the insurance benefit (private sector care). We conducted this study to determine immediate breast reconstruction rates among women undergoing mastectomy for cancer in the MHS by setting of care. METHODS: Using the linked Department of Defense's Central Cancer Registry and MHS Data Repository, the Department of Defense's medical claims database, we identified adult women who underwent mastectomy for breast cancer from 1998 to 2014. Patients were then subgrouped by setting of care (direct vs private sector care). The primary outcome was the rate and type of immediate breast reconstruction. Regression models were constructed to determine factors associated with receipt of immediate breast reconstruction. RESULTS: The final sample included 3251 women who underwent mastectomy for cancer in the direct (67.0%) or private sector care (32.6%) settings. The overall rate of immediate breast reconstruction was 29.9% with an upward trend noted throughout the study (P < 0.001). Overall, implant-based reconstruction (81.4%) was more common than tissue-based reconstruction (18.6%). Compared with direct care, the immediate breast reconstruction rate was significantly higher in the private sector care setting (49.3% vs 20.5%, P < 0.001) despite accounting for differences in clinical characteristics (adjusted odds ratio = 4.51, 95% confidence interval [3.72-5.46]). CONCLUSIONS: Immediate breast reconstruction in the direct care setting lags that in the civilian community during the study time period. Further research is needed to ascertain current immediate reconstruction rates and understand factors contributing to any differences in rates between care settings.

11.
JAMA Netw Open ; 7(9): e2431673, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-39250154

ABSTRACT

Importance: Ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) are the most treatable causes of out-of-hospital cardiac arrest (OHCA). Yet, it remains unknown if defibrillator pad position, placement in the anterior-posterior (AP) or anterior-lateral (AL) locations, impacts patient outcomes in VF or pVT OHCA. Objective: To determine the association between initial defibrillator pad placement position and OHCA outcomes for patients presenting with VF or pVT. Design, Setting, and Participants: This prospective cohort study included patients with OHCA and VF or pVT treated by a single North American emergency medical services (EMS) agency from July 1, 2019, through June 30, 2023. The study included patients with OHCA treated by a large suburban fire-based EMS agency that covers a population of 550 000. Consecutive patients with an initial EMS-assessed rhythm of VF or pVT receiving EMS defibrillation were included. Pediatric patients (younger than 18 years), interfacility transfers, arrests of obvious traumatic etiology, and patients with preexisting do-not-resuscitate status were excluded. Exposure: AP or AL pad placement. Main Outcomes and Measures: Return of spontaneous circulation (ROSC) at any time with secondary outcomes of pulses present at emergency department (ED) arrival, survival to hospital admission, survival to hospital discharge, and functional survival at hospital discharge (cerebral performance category score of 2 or less). Measures included adjusted odds ratios (aOR), multivariable logistic regressions, and Fine-Gray competing risks regression. Results: A total of 255 patients with OHCA were included (median [IQR] age, 66 [55-74] years; 63 females [24.7%]), with initial pad positioning documented as either AP (158 patients [62.0%]; median [IQR] age, 65 [54-74] years; 37 females [23.4%]) or AL (97 patients [38.0%]; median [IQR] age, 66 [57-74] years; 26 females [26.8%]). Patients with AP placement had higher adjusted odds ratio (aOR) of ROSC at any time (aOR, 2.64 [95% CI, 1.50-4.65]), but not significantly different odds of pulses present at ED arrival (1.34 [95% CI, 0.78-2.30]), survival to hospital admission (1.41 [0.82-2.43]), survival to hospital discharge (1.55 [95% CI, 0.83-2.90]), or functional survival at hospital discharge (1.86 [95% CI, 0.98-3.51]). Competing risk analysis found significantly greater cumulative incidence of ROSC among those at risk with initial AP placement compared with AL (subdistribution hazard ratio, 1.81 [95% CI, 1.23-2.67]; P = .003). Conclusions and Relevance: In this cohort study of patients with OHCA and VF or pVT, AP defibrillator pad placement was associated with higher ROSC compared with AL placement.


Subject(s)
Defibrillators , Out-of-Hospital Cardiac Arrest , Humans , Out-of-Hospital Cardiac Arrest/therapy , Out-of-Hospital Cardiac Arrest/mortality , Female , Male , Middle Aged , Prospective Studies , Aged , Defibrillators/statistics & numerical data , Emergency Medical Services/methods , Emergency Medical Services/statistics & numerical data , Ventricular Fibrillation/therapy , Treatment Outcome , Electric Countershock/statistics & numerical data , Electric Countershock/methods , Electric Countershock/instrumentation , Tachycardia, Ventricular/therapy , Cardiopulmonary Resuscitation/methods
12.
J Reprod Infant Psychol ; : 1-19, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39291693

ABSTRACT

BACKGROUND: Psychotic-like experiences (PLEs) refer to subclinical experiences consistent with psychosis that may include hearing, feeling or seeing things that others cannot, or experiencing unusual beliefs. These experiences appear to be more common during the perinatal period. There appear to be barriers which make it difficult for midwives to support mothers with mental health difficulties. However, it is important that midwives can provide support with PLEs. AIM: This study aimed to explore UK midwives' perspectives and perceptions relating to mothers' psychotic-like experiences in the perinatal period. METHODS: A qualitative study using semi-structured interviews with ten midwives recruited online was conducted. Transcripts were analysed using thematic analysis. RESULTS: Four themes were developed: (1) Identifying psychotic-like experiences would be complicated; (2) Psychotic-like experiences can feel overwhelming for women and midwives; (3) This is my responsibility: I'll do what I can to support women even if it's hard; and (4) The system feels unsafe and insecure which makes the anticipated role in supporting psychotic-like experiences harder. CONCLUSION: Midwives described their motivation to support mothers with PLEs but articulated many factors that made this difficult. The results emphasise the importance of training and guidance for midwives to support them being able to offer support and information to mothers. The findings also highlight the importance of systemic safety for midwives alongside support through supervision and reflective practice.

13.
Nucleic Acids Res ; 2024 Sep 17.
Article in English | MEDLINE | ID: mdl-39287137

ABSTRACT

RNA polymerase II (pol II) initiates transcription from transcription start sites (TSSs) located ∼30-35 bp downstream of the TATA box in metazoans, whereas in the yeast Saccharomyces cerevisiae, pol II scans further downstream TSSs located ∼40-120 bp downstream of the TATA box. Previously, we found that removal of the kinase module TFIIK (Kin28-Ccl1-Tfb3) from TFIIH shifts the TSS in a yeast in vitro system upstream to the location observed in metazoans and that addition of recombinant Tfb3 back to TFIIH-ΔTFIIK restores the downstream TSS usage. Here, we report that this biochemical activity of yeast TFIIK in TSS scanning is attributable to the Tfb3 RING domain at the interface with pol II in the pre-initiation complex (PIC): especially, swapping Tfb3 Pro51-a residue conserved among all fungi-with Ala or Ser as in MAT1, the metazoan homolog of Tfb3, confers an upstream TSS shift in vitro in a similar manner to the removal of TFIIK. Yeast genetic analysis suggests that both Pro51 and Arg64 of Tfb3 are required to maintain the stability of the Tfb3-pol II interface in the PIC. Cryo-electron microscopy analysis of a yeast PIC lacking TFIIK reveals considerable variability in the orientation of TFIIH, which impairs TSS scanning after promoter opening.

14.
JNCI Cancer Spectr ; 8(5)2024 Sep 02.
Article in English | MEDLINE | ID: mdl-39208282

ABSTRACT

BACKGROUND: Racial disparities in treatment and outcomes of rectal cancer have been attributed to patients' differential access to care. We aimed to study treatment and outcomes of rectal cancer in the equal access Military Health System (MHS) to better understand potential racial disparities. METHODS: We accessed the MilCanEpi database to study a cohort of patients aged 18 and older who were diagnosed with rectal adenocarcinoma between 1998 and 2014. Receipt of guideline recommended treatment per tumor stage, cancer recurrence, and all-cause death were compared between non-Hispanic White and Black patients using multivariable regression models with associations expressed as odds (AORs) or hazard ratios (AHRs) and their 95% confidence intervals (CIs). RESULTS: The study included 171 Black and 845 White patients with rectal adenocarcinoma. Overall, there were no differences in receipt of guideline concordant treatment (AOR = 0.76, 95% CI = 0.45 to 1.29), recurrence (AHR = 1.34, 95% CI = 0.85 to 2.12), or survival (AHR = 1.08, 95% CI = 0.77 to 1.54) for Black patients compared with White patients. However, Black patients younger than 50 years of age at diagnosis (AOR = 0.34, 95% CI = 0.13 to 0.90) or with stage III or IV tumors (AOR = 0.28, 95% CI = 0.12 to 0.64) were less likely to receive guideline recommended treatment than White patients in stratified analysis. CONCLUSIONS: In the equal access MHS, although there were no overall racial disparities in rectal cancer treatment or clinical outcomes between Black and White patients, disparities among those with early-onset or late-stage rectal cancers were noted. This suggests that factors other than access to care may play a role in the observed disparities and warrants further research.


Subject(s)
Adenocarcinoma , Black or African American , Healthcare Disparities , Neoplasm Recurrence, Local , Rectal Neoplasms , Adult , Aged , Female , Humans , Male , Middle Aged , Adenocarcinoma/ethnology , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Cause of Death , Guideline Adherence/statistics & numerical data , Health Services Accessibility/statistics & numerical data , Healthcare Disparities/ethnology , Healthcare Disparities/statistics & numerical data , Military Health Services/statistics & numerical data , Neoplasm Recurrence, Local/ethnology , Neoplasm Recurrence, Local/mortality , Neoplasm Staging , Odds Ratio , Practice Guidelines as Topic , Proportional Hazards Models , Rectal Neoplasms/ethnology , Rectal Neoplasms/mortality , Rectal Neoplasms/therapy , Rectal Neoplasms/pathology , United States/epidemiology , White
15.
J Mol Biol ; : 168770, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39214283

ABSTRACT

Gene expression is dependent on RNA Polymerase II (Pol II) activity in eukaryotes. In addition to determining the rate of RNA synthesis for all protein coding genes, Pol II serves as a platform for the recruitment of factors and regulation of co-transcriptional events, from RNA processing to chromatin modification and remodeling. The transcriptome can be shaped by changes in Pol II kinetics affecting RNA synthesis itself or because of alterations to co-transcriptional events that are responsive to or coupled with transcription. Genetic, biochemical, and structural approaches to Pol II in model organisms have revealed critical insights into how Pol II works and the types of factors that regulate it. The complexity of Pol II regulation generally increases with organismal complexity. In this review, we describe fundamental aspects of how Pol II activity can shape gene expression, discuss recent advances in how Pol II elongation is regulated on genes, and how altered Pol II function is linked to human disease and aging.

16.
Proc Natl Acad Sci U S A ; 121(34): e2408540121, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39150786

ABSTRACT

Most bacteria are surrounded by a cell wall that contains peptidoglycan (PG), a large polymer composed of glycan strands held together by short peptide cross-links. There are two major types of cross-links, termed 4-3 and 3-3 based on the amino acids involved. 4-3 cross-links are created by penicillin-binding proteins, while 3-3 cross-links are created by L,D-transpeptidases (LDTs). In most bacteria, the predominant mode of cross-linking is 4-3, and these cross-links are essential for viability, while 3-3 cross-links comprise only a minor fraction and are not essential. However, in the opportunistic intestinal pathogen Clostridioides difficile, about 70% of the cross-links are 3-3. We show here that 3-3 cross-links and LDTs are essential for viability in C. difficile. We also show that C. difficile has five LDTs, three with a YkuD catalytic domain as in all previously known LDTs and two with a VanW catalytic domain, whose function was until now unknown. The five LDTs exhibit extensive functional redundancy. VanW domain proteins are found in many gram-positive bacteria but scarce in other lineages. We tested seven non-C. difficile VanW domain proteins and confirmed LDT activity in three cases. In summary, our findings uncover a previously unrecognized family of PG cross-linking enzymes, assign a catalytic function to VanW domains, and demonstrate that 3-3 cross-linking is essential for viability in C. difficile, the first time this has been shown in any bacterial species. The essentiality of LDTs in C. difficile makes them potential targets for antibiotics that kill C. difficile selectively.


Subject(s)
Bacterial Proteins , Cell Wall , Clostridioides difficile , Peptidoglycan , Clostridioides difficile/enzymology , Clostridioides difficile/metabolism , Peptidoglycan/metabolism , Cell Wall/metabolism , Bacterial Proteins/metabolism , Bacterial Proteins/chemistry , Peptidoglycan Glycosyltransferase/metabolism , Peptidoglycan Glycosyltransferase/chemistry , Peptidoglycan Glycosyltransferase/genetics
17.
Article in English | MEDLINE | ID: mdl-39172306

ABSTRACT

PURPOSE: Breast cancer accounts for 30% of all female cancers in the US. Cytomegalovirus (CMV), a herpesvirus that establishes lifelong infection, may play a role in breast cancer. CMV is not oncogenic, yet viral DNA and proteins have been detected in breast tumors, indicating possible contribution to tumor development. CMV encodes cmvIL-10, a homolog of human cellular IL-10 (cIL-10) with potent immunosuppressive activities. We investigated the relationship between CMV infection, cytokines, and breast cancer. METHODS: We evaluated CMV serostatus and cytokine levels in plasma of women with benign breast disease (n = 38), in situ carcinoma (n = 41), invasive carcinoma, no lymph node involvement (Inv/LN-; n = 41), and invasive with lymph node involvement (Inv/LN+; n = 37). RESULTS: Fifty percent of the patient samples (n = 79) were CMV seropositive. There was no correlation between CMV status and diagnosis (p = 0.75). For CMV+ patients, there was a trend toward higher CMV IgG levels in invasive disease (p = 0.172). CmvIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.020). Similarly, cIL-10 levels were higher in CMV+ in situ patients compared to the Inv/LN- and Inv/LN+ groups (p = 0.043). The results were quite different in CMV- patients where cIL-10 levels were highest in Inv/LN- compared to benign, in situ, or Inv/LN+ (p = 0.019). African American patients were significantly associated with CMV+ status (p = 0.001) and had lower cmvIL-10 levels than Caucasian patients (p = 0.046). CONCLUSION: No association was observed between CMV IgG and diagnosis, but CMV infection influences cytokine production and contributes to altered cytokine profiles in breast cancer.

18.
Proc Natl Acad Sci U S A ; 121(36): e2318527121, 2024 Sep 03.
Article in English | MEDLINE | ID: mdl-39190355

ABSTRACT

Catalysis and translocation of multisubunit DNA-directed RNA polymerases underlie all cellular mRNA synthesis. RNA polymerase II (Pol II) synthesizes eukaryotic pre-mRNAs from a DNA template strand buried in its active site. Structural details of catalysis at near-atomic resolution and precise arrangement of key active site components have been elusive. Here, we present the free-electron laser (FEL) structures of a matched ATP-bound Pol II and the hyperactive Rpb1 T834P bridge helix (BH) mutant at the highest resolution to date. The radiation-damage-free FEL structures reveal the full active site interaction network, including the trigger loop (TL) in the closed conformation, bonafide occupancy of both site A and B Mg2+, and, more importantly, a putative third (site C) Mg2+ analogous to that described for some DNA polymerases but not observed previously for cellular RNA polymerases. Molecular dynamics (MD) simulations of the structures indicate that the third Mg2+ is coordinated and stabilized at its observed position. TL residues provide half of the substrate binding pocket while multiple TL/BH interactions induce conformational changes that could allow translocation upon substrate hydrolysis. Consistent with TL/BH communication, a FEL structure and MD simulations of the T834P mutant reveal rearrangement of some active site interactions supporting potential plasticity in active site function and long-distance effects on both the width of the central channel and TL conformation, likely underlying its increased elongation rate at the expense of fidelity.


Subject(s)
Catalytic Domain , Magnesium , Molecular Dynamics Simulation , RNA Polymerase II , Transcription, Genetic , RNA Polymerase II/metabolism , RNA Polymerase II/chemistry , RNA Polymerase II/genetics , Magnesium/metabolism , Magnesium/chemistry , Lasers , Protein Conformation , Electrons , Protein Binding , Adenosine Triphosphate/metabolism , Adenosine Triphosphate/chemistry , Binding Sites
19.
Prehosp Emerg Care ; : 1-7, 2024 Sep 17.
Article in English | MEDLINE | ID: mdl-39189823

ABSTRACT

OBJECTIVES: Disparities remain in survival after out-of-hospital cardiac arrest (OHCA) for women compared to men. Our objective was to evaluate differences in automated external defibrillator (AED) use before Emergency Medical Services (EMS) arrival and time from arrival to initial EMS defibrillation by EMS-assessed gender (women or men). METHODS: This was a secondary analysis of adult non-traumatic, EMS-treated OHCA cases in the Portland Cardiac Arrest Epidemiologic Registry from 2018 to 2021. Emergency Medical Services-witnessed cardiac arrests were excluded and the primary outcomes were pre-EMS AED application and the time from EMS arrival to first defibrillation among patients in a shockable rhythm at first rhythm assessment without pre-EMS AED application. We examined pre-EMS AED application rates overall and separately for law enforcement, in cases where they were on-scene before EMS without a lay bystander AED applied, and lay responders, in cases where law enforcement had not applied an AED. We used multivariable logistic and linear regressions to adjust for potential confounders, including age, arrest location, witness status, bystander CPR, year, and time from dispatch to EMS arrival. We accounted for clustering by county of arrest using a mixed-effects approach. RESULTS: Of the 3,135 adult, EMS-treated non-traumatic OHCAs that were not witnessed by EMS, 3,049 had all variables for analysis, of which 1,011 (33.2%) were women. The adjusted odds (adjusted odds ratio [95% CI]) for any pre-EMS placement of an AED was significantly higher for men compared to women (1.40 [1.05-1.86]). These odds favoring men remained when examining law enforcement AED application (1.89 [1.16-3.07]), but not lay bystander AED application (1.19 [0.83-1.71]). Among patients still in arrest on EMS arrival, with a shockable initial EMS rhythm, and without pre-EMS AED application, the time from EMS arrival on-scene to initial defibrillation was significantly longer for women compared to men (+0.81 min [0.22-1.41 min]). CONCLUSIONS: Women with OHCA received lower rates of pre-EMS AED application and delays in initial EMS defibrillation compared to men.

20.
J Environ Qual ; 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-39126277

ABSTRACT

The Long-Term Agroecosystem Research Network (LTAR), through its Common Experiment (CE) framework, contrasts prevailing and alternative agricultural practices for efficacy and sustainability within the indicator domains of environment, productivity, economics, and society. Invasive species, wildfire, and climate change are principal threats to Great Basin agroecosystems. Prescribed grazing may be an effective tool for restoring lands degraded by these disturbances. At the Great Basin (GB) LTAR site headquartered in Boise, ID, our contribution to the CE contrasts a prevailing (PRV), cattle grazing practice of fixed moderate stocking and duration with an alternative (ALT), prescribed grazing practice called high-intensity low-frequency (HILF) grazing where stocking and duration are tailored to suppress invasive annual grass competition with native or desirable plant species and thus promote recovery of rangelands degraded by annual grass invasion and recurrent wildfire. Preliminary results indicate cheatgrass density and fuel height have been reduced in ALT-treated paddocks compared to PRV paddocks. Since its inception in 2014, our GB CE has been a research co-production effort among ranchers, public land managers, and researchers. Future directions for this research will center on expanding the experiment to multiple study areas to better address the scope of the annual grass/wildfire problem. We expect this research will lead to effective and sustainable grazing practices for restoring >41 million hectares of degraded rangelands in the Great Basin and other areas of the western United States.

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