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International audience; Metal-mediated base pairs are formed by the connection of two nucleobases via coordination to a metal cation. The resulting metal-containing duplexes have been used in a large variety of applications ranging from allosteric control of functional nucleic acids to the construction of nanowires. Recently, enzymatic approaches are being developed for the construction of metal-mediated base pairs. Here, we have studied the possibility of constructing HgII- and AgI-mediated DNA/RNA hetero base pairs using primer extension reactions. The high thermodynamic stabilities of metal base pairs can be harnessed to trigger the formation of two rU-HgII-dT base pairs. Bypass experiments demonstrate the possibility of constructing RNA containing DNA sequences which are used in multiple applications including DNAzyme selections. These findings will be useful for the enzymatic construction of xenonucleic acid (XNA) based metal pairs.

Study question Does the intraovarian injection of autologous platelet rich plasma (A-PRP) improve the outcomes of subsequent in vitro fertilisation (IVF) treatments. Summary answer Intraovarian injection of A-PRP improves embryological performance and pregnancy outcomes in subsequent IVF treatments, but the beneficial effects may be lost with time. What is known already A-PRP has been widely used in other medical fields to optimise treatment outcomes. In IVF, emerging evidence has shown its potential benefit in promoting endometrial quality via release of a range of growth factors and cytokines. More recently it has been proposed that intraovarian injection of A-PRP may have the potential to “activate” some resting follicles in a selected group of patients. In this registered clinical trial, we aimed to evaluate embryology performance and pregnancy outcomes following ovarian injection of A-PRP in patients with poor ovarian function or premature ovarian failure. Study design, size, duration This is a registered (ID= ACTRN126190012061128) prospective clinical trial with recruitment commencing in November 2019. All participating women undergoing A-PRP treatment due to poor ovarian function or premature ovarian failure were reviewed for eligibility for this study. Inclusion criteria were restricted to women who had completed at least one IVF cycle before and after A-PRP injection as of January 2022. Participants/materials, setting, methods All A-PRP treatments were prepared using a commercial kit (Alocuro) approved by the Australian Therapeutic Goods Agency. Up to 3 subsequent IVF cycles post A-PRP injection were included for analysis. Embryological parameters included numbers of follicles, oocytes and embryos yielded per cycle. Paired comparisons were performed between cycles of the same patients before and after A-PRP injection. Cumulative ongoing pregnancy outcomes were also evaluated up to 3 IVF cycles post A-PRP injection. Main results and the role of chance 36 women were included in the analysis, average age 41.14±3.56 years with 4.61±2.91 unsuccessful previous IVF attempts at the time of A-PRP injection. Their serum FSH was reduced from 13.04±8.97 mIU/mL before A-PRP injection to 11.06±.56 mIU/mL post injection. In reference to the IVF cycle immediately before A-PRP injection, an improving trend in the embryology parameters was identified in the subsequent 1st, 2nd, and 3rd IVF cycles; as demonstrated in the numbers of follicles (2.39±1.76, 2.86±2.06, 2.52±1.65 and 2.46±1.66), oocytes (1.86±1.48, 2.56±2.08, 2.43±1.90 and 2.08±1.93) and embryos (1.30±1.03, 1.45±1.39, 1.80±1.67 and 1.20±1.48). Although the comparisons above did not reach statistical significance, the rise in oocyte numbers in the 1st IVF cycle was close to statistical significance (P = 0.08). It should also be noted that the highest improvement in follicle and oocyte numbers was seen in the 1st IVF cycle after A-PRP injection, while embryo number peaked at the 2nd IVF cycle. Three out of 36 women (P = 0.08) achieved ongoing pregnancies after the 1st round IVF cycles with inclusion of associated frozen embryo transfers as applicable. After the 2nd round, 4 out of the 36 women (P = 0.04) achieved ongoing pregnancy but no additional pregnancies from the 3rd round. Limitations, reasons for caution Comparisons performed in this study were not randomised, with the patients themselves used as their own controls. Therefore cycle associated variations may not be eliminated. Sample size was relatively small, and findings were restricted to a selected patient group. Wider implications of the findings Ovarian injection of A-PRP seems to improve both embryology performance and cumulative pregnancy outcomes. However the beneficial effect post injection seems to fade with time. A further randomised study is warranted to specify the timeframe of this diminishing effect in order to better guide clinical practice. Trial registration number ACTRN126190012061128

Background: The Netflix drama 13 Reasons Why (13RW) focusing on the suicide of an adolescent girl became a global phenomenon. It was accompanied by intense public debate about the risks of exposing youth to fictional portrayals of adolescent suicide. Aims: To explore adolescents' subjective perspectives and understanding of 13RW focusing on the portrayal of adolescent suicide. Method: We applied a thematic analysis to qualitative data from interviews with 25 New Zealand adolescents eliciting views on the show's portrayal of adolescent suicide. Results: Four themes were developed from the analysis: entertaining but not realistic; the unexpected shock factor; jumbled messages; and superficial conversations. Conclusion: This study contributes a youth perspective which has been missing from the debate on 13RW. This research highlights the way that youth, when given the opportunity, articulated a nuanced understanding of the representation of adolescent suicide in 13RW, viewing it as entertainment rather than a realistic depiction that added little in terms of suicide awareness and generated minimal opportunities for in-depth discussion.

International audience; While Nature harnesses RNA and DNA to store, read and write genetic information, the inherent programmability, synthetic accessibility and wide functionality of these nucleic acids make them attractive tools for use in a vast array of applications. In medicine, antisense oligonucleotides (ASOs), siRNAs, and therapeutic aptamers are explored as potent targeted treatment and diagnostic modalities, while in the technological field oligonucleotides have found use in new materials, catalysis, and data storage. The use of natural oligonucleotides limits the possible chemical functionality of resulting technologies while inherent shortcomings, such as susceptibility to nuclease degradation, provide obstacles to their application. Modified oligonucleotides, at the level of the nucleobase, sugar and/or phosphate backbone, are widely used to overcome these limitations. This review provides the reader with an overview of nonnative modifications and the challenges faced in the design, synthesis, application and outlook of novel modified oligonucleotides.

Like many human experiences, traumatic stress is highly gendered. Over the past several decades, a sub-stantial number of empirical studies have explored ethical issues in traumatic stress research. However, these studies have typically reported female samples or failed to account for the influence of gender in their analyses of mixed-sex samples. By extension, ethical issues that are relevant to male participants in traumatic stress research are poorly understood. After briefly exploring why the vulnerabilities of male participants are under-explored in traumatic stress research, this article highlights many ethical issues that are important to address when men participate in traumatic stress research, concluding with some sugges-tions for how these might be taken up to advance the field.

Metal-mediated base pairs are formed by the connection of two nucleobases via coordination to a metal cation. The resulting metal-containing duplexes have been used in a large variety of applications ranging from allosteric control of functional nucleic acids to the construction of nanowires. Recently, enzymatic approaches are being developed for the construction of metal-mediated base pairs. Here, we have studied the possibility of constructing HgII- and AgI-mediated DNA/RNA hetero base pairs using primer extension reactions. The high kinetic and thermodynamic stabilities of metal base pairs can be harnessed to trigger the formation of multiple rU-HgII-dT base pairs.

Surfboard paddling is an essential activity when surfing. Research investigating surfboard paddling, especially as it pertains to neuromechanical control and techniques used, is limited. Previous research made use of swim ergometers to examine surfboard paddling demands. The validity of using swim ergometers in surfboard paddling research and training deserves further analysis. To establish ecologically valid findings, researchers have begun to use swim flumes and still-water paddling environments to investigate paddling efficiency and technique. This emerging body of research has reported that muscle activation patterns, intensities, and timings differ as surfers move through different paddle stroke phases. A deeper understanding of paddling's neuromechanical control may help enhance the understanding of how to improve paddle performance and perhaps reduce injury risk. Therefore, the purpose of this review was to identify the gaps in the existing literature to help identify future research directions in relation to surfboard paddling techniques and neuromechanical control.

Exposure to suicide is a major factor for suicidality. Mental health professionals and first responders are often exposed to suicide while on-duty. The objective of this scoping review is to describe the state of current research on exposure to suicide among mental health professionals and first responders, focusing on the prevalence and impact of exposure to suicide, and to identify current gaps in the literature. We searched MEDLINE, Scopus, PsychNET, and Web of Science and identified 25 eligible papers. Between 31.5–95.0% of professionals had been exposed to suicide. Exposure to suicide had impacts on personal life, professional life, and mental health; and caused emotional distress. There was little research investigating exposure to suicide among police officers, firefighters, and paramedics. More research existed on mental health professionals, but none assessed exposure to suicide as a risk for suicide amongst this group. The review concludes that exposure to suicide is distressing for mental health professionals, and likely to be for first responder however, more research on these groups, especially paramedics, is required.

Macromolecules are potentially useful delivery systems for cancer drugs, as their size allows them to utilize the enhanced permeability and retention effect (EPR), which facilitates selective delivery to (and retention within) tumors. In addition, macromolecular delivery systems can prolong circulation times as well as protect and solubilize toxic and hydrophobic drug moieties. Overall, these properties and abilities can result in an enhanced therapeutic effect. Photodynamic therapy (PDT) combines the use of oxygen and a photosensitizer (PS), which become toxic upon light irradiation. We proposed that a PS encapsulated within a water-soluble macromolecule could exploit the EPR effect and safely and selectively deliver the PS to a tumor. In this paper, we describe the synthesis of a porphyrin-cored hyperbranched polymer that aggregated into larger micellar structures. DLS and TEM indicated that these aggregated structures had diameters of 45 and 20 nm for the solvated and nonsolvated species, respectively. The porphyrin-cored HBP (PC-HBP), along with the nonencapsulated porphyrin (THPP), were screened against EJ bladder carcinoma cells in the dark and light. Both THPP and PC-HBP displayed good toxicity in the light, with LD50 concentrations of 0.5 and 1.7 μM, respectively. However, in the dark, the nonincorporated porphyrin (THPP) displayed significant toxicity, generating an LD50 of 4 μM. On the other hand, no dark toxicity was observed for the polymer system (PC-HBP) at concentrations of 100 μM or less. As such, incorporation within the large polymer aggregate serves to eliminate dark toxicity while maintaining excellent toxicity when irradiated.

A ligand skeleton combining a 1,10-phenanthroline (phen) binding site and one or two heptadentate N3O4 aminocarboxylate binding sites, connected via alkyne spacers to the phen C3 or C3/C8 positions, has been used to prepare a range of heteronuclear Ru·M and Ru·M2 complexes which have been evaluated for their cell imaging, relaxivity, and photophysical properties. In all cases the phen unit is bound to a {Ru(bipy)2}2+ unit to give a phosphorescent {Ru(bipy)2(phen)}2+ luminophore, and the pendant aminocarboxylate sites are occupied by a secondary metal ion M which is either a lanthanide [Gd(iii), Nd(iii), Yb(iii)] or another d-block ion [Zn(ii), Mn(ii)]. When M = Gd(iii) or Mn(ii) these ions provide the complexes with a high relaxivity for water; in the case of Ru·Gd and Ru·Gd2 the combination of high water relaxivity and 3MLCT phosphorescence from the Ru(ii) unit provides the possibility of two different types of imaging modality in a single molecular probe. In the case of Ru·Mn and Ru·Mn2 the Ru(ii)-based phosphorescence is substantially reduced compared to the control complexes Ru·Zn and Ru·Zn2 due to the quenching effect of the Mn(ii) centres. Ultrafast transient absorption spectroscopy studies on Ru·Mn (and Ru·Zn as a non-quenched control) reveal the occurrence of fast (

Photodynamic therapy (PDT) exploits light-activated compounds for therapeutic use. It relies on a photosensitiser (PS) that is inactive in the absence of light. When irradiated, the PS absorbs light and is promoted to a higher energy, “excited” state (PS∗), which is either toxic to cells in itself or triggers formation of other species which are toxic to cells, and hence particular wavelengths of light can be used to induce light-dependent cell killing. In PDT occurring via the so-called type I and type II mechanisms, the PS∗ engages in energy transfer to dioxygen present in cells and tissues. This process generates highly reactive singlet oxygen (1O2) and/or other reactive oxygen species (ROS), which in turn cause damage in the immediate vicinity of the irradiation and ultimately can lead to cell death. Whilst the main focus of research for the last 50 years has been on organic molecules or porphyrins as sensitisers, there is now emerging interest in extending the use to transition metal (TM) complexes, which can display intense absorptions in the visible region, and many also possess high two-photon absorption cross-sections, enabling two-photon excitation with NIR light. As with any other type of photosensitiser, the issues to consider whilst designing a TM complex as a photosensitiser include cell permeability, efficient absorption of NIR light for deeper penetration, preferential affinity to cancer cells over healthy cells, targeted intracellular localisation and lack of side effects. This review summarises recent developments involving photosensitisers containing Ru(II), Os(II), Pt, Ir(III), and Re(I) ions, and the approaches used to address the above requirements. Several remarkable recent advances made in this area, including the first clinical trial of a metal complex as a photosensitiser, indicate the bright future of this class of compounds in PDT.

Fungal genomes display incredible levels of complexity and diversity, and are exceptional study systems for genome evolution. Here we used the Oxford Nanopore MinION sequencing platform to generate high-quality fungal genomes from complex metagenomic samples of lichen thalli. We sequenced two wolf lichens using one flow cell per sample, generating 17.1 Gbps for Letharia lupina and 14.3 Gbps for Letharia columbiana. The resulting L. lupina genome is one of the most contiguous lichen genomes available to date, with 49.2 Mbp contained on 31 contigs. The L. columbiana genome, while less contiguous, is still relatively high quality, with 52.3 Mbp on a total of 161 contigs. Each thallus for both species contained multiple distinct haplotypes, a phenomenon that has rarely been empirically demonstrated. The Oxford Nanopore sequencing technologies are robust and effective when applied to complex symbioses, and have the potential to fundamentally transform our understanding of fungal genetics.

The series of complexes [Os(bpy)3- n(pytz) n][PF6]2 (bpy = 2,2'-bipyridyl, pytz = 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, 1 n = 0, 2 n = 1, 3 n = 2, 4 n = 3) were prepared and characterized and are rare examples of luminescent 1,2,3-triazole-based osmium(II) complexes. For 3 we present an attractive and particularly mild preparative route via an osmium(II) η6-arene precursor circumventing the harsh conditions that are usually required. Because of the high spin-orbit coupling constant associated with the Os(II) center the absorption spectra of the complexes all display absorption bands of appreciable intensity in the range of 500-700 nm corresponding to spin-forbidden ground-state-to-3MLCT transitions (MLCT = metal-to-ligand charge transfer), which occur at significantly lower energies than the corresponding spin-allowed 1MLCT transitions. The homoleptic complex 4 is a bright emitter (λmaxem = 614 nm) with a relatively high quantum yield of emission of ∼40% in deoxygenated acetonitrile solutions at room temperature. Water-soluble chloride salts of 1-4 were also prepared, all of which remain emissive in aerated aqueous solutions at room temperature. The complexes were investigated for their potential as phosphorescent cellular imaging agents, whereby efficient excitation into the 3MLCT absorption bands at the red side of the visible range circumvents autofluorescence from biological specimens, which do not absorb in this region of the spectrum. Confocal microscopy reveals 4 to be readily taken up by cancer cell lines (HeLa and EJ) with apparent lysosomal and endosomal localization, while toxicity assays reveal that the compounds have low dark and light toxicity. These complexes therefore provide an excellent platform for the development of efficient luminescent cellular imaging agents with advantageous photophysical properties that enable excitation and emission in the biologically transparent region of the optical spectrum.

PREMISE OF THE STUDY Lichenized fungi are evolutionarily diverse and ecologically important, but little is known about the processes that drive their diversification and genetic differentiation. Distributions are often assumed to be wholly shaped by ecological requirements rather than dispersal limitations. Furthermore, although asexual and sexual reproductive structures are observable, the lack of information about recombination rates makes inferences about reproductive strategies difficult. We investigated the population genomics of Cetradonia linearis, a federally endangered lichen in the southern Appalachians of eastern North America, to test the relative contributions of environmental and geographic distance in shaping genetic structure, and to characterize the mating system and genome-wide recombination. METHODS Whole-genome shotgun sequencing was conducted to generate data for 32 individuals of C. linearis. A reference genome was assembled, and reads from all samples were aligned to generate a set of single-nucleotide polymorphisms for further analyses. KEY RESULTS We found evidence for low rates of recombination and for isolation by distance, but not for isolation by environment. The species is putatively unisexual, given that only one mating-type locus was found. Hindcast species distribution models and the distribution of genetic diversity support C. linearis having a larger range during the Last Glacial Maximum in the southern portion of its current extent. CONCLUSIONS Our findings contribute to the understanding of factors that shape genetic diversity in C. linearis and in fungi more broadly. Because all populations are highly genetically differentiated, the extirpation of any population would mean the loss of unique genetic diversity; therefore, our results support the continued conservation of this species.

The benefits of being well fed In eusocial insects, the vast majority of individuals sacrifice their reproductive potential to support the reproductive queen. Although this system has evolved repeatedly, there is still much debate surrounding its origin. Working with seven different species of ants, Chandra et al. used a transcriptomic approach to show that a single gene is consistently up-regulated in queens. This gene seems to confer reproductive status through integration with increased nutrition. In a clonal ant, larval signals disrupt this gene up-regulation, destabilizing the division of reproductive labor. Increasing levels of the associated peptide override these larval signals and establish eusociality. Science , this issue p. 398

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality. Advances in remote technologies and telemedicine provide new ways to monitor respiratory function and improve chronic disease management. However, telemedicine does not always include remote respiratory assessments, and the current state of knowledge for people with COPD has not been evaluated.Systematically review the use of remote respiratory assessments in people with COPD, including the following questions: What devices have been used? Can acute exacerbations of chronic obstructive pulmonary disease (AECOPD) be predicted by using remote devices? Do remote respiratory assessments improve health-related outcomes?The review protocol was registered (PROSPERO 2016:CRD42016049333). MEDLINE, EMBASE, and COMPENDEX databases were searched for studies that included remote respiratory assessments in people with COPD. A narrative synthesis was then conducted by two reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.Fifteen studies met the inclusion criteria. Forced expiratory volume assessed daily by using a spirometer was the most common modality. Other measurements included resting respiratory rate, respiratory sounds, and end-tidal carbon dioxide level. Remote assessments had high user satisfaction. Benefits included early detection of AECOPD, improved health-related outcomes, and the ability to replace hospital care with a virtual ward.Remote respiratory assessments are feasible and when combined with sufficient organizational backup can improve health-related outcomes in some but not all cohorts. Future research should focus on the early detection, intervention, and rehabilitation for AECOPD in high-risk people who have limited access to best care and investigate continuous as well as intermittent monitoring.

We describe an Ir(III)-based small-molecule, multimodal probe for use in both light and electron microscopy. The direct correlation of data between light- and electron-microscopy-based imaging to investigate cellular processes at the ultrastructure level is a current challenge, requiring both dyes that must be brightly emissive for luminescence imaging and scatter electrons to give contrast for electron microscopy, at a single working concentration suitable for both methods. Here we describe the use of Ir(III) complexes as probes that provide excellent image contrast and quality for both luminescence and electron microscopy imaging, at the same working concentration. Significant contrast enhancement of cellular mitochondria was observed in transmission electron microscopy imaging, with and without the use of typical contrast agents. The specificity for cellular mitochondria was also confirmed with MitoTracker using confocal and 3D-structured illumination microscopy. These phosphorescent dyes are part of a very exclusive group of transition-metal complexes that enable imaging beyond the diffraction limit. Triplet excited-state phosphorescence was also utilized to probe the O2 concentration at the mitochondria in vitro, using lifetime mapping techniques.

Recent surveys on California’s northern Channel Islands have highlighted the ubiquity of small, low-density lithic scatters across coastal terraces and interior ridgelines. These sites typically la...

Given concerns about suicide or self-harm content on Instagram, we conducted a systematic scoping review of peer-reviewed English language primary studies published between 2010–2019. Only ten studies had been published. Looking into purposive samples of Instagram posts tagged with self-harm related hashtags, studies report finding self-harm or suicide content in between 9–66% of their studied posts. Studies assessing Instagram’s efforts to tackle such content found they had not been very effective. Despite heterogeneity in study aims, use of terminology, samples, methods of analysis, and study outcomes, we aggregated and distinguished ‘content studies’ and ‘user studies’. Most studies showed concern for self-harm risk, but only one examined the relationship between self-harm posts and actual self-harm behaviours offline. It found such content had negative emotional effects on some users and reported preliminary evidence of potential harmful effects in relation to self-harm related behaviours offline, although causal effects cannot be claimed. At the same time, some benefits for those who engage with self-harm content online have been suggested. More research directly interviewing Instagram users to understand this phenomenon from their perspective is required. Finally, some ethical issues are discussed.

Ruthenium complexes, and especially ruthenium(II) polypyridyl complexes, have attracted a lot of attention as potential photosensitizers for photodynamic therapy. However, some are unsuitable due to their low cellular uptake, potentially due to their relatively low degree of lipophilicity, which prevents them from penetrating tumor cells. Here, we report the conjugation of a non-cell-penetrating ruthenium polypyridyl complex, [Ru(bipy)2-dppz-7-hydroxymethyl][PF6]2 (bipy = 2,2’-bipyridine, dppz = dipyrido[3,2-a:2;2’,3’-c]phenazine) (RuOH), to a highly hydrophobic biodegradable and biocompatible polylactide to enhance its cellular uptake. The ruthenium-polylactide conjugates were prepared by drug-initiated ring-opening polymerization of lactide through the formation of a zinc alkoxide initiator and formulated into nanoparticles by nanoprecipitation. They were characterized by means of nuclear magnetic resonance spectroscopy (NMR), matrix-assisted laser desorption/ionization – time of flight mass spectrometry (MALDI-TOF MS) and dynamic light scattering (DLS). Finally, their photo-therapeutic activity (λexc = 480 nm, 3.21 J cm-2) in cancerous human cervical carcinoma (HeLa) and non-cancerous retinal pigment epithelium (RPE-1) cells was tested alongside that of RuOH and their cellular uptake in HeLa cells was assessed by confocal microscopy and inductively coupled plasma - mass spectrometry (ICP-MS). All nanoparticles showed improved photophysical properties including luminescence and singlet oxygen generation, enhanced cellular uptake and, capitalizing on this, an improved photo-toxicity.

Objectives The bubble-positive expiratory pressure (PEP) device may be used for sputum clearance in people with daily sputum production. However, this device has never been studied in people with bronchiectasis. Hence, the objective of this study was to compare the effect of bubble-PEP device, the active cycle of breathing technique (ACBT) and no intervention (control) on sputum clearance in people with bronchiectasis. Methods This was a prospective, randomised cross-over trial with concealed allocation, assessor blinding and intention-to-treat analysis. Adult participants with stable bronchiectasis and productive of sputum daily were recruited. Participants performed 30-min of bubble-PEP, ACBT or control in random order whilst sitting, followed by 60-min of quiet sitting, on three separate days at the same time within a 10-day period. Primary outcome measure was wet weight of expectorated sputum during 30-min intervention, 60-min post intervention and total wet weight (30 min plus 60 min). Results Thirty-five-participants (11 males, mean [standard deviation] age 75 [8] years, forced expiratory volume in 1 s 72 [20] % predicted) were recruited and 34 completed the study. There was no significant difference in sputum wet weight between bubble-PEP and ACBT during 30-min intervention (mean difference [95% confidence interval]) -0.59 g [-1.37, 0.19] and total wet weight (0.74 g [-0.54, 2.02]). Sputum wet weight was significantly greater in bubble-PEP than ACBT at 60-min post intervention (1.33 g [0.19, 2.47]). Conclusion Sputum wet weight was significantly greater with bubble-PEP than control at all time periods, and greater than ACBT at 60-min-post. Bubble-PEP could be considered an alternative sputum clearance technique to ACBT.

BackgroundRespiratory complications remain a leading cause of morbidity and mortality in people with acute and chronic tetraplegia. Respiratory muscle weakness following spinal cord injury-induced tetraplegia impairs lung function and the ability to cough. In particular, inspiratory muscle strength has been identified as the best predictor of the likelihood of developing pneumonia in individuals with tetraplegia. We hypothesised that 6 weeks of progressive respiratory muscle training (RMT) increases respiratory muscle strength with improvements in lung function, quality of life and respiratory health.MethodsSixty-two adults with tetraplegia participated in a double-blind randomised controlled trial. Active or sham RMT was performed twice daily for 6 weeks. Inspiratory muscle strength, measured as maximal inspiratory pressure (PImax) was the primary outcome. Secondary outcomes included lung function, quality of life and respiratory health. Between-group comparisons were obtained with linear models adjusting for baseline values of the outcomes.ResultsAfter 6 weeks, there was a greater improvement in PImax in the active group than in the sham group (mean difference 11.5 cmH2O (95% CI 5.6 to 17.4), pConclusionsProgressive RMT increases inspiratory muscle strength in people with tetraplegia, by a magnitude which is likely to be clinically significant. Measurement of baseline PImax and provision of RMT to at-risk individuals may reduce respiratory complications after tetraplegia.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN 12612000929808).

International audience; RNA is often considered as being the vector for the transmission of genetic information from DNA to the protein synthesis machinery. However, besides translation RNA participates in a broad variety of fundamental biological roles such as gene expression and regulation, protein synthesis, and even catalysis of chemical reactions. This variety of function combined with intricate three-dimensional structures and the discovery of over 100 chemical modifications in natural RNAs require chemical methods for the modification of RNAs in order to investigate their mechanism, location, and exact biological roles. In addition, numerous RNA-based tools such as ribozymes, aptamers, or therapeutic oligonucleotides require the presence of additional chemical functionalities to strengthen the nucleosidic backbone against degradation or enhance the desired catalytic or binding properties. Herein, the two main methods for the chemical modification of RNA are presented: solid-phase synthesis using phosphoramidite precursors and the enzymatic polymerization of nucleoside triphosphates. The different synthetic and biochemical steps required for each method are carefully described and recent examples of practical applications based on these two methods are discussed.

A ligand skeleton combining a 1,10-phenanthroline (phen) binding site and one or two heptadentate N3O4 aminocarboxylate binding sites, connected via alkyne spacers to the phen C3 or C3/C8 positions, has been used to prepare a range of heteronuclear Ru·M and Ru·M2 complexes which have been evaluated for their cell imaging, relaxivity, and photophysical properties. In all cases the phen unit is bound to a {Ru(bipy)2}2+ unit to give a phosphorescent {Ru(bipy)2(phen)}2+ luminophore, and the pendant aminocarboxylate sites are occupied by a secondary metal ion M which is either a lanthanide [Gd(iii), Nd(iii), Yb(iii)] or another d-block ion [Zn(ii), Mn(ii)]. When M = Gd(iii) or Mn(ii) these ions provide the complexes with a high relaxivity for water; in the case of Ru·Gd and Ru·Gd2 the combination of high water relaxivity and 3MLCT phosphorescence from the Ru(ii) unit provides the possibility of two different types of imaging modality in a single molecular probe. In the case of Ru·Mn and Ru·Mn2 the Ru(ii)-based phosphorescence is substantially reduced compared to the control complexes Ru·Zn and Ru·Zn2 due to the quenching effect of the Mn(ii) centres. Ultrafast transient absorption spectroscopy studies on Ru·Mn (and Ru·Zn as a non-quenched control) reveal the occurrence of fast (1 ns) PET in Ru·Mn, from the Mn(ii) ion to the Ru(ii)-based 3MLCT state, i.e. MnII-(phen˙-)-RuIII → MnIII-(phen˙-)-RuII; the resulting MnIII-(phen˙-) state decays with τ ≈ 5 ns and is non-luminescent. This occurs in conformers when an ET pathway is facilitated by a planar, conjugated bridging ligand conformation connecting the two units across the alkyne bridge but does not occur in conformers where the two units are electronically decoupled by a twisted conformation of the bridging ligand. Computational studies (DFT) on Ru·Mn confirmed both the occurrence of the PET quenching pathway and its dependence on molecular conformation. In the complexes Ru·Ln and Ru·Ln2 (Ln = Nd, Yb), sensitised near-infrared luminescence from Nd(iii) or Yb(iii) is observed following photoinduced energy-transfer from the Ru(ii) core, with Ru → Nd energy-transfer being faster than Ru → Yb energy-transfer due to the higher density of energy-accepting states on Nd(iii).

To determine the proportion and physiological characteristics of nonobese patients with obstructive sleep apnea (OSA) and their response to prescribed therapy.Data from 163 consecutive in-laboratory diagnostic sleep studies for participants referred to an academic teaching-hospital sleep clinic for suspected OSA were assessed. Sleep and anthropometric parameters at baseline and follow-up (up to 22 mo) were examined and compared between obese and nonobese patients with a diagnosis of OSA (apnea-hypopnea index5 events/h sleep). A key nonanatomical contributor to OSA pathogenesis, the respiratory arousal threshold, was compared between groups.Twenty-five percent of the participants with a diagnosis of OSA had a body mass index (BMI) within the normal range (BMI25 kg/mA substantial proportion of patients with OSA are not obese. These patients are challenging to treat with existing therapies as they are less adherent and compliant with CPAP therapy. Nonanatomical contributors to OSA, such a low threshold for arousal, are likely to be particularly important in OSA pathogenesis in nonobese patients with OSA. These findings have important implications for the pathogenesis of OSA in nonobese patients and potential therapeutic targets for this group of patients.

Background and objective Telerehabilitation has the potential to increase access to pulmonary rehabilitation (PR) for patients with COPD who have difficulty accessing centre-based PR due to poor mobility, lack of transport and cost of travel. We aimed to determine the effect of supervised, home-based, real-time videoconferencing telerehabilitation on exercise capacity, self-efficacy, health-related quality of life (HRQoL) and physical activity in patients with COPD compared with usual care without exercise training. Methods Patients with COPD were randomized to either a supervised home-based telerehabilitation group (TG) that received exercise training three times a week for 8 weeks or a control group (CG) that received usual care without exercise training. Outcomes were measured at baseline and following the intervention. Results Thirty-six out of 37 participants (mean ± SD age = 74 ± 8 years, forced expiratory volume in 1 s (FEV1 ) = 64 ± 21% predicted) completed the study. Compared with the CG, the TG showed a statistically significant increase in endurance shuttle walk test time (mean difference = 340 s (95% CI: 153–526, P

Telerehabilitation, consisting of supervised home-based exercise training via real-time videoconferencing, is an alternative method to deliver pulmonary rehabilitation with potential to improve access. The aims were to determine the level of satisfaction and experience of an eight-week supervised home-based telerehabilitation exercise program using real-time videoconferencing in people with COPD. Quantitative measures were the Client Satisfaction Questionnaire-8 (CSQ-8) and a purpose-designed satisfaction survey. A qualitative component was conducted using semi-structured interviews. Nineteen participants (mean (SD) age 73 (8) years, forced expiratory volume in 1 second (FEV1) 60 (23) % predicted) showed a high level of satisfaction in the CSQ-8 score and 100% of participants reported a high level of satisfaction with the quality of exercise sessions delivered using real-time videoconferencing in participant satisfaction survey. Eleven participants undertook semi-structured interviews. Key themes in four areas relating to the telerehabilitation service emerged: positive virtual interaction through technology; health benefits; and satisfaction with the convenience and use of equipment. Participants were highly satisfied with the telerehabilitation exercise program delivered via videoconferencing.

The impact on researchers of working with sensitive data is often not considered by ethics committees when approving research proposals. We conducted interviews with eight research assistants processing clinical notes on emergency department presentations for deliberate self-harm and suicide attempts during a suicide prevention trial. Common experiences of working with the data included feeling unprepared for the level of detail in the records, being drawn deeply into individual stories, emotional exhaustion from the cumulative exposure to the data over long periods of time while working alone, and experiencing a heightened awareness of the fragility of life and the need for safety. The research assistants also reported on some of the strategies they had developed to cope with the sensitive nature of the data and the demands of the work. The ethical implications for suicide research reliant on non-clinically trained researchers exploring sensitive data are considered. These include the need for research leaders and ethics committees to be aware of the potential adverse mental health impacts for these researchers examining sensitive data and to make appropriate arrangements to minimize the mental health impacts of such work.

Study objectives To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. Methods Twelve patients with OSA (apnea-hypopnea index = 41 ± 8 events/h) were studied during 2 single night sleep studies conducted approximately 1 w apart after receiving 7.5 mg of zopiclone or placebo according to a double-blind, placebo-controlled, randomized, crossover design. The respiratory arousal threshold (epiglottic pressure immediately prior to arousal during naturally occurring respiratory events), genioglossus activity and its responsiveness to pharyngeal pressure during respiratory events, and markers of OSA severity were compared between conditions. Genioglossus movement patterns and upper airway anatomy were also assessed via magnetic resonance imaging in a subset of participants (n = 7) during wakefulness. Results Zopiclone increased the respiratory arousal threshold versus placebo (-31.8 ± 5.6 versus -26.4 ± 4.6 cmH2O, P = 0.02) without impairing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure during respiratory events (-0.56 ± 0.2 versus -0.44 ± 0.1 %max/-cmH2O, P = 0.48). There was substantial interindividual variability in the changes in OSA severity with zopiclone explained, at least in part, by differences in pathophysiological characteristics including body mass index, arousal threshold, and genioglossus movement patterns. Conclusions In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others. Clinical trial registration Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.

Although metal-ion-directed self-assembly has been widely used to construct a vast number of macrocycles and cages, it is only recently that the biological properties of these systems have begun to be explored. However, up until now, none of these studies have involved intrinsically photoexcitable self-assembled structures. Herein we report the first metallomacrocycle that functions as an intracellular singlet oxygen sensitizer. Not only does this Ru2 Re2 system possess potent photocytotoxicity at light fluences below those used for current medically employed systems, it offers an entirely new paradigm for the construction of sensitizers for photodynamic therapy.