TRANK1, which is associated with elevated circulating biomarkers of the impaired blood‐brain barrier in BD patients. In this review, we focus on the influence of intestine microbiota on the expression of bipolar gene TRANK1 and propose that intestine microbiota‐dependent type 1 interferon signalling is sufficient to induce the over‐expression of TRANK1, consequently causing the compromise of BBB integrity and facilitating the entrance of inflammatory mediators into the brain. Activated neuroinflammation eventually contributes to the occurrence and development of BD. This review provides a new perspective on how gut microbiota participate in the pathogenesis of BD. Future studies are needed to validate these assumptions and develop new treatment targets for BD.Bipolar disorder (BD) is a common psychiatric illness with high prevalence and disease burden. Accumulating susceptibility genes for BD have been identified in recent years. However, the exact functions of these genes remain largely unknown. Despite its high heritability, gene and environment interaction is commonly accepted as the major contributing factor to BD pathogenesis. Intestine microbiota is increasingly recognized as a critical environmental factor for human health and diseases via the microbiota‐gut‐brain axis. BD individuals showed altered diversity and compositions in the commensal microbiota. In addition to pro‐inflammatory factors, such as interleukin‐6 and tumour necrosis factor‐α, type 1 interferon signalling pathway is also modulated by specific intestinal bacterial strains. Disruption of the microbiota‐gut‐brain axis contributes to peripheral and central nervous system inflammation, which accounts for the BD aetiology. Administration of type 1 interferon can induce the expression of  The autoantibody of TRANK1 protein was originally found in the brain tissue of a mouse model of systemic lupus erythematosus. It is mainly produced and secreted by immune cells such as neutrophils and natural killer cells in the peripheral blood and is widely expressed in the cerebral cortex, including the hippocampus, amygdala and cerebellum.TRANK1 gene in the postmortem brain tissue of BD patients was significantly higher than that of healthy controls.TRANK1 were significantly involved in the biological processes related to synaptic plasticity, dendritic spine, axon guidance and circadian rhythm.TRANK1 rs71947856 variant was associated with circadian regulation and reported birth difficulties in patients with Kleine‐Levin syndrome, which is a rare disease characterized by severe episodic hypersomnia, with cognitive impairment and apathy or disinhibition.TRANK1 gene in BD has not been clarified so far.Epidemiological studies of twins have shown that the genetic heritability of BD is as high as 70%‐85%, suggesting that genetic factors play an important role in the pathogenesis of BD.TRANK1 may be involved in immune‐related signal regulation. In a mouse model where the interferon (IFN) regulatory factor 7 was knocked out or up‐regulated, it was found that the change in the expression level of this regulatory factor can affect the transcription level of TRANK1 through the type 1 IFN signalling pathway.TRANK1 through the STAT/JAK signalling pathway.TRANK1 gene in the prefrontal lobe was significantly increased, and the expression of matrix metalloproteinase 9 (MMP9) and plasma membrane vesicle‐associated protein‐1 (PV‐1) was up‐regulated, which indicated that the integrity of the blood‐brain barrier (BBB) was impaired, and the permeability was increased.TRANK1 is regulated by the IFN signalling pathway, and the TRANK1 gene may be an important mediator affecting BBB permeability and neuroinflammation in the brain. However, how the expression of TRANK1 gene is regulated under pathological processes of BD remains to be further studied.Previous studies have shown that 3TRANK1, its regulation on the intestinal immune responses may link gut microbes to host gene expression. On the other hand, stress in particular, along with other factors, such as diet choice and the HPA regulation, represents up‐to‐bottom regulation of the gut microbiota.Recent researches have taken an increasing focus on the microbiota‐gut‐brain (MGB) axis regulation in neuropsychiatric diseases.Faecalibacterium and Ruminococcaceae decreased in the BD patients, and the abundance of Faecalibacterium was negatively correlated with the severity of depression.Actinobacteria and Coriobacteria in the intestine was increased, and the abundance of Lactobacillus was positively correlated with serum IL‐6, lipid, tryptophan levels and other indicators.Preliminary studies have shown that the diversity and structure of the intestinal microbiota of BD patients are different from that of healthy individuals.Above research results suggest that the disturbance of intestinal microbiota may be an important environmental factor in the onset of BD. However, it is still unclear how the gut microbiota affects the MGB axis, which in turn leads to abnormal mood and behaviour in BD individuals.4The BBB is an important barrier for the exchange of substances and nutrients between the peripheral circulation and the central nervous system (CNS) and plays a key role in maintaining normal physiological functions of the brain.In recent years, studies have reported the influence of metabolites of intestinal microbiota on the BBB function, which may act as a protective or detrimental factor under different conditions.Notably, mounting evidence has confirmed the close relationship between BD and immune dysfunction.Taken together, the above findings indicate that intestinal dysbiosis may be related to the impairment of BBB integrity. BBB dysfunction facilitates the entrance of peripheral inflammatory mediators into the CNS, thus promoting neuroimmune response and participating in the occurrence and development of BD.5ARNTL.The interaction between microorganisms and host genome has been designated as one of the major research directions of the Human Microbiology Project.L acidophilus strains, rather than other probiotic strains, were able to induce IFN‐β production from murine bone‐marrow‐derived DCs in a TLR2‐dependent manner,Bifidobacterium bifidum.Citrobacter rodentium were enhanced by type 1 IFN‐dependent signalling.Debaryomyces hansenii, was found to impair mucosal healing in Crohn's disease intestinal tissue through the myeloid‐specific type 1 IFN‐CCL5 pathway.TRANK1 gene.TRANK1 was associated with impaired BBB function, as revealed by increased levels of MMP9 and PV‐1.TRANK1 and further damaged the integrity of the BBB, thus increasing its permeability and exacerbating the neuroinflammatory basis of BD ; Writing‐original draft (lead). Jiajun Jiang: Conceptualization ; Writing‐original draft . Peifen Zhang: Conceptualization ; Writing‐original draft . Caixi Xi: Conceptualization ; Writing‐original draft . Lingling Wu: Conceptualization ; Writing‐original draft . Xingle Gao: Conceptualization ; Writing‐original draft . Yaoyang Fu: Conceptualization ; Writing‐original draft . Danhua Zhang: Conceptualization ; Writing‐original draft . Yiqing Chen: Conceptualization ; Writing‐original draft . Huimin Huang: Conceptualization ; Writing‐original draft . Yiyi Zhu: Conceptualization ; Writing‐original draft . Shaohua Hu: Conceptualization (lead); Supervision (lead); Writing‐review & editing (lead).


Many researchers took advantage of the well‐established rubber hand illusion (RHI) paradigm to explore the link between the sense of body ownership and the different brain structures and networks. Here, we aimed to review the studies that have investigated this phenomenon by means of neurophysiological techniques.The MEDLINE, accessed by Pubmed and EMBASE electronic databases, was searched using the medical subject headings: “Rubber hand illusion” AND “Transcranial magnetic stimulation (TMS)” OR “Evoked potentials (EP)” OR “Event related potentials (ERP)” OR “Electroencephalography (EEG)”.Transcranial magnetic stimulation studies revealed a significant excitability drop in primary motor cortex hand circuits accompanying the disembodiment of the real hand during the RHI experience and that the perceived ownership over the rubber hand is associated with normal parietal–motor communication. Moreover, TMS provided causal evidence that the extrastriate body area is involved in the RHI and subsequently in body representation, while neuromodulation of ventral premotor area and the inferior parietal lobe did not result in an enhancement of embodiment. EP and ERP studies suggest that pre‐existing body representations may affect larger stages of tactile processing and support predictive coding models of the functional architecture of multisensory integration in bodily perceptual experience. High‐frequency oscillations on EEG play a role in the integrative processing of stimuli across modalities, and EEG activity in γ band activity in the parietal area reflects the visuotactile integration process. EEG studies also revealed that RHI is associated with the neural circuits underlying motor control and that premotor areas play a crucial role in mediating illusory body ownership.Neurophysiological studies shed new light on our understanding of the different aspects that contribute to the formation of a coherent self‐awareness in humans. Many researchers took advantage of the well‐established rubber hand illusion (RHI) paradigm to explore the link between the sense of body ownership and the different brain structures and networks. Here, we aimed to review the studies that have investigated this phenomenon by means of neurophysiological techniques. The following medical subject headings (MeSH) and free terms were searched: “rubber hand illusion (RHI)” AND “transcranial magnetic stimulation (TMS)” OR “repetitive transcranial magnetic stimulation (rTMS)” OR “evoked potentials (EP)” OR “event related potentials” (ERP) OR “electroencephalography (EEG)”. Original articles written in English were considered eligible for inclusion, while review articles and single case reports were excluded. Techniques that reproduce the well‐known rubber hand illusion, but in virtual reality, were excluded.For the selected titles, full‐text articles were retrieved, and reference lists of them were searched for additional publications. The principal investigators of included studied were contacted when necessary to require additional information. Two review authors independently screened the titles and abstracts of the initially identified studies and then assessed the methodological quality of each study and risk of bias, including blinding. This search strategy yielded 24 results .A flowchart Figure  illustraThe methodological and technical aspects of the reviewed TMS, EEG, and SEP studies are illustrated in the Tables 33.1Transcranial magnetic stimulation (TMS) is an approach that, if delivered repetitively, can influence brain function. Repetitive TMS (rTMS) can be applied as continuous trains of low frequency (LF) or bursts of higher‐frequency (HF) rTMS. Generally, LF rTMS (stimulus rates ≤1 Hz) induces inhibitory effects on motor cortical excitability, whereas HF rTMS (≥3 Hz) usually promotes an increase in cortical excitability  excitability was modulated by off‐line LF rTMS.Participants underwent the RHI after real or sham rTMS, either on the right hand, contralateral to the inhibited hemisphere or on the left hand in the Experiment 1, ipsilateral to the inhibited hemisphere, in Experiment 2 , respectively, were assessed. Only in Experiment 1, rTMS strengthened the illusory experience, as revealed by a significant increase of both measures in the real compared to sham group. This finding demonstrates that the down‐regulation of the M1 activity can lead to an attenuation of the sense of body ownership, so that the subject becomes more prone to incorporate an alien body part. This evidence also suggests the presence of a mutual interaction between the sense of body ownership and the motor system, shedding new light on the construction mechanisms of a coherent sense of self as an acting body.During the RHI, subjects experience an artificial hand as part of their own body, while the real hand is subject to a sort of “disembodiment.” To investigate whether this altered belief about the body also affect physiological mechanisms involved in body ownership, such as motor control, the effect of this illusion on the excitability of the motor pathways to the real (disembodied) hand has been assessed  when recalibration of the perceived position of the participant's real hand toward the rubber hand occurs. Off‐line LF rTMS in a double‐blind, sham‐controlled with subjects design was used to explore the role of the inferior posterior parietal lobule (IPL) in inducing the RHI directly  employs low intensities and has a robust, long‐lasting effect in normal subjects . The specific role of the PMv in generating the sense of ownership is still poorly understood. A study aimed at exploring the role of PMv in generating and experiencing the RHI , an area of the brain that is typically implicated in the perception of nonface body parts, in illusory body ownership. To investigate the possible causal role EBA in the RHI, sixteen healthy subjects took part in a sham‐controlled, 1 Hz rTMS experiment , can enhance tactile sensation in a group of 21 healthy subjects and one patient with cervical spinal cord injury  during the illusion were compared between schizophrenia patients and normal control subjects  is thought to be a pivotal area in RHI, to explore the effective connectivity between—and within—sensory and premotor areas involved in bodily perceptions, a dynamic causal modeling of touch‐evoked responses has been used by the same research group in 13 healthy subjects  in bodily perceptual experience.5The integration of multimodal stimuli is thought to be important for the promotion of adaptive behavior. Several studies have identified brain areas that respond to multimodal stimuli, but the temporal features are not been clarified. Initial ERP studies have demonstrated crossmodal attention effects, but the exact mechanisms underlying crossmodal integration have not been clarified. Electroencephalography (EEG) activity in the γ‐band can be considered as a correlate of multimodal integration. In the first study of Kanayama and colleagues, participants localized a tactile stimulus on their fingers while seeing visual stimuli on rubber hands with the same posture as their hands  in the parietal area of macaque monkeys is thought to modulate its activation and alter the extension of body image during tool‐use learning. To clarify the relationship between PC activation related to body image alterations and BDNF levels in humans, the relationship between human serum BDNF levels and EEG responses has been investigated during a visuotactile integration task involving a rubber hand . A recent study aimed at examining whether motor manipulation of the fake hand similarly affects the observer's motor system  rTMS over different brain areas. Two studies reported a significant RHI modulation only in the PPD, but in the opposite direction, depending on the stimulated area: while rTMS over the IPL attenuated the perceived shift toward the fake hand  offer superior temporal resolution for investigating this issue. EEG studies revealed that high‐frequency oscillations play a significant role in the integrative processing of stimuli across modalities  band were detected in the left PC, and the power values of these oscillations were positively correlated with serum BDNF levels. These results suggest that serum BDNF could play a role in modulating the cortical activity in response to visuotactile integration processes related to body image alteration in humans.Interestingly, patients with schizophrenia exhibit a greater susceptibility to the RHI (Asai et al., In particular, schizophrenia patients had significant alterations in long‐latency somatosensory evoked responses during the RHI (Peled et al., These findings support the hypothesis that associative higher‐level neuronal activity is abnormal in schizophrenia and suggest that the underlying neuropathology of schizophrenia involves higher‐level processing.7The findings of the reviewed neurophysiological studies dealing with the RHI phenomenon provide insight into the functional anatomy of multisensory integration and the perception of oneself and shed new light on our understanding of the different aspects that contribute to the formation of a coherent self‐awareness.None of the authors have potential conflicts of interest to be disclosed.KS, LuS, LeS, and VV contributed to literature search, data extraction, and data analysis. FV, SG, FT, and RN contributed to the project design and paper writing.


Partner availabilities can play an important role in enabling species interactions, where uneven partner availabilities can bias estimates of biotic specialization when using phylogenetic diversity indices. It is therefore important to account for partner availability when characterizing biotic specialization using phylogenies. We developed an index, phylogenetic structure of specialization (PSS), that avoids bias from uneven partner availabilities by uncoupling the null models for interaction frequency and phylogenetic distance. We incorporate the deviation between observed and random interaction frequencies as weights into the calculation of partner phylogenetic α‐diversity. To calculate the PSS index, we then compare observed partner phylogenetic α‐diversity to a null distribution generated by randomizing phylogenetic distances among the same number of partners. PSS quantifies the phylogenetic structure  of the partners of a focal species. We show with simulations that the PSS index is not correlated with network properties, which allows comparisons across multiple systems. We also implemented PSS on empirical networks of host–parasite, avian seed‐dispersal, lichenized fungi–cyanobacteria, and hummingbird pollination interactions. Across these systems, a large proportion of taxa interact with phylogenetically random partners according to PSS, sometimes to a larger extent than detected with an existing method that does not account for partner availability. We also found that many taxa interact with phylogenetically clustered partners, while taxa with overdispersed partners were rare. We argue that species with phylogenetically overdispersed partners have often been misinterpreted as generalists when they should be considered specialists. Our results highlight the important role of randomness in shaping interaction networks, even in highly intimate symbioses, and provide a much‐needed quantitative framework to assess the role that evolutionary history and symbiotic specialization play in shaping patterns of biodiversity. PSS is available as an R package at  We developed an approach to determine the phylogenetic structure of the partners that interact with a focal species while accounting for their availability. When applied in four empirical network datasets, we found that a large proportion of species interact with phylogenetically random partners. One strategy to account for partner availability is to generate the null distribution by calculating a phylogenetic diversity metric for sets of partners that are drawn from the pool of partner species in proportion to their availability  and c species in the columns (set B). Each element ija of I represents the interaction frequency between species i and species j, such that:First, let i be the sum of interaction frequencies recorded for species i,m be the sum of interaction frequencies across both rows and columns,Let Ajq be a parameter expressing the relative availability of species j. We can define jq as the ratio of the sum of interaction frequencies of species j to the marginal sum of interaction frequencies in the matrix ,Let jq can be determined empirically from measurements of partner abundance. The latter is preferable when such data are available i with partners k and s, ikaisa. The wMPD is used to compute the SESMPD index . This factor is an element of the sum used to compute Kullback–Leibler distances . However, the scenario where the index is undefined is extremely unlikely in natural networks and was never found in simulated networks. Equation i, which does not affect the behavior of klMPD.This mean of pairwise distances is now corrected for the availability of the partners through the KL weights. It takes larger values for species that interact non‐randomly with sets of more distantly related species, and it is undefined (0 in both numerator and denominator) for a species that interacts with its partners at the exact frequency that those partners are available , resulting in many species being generalists. However, d’ does not provide information about the phylogenetic structure of the partners of those taxa. Conversely, the distribution of −NRI values for that same set of species  in Figure d’ can occupy any region of the PSS space  reik/qk in equation klMPDi , as m = N1×N2×dens. Then, the simulated matrix of dimensions N1×N2 is populated with m interactions, such that the marginal sums of the interaction frequencies in the rows and the columns follow a lognormal distribution. This procedure results in heterogeneous distributions of both the number of links per species and the interaction frequencies per link.We simulated random matrices using the m = 5–4000) and fixed dimensions (50×50). We accomplished this by varying “dens” within the genweb function in bipartite. The marginal sum of interaction frequencies (m) sets a limit to the number of binary links in the simulated matrices because the marginal totals are constrained to follow a lognormal distribution. Therefore, the random matrices in the third set also span a range of connectance values, with matrices with higher m having higher binary connectance  from the null distribution generated as described for equation We simulated three sets of random matrices. In the first set, we assessed the values of PSS on random symmetric matrices with dimensions varying from 5×5 to 200×200. The second set consisted of random matrices with unequal numbers of columns and rows varying from 2×20 to 200×20. The average interaction frequency per link (dens) was kept at 2 for all matrix configurations in the first two sets. The third set contained random matrices with increasing marginal sum of interaction frequencies  using the simulated annealing algorithm developed by Dormann and Strauss  is calculated as if the network were quantitative (see equations jq) and the KL weights  mammals–fleas, an antagonistic network of interactions between small mammals and their ectoparasitic fleas (order Siphonaptera) that were sampled in four regions of Slovakia  with functions to compute PSS using interaction matrices and phylogenetic trees from the interacting species as input. Our R package has function dependencies from the R packages ape, bipartite, picante and vegan  and overdispersed (5.2%) scenarios. We observed high rates of Type II error (36%) in clustered scenarios when assessed at the plot level, which correspond to single rows in the CDMs.3.2r2 = .28 . PSS values for the fleas in the mammals–fleas dataset and the plants in the hummingbird pollination dataset were highly similar when calculated based on empirically estimated availability versus interaction frequencies as a proxy for availability  in the empirical networks Figure ,i,m, mos Figures ,n. The c Figures . Across y Figure . In conty Figure .44.1Phylogenetic structure of specialization integrates both partner availability and phylogenetic structure to characterize biotic specialization of species within interaction networks. As expected, when availability is roughly equal among partners Figure ,g, PSS cwMPD + regional null; Miller et al., m in equation The rates of Type I and Type II error observed for PSS are comparable to the best performing combination of phylogenetic diversity metric +null model as reported in a previous study . If we had done the same analysis in the context of all lichen‐forming fungi (which span multiple classes of Fungi), the partners of many cyanobacterial taxa would be highly clustered and some would be overdispersed. Likewise, the avian seed‐dispersal dataset consists of interactions that were sampled in a single region, the Atlantic Forest of Brazil  of cyanobacterial taxa associate with random partners Table . However4.6Patterns of phylogenetic diversity are not direct proxies for community assembly processes  into new areas might make opportunistic interactions advantageous in ecological and evolutionary timescales ; Data curation (lead); Formal analysis (lead); Funding acquisition ; Methodology (lead); Software (lead); Writing – original draft (lead); Writing – review & editing . Ian D. Medeiros: Conceptualization ; Methodology (supporting); Visualization (supporting); Writing – review & editing . Jean Philippe Gibert: Conceptualization (supporting); Methodology (supporting); Writing – review & editing (supporting). Pierre‐Luc Chagnon: Conceptualization (supporting); Methodology (supporting); Resources ; Writing – review & editing (supporting). Nicolas Magain: Resources ; Writing – review & editing (supporting). Jolanta Miadlikowska: Funding acquisition ; Resources ; Writing – review & editing (supporting). François Lutzoni: Conceptualization ; Funding acquisition ; Methodology (supporting); Project administration (lead); Supervision (lead); Writing – original draft (supporting); Writing – review & editing .Appendix S1‐S3Click here for additional data file.


The incorrect legend reads as “**** ST+EMS= strength training combined with electrical muscle stimulation.” The correct legend should read as 2 “BW+WB-EMS: body weight associated with whole body electrostimulation****.” The correct legend appears below.In the original article, there was a mistake in the legend for **Table 2**. **The lean mass signs †# need to be removed, since there was no statistical difference between pre versus post**. The corrected In the original article, there was a mistake in **Results** section It currently reads as “No differences were found in baseline parameters for any outcome parameters. As presented in In the original article, there was an error in the first paragraph of the The paragraph should read as “As presented in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Too many people living with chronic kidney disease are opting for and starting on hospital‐based dialysis compared to a home‐based kidney replacement therapy. Dialysis services are becoming financially unsustainable.This study aimed to assess the efficacy of coproductive research in chronic kidney disease service improvement to achieve greater sustainability.A 2‐year coproductive service improvement study was conducted with multiple stakeholders with the specific intention of maximizing engagement with the national health kidney services, patients and public.n = 50), multidisciplinary teams including doctors, nurses, psychologists, social workers, and so forth (n = 68), kidney charities, independent dialysis service providers and wider social services were part of this study.A national health kidney service , patients and families  and their potential, highlighted unmet social care needs for patients and families and informed service redesign. Education packages were reimagined to support the home dialysis agenda including opportunities for wider service input. The impacts of one size fits all approaches to dialysis on specialist workforce skills were made clearer and also professional, patient and public perceptions of key sustainability policies.Patient and key stakeholders mapped out new ways to link services to create more sustainable models of kidney health and social care. Maintaining principles of knowledge coproduction could help achieve financial sustainability and move towards more prudent adult chronic kidney disease services.Involved in developing research questions, study design, management and conduct, interpretation of evidence and dissemination. WRCNWelsh Renal Clinical NetworkMDTsMulti Disciplinary TeamsUHDUnit Haemodialysis also referred to as hospital‐based dialysisNICENational Institute for Health and Care ExcellencePDPeritoneal DialysisHHDHome HaemodialysisKRTKidney Replacement TherapyBAMEBlack, Asian, Minority, EthnicWKRUWales Kidney Research Unit1At least 10% of the global population is estimated to have chronic kidney disease (CKD).There are three main options available when a person goes into kidney failure: transplant, dialysis and supportive care without dialysis . Dialysis can occur in a hospital setting called unit haemodialysis (UHD) undertaken three times a week for 4 hour sessions at a time, or at home. If a person chooses home dialysis, there are generally two types of dialysis  available , both of which can be administered during the day or overnight depending on people's preferences and outcomes. National Institute for Health and Care Excellence (NICE) guidelines estimate that a minimum of 30% of the current dialysis population in the United Kingdom could be on home dialysis. NICE guidance also acknowledges the substantial impact that the different treatments will have on lifestyle and that people's values and preferences must be taken into account when presenting KRT options to them and their family.1.1Wales is one of the four devolved nations of the United Kingdom, with a devolved healthcare system and a population of around 3 million. The incidence and prevalence of CKD are higher in Wales than in the rest of the United Kingdom, affecting 6%–8% of the Welsh population .BOX 11The National Health Service (NHS) adopts the well‐established ‘Three Pillars of Sustainability: Social, Economic and Environmental’ model across all its health service improvement strategies and agendas for change.‘a way of working whereby citizens and decision makers, or people who use services, family, carers and service providers work together to create a decision or service which works for them all’.A key principle of prudent healthcare is coproduction, defined as 1.2an approach in which researchers, practitioners and the public work together, sharing power and responsibility from the start to the end of the project, including the generation of knowledge’.In a research context, coproduction is broadly defined as ‘Previous attempts to address low uptake of home dialysis have centred around shared decision making (SDM), specifically, the Making Good Decisions In Collaboration (MAGIC) model developed for the UK NHS.22.1We conducted a study with two elements—a health service improvement element and an empirical element that included an analysis of epidemiological big data, costs of dialysis modalities and a qualitative study of patient and carer perspectives. In this paper, we specifically focus on the health service improvement element and the coproductive methods and outcomes, which were deployed to help answer a specific coproductive research question: Can coproduction lead to more sustainable adult CKD services in Wales? This question was predefined by the funder as part of a themed national health and social care funding call under the umbrella of research for the patient and public benefit scheme. The question was interpreted for this study as ‘assessing the efficacy of coproduction to better understand the barriers to home dialysis and map alternate pathways’. Full details of the overall study are available in the published protocol.2.2This was a 2‐year coproductive study (October 18–20). The following were either key partners or settings in the study: kidney services covering all kidney healthcare in Wales  to ensure that coproduction was at the centre of all research activities and processes throughout. The UK standards are mapped against the full range of coproductive activities in this study with examples in File We present the purpose of coproduction mapped onto the principles of knowledge coproduction in sustainability research in Table 1.To create a vision of a more sustainable adult kidney service in Wales,2.To redesign service pathways in adult CKD,3.To review patient education materials and processes and4.To better understand patient and public attitudes towards the costs of kidney care and services.There were four specific components of the health improvement study, of which coproduction was fundamental to address:1.To create a vision of a more sustainable adult kidney service in Wales.Data collectionThe multidisciplinary research team, which included people with kidney disease, produced a framework with the headings ‘what is currently unsustainable in adult kidney services’, ‘what does good look like’, ‘how can co‐production help’ and ‘what is difficult to achieve through co‐production’. The headings were then linked to the various perspectives: people living with kidney disease, family members, multidisciplinary health and social care professionals, NHS, independent dialysis service providers, government, third sector and wider social contexts Table .People with kidney disease worked with the research team to cocreate Table To bolster these specifically curated meetings, the evolving framework in Table Data analysisList of key events and attendeesNorth Wales curated meeting: Total n = 30, n = 18 renal professionals , n = 8 family members, n = 4 people with kidney diseaseSouth Wales curated meeting: Total n = 20, n = 12 renal professionals , n = 2 family member, n = 2 people with kidney disease, n = 4 kidney industry partners.Transplant cafés: Total n = 21, n = 7 renal professionals , n = 12 people with kidney disease, n = 2 industry partners.In the following section, we summarize how and what data were collected and analysed for each coproductive element, and how data were used to achieve the intended outcomes.The research team reviewed Table 2.To redesign service pathways in adult CKDData collectionThe original draft of the service improvement pathway 'pathways to home' Figure  was desiThe research team worked to ensure that the draft pathways were shared with representatives from the full NHS MDTs; the specialist renal nurses in predialysis and home therapies, professionals allied to medicine including physiotherapists, dieticians and clinical psychologists, kidney social workers and youth workers, people living with kidney disease, family members, kidney third sector CEOs and staff working for kidney charities, and volunteer peer‐to‐peer support workers—many of whom were either living with kidney disease or a family member of someone with kidney disease. This took place over 16 months from March 2019 to June 2020.We did this by sharing the first drafts of the pathways at quarterly NHS specialist nurse meetings and quarterly professionals allied to medicine meetings . The research team also worked with kidney charity partners to set up specially coordinated Zoom meetings to present to people living with kidney disease, family members and charity provider executives. These Zoom meetings were developed into webinars, which were made available online on YouTube and promoted on social media  for people to refer and feedback into via comments, telephone and email communications. This process continued over 15 months at face‐to‐face and virtual meetings until no new options or additions were forthcoming and there was a sense of data saturation.Data analysisSummary of key events and attendeesAll Wales National Home Therapies meeting (29.04.19): Total n = 20, n = 18 renal professionals , n = 1 family member and kidney charity representative, n = 1 people with kidney diseasePresentation and meeting with Kidney patient ‘befrienders’ via kidney charity (12.09.19): Total n = 10, n = 2 family members, n = 8 people with kidney diseaseAll Wales Health and Wellbeing reference group (22.10.19): total n = 10, n = 9 renal professionals  n = 1 kidney charity provider.Analysis was integrated into the development of the pathways from the outset. We presented the current service pathway as a backdrop and then asked what needed to/should be added to improve uptake of home therapies. Each engagement event was an opportunity for refinement and clarification from the multiple perspectives. This helped to highlight gaps in terms of what the service did not currently have and then move onto possibilities for improvement across the multiple service pathways. The before and after snap shots helped set out the vision for what kidney services could look like at a fairly high level across Wales and to more easily present this in relevant ways to the multiple stakeholders for their input.3.To review patient education materials and processesData collectionThere were around 15 specialist nurses working across five kidney centres in Wales. We contacted each centre lead nurse and requested that they collate their current paper‐based education materials and send to the research team. We developed a simple pro forma education flow chart and requested that the nurses fill it in to illustrate their current education practice, from initial conversation through to making a choice of RRT. We also requested that all Wales figures for numbers of people on home dialysis from the WRCN were shared. The research team then invited the lead nurse of the only centre that was achieving the national guidelines of 30% of patients on home dialysis to come and present at a specially co‐ordinated coproductive multidisciplinary meeting  and explain how their service worked. Academic members of the research team were also invited (following a study update at an NHS quarterly meeting) to attend a house visit with a specialist nurse (from a different centre) to observe their initial conversations with a person needing renal replacement therapy and their family members.Data analysisSummary of key events and list of attendeesNational Chronic Kidney Disease specialist nurse meeting (22.11.19): Total n = 13, n = 9 kidney professionals , n = 2 family member, n = 2 people with kidney diseasePresentation from home therapies teams (25.11.19): Total n = 35, n = 12 kidney professionals , n = 10 family members, n = 13 people with kidney diseaseField visit with CKD nurse to home consultation (27.11.19) total n = 3, n = 1 specialist kidney nurse, n = 1 family member, n = 1 person living with kidney diseaseVisits to dialysis Units across Wales  total n = 17 people with kidney diseaseAfter the materials were collected, the research team reviewed their content alongside a review of the numbers of people on home dialysis across Wales by region and centre and presented the review as well as examples of education materials back to a group of professionals, people with kidney disease and family members for their input. Despite education processes looking broadly similar across centres, on paper, the review of the number of people on home dialysis varied significantly File . The lea4.To better understand patient and public attitudes towards the costs of kidney care and servicesData collectionAcademic members of the research team attended nonkidney disease‐related public events during the 18‐month data collection window of the study. This included hosting a market stall at the St. David's Day parade, presenting at the all Wales Involving people festival and attending local community group meetings with Black Asian Minority Ethnic individuals and groups to enhance opportunities for learning and interactive feedback with the public in Wales including minority and underrepresented groups. We attended the National Transplant games in Newport and the WRCNs ‘Renal Roadshow’ with a banner and preamble to introduce the topic of treatment option costs to the public and invite their opinion. We delivered presentations at kidney patient‐led conferences and meetings to discuss costs and gather perspectives with larger and smaller groups of kidney patients. We also approached social services commissioners in Wales to learn from their perspectives and invited commissioners to a specially co‐ordinated meeting on Zoom to discuss the sustainability of kidney services.Data analysisSummary of key events and list of attendeesSt David's Day parade Pembrokeshire (01.03.19): Total n = 40 members of the publicBangor University Centre for Health Economics invited seminar (14.05.20): Total n = 15 members of the public‘Renal Roadshowz’ West Wales (04.07.19): Total n = 40, n = 20 kidney professionals , n = 10 family members, n = 10 kidney patientsWorkshop with kidney ‘befrienders' (12.11.19): Total n = 9, n = 1 family members, n = 8 people living with kidney disease‘Home therapies café’ (07.02.20) total 9, n = 6 people with kidney disease, n = 3 family members.Analysis was built into the discussions with members of the public. We asked about their perceptions of costs and asked them to list which treatments they felt were the most to the least expensive. This was followed by opinions on service configurations and, in particular, if and how they felt social services could support a home‐first agenda. Field notes were collected from each engagement and presented back to the research team at core meetings for discussion.31.Creating a vision of a more sustainable adult kidney service in WalesPeople living with kidney disease could play a potentially vital role in addressing specific sustainability issues  all the way through to policy contexts and updating clinical practice  and uncertainty within the renal teams with how best to manage them as a result.New stepped stages in the pathway introduced opportunities for more MDT input, patient‐led support interventions and signposting to wider third sector and social services across all pathways. This could help reduce or prevent patients being siloed or treated solely on the basis of their current kidney treatment. It would also seek to eliminate service configurations that saw people finding themselves by default on unit/hospital dialysis with no clear alternate pathways  and in behaviour  helped to create a culture of a home‐first service. Many of these nurses even felt that the national targets were too low. They also expressed concern that It was too easy for people to opt for UHD nowadays, and that the pathway had become the norm rather than the exception in Wales. This particular team had developed over time a home dialysis‐led service with problem‐solving approaches to known barriers to home dialysis , of which they were very proud. Close working relationships and up‐to‐date expertise in the various dialysis treatments helped create a culture that questioned the status quo and a desire to change it (presentation from home therapies teams (25.11.19)).Paper‐based education  was having little impact. Patients rarely read the resources provided. Family members did, but this only exasperated patient and family member concerns and increased worry. There was also little evidence of resources especially developed for family members. In service configurations with high numbers of patients on home dialysis, the family were given equal attention by professionals and managed alongside, but separate to patients (field visit with CKD nurse to home consultation (27.11.19)).Professionals rarely, if ever, used predesigned paper‐based education materials as part of their conversations. They preferred to rely on their own expertise and rapport with the patient. During the study, some professionals began to reconsider what ‘education materials’ actually mean and how they can support a home therapies agenda. This began by shifting the purpose of education away from explaining dialysis and more towards showcasing living well on dialysis. People going through kidney replacement therapy education will always have a consultant and specialist nurse to manage their care and will have access to a wider MDT for more specific needs. Education programmes are needed to help and support these roles, signpost to their expertise and then fill gaps in professional knowledge, for example, lived experiences as told by patients. Peer‐led networks and opportunities to interact with more patients on home dialysis were considered essential, as was removing and decommissioning any information and literature that did not talk to a home‐first agenda  advice or cases where there was disagreement  as to what treatment to recommend Table , Bias.Finally, we also observed that a standard model of dialysis was deskilling some of the specialist workforce, for example, up‐to‐date knowledge of various types of dialysis, confidence in (re)approaching families who initially declined home dialysis or changed their minds and overall experience in communication techniques including SDM , but this needs to be underpinned with a shared vision from professionals in key influencing roles if models of care are to switch from acute to long‐term sustainable care packages. A significant gap was the lack of understanding (from the multiple perspectives) of dialysis monetary value—how much various services cost and how they are delivered. Policy contexts  were not well understood; generally, people understood potential service improvement initiatives as a cost‐cutting measure and could see  little potential benefits to them. Many healthcare professionals did not immediately connect potential impacts of UHD on long‐term patient outcomes, especially nonclinical impacts, for example, restrictions on travel, work, childcare and lifestyle. Many had never heard of the policy contexts or were unclear as to how these related to them.This study highlighted the 4.2As with previous research, we found that local practices or perhaps more accurately ‘individual personalities’ influence the uptake of home dialysis and help explain some of the observed variation between centres.Generally, previous research into kidney health service improvement has a high focus on clinical outcomes.outcomes in this study reinforce the assertions of Elwyn et al.approaches in this study have helped to identify what resources are already available and where additional investments may be needed. This contributes to the growing literature around global coproduction practice and value.The coproductive 4.31. Efficiency and effectiveness of health and care provision, 2. Availability of well‐trained health and care workers, 3. Costs and economic benefits, 4. Health and resilience of the population, 5. Contribution of carers and informal networks of care, 6. Integration of policy and practice with other sectors and building healthy and health creating communities and 7. Public and political acceptability and support), highlighting that two in particular need more emphasis—economic benefits and multisectoral partnerships. This study unpacked key issues within all seven factors  the wider health and social care agenda towards prudent healthcare.Knowledge gained from this study includes the coproduced vision of more sustainable services, improved pathways to home dialysis and opportunities for greater integration of social care services and highlights ways to more proactively involve people with kidney disease more directly in service reconfiguration. This learning and the methods to coproduce it have the potential for transferability to similarly configured global healthcare systems. Redesigned pathways may even be more easily adapted outside of Wales, which has an older, sicker and more deprived population than other countries, and health literacy is generally low. Although additional account may need to be taken of country‐specific social care systems and the ways in which they currently integrate with health services to make best and better use of existing resources.4.4This is the first all‐Wales co‐productive study to address the sustainability of adult CKD health and social care services from direct and indirect key stakeholder perspectives. We believe that this is the first application of the principles for knowledge coproduction in sustainability research in kidney health research and can be built upon in future research, quality improvement and service development initiatives.4.5The question can coproduction lead to more sustainable adult CKD services in Wales was the focus of this study. In this context, we have only been able to partially answer it. We do not know explicitly whether coproduction will lead to greater sustainability of kidney services as this was not conceptualized as a longitudinal study to monitor behaviour change over time. For this, more research is needed over a longer period, with a larger and more diverse population to build upon the work outlined in this study, which includes templates on ways to work coproductively with NHS MDTs, kidney charities and people living with kidney disease. The NHS now needs to implement the new clinical pathways and embrace the transformational roadmap to change that was co‐produced with patients.5Coproductive research helped start a conversation between key stakeholders and researchers about sustainability. Much more needs to be done to increase the overall understanding of NHS financial and service structures to ensure that this is not a barrier in any future coproduction. Coproduction has the capacity to identify and reverse unintended consequences of health service systems that have  grown based on perceived immediate need, with little evidence basis and over a very long time. More case studies are needed to provide exemplars of what key policy contexts look like in health service delivery to realize the ambitions of prudent healthcare at scale.The authors declare that there are no conflict of interests.Leah Mc Laughlin led on coproductive activities, conceptualized the coproduction and drafted the manuscript. Gail Williams co led on coproductive activities, drafted key service redesign pathways, produced home therapies reports, undertook data analysis and data integration and reviewed the manuscript. Gareth Roberts developed the overall study design, co led on some coproductive activities and reviewed the manuscript. David Dallimore contributed to the design of coproductive activities, supported overall coproduction, contributed to data analysis and data integrated and reviewed the manuscript. David Fellowes contributed to data analysis and data integration, and reviewed the manuscript. Joanne Popham provided key coproductive support to deliver objectives, key understanding of configuration of peer support workers and reviewed the manuscript. Joanna Charles supported the coproduction of some activities and supported sharing of interim findings. James Chess developed the overall study design, and supported data integration and analysis. Sarah Hirst Williams provided key understanding of NHS home therapy service configurations, coproduced data and reviewed the manuscript. Jonathan Mathews supported the overall coproductive activities, coordinated multiple group meetings, provided data sets and reviewed the manuscript. Judith Stone provided key coproductive support to deliver objectives, key understanding of charity providers configurations and their potential influences and reviewed the manuscript. Teri Howells supported the overall study design and supported coproductive development. Teri sadly passed away before this study was completed. Linzi Isaac supported the coproduction of activities, supported sharing interim findings with UK patients and reviewed the manuscript. Jane Noyes oversaw coproductive activities, conceptualized the coproduction and drafted the manuscript.This study was approved by Wales REC 5. REC No. 19/WA0020. IRAS ID: 255387.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.


Implemenation of patient‐reported outcomes (PRO) like quality of life can add the patient's perspective to traditional clinical outcomes of cancer rehabilitation in a structured and standardized way.To present useful steps for a successful implementation of routine electronic patient‐reported outcomes (ePRO) monitoring. The presented steps are exemplified by describing the procedure applied in an Austrian inpatient cancer rehabilitation centre.The suggested implementation steps are presented based on the structure of the replicating effective programmes framework, which was used for developing a pragmatic implementation strategy.We scheduled alternating trainings and process evaluations for audit and enhancement of procedures. In this way, the ePRO participation rates could be improved. Stakeholder involvement led to initiatives that included the integration of ePRO data into the medical discharge letter and the implementation of follow‐up assessments.Tailored changes in assessment procedures enabled the successful implementation of ePRO, which has been shown to be feasible before and after cancer rehabilitation. The continuous involvement of stakeholders paved the way for further projects initiated by medical staff as users themselves . Patients are the experts for reporting their subjective health status and quality of life. The gold standard to assess such data is the use of validated patient‐reported outcome (PRO) questionnaires.Due to the improved detection and treatment of cancer, the number of people dealing with an oncological disease, surviving it and needing rehabilitation is increasing.Implementing routine electronic quality of life assessments in oncology inpatient rehabilitation is feasible.An inclusive approach should involve all stakeholders to achieve the best result.Repeated evaluation and individual adjustments of the workflow support the adoption of new procedures.11.1Because of increasing cancer incidenceIncreasingly, the patients’ perspective on their cancer disease is being assessed using patient‐reported outcomes (PRO), which are defined as patients’ self‐reports about their health status without being interpreted or altered by another person.Over the whole course of cancer treatment, in which rehabilitation and follow‐up play an increasingly important role,Traditionally, paper‐pencil questionnaires are used for PRO data collection; this is generally associated with relatively laborious working procedures , prone to data input errors and requiring vast human resources. Electronic PRO (ePRO) monitoring can collect data in a cost‐effective and secure way and, depending on the tolerance of missing values within the software, data quality is generally higher than that of traditional paper‐pencil assessments.This paper presents useful steps for a successful implementation of routine ePRO monitoring in an oncological rehabilitation centre and explains by way of example how these steps were carried out in this particular case. The structure of the paper follows the four phases of the replicating effective programmes (REP)2The oncology rehabilitation centre was opened in January 2014, provides 120 inpatient beds and offers a two to three‐week multidisciplinary inpatient rehabilitation programme for adult cancer patients (including various diagnoses) with a Karnofskyx index of >70.2.1The medical director of the rehabilitation centre approached the software distributors to obtain their expertise regarding the following topics: developing an ePRO implementation strategy, providing the necessary software (including maintenance and IT support), data management and analysis. Besides communications via phone and e‐mail, six months before the opening of the rehabilitation centre an on‐site meeting of stakeholders  was held in order to develop a pragmatic implementation strategy on the basis of REP.33.1Patients’ PRO data were assessed twice: before admission to rehabilitation and up to three days before discharge during their psycho‐oncology closing meeting. Front desk staff responsible for ePRO monitoring was trained within another facility of the rehabilitation provider following their established working routine, which was adopted in exactly the same manner. For this reason, the same PRO instruments were used as in the other institution. Furthermore, to keep procedures same way, PRO‐assessment was initially implemented as paper‐pencil assessment  and changed to ePRO after a six‐month adaptation phase in June 2014 . Irrespective of data collection mode, patients received a reminder phone call by the front desk staff, if they had not provided their data 10 days before admission.3.2feasibility of ePRO assessments , operationalised by feedback prompted by users , feedback regarding the effect of applied adjustments of procedures;patients’ acceptance , operationalised by patients’ response rates , operationalised by training participation rates , unstructured collection of professional users’ feedback.Evaluating procedures is key to in order to recognise whether they work under real conditions, as they should. It is, therefore, important to define parameters that indicate whether certain goals have been achieved. To evaluate the success of ePRO implementation, the following outcome parameters were determined by the on‐site stakeholders:3.3the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ‐C30)the Hospital Anxiety and Depression Scale German Version (HADS‐D)the Short Screening Scale for DSM‐IV Post‐Traumatic Stress Disorder (SSS‐PSD)the EuroQOL‐5‐Dimensions (EQ‐5D‐3L)four additional yes‐no questions assessing the patient's wish for a special psycho‐oncology treatment focus/type of treatment, previous diagnosis of any psychiatric disorder and previous psychotherapeutic treatmentCompletion of the PRO assessment required approximately 30 to 45 minutes and included the followings instruments:3.4ePRO scores guided the frequency and focus of psycho‐oncology sessions, using patients’ HADS anxiety or depression scale scores and their special interest in psycho‐oncology treatment. If no (e)PRO data were available, the default frequency of sessions was assigned.3.5CHES is a software especially developed for electronic collection of PRO data  and its calculation, presentation and secure storage.Allocated user rights regulate access to different software features and differentiate between medical staff, administration officers and patients. Next to administrative features, ePRO data can be remotely collected via an online patient website/portal or onsite using a survey application. Health care professionals can access patients’ data, generate cross‐sectional or longitudinal reports, add ePRO data to the patient's hospital discharge letter and enter/retrieve information about specific interventions. Figure 4The implementation and evaluation process consisted of each three partially overlapping user training sessions and evaluations. Please refer to Figure 4.1Based on ePRO‐scores, the default frequency of four one‐on‐one psycho‐oncology sessions was increased to up to eight sessions. Neither administrative staff nor psycho‐oncologists reported any problems using the recommendations based on the automated algorithm or individually adjusted treatment plans to be inadequate.4.2May 2014: Educational session regarding the rationale for using PRO in cancer rehabilitation, benefits for patients and health care professionals and presentation of software features.October 2014: On‐site troubleshooting analysing data collection procedure and solving technical issues.December 2014: Group discussion on how ePRO could be more efficiently embedded into the clinical workflow.Members of the software company conducted three training sessions for rehabilitation centre personnel involved in ePRO, addressing different aspects of PRO assessments and encouraging open discussion:Approached staff members and stakeholders showed great interest in the provided trainings and evaluations with very high participation rates , even though attendance was voluntary.55.1During a two‐day participating observation of a software company member in October 2014, practical help in software handling was provided. The staff's feedback showed that the response rates were rather low (22%) and that they did not feel well prepared for ePRO‐related critical inquiries of patients. To improve response rates, the cover letter to patients was refined, presenting ePRO as a substantial part of the routine rehabilitation procedure. Furthermore, phone support for front desk stuff was provided between October 2014 and December 2014. By the end of December 2014, patients’ PRO response rates had increased from 22% to 83%.Many patients gave a negative feedback about the questionnaire SSS‐PSD being intrusive and not appropriate. As the adequacy of this measure with regard to content is disputable in a rehabilitation context, it was excluded from the ePRO assessment.5.2In April 2015, a stakeholder  update meeting took place, discussing the current status of the ePRO assessment procedure. Overall, no profound problems, regarding neither IT nor patient‐related aspects, had arisen since the first evaluation.Response rates of patients in ePRO assessments at the beginning of rehabilitation could be further increased to 98%. Since then, participation rates have settled at around 90%.Front desk staff reported reminder phone calls (if patients did not provide their PRO data 10 days before admission) to be less aversive for them, as the provided phone support made them feel better prepared for questions raised by patients. After the deletion of the SSS‐PSD questionnaire, negative feedback from participating patients considerably decreased.On the initiative of the medical director, it was decided to include selected ePRO scores into the medical discharge letter. The scores of six scales of the EORTC QLQ‐C30  were added by providing a table and bar charts. In order to facilitate the interpretation of the ePRO data for, eg, general practitioners, who are typically important medical contact persons for patients and usually not very familiar with ePRO data, norm values were also included.5.3In September 2015, a further stakeholder meeting was dedicated to the discussion of how ePRO assessments can be successfully extended into clinical routine, providing patients’ self‐report data to all health care professionals for their individual use during patient encounter. In addition, the meeting included in‐depth considerations about a feasible ePRO follow‐up procedure.5.4Feasibility: Specific interventions led to improved user feedback: case‐specific software training, advanced information of users about the rationale and benefits of ePRO, discussion about changes in procedures for less disruption of the clinical workflow and adjustments of the clinical information system.Patients’ response rates: After the second training and the adaptation of the cover letter, patients’ initial participation rates have been consistently high (increase from 22% to 83% and later 98%) and patients’ negative feedback has dropped to almost zero after adjustment of the used ePRO instruments (deletion of the SSS‐PSD).Professional users’ acceptance: Each training was attended by at least 80% of professional users, who gave predominantly positive feedback after evaluations. They were open to other areas of application of ePRO and engaged themselves in initiatives for further use of ePRO data.The predefined outcome parameters for successful implementation support the feasibility and acceptability of routine ePRO assessments:5.5The existing IT infrastructure of the rehabilitation centre for the collection and use of ePRO enables the conduct of, eg, follow‐up studies. A 1‐year follow‐up procedure  was implemented in early January 2017 and will contribute to the long‐term investigation of rehabilitation effects, which play an important role in terms of rehabilitation services’ sustainability . Reluctance to conduct PRO assessments continuously often relies on the fact that patients do not see any personal benefit in them and they get tired of just filling in questionnaires. Having access to their personal PRO scores and to tailored self‐help advice, however, involves the patients in their care, provides feedback and can thus generate individual benefit and a greater willingness to participate. This very strategy is used to increase the attractiveness of follow‐up ePRO assessments to patients and to prevent a common decrease in response rates during follow‐up assessments after initially high inclusion rates.6We presented useful steps for achieving a successful implementation of a routine ePRO assessment and exemplified them by describing the process of such an implementation at an oncological inpatient rehabilitation centre. Data on patients’ QOL and psychological distress before and after rehabilitation are reported elsewhere.As suggested by Snyder et al,6.1Though already putting a lot of effort into the pre‐condition and pre‐implementation phases, we can report on some important lessons learned within the presented implementation process. The importance of the careful choice of appropriate ePRO instrumentsThe second evaluation made obvious that the attitude of those staff members who had contact with patients posing critical questions about ePRO assessments plays an important role in their interaction with inquiring patients.6.2The implementation of ePRO prior to and after inpatient cancer rehabilitation was successful and feasible. This was achieved by following a pragmatic implementation strategy, adjusting procedures according to user feedback, conducting on‐site evaluations and providing tailored user training. Different stakeholders were involved over the whole course of implementation. Based on this inclusive approach, stakeholders engaged in further projects setting up follow‐up monitoring and integrating PRO data in the medical discharge letter. Strategic implementation and ongoing evaluation appear to ease the adoption of new techniques.


Clinical outcomes included visual analog scale (VAS) for low back pain and the Oswestry Disability Index (ODI). The distance between the adjacent spinous processes was measured from the preoperative and postoperative CT scan. We calculated and recorded the difference between preoperative and postoperative measurements. Technical procedures and advantages of interspinous plasty are introduced. The three patients showed improvement in terms of the postoperative VAS of low back pain  and ODI  at the 12‐month follow‐up. Compared postoperative ODI index, the ODI index increased from 26.7% to 33.3% and from 24.4% to 28.9% in two of the cases at the 12‐month follow‐up. At 1 week, CT confirmed an obvious reduction in the marginal osteophytes between the adjacent spinous processes. Compared with those on preoperative CT images, the distance between adjacent spinous processes on postoperative CT was enlarged from 1 to 4 mm, and a repeated CT scan 3 months later reconfirmed little recrudescent osteoproliferation. In selected cases, full‐endoscopic surgical treatment for chronic mechanical back pain as part of the phenomena of Baastrup's disease may be beneficial. The operations in this study were performed under local anesthesia, with satisfactory early clinical outcomes and a low incidence of complications or adverse events. This may be a feasible therapeutic method or an alternative option for patients who cannot tolerate general anesthesia surgery.The objective was to introduce a new endoscopic technique‐interspinous plasty for low back pain from Baastrup's disease; based on clinical manifestations, imaging findings and diagnostic test, to discuss a detailed diagnostic procedure for Baastrup's disease; and to explore the mechanism of interspinous plasty in pain relief. To our knowledge, there is no report about the results of endoscopic lumbar technique for Baastrup's disease. This study described the successful full‐endoscopic surgical treatment for Baastrup's disease, providing a brand‐new therapeutic method for patients. Clinical manifestations, imaging findings, including X‐ray, computed tomography (CT) and magnetic resonance imaging, and a “positive” diagnostic test with local anesthetic were used to confirm Baastrup's disease in the three included patients. The interspinous plasty procedure, which aimed to recover a physiological gap between the adjacent spinous processes, was performed by full‐endoscopic resection of marginal osteophytes. The removal of local inflamed tissue and reducing inflammation  The interspinous plasty, aimed to recover a physiological gap between the spinous processes, were performed by full‐endoscopic resecting marginal osteophytes. Our study was designed to describe the successful full‐endoscopic approach for low back pain from Baastrup's disease, providing a brand‐new therapeutic method for patients. Also known as “kissing spines” and lumbar interspinous bursitis, it is characterized by hyperostosis and sclerosis between adjacent spinous processesLow back pain from Baastrup's disease is implicated in mechanical contact between adjacent spinous processes, subsequently resulted in chronic interspinous inflammation. As a clinical syndrome, there are not well‐defined diagnostic criteria of Baastrup disease. In previous study, clinical diagnosis of Baastrup's disease typically relied on patients' symptoms and imaging findings. Baastrup's disease manifests clinically as a long‐term medical history of localized midline lumbar pain, which can be aggravated by lumbar extension and relieved by lumbar flexion.Characteristic imaging findings are usually presented with the “kissing” of closely approximated spinous processes and sclerosis of the articulating surfaces in standard lateral X‐ray. Computed tomography (CT) axial images and sagittal and coronal reconstructions show in detail that sclerosis, flattening and enlargement of the two adjacent spinous processes surfacesHowever, Baastrup's disease is frequently underdiagnosed and often missed owing to lack of knowledge of the disease process or improper diagnostic techniques. As a result, it may lead to inappropriate treatment, treatment delay, even no treatmentWith the rapid development of spinal endoscopic techniques in recent years, full‐endoscopic procedures represent a method of surgical treatment with a smaller “surgical footprint” to treat spinal pathology, such as lumbar disc herniation, lumbar spinal stenosis, and lumbar spondylolisthesisSpecific aims of our study are: (i) to introduce a new endoscopic technique‐interspinous plasty; (ii) to discuss a detailed diagnostic procedure of Baastrup's disease; and (iii) to explore the mechanism of interspinous plasty in pain relief.Inclusion criteria were as follows: (i) diagnosis of Baastrup's disease; (ii) interspinous plasty; (iii) persistent low back pain and conservative measures did not work‐well; (iv) evaluation of pain relief; and (v) case series. Exclusion criteria were as follows: (i) less than 18 years old; (ii) patients experienced radicular leg pain or neurogenic intermittent claudication; and (iii) history of other lumbar surgery.Three patients who experienced recurrent mechanical back pain for more than 1 year, but without associated leg pain were included in this study. Back pain increased with extension, was relieved by flexion and improved only minimally with nonsteroidal anti‐inflammatory drugs  and physical treatments . The focal midline back pain was directly reproduced by palpation over the spinous processes, but no tenderness was observed upon palpation of the lumbar facet joints. Profile views of X‐ray examinations at upright neutral, flexion, and extension positions were performed. Hyperostosis and osteosclerosis of the spinous processes were evaluated by CT. MRI was performed to evaluate edema and inflammation of the interspinous ligaments in fat‐suppressed T2‐weighted images  into the interspinous ligament  with a bevel was docked into the interspinous area and reconfirmed by C‐arm fluoroscopy.The interspinous plasty for case 1 was performed with the patient in the prone position under local anesthesia with 5 mL of 2% lidocaine mixed with 5 mL of normal saline. A blood pressure cuff, pulse oximeter and automatic electrocardiogram were utilized for monitoring. Based on anteroposterior and lateral C‐arm guidance, the surgeon inserted a needle with a 20 mL sterile syringe into the L4 and the superior margin of the L5 spinous processes until the ventral ligamentum flavum was exposed and adequate space was obtained. Significant, excessive extrusion of the ligamentum flavum can compress the nerve root and produce iatrogenic nerve root injury. After excision of the tissue, adequate hemostasis was performed on the internal tissue wound by plasma radiofrequency, and the incision was sewn after withdrawing the endoscopic working cannula  the score is calculated: ) × 100%. From 0% to 20% is considered mild dysfunction, 21%–40% is moderate dysfunction, 41%–60% is severe dysfunction, and 61%–80% is considered as disability. For cases with score of 81%–100%, either long‐term bedridden, or exaggerating the impact of pain on their life.All patients underwent the CT scanner using the 64‐slice spiral CT machine . The following parameter was measured on the CT radiographs: interspinous gap (the distance between the inferior margin of the superior spinous process and the upper margin of the inferior spinous process). An investigator measured the parameter three times, calculated and recorded its average. The interspinous gap was measured again from the postoperative CT scan. Preoperative and postoperative interspinous gaps were comparatively analyzed.Table The three patients showed improvement in terms of the postoperative VAS of low back pain  and ODI  at the 12‐month follow‐up. Compared postoperative ODI index, the ODI index increased from 26.7% to 33.3% and from 24.4% to 28.9% in two of the cases at the 12‐month follow‐up  confirmed an obvious reduction in marginal osteophyte between the adjacent spinous processes. Compared with those on preoperative CT images, the distance between the adjacent spinous processes on postoperative CT was enlarged from 1 to 4 mm (Fig. Chronic low back pain can lead to physical and psychological discomfort and negative effects on one's health and quality of lifeLumbar full‐endoscopic procedures have already become common surgical methods for spinal diseases such as lumbar disc herniation and spinal stenosis, with the clear advantages of safety and effectivenessDuring the 12‐month follow‐up, the ODI index increased from 26.7% to 33.3% and from 24.4% to 28.9% in two of the cases (Table 4‐5 spinous process space was widened on the posterior side and still narrow at the base (Fig. 4 spinous process was not the collision point at the collision moment. The key collision point, caused chronic low back pain, was located in the posterior side of L4‐5 spinous processes space, which had been enlarged by full‐endoscopic partial excision of the L4‐5 spinous processes. Local inflammatory responses to long‐term L4‐5 spinous process impingement was also a cause of chronic pain. The mechanism of pain relief by interspinous plasty may be associated with the surgical enlargement of the interspinous space and the removal of local inflamed tissue, as well as by reducing inflammation via intraoperative saline irrigation.One patient showed an improved VAS score for low back pain and an improved ODI after the operation and at the 12‐month follow‐up, but the postoperative CT showed that the Let al.Singla et al.et al.et al.et al.In 2007, Mitra There is conflicting evidence regarding the clinical efficacy of glucocorticoid infiltration. In general, glucocorticoids have some short‐term benefit for pain relief but no significant long‐term benefitet al.et al.Traditional surgical intervention includes excision of the intraspinous bursa and partial or total removal of the spinous process. Gold and Jang In our study, the patients suffered from a history of mechanical low back pain that increased with extension and was relieved by flexion, without radicular pain or intermittent claudication. The X‐ray images of our patients were characterized by contact between adjacent lumbar spinous processes, known as “kissing spine.” CT showed enlargement, hyperostosis and osteosclerosis between adjacent spinous processes leading to narrow interspinous gaps. MRI showed local inflammation and an edematous zone between the adjacent spinous processes on a fat‐suppressed T2‐weighted sequence. Given the abovementioned clinical manifestations and imaging findings, the patients were finally confirmed to have Baastrup's disease after a diagnostic test with local anesthetic was “positive.” The patients performed an immediate pain relief after the injection of local anesthetic, but localized back pain aggravated gradually in the next 48 h. After failed the conservative treatment, these appropriate patients were scheduled for interspinous plasty.The spinous processes, interspinous ligament, and part of the posterior ligamentous complex play a role in spinal stability4‐5 to reduce exposure (Fig. C‐arm fluoroscopy is an indispensable part of the endoscopic spine procedure that enhances surgical accuracy. The surgeon's exposure to ionizing radiation is harmful and is easily overlookedure Fig. . The abiUndeniably, first, the small sample size and short follow‐up were considered as a major limitation of the presented study. Second, there is no comparison group of other treatment options. Although the patients in this study achieved a good functional recovery, long‐term outcomes are unknown. Moreover, we are unable to draw a convincing conclusion that interspinous plasty is better than other treatments. Compared with spinal fusion, interspinous plasty performed lesser damage to spine motion. The full‐endoscopic approach for Baastrup's disease is a promising technique with its advantages of precision and being a minimally invasive procedure. However, further comparative studies need to be performed to evaluate the efficacy and safety of this method.Various techniques have been proposed to alleviate the mechanical low back pain associated with Baastrup's disease. The full‐endoscopic technique has the advantages of minimal trauma and radiation exposure, rapid recovery and a limited negative effect on spinal stability. This technique was performed under local anesthesia, with satisfactory early clinical outcomes, and avoided the excessive iatrogenic trauma of traditional open operations. In appropriate cases, the full‐endoscopic approach for chronic mechanical back pain as part of the phenomena of Baastrup's disease may be a feasible therapeutic method.


A patient with severe pectus excavatum, dilated ischemic heart disease, and indication for defibrillator implantation for primary prevention of sudden death underwent successful ultrasound‐guided serratus anterior plane block and parasternal block with intermuscular two‐incision technique implantation with no complications. At follow‐up, all the parameters resulted stable with excellent signal sensing. In case of severe pectus excavatum, an ultrasound‐guided serratus anterior plane block and parasternal block with intermuscular two‐incision technique implantation can be useful. It does not require implantation of transvenous or epicardial leads, preventing all related complications. It proved to be a safe and effective system for both primary and secondary prevention of sudden cardiac death.2A 66‐year‐old male patient with ischemic heart disease and severely reduced left ventricle ejection fraction reduction 25%), non‐sustained ventricular arrhythmias, and severe pectus excavatum  was evaluated for S‐ICD implantation  for primary prevention of sudden cardiac death according to current guidelines.5%, non‐s3To our knowledge, this is the first experience of successful S‐ICD implantation in a patient with severe pectus excavatum, performed by combining the intermuscular two‐incision technique with an ultrasound‐guided nerve block strategy for anesthesia/analgesia.The intermuscular 2‐incision approach for S‐ICD implantation was shown to be safe and to result in better cosmetic outcomes and shorter procedural times,In the present case, despite the severe anatomical deformity of the sternum, we succeed in tunnelling the lead using the 2‐incision technique, thus avoiding the superior parasternal incision. Nonetheless, the patient anatomy conditioned the parasternal tunnelling of the lead which was more cranial and lateral than normal. To compensate for the forced vector correction, we decided to position the S‐ICD generator more caudal and posterior than usual (see Figure In conclusion, paying attention to the positioning the system, the intermuscular two‐incision technique with ultrasound‐guided nerve block seems feasible for S‐ICD implantation even in cases of patients with severe chest deformities.4To confirm the feasibility of S‐ICD implantation in patients with severe chest deformities.To describe the implantation technique and the anesthesia/analgesia strategy that allowed successful implantation.Dr. Andrea Droghetti is a consultant for Boston Scientific. The other authors declare that they have no conflicts of interest.Fabrizio Guarracini, Massimiliano Marini, Mattia Strazzanti, and Roberto Bonmassari involved in acquisition of data and drafting of manuscript. Stefano Guarracini, Michele di Mauro, and Andrea Droghetti involved in drafting of the work. Roberto Bonmassari, Andrea Droghetti, and Michele Di Mauro involved in substantively revising the final version.The study was realized according to Helsinki Declaration, and all the ethical committees were respected.The authors have confirmed during submission that patient consent has been signed and collected in accordance with the journal's patient consent policy.


Dietary intakes of macronutrients, vitamins and minerals were assessed using 24‐h recalls at baseline, 3‐month midline and 6‐month endline, with repeat recalls in a subsample. Usual nutrient intake and micronutrient density distributions were modelled to estimate group means and prevalence of inadequacy. Group differences at midline and endline were tested using unequal variance t tests with bootstrapped standard errors. The egg intervention resulted in higher intakes of fat and protein and lower intakes of carbohydrates. The egg group had lower prevalence of inadequacy for selenium, vitamin A, riboflavin, vitamin B5, vitamin B12 and choline. Micronutrient density inadequacy was lower in the egg group for vitamin A and choline at midline and endline, riboflavin at midline and vitamin B5 at endline. Inadequacy of nutrient intakes or density remained highly prevalent in both groups for multiple micronutrients. Though the egg intervention increased intakes of protein and several micronutrients, total intakes and micronutrient density of multiple micronutrients remained far below recommendations.Eggs are a rich source of multiple nutrients that support child growth and development. Provision of eggs as a complementary food may improve dietary adequacy among young children at risk for undernutrition. Our objective was to test the impact of an egg intervention on the adequacy of total nutrient intakes and micronutrient density among 6‐ to 15‐month‐old Malawian children. Children 6 to 9 months old, living in Mangochi District, Malawi, were randomly assigned to the intervention group ( Eggs provide complete protein and several micronutrients critical for growth and development. This study analysed the impact of daily provision of eggs on nutrient intake adequacy among 6‐ to 15‐month‐old Malawian children.Though an egg complementary feeding intervention increased intakes of some nutrients essential for child growth and development, the diets of study participants remained highly inadequate in multiple micronutrients.To meet the micronutrient needs of young Malawian children, intensive programs to support dietary diversification and increase accessibility and use of multiple micronutrient powders or fortified foods may be required.112, choline and selenium  higher than children in the control group after 6 months of intervention, and stunting was reduced by 47% . The trial and primary outcomes have been previously described , moderate or severe acute malnutrition (mid‐upper arm circumference <12.5 cm), acute illness or injury warranting medical care, non‐singleton birth, or congenital condition or chronic illness that could impact growth, development or feeding. Caregivers participated in an information session about the study prior to completing the individual informed consent process and marking or signing a written consent form.Baseline assessments included anthropometry, questionnaires on demographics, socio‐economic status and food security  included all children from 11 villages out of the 72 villages in the study area. The subsample villages were selected by stratified random sampling from traditional government administrative areas. Because enrolment was slower than anticipated, recruitment into the subsample was expanded to include all children enrolling in the trial in June 2018.The 24‐h recall followed a multiple‐pass approach and was conducted using the Open Dietary Recall System (OpenDRS), an open‐access 24‐h recall form, deployed through SurveyCTO  on Android tablets . One hundred twenty‐six recipes were selected to represent the mixed dishes most commonly reported in the 24‐h recalls conducted in the first 11 months out of the 12 months of study implementation, as well as the range of distinct ingredient combinations and preparation methods. Study staff weighed all ingredients and the final cooked recipes using food scales. Each recipe was prepared 5 to 20 times, with more replicates for the most common recipes. For less common recipes, the cooks were asked to portion out ingredient quantities they would use to prepare the recipes, and cooked weights were estimated using yield factors from similar recipes. Median ingredient proportions, expressed as percentage of cooked recipe weight, were used to create standard recipes. For uncommon mixed dishes, recipes were estimated based on ingredient proportions and yield factors from similar recipes. Staff measured the weight and volume of samples from cooked recipes and locally purchased foods and drinks to obtain density estimates.2.2.3To calculate observed nutrient intakes, we converted portion sizes recorded in millilitres to grams using local food density data or density values from the University of Minnesota Nutrition Data System for Research (NDSR) data tables, 2017 edition  FAO, . As reco2.2.5https://osf.io/vfrg7/). p values less than 0.05 were considered significant unless otherwise stated. Descriptive statistics were used to summarize participant characteristics.All statistical analyses were conducted in SAS 9.4 . The statistical analysis plan was posted prior to starting analysis (n = 14). Standard errors and 95% confidence intervals for each outcome measure were generated by analysing 200 bootstrap samples drawn by simple random sampling with replacement. At baseline, all participants were pooled in nutrient intake models because energy and animal source food intakes were previously found to be the same between the egg and control groups  method for estimating usual nutrient intakes from 24‐h recall data with one recall per participant plus repeat recalls in a subsample was used for all dietary analyses . To estimate prevalence of inadequacy, we applied the nutrient intake requirement corresponding to the child's age on the day of the recall interview to pseudo‐individual intakes generated by the Monte Carlo simulation within the DISTRIB macro. This binary indicator of inadequacy was averaged across the simulated data to estimate prevalence of inadequacy. Estimated average requirements (EARs) or adequate intakes (AIs) for 6‐ to 12‐month‐old and 1‐ to 3‐year‐old children from the National Academies of Science, Engineering and Medicine (NASEM) were used as the cut‐offs for all nutrients except zinc and iron  and DISTRIB (v.2) macros published by NCI  . In the egg group, mean DIAAS was 94 at midline and 95 at endline. In the control group, mean DIAAS was 86 at midline and 88 at endline. In both groups and at all time points, the most frequently limiting amino acid was lysine.At midline and endline, children in the egg group had lower carbohydrate, higher fat and higher protein intakes than children in the control group Table . Carbohy5, vitamin B12 and choline at both midline and endline  that the egg intervention had modest impacts on the prevalence of inadequacy despite increasing intakes. To meet the micronutrient needs of this population, much more intensive programs supporting dietary diversification and delivering multiple micronutrient powders or fortified foods may be required, along with programs to address other constraints on growth such as infectious disease  or so high (e.g., vitamin BWe used 24‐h dietary recalls at baseline, midline and endline with repeat recalls in a subsample of participants to conduct a detailed analysis of nutrient intakes and micronutrient density among participants in the Mazira Project. The collection of detailed dietary intake data with repeat observations throughout the course of the intervention is a key strength of this study. An additional strength is our application of tools from NCI to model usual nutrient intakes and estimate prevalence of intake inadequacy after controlling for measurement error associated with day‐to‐day intake variation (NCI Division of Cancer Prevention Biometry Research Group, 12 (Dror & Allen, Our study is subject to the same limitations of all studies that rely on 24‐h dietary recall data, including omitted or added foods, errors in estimation of portion sizes and missing or inaccurate food composition data Gibson, . The stup values and confidence intervals that must be interpreted cautiously for very high or very low prevalence estimates. Where this method has yielded negative values for the lower confidence interval bound, we have retained it to acknowledge the imprecision in the estimate. A further potential methodological limitation is that we have not applied a correction for multiple hypothesis testing to the p values calculated from the bootstrap standard errors. However, the statistical tests are not independent due to the nature of the correlation of the nutrients within the food provided, and our key findings remain well below the p value threshold we would have obtained using a conservative Bonferroni correction based on analysis of 18 nutrients at each time point. We have interpreted our findings in consideration of the nutrient composition of eggs and the nutritional or public health significance of observed differences. Given these considerations, our conclusions are unlikely to be substantially affected by these methodological limitations.A limitation of our analytic approach is that using bootstrapping to generate standard errors for prevalence of inadequacy yields Our estimates of nutrient intakes and prevalence of nutrient intake inadequacy should be understood in the context of assumptions we made about nutrient intakes from breast milk. First, we used estimates of the nutrient contents of breast milk from the WHO and IOM (IOM Food and Nutrition Board, 5, vitamin B12, selenium and choline (Iannotti et al., In this dietary assessment of the Mazira Project complementary feeding trial, we found that provision of eggs for daily consumption to rural Malawian children age 6 to 15 months improved micronutrient intakes and intake adequacy for nutrients of which eggs are a rich source, such as vitamin A, riboflavin, vitamin BThe authors declare that they have no conflicts of interest.The Mazira Project randomized controlled trial was designed by CPS, CKL, KMM, LLI and ELP and conducted by CPS, KMM, BLC and CDA. Dietary data collection was designed and managed by BLC. Recipe data collection was conducted by ERW and BLC. Data analysis was performed by BLC and CDA. BLC wrote the manuscript. All authors provided critical revisions and approved the final version.Table S1. Nutrient composition of eggs purchased in Mangochi District, Malawi, 2018 and nutrient composition of eggs listed in FoodData Central††Table S2. Usual crude and digestibility‐adjusted amino acid intakes at 3‐month midline and 6‐month endline assessments, by treatment group, among children enrolled in the Mazira Project, Mangochi District, Malawi, 2018–2019Click here for additional data file.