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Reduction of smoking may increase the likelihood of eventual smoking cessation among those not ready to quit. We describe the development and acceptance of a smoking-reduction intervention that integrates telephone counseling sessions with newsletters. A computer-assisted telephone interviewing program generates real-time-tailored counseling delivered by lay interviewers. Pilot participants (n = 53) were adult smokers scheduled for outpatient procedures in a health maintenance organization, randomized to intervention or a control condition (quarterly mailings). Smoking levels were measured by self-report and biochemically. Among intervention participants continuing at 3 months, all but one rated their telephone support person positively on all dimensions. Counseling calls were 'about right' in number, and newsletters were perceived as quite personal. Intervention recipients reported smoking significantly fewer mean cigarettes per day at 3 months than at baseline, and significantly fewer than control participants. Comparisons were non-significant under intent-to-treat analyses and on biochemical measures. The program was well received by outpatients who were not ready to quit smoking, and was implemented successfully by telephone staff who had no previous smoking cessation counseling experience. An ongoing trial is evaluating effectiveness, cost and relationship to eventual cessation. [ABSTRACT FROM AUTHOR]

Innate immune signaling plays a significant role in the rapid cellular responses against foreign entities. An inflammasome is a large cytosolic polymer of a pattern recognition receptor with/without an adaptor protein, formed in response to these entities. Canonically, an inflammasome can recruit and lead to auto-activation of caspase-1, subsequent maturation and secretion of inflammatory cytokines, and pyroptosis. One particular inflammasome, the noncanonical inflammasome, is formed by caspase-4 or -5 (mouse caspase-11) upon binding of lipopolysaccharide and is essential for controlling gram-negative bacterial infection. However, prolonged hyper-activation of the non-canonical inflammasome has been implicated in the pathogenesis of inflammatory diseases and endotoxemia sepsis. This review will summarize the recent advances on the noncanonical inflammasome, its mechanism of activation, key cellular regulators and role in health and disease., (© 2022 The Author(s). Published by Elsevier Ltd on behalf of Tsinghua University Press.)

The in-depth understanding of the reported photoelectrochemical properties of the layered carbon nitride, poly(triazine imide)/LiCl (PTI/LiCl), has been limited by the apparent disorder of the Li/H atoms within its framework. To understand and resolve the current structural ambiguities, an optimized one-step flux synthesis (470 °C, 36 h, LiCl/KCl flux) was used to prepare PTI/LiCl and deuterated-PTI/LiCl in high purity. Its structure was characterized by a combination of neutron/X-ray diffraction and transmission electron microscopy. The range of possible Li/H atomic configurations was enumerated for the first time and, combined with total energy calculations, reveals a more complex energetic landscape than previously considered. Experimental data were fitted against all possible structural models, exhibiting the most consistency with a new orthorhombic model (Sp. Grp. Ama 2) that also has the lowest total energy. In addition, a new Cu(i)-containing PTI (PTI/CuCl) was prepared with the more strongly scattering Cu(i) cations in place of Li, and most closely matching with the partially-disorder structure in Cmc 2 1 . Thus, a complex configurational landscape of PTI is revealed to consist of a number of ordered crystalline structures that are new potential synthetic targets, such as with the use of metal-exchange reactions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Intrinsic cardiac adrenergic (ICA) cells regulate both developing and adult cardiac physiological and pathological processes. However, the role of ICA cells in septic cardiomyopathy is unknown. Here we show that norepinephrine (NE) secretion from ICA cells is increased through activation of Toll-like receptor 4 (TLR4) to aggravate myocardial TNF-α production and dysfunction by lipopolysaccharide (LPS). In ICA cells, LPS activated TLR4-MyD88/TRIF-AP-1 signaling that promoted NE biosynthesis through expression of tyrosine hydroxylase, but did not trigger TNF-α production due to impairment of p65 translocation. In a co-culture consisting of LPS-treated ICA cells and cardiomyocytes, the upregulation and secretion of NE from ICA cells activated cardiomyocyte β 1 -adrenergic receptor driving Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) to crosstalk with NF-κB and mitogen-activated protein kinase pathways. Importantly, blockade of ICA cell-derived NE prevented LPS-induced myocardial dysfunction. Our findings suggest that ICA cells may be a potential therapeutic target for septic cardiomyopathy., (© 2022. The Author(s).)

Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

Importance: Mammography screening currently relies on subjective human interpretation. Artificial intelligence (AI) advances could be used to increase mammography screening accuracy by reducing missed cancers and false positives., Objective: To evaluate whether AI can overcome human mammography interpretation limitations with a rigorous, unbiased evaluation of machine learning algorithms., Design, Setting, and Participants: In this diagnostic accuracy study conducted between September 2016 and November 2017, an international, crowdsourced challenge was hosted to foster AI algorithm development focused on interpreting screening mammography. More than 1100 participants comprising 126 teams from 44 countries participated. Analysis began November 18, 2016., Main Outcomes and Measurements: Algorithms used images alone (challenge 1) or combined images, previous examinations (if available), and clinical and demographic risk factor data (challenge 2) and output a score that translated to cancer yes/no within 12 months. Algorithm accuracy for breast cancer detection was evaluated using area under the curve and algorithm specificity compared with radiologists' specificity with radiologists' sensitivity set at 85.9% (United States) and 83.9% (Sweden). An ensemble method aggregating top-performing AI algorithms and radiologists' recall assessment was developed and evaluated., Results: Overall, 144 231 screening mammograms from 85 580 US women (952 cancer positive ≤12 months from screening) were used for algorithm training and validation. A second independent validation cohort included 166 578 examinations from 68 008 Swedish women (780 cancer positive). The top-performing algorithm achieved an area under the curve of 0.858 (United States) and 0.903 (Sweden) and 66.2% (United States) and 81.2% (Sweden) specificity at the radiologists' sensitivity, lower than community-practice radiologists' specificity of 90.5% (United States) and 98.5% (Sweden). Combining top-performing algorithms and US radiologist assessments resulted in a higher area under the curve of 0.942 and achieved a significantly improved specificity (92.0%) at the same sensitivity., Conclusions and Relevance: While no single AI algorithm outperformed radiologists, an ensemble of AI algorithms combined with radiologist assessment in a single-reader screening environment improved overall accuracy. This study underscores the potential of using machine learning methods for enhancing mammography screening interpretation.

Following successful resuscitation, a significantly impaired microcirculation has been identified. The severity of the impairment of microcirculation is closely related to that of vital organ dysfunction. Sublingual microcirculation is a traditional site for the measurement of tissue perfusion. In the present study, we investigated the bulbar conjunctival microcirculatory alterations following CPR and its relationship with the changes of sublingual microcirculation in a rat model of cardiac arrest.Male Sprague-Dawley rats (450-550 g) were utilized. Ventricular fibrillation was induced and untreated for 8 min followed by 8 min of CPR. Sublingual and bulbar conjunctival microcirculatory blood flow was visualized by a sidestream dark-field imaging device at baseline, 30 min, 1, 2, 4, and 8 h post-resuscitation. Both perfused vessel density (PVD) and microcirculatory flow index (MFI) were recorded.The post-resuscitation PVD and MFI were significantly decreased in both sublingual and bulbar conjunctival sites. Sublingual PVD decreased from baseline of 5.9 ± 0.3 to 3.1 ± 0.4 n/mm at 30 min post-resuscitation and MFI from 3.0 ± 0.0 to 1.5 ± 0.3 (both P < 0.05 vs. baseline). Bulbar conjunctival PVD was significantly reduced from baseline of 6.5 ± 0.6 to 3.9 ± 0.5 n/mm at 30 min post-resuscitation and MFI from 3.0 ± 0.0 to 1.2 ± 0.4 (both P < 0.05 vs. baseline). PVD, MFI, and cardiac function did not change significantly from the 30-min measurements in the surviving rats throughout the remainder of the study (both P > 0.05 vs. 30-min post-resuscitation). The decreases in sublingual microcirculatory blood flow were closely correlated with the reductions of bulbar conjunctival microcirculatory blood flow (PVD: r = 0.87, P < 0.05; MFI: r = 0.92, P < 0.05). Myocardial function was significantly impaired in all animals after resuscitation when compared with baseline values (P < 0.05). The impairments of both sublingual and bulbar conjunctival microcirculation were significantly correlated with the impairment of myocardial function.In the rat model of cardiac arrest, the changes in sublingual microcirculatory blood flow are closely correlated with that of bulbar conjunctival microcirculatory blood flow after successful resuscitation. The changes are correlated with the severity of post-resuscitation myocardial dysfunction. Our study testified sublingual site could be substituted by bulbar conjunctival at least in the rat model of cardiac arrest. The measurement of conjunctival microcirculation may provide an accessible and convenient option as sublingual site for monitoring microcirculation in humans.

Severe hemorrhagic shock and resuscitation is a state of global body ischemia and reperfusion that causes myocardial and cerebral dysfunction. We investigated whether remote ischemic preconditioning (RIPC) would reduce myocardial and cerebral ischemia and reperfusion injuries after hemorrhagic shock as the result of the K(ATP) channel activation. Twenty-one male rats were randomized into three groups: RIPC, RIPC with K(ATP) channel blocker, and control. Remote ischemic preconditioning was induced by four cycles of 5 min of limb ischemia followed by reperfusion for 5 min. Hemorrhagic shock was induced by removing 50% of the estimated total blood volume during an interval of 1 h. Thirty minutes after the completion of bleeding, the animals were reinfused with shed blood during the ensuing 30 min. The animals were monitored for 2 h and observed for an additional 72 h. Myocardial function was measured by echocardiography, and sublingual microcirculation was measured by a sidestream dark-field imaging device at baseline, 1 h after bleeding, 30 min after the completion of bleeding, 30 min after reinfusion, and hourly intervals thereafter. The survival and neurological function were evaluated at 12, 24, 48, and 72 h after reinfusion. At 2 h after reinfusion, ejection fraction and myocardial performance index were significantly better in the RIPC group than in the control group (P < 0.01). The sublingual microvascular flow index and perfused vessel density were significantly greater after reinfusion in the RIPC group than that in the control group (P < 0.01). The duration of survival was significantly longer, and neurological deficit score was significantly better in the RIPC group than the control animals (P < 0.01). Pretreatment with the K(ATP) channel blocker (glibenclamide) completely abolished the myocardial and cerebral protective effects of RIPC. We demonstrate, for the first time, that after severe hemorrhagic shock and resuscitation, RIPC mitigated myocardial and neurological dysfunction with improved survival by activation of the K(ATP) channel.

Clinician-scientists are becoming increasingly rare in medicine as a whole, but especially in ophthalmology. There is a structural gap between MD-PhD training and K-series awards where interested candidates go through residency and fellowship without any structured research exposure or involvement. Furthermore, the success rate of the MD-PhD and K awards leaves much to be desired. The authors propose a redeployment of training resources to reconfigure residency and fellowship training programs for interested candidates with sufficient additional time for a credible research project, augmented salary, and sound mentoring. Opportunities for research training in nontraditional pathways to diversify skill sets and build interdisciplinary teams also would be a prime objective of this novel "Learn-and-Earn" approach.

Background: Angiogenesis is a key process in several ocular disorders and cancers. Soluble Flt-1 is an alternatively spliced form of the Flt-1 gene that retains the ligand-binding domain, but lacks the membrane-spanning and intracellular kinase domains of the full-length membrane bound Flt-1 (mbFlt-1) protein. Thus, sFlt-1 is an endogenous inhibitor of VEGF-A mediated angiogenesis. Synthetic mopholino oligomers directed against splice site targets can modulate splice variant expression. We hypothesize that morpholino-induced upregulation of sFlt-1 will suppress angiogenesis in clinically relevant models of macular degeneration and breast cancer., Methods and Findings: In vivo morpholino constructs were designed to target murine exon/intron 13 junction of the Flt-1 transcript denoted VEGFR1&#95;MOe13; standard nonspecific morpholino was used as control. After nucleofection of endothelial and breast adenocarcinoma cell lines, total RNA was extracted and real-time RT-PCR performed for sFlt-1 and mbFlt-1. Intravitreal injections of VEGFR1&#95;MOe13 or control were done in a model of laser-induced choroidal neovascularization and intratumoral injections were performed in MBA-MD-231 xenografts in nude mice. VEGFR1&#95;MOe13 elevated sFlt-1 mRNA expression and suppressed mbFlt-1 mRNA expression in vitro in multiple cellular backgrounds (p<0.001). VEGFR1&#95;MOe13 also elevated sFlt/mbFlt-1 ratio in vivo after laser choroidal injury 5.5 fold (p<0.001) and suppressed laser-induced CNV by 50% (p = 0.0179). This latter effect was reversed by RNAi of sFlt-1, confirming specificity of morpholino activity through up-regulation of sFlt-1. In the xenograft model, VEGFR1&#95;MOe13 regressed tumor volume by 88.9%, increased sFlt-1 mRNA expression, and reduced vascular density by 50% relative to control morpholino treatment (p<0.05)., Conclusions: Morpholino oligomers targeting the VEGFR1 mRNA exon/intron 13 junction promote production of soluble FLT-1 over membrane bound FLT-1, resulting in suppression of lesional volume in laser induced CNV and breast adenocarcinoma. Thus, morpholino manipulation of alternative splicing offers translational potential for therapy of angiogenic disorders.

A precision flow-controlled rubidium-82 generator has been constructed to deliver 76-sec Rb-82 at either fast or slow flow rates for bolus or constant-infusion studies. A stepping motor drive is interfaced to a microprocessor for pulsed control of flow rate to deliver the saline eluant solution from a large-volume (150 ml) machined pumping syringe through an alumina column that retains the 25-day Sr-82 parent. The generator system delivers 70-90% of the maximum Rb-82 activity in a 20-25 ml bolus elution of 2% NaCl. The Sr-82/Sr-85 breakthrough is 10(-7) - 10(-6). both yield and breakthrough are functions of column length and flow rate. Six separate Sr-82 loadings of the generator were evaluated over a period of nearly 2 yr in studies of myocardial blood perfusion and permeability changes in the blood-brain barrier. Sterility and apyrogenicity of the Rb-82 eluate were maintained during multiple elutions and long-term use of 3-4 mo for each generator loading.