Quantitative proteome comparison of human hearts with those of model organisms.

Delineating human cardiac pathologies and their basic molecular mechanisms relies on research conducted in model organisms. Yet translating findings from preclinical models to humans present a significant challenge, in part due to differences in cardiac protein expression between humans and model organisms. Proteins immediately determine cellular function, yet their large-scale investigation in hearts has lagged behind those of genes and transcripts. Here, we set out to bridge this knowledge gap: By analyzing protein profiles in humans and commonly used model organisms across cardiac chambers, we determine their commonalities and regional differences. We analyzed cardiac tissue from each chamber of human, pig, horse, rat, mouse, and zebrafish in biological replicates. Using mass spectrometry-based proteomics workflows, we measured and evaluated the abundance of approximately 7,000 proteins in each species. The resulting knowledgebase of cardiac protein signatures is accessible through an online database: atlas.cardiacproteomics.com. Our combined analysis allows for quantitative evaluation of protein abundances across cardiac chambers, as well as comparisons of cardiac protein profiles across model organisms. Up to a quarter of proteins with differential abundances between atria and ventricles showed opposite chamber-specific enrichment between species; these included numerous proteins implicated in cardiac disease. The generated proteomics resource facilitates translational prospects of cardiac studies from model organisms to humans by comparisons of disease-linked protein networks across species.

Gating kinetics and pharmacological properties of small-conductance Ca2+-activated potassium channels.

Small-conductance (SK) calcium-activated potassium channels are a promising treatment target in atrial fibrillation. However, the functional properties that differentiate SK inhibitors remain poorly understood. The objective of this study was to determine how two unrelated SK channel inhibitors, apamin and AP14145, impact SK channel function in excised inside-out single-channel recordings. Surprisingly, both apamin and AP14145 exert much of their inhibition by inducing a class of very-long-lived channel closures (apamin: τc,vl = 11.8 ± 7.1 s, and AP14145: τc,vl = 10.3 ± 7.2 s), which were never observed under control conditions. Both inhibitors also induced changes to the three closed and two open durations typical of normal SK channel gating. AP14145 shifted the open duration distribution to favor longer open durations, whereas apamin did not alter open-state kinetics. AP14145 also prolonged the two shortest channel closed durations (AP14145: τc,s = 3.50 ± 0.81 ms, and τc,i = 32.0 ± 6.76 ms versus control: τc,s = 1.59 ± 0.19 ms, and τc,i = 13.5 ± 1.17 ms), thus slowing overall gating kinetics within bursts of channel activity. In contrast, apamin accelerated intraburst gating kinetics by shortening the two shortest closed durations (τc,s = 0.75 ± 0.10 ms and τc,i = 5.08 ± 0.49 ms) and inducing periods of flickery activity. Finally, AP14145 introduced a unique form of inhibition by decreasing unitary current amplitude. SK channels exhibited two clearly distinguishable amplitudes (control: Ahigh = 0.76 ± 0.03 pA, and Alow = 0.54 ± 0.03 pA). AP14145 both reduced the fraction of patches exhibiting the higher amplitude (AP14145: 4/9 patches versus control: 16/16 patches) and reduced the mean low amplitude (0.38 ± 0.03 pA). Here, we have demonstrated that both inhibitors introduce very long channel closures but that each also exhibits unique effects on other components of SK gating kinetics and unitary current. The combination of these effects is likely to be critical for understanding the functional differences of each inhibitor in the context of cyclical Ca2+-dependent channel activation in vivo.

Pharmacological inhibition of SK-channels with AP14145 prevents atrial arrhythmogenic changes in a porcine model for obstructive respiratory events.

BACKGROUND: Obstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions. We investigated atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small-conductance Ca2+ -activated K+ (SK)-channel inhibition in a porcine model for obstructive respiratory events. METHODS: In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 s, every 10 min, three times before and three times during infusion of the SK-channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (pre-INAP), during (INAP) and after (post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. Ventricular arrhythmicity was evaluated by heart rate adjusted QT-interval duration (QT-paced) and electromechanical window (EMW) shortening. RESULTS: During vehicle infusion, INAP transiently shortened AERP (pre-INAP: 135 ± 10 ms vs. post-INAP 101 ± 11 ms; p = .008) and increased AF-inducibility. QT-paced prolonged during INAP (pre-INAP 270 ± 7 ms vs. INAP 275 ± 7 ms; p = .04) and EMW shortened progressively throughout INAP and post-INAP (pre-INAP 80 ± 4 ms; INAP 59 ± 6 ms, post-INAP 46 ± 10 ms). AP14145 prolonged baseline AERP, partially prevented INAP-induced AERP-shortening and reduced AF-susceptibility. AP14145 did not alter QT-paced at baseline (pre-AP14145 270 ± 7 ms vs. AP14145 268 ± 6 ms, p = .83) or QT-paced and EMW-shortening during INAP. CONCLUSION: In a pig model for obstructive respiratory events, the SK-channel-inhibitor AP14145 prevented INAP-associated AERP-shortening and AF-susceptibility without impairing ventricular electrophysiology. Whether SK-channels represent a target for OSA-related AF in humans warrants further study.

LIBRETTO-432, a phase III study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive non-small-cell lung cancer.

Selpercatinib, a first-in-class, highly selective and potent central nervous system-active RET kinase inhibitor demonstrated clinically meaningful activity with manageable toxicity in pretreated and treatment-naive advanced/metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). LIBRETTO-432 is a global, randomized, double-blind, phase III trial evaluating selpercatinib versus placebo in stage IB-IIIA, RET fusion-positive NSCLC, previously treated with definitive surgery or radiation; participants must have undergone available anti-cancer therapy (including chemotherapy or durvalumab) or not be suitable for it, per investigator's discretion. The primary end point is investigator-assessed event-free survival (EFS) in the primary analysis population (stage II-IIIA RET fusion-positive NSCLC). Key secondary end points include EFS in the overall population, overall survival, and time to distant disease recurrence in the central nervous system.

Selpercatinib is approved in multiple countries for the treatment of advanced or metastatic RET-altered lung cancers. Selpercatinib has shown promising efficacy and safety results in patients with advanced/metastatic RET fusion-positive NSCLC. This is a summary of the LIBRETTO-432 study which compares selpercatinib with placebo in patients with earlier stages (stage IB-IIIA) of RET fusion-positive NSCLC, who have already undergone surgery or radiotherapy and applicable adjuvant chemotherapy. This study is active and currently recruiting new participants. This trial will evaluate how long people live without evidence of cancer recurrence, both during and after treatment. Side effects will also be evaluated in this study. Clinical Trial Registration: NCT04819100 (ClinicalTrials.gov).

[Distribution and gene characteristics of H3, H4 and H6 subtypes of low pathogenic avian influenza viruses in environment related avian influenza viruses during 2014-2021 in China].

Objective: To analyze the characteristics of low pathogenic H3, H4 and H6 subtypes of avian influenza viruses in environment related avian influenza viruses in China from 2014 to 2021. Methods: Surveillance sites were located in 31 provinces, autonomous region and municipalities to collect environmental samples related to avian influenza, detect the nucleic acid detection of influenza A virus, isolate virus, deeply sequence, analyze pathogenicity related molecular sites, and determine the distribution and variation characteristics of common H3, H4 and H6 subtypes of avian influenza virus in different regions, places and sample types. Results: A total of 388 645 samples were collected. The positive rate of low pathogenic H3 (0.56‰) and H6 (0.53‰) was higher than that of H4 (0.09‰). The positive rate of H4 subtype virus in live poultry market was higher than that in other places, and the difference was statistically significant. The positive rate of H3 and H6 subtypes in sewage samples was higher than that in other samples, and the difference was statistically significant. The positive rate of H3, H4 and H6 viruses in the south was higher than that in the north, and the difference was statistically significant. December was the most active time for virus. The analysis of pathogenicity related molecular sites showed that H3, H4 and H6 subtypes of viruses combined with avian influenza virus receptors, and some gene sites related to increased pathogenicity had mutations. Conclusion: The H3, H4 and H6 subtypes of low pathogenic avian influenza viruses have a high isolation positive rate in the live poultry market and sewage. The distribution of the three subtypes of viruses has obvious regional and seasonal characteristics, and the genetic characteristics still show the feature of low pathogenic avian influenza.

Effects of the prebiotic inulin-type fructans on post-antibiotic reconstitution of the gut microbiome.

AIMS: Interventions using prebiotic inulin-type fructans (ITFs) are widely prescribed to modulate the gut microbiota composition and activity to promote health. However, the impacts of ITFs on post-antibiotic reconstitution of the gut microbiome remain incompletely understood. The aim of the present study was to investigate the effects of ITFs supplementation on intestinal inflammation, the composition of the intestinal microbiota and the colonic transcriptome after antibiotic treatment. METHODS AND RESULTS: Male BALB/c mice were subjected to an antibiotic cocktail (ABx) treatment for 7 days, and their microbiomes were then reconstituted either spontaneously or with ITFs supplementation (5%) for 14 days. Our data showed that ITFs supplementation delayed the recovery of antibiotic-induced colitis compared with the spontaneous recovery. Neither ITFs supplementation nor spontaneous recovery could restore the microbial community composition at the genus level back to its initial composition. ITFs supplementation increased the relative abundance of some beneficial bacteria and butyrate levels, but resulted in selective blooms of some opportunistic pathogens and elevated the pathways associated with diseases linked to gut microbiota function. Both ITFs supplementation and spontaneous recovery could restore the colonic transcriptome nearly to the initial profile to a certain extent; however, ITFs supplementation delayed the restoration of the immunoglobulin genes compared to spontaneous recovery. CONCLUSION: These data showed that post-antibiotic ITFs consumption did not always lead to beneficial effects but might lead to potential adverse effects in the context of dysbiosis. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings highlighted that caution is required when supplementing ITFs to restore intestinal homeostasis in the context of dysbiosis resulting from broad-spectrum antibiotics.

Viscosity dynamics and the production of extracellular polymeric substances and soluble microbial products during anaerobic digestion of pulp and paper mill wastewater sludges.

The production processes of the pulp and paper industry often run in campaigns, leading to large variations in the composition of wastewaters and waste sludges. During anaerobic digestion (AD) of these wastes, the viscosity or the production of extracellular polymeric substances (EPS) and soluble microbial products (SMP) may be affected, with the risk of foam formation, inefficient digester mixing or poor sludge dewaterability. The aim of this study was to investigate how viscosity and production of EPS and SMP during long-term AD of pulp and paper mill sludge is affected by changes in organic loading rate (OLR) and hydraulic retention time (HRT). Two mesophilic lab-scale continuous stirred tank reactors (CSTRs) were operated for 800 days (R1 and R2), initially digesting only fibre sludge, then co-digesting fibre sludge and activated sludge. The HRT was lowered, followed by an increase in the OLR. Reactor fluids were sampled once a month for rheological characterization and analysis of EPS and SMP. The production of the protein fraction of SMP was positively correlated to the OLR, implicating reduced effluent qualities at high OLR. EPS formation correlated with the magnesium content, and during sulphate deficiency, the production of EPS and SMP increased. At high levels of EPS and SMP, there was an increase in viscosity of the anaerobic sludges, and dewatering efficiency was reduced. In addition, increased viscosity and/or the production of EPS and SMP were important factors in sludge bulking and foam formation in the CSTRs. Sludge bulking was avoided by more frequent stirring.

Clinical and pathological comparisons of adnexal torsion between pregnant and non-pregnant women.

AIM: We evaluated and compared the clinical and pathological differences between pregnant and non-pregnant women with adnexal torsion. METHODS: We retrospectively reviewed 239 women with adnexal torsion from January 2006 to December 2015 in a tertiary hospital. The clinical and pathological differences between pregnant and non-pregnant women who underwent surgery for adnexal torsion were analyzed. RESULTS: The most common pathologies were corpus luteum cysts in pregnant women and dermoid cysts in non-pregnant women. Eight of the pregnant women (24.2%) had a history of exogenous ovarian stimulation, and their episodes were only caused by corpus luteum or a stimulated ovary. In pregnant women, 72.7% of the torsion occurred before the 14th week of gestation. CONCLUSION: The common pathology causing adnexal torsion was different, depending on the pregnancy status. Exogenous ovarian stimulation increases the risk of adnexal torsion, and the majority of episodes occurred in the first trimester in pregnant women.

Substrate and operational conditions as regulators of fluid properties in full-scale continuous stirred-tank biogas reactors - implications for rheology-driven power requirements.

Understanding fluid rheology is important for optimal design and operation of continuous stirred-tank biogas reactors (CSTBRs) and is the basis for power requirement estimates. Conflicting results have been reported regarding the applicability of total solid (TS) and/or total volatile solid (TVS) contents of CSTBR fluids as proxies for rheological properties. Thus, the present study investigates relationships between rheological properties of 12 full-scale CSTBR fluids, their substrate profiles, and major operational conditions, including pH, TS and TVS contents, organic loading rate, hydraulic retention time, and temperature. Rheology-driven power requirements based on various fluid characteristics were evaluated for a general biogas reactor setup. The results revealed a significant correlation only between the rheological fluid properties and TS or TVS contents for sewage sludge digesters and thermophilic co-digesters (CD), but not for mesophilic CD. Furthermore, the calculated power requirements for pumping and mixing, based on the various fluid characteristics of the studied CSTBRs, varied broadly irrespective of TS and TVS contents. Thus, this study shows that the TS and/or TVS contents of digester fluid are not reliable estimators of the rheological properties in CSTBRs digesting substrates other than sewage sludge.

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.

BACKGROUND: Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib. METHODS: We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment. FINDINGS: Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). INTERPRETATION: Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib. FUNDING: F Hoffmann-La Roche.

pH-dependent inhibition of K2P3.1 prolongs atrial refractoriness in whole hearts.

In isolated human atrial cardiomyocytes, inhibition of K2P3.1 K(+) channels results in action potential (action potential duration (APD)) prolongation. It has therefore been postulated that K2P3.1 (KCNK3), together with K2P9.1 (KCNK9), could represent novel drug targets for the treatment of atrial fibrillation (AF). However, it is unknown whether these findings in isolated cells translate to the whole heart. The purposes of this study were to investigate the expression levels of KCNK3 and KCNK9 in human hearts and two relevant rodent models and determine the antiarrhythmic potential of K2P3.1 inhibition in isolated whole-heart preparations. By quantitative PCR, we found that KCNK3 is predominantly expressed in human atria whereas KCNK9 was not detectable in heart human tissue. No differences were found between patients in AF or sinus rhythm. The expression in guinea pig heart resembled humans whereas rats displayed a more uniform expression of KCNK3 between atria and ventricle. In voltage-clamp experiments, ML365 and A293 were found to be potent and selective inhibitors of K2P3.1, but at pH 7.4, they failed to prolong atrial APD and refractory period (effective refractory period (ERP)) in isolated perfused rat and guinea pig hearts. At pH 7.8, which augments K2P3.1 currents, pharmacological channel inhibition produced a significant prolongation of atrial ERP (11.6 %, p = 0.004) without prolonging ventricular APD but did not display a significant antiarrhythmic effect in our guinea pig AF model (3/8 hearts converted on A293 vs 0/7 hearts in time-matched controls). These results suggest that when K2P3.1 current is augmented, K2P3.1 inhibition leads to atrial-specific prolongation of ERP; however, this ERP prolongation did not translate into significant antiarrhythmic effects in our AF model.

Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy.

Small-conductance Ca(2+)-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle.

Biophysical characterization of inwardly rectifying potassium currents (I(K1) I(K,ACh), I(K,Ca)) using sinus rhythm or atrial fibrillation action potential waveforms.

Although several physiological, pathophysiological and regulatory properties of classical inward rectifier K+ current I(K1), G-protein coupled inwardly-rectifying K+ current I(K,ACh) and the small-conductance Ca2+ activated K+ current I(K,Ca) have been identified, quantitative biophysical details remain unclear. Both I(K1) and I(K,ACh) are implicated in atrial fibrillation (AF), and recently also I(K,Ca) has been speculated to be linked with the genesis and sustainability of AF. All these three currents have been shown to be involved in the electrical remodeling in the atria of patients suffering from AF, and it is therefore important to characterize their biophysical properties and compare their relative current contribution in atrial electrophysiology in both sinus rhythm (SR) and AF. The aim of this study is to investigate the contribution of the three potassium currents when subjected to voltage protocols adapted from atrial action potentials recorded in human tissue at 1 and 3 Hz. The current recordings were performed in the HEK-293 heterologous cell system expressing either I(K1), I(K,ACh) or I(K,Ca) to establish the individual contribution of each of these currents during the voltage changes of atrial action potential waveforms. I(K1) primarily contributes to the atrial electrophysiology at the latter part of repolarization and during the diastolic phase, while both I(K,Ca) under high [Ca2+]i and I(K,ACh) contribute relatively most during repolarization.

Anaerobic digestion of alkaline bleaching wastewater from a kraft pulp and paper mill using UASB technique.

Anaerobic digestion of alkaline kraft elemental chlorine-free bleaching wastewater in two mesophilic, lab-scale upflow anaerobic sludge bed reactors resulted in significantly higher biogas production (250±50 vs. 120±30 NmL g [Formula: see text]) and reduction of filtered total organic carbon (fTOC) (60±5 vs. 43±6%) for wastewater from processing of hardwood (HW) compared with softwood (SW). In all cases, the gas production was likely underestimated due to poor gas separation in the reactors. Despite changes in wastewater characteristics, a stable anaerobic process was maintained with hydraulic retention times (HRTs) between 7 and 14 h. Lowering the HRT (from 13.5 to 8.5 h) did not significantly affect the process, and the stable performance at 8.5 h leaves room for further decreases in HRT. The results show that this type of wastewater is suitable for a full-scale implementation, but the difference in methane potential between SW and HW is important to consider both regarding process dimensioning and biogas yield optimization.

Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg-1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg-1 AP30663, 5 mg kg-1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg-1 and 5 mg kg-1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg-1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .

Lung protection effect of EIT-based individualized protective ventilation strategy in patients with partial pulmonary resection.

OBJECTIVE: This study aimed to evaluate the lung protection effect of an individualized protective ventilation strategy based on lung impedance tomography (EIT) technology in patients with partial pulmonary resection. PATIENTS AND METHODS: Eighty patients of any gender, American Society of Anesthesiologists (ASA) classification I-II, age 30-64 years and body mass index (BMI) 18-28 kg/m2 who underwent elective thoracoscopic partial lung resection were selected and divided into 2 groups (n=40) using the random number table method: [positive end-expiratory pressure (PEEP) by electrical impedance tomography (EIT)] PEEPEIT group (experimental group) and control group. The PEEPEIT group used volume-controlled ventilation after one-lung ventilation, setting a tidal volume of 6 ml/kg and titrating the optimal PEEP value by EIT. Group C used volume-controlled ventilation after one-lung ventilation, setting a tidal volume of 6 ml/kg and a PEEP of 5 cm H2O. Clinical data were collected and recorded at 5 min after double lung ventilation (T0), single lung ventilation, 30 min after PEEP setting (T1), 60 min after PEEP setting (T2), the end of surgery, 10 min after resumption of double lung ventilation (T3) and 10 min after removal of the tracheal tube (T4), and serum surface active substance-associated protein-A (SP-A) concentrations were measured at T0, T3 and 1 d after surgery (T5). RESULTS: PEEP values were higher in the PEEPEIT group than in the control group at T1 and T2 (p-value <0.05); oxygenation index (OI) was higher in the PEEPEIT group compared to the control group at T2 and T3 (p-value <0.05); pulmonary dynamic compliance (Cdyn) was higher in the PEEPEIT group compared to the control group at T1 and T2 (p-value <0.05); intrapulmonary shunt rate (Qs/Qt) was lower in the PEEPEIT group compared to the control group at T1, T2 and at T3, the intrapulmonary shunt rate (Qs/Qt) was reduced in the PEEPEIT group compared to group C (p-value <0.05); at T5, the SP-A protein was reduced in the PEEPEIT group compared to group C. There was no statistically significant difference in the incidence of postoperative pulmonary complications between the two groups (p-value >0.05). CONCLUSIONS: The EIT-guided individualized protective ventilation strategy has a lung-protective effect in patients undergoing thoracoscopic partial lung resection.

ABHD2 deficiency aggravates ovalbumin-induced airway remodeling through the PI3K/Akt pathway in an animal model of chronic asthma.

Airway remodeling is a major pathological characteristic of chronic obstructive pulmonary disease (COPD). This study aimed to investigate the effect of Abhd2 deficiency on ovalbumin (OVA)-induced airway remodeling and inflammation in vivo. Abhd2-deficient mice were used to establish an OVA-induced asthma model. Lung tissues were analyzed using hematoxylin and eosin (HE) staining, Masson staining, immunohistochemistry, quantitative reverse transcription- polymerase chain reaction (qRT-PCR), and western blotting were used to determine the role of Abhd2 in the regulation of OVA-induced airway remodeling and inflammation. Our findings revealed that the RNA expression of inflammatory factors, including IL-1ß, IL-6, IL-4, and IL-13, was significantly increased in OVA-induced Abhd2 Gt/Gt asthmatic mice. The expression of IFN-γ was decreased significantly in OVA-induced Abhd2 Gt/Gt asthmatic mice. The protein expression of airway remodeling factors, including α-SMA, type I collagen, and Ki67, was also increased in OVA-induced Abhd2 Gt/Gt asthmatic mice compared to that in OVA-induced wild-type (WT) mice. Additionally, Abhd2 deficiency promoted the expression of p-Akt in tissues of the asthma model. These results suggest that Abhd2 deficiency exacerbates airway remodeling and inflammation through the PI3K/Akt pathway in chronic asthma.

Sulfide in engineered methanogenic systems - Friend or foe?

Sulfide ions are regarded to be toxic to microorganisms in engineered methanogenic systems (EMS), where organic substances are anaerobically converted to products such as methane, hydrogen, alcohols, and carboxylic acids. A vast body of research has addressed solutions to mitigate process disturbances associated with high sulfide levels, yet the established paradigm has drawn the attention away from the multifaceted sulfide interactions with minerals, organics, microbial interfaces and their implications for performance of EMS. This brief review brings forward sulfide-derived pathways other than toxicity and with potential significance for anaerobic organic matter degradation. Available evidence on sulfide reactions with organic matter, interventions with key microbial metabolisms, and interspecies electron transfer are critically synthesized as a guidance for comprehending the sulfide effects on EMS apart from the microbial toxicity. The outcomes identify existing knowledge gaps and specify future research needs as a step forward towards realizing the potential of sulfide-derived mechanisms in diversifying and optimizing EMS applications.

Perioperative opioids and survival outcomes in resectable head and neck cancer: A systematic review.

BACKGROUND: Opioids are a mainstay in pain control for oncologic surgery. The objective of this systematic review is to evaluate the associations of perioperative opioid use with overall survival (OS) and disease-free survival (DFS) in patients with resectable head and neck cancer (HNC). METHODS: A systematic review of PubMed, SCOPUS, and CINAHL between 2000 and 2022 was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating perioperative opioid use for patients with HNC undergoing surgical resection and its association with OS and DFS were included. RESULTS: Three thousand three hundred seventy-eight studies met initial inclusion criteria, and three studies representing 562 patients (intraoperative opioids, n = 463; postoperative opioids, n = 99) met final exclusion criteria. One study identified that high intraoperative opioid requirement in oral cancer surgery was associated with decreased OS (HR = 1.77, 95% CI 0.995-3.149) but was not an independent predictor of decreased DFS. Another study found that increased intraoperative opioid requirements in treating laryngeal cancer was demonstrated to have a weak but statistically significant inverse relationship with DFS (HR = 1.001, p = 0.02) and OS (HR = 1.001, p = 0.02). The last study identified that patients with chronic opioid after resection of oral cavity cancer had decreased DFS (HR = 2.7, 95% CI 1.1-6.6) compared to those who were not chronically using opioids postoperatively. CONCLUSION: An association may exist between perioperative opioid use and OS and DFS in patients with resectable HNC. Additional investigation is required to further delineate this relationship and promote appropriate stewardship of opioid use with adjunctive nonopioid analgesic regimens.

Case Report: Complete pathologic response to neoadjuvant selpercatinib in a patient with resectable early-stage RET fusion-positive non-small cell lung cancer.

The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug's approval for this indication. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response. A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC.