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Graphical AbstractSudden cardiac death after early-onset myocardial infarction. MI, myocardial infarction; SCD, sudden cardiac death.

Development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is a clinical issue in patients with epidermal growth factor receptor gene (EGFR)-mutated non–small cell lung cancer (NSCLC). The aim of this study was to investigate the potential of combining gefitinib and pemetrexed in preventing the acquisition of resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines harboring EGFRexon 19 deletion.

Parkinson’s disease is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiologic assay. Electrically induced and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, whereas acetylcholine levels were assayed in the incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors were assessed by immunohistochemistry or western blot assay. As compared with control rats, at week 4, 6-OHDA–treated animals displayed the following changes: decreased in vivo colonic transit rate, impaired electrically evoked neurogenic cholinergic contractions, enhanced carbachol-induced contractions, decreased basal and electrically stimulated acetylcholine release from colonic tissues, decreased ChAT immunopositivity in the neuromuscular layer, unchanged density of HuC/D immunoreactive myenteric neurons, and increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were also detected at week 8 post 6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate.

Low Back Pain and Associated Presenteeism among Hospital Nursing Staff: Angelo d’ERRICO, et al. Department of Epidemiology, Local Health Unit TO3, Italy— In spite of the high prevalence of low back pain (LBP) and presenteeism previously observed among nurses, no study has assessed the risk of presenteeism specifically due to LBP in nursing staff. Therefore, aim of the present study was to assess prevalence and risk factors of presenteeism due to LBP among hospital nursing personnel. 174 female nurses underwent a clinical interview and filled in a questionnaire on sociodemographics, LBP symptoms and associated sickness absence, mental symptoms, burnout and on exposure to workplace organizational, psychosocial and ergonomic factors; 111 subjects affected by LBP were included in the analysis. The effect of sociodemographic and workplace characteristics on presenteeism was examined through multivariate Poisson robust regression models. Prevalence of presenteeism due to LBP was 58%, with wide differences between registered nurses and nursing aides (p=0.001). Only a few workplace factors were significantly associated with presenteeism, including frequent stooping, which decreased the risk of presenteeism, and good working climate and procedural justice, which increased it. Presenteeism due to LBP was very high among registered nurses and was influenced only by workplace, but not by sociodemographic characteristics. Presenteeism due to LBP among registered nurses should be closely monitored, and effort should be made to reduce it to prevent future work disability associated with LBP.

Proteases and proteinase-activated receptor (PAR) activation are involved in several intestinal inflammatory conditions. We hypothesized that serine proteases and PAR activation could also modulate the intestinal injury induced by ischemia-reperfusion (I-R). C57Bl/6 mice were subjected to 90 minutes of intestinal ischemia followed or not by reperfusion. Sham-operated animals served as controls. After ischemia, plasma and tissue serine protease activity levels were increased compared to the activity measured in plasma and tissues from sham-operated mice. This increase was maintained or further enhanced after 2 and 5 hours of reperfusion, respectively. Trypsin (25 kDa) was detected in tissues both after ischemia and 2 hours of reperfusion. Treatment with FUT-175 (10 mg/kg), a potent serine protease inhibitor, increased survival after I-R, inhibited tissue protease activity, and significantly decreased intestinal myeloperoxidase (MPO) activity and chemokine and adhesion molecule expression. We investigated whether serine proteases modulate granulocyte recruitment by a PAR-dependent mechanism. MPO levels and adhesion molecule expression were significantly reduced in I-R groups pre-treated with the PAR1antagonist SCH-79797 (5 mg/kg) and in Par2−/−mice, compared, respectively, to vehicle-treated group and wild-type littermates. Thus, increased proteolytic activity and PAR activation play a pathogenic role in intestinal I-R injury. Inhibition of PAR-activating serine proteases could be beneficial to reduce post-ischemic intestinal inflammation.

The non‐imidazole H3 receptor antagonist UPR1056 was dosed in plasma samples from rats individually administered with a single i.p. dose of 1.25 mg/kg by means of a newly validated HPLC‐MS method. UPR1056 was extracted from rat plasma by protein precipitation with acetonitrile and was separated by linear gradient elution, employing water and methanol both additioned with 0.05% trifluoroacetic acid as mobile phases. UPR1056 was detected in MS using an electrospray ion source operating in positive ion mode. Acquisition was performed in single ion monitoring mode at m/z=349.3. The method was validated over the concentration range of 17.43–1743 ng/mL (50–5000 pmol/mL). Within‐ and between‐run precision for the low, mid and high quality controls (QC) levels were 6.75% or less and accuracy ranged from 95.8 to 107.6%. The lower limit of quantification was 17.43 ng/mL. The analysis of the time course of UPR1056 concentrations over the 24‐h period revealed a Cmaxof 1147 ng/mL after 2 h from peripheral administration of the non‐imidazole H3‐receptor antagonist, with a prolonged elimination half‐life of over 9 h.

Transcatheter left atrial appendage occlusion (LAAO) has emerged as a reliable tool to prevent thromboembolic events, in particular ischemic stroke, in patients with atrial fibrillation (AF) in the absence of mitral stenosis/valve prosthesis and contraindication to oral anticoagulation (OAC). Antiplatelet therapy (APT) is required after device implantation to prevent device–related thrombus (DRT). Previous studies provided conflicting results on the optimal APT regimen after LAAO. Thus, herein we aimed at assessing the comparative effectiveness and safety of distinct APT regimens. We conducted a real–world single–center observational study including consecutive AF patients that underwent LAAO at the University Hospital of Parma between October 2010 and June 2021. Clinical follow–up included all successfully implanted patients. Primary endpoint was net efficacy outcome, a composite of any ischemic or hemorrhagic event. Secondary endpoints were ischemic (any of the following: ischemic stroke, transient ischemic attack [TIA], DRT, systemic embolism) and hemorrhagic (major [≥3] bleedings according to Bleeding Academic Research Consortium [BARC] classification) complications alone. We enrolled a total of 130 patients (median age 77.0 [72.7;81.0] years; 78 [60.0%] men). History of hemorrhagic stroke in OAC (74 [56.9%]) was the main indication for LAAO. Technical procedure success was achieved in 123 (94.6%) patients. According to multidisciplinary team evaluation, immediately after LAAO, 39 (31.7%) patients received short (≤ 1 month)–dual APT (DAPT) consisting of cardioaspirin and clopidogrel, 35 (28.5%) long (>1, ≤12 months)–DAPT and 49 (39.8%) single APT (SAPT). At a median follow–up of 32 months, the incidence of primary endpoint was significantly lower in short–DAPT group (3 [7.7%] vs. 7 [20.0%] in long–DAPT vs. 14 [28.6%] in SAPT, p = 0.049], mainly driven by a lower occurrence of bleeding endpoint (0 [0.0] vs. 4 [11.4%] in long–DAPT vs. 9 [18.4%] in SAPT, p = 0.020) without differences in the incidence of ischemic endpoint (p = 0.916). Finally, comparison of the Kaplan–Meier curves showed that short–DAPT group had a higher primary endpoint–free survival (p = 0.015) compared to the others. In summary, our study highlighted that short (≤ 1 month)–DAPT regimen after LAAO is associated with better outcomes, mainly driven by reduction of major bleedings. Strong evidences arising from randomized trials are warranted to support these findings.

New series of 5-alkoxy-benzopyranopyrimidine derivatives were developed from the chemical modulation of the substituent in position 2 of the scaffold, with the aim to produce analgesic/antiphlogistic agents more potent than analogues previously reported. The 2-hydrazino derivatives exhibited a good analgesic activity in writhing test; the analgesic doses of the compounds did not affect mice spontaneous locomotor activity thus any confounding sedative effect could be excluded. These derivatives revealed an aspirin-like profile with a strong inhibition of AA-induced platelet aggregation, probably due to a strong, non selective, inhibition of cyclooxygenases. In spite of the inhibition of COX activity displayed in vitro, the compounds did not cause gastric damage in rats after acute oral administration. A different pharmacological profile was observed for the 2-azido derivatives, particularly in vivo.

We hypothesized that proteinase-activated receptor-2 (PAR2) modulates intestinal injuries induced by ischemia/reperfusion. Ischemia (1 hour) plus reperfusion (6 hours) significantly delayed gastrointestinal transit (GIT) compared with sham operation. Intraduodenal injection of PAR2-activating peptide SLIGRL-NH2significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR2−/−mice compared with PAR2+/+. SLIGRL-NH2significantly accelerated transit in ischemia/reperfusion in PAR2+/+but not in PAR2−/−mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP8–37and RP67580, respectively, abolished the SLIGRL-NH2-induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH2; this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP8–37. Intestinal PAR2mRNA levels were not affected by SLIGRL-NH2in ischemia/reperfusion. We propose that PAR2modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR2effect on transit might be mediated by CGRP and substance P, whereas the effect on tissue damage appears to involve substance P but not CGRP. PAR2might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion.

A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M2 receptors using [3H]N-methylscopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a−10a and : −12 . The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M1−M3 muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [35S]GTPγS binding assays using human M2 receptors overexpressed in CHO cells revealed that a weak intrinsic efficacy was preserved in : −12 . Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixed.

Myocarditis has been recognized as a rare complication of SARS-CoV-2 infection even in the absence of lung involvement and recent histological findings suggest that COVID-19-related myocardial damage may differ from other typical lymphocytic myocarditis associated with other viruses and could be possibly linked to diffuse infiltration of monocytes and macrophage leading to microvascular dysfunction and cell necrosis. SARS-CoV-2 vaccines have been well tolerated and associated with decreasing burden of disease in areas with high vaccination rates. Minor side-effects have been frequently described, mainly after second dose. Here, we report our findings in four male patients consistent with acute myocarditis at our Institutional Hospital; all four had recently received a second-dose mRNA vaccine. All presented with acute chest pain associated with biomarker evidence of myocardial injury and were hospitalized. None of them had a previous history of SARS-CoV2 infection. All of them showed markedly abnormal EKG findings with diffuse ST segment elevation and laboratory tests revealed elevated high-sensitivity (hs) troponin T levels and C-reactive protein with no peripheral eosinophilia. All patients underwent nasopharyngeal swabbing and the specimens were tested for common respiratory viruses by RT-PCR and resulted all negative. All patients underwent CMR scan during hospitalization. The hospital course was benign for all patients without evidence of arrhythmias or heart failure, in all cases we performed a conservative treatment with nonsteroidal anti-inflammatory drugs and colchicine with progressive normalization of troponin levels before discharge. Our cases presented features of acute myocarditis with a temporal association with the mRNA Covid-19 vaccination, in absence of other apparent causes (in fact none had viral prodromes) nor COVID-19 infection in the prior year. Several reports in the past months had suggested a possible association between the mRNA Covid-19 and myocarditis, most of the cases presenting in young males, after the second dose and with a favourable course. Thus, given the potential risk of cardiac involvement after SARS-CoV-2 infection even in younger adults, the risk-benefit decisions favours vaccination for population immunity. Despite this, the potential mechanisms of SARS-CoV-2 vaccine-related myocarditis seem different from the previously described eosinophilic myocarditis after smallpox vaccination remain unclear and vaccine adverse event reporting remains of high importance. Figure 1 shows one acute MRI scan with STIR, T2-map and LGE in short-axis and apical four-chamber view.

Two subseries of nonquaternized (5a–10a)Figure 1Figure 2Concentration–response curves of 9aon (RVD) rabbit vas deferens twitch responses, (GPA) electrically-driven guinea pig left atrium inotropism and (GPI) guinea pig ileum resting tone. Lack of M1agonism (•), M2partial agonism (□) and M3full agonism (▴) are expressed as percentage of the maximum response to oxotremorine in the different preparations. Each point is the mean of five experiments and vertical lines indicate SEM.Scheme 2(a) Pyrrolidine, DMF; (b) NMe2, DMF; (c) C2H2O4, ether; (d) CH3I, ether.and quaternized derivatives (5b–10b)related to oxotremorine and oxotremorine-M were synthesized and tested. The agonist potency at the muscarinic receptor subtypes of the new compounds was estimated in three classical in vitro functional assays: Mlrabbit vas deferens, M2guinea pig left atrium and M3guinea pig ileum. In addition, the occurrence of central muscarinic effects was evaluated as tremorigenic activity after intraperitoneal administration in mice. In in vitro tests a nonselective muscarinic activity was exhibited by all the derivatives with potencies values that, in some instances, surpassed those of the reference compounds (i.e. 8b). Functional selectivity was evidenced only for the oxotremorine-like derivative 9a, which behaved as a mixed M3-agonist/Ml-antagonist (pD2=5.85; pA2=4.76, respectively). In in vivo tests nonquaternary compounds were able to evoke central muscarinic effects, with a potency order parallel to that observed in vitro.