Bigger Isn’t Always Better: An Analysis of Court Efficiency Using Hierarchical Linear Modeling

One important measure of trial court efficiency is overall case length—that is, the elapsed time from a case’s initial filing to its final disposition. Using a large, recent dataset from nearly 7000 federal civil cases, we find that two variables are particularly useful in predicting overall case length: the total number of attorneys filing an appearance in the case, and the number of authorized judgeships for a given district court. Further, we find a significant and surprising interaction between these two variables, indicating that smaller courts are more efficient than larger courts at processing civil cases when more than three attorneys appear in a case, but that the opposite holds true when three attorneys or fewer appear in a case

Acinetobacter baumannii targets human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) for invasion of pneumocytes

Multidrug-resistant Acinetobacter baumannii is regarded as a life-threatening pathogen mainly associated with nosocomial and community-acquired pneumonia. Here, we show that A. baumannii can bind the human carcinoembryonic antigen- related cell adhesion molecule (CEACAM) receptors CEACAM1, CEACAM5, and CEACAM6. This specific interaction enhances A. baumannii internalization in membrane- bound vacuoles, promptly decorated with Rab5, Rab7, and lipidated microtubule- associated protein light chain 3 (LC3). Dissecting intracellular signaling pathways revealed that infected pneumocytes trigger interleukin-8 (IL-8) secretion via the extracellular signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) signaling pathways for A. baumannii clearance. However, in CEACAM1-L-expressing cells, IL-8 secretion lasts only 24 h, possibly due to an A. baumannii-dependent effect on the CEACAM1-L intracellular domain. Conversely, the glycosylphosphatidylinositol- anchored CEACAM5 and CEACAM6 activate the c-Jun NH2-terminal kinase (JNK)1/ 2-Rubicon-NOX2 pathway, suggestive of LC3-associated phagocytosis. Overall, our data show for the first time novel mechanisms of adhesion to and invasion of pneumocytes by A. baumannii via CEACAM-dependent signaling pathways that eventually lead to bacterial killing. These findings suggest that CEACAM upregulation could put patients at increased risk of lower respiratory tract infection by A. baumannii. IMPORTANCE This work shows for the first time that Acinetobacter baumannii binds to carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), CEACAM5, and CEACAM6. This binding significantly enhances A. baumannii internalization within alveolar host cell epithelia. Intracellular trafficking involves typical Rab5 and Rab7 vacuolar proteins as well as light chain 3 (LC3) and slowly progresses to bacterial killing by endosome acidification. CEACAM engagement by A. baumannii leads to distinct and specific downstream signaling pathways. The CEACAM1 pathway finely tunes interleukin- 8 (IL-8) secretion, whereas CEACAM5 and CEACAM6 mediate LC3-associated phagocytosis. The present study provides new insights into A. baumannii-host interactions and could represent a promising therapeutic strategy to reduce pulmonary infections caused by this pathogen

RflM mediates target specificity of the RcsCDB phosphorelay system for transcriptional repression of flagellar synthesis in Salmonella enterica: Repression of flhDC transcription by a RcsB-RflM complex

The bacterial flagellum enables directed movement of Salmonella enterica towards favorable conditions in liquid environments. Regulation of flagellar synthesis is tightly controlled by various environmental signals at transcriptional and post- transcriptional levels. The flagellar master regulator FlhD₄C₂ resides on top of the flagellar transcriptional hierarchy and is under autogenous control by FlhD₄C₂- dependent activation of the repressor rflM. The inhibitory activity of RflM depends on the presence of RcsB, the response regulator of the RcsCDB phosphorelay system. In this study, we elucidated the molecular mechanism of RflM- dependent repression of flhDC. We show that RcsB and RflM form a heterodimer that coordinately represses flhDC transcription independent of RcsB phosphorylation. RcsB-RflM complex binds to a RcsB box downstream the P1 transcriptional start site of the flhDC promoter with increased affinity compared to RcsB in the absence of RflM. We propose that RflM stabilizes binding of unphosphorylated RcsB to the flhDC promoter in absence of environmental cues. Thus, RflM is a novel auxiliary regulatory protein that mediates target specificity of RcsB for flhDC repression. The cooperative action of the RcsB-RflM repressor complex allows Salmonella to fine-tune initiation of flagellar gene expression and adds another level to the complex regulation of flagellar synthesis

Neonatal obstructive nephropathy induces necroptosis and necroinflammation

Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed necrosis mediated by the receptor-interacting serine/threonine-protein kinase-3 (RIPK3) and the pseudokinase mixed lineage kinase domain-like (MLKL). Necrosis induces inflammation and stimulates cell death in an autoamplification loop named necroinflammation. Here, we studied necroptosis and necroinflammation in obstructive nephropathy induced by unilateral ureteral obstruction (UUO) in neonatal C57Bl/6J mice. Ureteral obstruction induced tubular dilatation, tubular basement membrane thickening, cast formation, and increased expression of kidney injury molecule-1 (KIM-1). Morphological investigations showed either apoptotic or necrotic cells in the tubular compartment. Biochemical analysis revealed increased caspase-8 activity and upregulation of RIPK3 as well as phosphorylated-MLKL in UUO-kidneys. Pro-inflammatory cytokines (IL-1 alpha, INF-gamma, TNF-alpha) were upregulated following UUO. Taken together we show that necroptosis and necroinflammation are accompanied phenomena in neonatal kidneys with obstruction. These findings may help to develop novel strategies to treat congenital obstructive nephropathy

Nietzsche and Amor Fati

This paper identifies two central paradoxes threatening the notion of amor fati [love of fate]: it requires us to love a potentially repellent object (as fate entails significant negativity for us) and this, in the knowledge that our love will not modify our fate. Thus such love may seem impossible or pointless. I analyse the distinction between two different sorts of love (eros and agape) and the type of valuation they involve (in the first case, the object is loved because we value it; in the second, we value the object because we love it). I use this as a lens to interpret Nietzsche?s cryptic pronouncements on amor fati and show that while an erotic reading is, up to a point, plausible, an agapic interpretation is preferable both for its own sake and because it allows for a resolution of the paradoxes initially identified. In doing so, I clarify the relation of amor fati to the eternal return on the one hand, and to Nietzsche?s autobiographical remarks about suffering on the other. Finally, I examine a set of objections pertaining both to the sustainability and limits of amor fati, and to its status as an ideal

Research priorities of people living with Turner syndrome

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148393/1/ajmgc31676.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148393/2/ajmgc31676_am.pd

Dialogues with parents: a parental support and empowerment program based on the Touchpoints Model

“Dialogues with Parents-welcoming, listening, and empowering” aimed to understand the impact of an innovative approach supporting parents with identified social/emotional vulnerabilities. Program goals included the promotion of positive parenting, the expansion of parents' knowledge and skills, and the enhancement of parent–child interactions. Based on the Brazelton Touchpoints Developmental-Relational Frameworks, the program applied strength-based assumptions and relationship-based practices to underpin empathic and collaborative relationships with families, seeking to strengthen their confidence in parenting. Two modalities were offered with a modular structure from prenatal–newborn to 6 years. Both included 10 modules, one in which the same group of parents carried out the complete sequence of sessions (Continuous Group) and a second in which parents selected one Touchpoint according to their needs and “drop in” to the session(s) of their choice (Touchpoints 1 by 1 Group). Data were gathered through satisfaction questionnaires at the end of each encounter. A focus group was also held with parents from the Continuous Group. The difference between applications (248) and total participation (99) indicates that parent's interest in participating is high but only a third managed to join the groups. Nevertheless, the results were very positive, highlighting the quality of the Touchpoints approach and program implementation, namely its impact on improving parents' understanding of children's development and of their own role in parenting. Parents particularly valued the opportunity to actively participate in the encounters and, in the Continuous Group, the usefulness of the encounters for themselves as a person and as parents

Perioperative pain management and opioid-reduction in head and neck endocrine surgery: An American Head and Neck Society Endocrine Surgery Section consensus statement

BACKGROUND: This American Head and Neck Society (AHNS) consensus statement focuses on evidence-based comprehensive pain management practices for thyroid and parathyroid surgery. Overutilization of opioids for postoperative pain management is a major contributing factor to the opioid addiction epidemic however evidence-based guidelines for pain management after routine head and neck endocrine procedures are lacking. METHODS: An expert panel was convened from the membership of the AHNS, its Endocrine Surgical Section, and ThyCa. An extensive literature review was performed, and recommendations addressing several pain management subtopics were constructed based on best available evidence. A modified Delphi survey was then utilized to evaluate group consensus of these statements. CONCLUSIONS: This expert consensus provides evidence-based recommendations for effective postoperative pain management following head and neck endocrine procedures with a focus on limiting unnecessary use of opioid analgesics

MRI Surveillance and Breast Cancer Mortality in Women With <i>BRCA1</i> and <i>BRCA2</i> Sequence Variations

Importance: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures: Entrance into an MRI surveillance program. Main Outcomes and Measures: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P  Conclusion and Relevance: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.</p