Patterns in the Use of Emergency Telemedicine Support in the Management of Traumatic Road Crashes.

Objective: The introduction of emergency telemedicine care models is a common theme in health jurisdictions that include rural and remote populations. How the availability of these models influences the way clinicians manage traumatic road crashes is not yet fully understood. This study seeks to compare road crashes where telemedicine was and was not used and to identify any variables that may increase the likelihood of telemedicine usage by treating clinicians. Methods: Road crashes reported in the state Department of Transport and Main Roads (Queensland, Australia) crash database between January 1, 2019, and November 30, 2020 (n = 23,734) were compared to videoconferencing call logs to determine which crashes resulted in treatment that was supported by telemedicine (n = 204). Analysis was performed to examine differences in characteristics related to the crash depending on whether telemedicine support was requested. Results: Road crashes where telemedicine support was requested on average involved more casualties (1.6 vs. 1.41; t(11,287) = -3.26, p < 0.001, relative risk = 1.13). Crashes that occurred in rural settings accounted for most requests for telemedicine (65.68%; X2 = 159.2, p < 0.001) and a greater percentage of crashes in remote locations (3.36% vs. 2.35%; X2 = 256.97, p < 0.001, relative risk = 1.43). The use of telemedicine support for crashes was associated with a 13% increase in the mean number of casualties, compared to crashes where telemedicine support was not used. Conclusion: Telemedicine support is requested by clinicians providing emergency treatment in the management of road crashes that produce more severe injuries, involve multiple casualties, and take place in more rural settings or remote locations.

Comparison of patient responses to telehealth satisfaction surveys in rural and urban populations in Queensland.

Objective Telehealth has for many years been identified as a potential contributor to reducing healthcare access inequality. For these benefits to be realised, patients must be accepting and satisfied with the delivery of healthcare in this manner. Measuring patient satisfaction across a large geographical area is important to ensure that investments in telehealth are delivering the benefits that are intended. Methods A brief survey was automatically issued on completion of a patient's telehealth appointment, requesting patient feedback on their experience and information on the location of where they participated in the appointment. These results were compared to an article review which sought examples of other patient satisfaction measures that compared rural and urban populations. Results No significant correlations between survey responses and established demographic indices were found. When stratified by the Modified Monash Model band from which the patient participated in their telehealth appointment from, an ANOVA test determined that rurality was not a predictor of survey response. A review of articles found four articles that compared rural and urban satisfaction responses. Conclusion No evidence of a patient's location influencing their satisfaction with telehealth was observed. This may be attributed to a variety of technical improvements introduced over the past 5-10 years that have made participating in telehealth appointments less technically demanding and more accessible. Telehealth is likely to be contributing to a reduction in healthcare access inequality in Queensland.

Structural basis for clearing of ribosome collisions by the RQT complex.

Translation of aberrant messenger RNAs can cause stalling of ribosomes resulting in ribosomal collisions. Collided ribosomes are specifically recognized to initiate stress responses and quality control pathways. Ribosome-associated quality control facilitates the degradation of incomplete translation products and requires dissociation of the stalled ribosomes. A central event is therefore the splitting of collided ribosomes by the ribosome quality control trigger complex, RQT, by an unknown mechanism. Here we show that RQT requires accessible mRNA and the presence of a neighboring ribosome. Cryogenic electron microscopy of RQT-ribosome complexes reveals that RQT engages the 40S subunit of the lead ribosome and can switch between two conformations. We propose that the Ski2-like helicase 1 (Slh1) subunit of RQT applies a pulling force on the mRNA, causing destabilizing conformational changes of the small ribosomal subunit, ultimately resulting in subunit dissociation. Our findings provide conceptual framework for a helicase-driven ribosomal splitting mechanism.

Telemedicine or In-Person: Referral Letter Content Influencing How a Patient Receives Treatment.

Objective: This study investigated hospital-based specialist services that provide both traditional hospital outpatient appointments (in-person) or through a live videoconferencing session (telehealth) to referred patients. Referral letters submitted to these clinics were assessed against an inclusion criterion and grouped according to which of delivery method the patient received for their appointment (in-person or telehealth). These groups were then compared for differences to see what factors, if any, influence the likelihood of a patient being offered a telehealth appointment. Methods: An extract of all referral letters meeting inclusion criteria between July 01, 2019 and June 30, 2020 were collected (n = 441). Letters were grouped according to delivery modality (in-person or telehealth) and differences between the groups, including variables such as patient demographics, clinical condition, and urgency and the reviewing clinician were assessed for associations. Results: This study observed that where the referring clinician suggested a telehealth appointment for their patient, this was more likely to be offered (38.25%) compared with referrals that did not (7.36%) (x 2 1 = 28.33, p = 0.1857, odds ratio = 2.77). Patients were more likely to be offered a telehealth appointment the further they lived from the treating facility (T = -4.51 on 106.59 df, p = 1.622 e-05). Variation in the selection of delivery modality among reviewing clinicians was also observed (x 2 1 = 42.334, p < 1.42e-08). Discussion: Existing research indicates there is a strong link between the perceptions clinicians as individuals have of telehealth and a willingness to offer this modality to patients. Despite this, specific information about a patient contained within a referral letter may influence the delivery modality that the patient will be offered for their initial appointment. It is important that this information is more routinely included in letters sent by referring clinicians to hospital-based specialist services. It is equally important that when included, this information is identified and actioned by reviewing clinicians in a consistent way. Doing so will benefit patients by increasing the likelihood that they will receive specialist outpatient care in a manner that suits them best.

Probing the side chain tolerance for inhibitors of the CD95/PLCγ1 interaction.

Proceeding our effort to study protein-protein interaction between the death receptor CD95 and phospholipase PLCγ1, we present in the current work chameleon-like traits of peptidomimetic inhibitors. Minute analysis of the interaction suggests that most of the binding energy relies on van der Waals contacts rather than more specific features, such as hydrogen bonds or salt bridges. The two most important positions of the peptoid for its interaction with PLCγ1 (Arg184 and Arg187) were modified to test this hypothesis. While Arg184 proves to be exchangeable for Trp, with no alteration in affinity, the nature of the amino acid replacing Arg187 is more dependent on its positive charge. However, affinity can be partially recovered by increasing van der Waals interactions. Overall, this study shows that for both positions, a subtle balance exists between hydrophobicity, surface contacts and affinity for CD95/PLCγ1, and provides information for the generation of new therapeutic compounds toward this druggable target.

Synthesis of peptidomimetics and chemo-biological tools for CD95/PLCγ1 interaction analysis.

The death receptor CD95 (also known as Fas) induces apoptosis through protein/protein association and the formation of the death-inducing signaling complex. On the other hand, in certain biological conditions, this receptor recruits different proteins and triggers the formation of another complex designated motility-inducing signaling complex, which promotes cell migration and inflammation. This pathway relies on a short sequence of CD95, called calcium-inducing domain (CID), which interacts with the phospholipase PLCγ1. To better understand how CID/PLCγ1 interaction occurs, we synthesized different α-AA peptides mimicking CID. Some of these peptidomimetics are as potent as the natural peptide to disrupt the CID/PLCγ1 interaction and cell migration, and showed improved pharmacokinetic properties. We also generated biotinyl- and palmitoyl-labelled peptidomimetics, useful chemico-biological tools to further explore the pro-inflammatory signal of CD95, which plays an important role in the pathogenesis of lupus and other autoimmune diseases.

Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation.

CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLCγ1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLCγ1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLCγ1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.

Home-based telehealth service for swallowing and nutrition management following head and neck cancer treatment.

Introduction Following (chemo)radiotherapy (C/RT) for head and neck cancer (HNC), patients return to hospital for regular outpatient reviews with speech pathology (SP) and nutrition and dietetics (ND) for acute symptom monitoring, nutritional management, and swallowing and communication rehabilitation. The aim of the current study was to determine the feasibility of a home-based telehealth model for delivering SP and ND reviews, to provide patients with more convenient access to these appointments. Methods Service outcomes, costs, and consumer satisfaction were examined across 30 matched participants: 15 supported via the standard model of care (SMOC), and 15 via the home-based telehealth model of care (TMOC). Results All patients were successfully managed via telehealth. The TMOC was more efficient, with a reduced number ( p < 0.003) and duration ( p < 0.01) of appointments required until discharge. Significant patient cost savings ( p = 0.002) were reported for the TMOC due to decreased travel requirements. While staff costs were reduced, additional telehealth equipment levies resulted in a lower but non-significant overall cost difference to the health service when using the TMOC. High satisfaction was reported by all participants attending the TMOC. Discussion The findings support the feasibility of a home-based telehealth model for conducting SP and ND reviews post C/RT for HNC.

Effects of two dominance manipulations on the stress response: Cognitive and embodied influences.

In response to stress, physiological and mental resources are allocated towards those systems that are needed for rapid responding in terms of fight or flight. On the other hand, long term regenerative processes such as growth, digestion and reproduction are attenuated. Levels of the sex steroid testosterone are reduced in participants that suffer from chronic stress. However, beyond its role for reproductive functions, testosterone plays an important role in the regulation of social status and dominance, testosterone levels increase during competition or when the social status is challenged. The Trier Social Stress Test (TSST), a laboratory stressor with a substantial social-evaluative component, can provoke an increase in salivary testosterone levels. Still, so far the reported findings regarding acute stress effects on testosterone are equivocal, possibly due to moderating effects. In this study we experimentally manipulated social dominance in 56 healthy participants (28m) by two independent manipulations (body posture and cognitive role taking) and subjected them to the TSST. We analyzed salivary testosterone and cortisol levels as dependent measures for the endocrine stress response. The role taking manipulation interacted with the testosterone response: we found the strongest increase when participants had to put themselves in a dominant (vs. submissive) role. Our results suggest that transient changes in testosterone levels during stress reflect a response to status threat that is affected by social dominance.

Modular Synthesis of Arylacetic Acid Esters, Thioesters, and Amides from Aryl Ethers via Rh(II)-Catalyzed Diazo Arylation.

One-pot formation of arylacetic acid esters, thioesters, and amides via Rh(II)-catalyzed arylation of a Meldrum's acid-derived diazo reagent with electron-rich arenes is described. The methodology was used to efficiently synthesize an anticancer compound.

Copper-catalyzed borylative coupling of vinylazaarenes and N-Boc imines.

Cu-catalyzed three-component couplings of vinylazaarenes, B2(pin)2, and N-Boc imines are described. Oxidation of the initially formed boronate gives azaarene-containing, Boc-protected amino alcohols with reasonable to good diastereoselectivities.

All-Carbon [3+3] Oxidative Annulations of 1,3-Enynes by Rhodium(III)-Catalyzed C-H Functionalization and 1,4-Migration.

1,3-Enynes containing allylic hydrogens cis to the alkyne function as three-carbon components in rhodium(III)-catalyzed, all-carbon [3+3] oxidative annulations to produce spirodialins. The proposed mechanism of these reactions involves the alkenyl-to-allyl 1,4-rhodium(III) migration.

Direct Synthesis of 5-Aryl Barbituric Acids by Rhodium(II)-Catalyzed Reactions of Arenes with Diazo Compounds.

A commercially available rhodium(II) complex catalyzes the direct arylation of 5-diazobarbituric acids with arenes, allowing straightforward access to 5-aryl barbituric acids. Free N-H groups are tolerated on the barbituric acid, with no complications arising from N-H insertion processes. This method was applied to the concise synthesis of a potent matrix metalloproteinase (MMP) inhibitor.

Effects of approach-avoidance related motor behaviour on the startle response during emotional picture processing.

Motivational states may be induced by affective foreground stimulation or via proprioceptive feedback by certain postures or body movements. In the present study, we addressed the question of an interaction between basic motor actions and the valence of visual stimuli in an affective modulation of startle paradigm: is the potentiation for aversive and the attenuation for pleasant stimuli more pronounced when the muscles for a congruent approach or avoidance action are activated? Thirty-four volunteers (20 female) watched emotional pictures on a computer screen while simultaneously contracting the flexor vs. extensor muscles of the upper arm. After 3-4s, an acoustic startle stimulus (105dB, binaural, instantaneous rise time) was presented via headphones. Arm movement interacted with picture valence: flexion, compared to extension, increased affective startle modulation (F=4.32, p<0.05). This result suggests integration and not simple summation of postural and body movement effects on startle reflexivity.

Synthesis of spirocyclic enones by rhodium-catalyzed dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes.

The dearomatizing oxidative annulation of 2-alkenylphenols with alkynes and enynes proceeds with high yields and regioselectivities under Rh(III) catalysis. These reactions are successful using Cu(OAc)2 or air as the stoichiometric oxidant, and provide spirocyclic enones, the basic ring system of which appears in several natural products. Application of this process to the preparation of a highly functionalized tetracycle is also demonstrated.

C═N-containing azaarenes as activating groups in enantioselective catalysis.

Nitrogen-containing aromatic heterocycles (azaarenes) are of widespread chemical significance, and chiral compounds containing azaarenes feature prominently in pharmaceuticals, agrochemicals, and natural products. This Perspective highlights the use of a relatively underdeveloped strategy to prepare chiral azaarene-containing compounds: exploitation of the C═N bond embedded within certain azaarenes to activate adjacent functionality in catalytic asymmetric reactions. Work in this area has resulted in the development of several different types of catalytic enantioselective processes, including reductions, nucleophilic additions, and reductive couplings. It is hoped that this Perspective will encourage more researchers to work in this promising area.

Heart rate response to post-learning stress predicts memory consolidation.

Stressful experiences are often well remembered, an effect that has been explained by beta-adrenergic influences on memory consolidation. Here, we studied the impact of stress induced heart rate (HR) responses on memory consolidation in a post-learning stress paradigm. 206 male and female participants saw 52 happy and angry faces immediately before being exposed to the Cold Pressor Test or a non-stressful control procedure. Memory for the faces and their respective expression was tested twice, after 30 min and on the next day. High HR responders (in comparison to low HR responders as well as to the non-stressful control group) showed enhanced recognition memory one day after learning. Our results show that beta-adrenergic activation elicited shortly after learning enhances memory consolidation and that the stress induced HR response is a predictor for this effect.

C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB-L-isoDMDP compared to miglitol and miglustat.

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 µM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.

Diastereo- and enantioselective Pd(II)-catalyzed additions of 2-alkylazaarenes to N-Boc imines and nitroalkenes.

A chiral Pd(II)-bis(oxazoline) complex was found to be highly effective in promoting the first direct diastereo- and enantioselective addition of alkylazaarenes to N-Boc aldimines and nitroalkenes under mild conditions. Deprotection of Boc-protected products proceeded readily to provide amines in high yields.

Pharmacological chaperones for human α-N-acetylgalactosaminidase.

Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal α-N-acetylgalactosaminidase (α-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human α-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human α-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-Å crystal structures of human α-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.