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Coulomb interactions govern most optoelectronic properties in semiconductors including bandgap, excitons, polaron formation, light absorption, interaction of carriers with defects, charge and energy transport. A clear signature of the strength of many-body Coulomb interactions is the exciton binding energy (Eb). As such, the importance of Eb is perhaps second only to the fundamental band gap (Eg) in understanding the physics and efficiency of low-dimensional semiconductors. However, despite their importance, Eg and Eb are difficult to measure. Here, by choosing 2D halide perovskites as the material and electroabsorption as the experimental probe, we measure Eg and Eb with a precision that is an order of magnitude better than typical methods. The Eb values are both lower than previous literature reports and lower than expected from standard theory. Using dielectric spectroscopy, density functional theory, and quantum mechanical modeling, we demonstrate these low Eb values are a consequence of unique screening effects, such as superlattice screening and phonon screening. We demonstrate a clear correlation between Eb and Eg and provide design principles in order to a priori tune Eg and Eb to their optimal values. As such, this work lays the blueprint for Eg-Eb engineering of low-dimensional semiconductors, as an even more useful replacement to simply band gap engineering.

Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex at 3.1 Å resolution. Unexpectedly, the BoNT/X complex is stable and protease resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency bothin vitroandin vivo. Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents weak ganglioside binding and exposed hydrophobic surfaces.

Background While the delivery of healthcare services within prison systems is underpinned by different models, access to timely and optimal healthcare is often constrained by multifaceted factors. Telehealth has been used as an alternative approach to conventional care. To date, much of the focus has been on evaluation of telehealth interventions within certain geographical contexts such as rural and remote communities. Therefore, the aim of this systematic review was to synthesise the evidence base to date for the impacts of, and outcomes from, telehealth delivered in prisons. Methods This systematic review was underpinned by best practice in the conduct and reporting of systematic reviews. A systematic search was conducted to reinforce the literature selection process. The modified McMaster Critical Appraisal Tool was used to assess the methodological quality of the included studies. A narrative synthesis of the study outcomes was undertaken. Results Twenty-nine quantitative studies were included. Telehealth interventions were greatly varied in terms of types of healthcare services, implementation process and intervention parameters. Methodological concerns such as rigour in data collection and analysis, and psychometric properties of outcome measures were commonly identified. Process-related outcomes and telehealth outcomes were the two overarching categories identified. Conclusion This systematic review provides mixed evidence on the impact of, and outcomes from, telehealth in prisons. While the evidence base does highlight some positive impacts of telehealth, which at the least, is as effective as conventional care while achieving patient satisfaction, it is also important to consider the local context and drivers that may influence what, when and how telehealth services are provided. Addressing critical factors throughout the lifecycle of telehealth is equally important for successful implementation and sustainability.

Botulinum neurotoxin (BoNT) serotype A inhibits neurotransmitter release by cleaving SNAP-25 and represents an established pharmaceutical for treating medical conditions caused by hyperactivity of cholinergic nerves. Oversecretion from non-neuronal cells is often also the cause of diseases. Notably, excessive release of inflammatory messengers is thought to contribute to diseases such as chronic obstructive pulmonary disease, asthma, diabetes etc. The expansion of its application to these medical conditions is prevented because the major non-neuronal SNAP-25 isoform responsible for exocytosis, SNAP-23, is, in humans, virtually resistant to BoNT/A. Based on previous structural data and mutagenesis studies of SNAP-23 we optimized substrate binding pockets of the enzymatic domain for interaction with SNAP-23. Systematic mutagenesis and rational design yielded the mutations E148Y, K166F, S254A, and G305D, each of which individually increased the activity of LC/A against SNAP-23 between 3- to 23-fold. The assembled quadruple mutant showed approximately 2000-fold increased catalytic activity against human SNAP-23 in in vitro cleavage assays. A comparable increase in activity was recorded for the full-length BoNT/A quadruple mutant tested in cultivated primary neurons transduced with a fluorescently tagged-SNAP-23 encoding gene. Equipped with a suitable targeting domain this quadruple mutant promises to complete successfully tests in cells of the immune system.

The in vitro potency of botulinum neurotoxin (BoNT) serotypes is often measured by monitoring cleavage of their soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein substrates. A frequently used method is Western blot, whereby the full-length protein and cleaved form migrate at different molecular weights. Until now, it has been extremely difficult to detect the cleaved cellular form of the SNARE protein vesicle associated membrane protein 1, 2 or 3 (VAMP1, 2 or 3) by Western blot. These VAMP isoforms are the substrates of BoNT serotypes BoNT/B, D, F and G as well as tetanus neurotoxin. Using custom made anti-VAMP antibodies against epitopes either side of the cleavage sites for BoNT/B, BoNT/D and BoNT/F, we have successfully detected the cleaved C-terminal VAMP fragment in cortical neurons. These new antibodies enable quantitative assessment of the potency of VAMP-cleaving neurotoxins by a gain of signal Western blot assay.

Telehealth is an alternative method of delivering health care to people required to travel long distances for routine health care. The aim of this systematic review was to examine whether patients and their caregivers living in rural and remote areas are satisfied with telehealth videoconferencing as a mode of service delivery in managing their health. A protocol was registered with PROSPERO international prospective register of systematic reviews (#CRD42017083597) and conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic search of Ovid Medline, Embase, CINAHL, ProQuest Health Research Premium Collection, Joanna Briggs Institute and the Cochrane Library was conducted. Studies of people living in rural and remote areas who attended outpatient appointments for a health condition via videoconference were included if the studies measured patient and/or caregivers’ satisfaction with telehealth. Data on satisfaction was extracted and descriptively synthesised. Methodological quality of the included studies was assessed using a modified version of the McMaster Critical Review Forms for Quantitative or Qualitative Studies. Thirty-six studies of varying study design and quality met the inclusion criteria. The outcomes of satisfaction with telehealth were categorised into system experience, information sharing, consumer focus and overall satisfaction. There were high levels of satisfaction across all these dimensions. Despite these positive findings, the current evidence base lacks clarity in terms of how satisfaction is defined and measured. People living in rural and remote areas are generally satisfied with telehealth as a mode of service delivery as it may improve access to health care and avoid the inconvenience of travel. Refereed/Peer-reviewed

In contrast to the prevailing arguments presented in the current review, the incidence of neutralising antibody (NAb) formation is not a significant issue for any of the present type A therapeutic botulinum neurotoxin (BoNT) products. Furthermore, clinical non-responsiveness is poorly correlated with the presence of NAbs. The overriding evidence supports the view that the rate of NAb formation is low, does not differ significantly between the different type A BoNT products and that it is not the major factor in clinical response. BoNT products are highly effective and important therapies for the treatment of a variety of neurological and non-neurological conditions.

We have purified and characterized recombinant botulinum neurotoxin serotype FA (BoNT/FA). This protein has also been named as a new serotype (serotype H), but the classification has been controversial. A lack of well-characterized, highly pure material has been a roadblock to study. Here we report purification and characterization of enzymatically active, and of inactive nontoxic, recombinant forms of BoNT/FA as tractable alternatives to purifying this neurotoxin from native Clostridium botulinum. BoNT/FA cleaves the same intracellular target proteins as BoNT/F1 and other F serotype BoNTs; the intracellular targets are vesicle associated membrane proteins (VAMP) 1, 2 and 3. BoNT/FA cleaves the same site in VAMP-2 as BoNT/F5, which is different from the cleavage site of other F serotype BoNTs. BoNT/FA has slower enzyme kinetics than BoNT/F1 in a cell-free protease assay and is less potent at inhibiting ex vivo nerve-stimulated skeletal muscle contraction. In contrast, BoNT/FA is more potent at inhibiting neurotransmitter release from cultured neurons.

Introduction There is consistent evidence to indicate people living in rural and remote regions have limited access to healthcare and poorer health outcomes. One way to address this inequity is through innovative models of care such as telehealth. The aim of this pilot trial was to determine the feasibility, appropriateness and access to a telehealth clinic. In this pilot trial, the telehealth clinic outcomes are compared with the outreach clinic. Both models of care are commonly utilised means of providing healthcare to meet the needs of people living in rural and remote regions. Methods A prospective audit was conducted on a Spinal Assessment Clinic Telehealth pilot trial for patients with spinal disorders requiring non-urgent surgical consultation. Data were recorded from all consultations managed using videoconferencing technology between the Royal Adelaide Hospital and Port Augusta Community Health Service, South Australia between September 2013 and January 2014. Outcomes included analysis of process, service activity, clinical actions, safety and costs. Data were compared to a previous spinal assessment outreach clinic in the same area between August and December 2012. Results There were 25 consultations with 22 patients over the five-month telehealth pilot trial. Spinal disorders were predominantly of the lumbar region (88%); the majority of initial consultations (64%) were discharged to the general practitioner. There were three requests for further imaging, five for minor interventions and three for other specialist/surgical consultation. Patient follow-up post telehealth pilot trial revealed no adverse outcomes. The total cost of AUD$11,187 demonstrated a 23% reduction in favour of the spinal assessment telehealth pilot trial, with the greatest savings in travel costs. Discussion The telehealth model of care demonstrated the efficient management of patients with spinal disorders in rural regions requiring non-urgent surgical consultation at low costs with no adverse outcomes reported.

Botulinum neurotoxins (BoNTs) are used extensively as therapeutic agents. Serotypes A and B are available as marketed products. Higher doses of BoNT/B are required to reach an efficacy similar to that of products containing BoNT/A. Advances in our understanding of BoNT/B mechanism of action have afforded the opportunity to make rational modifications to the toxin aimed at increasing its activity. Recently, a mutation in the light chain of BoNT/B (S201P) was described that increases the catalytic activity of the isolated BoNT/B light chain in biochemical assays. In this study, we have produced two full-length recombinant BoNT/B toxins in E.coli–one wild type (rBoNT/B1) and one incorporating the S201P mutation (rBoNT/B1(S201P)). We have compared the activity of these two molecules along with a native BoNT/B1 in biochemical cell-free assays and in several biological systems. In the cell-free assay, which measured light-chain activity alone, rBoNT/B1(S201P) cleaved VAMP-2 and VAMP-1 substrate with an activity 3–4-fold higher than rBoNT/B1. However, despite the enhanced catalytic activity of rBoNT/B1(S201P), there was no significant difference in potency between the two molecules in any of the in vitro cell-based assays, using either rodent spinal cord neurons or cortical neurons. Similarly in ex vivo tissue preparations rBoNT/B1(S201P) was not significantly more potent than rBoNT/B1 at inhibiting either diaphragm or detrusor (bladder) muscle activity in C57BL/6N and CD1 mice. Finally, no differences between rBoNT/B1 and rBoNT/B1(S201P) were observed in an in vivo digit abduction score (DAS) assay in C57BL/6N mice, either in efficacy or safety parameters. The lack of translation from the enhanced BoNT/B1(S201P) catalytic activity to potency in complex biological systems suggests that the catalytic step is not the rate-limiting factor for BoNT/B to reach maximum efficacy. In order to augment the efficacy of BoNT/B in humans, strategies other than enhancing light chain activity may need to be considered.

The modern soldier is faced with a complex moral and psychological landscape. As Nancy Sherman puts it in The Untold War: Inside the Hearts and Minds of our Soldiers, ‘soldiers go to war to fight external enemies… but most fight inner wars as well.’ The modern soldier is no longer simply a warrior: he (or she) is at once a peacekeeper, diplomat, leader, sibling and friend. In the face of such challenges, some responsible for the teaching of soldiers have endeavoured to incorporate a character-based training programme, designed to develop virtues that will assist soldiers in fulfilling the multiple roles required of them. However, these training programmes are stymied by the dearth of virtue-based discussion within the most influential guide to the moral conduct of soldiers: just war theory (JWT). JWT remains a primarily deontic system in which rights, duties and law are generally perceived as the most important considerations. Aretaic ethics has a great deal to offer both JWT and military education progra...

In the article 'After-birth abortion: why should the baby live?' arguments are made in favour of the moral permissibility of intentionally killing newborn infants, under particular conditions. Here we argue that their arguments are based on an indefensible view of personhood, and we question the logic of harm and interest that informs their arguments. Furthermore, we argue that the conclusions here are so contrary to ordinary moral intuitions that the argument and conclusions based upon it-including those which defend more mainstream methods of abortion-should be treated with immediate suspicion.

Generally speaking, just war theory (JWT) holds that there are two just causes for war: self-defence and ‘other-defence’. The most common type of the latter is popularly known as ‘humanitarian intervention’. There is debate, however, as to whether these can serve as just causes for preventive war. Those who subscribe to JWT tend to be unified in treating so-called preventive war with a high degree of suspicion on the grounds that it fails to satisfy conventional criteria for jus ad bello; – particularly the just cause and last resort criteria. Francisco di Vitoria held that the only just cause for war was ‘a wrong received’, which renders impossible any justification for preventive war. There are assumptions implicit in recent military practice, however – most notably, the US-led invasion of Iraq in 2003 – that challenge this ban on preventive war. Interestingly, both supporters and critics attempt to justify their views through the broader logic of JWT; viz., through a conception of what is good for both political communities and individuals, and through a legitimate defence of these goods. Supporters point to situations where so-called rogue states represent ‘grave and imminent risk’ of committing acts of aggression as grounds that justify preventive war; critics argue that to attack another political community on the basis of crimes not yet committed is a breach of the very rights JWT was created to defend. The advocate of preventive war does not appreciate important aspects concerning the morality of war. In the ongoing tension between Iran and The United States and her allies – if the rhetoric is to be believed – I am asked to tolerate a threat to my security and liberty, and to risk suffering aggression in defence of the rights of the antagonistic, but not yet aggressive, state. The crucial question is how such tolerance and risk fit in with the logic of just war: at what point, if any, does the risk of being attacked become great enough to justify declaring war in anticipation? In this paper I highlight some of the theoretical and practical difficulties in determining what counts as a grave and imminent threat, focusing especially on the complicated case of ‘imminence’ in the face of so-called ‘Weapons of Mass Destruction’. Secondly, I will argue that not only is the notion of preventive war inconsistent with the defence of the rights of political communities that JWT requires; it is also forbidden by the proportionality requirement of jus ad bellum. A risk of being subjected to aggression is the price for global peace. Whilst political communities can do much to prevent aggression and prepare themselves in case it occurs, the conditions for just war require that this prevention and preparation stop short of declaring war. We must live with a certain degree of risk in this area.

Synchrotron radiation microangiography is a powerful tool for assessing adverse changes in pulmonary vessel density associated with primary pulmonary hypertension (PH). Congestive heart failure (CHF) leads to a `secondary' onset of PH, yet it is unknown whether secondary PH is also associated with reduced vessel density. This study utilized synchrotron radiation to assess both pulmonary vessel density and endothelial function in a Dahl rat model of CHF with secondary PH. High salt-fed Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were anesthetized and microangiography was performed to assess the pulmonary vessel density and vascular responses to (i) sodium nitroprusside (5.0 µg kg−1min−1), (ii) acetylcholine (3.0 µg kg−1min−1) and (iii) ET-1Areceptor blockade, BQ-123 (1 mg kg−1). Dahl-S rats developed CHF and secondary PH as evident by endothelial dysfunction, impaired vasodilatory responses to acetylcholine, enhanced vasodilatory responses to BQ-123 and extensive pulmonary vascular remodeling. Consequently, the pulmonary vessel density was adversely reduced. Interestingly, the etiology of secondary PH manifests with structural and functional changes that are comparable with that previously reported for primary PH. One important discrepancy, however, is that ET-1 modulation of pulmonary vessels is most striking in vessels with a diameter range of 100–200 µm in secondary PH, in contrast to a range of 200–300 µm in primary PH. Such discrepancies should be considered in future studies investigating primary and secondary forms of PH.

Targeted secretion inhibitors (TSI) are a new class of biopharmaceuticals designed from a botulinum neurotoxin protein scaffold. The backbone consists of the 50-kDa endopeptidase light chain and translocation domain (N-terminal portion of the heavy chain), lacks neuronal toxicity, but retains the ability to target cytoplasmic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. TSI are produced as single-chain proteins and then cleaved post-translationally to generate functional heterodimers. Precise proteolytic cleavage is essential to activate the protein to a dichain form. TSI are themselves highly specific proteases. We have exploited this activity to create self-activating enzymes by replacing the native proteolytic site with a substrate SNARE peptide for the TSI protease. We have also created cross-activating backbones. By replacing the proteolytic activation site in one backbone with the substrate SNARE peptide for another serotype, controlled activation is achieved. SNARE peptides encompassing the whole of the coiled-coil region enabled complete activation and assembly of the dichain backbone. These engineered TSI backbones are capable of translocating their enzymatic domains to target intracellular SNARE proteins. They are also investigative tools with which to further the understanding of endopeptidase activity of light chain in SNARE interactions.

This paper compares two approaches to the moral justifications for killing in war: the forfeiture approach, which sees killing as justified when the victim has forfeited his or her right not to be killed, and the double-effect approach, which argues that even if intentional killing is absolutely prohibited, that killing can still be morally acceptable under certain conditions, most notably if it is not the intended, desired outcome of a person’s chosen action. The double-effect approach is considered out of fashion in contemporary military ethical literate. I argue that it warrants equal attention as an internally viable and coherent account of the morality of killing, and is preferable in at least one way: that it protects combatants from being necessarily culpable of killing merely by serving in active combat positions. By defending an alternate framework to the forfeiture approach to killing which is most popular in today’s military ethical literature, I provide an opportunity for new and increased philosophical reflection and discourse on the ethics of killing, as well as new opportunity for defenders of double-effect to make a substantive contribution to the field. This paper demonstrates the internal consistency of arguments that seek to utilise DDE, including its relevance to individual self-defence and individual killing in war.

Aims Survival from out-of-hospital cardiac arrest is increased by bystander cardiopulmonary resuscitation (CPR). Bystander performance can be improved when CPR instructions are delivered by a calltaker at the Emergency Communications Centre. Little is known about a young person's ability to understand these instructions and perform CPR correctly. We assessed the ability of a group of untrained young people to effectively apply these directions to an adult resuscitation manikin. Methods 87 youngsters aged 7–15 years with no previous training in CPR were separately equipped with a mobile phone and an adult assessment manikin. They phoned the emergency number (111) and were automatically diverted to a senior emergency medical dispatcher (EMD). The EMD delivered resuscitation instructions which complied fully with Medical Priority Dispatch System (version 12.1). Performance was monitored using a Laerdal Computerised Skill Reporting System. Results Average compression depth increased with age from 10.3 mm to 30 mm for 8 and 15 year olds respectively. 100 compressions per minute was achieved in youngsters aged 10 years and older but the rate fatigued over time and improved after interruption for two ventilations. Those aged 11 years and older consistently compressed the chest from 31 mm to 50 mm. Only one participant could successfully ventilate the manikin by mouth-to-mouth. Conclusion This study demonstrates that untrained youngsters should perform compression-only CPR. From 11 years of age, they can effectively perform dispatcher-directed CPR by compressing the chest at an appropriate rate and depth. However, their technique benefits from formal training.

Small GTPases and coiled-coil proteins of the golgin family help to tether COPI vesicles to Golgi membranes. At the cis-side of the Golgi, the Rab1 GTPase binds directly to each of three coiled-coil proteins: p115, GM130, and as now shown, Giantin. Rab1 binds to a coiled-coil region within the tail domain of p115 and this binding is inhibited by the C-terminal, acidic domain of p115. Furthermore, GM130 and Giantin bind to the acidic domain of p115 and stimulate p115 binding to Rab1, suggesting that p115 binding to Rab1 is regulated. Regulation of this interaction by proteins such as GM130 and Giantin may control the membrane recruitment of p115 by Rab1.