Diagnosing urinary tract infections (UTI) in nursing home residents is complex, due to frequent non-specific symptomatology and asymptomatic bacteriuria. The objective of this study was to explore health care professionals’ perceptions of the proposed use of inflammatory marker Point-Of-Care Testing (POCT) in this respect.n = 12) and nurses (n = 6) from 13 nursing homes in the Netherlands. Most respondents were not familiar with inflammatory marker POCT, while some used POCT for respiratory tract infections. Both the interview guide and the analysis of the interview transcripts were based on the Consolidated Framework for Implementation Research.We conducted a qualitative inquiry (2018–2019) alongside the multicenter PROGRESS study (NL6293), which assessed the sensitivity of C-reactive protein and procalcitonin POCT in UTI. We used semi-structured face-to-face interviews. The participants were physicians (All respondents acknowledged that sufficiently sensitive POCT could decrease diagnostic uncertainty to some extent in residents presenting with non-specific symptoms. They primarily thought that negative test results would rule out UTI and justify withholding antibiotic treatment. Secondly, they described how positive test results could rule in UTI and justify antimicrobial treatment. However, most respondents also expected new diagnostic uncertainties to arise. Firstly, in case of negative test results, they were not sure how to deal with residents’ persisting non-specific symptoms. Secondly, in case of positive test results, they feared overlooking infections other than UTI. These new uncertainties could lead to inappropriate antibiotics use. Therefore, POCT was thought to create a false sense of confidence.Our study suggests that inflammatory marker POCT will only improve UTI management in nursing homes to some extent. To realize the expected added value, any implementation of POCT requires thorough guidance to ensure appropriate use. Developing UTI markers with high negative and positive predictive values may offer greater potential to improve UTI management in nursing homes.The online version contains supplementary material available at 10.1186/s12877-020-01853-9. The most common infections in nursing home residents involve the urinary tract –3. At anDiagnostic tests to confirm UTI in nursing home residents are not yet available. Our current research focuses on the sensitivity of two blood inflammatory markers , measured in point-of-care testing (POCT) to support diagnosing UTI . ProvideTo ensure realization of its potential added value in improving appropriate antibiotic use, POCT should be carefully implemented in nursing home practice. However, any successful implementation of health care innovations is complex , 19. CurIn this qualitative study, we used semi-structured interviews to identify physicians’ and nurses’ perceptions of the proposed use of inflammatory marker POCT in the management of UTI in nursing home residents.The present study was conducted alongside the PROGRESS study (NL6293) , which aWithin this convenience sample of nursing home organizations, we used purposive sampling to maximize the variety of respondents in the study . This hen = 12) and nurses (n = 6), as both professions were involved in UTI management at that time and expected to be involved in the future use of the inflammatory marker POCT  to ensure reliability. The coding tree  and users , and covered somatic, psychogeriatric as well as rehabilitation care. The majority of participants were female (14 out of 18). The median number of years of work experience was 17 (range 0.5–35 years).All 18 physicians and nurses we invited agreed to participate  has no added value as there is no diagnostic uncertainty, but that attaining such diagnostic certainty was only possible in a small minority of nursing home residents able to adequately express complaints.Well, if you’re not in doubt, then there’s no need, is there? If someone shows the full set [of symptoms], then in my view there’s no point in confirming it with POCT.A-IVThen it’s fairly obvious. But the group who are able to express this clearly and accurately is very small.B-IVThe other respondents implicitly agreed with this limitation of the scope of POCT, as they only discussed testing in the context of residents with non-specific symptoms.All respondents primarily expected POCT to decrease diagnostic uncertainty by ‘ruling out’ UTI in residents with non-specific symptoms. Negative test results were considered to be an objective measure of the absence of UTI.But sometimes you’re faced with people where you think: well, this is really very very different from what we usually see. And you then want to exclude [a UTI] some way or other, as it might still be that.A-IISo you want to have something more objective [...] regarding the severity of illness, to help you decide. So that [if the POCT] is below 20, you think, well, we can just as well wait and see.A-VIIIBut several respondents expressed concerns about false negative test results, which could lead to erroneously withholding antibiotic treatment in nursing home residents with a UTI.So I test it, and it’s a CRP [POCT] of 2. So at any rate you know it’s not an obvious infection. [But] I’m not sure it’s that reliable.A-VThe danger might be that someone is not treated who should be treated, as they would otherwise become more severely ill of their complaints persist.C-IHaving POCT as an objective measure in addition to clinical reasoning was perceived as important to convince others, such as family members and professional caregivers, of the appropriateness of withholding antibiotic treatment from residents with non-specific symptoms.If POCT is zero, you can then say well, this is definitely not it. So you have a stronger argument. [ … ] You have an objective finding, in addition to what I see or hear myself. Not that I think that’s not reliable, but relatives often want a test or a scan.B-IIHowever, some respondents also admitted that POCT as an objective measure was of additional importance to corroborate their own clinical reasoning, for instance because it could support them in taking another direction in their diagnostic reasoning than just considering UTI.You want to check that your clinical impression is right. We doctors like that. To have some proof.A-VIAnd that enables you to change direction sooner with this, well, in this area.A-IIAlthough POCT was perceived as helpful for ‘ruling out’ UTI in nursing home residents with non-specific symptoms, their symptoms generally persisted. Respondents reported that in such cases diagnostic uncertainty remained. Hence, this could induce a feeling of unease, which in turn could lead to prescribing antibiotics after all.But I would be [ … ] skeptical at first. Like, well, the CRP [POCT] is lower, so now I can’t treat them for UTI. [But] what then?C-IAnd so you either start to treat because you feel you have to do something [ … ] Or you don’t, and then the complaints often persist anyway … And so at a later stage you still start to treat.A-VAlmost all respondents additionally thought POCT was a useful tool for ‘ruling in’ UTI. The inability of many nursing home residents to adequately express their symptoms made it difficult to rely on clinical reasoning alone. As an objective measure, POCT could reduce this diagnostic uncertainty, since positive test results would confirm UTI diagnosis and justify antibiotic treatment.That would be really helpful. [ … ] You can do an abdominal exam. But is it tender: is it constipation or a bladder infection? Or do they just dislike the fact that you’re touching their belly? So for us, diagnostics is still a kind of intuition, and such a test would actually …A-IVAnd if I then also find an elevated CRP [POCT], that would be an argument to say this is really a UTI. As I don’t have any other instrument.B-ISome respondents also thought that POCT could speed up the diagnostic process, and thus the start of antibiotic treatment for UTI, as it is a ‘rapid test’, and its objective nature could compensate for suboptimal clinical attention.Perhaps it’s more a matter of seeing that if the POCT is elevated, you’ll give an antibiotic sooner, whereas that person would only become really ill tomorrow; so you [ … ] can get a timely start.D-IBut at [psychogeriatric wards] for instance, where there is less close clinical surveillance, there might be a group that you could treat a bit sooner.A-VYet, in order to fulfil its supporting role in ‘ruling in’ UTI, it was acknowledged that POCT values should exceed a certain threshold in residents with a UTI, even in residents with non-severe illness or presenting with non-specific symptoms. The latter was doubted by some respondents.People may not be completely healthy, but not terribly ill either, so you think: it might be a UTI. But whether [ a POCT] would really rise that much in that kind of infection [ … ] I wonder.B-IVDespite the perceived advantage of POCT for ‘ruling in’ UTI, various respondents thought that positive test results might give rise to new diagnostic uncertainties. Due to the limited specificity of general inflammatory markers, positive results could also indicate the presence of other infections. Therefore, treatment decisions remained dependent on clinical reasoning.You don’t know where the infection is located. It doesn’t have a specific … It could be anywhere. [ … ] You get all kinds of infections with the same signs. [ … ] You have to look at that carefully. [ … ] So [POCT] is just an addition to the toolkit.B-IAs a result, some respondents feared that the limited specificity of a POCT could lead to inadequate treatment, such as prescribing antibiotics for UTI while the resident is actually suffering from another infection.If you have someone with vague symptoms and a high [POCT], do you then know it’s a urinary tract infection? [ … ] The danger is that there’s an infection elsewhere, and that you treat them with nitrofurantoin and that that has no effect.B-IVHence, in the case of non-specific symptoms, some respondents recommended either combining POCT with further examination of clinical symptoms to exclude infections other than UTI, or not to use POCT at all in residents suspected of having another infection besides UTI.You preferably want to get it in context as much as possible. So not someone who also happens to have a cough and has just arrived on the rehabilitation ward, and might have a cystitis. Cos then you don’t know what you’re measuring.A-VPOCT was thought to reduce diagnostic uncertainty if the test results matched the respondents’ clinical reasoning. In case of disagreement between the two assessments, respondents reported different ways of balancing them against each other. Sometimes, clinical reasoning prevailed: respondents explained how they would either refrain from antibiotic treatment in residents who were not very ill despite positive tests results, or would start such treatment in severely ill residents despite negative test results.When I see a CRP of 100 and the patient doesn’t appear ill at all, I will not refer them to hospital straight away purely on [the basis of] this CRP.A-VSometimes you might do a POCT … And then you think, well, that’s not very high. And still the patient is so ill that you give them an antibiotic anyway.D-IIIn other situations of disagreement, POCT results would overrule clinical reasoning. For instance, some respondents reported they would start antibiotic treatment in response to positive test results in residents who were not very ill. An important reason to do so was the general frailty of the resident.And in case of doubt; if I do see an elevated CRP [POCT] that makes me think right, there’s something going on there. And especially if it’s a very vulnerable patient, then I’ll think: let’s start treatment anyway.B-IIWhen balancing the results of POCT with the clinical work-up, some respondents acknowledged the importance of support for nursing home staff in the interpretation of POCT, given the characteristics of a particular test.I think it’s more important for us to get clinical training about how to interpret test results and when to use them. [ … ] How about the specificity and sensitivity, can you use it to rule out, can you use it to rule in?B-IIIYou ought to know the predictive value of a test. [ … ] It’s just that we tend to forget that all the time.D-IISeveral indications other than diagnosing UTI were mentioned for POCT. Firstly, respondents suggested that POCT could be useful to (1) demonstrate if a resident is suffering from any infection in general, as well as to (2) confirm specific infections that are common in nursing home residents.And also to decide whether someone is not the way they usually are, or we can’t find out exactly what’s the matter. Then it’s sometimes interesting to know, well, could [it] have to do with an infection?A-VIIIThat would be good, as for instance cellulitis, that’s sometimes an unclear picture here at the nursing home. [ … ] Then you have a much more powerful argument to start antibiotics.A-VSecondly, respondents explained that POCT could be helpful in distinguishing infectious from non-infectious disorders with comparable clinical manifestations.Of course sometimes you get vague abdominal symptoms that make you think: is this a cholecystitis or gall stones or what? I could imagine that you might be able to differentiate with that too.A-IVThirdly, POCT was regarded as a useful tool to indicate infection severity, to monitor the course of an infection, or to predict a resident’s prognosis in general. In such cases, POCT could, for instance, help to decide whether to consult a specialist or whether to refer a resident to an emergency department.Yeah, sometimes you get people who deteriorate, and you can’t put your finger on it. Is it an airways infection rather than a urinary infection? So you’re at a loss. And you then check which way it’s developing. For prognosis too.A-IVIf people are ill and you ask yourself can I safely leave this patient here or should I refer them to an orthopedist for a check-up as we’re thinking it might be an infection of the hip, for instance.D-IIAt the same time, most respondents questioned the evidence base for these other roles, and noted that cut-off values for interpreting POCT results should be, but were currently not, available for these additional applications.Except, well, it’s not really intended for, we don’t have official cut-off values. Well. So then it’s still your own interpretation of the overall …A-VIIIWell, so where’s the threshold? I think it’s very important to put it in context and link it to the evidence base.A-VIn our qualitative study, we examined the expected use and benefits of inflammatory marker POCT to support UTI diagnosis and appropriate antibiotic use in nursing home residents. The intended users expected that POCT would to some extent reduce diagnostic uncertainty in residents with non-specific symptoms. They primarily regarded POCT as an instrument to rule out UTI and withhold antibiotics accordingly. However, in the case of negative test results, they would still feel uncertain about how to deal with persistent non-specific symptoms. In addition, they expressed that using a sufficiently sensitive POCT could be helpful to rule in UTI and serve as additional confirmation to justify starting antibiotic treatment. However, in the case of positive test results, POCT was also expected to introduce new diagnostic uncertainties, due to the limited specificity of general inflammatory markers, which in the case of other infectious or inflammatory diseases could result in false positive findings. Because of the limited specificity, the intended users also perceived POCT as a useful tool to identify and monitor other infections that are common in nursing home residents. Irrespective of its purpose, respondents generally expected that POCT carried a risk of creating a false sense of confidence. Therefore, carefully balancing test results with clinical symptoms would remain important in UTI management in residents presenting with non-specific symptoms.Physicians and nurses in our study primarily regarded POCT as a helpful tool to rule out UTI, which indicates that they are mainly in need of diagnostic evidence to withhold antibiotics in nursing home residents presenting with non-specific symptoms. Supportive diagnostics could corroborate their own decision-making, which currently relies solely on subjective assessments, and could strengthen their arguments towards care assistants and family members, who might demand antibiotics. In previous studies, general practitioners similarly emphasized that POCT for RTIs contributes to a more robust diagnosis and benefits the management of patients’ expectations about prescribing antibiotics –23, 30. Our results indicate that if general inflammatory marker POCT is to be implemented in UTI management in nursing homes, attention needs to be paid to several issues. Firstly, it should be clear to the intended users how to interpret POCT results, given the positive and negative predictive values in the setting where the test is used. Secondly, health care professionals using POCT could benefit from additional communication training. Similar to studies in general practice –23, our out, respondents regarded POCT as a useful tool to rule in UTI. Yet, they noted that other infectious diseases that are prevalent in nursing homes could cause false positive test results due to the non-specific nature of inflammatory markers. In such cases, new diagnostic uncertainties could arise which again could misguide antibiotics treatment decisions. Compared to previous studies, this is a new finding, which applies especially to the unique population of nursing home residents with their limited ability to express specific symptoms compared to other (adult) populations [Apart from ruling ulations , 7. The ulations , 36. StiIn view of the non-specific nature of inflammatory markers, various other potential uses of POCT were mentioned by our respondents, e.g., diagnosing and monitoring other infectious and inflammatory diseases. Although such an extension of the scope of POCT is in line with findings in general practice , severalThe number of respondents in our study was limited, and the analysis was not conducted in parallel to the data collection. Therefore, data saturation could not be ensured. Also, comparing different subgroups  was not possible. Such a comparison might be of interest in future studies. However, given our heterogeneous sample, we assume that our rich data adequately reflect the wide variety of perceptions regarding the added value and conditions for implementation of inflammatory marker POCT in the management of UTI in nursing home residents .The sensitivity of POCT in UTI had not yet been established at the time of this study. It is unlikely that this has influenced our results, however, as most respondents mentioned sufficient sensitivity as a requirement for effective POCT use. Once adequately high sensitivity of POCT in UTI is established, further research in nursing homes should be conducted to gather additional information on interpreting cut-off levels and intermediate test results, as was done in previous studies in general practice , 23.At the time of this study, POCT was not yet being used to diagnose UTI in nursing home residents. Only two of our respondents were actually working with an inflammatory marker POCT, although this was for suspected RTI. As gaining experience in using a new test may require some time, and perceptions on POCT may change during its use, further studies should explore perceptions during or after POCT implementation.Our qualitative study indicates that inflammatory marker POCT has limited perceived added value for UTI management in nursing home residents. Future users expected POCT to reduce existing diagnostic and treatment uncertainties to some extent, but also to introduce new such uncertainties, and therefore merely create a false sense of confidence. In order to improve UTI management, inflammatory marker POCT, if found sufficiently sensitive, should be implemented very carefully to ensure appropriate use. Developing UTI markers with sufficient negative and positive predictive values may be more beneficial in improving UTI management in nursing homes.This manuscript was written in accordance with the COREQ reporting guidelines .Additional file 1. Interview guideAdditional file 2. Coding tree


The natural integration of mobile phones into the daily routines of families provides novel opportunities to study and support family functioning and the quality of interactions between family members in real time.This study aimed to examine user experiences of feasibility, acceptability, and reactivity  of using a smartphone app for self-monitoring of family functioning with 36 participants across 15 family dyads and triads of young adolescents aged 10 to 14 years and their parents.Participants were recruited from 2 family wellness centers in a middle-to-upper income shopping area and a low-income school site. Participants were instructed and prompted by alarms to complete ecological momentary assessments (EMAs) by using a smartphone app over 2 weeks 4 times daily . The domains assessed included parental monitoring and positive parenting, parent involvement and discipline, parent-child conflict and resolution, positive interactions and support, positive and negative affect, sleep, stress, family meals, and general child and family functioning. Qualitative interviews assessed user experiences generally and with prompts for positive and negative feedback.The participants were primarily white and Latino of mixed-income- and education levels. Children were aged 10 to 14 years, and parents had a mean age of 45 years (range 37-50). EMA response rates were high (95% to over 100%), likely because of cash incentives for EMA completion, engaging content per user feedback, and motivated sample from recruitment sites focused on social-emotional programs for family wellness. Some participants responded for up to 19 days, consistent with some user experience interview feedback of desires to continue participation for up to 3 or 4 weeks. Over 80% (25/31) of participants reported increased awareness of their families’ daily routines and functioning of their families. Most also reported positive behavior changes in the following domains: decision making, parental monitoring, quantity and quality of time together, communication, self-regulation of stress and conflict, discipline, and sleep.The results of this study support the feasibility and acceptability of using smartphone EMA by young adolescents and parents for assessing and self-monitoring family daily routines and interactions. The findings also suggest that smartphone self-monitoring may be a useful tool to support improvement in family functioning through functions of reflection on antecedents and consequences of situations, prompting positive and negative alternatives, seeding goals, and reinforcement by self-tracking for self-correction and self-rewards. Future studies should include larger samples with more diverse and higher-risk populations, longer study durations, the inclusion of passive phone sensors and peripheral biometric devices, and integration with counseling and parenting interventions and programs. Research demonstrates that family processes in daily routines and settings have significant impacts on children’s development and well-being -4. The fEngaging families in therapeutic activities addressing family processes in real time during daily routines is a persistent challenge in interventions and research . The broevents   taken another kind of like testy thing. I always liked taking them and I hardly took ‘em, so this was like, “Finally. Yay! I can do another one.”male child (14 years), family 5The same participant also noted the convenience of smartphone surveys in comparison to web-based surveys on a computer:I think it’s better, kind of, to take the phone surveys because it’s kind of way more convenient for people that are busy, ‘cause they’re shorter and you can take ‘em wherever, anywhere you go. …Web surveys, you have to be on a computer, and you have to have time. And, so it may not be useful or good for people with a busy schedule.male child, 14 years, family 5Participants reported a few minor technical problems associated with the mobile phone, such as slow uploading of data or having to power the phone off and on to upload data. Some participants reported problems with the app freezing or force closing when they were trying to complete a survey. A few participants reported that they were not receiving reminders  to complete the surveys after a period.Some participants noted that the survey questions needed to be geared toward the time of year. For example, for a number of participants who participated during the summer school break, questions about school and homework were inappropriate:There were parts that didn’t seem to apply because it seemed like the survey was sort of designed to assess children when they’re in school. So, since it’s summer, sometimes, you know, the questions didn’t seem to apply, and then particularly with the, the final assessment, there was a lot of stuff about school. So, some things we didn’t know how to respond to…mother, family 6With regard to the smartphone EMA, 10 participants reported finding the end of day bedtime survey burdensome because it was long, and several noted being tired:The only thing that I would say is, I thought the evening one was really long. And, I think that the evening one should have been short. I think the length should have switched…[the] afternoon could have been the longer one, and the evening one could have been shorter, because I… I took it at like ten or whatever, and I was already really tired and I didn’t really want to take a really long survey.male child, 13 years, family 8Some noted the value of the longer end of the day survey. For example, one mother noted the end of the day survey allowed her to reflect on her day:Yeah, I mean, obviously, the last one of the day was longer, so that was the only thing. Like if I wasn’t taking it at a decent hour, and I was super tired… that was the only, the only thing about that. But, I mean, I think that’s when you have to have the long one because that’s when you’re really reflecting on everything that happened that day.mother, family 8Some participants also felt that there were just too many surveys to do each day:Well, I think having to answer four times a day was too much. I would have preferred like breakfast, lunch and dinner. The wake up and the, you know, so that was a little annoying, just a little bit. And then, after so many days, it was like, “Oh my God. Did I do this?”mother, family 5Some participants noted the value of multiple surveys over the course of the day for transient states as a means of checking in and reflecting:I think it was good timing ‘cause, you know, in the morning, when you wake up, you have a different mood, and then in the afternoon, you have a different, and then you have different like every two hours or three.female child, 12 years, family 13A few participants noted that it was difficult to complete surveys on weekends when daily activities and schedules are less routine:I know that some days, it was more of a challenge to complete them kind of in the actual set time, especially on the weekends is really hard because by not being sort of on that same schedule.mother, family 1Most participants found the 2-week study period a good time period:No, I think that’s perfect [two weeks]. I think that was really, that was really good. It, it was just long enough to where it became a habit and you’re makin’ sure you aren’t forgetting it. And then, but then towards the, near the end, you can just tell for, lookin’ forward to just bein’ finished ‘cause it does become a burden…father, family 1However, a few participants suggested a longer duration, particularly to support behavior change:I, to be honest with you, I found myself wanting to continue….Two weeks would be a minimum. A month would be a maximum. You know, for me in my imaginary world - three weeks would be ideal, just because it, it gives you that, that first week - it was more about, “Hey,” at least for me, it was like, “Okay. Let’s just follow the behavior.” The second week, it was like, “Okay. How am I gonna improve the behavior.” But now, I don’t have a chance to see if, to implement it, and to see how, how it’s going. So, I was like, “Hey, okay. We have to give the phones back, alright.” (laughter) So, that, that left, that left me wanting more.mother, family 2Probably about a week longer, but any more than that, I think it would have gotten like really repetitive and the answers would have all been the same.female child, 13 years, family 7Participants noted that they would have liked the feedback from their participation in the study to know the findings from the survey and how these could help them and their families improve their relationships. Parents were very interested in getting more feedback from the study to improve their parenting skills and strategies. For example:I think, eventually, if this was gonna be something more, intervention oriented, it would be interesting, that kind of assessment, even if it’s something like, sort of the average, an average for the family and, and how that changes depending on, sleep or, I don’t know. Changes in communication. I’m kind of more interested in just our overall picture as a family. And, where we need to improve…and I could sort of pick up on that based on the things that we were being asked.mother, family 6Over 80% (25/31) of the participants reported increased awareness of their relationship dynamics with their child/parent, their own behavior, or their communication styles. Of the 5 participants who did not report changes in awareness of their family routines, 4 were children. For many participants, study participation provided novel opportunities to reflect on their family routines in general:I thought it was a very good exercise in terms of just self-reflection on things you do every day… you get on automatic pilot sometimes. You don’t stop and really consider, “How, how did that go?” (laughter) So, I like that aspect because it sort of forced me to check in with myself and see how things were going.mother, family 1It’s basically somethin’ out of the ordinary, (laughter) to kind of express your feelings throughout the day. …But, to me, it was a productive kind of thing because, when you’re thinkin’ about what’s goin’ on for the day, you were able to reply too. I thought I was just holding it in, letting it out, you know, at the end of the week or somethin’.father, family 5One child noted increased awareness of his lack of contribution to household chores from 1 of the question prompts:This question in particular, “I’m not as responsible as I should be.” I answered that, I’m like, “You know what? I, I think I agree with that.” And, that made me feel kind of bad. So, from, from that point on I started doing, now I unload the dishwasher.male child, 12 years, family 11These themes of reflection-seeding behavior change are represented throughout participants’ feedback on their experiences in more specific domains (described below).Several parents reflected on decision making in the family as a result of self-monitoring. For example, 1 noted:Well, it made me think about how we decide is this something we’re gonna give [daughter] input into? Or, is this something we just decide because, you know, we’re the parents? It kind of made me think, sometimes do we give her too much input? (laughter)mother, family 10I see. You were becoming aware of how family decisions were…?interviewerYeah, how family decisions were made I really wish my husband could have taken it. It would be good for him too. And, it was just kind of interesting to think about…mother, family 10Children, in particular, described increased awareness of parental monitoring. For example, 1 child noted:I realized my mom stays out of my life and I stay out of hers. (laughter)… ‘Cause, I don’t, I tell my mom some things….And, she never really asks what I’m doing. Like she, she pretty much knows like “he was outside,” or “he was on the computer.” She doesn’t know specifically what I’m doing, but she’s always got a vague idea, so….I think that’s what I realized the most…some of the different questions like, “Did your parent know where you were at night?” …It made me realize, yeah, she pretty much always knows where I am, even when I’m not using my phone. So, I’m like, “I guess we are pretty connected.”male child, 12 years, family 11Participants reflected that the quantity and quality of time spent together were both important. One parent reported becoming aware of how seldom her family ate together:It makes you think about stuff. Like, are we talking? Are we eating together? And, it’s kind of embarrassing like, “Ugh,” we eat alone, or so and so ate with so and so. You know? That was cool for us as a family to think, “Oh my gosh. We don’t eat together.”mother, family 5In addition to self-reflective functions, families noted how EMA/diary self-monitoring helped them to be more accountable or consistent with their values or goals for their families. For example, 2 parents indicated an element of accountability from self-monitoring in regard to time with family:The process and the idea behind it, I thought was actually really good, ‘cause it helps you be more conscious about spending time with your child and in, especially ‘cause you know you’re gonna be reporting it later, so you want to make sure you have some good things to put in there, as opposed to bad. So, I think it helps people be conscious of that relationship.father, family 1This father noted how the anticipation of reporting influenced his behavior. One mother noted more direct reminder functions:But… it does make you think that maybe you should… just be more in touch, communicate more. You know, one thing that struck me was… the leisure time, spending fun time with your child…I’m working full-time, I’m not gonna have that, but on the weekend, you know? … I think it does sort of, at least for me, remind me that I do need to spend fun time with my child….mother, family 6Her daughter also noted becoming aware of needing to spend more time with her parents and considering a change in her routine:I’d think back on like how I reacted to some things or the interaction I had with my parents. Like maybe I should be out in the house more, not in my room.female child, 14 years, family 6Participants noted reflection, awareness, and some changes in patterns of communication in the family, including themes of limited time, positive or negative tone, praise or critique, and openness. For example, a mother stated:I liked it [self-monitoring app]. It actually made me more aware of how my daughter and I communicate, and when we communicate.mother, family 10Another mother noted how she became aware of how little she communicated with her child:But, in terms of the way I interact with my son, it was good because I didn’t realize how little I actually communicated with him. So, in some ways, I felt good about myself because I felt like, “Oh, well, I think I really trust my son because I don’t feel a need to constantly see what he’s doing or talk to him.” But then on the other hand, I thought, “Wow, two weeks has gone by and, really, we didn’t make time to talk.” So, it just made me a lot more aware.mother, family 11The son in this family also noted reactivity to self-monitoring and becoming aware of limited communication with his mother and that most often it involved giving him instructions:I realized, I don’t spend that much time communicating with her. Like it’ll be like 10 minutes here, 20 minutes there, a minute there. Usually, it’s just we talk for a second and say like, “You gotta do this.” I’m like, “Okay.” And then I go do that, and that’s pretty much it.male child, 12 years, family 11Other families noted that self-monitoring reactivity led to more frequent communication:I ended up speaking more to them - to my wife and my, my son, my other son too. Trying to eat dinner with them, trying to make more family time, you know?father, family 5A few participants noted increased awareness of needing to focus on positive communication and not just negative issues, and making changes based on this awareness:I don’t think that either S. [father] or I are big complimenters and,…it tends to run more negatively, which I think when you really think about it, you go, “Oh, that’s not, that’s not really how I want to be, and that’s not how I feel, really.” It’s just trying to keep him afloat and making progress all the time, that you sort of get in these grooves. And so, I do think it was helpful, like I tried to… compliment him when he did something well.mother, family 8One father noted how the EMA questions also functioned as reminders for him:I guess you don’t always tell your kids that they’re doin’ a good job. Like I, after the surveys, I started makin’ a point to tell him he was doin’ a good job. (laughter) So, I guess that that’s probably a good thing that the surveys tell you, is to remind you to remind, to let your kids know when they’re doing well or not.father, family 1Another parent noted how reactivity to self-monitoring functioned by modeling questions that deepen levels of communication with her son around the domains assessed:So, there is that element of both of us are doing these surveys and then, for me, part of it was, “Okay, I want to start asking you these questions since I don’t really ask you these questions.” So, I would actually ask him more about the ins and outs of his day more, and then he would talk to me more about it ‘cause I was asking him for this information. …So, in a way, I was getting more information from him, and we were discussing more between the two of us than we would, normally, if I wasn’t doing the survey.mother, family 3Similarly, her son reflected that their improved communication made him feel closer to his parent:I enjoyed getting closer to my mom throughout the study because she’d always ask me questions that she wouldn’t really normally ask me, and we got a little closer through that.male child, 13 years, family 3EMA self-monitoring was also reported to support the self-regulation of stress and staying calm, including during conflicts and their resolution. For example, 1 parent noted that self-monitoring helped her focus on trying to stay calm when interacting with her child:Well, I tried to become more of being calm (laughter) and not yelling. And, that was really it. …I mean, obviously, if you’re tired or you’re, somethin’ else is going on, it’s hard to do that. But, when I was in a relaxed state, it made me mindful of, “Okay, when she does something that annoys you, just be calm about it, and try and work through it.” It doesn’t always happen. But, it did make me more cognizant to try and just be more patient and talk with her - depending on what it was.mother, family 10Similarly, a child noted that self-monitoring helped her and her mother identify what was making them angry and enabled them to resolve conflict:When my mom and I would argue, and we would put it down [in the app], …we were like, “oh, we’re actually mad about something,” and then we would start thinking about like…Actually think about what happened.…and then we would talk and apologize.female child, 12 years, family 2And then you would talk and apologize. Is that something you did before?interviewerNot really because we wouldn’t think about it, we’d just get mad (laughter).female child, 12 years, family 2One child became aware that she could not remember why she was angry with her parent:I think before I took the survey, I just wouldn’t think about why I was mad at her. I’d just be so mad. But then when I sat down and took the survey, and it was sayin’ what was it about - I was like, “Wait. I don’t even remember, anymore, what it was about.”female child, 10 years, family 9One mother noted that the EMA self-monitoring helped her communicate more calmly with her child when they were in conflict by reflecting on and using conflict resolution strategies represented in the EMA response options:Well, there’s a certain question, for example, about, “Did you try to speak to your child calmly?”…The first time that I’m reading through them, I was like, “I don’t know. Did I even try? (laughter) Did I just start yelling? Did I?” It…literally had me stop and, and take a step back and remember the whole scenario. You know, literally picture by picture, and break it down. And then, I caught myself, it’s like, “I didn’t even try.” …and so after that, it was like, “Okay, let me try to speak to her calmly. Let me try and explain, you know, why the chair is yellow, and why the sky is blue.” (laughter) ….And, towards the end of these last two weeks, I wasn’t trying, I was speaking to her calmly.mother, family 2This mother also noticed her child using more positive reinforcement in her communication with a sibling, based on her initial reactivity to EMA and then her daughter modeling the behavior:I noticed that she started it with her sister with the, “Hey, Sophie, I, thank you for helping me do the dishes for mom.” You know, something like that out of the blue. Or, she had to throw the trash out and, “Oh, Sophie - thanks for taking the trash out. I, I really appreciate that.”…It was a change. It was an actual, positive change, and it was after she caught on to what I was doing.mother, family 2Although parents were generally not very comfortable talking about disciplining their children, many discussed becoming more aware of patterns of discipline or rules in their families. Some parents were more comfortable talking about rewarding or praising their children and were consciously working on improving their positive reinforcement of their children’s behavior. For example, a mother spoke about becoming more aware of limits and ground rules:You know, and, and maybe because of the older one, she’s testing limits. You know, and it’s like, “Okay, but these are the ground rules. We have to establish ground rules… And yes, I can switch things around as you grow, and I can bend and lean, but, these are the ground rules and these are the consequences for these actions. And, vice versa - if you do good, you, you get good. If you do bad - you get bad.” So, that’s, I did it, and I hadn’t even thought about that until right now that you asked me again. (laughter) But, I set them down and it’s like, “Okay, you know what? Let’s just be clear about that.” And, I don’t think I would have even thought about it if it wasn’t asking me daily (laughter) about consequences and actions, and, and do I act out in anger, or if I’m tired, or you know?mother, family 2This mother also noted how reactivity to the EMA question and response content influenced her parenting behaviors. Another parent reported:About the [questions], what happened when she did a good job or behaved well this morning? …About half-way through the week, I realized that, I guess I’m really hugging and kissing her when I’m feeling like she behaved well, but I’m not hugging and kissing her and saying, “Oh, you did such a good job.”mother, family 9In this example, reactivity to self-monitoring resulted in moving away from awareness to changing her behavior to more actively reinforce her child’s good behavior.Finally, both children and parents noted that the study made them realize the importance of sleep in their daily routines and self-monitoring:It helped me ‘cause it, with the questions…on the wake up, like how many hours of sleep, and I’d be tired, and I’d look at the time,...and then I’d be like, “Oh, I only got like seven hours.” And then the day where I’d wake up better, I’d be like, “Oh, I had nine hours,” so that’s better for me.male child, 14 years, family 5Another parent gave an example of reflecting on the potential relationship between family conflict and sleep:Like was there more conflict when I was sleep deprived? (laughter)mother, family 1In this example, self-monitoring reactivity first resulted in a strong awareness of sleep and functioning. One mother noted how responding to sleep questions seeded motivation:I thought the sleep one was a very good question, ‘cause then when I would answer it, I thought, “Ooh, yeah. I better get some more sleep.”mother, family 11Overall, these results demonstrate how reactivity to EMA self-monitoring typically begins with increased awareness of behavior, followed by associations with antecedents or consequences. Then, some participants experienced motivation to change, with behavior changes supported by reminder functions of EMA prompts , accountability to subsequent reporting, and tracking of goal progress and outcomes.The results of this study support the high feasibility and acceptability of using a smartphone EMA by young adolescents and parents for assessing and self-monitoring family daily routines and interactions over 2 weeks, as evidenced by high response rates of 95% and greater and in user-experience interviews. Some participants suggested that a third or fourth week of self-monitoring would further enhance the behavioral changes that they initiated. Some participants also reported preferring fewer surveys each day and fewer questions, particularly when considering a longer duration of self-monitoring beyond 2 to 3 weeks.Our findings also suggest that smartphone self-monitoring may be a useful tool to support improvement in family functioning through functions of reflection on antecedents and consequences of situations, prompting positive and negative alternatives, seeding goals, and reinforcement by self-tracking for self-correction and self-rewards. These functions are core elements of self-regulation -17, whicjob to keep their children safe and seemed to be more comfortable discussing consequences or negative reinforcements. Some research has conceptualized that parenting practices and discipline may be moderated by the interaction of parental beliefs and ethnicity [Our primary findings also suggest there was a potential indication of ethnic and/or income differences among parents in discussing discipline, rewards, and punishments that may warrant further exploration in future research. However, the small sample size does not warrant inferences as a primary result. White parents, from the higher-income site, seemed to be more comfortable discussing parenting practices with an emphasis on rewards and expectations and de-emphasizing punishments or negative reinforcements. Latino parents, from the low-income site, were more inclined to focus on parenting as a thnicity . HoweverThis pilot study had several notable limitations. First, the sample size was small in terms of the number of families. Nonetheless, the overall number of participants is typical and acceptable for a qualitatively focused pilot study focused on user experience and feedback, and saturation of themes was achieved. The sample lacked representation from African American and Asian-American families, lower-income white families, and higher-income Latino families. Second, the family wellness center recruitment sites attracted families primed for motivation to improve their family functioning, as did the recruitment material framing the study as seeking support in developing and testing mobile apps to assess and improve family functioning. Third, our measure/domain selection reflects assumptions for successful parenting and interactions that are prevalent in family assessment tools and evidence-based interventions for risky adolescents, while also including domains reflecting resiliency. Fourth, it is important to note that the steep rise in mobile phone use among children and adolescents has also raised concerns about possible adverse effects such as addictive tendencies, depression, anxiety, sleep disruption, and cyberbullying ,47. FiftFuture research should evaluate reactivity to EMA and diary self-monitoring as a tool to improve family routines in larger and more diverse samples of families, with statistical power to robustly examine behavioral, symptom, state, and functioning changes. Further research could also consider recruiting families coping with challenges such as chronic illnesses, substance abuse, or conduct problems. Future studies should also include longer follow-up periods to examine the sustainability of self-monitoring and decreasing burden over time and the significance of behavior changes indicated by participants in this study. Furthermore, future studies could also provide empirical and theoretical insight into how sibling relationships can serve as important contexts for individual development and family functioning. Due to participant feedback about frequency and duration of assessments, future studies using frequent assessments for highly transient states or frequent behaviors  should be short in duration  to minimize response burden over shorter assessment periods  . Conversjust-in-time interventions. Further research is needed on self-monitoring as a purely self-directed intervention activity and the potential for enhancing therapeutic relationships.Due to the increasing ease of implementing EMA and diary self-monitoring via smartphones, practitioners may reconsider using smartphones to enhance psychotherapy, parenting programs, and other counseling modalities. Conversely, researchers using EMA and diaries should examine reactivity more consistently and robustly. Real-time data visualization tools  hold the potential to make self-monitoring more salient and actionable through use in counseling sessions for problem solving, feedback, praise, and goal refinement. Machine learning algorithms also hold promise for detecting patterns and anticipating change points to trigger automated in-the-moment or


Children with respiratory tract infections (RTIs) use more primary care appointments than any other group, but many parents are unsure if, and when, they should seek medical help and report that existing guidance is unclear.To develop symptom-based criteria to support parental medical help seeking for children with RTIs.A research and development/University of California Los Angeles (RAND/UCLA) appropriateness study to obtain consensus on children’s RTI symptoms appropriate for home, primary, or secondary health care in the UK.A multidisciplinary panel of 12 healthcare professionals — six GPs, two pharmacists, two NHS 111 nurses, and two emergency paediatric consultants — rated the appropriateness of care setting for 1134 scenarios in children aged >12 months.Panellists agreed that home care would be appropriate for children with ≤1 week of ‘normal’ infection symptoms . The presence of ≥2 additional symptoms generally indicated the need for a same-day GP consultation, as did the presence of shortness of breath. Assessment in the emergency department was considered appropriate when ≥3 symptoms were present and included shortness of breath or wheezing.The authors have defined the RTI symptoms that parents might regard as ‘normal’ and therefore suitable for care at home. These results could help parents decide when to home care and when to seek medical help for children with RTIs. The aim of this study was to develop symptom-based criteria that parents could use when considering how to respond to a child who has had respiratory infection symptoms for ≤1 week.Safer, cost-effective, and more pragmatic interventions are needed to help parents make appropriate use of scarce primary care resources13The research and development/University of California Los Angeles (RAND/UCLA) Appropriateness Method (RAM) is used to help develop guidance on responses to healthcare scenarios, especially where ‘robust scientific evidence’ is lacking or contested.9–11,14–16 these were then compared with existing evidence  and verified by three clinical academics in general practice and paediatric emergency medicine.The RAM scenarios were developed iteratively by identifying and prioritising scenarios based on best practice;‘up to a week of respiratory infection symptoms  with or without eating adequately and normal conscious level’. Next, two key variable parameters were identified: first, the child’s age — (a) 12–23 months; (b) 24 months–4 years and 11 months; and (c) 5–12 years); and, second, their past medical history — previously well aside from usual childhood illnesses, with or without asthma; or a previous admission for asthma, bronchiolitis, or other respiratory condition. Six symptoms were then prioritised as of concern to parents: ear pain; wheeze (defined as ‘wheeze or noisy breathing’); shortness of breath; reduced fluid intake; less active or socially interactive than usual; and high fever. Finally, three appropriate ‘next steps’ were identified for panellists to consider as the parental response to each scenario. These were: monitor, home care, go to pharmacy, or routine (non-urgent) GP appointment; seek a same-day GP (in hours) or NHS 111 (out-of-hours) appointment; or go to emergency department (ED)/telephone 999. Together, these resulted in 1134 unique scenarios.First, a clinical ‘stem’ was devised, describing common symptoms that the ‘average’ child with a normal respiratory infection might have: Three clinicians, known to the last and fifth authors, provided feedback on the study documents and on the ‘stem’ and ‘symptoms’ scenarios to corroborate clinical relevance. Additionally, study documents and scenarios were then presented at a dedicated project public and patient involvement group within the NIHR Greater Manchester Patient Safety Translational Research (GMPSTR) Centre.A multidisciplinary panel of 12 healthcare professionals was recruited. These professionals were recruited through snowball sampling, starting with the fifth and last authors of this study, in addition to utilising the local Clinical Research Network (CRN). The panel consisted of six GPs, two pharmacists, two NHS 111 nurses, and two hospital emergency paediatric consultants.The RAM process entailed two rounds of ratings with each panellist rating each scenario on a 9-point integer scale, where 1 rates the next step as completely inappropriate and 9 rates it as completely appropriate. Round 1 was conducted by email on a Microsoft Excel (version 2016) rating sheet in May 2019 with panellists rating each of the 1134 clinical scenarios individually, without discussion.17 The moderator raised particular areas of disagreement from round 1 and resolved any issues regarding the understanding of the rating scale.17 Unlike a postal or online method, the strength of the face-to-face meeting is the opportunity for real-time panel discussion and interaction. Panellists then discussed and individually re-rated each scenario on the Excel sheets.17 Panel members were not required to reach consensus.17 The panel was co-chaired by two of the authors, one an expert in RAM,13,18–21 and one a GP expert in RTI,14,22,23 neither of whom contributed to the RAM scores.Round two comprised a one-day, face-to-face meeting held in June 2019. Panel members were presented with data from round one outlining the distribution of all panel members’ ratings, the median, and their own individual data from round one for each of the 1134 scenarios.17,19 Agreement was defined by at least 9 of the 12 (75%) panel members rating the same 3-point region on the 9-point integer scale, that is, 1–3; 3–5, 6–8, and so on. A proposed action was then categorised as an ‘appropriate’ next step with agreement if a scenario was rated 7–9 points , or ‘inappropriate’ with a rating of 1–3 points with agreement (median 1–3 points). Disagreement was defined as ≥4 panellists (≥33%) rating a scenario in both the 1–3 points range and 7–9 points range on the 9-point integer scale. Where the next step was to go to ED/telephone 999, these categories were separated to dichotomise depending on urgency: an overall panel median of 7–8 points indicated taking the child to the ED would be the appropriate next step, while a median of 9 points indicated that telephoning 999 would be appropriate. Ratings of clinical scenarios without agreement or disagreement that the next step was either appropriate or inappropriate, or that had a panel median of 4–6 points with agreement, were considered equivocal.Data from round two were collated and double entered by the first and sixth authors. These data were analysed to determine the median rating of the appropriateness of the next step  and the level of consensus within the panel for each scenario. Definitions for ‘agreement’, ‘disagreement’, and ‘equivocal’ were as previously published.The clinical stem emphasising the presence of symptoms of RTI for ≤1 week in a child, preceded the rating of the scenarios. Supplementary Table S1 summarises the results of round 2 ratings. Supplementary Table S2 shows the number of scenarios in which each next step was considered appropriate by the number of symptoms present. Increasing numbers of symptoms were generally associated with escalation of care from home care to NHS 111/GP to ED/999. Past medical history of hospital admission for asthma, bronchiolitis, or other respiratory condition had a nominal impact on panel ratings. The threshold for accessing healthcare services generally increased with the age of the child.Panellists agreed that home care, with or without the support of a pharmacist, is appropriate for the children described in the clinical stem of the scenario. Additionally, the panel rated home care appropriate after this initial timeframe, where the child has ear pain only (irrespective of age) and in children aged ≥5 years in the presence of ear pain and reduced fluid intake or presenting as less socially interactive than usual .Supplementary Table S3 shows that ear pain, being less socially interactive than usual, reduced fluid intake, and high fever were rated by the panel as being most likely to be suitable for home care if they are the only symptoms present.Supplementary Table S4 shows that combinations of ≥2 symptoms in addition to the clinical stem were generally seen as appropriate for NHS 111 or same-day GP appointment, particularly where the child has shortness of breath, wheeze, or a high fever.Supplementary Table S5 shows that symptoms most likely to be rated as appropriate for ED assessment were shortness of breath, wheeze, and high fever.The panel identified that generally it would be appropriate for children with ≥5 symptoms to attend the ED. They were also in agreement that it would be appropriate in most circumstances for a parent of a child aged 12–23 months with all six symptoms and a past medical history of admission for a respiratory condition to call 999.A representative multidisciplinary panel of professionals responsible for the care of children with RTIs used the RAND/UCLA Appropriateness Method to agree criteria to support parents deciding if, when, and where to access health services for children with ≤1 week of RTI symptoms. Scenarios took in to account the child’s age, past medical history, and symptoms. Panellists agreed that parents of an ‘average’ child with ≤1 week of respiratory infection symptoms including cough, sore throat, and/or runny nose, with or without eating adequately, with or without ear pain, and a normal conscious level would be appropriate for home care.In this study, criteria to identify children with symptoms of RTI suitable for home care were developed and the study found that it is often appropriate for them to be managed without medical input. If implemented, these findings could support improved health care-seeking behaviour, by providing a clear and evidence-based information source, allowing pressured services to focus care where most needed.To the authors’ knowledge, this is the first time any attempt has been made to establish criteria for parents to guide them in health care-seeking behaviour. The present study identified and prioritised scenarios based on best practice and in comparison with existing evidence using the validated RAND/UCLA method. Panellists represented the full range of healthcare services available to parents of children with RTIs.24 However, each additional symptom exponentially increases the number of scenarios. Similarly, the present results pertain only to children aged ≥12 months because it was considered that many clinicians would advise parents of younger children to seek help if they had any concerns. Second, the method is only possible by considering the ‘average’ child. Health services and parents wishing to use these criteria need to be aware that where a child is no longer considered ‘average’, a parent’s knowledge of, and concern about, their child is paramount. Third, by providing a set number of additional symptoms, it is possible that panel members would have automatically deemed a child with none to be appropriate for self-management and a child with all additional symptoms in need of 999 assistance, as this would be the simplest way to approach the high volume of difficult decisions they were being asked to make. Finally, this research does not provide any reassurance for parents who have children with RTI symptoms for >1 week (unless ear pain is the only additional symptom; All studies of this type have limitations. First, the authors would have liked to vary the presence of other symptoms such as cough, sore throat, rash, and phlegm, along with their severity and duration.25 Previous studies have attempted to modify help-seeking behaviour through parental education,26 but the evidence provided within these resources was not developed using RAM or developed using a panel representing a full range of healthcare professional expertise. The interventions developed were primarily based on the experiences of authors,27–29 or through the convening of a multidisciplinary group,30 with the booklets developed then being reviewed by parents and other professionals.28,29 One study developed an instruction booklet for parents of a child with acute otitis media by surveying 12 physicians to develop a criteria of essential information.31 Criteria were included in the final booklet if they were selected as being appropriate by >75% of the physicians.31The present study builds on work of the HAPPY AUDIT by providing greater insight into RTI symptoms in children and decision making before accessing the GP.13 However, this is a minimum prerequisite for a quality measure and subsequent development work would be required to provide empirical evidence of higher types of validity as well as reliability, acceptability, and other measures.13 Second, prospective cohort methods could be used with parents recording symptoms in children to confirm the appropriateness of help-seeking behaviour suggested by the present findings. Third, this method could be scaled up to provide help-seeking criteria to a broader range of conditions and scenarios where there is evidence of uncertainty regarding the appropriateness of current healthcare use.Clinicians and policymakers may wish to use and promote criteria presented in this study to parents to help inform health care-seeking decision making. Any symptom may be regarded as abnormal and therefore requiring treatment; these criteria could be considered useful to distinguish ‘normal’ from ‘abnormal’ infections. The authors think there are three areas of fruitful future research. First, the authors have conducted a co-design event with parents, GPs, pharmacists, 111 staff, and ED consultants to consider the most user-friendly modes of result dissemination and the potential for a decision-support resource for parents, which will be reported separately. The criteria have face validity based on expert professional opinion and available evidence.


Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the ‘dark’ proteome.The Database of Protein Disorder (DisProt, URL:  About 20 years ago, the concept of the intrinsic structural disorder of proteins came into being ,2. SinceFor example, it was recently recognized by ‘omics’ data analyses that about half of eukaryotic proteins are ‘dark’, in the sense that we have no information on their 3D structure , which pThe prediction of protein disorder from sequence was on the menu of the Critical Assessment of Protein Structure Prediction (CASP), a community-wide experiment of predicting protein structures from sequence , for manSeveral recent breakthroughs have also signaled the vitality of the field. An unsettled question with IDPs/IDRs is whether their structural disorder persits in the crowded interior of cells. Whereas diverse indirect evidence indicates that this is the case , only inAnother aspect of the functionality of IDPs is that they often mediate protein-protein interactions, mostly by folding upon partner binding , but somIt is without doubt that we cannot afford to ignore this intrinsically disordered, yet functionally important part of the proteome. Not only does structural disorder play an exquisite role in cellular signaling and regulation , it is aDue to these challenges, it is important to update and upgrade DisProt, the primary database of protein disorder. Whereas predicted disorder features are available in MobiDB , which hDisProt has been completely redesigned with an extended and updated functional classification scheme that relies on functional/structural aspects of annotated regions and incorporates a novel functional class ‘biological condensation’. Annotation concepts have been formalized in a new Disorder Ontology (DO), which is maintained by the entire DisProt community.DisProt 8 also has many novel features that make it easier to search. The graphical interface has been redesigned and a new entry format provides greater flexibility, simplifies maintenance and allows the capture of more information from the literature.Lastly, we made significant improvements on the new annotation interface used by DisProt curators to populate the database. It is now easier to use and leverages curators’ work by enabling text-mining technologies, integrating third-party information on-the-fly and implementing several validation checks.In recent work, specific sequence features have been associated with different disorder ‘flavours’ and mapped on a large scale . This inThe way disorder information is represented in the literature is inherently complex. Articles describe functional and structural aspects, where IDPs are strictly connected to dynamic behavior. DisProt tries to capture as much biological knowledge as possible while at the same time providing simple and clear annotations. The idea is to optimize user experience and improve data exchange with other major annotation resources.The major change compared to the previous release is the new annotation paradigm. In DisProt 7, experimental methods represented the annotation core of a DisProt region and function terms were used as attributes. Now the core of an annotation is the functional/structural aspect of a region and the experimental method is an attribute representing the quality of the annotation. Both functional/structural aspects and the type of evidence are encoded in a controlled vocabulary, in line with other core data resources (e.g. UniProtKB). In the new DisProt region format, a ‘statement’ field has been introduced to track the literature text supporting the evidence. When the text is too long or complicated, a curator statement is provided instead. All ‘statements’ are available from the website and could be used to train text-mining algorithms and to highlight sentence-based annotations on abstracts and full text articles. A new ‘obsolete’ field has been introduced in order to track regions which have been excluded from the current release. It also includes the reason for obsolescence, usually changes in the reference sequence due to UniProKB updates or curator errors.At present, functional terms can be associated to a subset of disordered residues, i.e. to a region shorter than the one for which disorder has been experimentally evaluated. For example, a paper describing a folding upon binding event can provide two DisProt records, one region spanning the folding residues and another showing the interacting ones. All regions have now a region identifier field which is unique and stable, i.e. it is never reused and becomes obsolete if the reference sequence changes. Functional and structural vocabulary terms along with experimental methods have been encoded in a new Disorder Ontology (DO).In order to describe the different functional aspects of IDPs and the experimental methods used to characterize them, an annotation scheme was introduced in DisProt 7. A more formalized version of the disorder ontology was implemented in DisProt 8, to move towards a descriptive, interoperable and collaborative ontology of IDPs. This is the first release of the Disorder Ontology in the specific Biomedical Ontology (OBO) or the Web Ontology Language (OWL) formats ,33. BesiAn identifier was assigned to each term in the ontology. It gives each label an 8-character accession code (e.g. ‘DO:00001’), with the string ‘DO:’ to indicate the disorder ontology and five numeric characters to indicate the term unambiguously. Mirroring the Gene Ontology, accession numbers are assigned incrementally and there is no relationship between accession codes and the ontology topology.We have reviewed the terms and organization of the whole ontology, paying particular attention to the ‘Function’ category. We made some straightforward changes, for example, we split ‘Fatty acylation ’ into a renamed parent class ‘Fatty acylation’ and its new children terms ‘Myristoylation’ and ‘Palmitoylation’. A new functional term was also introduced to annotate different phenomena related to ‘Biological condensation’ (DO:00040). It describes proteins that undergo phase separation from a solution, e.g. either to form a dynamic liquid droplet  or a hydrogel (DO:00042). It also includes cellular protein condensates , regardless of their existence in physiological or pathological states . This class provides an initial scheme to annotate the relevant but still scarce information available about protein condensates, and we expect this subset of the hierarchy to be modified (possibly by conforming its own sub-ontology) as the field matures.The distinction between structural states and dynamic events, like disorder-to-order transitions, has been made clearer. Previously ‘Structural state’ terms were part of the ‘structural transition’ category and ‘disorder’ was only used implicitly. Now, a new ‘structural state’ category has been created and it includes ‘disorder’, ‘order’, ‘pre-molten globule’ and ‘molten globule’ terms. In the future, structural states will be annotated in conjunction with the corresponding environmental conditions affecting the conformation , temperature, etc.).All experimental methods are now encoded under the ‘detection method’ branch. An overlap with other ontologies exists, but it is not complete or the definition of the same experiment is often slightly different. For example, in DisProt the term ‘crystallography’ includes ‘missing electron density’ as a child. In other ontologies ‘crystallography’ always indicates methods for structural determination. A new ‘electron cryomicroscopy’ (DO:00128) term has been also introduced in DisProt 8.The Disorder Ontology (version 0.1.0) is maintained by the DisProt consortium and is available to be adopted by other databases for general use. In the future, it will be made available also from third party dedicated repositories.5 literature triage infrastructure . In particular, curators can use a dedicated service from the NextAtructure  to rank tructure  to automThe annotation interface implements the concept of ownership and user privileges. DisProt distinguishes two types of users, curators and reviewers. Curators can edit only entries that they have created, while reviewers can modify all entries. Before release, the reviewers check all annotations to ensure high quality of the data. Curators are experts in the field and trained to meet DisProt annotation standards. As a community database, DisProt looks for new curators. Curator candidates are enrolled upon an evaluation of the curriculum and curation skills.Access to the annotation interface is restricted to registered curators and provided through Google Authentication (based on the OAuth 2.0 protocol) or the ELIXIR authentication and authorization infrastructure system . In the DisProt versioning has been improved. A numeric identifier indicates the version of the database entry, e.g., version ‘8.0’ and a ‘<year>_<month>’ code indicates the version (timestamp) of annotated data, e.g. ‘2019_09’.Since the last release, both the number of proteins and regions has almost doubled. DisProt 8 contains 1556 proteins and 3511 sequence segments annotated as disordered, which cover 19.7% of the number of residues. These numbers become 1390 proteins, 3041 regions and 18.7% of disorder content when ambiguous evidence is not considered. Previous annotations have been fixed and updated. Regions shorter than ten residues are no longer allowed and existing short regions were marked as obsolete as the majority are flexible loops annotated from X-ray experiments that do not represent disorder-related functional sites. Regions ending outside the sequence, regions with a start index of zero instead of one and entries for which the reference sequence in UniProtKB changed, were corrected and, when necessary, new records were created manually.Figure The statistics on annotation data for the main branches of the disorder ontology are reported in Figure Different ontology aspects (‘namespace’ field in DisProt records), are shown with different colors. In red the ‘structural state’ terms show as the majority of region records in DisProt are annotated as disordered. Only five proteins are annotated with the ‘order’ term. In the future, curators will be encouraged to also track information about order, in particular when relevant for structural transitions. Transitions are mainly covering folding events (‘disorder to order’), 365 proteins and 36 200 residues, and not the contrary. The majority of interaction partner annotations refers protein and nucleic acid binding. Binding residues are, however, overestimated since in the previous DisProt version, due to hard constraints in the database schema, it was not possible to narrow region boundaries to real interacting positions. Binding positions will become more precise in the future. The new term introduced in DisProt 8, ‘Biological condensation’ (DO:00040) has been assigned to a total of 20 proteins, 29 regions and 2610 residues. The new ‘electron cryomicroscopy’ (DO:00128) term, which is a child of ‘crystallography’, covers 34 proteins, 67 regions and 4726 residues.Darker segments in Figure The DisProt website has been completely redesigned, improving the user experience, visualization and functionalities. Additionally, a big effort was made to develop the DisProt Application Programming Interface (API) to enable users to retrieve a single entry or a region and to perform advanced searches via RESTful endpoints (URLs). The new API and distribution formats are extensively documented in the help page.The entry page is composed of three main sections. On the top, general information of the protein including name, DisProt ID, organism, sequence length, MobiDB and UniProtKB accession numbers are provided. On the top right, it is possible to select the DisProt version and hide/show ambiguous/obsolete evidence. A download dropdown button allows saving the whole entry data in JSON, TSV (tab-separated) or the corresponding sequence in FASTA format.A new dynamic feature viewer allows to visualize DisProt evidence mapped onto sequence. The feature viewer shows two tracks by default, DisProt consensus and domains, the latter including Pfam  and GeneThe feature viewer can be expanded to see sub tracks and it is possible to zoom in and out specific regions, customize the view and download a high quality image. Region tooltips are activated on mouse over and provide detailed information about the corresponding annotation.Region details are also provided on the bottom of the page, organized in a dynamic list of boxes. A search box, which supports regular expressions, allows to filter the list of regions. The filter is also applied to the feature and sequence viewers (right) in real time, for example, by typing ‘nuclear magnetic resonance’ it is possible to select only region evidence from NMR experiments.DisProt implements both a database and a BLAST search , both avDisProt provides programmatic access to perform a search through REpresentational State Transfer (or RESTful) Web Service API. A single entry or evidence can be retrieved by using DisProt or UniProtKB identifiers. Additionally, a text search against the entire database can be performed by specifying query fields  directly as URL parameters in the HTTP request. JSON, TSV and FASTA formats are supported.In the previous release, DisProt disorder annotations were polished and major errors were fixed but the number of newly annotated proteins was limited. In DisProt 8, disorder annotations doubled and a robust infrastructure has been put in place to leverage and accelerate the annotation process. The database format has been improved to be flexible enough to capture essential information from the literature but, at the same time, keeping disorder representation simple and clear. A new disorder ontology has been formalized with the aim of improving maintenance and data exchange with core data resources. The new ontology is versioned and provides a hierarchy to facilitate term traversal. Article sentences tracking statements about disorder experimental evidence are now captured providing a corpus for the implementation of new text-mining models. New protein examples are used as ground-truth to evaluate prediction methods as in the Critical Assessment of Disorder Annotation (CAID). DisProt long term sustainability is guaranteed by the centrality of DisProt in several initiatives involving large communities of bioinformaticians working on disorder, such as the IDPfun Marie Curie RISE and the ELIXIR IDP User Community.


This paper presents a broad perspective on how mental disease relates to the different evolutionary strategies of men and women and to growth, metabolism, and mitochondria—the enslaved bacteria in our cells that enable it all. Several mental disorders strike one sex more than the other; yet what truly matters, regardless of one’s sex, is how much one’s brain is “female” and how much it is “male”. This appears to be the result of an arms race between the parents over how many resources their child ought to extract from the mother, hence whether it should grow a lot or stay small and undemanding. An uneven battle alters the child’s risk of developing not only insulin resistance, diabetes, or cancer, but a mental disease as well. Maternal supremacy increases the odds of a psychosis-spectrum disorder; paternal supremacy, those of an autism-spectrum one. And a particularly lopsided struggle may invite one or the other of a series of syndromes that come in pairs, with diametrically opposite, excessively “male” or “female” characteristics. By providing the means for this tug of war, mitochondria take center stage in steadying or upsetting the precarious balance on which our mental health is built. Honour thy father and thy mother.—Exodus 20:12In mammals, females carry two large, virtually identical sex chromosomes; males, instead, a large and a small one that are quite dissimilar from one another. Hence, in females the effects of a faulty gene sitting on either chromosome can be compensated by a healthy one on the other, but in males it cannot . This mamentalistic skills [mechanistic skills [Even though men are worse off overall, each sex appears especially exposed to problems related to its particular talents . On avec skills ,5: commuc skills . On averc skills , that isc skills : using tadult brain is rapidly changed toward either male- or female-typical proportions, respectively, by high levels of testosterone and estrogen. These changes are behaviorally relevant, with testosterone addition increasing spatial ability and decreasing verbal fluency, and testosterone suppression doing the converse . That treatment ). Similareatment .men with anorexia nervosa or other eating disorders [The more you have, the more you can lose. As a case in point, Alzheimer’s ,14 and Pisorders .and more vulnerable than the average man in tasks that require mentalistic skills, the average man better and more vulnerable than the average woman in tasks that require mechanistic ones. Yet most of us are not average but sport a mix of strengths and weaknesses that are not all exclusively mentalistic or mechanistic. In fact, what matters is not whether we are females or males but how much our brain is “female” and how much it is “male”. This brings us to two sets of disorders that may be viewed as pathological extremes of a typically “male” [The evidence thus suggests that the average woman is better y “male” ,22 and ay “male” ,24 brainAll these syndromes are heterogeneous: patients with the same diagnosis can present vastly different symptoms ,26. WhatThat autism might be male-typical and psychosis female-typical is consistent with the psychiatric repercussions of abnormal dosages of X chromosome. Turner syndrome, in which one of the two X chromosomes is partly or entirely missing, not only reduces the affected women’s risk of psychosis-spectrum illnesses, but it also raises their chances of developing autism or autistic traits ,36. ChroThe X and Y chromosomes reside in the cell nucleus, but some of the genetic material we carry sits inside the mitochondria. These genes are normally inherited just from the mother, rather than from both parents ,39. Sincupon (epi in Greek) the genes.Both autism-spectrum and psychosis-spectrum disorders are to some extent heritable, but whether and how they will develop also depends on the environment. The environment does not alter the genes themselves, but can change their activity—most notably, whether they are expressed or silenced; this ensures that the organism adapts to the circumstances to the best of its abilities. Such flexibility is obtained through epigenetic processes, which act IGF2, which during gestation drives the production of the growth-promoting hormone IGF2 (insulin-like growth factor 2), and H19, which instead restricts growth. Increased growth appears to go together with the autistic spectrum, decreased growth with the psychotic one [As a case in point, these processes control two genes that play a central role in regulating growth: otic one . In stepotic one ) with a otic one  and smalotic one  risk of otic one . Likewisotic one . Childreotic one . It has otic one  that—viaotic one .IGF2 gene, hence less silencing of it [A particularly prominent epigenetic process involves methylation—the addition of a methyl group to a gene, or nearby protein, so that it can no longer be read. Methyl groups are provided by SAM (S-adenosyl methionine ), a remang of it . This reng of it . The manng of it .Indeed, the symptoms of epigenetic disorders turn out to be strikingly similar to those of mitochondrial disease . After aConspicuous among the epigenetic processes implicated in both brain growth and brain disease is genomic imprinting—the silencing of either the paternal or maternal copy of a gene before it is passed on to the offspring. At least 228 of our genes are imprinted, an estimate that keeps increasing . This seIGF2 and H19. Tellingly, of the IGF2 gene, which increases fetal growth, normally the paternally inherited copy is expressed but the maternal one is not. Conversely, of the H19 gene, which restricts such growth, the maternally inherited copy is expressed but the paternal one is not. It thus appears that with regard to how many resources the offspring should fetch in the early stages of its development, a battle is going on between the parents [Unsurprisingly, different circumstances induce different evolutionary strategies. These come to the fore, for example, in how parents go their separate ways in imprinting  parents ,67.IGF2 and H19: together, these two imprinted genes are responsible for nearly a third of the variation in birth weight [Indeed, during the time the mother is the only provider, paternal imprinting pushes for more growth-promoting hormones, a bigger placenta to siphon off more maternal resources, more insulin to extract more glucose from the mother’s bloodstream, a larger pancreas with which to produce this insulin, and a robust appetite after birth ,69. Mateh weight . And theh weight . Complich weight ,73), whiAfter the child has been weaned, when the father is better positioned to lend a hand and possibly become a major provider, paternal imprinting no longer pushes for either growth or appetite. The effects of IGF2 taper off, and the show goes on with other growth hormones that are not affected by imprinting. Maternal imprinting, instead, keeps promoting fat storage and, for the first time, stimulates a big appetite for foods that could just as well be provided by the father or other family members ,74. In tThere might be more to this story than just growth and appetite. It has been suggested ,28; see .One typically thinks of the imprinting conflict between parents as a two-way struggle, but there is of course a third party involved. Imprinting involves epigenetic silencing, and for it to proceed normally, the supporting mitochondria must function normally too—which is not always the case.Because our genes normally come in pairs, one from each of our parents, a defect in one copy can in principle be mitigated or compensated by the other. Of imprinted genes, however, one copy is silenced and thus cannot mitigate or compensate anything. And even if nothing is wrong with the gene itself, a problem can arise with the imprinting mechanism or with the production or dispatching of the nutrients or energy it requires. It is no surprise, then, that imprinted genes are disproportionately often implicated in disease. Interestingly, several imprinting-related disorders also come in pairs: both are caused by an anomaly in the exact same gene, but in one the problem lies with the paternally inherited copy, in the other with the maternally inherited one. And despite the close link between the two disorders, their characteristics tend to be diametric opposites.IGF2 and H19 on chromosome 11, mentioned before. If IGF2 is underexpressed or H19 overexpressed, the baby risks being born with Silver–Russell syndrome; if it is the other way around, with Beckwith–Wiedemann syndrome [One such pair of disorders involves the growth-promoting and growth-restricting genes syndrome ,75,76. Isyndrome . Childresyndrome . Those wsyndrome ,79. A pesyndrome . Also, tsyndrome .Another instructive pair of disorders concerns imprinted genes on chromosome 15 ,75,76,81MECP2, sits on the X chromosome [MECP2 might be repressing genes that are important while neurons are still developing but detrimental afterwards [One important gene implicated in silencing by methylation, romosome . The expterwards . MutatioMECP2 gene on the paternally inherited X chromosome [MECP2 gene on the maternally inherited X chromosome; because, in sons, a faulty maternal X chromosome cannot be compensated by a paternal one, men feature the full disorder, whereas women may show no symptoms or a mild intellectual disability only [MECP2 duplication syndrome in boys, in which the MECP2 gene is not defective but duplicated, is accompanied by autistic symptoms instead [Rett syndrome is due to a defective romosome  and afferomosome ,89. PPM-ity only ,91. PPM-ity only . Interes instead .MECP2 gene affects the expression of nuclear genes that regulate mitochondrial functions [MECP2 gene has been knocked out, contain malformed, poorly functioning mitochondria that produce little energy and a lot of free radicals [MECP2 gene at all but harbor mutations in their mitochondrial DNA [Rett syndrome (which has been studied much more than PPM-X syndrome) has many characteristics in common with mitochondrial disorders, ranging from delayed development and muscle weakness to seizures and heart problems ,94. Eithradicals ,94. Antiradicals . Furtherrial DNA .Dysfunctional mitochondria and high levels of free radicals have also been linked to Beckwith–Wiedemann , Angelmawith the brain should be searched in the brain is naive as well as misleading [Mitochondrial disease can show up with primarily psychiatric symptoms , and mutsleading . It seemsleading .To best understand a disease, one can zoom in on its details but also zoom out to see how it relates to other ones. The latter is what has been done here: this paper has presented a broad perspective on how mental disorders are tied to the evolutionary strategies of the two sexes and to growth, metabolism, and mitochondria.The sexes differ in their vulnerability to mental disease, and individuals who sport too much X-chromosome material—too much “femaleness”, so to speak—tend to have mental diseases opposite to those who sport too little. So do, for example, people with Klinefelter or Triple-X syndrome as opposed to those with Turner syndrome. Yet the heart of the matter is not so much being a man or a woman but having, quite irrespective of one’s sex, a female- or male-typical brain. A “female” brain raises the odds of psychosis-spectrum disorders such as major depression, bipolar disease, and schizophrenia; a “male” one, those of autism-spectrum disorders such as attention-deficit/ hyperactivity disorder, obsessive-compulsive disorder, and autism.Being born with an extreme male or female brain appears to follow from a tug of war between father and mother over how many resources their child should extract from the mother, and thus how vigorously it should feed and how much it ought to grow. An uneven battle not only alters the risk that the child develops insulin resistance, diabetes, or cancer; but can also invite one or the other of a pair of mental disorders with diametrically opposite physical and mental characteristics—genetic syndromes such as Beckwith–Wiedemann and Silver–Russell, Angelman and Prader–Willi, Rett and PPM-X. Mitochondria play an outstanding role in enabling such a battle between our parents , and thu