Citizen involvement in COVID-19 contact tracing with digital tools: a qualitative study to explore citizens' perspectives and needs.

BACKGROUND: Contact tracing (CT) is a key strategy when dealing with outbreaks of infectious diseases such as COVID-19. The scale of the COVID-19 pandemic has often left public health professionals (PHPs), who are responsible for the execution of CT, unable to keep up with the rapid and largescale spread of the virus. To enhance or support its execution, and potentially lower the workload for PHPs, citizens may be more actively involved in CT-tasks that are commonly executed by PHPs (referred to as 'self-led CT'). There is limited insight into citizens' perspectives on and needs for self-led CT for COVID-19. This study aims to explore the perspectives and needs of Dutch citizens on taking more responsibilities in the execution of CT for COVID-19, potentially through the use of digital tools. METHODS: An exploratory qualitative study was performed, in which online semi-structured interviews were conducted. Questions were based on the Reasoned Action Approach and Health Belief Model. Interviews were audio-recorded and transcribed verbatim. A thematic analysis was conducted to identify citizens' perspectives and needs to participate in self-led CT. RESULTS: We conducted 27 interviews with Dutch citizens. Seven main themes were identified from the interviews: 1) 'Citizens' perspectives on self-led CT are influenced by prior experiences with regular CT', 2) 'Citizens' felt responsibilities and the perceived responsibilities of the PHS in CT shape their perspectives on self-led CT', 3) 'Anticipated impacts of self-led CT on the CT-process', 4) 'Citizens' attitude towards the application of self-led CT depends on their own perceived skills and the willingness and skills of others', 5) 'Shame and social stigma may hamper participation in self-led CT', 6) 'Concerns about privacy and data security: a barrier for self-led CT', and 7) 'Citizens' perspectives and anticipated needs for the implementation and application of self-led CT in practice'. CONCLUSIONS: Most interviewees hold a positive attitude towards self-led CT and using digital tools for this purpose. However, their intention for self-led CT may depend on various factors, such as prior experiences with regular CT, and their perceived self-efficacy to participate. Perspectives and needs of citizens should be considered for the future implementation of self-led CT in practice.

Efficacy of a hybrid technique of simultaneous videolaryngoscopy with flexible bronchoscopy in children with difficult direct laryngoscopy in the Pediatric Difficult Intubation Registry.

Children with difficult tracheal intubation are at increased risk of severe complications, including hypoxaemia and cardiac arrest. Increasing experience with the simultaneous use of videolaryngoscopy and flexible bronchoscopy (hybrid) in adults led us to hypothesise that this hybrid technique could be used safely and effectively in children under general anaesthesia. We reviewed observational data from the international Pediatric Difficult Intubation Registry from 2017 to 2021 to assess the safety and efficacy of hybrid tracheal intubation approaches in paediatric patients. In total, 140 patients who underwent 180 attempts at tracheal intubation with the hybrid technique were propensity score-matched 4:1 with 560 patients who underwent 800 attempts with a flexible bronchoscope. In the hybrid group, first attempt success was 70% (98/140) compared with 63% (352/560) in the flexible bronchoscope group (odds ratio (95%CI) 1.4 (0.9-2.1), p = 0.1). Eventual success rates in the matched groups were 90% (126/140) for hybrid vs. 89% (499/560) for flexible bronchoscope (1.1 (0.6-2.1), p = 0.8). Complication rates were similar in both groups (15% (28 complications in 182 attempts) hybrid; 13% (102 complications in 800 attempts) flexible bronchoscope, p = 0.3). The hybrid technique was more likely than flexible bronchoscopy to be used as a rescue technique following the failure of another technique (39% (55/140) vs. 25% (138/560), 2.1 (1.4-3.2) p < 0.001). While technically challenging, the hybrid technique has success rates similar to other advanced airway techniques, few complications and may be considered an alternative technique when developing an airway plan for paediatric patients whose tracheas are difficult to intubate under general anaesthesia.

Dutch public health professionals' perspectives and needs regarding citizen involvement in COVID-19 contact tracing through digital support tools: an exploratory qualitative study.

BACKGROUND: Contact tracing (CT) is an important, but resource-intensive tool to control outbreaks of communicable diseases. Under pandemic circumstances, public health services may not have sufficient resources at their disposal to effectively facilitate CT. This may be addressed by giving cases and their contact persons more autonomy and responsibility in the execution of CT by public health professionals, through digital contact tracing support tools (DCTS-tools). However, the application of this approach has not yet been systematically investigated from the perspective of public health practice. Therefore, we investigated public health professionals' perspectives and needs regarding involving cases and contact persons in CT for COVID-19 through DCTS-tools. METHODS: Between October 2020 and February 2021, we conducted online semi-structured interviews (N = 17) with Dutch public health professionals to explore their perspectives and needs regarding the involvement of cases and contact persons in CT for COVID-19 through DCTS-tools, in the contact identification, notification, and monitoring stages of the CT-process. Interviews were audio recorded and transcribed verbatim. A thematic analysis was performed. RESULTS: Four main themes related to Dutch public health professionals' perspectives and needs regarding involving cases and contact persons in CT for COVID-19 through DCTS-tools emerged from the data: 'Distinct characteristics of CT with DCTS-tools'; 'Anticipated benefits and challenges of CT for COVID-19 with DCTS- tools'; 'Circumstances in CT for COVID-19 that permit or constrain the application of DCTS-tools'; and 'Public health professionals' needs regarding the development and application of DCTS-tools for CT'. Public health professionals seem to have a positive attitude towards involving cases and contact persons through DCTS-tools. Public health professionals' (positive) attitudes seem conditional on the circumstances under which CT is performed, and the fulfilment of their needs in the development and application of DCTS-tools. CONCLUSIONS: Dutch public health professionals seem positive towards involving cases and contact persons in CT for COVID-19 through DCTS-tools. Through adequate implementation of DCTS-tools in the CT-process, anticipated challenges can be overcome. Future research should investigate the perspectives and needs of cases and contact persons regarding DCTS-tools, and the application of DCTS-tools in practice.

Complications associated with paediatric airway management during the COVID-19 pandemic: an international, multicentre, observational study.

Respiratory adverse events in adults with COVID-19 undergoing general anaesthesia can be life-threatening. However, there remains a knowledge gap about respiratory adverse events in children with COVID-19. We created an international observational registry to collect airway management outcomes in children with COVID-19 who were having a general anaesthetic. We hypothesised that children with confirmed or suspected COVID-19 would experience more hypoxaemia and complications than those without. Between 3 April 2020 and 1 November 2020, 78 international centres participated. In phase 1, centres collected outcomes on all children (age ≤ 18 y) having a general anaesthetic for 2 consecutive weeks. In phase 2, centres recorded outcomes for children with test-confirmed or suspected COVID-19 (based on symptoms) having a general anaesthetic. We did not study children whose tracheas were already intubated. The primary outcome was the incidence of hypoxaemia during airway management. Secondary outcomes included: incidence of other complications; and first-pass success rate for tracheal intubation. In total, 7896 children were analysed (7567 COVID-19 negative and 329 confirmed or presumed COVID-19 positive). The incidence of hypoxaemia during airway management was greater in children who were COVID-19 positive (24 out of 329 (7%) vs. 214 out of 7567 (3%); OR 2.70 (95%CI 1.70-4.10)). Children who had symptoms of COVID-19 had a higher incidence of hypoxaemia compared with those who were asymptomatic (9 out of 51 (19%) vs. 14 out of 258 (5%), respectively; OR 3.7 (95%CI 1.5-9.1)). Children with confirmed or presumed COVID-19 have an increased risk of hypoxaemia during airway management in conjunction with general anaesthesia.

Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat.

Long-term habituation to a novel environment is one of the most elementary forms of nonassociative learning. Here we studied the effect of pre- or posttraining intrahippocampal administration of drugs acting on specific molecular targets on the retention of habituation to a 5-min exposure to an open field measured 24 h later. We also determined whether the exposure to a novel environment resulted in the activation of the same intracellular signaling cascades previously shown to be activated during hippocampal-dependent associative learning. The immediate posttraining bilateral infusion of CNQX (1 microg/side), an AMPA/kainate glutamate receptor antagonist, or of muscimol (0.03 microg/side), a GABA(A) receptor agonist, into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation. The NMDA receptor antagonist AP5 (5 microg/side) impaired habituation when infused 15 min before, but not when infused immediately after, the 5-min training session. In addition, KN-62 (3.6 ng/side), an inhibitor of calcium calmodulin-dependent protein kinase II (CaMKII), was amnesic when infused 15 min before or immediately and 3 h after training. In contrast, the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059, and the protein synthesis inhibitor anisomycin, at doses that fully block memory formation of inhibitory avoidance learning, did not affect habituation to a novel environment. The detection of spatial novelty is associated with a sequential activation of PKA, ERKs (p44 and p42 MAPKs) and CaMKII and the phosphorylation of c-AMP responsive element-binding protein (CREB) in the hippocampus. These findings suggest that memory formation of spatial habituation depends on the functional integrity of NMDA and AMPA/kainate receptors and CaMKII activity in the CA1 region of the hippocampus and that the detection of spatial novelty is accompanied by the activation of at least three different hippocampal protein kinase signaling cascades.

Rapid and transient learning-associated increase in NMDA NR1 subunit in the rat hippocampus.

Several lines of evidence indicate that glutamate NMDA receptors are critically involved in long-term potentiation (LTP) and in certain forms of learning. It was previously demonstrated that memory formation of an inhibitory avoidance task in chick is specifically associated with an increase in the density of NMDA receptor in selected brain regions. Here we report on the effect of a one trial inhibitory avoidance training in rats, a hippocampal-dependent learning task, on the levels of different subunits of the glutamate NMDA receptor in synaptic plasma membranes (SPM) isolated from the hippocampus. Training rats on a one trial inhibitory avoidance task results in a rapid, transient and selective increase (+33%, p < 0.05) in NMDA NRI subunit expression in hippocampal SPM of rats sacrificed 30 min posttraining. No changes were observed at 0 or 120 min after training or in shocked animals in comparison to naive control rats. In addition, no training-associated increase in the levels of NMDA NR2A and NR2B or AMPA GluR 2/3 subunits was observed at any timepoint tested. In conclusion, the present findings support the hypothesis that alterations in expression of synaptic NMDA NR1 subunits in the hippocampus are specifically associated with memory formation of an inhibitory avoidance task and strongly suggest that hippocampal NMDA receptors are crucially involved in the neural mechanisms underlying certain forms of learning.

Experience-dependent decrease in synaptically localized Fra-1.

The Fos family of transcription factors has been repeatedly shown to participate in the long-term neural responses associated with a variety of physiological stimuli, including activity-dependent plastic processes. Quite recently, several transcription factors have been found in synaptic regions, localized in dendrites and presynaptic terminals. Here we show that the transcription factor Fos-related antigen-1 (Fra-1) was detected in synaptosomes (Syn) and synaptic plasma membrane (SPM) fractions from the rat cerebral cortex and hippocampus as a single band migrating with M(r) 42-43 kDa. The 55-kDa c-Fos protein was also detected in syn and SPM fractions. Conversely, the inducible 62-65-kDa c-Fos is present in nuclear fractions from metrazole-treated animals (positive control), but not in Syn or SPM fractions. Furthermore, no Fra-2, Fos B or c-Jun immunoreactivities were detected in these same synaptic regions. DNA-mobility shift assays showed the presence of specific AP-1 binding activity in synaptic protein extracts. Immunoelectronmicroscopic analysis of cortical and hippocampal tissues revealed that Fra-1 and Fos-like immunoreactivities are localized in association with presynaptic plasma membranes. One trial inhibitory avoidance training, a hippocampal-dependent task, is associated with a time-dependent decrease (-31%) in Fra-1, but not in 55-kDa c-Fos, levels in hippocampal SPM fractions. In hippocampal homogenates, we do not detect significant changes in Fra-1 immunoreactivity, suggesting that this behavioural experience is probably accompanied by a subcellular redistribution of Fra-1 protein. These results suggest that Fra-1 may participate in the communication between synapse and the nucleus and in experience-dependent hippocampal plasticity.

Involvement of hippocampal PKCbetaI isoform in the early phase of memory formation of an inhibitory avoidance learning.

Several evidences demonstrate that protein kinase C (PKC) is involved in hippocampal long-term potentiation (LTP) and in different forms of learning, including inhibitory avoidance training in rats. Here, we evaluated the levels of conventional PKC isozymes (alpha, betaI, betaII, gamma) in synaptic plasma membrane (SPM) fractions isolated from hippocampus of rats subjected to a one-trial inhibitory avoidance paradigm. At 0, 30 and 120 min after training, there was a significant increase in the total amount of PKCbetaI. Densitometric analysis of the immunoblots showed an increase of 142+/-11% at 0 min, 193+/-16% at 30 min and 156+/-6% at 120 min after training relative to shocked control values. No changes were found in PKCbetaI levels in SPM fractions of the shocked animals relative to naive control values. No training-specific increments in the levels of PKCalpha, betaII and gamma were observed at any time point tested. However, an increase in PKCgamma levels was found in trained and shocked animals sacrificed 120 min after each experimental procedure. In addition, bilateral microinjections of a fairly selective inhibitor of PKCbetaI isozyme into the CA1 of the dorsal hippocampus produced amnesia when given 10 min before training, or 50, 110, but not 170 min, after training. Thus, the present findings demonstrate the participation of PKCbetaI in the early synaptic events responsible for the acquisition and consolidation of an inhibitory avoidance learning, and suggest a putative role of this presynaptic isozyme on the enhanced PKC-dependent B-50/GAP-43 phosphorylation previously detected by us during this associative learning.

Experience-dependent increase in cAMP-responsive element binding protein in synaptic and nonsynaptic mitochondria of the rat hippocampus.

Cyclic AMP-responsive element binding protein (CREB) plays a pivotal role in the formation of long-term memory in Drosophila, Aplysia, mice and rats. Recently, we were able to demonstrate that CREB and its serine 133 phosphorylated form p-CREB are localized in synaptic and nonsynaptic mitochondria of the rat brain. Here we report on the effect of a one-trial inhibitory avoidance training procedure on mitochondrial CREB from the rat hippocampus. This aversively motivated training task is associated with a time-dependent increase (34-35%) in both p-CREB and CREB immunoreactivities detected in synaptic mitochondria of the hippocampus. In nonsynaptic mitochondria, p-CREB levels increased in both trained and shocked animals. In addition to CREB, two CRE-element binding repressors, CREB-2 and CREM-1, were also detected in purified brain mitochondria. No changes were observed in CREB-2 and CREM-1 immunoreactivities in hippocampal synaptic mitochondria after an inhibitory avoidance training. Taken together the present findings represent the first evidence showing that brain mitochondrial CREB may participate in plasticity-dependent changes associated with a behavioural training procedure.

Synthesis and anti-human immunodeficiency virus type 1 integrase activity of hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters.

A series of new hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters were synthesized in order to obtain compounds targeting the human immunodeficiency virus (HIV) type 1 integrase (IN). The esters were tested for anti-IN and anti-reverse transcriptase (RT) activity in enzyme assays and for anti-HIV-1, anti-proliferative and anti-topoisomerase activity in cell-based assays. In enzyme assays, the two gallic acid flavon-3-yl esters showed a notable IN inhibition (IC50 values were 8.3 and 9.1 microM, respectively), while the two caffeic acid flavon-3-yl esters exhibited a modest activity (IC50 75 and 60 microM, respectively). Replacement of hydroxyl groups resulted in loss of potency. Caffeic acid 3',4'-dichloroflavon-3-yl ester also inhibited the RT activity whereas it was not active on human topoisomerases. It therefore represents an interesting example of a compound specifically targeting more than one step of the virus replication cycle.

N-omega-carbethoxypentyl-4-quinolones: a new class of leukotriene biosynthesis inhibitors.

6-[(4-Quinolinyl)oxy]hexanoic acids and the corresponding esters were designed and synthesized as inhibitors of the production of arachidonic acid metabolites. The inhibitory activities were assayed in vitro by evaluation of serum leukotriene B4 and thromboxane B2 production. While all 6-[(4-quinolinyl)oxy]hexanoic acids and their esters proved to be inactive, the N-alkyl-4-quinolones, obtained as by-products in their synthesis, were found to be a new class of leukotriene biosynthesis inhibitors.

Role of hippocampal NO in the acquisition and consolidation of inhibitory avoidance learning.

Nitric oxide (NO), an unconventional neurotransmitter in the brain, has been postulated as a retrograde intercellular messenger necessary for the induction, but not the maintenance phase, of activity-dependent forms of synaptic plasticity in the hippocampus. Here we report on the effects of an inhibitory avoidance learning task on hippocampal NO synthase (NOS) activity and on the effects of intrahippocampal infusion of a NOS inhibitor in the acquisition and consolidation of this task in rats. NOS activity increases by 45% in the hippocampus immediately after training (0 min) but not at 60 min after training. No changes were observed in cerebellar NOS activity. The bilateral intrahippocampal microinjection of nitro-arginine (NO-arg), an NOS inhibitor, provoked retrograde amnesia for the inhibitory avoidance when given 10 min before or immediately after training, but not 60 min after training. These results suggest that NO-regulated processes in the hippocampus play an important role at the time of training or very shortly thereafter of an inhibitory avoidance learning.

Effect of chloro-, cyano-, and amidino-substituted flavanoids on enterovirus infection in vitro.

Synthetic flavans, isoflavans and isoflavenes substituted with chloro, cyano and amidino groups were tested for their in vitro activity against poliovirus type 2, Coxsackie virus B4, echovirus type 6 and enterovirus 71. Plaque-reduction assays showed that substituted 3-(2H)-isoflavenes, carrying a double bond in the oxygenated ring, possess antiviral activity higher than that of the corresponding isoflavans. The most effective compounds were 4'-chloro-6-cyanoflavan and 6-chloro-4'-cyanoflavan. Studies on the mechanism of action of these two compounds suggested an effect on the early stages of viral replication.

Evidence for the involvement of hippocampal CO production in the acquisition and consolidation of inhibitory avoidance learning.

Carbon monoxide (CO), produced through the action of haem oxygenase (HO) isoenzymes, has been recently postulated as a retrograde messenger in the early stages of long-term potentiation (LTP). In the present study, rats submitted to an inhibitory avoidance task there is a significant increase (+76%) in hippocampal HO activity immediately after training (0 min), but not at 60 min post-training. No changes were observed in cerebral cortical and cerebellar HO activity. Bilateral intrahippocampal infusion of the HO inhibitor zinc-protoporphyrin-IX (ZnPP) (2 micrograms side-1) caused full amnesia for inhibitory avoidance when given 10 min before training or immediately after training, but not 60 min after training. These findings provide evidence that CO production in the hippocampus is important for the early stages of memory processing of an inhibitory avoidance training.

Sexual differences in the effect of the GABAergic system on LH secretion and in the hypothalamic ontogenesis of GABAA receptors in prepubertal rats.

The administration of aminooxyacetic acid (AOAA), which increases hypothalamic GABA concentrations, induced a significant increase in LH levels in female rats of 12, 16 and 18 days of age. This stimulatory effect of AOAA on serum LH levels was not observed at 21 and 25 days of age whereas a significant decrease in the LH concentrations by AOAA was found at 30 days of age. The neonatal androgenization of female rats abolished the effects of AOAA and no effects of AOAA were found in male rats at the different ages studied. The muscimol binding sites in medial basal and preoptic anterior hypothalamic areas showed a significant different sexual ontogenic pattern. Males rats castrated at birth showed a very similar ontogenic pattern of [3H]muscimol binding sites to female rats and significantly different to male control rats. It is concluded that there are sexual differences in the effect of GABAergic system on LHRH-LH secretion and in the development of hypothalamic GABAA receptors during sexual maturation. These differences are probably connected with the neonatal exposure to androgens that would induced changes in the composition and probably in the properties of GABAA receptor that in turn modified its effects on LHRH neurons.

Synthesis of some guanylhydrazones and imidazolinylhydrazones as thromboxane-synthase and platelet aggregation inhibitors.

The imidazolinylhydrazones of (3-pyridinyloxy)-acetaldehyde and of 6-[3-(2-formyl-pyridinyl)oxy]hexanoic acid were synthesized as cyclic analogues of the corresponding guanylhydrazones which were found to be selective inhibitors of human thromboxane-synthase. The benzene isosters were also prepared in order to define the importance of the ring nitrogen for the activity. Moreover, the guanyl- and imidazolinyl-hydrazones of two 6-[(3-pyridinyl)oxy]hexanoic acids showing in the 2 position an alkyl chain with an alpha, beta-unsaturated ketonic function were prepared. Imidazolinylhydrazones 7 and 18 are selective inhibitors of thromboxane-synthase, while the two guanylhydrazones 14 and 15 which do not affect prostanoid biosynthesis seemed to be antagonists at the thromboxane receptor.

Effect of various training procedures on performance in an elevated plus-maze: possible relation with brain regional levels of benzodiazepine-like molecules.

Rats submitted to one, two, or seven sessions of exploration to a new environment (habituation) or exposed to an inhibitory avoidance training showed different degrees of anxiety, evaluated by the elevated plus-maze test. Also, the brain regional levels of benzodiazepine (BDZ)-like molecules in rats submitted to one, two, or seven sessions of habituation were differentially decreased with respect to nontrained rats. The percentage of time spent in the open arms of the elevated plus-maze for each group correlates with the data of decrease in the BDZ-like immunoreactivity in amygdala (r = 0.77, p < 0.0005), hippocampus (r = 0.68, p < 0.0005), and septum (r = 0.57, p < 0.005). These results suggest that the limbic system responds to anxiogenic experiences by changing the BDZ-like molecule levels in relation to the degree of anxiety and/or stress that accompany these experiences.

Constituents of Eriobotrya japonica. A study of their antiviral properties.

The CHCl3 extract of Eriobotrya japonica from an Italian source was shown to contain four new triterpene esters, namely, 23-trans-p-coumaroyltormentic acid [1], 23-cis-p-coumaroyltormentic acid [2], 3-O-trans-caffeoyltormentic acid [3], and 3-O-trans-p-coumaroylrotundic acid [4], in addition to three common ursolic acid derivatives 5, 6, and 7. An investigation of the antiviral properties of compounds 1-7 revealed that only 3 significantly reduced rhinovirus infection. The compounds were ineffective towards human immunodeficiency virus type 1 (HIV-1) and Sindbis virus replication.