Anti-inflammatory reliever therapy (AIR) for asthma.

SABA overuse is prevalent and dangerous in asthma. Use of anti-inflammatory relievers (ICS/formoterol) in asthma mitigates against risk associated with SABA overuse and poor ICS adherence, and is the preferred approach for asthma management. https://bit.ly/4aHOLn8.

The thienopyridine A-769662 and benzimidazole 991 inhibit human TASK-3 potassium channels in an AMPK-independent manner.

Heteromeric Tandem pore domain Acid Sensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP-activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK-3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK-1, with Ser55 representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK-3 potassium channels expressed in human embryonic kidney (HEK)-293 cells. Two structurally unrelated AMPK activators, the thienopyridine A-769662 (100-500 µM) and the benzimidazole 991 (3-30 µM) inhibited hTASK-3 currents in a concentration-dependent manner, while the 4-azabenzimidazole MK-8722 (3-30 µM) partially inhibited hTASK-3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10-100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK-3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A-769662 (300 µM) also inhibited hTASK-3 channel currents in HEK-293 cells that stably over-expressed an AMPK-ß1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A-769662. We therefore identify A-769662 and 991 as novel hTASK-3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK-3 channel currents.

TEMPORARY REMOVAL: A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF BRENSOCATIB IN PATIENTS WITH NON-CYSTIC FIBROSIS BRONCHIECTASIS - THE ASPEN TRIAL.

This abstract has been temporarily removed at the request of the author. A replacement will appear as soon as possible, or the abstract will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Linking intraspecies variability of Salmonella enterica isolates under acidic conditions to genotype.

There is a lack of information about Salmonella enterica strains under acidic conditions and their association with their genome. This study characterized intraspecies variability in the growth of 167 S. enterica isolates under two acid conditions (pH 4 and 5) and linked to the whole genome sequencing (WGS) data. A total of 1002 curves for each condition were obtained using turbidimetry measurements, and Baranyi and Roberts model was used to estimate the maximum rate of change (rcmax; OD600 nm h-1). Strains were categorized into slow, intermediate, and fast; and associations with their WGS data were performed. Huge variability in r c max ¯ $\overline {{\mathrm{r}}{{{\mathrm{c}}}_{{\mathrm{max}}}}} $ was observed at both conditions (pH 5 = 0.016-0.066 OD600nm h-1 and pH 4 = 0.003-0.028 OD600nm h-1). The majority of isolates was classified as intermediate r c max ¯ $\overline {{\mathrm{r}}{{{\mathrm{c}}}_{{\mathrm{max}}}}} $ (59.5% at pH 5 and 46.1% at pH 4). Strains classified as fast had a low frequency of allABCD genes at both pHs, and any of them having the presence of pefABCD, spvBCR, aadA2, dfrA12, and gyrA_D87G genes were linked to virulence or antimicrobial resistance. This study suggests that strains with fast capacity for growth under acidic conditions could have a fitness cost in their virulence or resistance potential. PRACTICAL APPLICATION: Data presented in this study could be used to select representative strains to evaluate the exposure assessment in different food items, mainly the growth and survival in acidic foods.

miRNA-mediated control of gephyrin synthesis drives sustained inhibitory synaptic plasticity.

Activity-dependent protein synthesis is crucial for long-lasting forms of synaptic plasticity. However, our understanding of translational mechanisms controlling GABAergic synapses is limited. One distinct form of inhibitory long-term potentiation (iLTP) enhances postsynaptic clusters of GABAARs and the primary inhibitory scaffold, gephyrin, to promote sustained synaptic strengthening. While we previously found that persistent iLTP requires mRNA translation, the mechanisms controlling plasticity-induced gephyrin translation remain unknown. We identify miR153 as a novel regulator of Gphn mRNA translation which controls gephyrin protein levels and synaptic clustering, ultimately impacting inhibitory synaptic structure and function. iLTP induction downregulates miR153, reversing its translational suppression of Gphn mRNA and promoting de novo gephyrin protein synthesis and synaptic clustering during iLTP. Finally, we find that reduced miR153 expression during iLTP is driven by an excitation-transcription coupling pathway involving calcineurin, NFAT and HDACs, which also controls the miRNA-dependent upregulation of GABAARs. Together, we delineate a miRNA-dependent post-transcriptional mechanism that controls the expression of the key synaptic scaffold, gephyrin, and may converge with parallel miRNA pathways to coordinate gene upregulation to maintain inhibitory synaptic plasticity.

Incidence of Ipsilateral Femoral Neck and Shaft Fractures in Pediatric and Adolescent Patients.

OBJECTIVES: To identify the incidence, patient characteristics, and effectiveness of radiographic screening methods for detecting ipsilateral femoral neck and shaft fractures in pediatric and adolescent trauma patients. DESIGN: Retrospective cohort study. SETTING: This study was conducted at a tertiary pediatric trauma hospital. PATIENT SELECTION CRITERIA: Patients younger than 18 years treated for a femoral shaft fracture between 2004 and 2018 were reviewed. Pathologic (metabolic bone disease or bone lesion), periprosthetic, and penetrating traumatic femoral shaft fractures were excluded. OUTCOME MEASUREMENTS AND COMPARISONS: Patient demographics, mechanisms of injury, treatment methods, and associated injuries were analyzed. Pretreatment x-rays and computed tomography (CT) scans were reviewed for the identification of ipsilateral femoral neck and shaft fractures. RESULTS: Among the 840 pediatric patients included in this study, 4 patients (0.5%) sustained ipsilateral femoral neck and shaft fractures. All the femoral neck fractures were observed in adolescents (aged 13-17 years) and involved in high-energy traumas. In adolescents involved in high-energy trauma, the incidence increased to 1.7%. Pretreatment sensitivity of both x-rays and CT scans was only 50% for the detection of femoral neck fractures. CONCLUSIONS: This study reveals that ipsilateral femoral neck and shaft fractures in pediatric patients are rare, occurring in adolescents involved in high-energy trauma. The findings suggest the need for a selective, rather than routine, use of CT scans based on the patient's age and the mechanism of injury. The use of alternative imaging methods such as magnetic resonance imaging should be considered to balance diagnostic accuracy while minimizing radiation exposure. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Changing times: trends in risk classification, tumor upstaging, and positive surgical margins after radical prostatectomy - results from a contemporary National Cancer Database study.

PURPOSE: Recent advancements in screening, prostate MRI, robotic surgery, and active surveillance have influenced the profile of patients undergoing radical prostatectomy (RP). We sought to examine their impact on trends in clinicodemographic, risk classification, and adverse pathology in men undergoing surgery. METHODS: We queried the National Cancer Database for clinicodemographic, risk group, and pathology data in men undergoing upfront RP between 2006 and 2020. Patients were categorized by NCCN risk groups, and trends were assessed among 2006-2010, 2011-2015, and 2016-2020 periods. Endpoints included rates of pT3, positive surgical margins (PSM), pathologic upstaging, and Gleason grade group (GG) upgrading. RESULTS: 610,762 patients were included. There were significant increases in African Americans (9.8-14.1%), comorbidities (2.1-5.2% with Charlson scores > 1), and robot-assisted RP (78-84%). Over the three time periods, high-risk cases increased from 15 to 20 to 27%, and intermediate-risk from 54 to 51 to 60%. Overall rates of pT3 rose from 20 to 38%, and PSM from 20 to 27% (p < 0.001). Pathologic upstaging increased in low (6-15%), intermediate (20-33%), and high-risk groups (42-58%) -p < 0.001. Gleason upgrading rose in low-risk (45-59%, p < 0.001), with slight reductions in the intermediate and high-risk groups. CONCLUSIONS: Recent trends in RP indicate a shift towards more advanced disease, evidenced by increasing rates of pT3, PSM, and pathologic upstaging across all NCCN risk groups. These findings emphasize the need for a careful balance in applying fascia and nerve-sparing techniques to avoid compromising oncological safety.

Intraoperative guidance of pancreatic cancer resection using a toll like receptor 2 targeted fluorescence molecular imaging agent.

To increase the achievement of negative R0 surgical margins and increase the low survival rates of pancreatic cancer, improvements in assessing tumor margins during surgical resections are needed. This can be accomplished by using pancreatic cancer-targeted fluorescence molecular imaging agents to intraoperatively detect tumor margins in real-time. Since toll like receptor 2 (TLR2) is broadly expressed among many cancer types including pancreatic adenocarcinomas, a high-affinity TLR2-targeted fluorescence molecular imaging agent (TLR2L-800) was developed. We investigate the potential for increased survival by employing real-time intraoperative tumor detection in a preclinical orthotopic human pancreatic xenograft tumor model using TLR2L-800. Three cohorts of nude mice bearing orthotopic human pancreatic xenograft tumors were intravenously injected with TLR2L-800. At 24 h postinjection, one cohort underwent in vivo fluorescence-guided surgical removal of tumors using a real-time fluorescence imaging platform, a second cohort underwent visible light surgery, and a third cohort did not undergo surgery. A fourth, non-tumor-bearing cohort was administered TLR2L-800 with no surgery. At 41 d post-surgery, the survival rates were 53% for the fluorescence-guided surgery group and 0% for both the visible light surgery group and the tumor-bearing no surgery group. The overall 200 d survival rate of 35% for the fluorescence-guided surgery group was significant compared to 0% for the visible light surgery group (p-value=0.0018). This study demonstrates the potential of increasing disease-free survival for patients with pancreatic cancer by increasing the attainment of R0 margins using a novel tumor-targeted lipopeptide ligand-based fluorescence molecular imaging agent, TLR2L-800, during real-time fluorescence-guided surgery.

Evaluating 4Kscore's role in predicting progression on active surveillance for prostate cancer independently of clinical information and PIRADS score.

BACKGROUND: 4Kscore is used to aid the decision for prostate biopsy, however its role in active surveillance (AS) has not been investigated in a magnetic resonance imaging (MRI)-based protocol. Our objective was to assess the association between 4Kscore and progression in men undergoing AS on a prospective MRI-based protocol. METHODS: This was a single-institution, single-arm, non-therapeutic, interventional trial of 166 men with biopsy-confirmed prostate cancer enrolled between 2014-2020. Patients were placed on a trial-mandated AS protocol including yearly multiparametric (mp)MRI, prostate biopsy, and 4Kscore followed for 48 months after diagnosis. We analyzed protocol-defined and grade progression at confirmatory and subsequent surveillance biopsies. RESULTS: Out of 166 patients, 83 (50%) men progressed per protocol and of them 41 (24.7% of whole cohort) progressed by grade. At confirmatory biopsy, men with a baseline 4Kscore ≥ 20% had a higher risk of grade progression compared to those with 4Kscore < 20% (OR = 4.04, 95% CI: 1.05-15.59, p = 0.043) after adjusting for National Comprehensive Cancer Network (NCCN) risk and baseline PIRADS score. At surveillance biopsies, most recent 4Kscore ≥ 20% significantly predicted per protocol (OR = 2.61, 95% CI: 1.03-6.63, p = 0.044) and grade progression (OR = 5.13, 95% CI: 1.63-16.11, p = 0.005). CONCLUSIONS: For patients on AS, baseline 4Kscore predicted grade progression at confirmatory biopsy, and most recent 4Kscore predicted per-protocol and grade progression at surveillance biopsy.