To co‐design and test the acceptability of a peer‐led web‐based resource (PLWR) for cancer carers to provide practical and emotional advice on common issues.A six‐step co‐design model informed PLWR development. Content was developed through three cancer carer workshops and monthly meetings with an expert advisory team (n = 12). User‐testing was conducted via web‐based survey and telephone interview. Descriptive statistics and thematic analysis were utilised. Google analytics explored site visits, commonly used components, and time spent using the PLWR.The PLWR was developed to deliver cancer carer information tailored to each stage of the illness trajectory regardless of cancer type, in the form of videoed personal experiences. From November to May 2018, there were 2789 unique visits to the PLWR with 743 returners. The majority of time was spent on the full unclipped peer stories (414 views), and diagnosis‐specific information (159 views), with less time spent on bereavement, cancer treatment, or self‐care (120 views each). Fifty‐five individuals completed the resource evaluation, with 10 participating in telephone interviews. Fifty‐four carers rated the resource as excellent, useful, and easy to use. The web‐based videos were regarded as convenient as and less burdensome than written information. The resource provided relevant information, potentially reducing isolation and uncertainty.The content and design of the PLWR appear acceptable to cancer carers. The co‐design model is an effective way to develop appropriate information for service users and could be utilised as a framework for development of other interventions in a variety of disease groups. The acceptability of the resource was determined through user testing, examining carer's experiences of using the PLWR, and their ratings of the various components.2The project was conducted in two phases: (1) a four‐step co‐design model to inform the development of the resource and (2) user testing evaluating resource acceptability see . Develop2.1Early PLWR development was underpinned by a number of studies and a systematic literature review conducted by the authors identifying unmet needs in cancer carers.2.1.1To develop the PLWR content, cancer carers were asked to commit to three consecutive workshops at the regional cancer centre, the largest cancer unit in the region serving both urban and rural localities. Cancer carers who volunteered to participate in the workshop cared for patients of varying cancer sites and stages (n = 8). Carers were recruited via an email invite to the regional Northern Ireland Research Consumer Forum. This group includes carers and patients affected by cancer and ensures that the user voice informs research development. Each workshop was facilitated by OS and GP, recorded, transcribed, and thematically analysed see . ThroughFollowing workshops, PLWR development was supported via six quarterly meetings with an expert advisory team. Advisory team meetings were facilitated and recorded by OS and TMcS. The expert team consisted of carers, academics, a men's health expert, cancer charity representatives, and health care professionals (nursing and medicine) (n = 12) who were purposely selected to represent a wide range of expertise. Advisory group discussions focused on refining written content, design, tone, graphics, and usability see . Those tDifferent to those carers who volunteered in the workshop, we also recruited cancer carers to design and develop peer‐led information videos for inclusion in the PLWR. Recruitment of volunteers was conducted via an email distribution to cancer voluntary agencies in the region (n = 20). These charities provide support and advocacy in urban and rural locations for families affected by cancer. Fifteen carers, who cared for a range of cancer patients currently or in the past, volunteered to allow their final interviews to be included in the PLWR. Some carers did not provide consent, and therefore this video material was removed. These 15 carers, guided by the project team, were interviewed by a film director regarding their experiences of caring across the illness journey.Six cancer‐related professionals  also contributed videoed advice and tips for coping in the caring role.2.1.2Information gathered in step 1 was combined and used to develop draft content and PLWR structure. Videos were clipped and themed for inclusion in various sections that mapped the cancer journey, eg, “diagnosis,” “treatment,” and “bereavement.” These trajectory markers were directed by earlier workshop consultations. Development of the PLWR prototype was supported by a film production company and expert web‐designers.2.1.3An unstructured feedback session with six cancer carers who participated in earlier workshops was conducted at the regional cancer centre to gather early views and experiences of users' interactions with the resource. A demonstration of the full PLWR was given. Following the demonstration, cancer carers were encouraged to provide their thoughts on the website and provide suggested changes. These discussions were recorded and themed.2.1.4Changes were made to the resource based on this iterative development. Following agreement with advisory group, these included changes in content, music, and titles of PLWR components .2.22.2.1A different group of carers were recruited to evaluate the PLWR. A multiple‐methods design combining a web‐based survey with an optional semi‐structured telephone interview was used. The survey and interview questions were designed by the advisory team based on earlier research.Self‐identified cancer carers were given a personal 5‐minute, one‐to‐one demonstration of the PLWR on an iPad by OS and TMcS in the outpatient clinics. Carers were given a promotional bookmark and pen with the website details and asked to review the entire PLWR at home including all videos and written material. Carers who accessed the website were requested to complete the web‐based survey including a demographic questionnaire  and Likert style survey containing 11 items focusing on content, graphics, videos, relevance, and overall look see . RespondCompleted surveys were downloaded to SPSS version 22Carers were offered via a link on the PLWR an optional telephone semi‐structured interview with TMcS. This interview focused on the experiences of using the website, usefulness, and ideas for change. Interviews and open‐ended responses were conducted until the point of data saturation.2.2.2Carer responses in step 5 were used to identify need for refinement.33.13.1.1The website was created over a period of 10 months (April 2017 ‐ January 2018). The co‐design process highlighted the need for the PLWR to provide information tailored to specific points of the caring trajectory  with 54% returning twice and 30% making up to 20 visits see . Peer‐leContent focusing on supporting children  and the emotional aspects of caring  were less frequently visited. Of the 2769 visits, 1600 visitors accessed multiple components of the resource with the first point of information accessed mainly “getting through treatment” information, “caring for you,” and “financial employment” information before accessing other components.The most common referral pathway for visitors to the site was Facebook , Google , and direct (from the link provided) . The majority of visitors accessed the website via a mobile device .Of the 55 who completed the evaluation, 54 rated all features as excellent or good, with only one carer rating the relevance of the website as poor. Cancer carers reported being highly satisfied with the resource and viewed it as useful and relevant.Thematic analysis of the 54 open‐ended responses and 10 telephone interviews identified four key themes: meeting information needs; peer delivery of information; web‐based delivery of information; and negative experience of the resource.Carers perceived the website as a valuable resource due to the current lack of tailored information available. They noted that they often felt ignored within the health care system and that this resource helped to reduce this feeling of isolation. Carers expressed that prior to accessing the website they felt ill‐prepared for caring and that HCP time was focused on preparing patients. They reported that the website offered the necessary information needs that in turn reduced stress.‘[I am] very impressed overall. Excellent website, as it focuses entirely on the needs of a carer of someone with cancer. It's important to get the word out there about its existence’ .One caregiver summed up their positive reflections on the website:Hearing others report similar emotions and experiences in peer‐led videos was reported to reduce feelings of helplessness and uncertainty surrounding the caregiving role. Carers reported that they found the experiences of peers motivating and inspiring. The use of peer‐led videos was particularly helpful in providing emotional and practical support as the carers felt that the tips and techniques could easily be implemented in day to day life.‘Sometimes I feel so alone and confused. I feel helpless. It really helped hearing that I'm not alone and that other people feel the same’ .The use of real life experiences was described by several carers as desolating and reassuring which in turn helped carers to feel less alone.Carers reported that absorbing information in written form whilst caring for someone who has cancer as very challenging due to limited personal time and high emotions which can make it difficult to concentrate to read. Providing videoed information was viewed as convenient as and less burdensome than reading. Carers reported that the web‐based format allowed them to receive tips and advice in a fast and convenient way. This was viewed to be beneficial, particularly those who lived in rural areas.Carers reported that the website was easy to use due to the clear layout and straightforward access to relevant information.‘[I liked the] easy access to information … It was set out in sections that allows everyone to reference depending on their caring situation’ .The themed sections also appealed to carers, providing ease of access to specific supports without the need to read irrelevant material.Three people reported negative experiences of using the website. One person stated they found that listening to other people's experiences lowered their mood. Two reported that they felt the resource did not represent male carers or families with younger children.“Maybe a way to post questions and chat with other people who have a loved one with cancer so that we can support each other” .They reported that the website would benefit from an interactive function to facilitate and moderate questions, answers, debates, and general communication. Carers expressed that having the opportunity to interact directly with other carers would provide an additional layer of support.4The international cancer carer literature recognises the need to support carers, but few interventions have been rigorously developed and evaluated.Google analytics demonstrated that demand for the resource was good with 2800 visits within 6 months and 750 repeat visits, of these repeat visitors 70% visited the site multiple times. Set in the context of 9000 new cancer cases per year in Northern Ireland,In terms of content, site visitors made significantly more visits to the peer‐led aspects compared with the professional‐led content. However, when accessed, HCP content was viewed for prolonged periods (approx. 4 minutes). Despite a higher number of visits to the peer‐led components, finance and employment information was the most commonly first viewed component, followed by the themed carer stories of “treatment” and “caring for you” information, suggesting these as a potential support priority for carers. This supports earlier studies which suggest that finance is often an unmet need for caregivers.Carers reported that the resource provided information which helped to normalise emotions and what to expect in the caring role. This social comparison allowed carers to receive information and affiliation with those carers who had survived the experience thus gaining confidence.Carers reported strong acceptability for peer‐led videos reporting that the PLWR reduced isolation, provided emotional support, and reduced uncertainty. This is reflective of the peer‐led literature which demonstrates that participants are highly accepting of peer support, reporting high levels of satisfaction, shared experience, and empathic understanding.4.1Fifty‐five carers participated in user testing of the resource which is a small proportion of the visitors to the site. Potentially carers that viewed the resource negatively were less likely to participate in the evaluation, with responders feeling obliged to comment in a socially desirable way. To overcome this limitation, future studies should consider a purposive sample where carers are asked to instantly discuss their views to someone outside the research team using a think aloud technique.4.2Ongoing evaluation is necessary in order to provide definitive evidence whether the PLWR provides benefits for cancer carers. The PLWR will continue to be implemented regionally with ongoing evaluation. Given the relatively small cost associated with developing the website (£25 000) set against the number of carers who can access the resource, and limited costs associated with updating, the PLWR has the potential to demonstrate positive outcomes for carers in a cost‐effective way.An e‐platform promotes sustainability and future‐proofing. However, one of the main challenges facing web‐based resources is the ongoing responsibility and funding required to maintain the PLWR. The co‐design approach in development has ensured agreement between the voluntary and statutory sector to make available a link to the resource at a regional level.The co‐design process was complex resulting in a series of iterative changes and improvements; future research should measure the impact and outcomes associated with co‐design.The PLWR could easily be implemented into routine clinical practice across numerous countries. Furthermore, the intervention model may be relevant to develop and test with carers of other conditions. Currently, the CCC is being adapted for use in Vietnam, and we have plans to continue to make culturally specific adaptions to meet the needs of cancer carers internationally. In addition, the six‐step co‐design model developed by the team is an effective way to develop appropriate information for service users and could be utilised as a framework for development of other interventions in a variety of disease groups.5Through the process of co‐design, we developed a web‐based resource targeted to cancer carers. We demonstrated the PLWR appears acceptable to carers. Ongoing research is required to test the effectiveness of the resource on caregiver outcomes. There is the potential to extend CCC beyond the regional resource, and progress is already being made towards an internationally relevant web‐based resource for cancer carers. The co‐design model should be used in future service user intervention development to ensure appropriate, relevant content that is accessible by all stakeholders.None.Reviewed by Queen's University Governance Procedures and Belfast Health and Social Care Trust. Full Ethical approval was not required as project was categorised as Public and Patient Involvement and Service Evaluation.Data S1. Supporting InformationClick here for additional data file.


Molluscs are extremely diverse invertebrate animals with a rich fossil record, highly divergent life cycles, and considerable economical and ecological importance. Key representatives include worm‐like aplacophorans, armoured groups  and the highly complex cephalopods. Molluscan origins and evolution of their different phenotypes have largely remained unresolved, but significant progress has been made over recent years. Phylogenomic studies revealed a dichotomy of the phylum, resulting in Aculifera (shell‐less aplacophorans and multi‐shelled polyplacophorans) and Conchifera . This challenged traditional hypotheses that proposed that molluscs gradually evolved complex phenotypes from simple, worm‐like animals, a view that is corroborated by developmental studies that showed that aplacophorans are secondarily simplified. Gene expression data indicate that key regulators involved in anterior–posterior patterning (the homeobox‐containing Hox genes) lost this function and were co‐opted into the evolution of taxon‐specific novelties in conchiferans. While the bone morphogenetic protein (BMP)/decapentaplegic (Dpp) signalling pathway, that mediates dorso‐ventral axis formation, and molecular components that establish chirality appear to be more conserved between molluscs and other metazoans, variations from the common scheme occur within molluscan sublineages. The deviation of various molluscs from developmental pathways that otherwise appear widely conserved among metazoans provides novel hypotheses on molluscan evolution that can be tested with genome editing tools such as the CRISPR/Cas9  system. I.et al.,et al.,a,Having conquered almost all terrestrial and aquatic habitats on Earth, molluscs are among the best‐known animals on the planet. The exploitation of some representatives as sources of food  or jewellery (e.g. pearls) and, more recently, for biomedical applications [e.g. toxins from cone snails in the treatment of neural diseases such as epilepsy, Parkinson's, Alzheimer's or pain management  and not a polyplacophoran‐like LCAM, most likely with serially arranged dorso‐ventral musculature and an unsegmented body, two features that are also commonly assigned to Kimberella   and is still expressed during ontogeny of recent polyplacophorans and aplacophorans, where seven dorso‐ventral muscle units form first  Fig. . This seKimberella is an early stem‐line mollusc and whether or not other debated fossils such as Acaenoplax, Wiwaxia, Halkieria, or the newly described Calvapilosa belong to the molluscan stem, are members of later‐branching molluscan sublineages, or do not constitute molluscs at all  gene functions at various taxonomic levels. In the following, the major recent advances in molluscan phylogenetics and developmental biology are outlined and interpreted in an integrated evolutionary framework. In addition, remaining key questions and hypotheses are pointed out that can now be addressed with the aid of state‐of‐the‐art technologies.The recent progress in molluscan phylogenetics is supplemented by numerous comparative developmental studies at the morphological, cellular, and molecular levels that have provided significant insights into lineage‐specific evolutionary pathways concerning body plan formation, the emergence of morphological novelties, and conserved II.Molluscan interrelationships have been contentious for a long time. In the pre‐genomic era, cladistic analyses based on morphological data sets largely agreed on a phylogenetic scenario that placed the aplacophoran taxa (Neomeniomorpha and Chaetodermomorpha) as the earliest extant offshoots, either with a monophyletic Aplacophora as sister to the remaining molluscs (Testaria), of which Polyplacophora was considered the sister clade to all primarily single‐shelled forms (Conchifera) Waller, , or withAt that time, morphological data had largely been restricted to adult life‐cycle stages for most of the crucial class‐level taxa. Solid ontogenetic (morphogenetic) data for both aplacophoran taxa, the polyplacophorans, the scaphopods, as well as the basally branching bivalve and gastropod lineages were virtually non‐existent (a)et al.,via trochophore‐ and veliger‐type larvae . This is the type of shell that derives from a dorsal shell field that forms by invagination and subsequent evagination of ectodermal cells  et al.,et al.,et al.,Together with the recent advances in molluscan phylogeny including the revived Aculifera–Conchifera concept, a wide array of novel data on molluscan genomics and comparative development (EvoDevo) have become available, providing an important window into evolutionary pathways and common ground patterns of various lineages. Accordingly, it was shown that during ontogeny, neomeniomorph aplacophorans recruit their body wall muscles from a complex arrangement of larval muscular subsets that are gradually incorporated into the adult tube‐like body , have been described. Taken together, these data show that the last common aculiferan ancestor had an overall polyplacophoran‐like morphology with a suite of highly complex muscle systems and a series of seven dorso‐ventral muscles, most likely accompanied by seven shell plates  retained this sevenfold arrangement of shell plates (multiplied in rows 2–6 in multiplacophorans), while extant polyplacophorans acquired an eighth plate secondarily and recent aplacophorans lost their shell plates altogether Haliotis discus hannai   et al.,Gibbula varia  for which the full set of the 11 molluscan Hox genes was investigated . Instead of being confined to domains along the anterior–posterior axis, Gibbula Hox genes are expressed highly structure‐specific and were found in cells of the larval apical organ, the foot, the shell field, and the prototroch , and two deep‐sea mussels, showed a disorganized arrangement of the Hox genes  in this stage, and quantitative analyses revealed staggered temporal expression of individual Hox genes within four  Patinopecten yessoensis subclusters  follow the gastropod–cephalopod pathway of organ‐specific Hox gene expression.As with Taken together, molluscs, and in particular the conchiferans, appear to show a complex interplay employing multiple changes in genomic architecture and gene functions that most likely contributed to the evolution of lineage‐specific morphological novelties. The expected release of additional genomes in the near future will provide an important resource to test which of these molecular mechanisms have contributed to the various apomorphic features of individual molluscan subtaxa.(b)et al.,Dpp (the invertebrate homolog of the vertebrate Bmp2/4) is largely expressed dorsally in protostome animals, while its antagonists such as Chordin or Noggin have a predominantly ventral expression domain , that subsequently migrate into the cell nucleus where they activate downstream target genes  involved in establishing neural and dorso‐ventral identity remained elusive. To this end, a recent experimental study on the model gastropod Ilyanassa obsoleta revealed that Dpp is intensely expressed on the dorsal side and co‐localized with phosphorylated SMADs, indicating that BMP‐signalling is functional on the dorsal side  and novel (induction of neuroectoderm formation) functions. Since no further data are available for other molluscan taxa, it is currently impossible to assess the broader implications of these findings for molluscan body plan evolution. However, the study demonstrates that, similar to the Hox genes, the Dpp/BMP pathway seems to exhibit a certain degree of plasticity within Mollusca.Bilaterian animals are not only characterized by a distinct anterior–posterior axis but also by defined dorsal and ventral body regions. The underlying regulatory network that commonly determines dorso‐ventral polarity is the Dpp/BMP signalling pathway et al.,Biomphalaria glabrata (ram's horn snail) and Lymnaea stagnalis (pond snail), that both have sinistrally and dextrally coiling individuals, revealed that handedness is maternally inherited  and Crepidula fornicata , where mRNAs are asymmetrically distributed already at early cleavage stages  was accompanied by reversed Nodal/Pitx expression. The resulting fertile females maintained the externally imposed chirality but in turn produced offspring with the genetically determined handedness and not the one forced upon their mothers , and an anteriorly positioned mantle cavity  system in molluscs  have retained a conserved, staggered Hox gene expression motif along the anterior–posterior body axis, while gastropods and cephalopods appear to deviate from this pattern and instead show Hox transcripts in lineage‐specific structures, suggesting that these key developmental regulators were recruited into the evolution of conchiferan morphological novelties.The plasticity of molluscan developmental gene expression is further demonstrated by components of other axial‐patterning pathways such as the Dpp/BMP and the Nodal signalling cascades that likewise show considerable differences between molluscan subtaxa. Joining forces in a holistic framework where organismal knowledge is combined with large‐scale sequencing efforts and MorphoEvoDevo approaches will undoubtedly uncover many of the stories yet deeply hidden in molluscan evolutionary history.


In the UK, upon completion of undergraduate medical training, doctors enter postgraduate training in a generic 2‐year programme called the Foundation Programme (FP). In the FP, trainees typically rotate through six 4‐month clinical placements. Five placements normally occur in the secondary care environment and one in a primary care setting, commonly in general practice (GP). Trainees rotate (change venues) frequently, have short times to accommodate to the dynamic work environments, and experience difficulties in building rich relationships with patients, supervisors and the caring team. Trainees also find it challenging to access support. For some trainees, the timing of their GP placement comes after they have had to make choices around specialty training. Others find the experience insufficient to enable them to make an informed career choice.In August 2016 the North West of England Foundation School (NWoEFS) began its pilot of Longitudinal Integrated Foundation Training (LIFT), based upon the success of Harvard Medical School's Cambridge Integrated Clerkship. The LIFT initiative aims to animate the best of an apprenticeship model. This programme provides more exposure to primary care over the 2‐year period. It was designed to address the contextual difficulties found in traditional rotations, to enhance trainees’ transferable clinical and communication skills and to foster trainees’ understanding of the National Health Service. Trainees spend 1.5 days each week within the same GP setting for the 2 years. During the remaining 3.5 days, they rotate every 4 months around hospital specialties as per traditional FP training. Under this longitudinal model, the GP placement provides educational continuity.To date, 47 trainees and their supervisors have engaged in LIFT through a full 2‐year FP training cycle. Researchers at NWoEFS are evaluating LIFT through interviews, focus group discussions and online surveys. Trainees and supervisors alike have required information and support to adapt to the scheme. Coordinating the rota has facilitated concurrent working across primary and secondary care. The leaders have identified and worked to address logistical and financial needs, especially around backfill of ‘lost’ hospital time and supply of GP supervisors.We have analysed trainees’ and supervisors’ perspectives. As the pilot nears its conclusion, many supervisors have expressed the hope that LIFT continues. Supervisors feel that the programme overcame challenges experienced during the initial phase  and that it has numerous advantages. Supervisors consider LIFT trainees to often have greater clinical knowledge, independent decision‐making skills, greater patient‐centredness and improved ability to take a holistic approach to patients and their care in comparison with their non‐LIFT counterparts. Supervisors have built strong and effective relationships with trainees, offer better pastoral as well as educational support, and over time have built sufficient connections with trainees to be able to offer increased challenge to them. Trainees who have participated in LIFT have demonstrated that although initially they felt less experienced in secondary care than peers working a 5‐day hospital week, as anticipated by supervisors, they have become aligned with non‐LIFT trainees or even surpassed them. The pilot has generated practical lessons for future education and care delivery.


Mycobacterium tuberculosis, including multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains, in human populations, threatens tuberculosis control worldwide. Differently from many other bacteria, M. tuberculosis drug resistance is acquired mainly through mutations in specific drug resistance‐associated genes. The panel of mutations is highly diverse, but depends on the affected gene and M. tuberculosis genetic background. The variety of genetic profiles observed in drug‐resistant clinical isolates underlines different evolutionary trajectories towards multiple drug resistance, although some mutation patterns are prominent. This review discusses the intrinsic processes that may influence drug resistance evolution in M. tuberculosis, such as mutation rate, drug resistance‐associated mutations, fitness cost, compensatory mutations and epistasis. This knowledge should help to better predict the risk of emergence of highly resistant M. tuberculosis strains and to develop new tools and strategies to limit the development and spread of MDR and XDR strains.At present, the successful transmission of drug‐resistant  In 2015, TB affected approximately 10.4 million people and killed 1.8 million of them , an infectious airborne disease mainly caused by hem WHO, . The curhem WHO, . This efhem WHO, . The reghem WHO, . Indeed,hem WHO, . The trehem WHO, .BOX 11Acquired resistance: the ability of a bacterial population to resist the activity of a particular drug to which it was previously susceptible.Biological fitness: the capability of an individual with a certain genotype to reproduce and survive in a competitive environment.Clonal interference: competition between lineages (“clones”) arising from different beneficial mutations to reach the fixation in asexual organisms.Compensatory mutation: a second‐site mutation acquired that arises after the acquisition of resistance mutation and that lessens or alleviates the fitness cost associated with the acquisition of the resistance‐associated mutation.Cross‐resistance: the acquisition by a microbe of resistance to one drug through direct exposure and the gain, in parallel, of resistance to one or more other drugs to which it has not been exposed.Epistasis: a form of interaction between genes or mutations that influences a phenotype. Epistasis occurs when the combined fitness effect of multiple alleles from same locus or different loci is different from the sum of the individual allele effects.Extensively drug resistance (XDR): MDR (see below) Mycobacterium tuberculosis also resistant to at least one of the three‐second‐line injectable drugs  and one fluoroquinolone .Fitness cost of resistance mutation: a decrease in the relative fitness of the drug‐resistant mutants in comparison with their drug‐susceptible counterparts.Genetic drift: random changes in the frequency of alleles over time usually in small populations.Innate resistance: the innate ability of a bacterial species to resist activity of a particular drug.Linkage disequilibrium: the nonrandom association of alleles at different loci.Multidrug resistance (MDR): Mycobacterium tuberculosis resistant at least to isoniazid and rifampicin, the two more potent fist‐line drugs.Mutation rate: the number of mutations per nucleotide site (bp) per generation. It is worth noting that in the case of antibiotic resistance, the mutation rate is frequently defined as the rate of resistance acquisition (see below).Negative epistasis: if the cost of double mutant in the absence of antimicrobial use is higher than the total cost of each resistance determinant on its own.Parallel evolution: evolution of a similar trait in closely related, independently evolving lineages.Positive epistasis: if the cost of double mutant in the absence of antimicrobial use is smaller than the total cost of each resistance determinant on its own.Purifying selection: selection reducing the frequency of deleterious alleles in a population.Rate of resistance acquisition: the in vitro frequency at which detectable mutants arise in a bacterial population in the presence of a given antibiotic concentration.Mycobacterium tuberculosis is a highly clonal bacteria (absence of recombination) with an extremely conserved genome and a long history of co‐evolution with humans    to 10−25 mutants per population . Furthermore, clinical data estimated that the population size in active pulmonary disease ranges between 107 and 1010 bacilli  than in lineage 4 (Euro‐American). In addition, the authors also demonstrated that the risk of de novo MDR acquisition before treatment is higher (approximately 22‐fold) in macaques infected with M. tuberculosis strains of lineage 2 than in animals infected with lineage 4 strains. These data are consistent with the high drug resistance potential of lineage 2 observed in many epidemiological studies  and the quality of TB control programmes also strongly influence the speed of drug resistance spread , but more than 80% of rifampicin‐resistant isolates display mutations in three codons rpoB531, 526 and 516   Beijing strains than in ancient  ones , are more frequently found in clinical drug‐resistant isolates , such as frame‐shift nucleotide deletions or insertions, are found less frequently in clinical than in in vitro mutants , China  and Korea   mutations in the rpoB gene . This model generates a strong linkage disequilibrium that may favour the coexistence of two or more particular drug resistance‐associated alleles.The high diversity of mutations in 7.2M. tuberculosis, a finding suggests that it could play an important role in the emergence and evolution of MDR and XDR M. tuberculosis strains . Borrell et al. (M. smegmatis as model organism. The authors demonstrated that 35% (6/17) of double mutants carrying specific rpoB and gyrA mutations associated with rifampicin and fluoroquinolone resistance have a significant higher fitness than the corresponding single drug‐resistant mutants. In particular, the gyrA N94G mutation was associated with improved fitness in all double mutants, irrespectively of the rpoB mutation. In an interesting manner, the mutation combinations obtained in vitro in M. smegmatis correspond to the most common mutations detected among MDR and XDR clinical isolates in high MDR TB burden countries  clinical rifampicin‐resistant mutants carry putative compensatory mutations in either rpoA or rpoC genes support the hypothesis that these two mutation types interact also in M. tuberculosis  is favoured in clinical MDR isolates, suggesting that these genotypes lead to primary MDR infections. In an important way, the emergence of XDR TB seems to be caused by the transmission of XDR strains directly from person to person rather than by inadequate MDR treatment , intrinsic factors, such as compensatory mechanisms, reduced fitness cost, clonal interference, mutation rate and epistasis, also promote the emergence of MDR and XDR strains worldwide.The most frequent drug resistance mutations in clinical isolates worldwide are often associated with high levels of resistance and low/no fitness costs, or combined with compensatory mutations to restore the bacterial fitness. This strongly suggests that epistatic interactions influence the evolution of drug resistance in In an important way, the Beijing lineage is rapidly spreading worldwide. This lineage is associated with MDR TB as well as with high level of drug resistance and fitness‐compensatory mutations (Casali et al., M. tuberculosis. More work is needed to increase our knowledge on all the forces that drive drug resistance in M. tuberculosis for better controlling the emergence and rapid spread of highly drug‐resistant strains. As suggested by the levels of drug resistance reached globally, we are losing the arms race against bacteria including M. tuberculosis (Bañuls et al., M. tuberculosis, as many pathogens, has a complex ecology and evolution and is also evolving and fluctuating through time and space according to local contexts (Bañuls et al., It is unfortunate that, some drug resistance mechanisms remain unclear and many mechanisms of fitness‐compensatory evolution and epistasis have not been investigated in None declared.


In the pool of nanostructured materials, silicon nanostructures are known as conventionally used building blocks of commercially available electronic devices. Their application areas span from miniaturized elements of devices and circuits to ultrasensitive biosensors for diagnostics. In this Review, the current trends in the developments of silicon nanowire‐based devices are summarized, and their functionalities, novel architectures, and applications are discussed from the point of view of analog electronics, arisen from the ability of (bio)chemical gating of the carrier channel. Hybrid nanowire‐based devices are introduced and described as systems decorated by, e.g., organic complexes , aimed to substantially extend their functionality, compared to traditional systems. Their functional diversity is explored considering their architecture as well as areas of their applications, outlining several groups of devices that benefit from the coatings. The first group is the biosensors that are able to represent label‐free assays thanks to the attached biological receptors. The second group is represented by devices for optoelectronics that acquire higher optical sensitivity or efficiency due to the specific photosensitive decoration of the nanowires. Finally, the so‐called new bioinspired neuromorphic devices are shown, which are aimed to mimic the functions of the biological cells, e.g., neurons and synapses. Namely, the change of the concentration of electrical charges in the microenvironment , in a close proximity to the transducer, makes an enormous contribution to the modulation of channel conductivity.Advances in micro‐ and nanofabrication technologies have dramatically improved the quality and performance of the electronic devices, while reducing costs and overall dimensions. One of the prominent examples is the transistor that has faced a scalability evolution like no other element of the circuits: from the first demonstrated macroscale point‐contact germanium transistor in 1948 at Bell LaboratoriesFigureFigureApart from active participation in the progression of the new‐generation bio‐ and chemical sensors, the nanoscale elements also play a crucial role in the development of opto‐ and biomimetic electronics (see x) that is typically formed in the ambient conditions is of outmost importance to insulate the semiconductor channel, while enabling the field effect and keeping a good gate potential coupling. In parallel to the silicon oxide, researchers have also been studying the possibility of deposition of high‐k dielectric layers preventing the current leakage at ultra‐nanoscales, and improved response in terms of surface potential change,x offers the chemistry possibilities for easy integration of biological receptors and more specific detection. Their potential biocompatibility is a plus for biomedical applications and biological investigations.During the last decade 1D nanostructures, and in particular semiconductor silicon nanowires (SiNWs), have attracted attention as highly efficient elements of transistor elements due to their high level of complementary metal‐oxide semiconductor (CMOS) compatibility,In a classical metal–oxide–semiconductor field‐effect transistor (MOSFET), the gate terminal is in direct contact with a thin dielectric layer that surrounds the semiconductor channel. When evolving from the original transistor structure, an ion‐sensitive field‐effect transistor (ISFET) operates in a liquid environment in which the gate electrode is replaced by the charged ionic content of a liquid solution in contact with the dielectric layer, and a relative reference point of a potential difference through the liquid defined by a reference electrode.−12m. Only 3 and 4 years later, they could demonstrate large arrays of individually addressable sensors for multiplexed detection of single virusesThe integration of the nanowires into the sensors made a great impact on ISFET technology. Ion‐sensitive potentiometric devices were revolutionizedDefinitely, silicon has been attractive also as a photodetecting material due to the convenient integrability with CMOS technology.In the following, we focus on exploring the functional diversity of nanowire‐based devices considering their architecture as well as areas of their applications. To do so, we start from the assumption that a SiNW‐based electronic device, decorated by, e.g., organic complexes , is generally a hybrid device. Thus, hybrid devices possess substantially extended functionality, compared to the conventional device, e.g., transistor, resistor, or diodes2We start with the fabrication methodologies giving as a result a variety of SiNW and multiple electronic device types containing them. Such devices are used for a broad range of applications which are summarized below.4 is done via a vapor–liquid–solid (VLS) mechanism using metallic nucleation catalysts like gold nanoparticles,Figure3H8)The SiNWs used for most of the aforementioned applications are fabricated following different sets of approaches that one can divide into two categories: bottom‐up and top‐downFor further integration into devices and circuits, the fabricated nanowires need to be transported to the receiver support, where the chip can be finally fabricated with several individually addressable devices  is also an important factor to be considered during fabrication. A common and simple approach is to grow a silicon dioxide layer by thermal oxidation, which shows low interface trap densities.3Nanowire‐based potentiometric (bio)sensors represent one of the largest groups in the family of the hybrid devices sensors. The research community in the FETs field has worked for the last years to enhance the sensitivity following different strategies in the design and fabrication of the FETs as well as in the chemical modification of the surface.3.1Vsurface is the surface potential, Vliquid is the liquid potential (determined by the reference electrode), α is the relative surface sensitivity with a Nernst limit of α ≤ 1 and 59.5 mV/pH, and pI is the isoelectric point of the surface.The simplest measurement of ionic composition in a liquid environment can be performed using an FET is pH measurement, due to the high mobility of the protons compared to the other charged species. pH sensitivity is also a parameter used as a benchmark to assess the FET quality. When measuring pH, in an ideal situation and at room temperature, and according to the Nernst equation that governs the processes taking place, the theoretical maximum shift is limited to 59.2 mV/pH.2 sintering process to increase the number of surface‐binding sites,k oxide layers like HfO2 and Al2O3,Unlike to the theoretical maximum given by Nernst limit, surface imperfections  give, as a result, a usual value of around 30 mV/pH.FigureAlthough a simple pH measurement might not have much interest by itself, there is a number of reasons for which it is interesting to perform it. First, this can be a method to evaluate the quality of the FET. Second, there are countless (bio)chemical and biological reactions that have a pH change as a result, such as microbiological metabolic activity,When the length of SiNWs is shortened to below 25 nm, the density of charged surface sites is extremely reduced, making the FET relatively inert to pH changes.In contact with complex biological fluids, the biosensor response can be deteriorated through time due to attachment of proteins, cellular debris or cells, namely biofouling.3.2Figure−3m), since the protonation/deprotonation processes occurred in the HPTS below the 0.7 nm Debye length. Ibarlucea et al.Escherichia coli bacteria as model organism growing in microbiologically relevant media  utilizing honeycomb shape SiNW‐FETs patterned by electron beam lithography with immobilized monoclonal antibodies, one order of magnitude below the suggested threshold limit. Tran et al.Figure4F wet etching, with the size comparable to that of an antibody. They used this trench to immobilize by photochemical hydrosilylation of an antibody against the H1N1 Avian Influenza Virus (AIV), while passivating the rest of the surface with the nonreacting octadecyltrichlorosilane (OTS). By integration with a microfluidic channel, they could demonstrate the binding of single H1N1 Hemagglutinin antigens , respectively, modulating the FET conductivity. Kim et al.s Figure b. Regardm Figure c.The downside of using antibodies or large DNA sequences is their size as mentioned in Figure 3.4l‐lysine (PLL) layer over the negatively charged surface of the high‐k hafnium oxide used as the top oxide layer  solution, while the buffer had to be more than ten times diluted in order to observe a signal change when no PEG was present. Then, at 100 × 10−3m PB, a clear sensing response was observed between 10 × 10−6 and 1000 × 10−6m. Although the detection was not specific due to absence of bioreceptor, this was later accomplished−6m, with regeneration possibility by a separation of the analyte using guanidinium chloride.A more general methodology was described by Gao et al. to efficiently increase the Debye length, useful to perform detection in high ionic strength solutions regardless of the bioreceptor used. It involved the modification of the surface with a porous and biomolecule permeable polymer Figure b. More s3.5FigureAn alternative to the classic receptors like DNA or antibodies is the use of smaller receptors Figure10 to h2+ or Na2+ are used to screen those charges and improve the hybridization yield, which would be counterproductive with an FET measurement. The ssDNA can be substituted for a peptide nucleic acid (PNA),−15m to distinguish the ΔF508 mutation site in the cystic fibrosis transmembrane receptor (CFTR) gene from the wild type.For the specific case of DNA detection, there is an added disadvantage coming from the traditional use of ssDNA as bioreceptor. It consists on the repulsive forces due to the negative charges in the phosphate groups of the molecule backbone. Usually high ionic buffers or divalent cations such as Mg−6m concentration of cardiac troponin T (cTnT) in every ionic strength that they compared, up to 1× PBS (around 150 × 10−3m ionic strength). Then, by using the F(ab′)2 fragment (both recognition sites bound with the Fc portion digested), they could demonstrate real‐time picomolar–nanomolar detection in undiluted desalted serum. The influence of the receptor density was also analyzed by comparing different incubation times for the used linker, glutaraldehyde. A moderate value was preferable, allowing us to have an appropriate number of receptors with enough flexibility, to adopt conformations closer to the nanowire surface.Instead, if the receptor is an antibody, it can be fragmented into smaller parts. Elnathan et al.2+.TableOther lesser‐known small molecules can present a good affinity toward some concrete analytes. It has been possible to exploit the known intermolecular interactions to apply them in the detection of prion proteins using thiamine,3.6FigureHaving mentioned that the reason of sensitivity loss in high ionic strength samples comes from the screening of the signal by excess of nontarget ions in the solution, it seems an obvious strategy trying to get rid of those ions. The common procedure for this is to dilute the sample. If one carries this to the limit, the way to get rid of all ions is simply removing the liquid from the nanowire surface. Some works have already demonstrated that it is possible to measure highly sensitive detection of charged molecules in air. Choi et al.−3m ionic strength buffer could be sensed. Later, Laborde et al.d‐lysine layer covalently attached to the silanized surface. It is well known that cells attach and flatten on surface coated with the polymer due to the difference between the polycationic polymer and the polyanionic cell membrane.In the works published by Carrara's group, the binding of molecules at such low concentrations was also confirmed by impedance measurements under alternating current (AC) excitation, which demonstrates that impedance measurements using FETs are valid for ultrasensitive detection.Although without particular improvement toward the measurement in high ionic strength, a new biomolecule quantification method was recently demonstrated based on the hysteretic behavior of the transfer curvesTableAn overview of the detection capabilities of alternative measuring modes is shown in 3.7FigureThe rapid demographic changes with increasing growth of the population and limiting resources require improving the biomedical technologies toward cost–effectiveness, compactness and modularity, and higher throughput. The operation of portable and compact devices by ordinary people opens existing possibilities allowing easy, fast, and cost‐efficient implementation of different application‐specific (bio)chemical processes in order to conduct on‐site testing at home, office, or school. Despite some achievements made in recent years, the combination of all these features in a single portable biosensing system proves to be a difficult task. Considering the miniature size and all the previously described fabrication and chemical modification methods, nanoscale ISFETs packaged in a small chip can be ideal candidates for this, integrated with additional circuits and in lab‐on‐a‐chip setups where further processing steps can be automatized. New approaches for connecting nano‐ to microworld involve higher requirements to system integration approaches as fabrication of dense, reliable, and scalable sensor arrays enabling massive parallelism and high throughput, including readout and front‐end electronic systems. The key features of a modular sensing platform should include compactness of conditional electronics, disposable, and cost‐effective sensor part, user‐friendly software interface, integrated packaging solutions for the measurement in liquid medium, and multiplexing capabilities. The CMOS technology fulfills all these tasks and brings many advantages in integrated chips for biochemical applications Figure12.188,Livi et al. presented a sensor system consisting of top‐down fabricated SiNW FET arrays and CMOS readout.Additional nonelectronic solutions can be added to small‐sized chips, in the form of microfluidic channels, that can manipulate the sample or other reagents. These include from simple channels for delivery and separation of low‐volume samplesA complete system comprising the FETs and all the surrounding structures with various functions are ideal to perform complex tasks such as analyzing complex fluids and their dynamics.4In parallel to the biosensing platforms, SiNWs are attractive building blocks for the integration in optoelectronic devices based on the deep understanding of fabrication processes, as well as in material physics. The structural property of nanowires, e.g., a large aspect ratio, provides the unique advantages to the conventional photonic‐integrated devices, keeping low power consumption. As light‐emitting devices such as light‐emitting diodes (LEDs) or lasers, SiNWs do not represent the best solution, due to their indirect energy bandgap structure, which significantly reduces gain coefficient.In spite of existing various direct bandgap semiconductors like GaAs or InP for photodetection, SiNW is a motivating material based on the matured silicon industry in which the Si‐based CMOS integration process has already been established.In this section, we report and discuss the current status, advances, and future in the area of photodetecting devices including photovoltaics using SiNW.4.1Due to the unique and controversial optoelectronic properties of 1D nanostructures, researchers actively contribute to the better understanding of the optical response of SiNWs and respective device applications.In 2005, photocurrent in an individual SiNW FET was measured by Ahn et al. using optical scanning measurementFigureThe first report of the doping effect in photoconductance of SiNWs was published in 2006.G = I/eF FigureAs shown in the previous studies, the surface (or interface) trap states play a dominant role in optoelectronic properties in nanowire devices which is comparably negligible in bulk Si devices. Figure In addition, Si crystallinity‐related studies have been published during the last years. Shiri et al. investigated the photoinduced carrier dynamics of strained intrinsic SiNW FET with 1.7 nm diameter using Monte Carlo simulations.Taking the well‐known optical properties of SiNWs into consideration, flexible and partially transparent SiNW photodetectors were fabricated on a polyethyleneterephthalate substrate.4.2The traditional photodetector structure is a two‐terminal junction diode. The goal of early studies of NW photodiodes was to overcome low light sensitivity originated from the nanometer scale. In order to amplify the current signal, the avalanche photodiodes were fabricated by making the junction like p–nTo improve the photodetecting performance like FF, researchers have been developing vertical SiNW structures and implementation techniques which have become a popular trend in photodiodes research up to now.4.3SiNW heterostructures have been widely studied to improve the photodetecting performance. The main photoconductive material is SiNW which is supported by cooperating materials such as Au,Graphene is used to widen the detectable spectrum region. An NIR photodetector was fabricated with vertical SiNW arrays that were covered with Au nanoparticles decorated graphene on the top of the vertical NWs.3NH3PbI3)/SiNW core–shell photodetector could detect NIR light.2Si/Pt2SiNW axial heterostructure with the in situ transmission electron microscopy (TEM) observation. Pt/Ni/Si ternary NW heterostructure shows the excellent infrared‐sensing property, which is not shown with the Ni2Si/Pt2SiNW heterostructure. Those inorganic heterostructures show the ability to tune and broaden the detecting spectra of light by coating SiNWs with a plasmonic metal film or nanoparticles, which can overcome the limitation of the bandgap of SiNWs.In addition, metal/semiconductor vertical core–shell photodetectors such as Ag/SiFigureMeanwhile, many groups have developed organic and SiNW hybrid photodetectors to exploit the excellent photosensitive properties of organic molecules as shown in 2 dielectric layer to realize the optical gate literally.The next featured application is a complementary logic gate consisting of n‐ and p‐type SiNW FETs covered with porphyrin.Apart from porphyrin as a bioinspired gate structure, a light‐gated membrane protein residing within a lipid bilayer, of SiNW FETs was demonstratedThe publications about hybrid SiNW photodetectors just started to increase since 2011. The hybrid SiNW devices are promising elements as the next‐generation photodetectors, due to the various functions of combined photosensitive materials and large degree of freedom in material selection. The large surface‐to‐volume ratio of nanowires can maximize the surface charging effect induced from the outer coated material. It is also attractive to device designers who can imagine many varieties in applications with diverse optical‐sensitive materials from small molecules to polymers or plasmonic metals. However, organic‐coupled devices still suffer from the slow switching speed and instability in variable environmental conditions.4.42 emission.PV cells, i.e., solar cells, have been explosively growing over the past decade with urgent requirement to seek the sustainable energy source in accordance with the environmental and commercial requirement for the reduction of COIn 2005, the first SiNW PV application was reported.The PV behavior is improved in junction structures.4.5In addition to the control of doping and geometry of SiNWs, recent studies have stepped toward hybrid SiNW heterojunctions decorated with optically functional materials from plasmonic metal nanoparticles, QDs, to organic materials. The inorganic hybrid materials combining to SiNWs are similar to hybrid photodetectors, but the organic materials tend to be conductive polymers to collect photoinduced electrons.By electrical coupling the auxiliary nanomaterials and SiNWs, one can tune the absorption efficiency of the device. Metal nanoparticles, e.g., Ag nanocrystals, were decorated on core–shell SiNW p–n junctions to exploit the localized surface plasmons.The other branch of the hybrid solar cells is hybrid organic/SiNW heterojunction devices that have shown outstanding properties, such as comparably high PCE among various SiNW‐based solar cells, as well as low‐cost and low‐temperature processing. The most commonly used organic material forming a heterostructure on a  SiNW is poly:poly(styrenesulfonate) (PEDOT:PSS) which is a transparent and conductive polymer playing a key role as hole‐/electron‐transporting/emitter layer. This organic hybrid structure replaces conventional Si‐based p–n junction. Table tert‐butylphenyl)‐1,3,4‐oxadiazol‐5‐yl) benzene (OXD‐7).2) interlayer between SiNW and PEDOT:PSS dramatically increases PCE (14.7%)Figure2 layer helps the PEDOT:PSS flow into space between NWs. Because of the high hole‐tunneling rate through the TiO2, high carrier transport was observed.The effective PV cells reaching near 13% efficiency are including additional organic layers like 1,1‐bis[(di‐4‐tolylamino)phenyl]cyclohexane (TAPC)There are several studies that obtain high efficiency  is to develop the computing machine that would resemble the functions of the brain.p‐phenylene vinylene] (MEH‐PPV) and an ionic conductive layer of RbAg4I5 were stacked on the SiO2 insulting layer. Voltage spikes on the polymer layer transient ionic fluxes and modify nonvolatile ion storage, which provide synaptic plasticity. In 2017, Si nanomembrane transistors gated by chitosan membraneFigureSiNWs represent an excellent building block to form the brain‐inspired devices, e.g., for transistor integration combining with memristive dielectric material, which could be mobile‐ion‐doped oxide or gel structure. Lai et al. provided the initial concept of synaptic transistor using Si MOS transistors.2/Si3N4 gate stackOn the other hand, Hur et al. developed synaptic transistors using Si‐based Fin‐channel with poly‐Si/SiOUp to now, SiNW‐based artificial neurons or synapses are not reported up to our knowledge. However, since the transistor has a striking structural similarity to a neuron,6Nanowires as a part of silicon technology are a promising building block of the devices and circuits with a demonstrated prominent future. Multiple alternative fabrication and configuration strategies can adapt to specific needs, while the standard procedures can result in the development of arrays with thousands of individually addressable devices in a tiny circuit integrated with other functionalities.Major part of the published results on SiNW‐based devices are dedicated to their performance as (bio‐)sensors and are focused on the description of the phenomena/effects, caused by external stimuli  on the channel conductance. As described above, SiNW FETs are already capable of detecting very small concentrations of biomolecules in complex samples following the appropriate techniques, and this can be a strong and convenient advance pushing the biomedical field to reduce the workload of clinics and hospitals. However, in order to reach the aforementioned application phases, nanowire‐based sensorics should grow up beyond the device level and evolve into the system level, where individual sensor elements are embedded into the properly designed conditional electronics network for data collection, filtering, amplification, and further transfer. Complete biomarker panels, mutations, or genetic diseases along the whole genome, infectious diseases, and many other targets can be the objective of a single chip.However, one inevitable hurdle to solve is how to give a different functionality to each of the sensors of such high‐density chip considering the small separation between them. Localized Joule heatingFurther, SiNW photodetectors and their physics have been studied adapting various inorganic or organic material and structural combination.The bioinspired SiNW devices are a comparably new, but extremely fast‐growing, field. For these devices, a hybrid property is fundamental to emulate the biological phenomena based on ion transport. Although there are not many silicon‐based devices available yet, it is anticipated that a variety of applications will be published that take advantage of the electrical characteristics of Si. As the development of recent neuromorphic cells began with the study of emerging memory devices, Si‐based memory that utilizes the trap characteristics will be able to be fused.The major challenges that we need to overcome include i) the instability of some organic materials that are difficult to maintain and persist for a long time, and ii) interface trap states caused by heterostructures which could slow down the overall speed. Therefore, it is necessary to search for new organic or inorganic materials to solve the problems and further attempts to study, or actively use, the physics of interface traps. In this respect, the hybrid device architecture is a hot research topic that opens a broad range of new possibilities that can be added to the spectrum of already demonstrated existing strong technologyThe authors declare no conflict of interest.


An ideal radiosensitizer holding an enhanced tumor retention can play an incredible role in enhancing tumor radiotherapy. Herein, a strategy of acid‐triggered aggregation of small‐sized gold nanoparticles (GNPs) system within tumor is proposed and the resulting GNPs aggregates are applied as a radiosensitizer in vitro and in vivo. The GNPs system with the acid‐triggered aggregation achieves an enhanced GNPs accumulation and retention in cancer cells and tumors in the form of the resulted GNPs aggregates. As a consequence, the radiosensitization effect shows significant improvement in cancer radiotherapy, which is shown in the studies of DNA breakage and the comet assay, and the sensitizer enhancement ratio (SER) value of the GNPs system (1.730) with MCF‐7 cancer cells is much larger than that of the single GNPs (1.16). In vivo antitumor studies reveal that the GNPs system also enhances the sensitivity of MCF‐7 tumor xenograft to radiotherapy. Furthermore, the GNPs aggregates improve the signal of small GNPs in vivo photoacoustic imaging. This study provides a new strategy and insights into fabricating nanoaggregates to magnify the radiosensitive efficiency of nanosystems in cancer radiotherapy. Radiotherapy (RT)In recent years, it has been shown that nanomaterials hold promising prospects in enhanced radiotherapeutic strategies because of their superiorities in biomedical applications.3O4@1 NPs by using an enzyme‐instructed condensation reaction, which hold a specificity for T2 enhanced MR imaging in tumor apoptosis and might be applied to detect the chemotherapeutic efficiency of tumors in routine preclinical studies in near future.On the basis of the excellent tumor penetration and rapid clearance of small‐sized nanomaterials, it is very promising that the ≈30 nm GNPs can be developed as potential radiosensitizers to solve the problem of backflow and random diffusion of the retained GNPs within tumors.SchemeNevertheless, there is still no report of using the acid‐triggered aggregation strategy for enhanced RT of cancer. Herein, we developed a GNPs system based on the acid‐triggered aggregation of ≈30 nm GNPs to serve as a novel radiosensitizer for enhanced RT Scheme1. It c1H NMR results  showed that side chain amino of Lys was successfully modified with DA by the chemical shift change from peak a to peak b.1H NMR result , indicating the occurrence of charge reverse of this compound through the sensitive hydrolysis of dimethylmaleic amide under the mildly acidic environment. Then, GNPs‐A and GNPs‐B was prepared through metal coordination of “Au‐S” between GNPs and peptide A or DA‐grafted peptide B, respectively. Finally, the GNPs system was achieved by the mixture of GNPs‐A and GNPs‐B (1:1). As shown in FigureThe small‐sized GNPs were firstly synthesized by the citrate‐reduction method, and their diameters were about 28.2 nm, which was confirmed by dynamic light scattering (DLS) and transmission electron microscope (TEM) . Subsequently, the purity and identity of these two peptides  we synthesized were confirmed by liquid chromatograph‐mass spectrometer (LC‐MS) . Thirdly, DA was grafted onto the side chain of peptide B through the reaction between carboxyl groups of DA and amino groups of peptide B, and 1000‐SH labeled GNPs system. As shown in Figure S10A in the Supporting information, the fluorescence intensities of individual GNPs‐A or GNPs‐B were very low, showing less GNPs was internalized by MCF‐7 cells. However, the intracellular green fluorescence intensity of GNPs system was significantly increased and made much stronger than that of individual GNPs‐A or GNPs‐B groups, which suggested that the GNPs system aggregated together, triggered by acidic environment of cancer cells, and resulted in stronger fluorescence intensity. Meanwhile, the results of flow cytometry  also showed the similar tendency with above observation. Moreover, this enhanced cellular uptake behavior of GNPs system showed time‐dependent and dose‐dependent manner . In addition, the cellular uptake was also studied by TEM . It could be clearly seen that a lot of GNP aggregations were located in the cytoplasm for GNPs system group, and only indistinct particles were observed for individual GNPs‐A or GNPs‐B groups, which further confirmed that the GNPs system possessed acid‐triggered aggregation property and could enhance the cellular uptake of GNPs.Having confirmed the ability of GNPs system for acid‐triggered aggregation in solution, we next investigated whether this property could be achieved in cellular levels. The cellular uptake of GNPs system was studied in MCF‐7 cells by using confocal microscope which was based on the green fluorescence of FITC‐PEGFigure−1 calculated by Figure −1. The inconspicuous difference of GNPs system for SER value between 50 and 100 µg mL−1 can be explained by that the size of GNPs aggregation could not be infinitely increased even in the acidic medium, which has been confirmed in Figure After achieving the acid‐triggered aggregation of GNPs system both in solution and in cellular level, we investigated the radiosensitization of GNPs system in vitro. Firstly, the pictures which were shown in To study the enhanced radio‐sensitization of GNPs system from radio‐sensitizing mechanism, the double‐strand breaks (DSBs) of DNA inside cancer cells were monitored by γ‐H2AX staining to appraise the efficiency of DNA damage during RT.1 phase and S phase than that of the control group. Owing to the most sensitive to radiation of the G2/M phased cells, the cells incubated with GNPs might be easily killed by RT, and the cell‐killing efficiency of GNPs system might be highest because that the most cells distributed in the G2/M phase.In addition, the cell cycle distribution study was applied to further evaluate the potential mechanism of GNPs‐induced radio‐sensitizing effects. After being incubated with GNPs system or GNPs‐A (GNPs‐B), the cell cycle presented a subtle change which compared to control group Figure F. BrieflFigureAfter achieving the desirable radiosensitive effect of GNPs system by using the acid‐triggered aggregation in vitro, we then evaluated its functions in vivo, including pharmacokinetics, tissue distribution, toxicity, and tumor retention. All animal experiments were performed according to the protocol approved by Chinese Academy of Medical Science and Peking Union Medical College and following the Guiding Principles under the Care and Use of Animals of the American Physiological Society. Firstly, the GNPs system showed a rapid blood clearance and a similar curve to that of GNPs‐PEG2000 Figure3A, whiIn this study, as a novel sensitizer, an ideal accumulation and retention in tumors is of critical importance for GNPs system, which can play a vital role in improving radiotherapeutic efficiency based on the level of tumor. Hence, tumor retention of GNPs system was studied in BALB/c nude mice bearing MCF‐7 tumors at 24, 48, and 72 h post injection, respectively. As shown in Figure −1) at pH 7.4 and pH 6.5 was studied by PA imaging system, and GNPs‐PEG2000 as the control. As shown in FigureOwing to the high density and extinction coefficients, GNPs can be used as contrast agents for PA imaging.Subsequently, their in vivo imaging effects were studied and the results were shown in Figure FigureFinally, the radiosensitive effects of GNPs system were studied in the MCF‐7‐luciferase tumor bearing mice model. As shown in Meanwhile, both of the tumor weights Figure D, HE staIn summary, a novel tumor microenvironment sensitive radiosensitizer was developed based on the acidic‐induced GNPs aggregation system, which was composed of small GNPs modifying different charged peptide on the surface. Once arriving into the tumor with acidic pH, the surface charge of small GNPs with charge reversal property could be changed from negative to positive, resulting in the electrostatic interaction with another negatively charged GNPs and thus forming large‐sized GNPs aggregates. This GNPs aggregates have much longer tumor retention ability by blocking the migration and backflow of GNPs. Compared with small GNPs, the GNPs aggregates could significantly amplify the radiosensitive efficiency and improve SER10 value to reduce the radiation dose so as to alleviate the radiation damage for healthy tissues. At normal pH during circulation and distribution, the GNPs system showed a rapid blood clearance and a lower phagocytosis by RES system, leading to a radiosensitive specificity for tumors. Additionally, the GNPs aggregation could also improve the PA signal which was in favor of imaging‐guided enhanced RT for tumors. Therefore, the tumor microenvironment–triggered GNPs aggregation system we constructed is a promising strategy for the enhanced tumor RT.The authors declare no conflict of interest.SupplementaryClick here for additional data file.


DNA damage‐inducible transcript 3 protein (FUS:DDIT3) is a chimeric fusion oncoprotein present in 90% of human myxoid liposarcomas (MLS). The study by Trautmann et al in this issue of EMBO Molecular Medicine utilizes a drop‐out RNAi screen to establish hyperactive Yes‐associated protein 1 (YAP1), a major downstream nuclear effector of the Hippo signaling pathway, as a selectively essential transcript promoting viability and growth of MLS. These observations add to a growing body of evidence underscoring the importance of dysregulation of Hippo signaling in soft‐tissue sarcomas expressing fusion oncoproteins and identify a novel target for therapeutic intervention in MLS. Comprehensive molecular characterization pipelines are needed to screen patients with advanced soft‐tissue sarcomas for the presence of druggable alterations, including but not limited to nuclear YAP1 expression in MLS, to facilitate treatment decisions and advance therapy.Fused in sarcoma:  Fusion genes are common types of oncogenes in human cancers, resulting in new, hyperactive combinations of regulatory elements and functional protein domains. The discovery of fusion oncogenes in the 1970s stimulated the development of potent therapeutics such as imatinib, a tyrosine kinase inhibitor for the treatment of myeloid leukemias expressing the breakpoint cluster region: abelson murine leukemia viral oncogene homolog 1 (BCR:ABL1) kinase fusion. Imatinib was coined as a magic bullet to treat cancer. Since then, dozens of other fusion oncoproteins have been identified in hematological cancers, tumors of the central nervous system, carcinomas, and sarcomas. Many of them are tumor‐specific and provide immense diagnostic value due to their inherent expression in certain tumor types. The fusion oncogene fused in sarcoma: DNA damage‐inducible transcript 3 protein (FUS:DDIT3) originates from a chromosomal translocation t  in 90% of human myxoid liposarcomas (MLS), belongs to the FET  family of chimeric oncoproteins, and contains the N‐terminal domain of FUS juxtaposed to the DNA binding domain of the transcription factor DDIT3. FET‐family and many other transcription/chromatin factor fusions are typically associated with low tumor mutational burdens, occur early in tumorigenesis to initiate and drive malignancy, and should qualify as ideal targets to selectively attack fusion‐positive tumor cells. Yet, their discovery in leukemias and sarcomas has not translated into improvements in treatment and survival rates, because they act as transcriptional dysregulators and successful pharmacological modulation using small molecules has not been possible thus far . When Hippo signaling is inactive, for example during malignant transformation, YAP and TAZ localize to the nucleus, where they serve as transcriptional co‐activators for TEA domain‐containing sequence‐specific (TEADs) and other transcription factors in order to promote tumorigenic events  combined with dasatinib  and thereby identify candidates for early phase clinical trials.Liposarcomas account for 15–20% of all soft‐tissue sarcomas, and 20–30% are of the myxoid or myxoid round cell subtype. The latter arise preferentially in adolescents and younger adults, and they are characterized by a high rate of hematogenous metastases to extrapulmonary sites and/or recurrent tumors in up to 40% of patients. Local and/or distant failures typically take place within the first 5 years after diagnosis, but later events are not unusual. Surgery preceded or followed by radiation therapy represents the mainstay of treatment, resulting in 10‐year overall survival rates of approximately 70%. Although there is evidence to suggest that MLS tumors are chemotherapy‐sensitive, and despite the encouraging results in phase I/II studies of trabectedin, a marine‐derived novel anti‐cancer agent, neoadjuvant or adjuvant chemotherapy has never been associated with a clear survival benefit (Chowdhry


Our understanding of the long‐term complications of HIV infection and their interaction with ageing and treatment evolves as the bulk of the population of people living with HIV ages. We have a reasonable understanding of what living with HIV means for middle aged (50 to 64 years) men in upper income countries. We are only beginning to grasp how ageing with HIV plays out for women The evolution of our understanding of ageing with HIV began after sulfamethoxazole and trimethoprim (Bactrim) prophylaxis combined with AZT modestly improved survival and we recognized HIV‐associated neurocognitive disorder (HAND). Once double and triple combination therapy became widespread, we began seeing higher rates of cancer, cardiovascular disease, renal insufficiency and liver disease among people living with HIV (PLHIV). First attributed to treatment toxicity, these conditions were later recognized as longer‐term complications of HIV We also began to talk about “accelerated ageing” and “frailty,” but these concepts may have been a bit exaggerated An important theme in ageing is that no two people age in the same way. With advanced age, the most salient issue is not the number of years one has lived, but the cumulative “slings and arrows of outrageous fortune” that they have experienced in their lives, including multimorbidity and polypharmacy We may see growing disparities in health outcomes among those ageing with HIV as they reach more advanced ages. Those who achieved viral load suppression prior to experiencing substantial CD4 loss, who either stop or never start smoking or drinking harmful amounts of alcohol, those who avoid excessive weight and who are physically active will experience “successful ageing” Nevertheless, while the incidence of major comorbid diseases demonstrates variable associations with age, risks are typically accentuated with advancing age and often in a nonlinear manner. When PLHIV are compared with age‐matched uninfected individuals, their excess risk for anal, lung, liver and oral cavity/pharyngeal cancers increases after 50 years of age While we have made miraculous strides in extending life and quality of life with HIV infection Ageing with HIV will likely remain somewhat different from ageing without HIV, but much can be learned from the geriatric literature regarding deprescribing, nonpharmacologic symptom management, transitions in care and end‐of‐life planning. We do not yet know what the next several decades will hold, but it is likely that we will see increased cancer incidence, greater numbers of extended care admissions, and, eventually, higher age‐related mortality. Care providers and clinical researchers will need to adapt what has been learned in other ageing populations to PLHIV as they age beyond 65 and 70 years.No conflict.ACJ conceived of the idea for this editorial and wrote the first draft.JT reviewed the draft, edited the scientific content and constructed the figure.


The association between preceding infection of hepatitis E virus (HEV) and Guillain–Barre syndrome (GBS) has been found for more than a decade, while hepatitis E virus‐associated Guillain–Barre syndrome (HEV‐associated GBS) still remains poorly understood. Initially discovered in 2000, the association between GBS and HEV has been focused by neurologists increasingly. Five percent of patients with GBS had preceding acute HEV infection in the Netherlands and higher rate was found in Bangladesh (11%) where HEV is endemic.An extensive review of relevant literature was undertaken.Hepatitis E virus infection may induce GBS via direct viral damage according to recent research findings. On the other hand, the presence of antiganglioside GM1 or GM2 antibodies in serum of some HEV‐associated GBS patients indicates that HEV infection may trigger GBS by activating autoimmune response to destroy myelin or axon mistakenly. Management of HEV‐associated GBS has no obvious difference from GBS. It mainly consists of supportive therapy and immunotherapy. Intravenous immunoglobulin (IVIG) or plasma exchange (PLEX) was used in most reported cases, which is the main strategy for clinical treatment of HEV‐associated GBS. Whether antiviral therapy could be additional strategy other than the routine therapy to shorten the length of disease course is one of the most urgent problems and requires further study.An overview of possible pathogenesis will gain a first insight into why HEV, traditionally recognized as only hepatotropic, can induce many neurological disorders represented by GBS. Moreover, understanding of the underlying mechanisms may contribute to development of a novel therapeutic strategy. This review also summarizes management and clinical characteristics of HEV‐associated GBS, aiming to achieve early recognition and good recovery. In this review, we gain a first insight into the possible pathogenesis mechanisms and summarize current therapeutic strategies and clinical characteristics of hepatitis E virus‐associated Guillain–Barre syndrome. Meanwhile, we also emphasize the possibility of development of a novel therapy. HEV infection is usually acute and self‐limiting, while it may become chronic in immunocompromised individuals . Although AIDP was more common in reported cases, any other types of GBS may follow HEV infection. About two‐thirds of patients have preceding infection within 3 weeks before onset of weakness  for HEV in serum samples support a definite HEV infection. Serologic test and RT‐PCR for other pathogens should be performed to rule out the possibility of cross‐reactivity. In 59 cases reported, the positive rate for IgM serum was 100%. Among the 44 cases with available details of RNA test in serum or/and CSF, 19 out of 59 cases (43.18%) were positive. In a word, the definition of acute HEV infection is the presence of anti‐HEV IgM using enzyme‐linked immunosorbent assay (ELISA), with or without IgG, and supplemented by detection of HEV RNA in serum using RT‐PCR  in the past few decades  had experienced complete neurological recovery within several weeks to several months Table . The rec8Hepatitis E virus infection was frequently associated with GBS or variants of GBS. Two possible pathogenesis mechanisms have been proposed and require further study to explore more details. One novel point of view is raised that HEV can induce GBS by damaging neurological system directly by means of viral replication, versus with traditional indirect immune response mechanism. Although PLEX or IVIG has been widely used to treat HEV‐associated GBS, it is worth discussing whether antiviral monotherapy or combination of ribavirin and immunotherapy can be used as a novel treatment. If the pathogenesis was clarified sufficiently, the answer to the question would be straightforward because direct neural infection could respond well to antiviral therapy. Prevention and early diagnosis of HEV‐associated GBS can be difficult and challenging because prodromal symptoms of infection are usually asymptomatic or mildly symptomatic. For physicians, it is particularly important to aware of this underlying trigger of GBS in their workup.The authors declare no financial or other conflict of interests.


Nurses are teachers to their patients and need to know best practices for diverse families living with dementia. Little is known about Hispanic beliefs around dementia knowledge and self‐efficacy that may have an impact on the learning situation.A pre‐/postresearch design was used in this intervention study with a baseline assessment of dementia knowledge and caregiver self‐efficacy and a reassessment at training completion.Investigation of education training with two caregiver groups caring for persons with dementia: Caucasian and Hispanic. Convenience sample consisted of 567 Caucasians and 104 Hispanic dementia caregivers. Groups received training in their primary language accompanied by a training book  also in the primary language.Dementia knowledge and caregiver self‐efficacy increased in both groups with the Hispanic group demonstrating significantly greater increase in self‐efficacy. The Caucasian group had a significantly greater increase in the dementia knowledge compared with the Hispanic group. The lanHispanics constitute the third fastest growing population in the United States. This population is projected to increase to 119 million in 2060, representing a 115 per cent increase from 2014. By 2060, 29 per cent  of the USA is projected to be Hispanic . The older Hispanic community continues to age with the number of Hispanics over the age of 65 doubling by year 2030  prior to training participation and at training end.22.1This intervention study used a pre‐ and postresearch design with baseline assessment of carers occurring prior to the workshop and reassessment at workshop end. The final convenience sample of workshop attendees were 567 Caucasian, non‐Hispanic family carers and 104 Hispanic family carers. The Caucasian carers were recruited from their communities through service providers and community marketing by the trainers. Hispanic carers were recruited through the Hispanic Ministries in the United Methodist Churches in their respective towns. Inclusion criterion was that the carer must currently be caring for someone living with dementia. Most Hispanic carers (79.1%) were female and less than 60 years of age while the Caucasian carers (71.3%) were female and more than 60 years of age. Most of the carers from both groups were from urban areas and had been caregiving for <5 years. Table A successful training workshop requires a structured educational plan with appropriate printed materials to facilitate learning and allows active participation. All trainers (Hispanic and Caucasian) used the same training programme—Dealing with Dementia Guide. The Dealing with Dementia Guide for Carers was originally developed by the Rosalynn Carter Institute for Caregiving (RCI) as part of the evidence‐based carer support programme RCI REACH . RCI REACH is a powerful multi‐component carer support programme delivered one on one by a Certified Carer Coach over a 6‐month period. One hundred per cent of carers who participated in the original RCI REACH programme rated the Guide as very helpful in their evaluation of the programme  4‐hr training workshop focuses on teaching carers how to use this vast resource guide. The training is conducted in a classroom‐style workshop. Carers are led through the DWD guide from front to back, highlighting topics that are known quagmires for carers and pointing out the topics they may want to return to review later. Every participant receives a guide to take home. The workshop's underlying theme is to connect with, applaud and empower both family and professional carers. The examples and tips shared during the workshop demonstrate a deep understanding of the caregiving experience and offer suggestions for managing daily challenges. Book topics include depression, dementia behaviours such as aggression and communication challenges, self‐care, stress management, seeking and accepting help, creating dementia‐friendly lifestyles and problem‐solving.The workshop training leaders had various educational backgrounds, but all received the same instruction on how to conduct the 4‐hr dementia education from the Rosalynn Carter Institute for Caregiving (RCI) staff (authors of the Guide). These leaders (41 Caucasian with English as first language and 1 Hispanic with Spanish as first language) completed a 1‐day Trainer Class in which they were instructed in the background of the DWD Guide, the theme of the workshop  and operational issues around delivery and expectations from RCI. To complete the training and demonstrate mastery of skill required for a DWD Master Trainer, each individual delivered a mock workshop with at least three observers critiquing performance. The mock workshop allowed the new trainee to practice the delivery of content required and share real‐life examples. With approval from the observers, the workshop training leader was prepared to conduct the community training workshops.2.2This study was approved (IRB#15‐009) by the Institutional Review Board of the Georgia Southwestern State University. Each participant also signed a consent form available in their primary language.2.3The primary objective of the study, which was based on Knowles Adult Learning Theory Knowles, , was to Over a period of 1 year, a total of 10 four‐hour workshops were held with Hispanic carers and 25 four‐hour workshops were held with Caucasian carers. Data were collected at the beginning of the workshop (before training started) and at training end with reliable and valid tools  and through observation by the workshop leaders.2.4In addition to obtaining demographic information on each training workshop participant, two valid and reliable scales were used to capture data related to self‐efficacy and knowledge of Alzheimer's Disease/Dementia. The Revised Scale for Caregiving Self‐Efficacy (RSCSE) is a 15‐item measure. It contains three subscales —Self‐efficacy for Obtaining Respite, Self‐efficacy for Responding to Disruptive Patient Behaviors and Self‐efficacy for Controlling Upsetting Thoughts about caregiving. The scale rated the degree of confidence from 0%–100%, where a 0% confidence meant that the carer could not do it at all, a 50% confidence meant that if the carer gave it his or her best effort, chances were about 50–50 that the carer could perform the activity and a 100% confidence meant the carer is certain he or she can do it. A total score was calculated by summing the responses, ranging from 0–500. Scales can be used separately or together. Past studies reported an alpha coefficients of 0.080 (reliability) or greater for each of the three of the subscales  was used to assess the carers' knowledge about Alzheimer's Disease. The 30‐item, true/false scale addressed seven content domains that encompassed the breadth of information: risk factors, assessment and diagnosis, symptoms, course, life impact, caregiving and treatment and management. A total score ranged from 0–30. Studies show that the ADKS has adequate reliability  and validity  and Alzheimer's knowledge (ADKS) from baseline to programme end assessment  or part‐time (20.8%) positions, while 54.1% of Caucasian non‐Hispanic family carers were not employed (retired).Hispanic carers reported less education than Caucasian non‐Hispanic carers: 68.5% of Hispanic carers received 11 or less years of education and 10.1% received higher education (college). Comparatively, 1.6% of Caucasian non‐Hispanic carers received 11 or less years of education and 83.1% received higher education (college and higher). Last, most (82.5%) of Caucasian non‐Hispanic family carers were the immediate relatives of the care recipients, composed by spouses/partners, parents and children. In Caucasian families, the carer was the child caring for a parent, whereas the Hispanic carer was more often a non‐immediate relative of the family member.4The purpose of this intervention study conducted a comparison of the results of training with two carer groups caring for persons with dementia: Caucasian (primary English speaking) and Hispanic (primary Spanish speaking). Healthcare providers working with these populations can use the lessons learned from this comparison as they incorporate healthcare training for individuals caring for someone with dementia. Conflicts may occur between nurses' cultural values and care practices in dementia care settings; thus, there is a need for ongoing education to decrease the possibility of such conflicts  training workshop has led to statistically significant increases on the SE and ADKS of carers for both Hispanic and Caucasian groups. The net increase in the positive DWD effect on SE of carers was significantly different between the two groups: the SE increase in Hispanic carers was significantly greater than that of the Caucasian non‐Hispanic carers. This is an interesting result as the education levels of the Hispanic group were lower than the Caucasian non‐Hispanic group. Earlier research  in ADKS score were quite close between the groups. However, the ADKS scores (both baseline and after follow‐up) of the Caucasian carers were significantly higher than those of the Hispanic carers. This may be explained by the lower educational level. Researchers have found that Hispanics providing care to a family member with Alzheimer's disease and related dementias face numerous language, literacy and cultural barriers to accessing and housing health services  and increased dementia knowledge levels for the Hispanic carers in this study.No Conflict of Interest.