Behavioral variant frontotemporal dementia (bvFTD) is the second leading cognitive disorder caused by neurodegeneration in patients under 65 years of age. Characterized by frontal, insular, and/or temporal brain atrophy, patients present with heterogeneous constellations of behavioral and psychological symptoms among which progressive changes in social conduct, lack of empathy, apathy, disinhibited behaviors, and cognitive impairments are frequently observed. Since the histopathology of the disease is heterogeneous and identified genetic mutations only account for ~30% of cases, there are no reliable biomarkers for the diagnosis of bvFTD available in clinical routine as yet. Early detection of bvFTD thus relies on correct application of clinical diagnostic criteria. Their evaluation however, requires expertise and in-depth assessments of cognitive functions, history taking, clinical observations as well as caregiver reports on behavioral and psychological symptoms and their respective changes. With this review, we aim for a critical appraisal of common methods to access the behavioral and psychological symptoms as well as the cognitive alterations presented in the diagnostic criteria for bvFTD. We highlight both, practical difficulties as well as current controversies regarding an overlap of symptoms and particularly cognitive impairments with other neurodegenerative and primary psychiatric diseases. We then review more recent developments and evidence on cognitive, behavioral and psychological symptoms of bvFTD beyond the diagnostic criteria which may prospectively enhance the early detection and differential diagnosis in clinical routine. In particular, evidence on specific impairments in social and emotional processing, praxis abilities as well as interoceptive processing in bvFTD is summarized and potential links with behavior and classic cognitive domains are discussed. We finally outline both, future opportunities and major challenges with regard to the role of clinical neuropsychology in detecting bvFTD and related neurocognitive disorders. Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterized by early progressive changes in behavior, social conduct, emotional processing as well as specific cognitive impairments , 2. AccobvFTD is the most frequent clinical syndrome of FTD . Fronto-Temporal Lobar Degeneration (FTLD) is the broader pathological disease spectrum also encompassing FTD, motoneuron disease (MND), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Estimated prevalence rates highly vary depending on the employed diagnostic criteria which have been considerably refined during the last two decades –3. PrevaAs FTLD is a heterogenous pathophysiological entity, bvFTD can be caused by different underlying pathologies –15. MostOn the anatomical level, meta-analyses of the atrophy profile of patients with bvFTD found significant clusters of reduced brain volume in frontomedian areas, in the superior frontal sulcus, parts of the thalamus and insula as well as in striatal regions –27. FocaAs a result of the heterogeneity regarding the underlying pathology of bvFTD, there are currently no reliable, specific, and established biomarkers available to clinicians. A correct and early diagnosis is nevertheless crucial for disease management, initiation of treatment as well as support of the usually highly distressed caregivers . DiffereAfter an initial paper in 1994, the first comprehensive consensus criteria for bvFTD from the FTDC, an international group of experts on FTD, were released in 1998 . These cDespite consensus text definitions of the FTDC clinical criteria, clinicians today still face the problem that the criteria have not been standardized by means of “tests” or clinical scales and even the methods of their assessment  are not consistently specified and likely differ considerably across centers. In addition, some studies have underlined a substantial overlap between symptoms of specific primary psychiatric diseases  and symptoms of bvFTD. These shared symptoms may explain why bvFTD patients are frequently misdiagnosed with psychiatric disorders as outlined before , 12, butAnother important criticism toward the current FTDC criteria for bvFTD is that some exclusion criteria  seem overly restrictive and may lead to false exclusions . In the A standardized clinical-neurological examination is critical when an initial suspicion of bvFTD is raised, mainly to exclude alternative causes for the symptoms. For example, ~10% of patients with FTD develop MND and 10–15% of patients with MND also meet criteria for bvFTD , 42. BecPatients with bvFTD usually have a diminished or absent sense for the behavioral, cognitive, or psychological changes that are reported by their relatives or co-workers (sometimes referred to as anosognosia). Unlike the lead symptoms of other early neurocognitive disorders, cognitive, or behavioral symptoms are thus rarely spontaneously reported by patients with bvFTD. If they are, reports are usually brief or shallow, in a stereotypical manner and without showing a coherent sense of either suffering from the symptoms or being overly worried about them. During anamnesis, patients with early bvFTD may even remain to be affectively indifferent when directly confronted with reports of negative consequences of their pathological behaviors  or with negative feedback . Although an anosognosia or lack of insight into cognitive and behavioral symptoms may sometimes also be observed in patients with AD, a striking difference in patients with bvFTD is a frequent lack of appropriate emotional participation or affective involvement during the clinical assessment and diagnostic procedure . Such typical clinical observations during anamnesis may be used to develop an initial suspicion of bvFTD but are highly subjective and require clinical expertise. Only few attempts on the other hand have been published to standardize behavioral observations of patients with bvFTD in clinical contexts  or in hoCaregiver reports are so far the main source of information for clinicians to detect and diagnose bvFTD in early disease stages. As psychological and behavioral changes are the lead clinical symptoms of patients with bvFTD they should be assessed extensively through caregiver interviewing, as these information principally allow for a diagnostic differentiation against other common neurodegenerative dementia syndromes like AD . As poinStandardized clinical rating scales that aim at staging symptoms severity in patients with FTLD may thus help clinicians to guide and structure the caregiver anamnesis as well as quantify longitudinal changes of symptoms. The well-known Clinical Dementia Rating scale (CDR) is available in a modified version in order to include behavioral and language dysfunctions geared toward patients with FTD . The scaSeveral other standardized scales to specifically assess behavioral changes in patients with frontal lobe syndromes are also available . Importantly, for a new clinical diagnosis of “possible bvFTD,” it is sufficient that any three of the following criteria  are fulfilled . Moreover, the criteria require that these symptoms are new and develop “early” i.e., within the first three years of the suspected disease onset. For a higher diagnostic level of evidence (“probable bvFTD”), the criteria require focal atrophy on MRI and/or hypometabolism on PET in frontal or anterior temporal cortices or alternatively, a documented decline of behavioral or cognitive symptoms over time .Socially inappropriate behaviors like inappropriate familiarity or a lack of distance  during the anamnesis or during the cognitive assessment  are often subtle signs of early behavioral disinhibition in bvFTD. Difficulties to inhibit irrelevant stimuli from the environment is often considered as a key feature of bvFTD and patients often struggle to focus on a task because of distractors , a sympAs a behavioral syndrome, apathy could manifest itself as a range of concepts, such as emotional blunting, poor initiation or persistence, indifference to choices, reduced curiosity, lack of interest, and activities, difficulties in implementing actions and social withdrawal. Diminished goal-directed behaviors and intellectual activities (such as reading) as well as diminished responsiveness to emotion are however consensually considered as central to apathy and are among the most frequent symptoms of bvFTD –83. AlonA diminution or lack of empathy is frequently observed in bvFTD in everyday social contexts and often has considerable negative consequences on caregivers . Lack ofPatients with bvFTD frequently become rigid and inflexible regarding daily routines, which they want to preserve, and a substantial proportion develops unusual rituals or behaviors such as hoarding or collecting, similarly to what is observed in obsessive-compulsive disorders . Other aPatients with bvFTD show significantly stronger changes in stereotypic/altered eating behaviors compared to AD patients . A markeAlthough cognitive dysfunctions are numerically less weighted in the FTDC criteria for bvFTD, representing only 1 out of 6 criteria, the assessment of cognitive performance remains crucial for clinical diagnosis and patient management. Given that the previously described behavioral and psychological changes are often more visible in bvFTD, substantial cognitive impairments  may easily be overlooked. Recent studies have shown that the vast majority of patients with bvFTD already present with major cognitive dysfunctions in early disease stages when compared with normative data stratified for age and education , 117. PrThe neuropsychology item in the current criteria requires a cognitive profile of “executive/generation deficits with relative sparing of memory and visuospatial functions” which primarily aims at delineating the cognitive profile of patients with bvFTD from patients with AD . An arraExecutive functions is an umbrella term for cognitive processes that rely on higher-order cognitive control mechanisms that are proposed to be mainly subserved by a large fronto-parietal network , 127. AlDisappointing results in terms of clear discriminative abilities have been shown for the Stroop tests , 142, thVerbal abstraction deficit as evaluated by categorization/similarities tasks is observed in bvFTD as opposed to AD, during the early stages of the disease , 152. ThDesign/figural fluency tasks  are not differentially impaired in bvFTD compared to AD  althoughThe Brixton test did not show any dissociation between bvFTD and AD , 161. ThAuditory attention and verbal working memory deficits have been retrieved through digit span forward and digit span backward tasks respectively, , 144 andRelative sparing of episodic memory remains a diagnostic feature in the neuropsychological criterion for bvFTD and has been historically heralded as one of the clinical gold standards to distinguish bvFTD from AD. However, this notion has been challenged by a study showing that bvFTD could present with severe amnesia, similarly to what is observed in AD . The criDrawing or copying of spatially complex  figures and abstract forms  is a multifactorial process relying on a widespread bilateral neural network from temporo-occipital to parietal and lateral frontal areas , 187. FrTaken together, although the majority of studies have confirmed patients with bvFTD to show executive impairment, the proposed prototypical “profile” of pronounced executive dysfunction in bvFTD seems to be of low specificity and the cognitive dysfunctions displayed by patients with bvFTD are more heterogeneous than previously assumed. Although studies conducted in pre-diagnosed genetic bvFTD patients show that attention and executive functions could be early markers of MAPT or GRN mutations , 202, thIn the following section we aim to review newer developments regarding the early detection of bvFTD mainly through cognitive domains currently not mentioned in the FTDC criteria and to give practical suggestions regarding their assessment in clinical routine.Social cognition refers to a set of cognitive processes devoted to, or at least critically involved in, normal social interactions. This conceptual and somewhat arbitrary definition allows disentangling some mechanisms quite specific to the social dimension of cognition from others that may not be considered as specifically “social” despite their importance in interpersonal relationships such as language . AffectiAn impairment in theory of mind abilities has been extensively described in bvFTD , 223. DeEmotion recognition deficits in bvFTD have also been very well described since the earliest studies. Static , 235 as Self-related representations are impaired in bvFTD which is sometimes considered as a “prototypical disorder of the self” . PatientWhile social norms and rules processing deficits have never been assessed through objective testing in bvFTD unlike in other conditions , converOnly a few objective tasks have been used to assess reward processing in bvFTD but they showed that reward processing deficits are also very commonly observed in this disease. Patients could present a general deficit in reward valuation , 263 andAlthough the aforementioned tasks could be considered as assessing “decision-making” because they frequently involve binary choices between two items that are modulated by reward or punishment, the concept of decision making has mostly been retained to describe choices based on more complex information processing. In this context, apart from one exception , the IowWhile direct relationships between specific dysfunctions of social and affective cognition and abnormal behavior in bvFTD still have to be investigated in depth, social cognition assessment offers an objective evaluation of abilities that may drive many aspects of behavior. For example, a deficit in emotion recognition may prevent patients to recognize sadness, fear or anger in others' faces and to adapt their behavior accordingly. An impairment of theory of mind abilities would prevent patients to grasp others' mental states or feelings and thus to predict others' perspectives or actions, leading to behaviors that might appear egocentric or selfish. Similarly, a pathological theory of mind or empathy deficit could lead to commit abuses , or to bThe identification of social and affective cognition as a distinct cognitive domain  allows Still relatively poorly understood, apraxia is a multifactorial cognitive disorder affecting skilled movement, tool-use and/or gesturing on command despite intact task comprehension and basic sensorimotor functions . ImpairmDespite explicit recommendations in consensus diagnostic guidelines for early neurodegenerative dementia syndromes  as well Regarding neural correlates of praxis impairments, large-scaled lesion studies in patients with stroke imply that limb praxis skills are subserved by densely interconnected but also segregated functional neuroanatomical networks involving parietal, temporal and frontal cortices mainly within the left hemisphere –308. MorTo our knowledge, only one study specifically investigated correlations between praxis performance and brain volume in patients with early stage bvFTD and AD so far . The autThe neural correlates of deficits in buccofacial praxis abilities  are however, mostly unknown regardless of whether investigating patients with stroke or neurodegenerative diseases. Anecdotal evidence however, points toward involvement of  frontal areas and the frontal operculum in buccofacial praxis abilities and/or imitation of face postures , 311–313Praxis dysfunction in bvFTD and other neurodegenerative dementia syndromes may well be tested with standardized assessment tools designed for stroke patients . F. F341)].An important future role of clinical neuropsychology will emerge with the evaluation and comparison of newly developed biomarkers by means of employing the complex assessment methods for behavioral, psychological symptoms as well as cognitive functions in patients with suspected bvFTD and competing diagnoses. Besides its role in cognitive rehabilitation, expertise in clinical neuropsychology will thus continue to play an important role in the detection and diagnosis of early bvFTD even and particularly in the light of emerging biomarkers for the disease.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.MB would like to disclose that he is the main author of the mini-SEA. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MI declared a past co-authorship with one of the authors MB to the handling editor.


Humans exert a great deal of control over our local environments–selecting and arranging the many objects around us on the basis of conflicting task-demands, aesthetic preferences, and habitual convenience. Because routine behaviour necessitates that we regularly find and access these objects, the particular arrangements we choose can influence the likelihood and difficulty of engaging in different tasks and actions. Despite this importance, relatively little research has directly examined human organizational behaviours and tendencies. Here we investigate how objects in a computer-based search task are freely and dynamically arranged by participants over time, while manipulating the statistics of the target sequence. We report common organizational behaviours including reduction of distance between targets as well as separation of target subsets with high community. However, the extent of these behaviours and their relationship to individual differences in performance varies as a function of the target sequence structure. In particular, tasks composed of a larger number of smaller groups of targets lead to better organizational and performance outcomes than tasks composed of fewer larger groups. Though many animals actively shape the environment to suit their needs . Rarer still is the discussion of long term organization. The conjunction of these two categories–long term pragmatic organization–exhibits two particularly important characteristics: 1) these organizational decisions are probabilistic; they are driven by expected future demands rather than an explicit immediate goal, and 2) these decisions concern multiple goals, reflecting the need to balance and coordinate different sets of demands in contrast to a single task-specific set. Indeed, where much of the prior literature has focused on the value of short- and medium-term epistemic actions in limiting behavioral choices and outcomes, we suggest that long-term pragmatic decisions often serve instead to increase the range of available actions to support flexibility for future tasks that may be conflicting or underspecified. This type of organizational behaviour is arguably of central importance to understanding our relationship to space, as it provides the stable ‘background’ in which individual tasks must unfold (cf. ‘environment stabilization’ )searched for, absent explicit instructions to memorize, with indirect evidence arising from decreased search times and accurate early search trajectories , and, andsears  arise from a small number of long-distance object movements, in contrast to counterproductive reorganizations which involve a greater number of short-distance object movements. This suggests that spatial organization, in the present context, is best understood as a deliberate but incremental process. Collectively, these observations provide new insight into the nature of human organization, and inform related theories of routine action, planning, and metacognition. We argue the observed organizational behaviours can be understood as long-term pragmatic actions–actions that are neither explicitly driven by the immediate needs of the task, nor directly related to reducing cognitive burdens, but instead are helpful in reducing the expected effort for both current and future predicted needs.


People at high-risk for lung cancer—current/former smokers, aged 40+ years, with serious lung comorbidity  and living in highly deprived areas—are more likely to delay symptom presentation. This qualitative study aimed to understand the influences on early presentation with lung cancer symptoms in high-risk individuals and intervention preferences.Semi-structured qualitative interviews with 37 high-risk individuals (without a cancer diagnosis), identified through seven GP practices in socioeconomically deprived areas of England, Scotland and Wales (most deprived 20%). A symptom attribution task was used to explore lung symptom perception and help seeking, developed using Leventhal’s Common Sense Model. Four focus groups with 16 high-risk individuals and 12 local stakeholders  were conducted to explore preferences for an intervention to promote early lung cancer symptom presentation. Data were synthesised using Framework analysis.Interviews. Preoccupation with managing ‘treatable’ short-term conditions (chest infections), led to avoidance of acting on ‘inevitable and incurable’ long-term conditions (lung cancer). Feeling judged and unworthy of medical help because of their perceived social standing or lifestyle deterred medical help seeking, particularly when difficult life circumstances and traumatic events led to tobacco and alcohol addiction. Focus groups. Participants recommended multifaceted interventions in community venues, with information about lung cancer symptoms and the benefits of early diagnosis, led by a trained and non-judgemental facilitator.Individual and area level indicators of deprivation confirmed that interview participants were highly deprived. This study was novel in engaging a high-risk population to gain an in-depth understanding of the broader contextual influences on lung cancer symptom presentation. Perceived lack of health service entitlement and complex lives facilitated avoidance of recognising and presenting with lung cancer symptoms. Community-based interventions have the potential to empower disadvantaged populations to seek medical help for lung symptoms. This was the first study to use in-depth qualitative methods to explore how to engage high-risk individuals from socioeconomically deprived areas in early lung cancer diagnosis.A major strength of this study was the proactive and rigorous sampling procedures used to ensure that our sample was at high risk for lung cancer.Assessment of individual and area level indicators of deprivation confirmed that interview participants were highly deprived; all participants resided in the 20% most deprived areas of the three UK nations, and most participants were unemployed/seeking benefits and/or rented social housing.To overcome the methodological limitations associated with studying anticipated or retrospectively recalled cancer symptom presentation, we recruited participants with no previous diagnosis of lung cancer and did not mention lung cancer in the interview study materials or during completion of the symptom attribution task.Opportunistic recruitment of focus group participants who may have been more favourably disposed to an intervention was a potential study limitation.Lung cancer is the leading cause of cancer mortality worldwide.Multiple symptoms and risk factors for lung cancer including older age, smoking, the presence of a lung comorbidity and socioeconomic deprivation increase the likelihood that a patient presenting to their GP with symptoms indicative of lung cancer will receive a cancer diagnosis.The presence of lung comorbidity such as chronic obstructive pulmonary disease (COPD) and history of smoking have been associated with a lower likelihood of presenting with lung cancer symptoms early.Strategies to prompt earlier help seeking for lung cancer symptoms are required. However, evidence is limited regarding optimal methods for promoting earlier presentation through interventions targeted at high risk, highly deprived groups. Mass mediaThe current study used a combination of interviews and focus groups to explore potential barriers to early lung cancer diagnosis and strategies to encourage early help seeking with individuals who are the high risk for lung cancer. Qualitative interviews were used to gain an in-depth understanding of the processes and motivations involved in symptom attribution and medical help seeking for potential lung cancer symptoms in high risk, highly deprived individuals. We targeted socioeconomically deprived areas across three nations of the UK to approach potential participants, and used rigorous sampling procedures to ensure that our sample were high risk for lung cancer. The focus groups were conducted in highly deprived areas with stakeholders who lived or worked in these communities. To our knowledge, this was the first study to explore the influences on early lung cancer diagnosis and intervention preferences targeted at high-risk groups living in the most deprived areas of the UK.The Consolidated Criteria for Reporting Qualitative Research10.1136/bmjopen-2018-025902.supp1Supplementary file 1Thirty-seven interview participants were recruited through seven primary care general medical practices (GP) in South Wales (Cwm Taf: three practices), England (Liverpool: one practice) and Scotland (Aberdeen: three practices). Using routinely published index of multiple deprivation (IMD) data for England, Scotland and Wales, GP practices with the highest proportion of their patients that reside in the most deprived quintile were contacted. Practice managers were asked to screen GP practice databases purposively for eligible study participants: men and women over the age of 40 years, who were current or former smokers, with a lung condition . To overcome methodological limitations associated with retrospective recall, we recruited participants with no previous diagnosis of lung cancer. Participants were initially recruited from GP practices in Cwm Taf, where practice managers were asked to screen databases for current and former smokers, with no parameter set for number of years since quit attempt. Due to an initially high response rate from former smokers in Cwm Taf, subsequent participants in Aberdeen and Liverpool were sampled purposively according to smoking history. One GP practice in Aberdeen was asked to recruit current smokers and recent quitters (within 10 years). Two GP practices in Aberdeen and one GP practice in Liverpool recruited current smokers only.To ensure that participants from highly deprived areas were invited to take part in the study, individual postcodes were screened by the research team. Eligible patients from the initial database screen were assigned a pseudo-anonymised participant identifier (PID). PID and postcode were checked against IMD score, and those that resided in the most deprived IMD quintile were eligible for the study. The final list of potentially eligible participants was checked by the GP for ability to provide informed consent, considered by the GP to be a risk to the interviewer or themselves and general health status (e.g. very seriously ill). Participants were excluded if they were diagnosed with lung cancer, were terminally ill or did not have capacity to consent.Sixteen participants for the focus groups with members of the public were recruited opportunistically through primary care or local community groups. Participant recruitment through primary care employed the same methods as those used to invite the interview participants. PIDs were checked to ensure that those who took part in the focus groups had not already participated in the interviews. Additional participants were recruited opportunistically through local community respiratory support groups and non-health-related groups in the local community centre. Local community group organisers in areas of high deprivation were contacted and asked for help to recruit members of the public in our target group. Local health service planning groups and health board staff facilitated recruitment of 12 participants for the healthcare professional and community partner focus groups.The study received ethical approval from Southampton Central- Hampshire A Research Ethics Committee (16/SC/0589). Written consent and permission to audio-record were obtained on the day of the interviews and focus groups.Eligible participants were invited by letter with more detailed study information attached, with a reminder at two weeks to non-respondents. Those who returned the study reply slip via a FREEPOST envelope were contacted by the interviewer (GMMcC or JH) to arrange a suitable time and date for the interview, to outline the study and answer any questions.Interviews were conducted using a semi-structured topic guide to facilitate a discussion about illness perceptions and coping strategies; development was guided by the Common Sense Model10.1136/bmjopen-2018-025902.supp2Supplementary file 2https://www.nice.org.uk/guidance/cg121). The symptoms were re-worded to simplify the language in line with wording found on the National Health Service (NHS) Choices website for lung cancer symptoms and any reference to time scale of symptoms was removed , home ownership, occupation and educational attainment. Interviews were conducted until data saturation  working in areas of deprivation with people with smoking history and/or lung conditions were sent information about the study and invited to take part in focus groups. Focus group participants were explicitly informed that the study was about the development of an intervention about lung cancer. A mutually convenient time, date and location for the focus groups was agreed. The focus groups were conducted using a semi-structured topic guide to explore preferences for an intervention to promote earlier lung cancer diagnosis. Separate topic guides were used for the public and professional groups online . ParticiMost interviews (n=34) took place face-to-face in participant’s own homes, with three taking place in a café, local community centre or over the telephone, and lasted between 46 and 146 min (mean 83 min). Family members were present for three interviews but did not participate in the study. Focus groups took place in primary care settings (n=2) or local community centres (n=2). Members of the public who took part in the interviews or focus groups were compensated with a £10 shopping voucher. Healthcare professionals and community partners were not reimbursed for their time.Interviews and focus groups in England were conducted by JH (PhD), a trained and experienced female qualitative Research Fellow and Medical Sociologist. The Welsh and Scottish interviews and focus groups were conducted by GMMcC (PhD), a female Health Psychologist and trained qualitative Research Associate.Interviews and focus groups were audio-recorded and transcribed verbatim. Anonymised transcripts were analysed in detail using the Framework method.The data were analysed in five stages: familiarisation, identification of a thematic framework, indexing, charting and interpretation. A separate index was created on Microsoft Excel for the interview and focus group data; however, wherever possible, overlap was coded using the same indexing terms, for example, ‘barriers to symptom presentation’ was commonly discussed in both the interview and focus groups. The index was developed by two researchers (GMMcC and JH). Themes were generated independently and consolidated through discussion in nine interpretation workshops over a nine-month period by GMMcC and JH. The different perspectives of the researchers as noted above was a benefit during analysis and interpretation. Field notes were recorded for each interview and focus group, and incorporated into discussion during the analysis workshops. Although not formally incorporated into the analysis plan, the positioning of each symptom in the attribution task was considered during interpretive workshops. Interpretive themes were generated by JH and GMMcC, and developed with all authors in monthly management meetings. Transcripts and study findings were not checked by participants; however, all participants were mailed a summary of the study findings.www.readabilityformulas.com).Patient and public representatives (AMT and GN) were involved in the design of the study and interpretation of study findings in monthly management group meetings. All study materials and topic guides were developed with lay input (AMT and GN) and written to a reading age of 10 years due to potentially low literacy. Reading age was calculated using the Automated Readability Index  of their lung condition, other pre-existing comorbidities or smoking habit and were consequently normalised and perceived not to require medical help. Changes to vague or respiratory-type lung cancer symptoms were only taken seriously when remarked on by friends and family or when they impacted on daily life.Symptoms that could indicate a chest infection were reportedly constantly monitored. Participants discussed using sophisticated strategies such as noticing changes in the colour and consistency of their phlegm or subtle audible changes in their cough to actively detect chest infections. Such strategies were considered important to facilitate early detection and treatment for chest infections through their primary care provider or with rescue packs (emergency packs of steroids and antibiotics that can be kept at home), due to lung condition.Constant monitoring of phlegm for control of lung condition meant that participants could and would notice haemoptysis, but few reported actively looking for haemoptysis on a regular basis. Disparity between actual and anticipated medical help seeking was reported for haemoptysis. Most participants had not previously experienced haemoptysis, but would anticipate seeking medical help immediately due to the potentially serious nature of blood. However, some participants who had previously or were currently experiencing haemoptysis attributed the presence of blood to non-cancer causes such as their stomach ulcer or a previous influenza jab. One participant ascribed the blood in their cough to lung cancer. Some of the participants with experience of haemoptysis did not seek medical help.Participants reported seeking medical help quickly when symptoms were easy to detect, were attributed to what was perceived as a treatable cause and represented an immediate health threat, that is, a chest infection due to lung condition. Participants could often request an appointment the same day as permitted by their GP surgery policies. Prompt help seeking was reportedly due to fear of not being able to breathe and the potentially life-threatening nature of chest infections, and is likely to reflect the need to maintain good health in the short term.The focus on maintaining short-term health may reflect low general expectations of health, where some participants disclosed surprise at living beyond 60 years of age. In addition, due to fear of potentially hearing bad news, some participants expressed a preference to not ask questions during a consultation or yearly review with the nurse. Participants discussed prioritising day-by-day living over long-term planning, thereby focusing on health in the short term.Most participants discussed scepticism about the link between lung cancer and smoking. Conversely, participants thought that lung cancer was inevitable due to their current or former lifestyle, including smoking history, working conditions, their lung condition and the reported incidence of lung cancer in their community. For many participants, the topic of lung cancer arose spontaneously. Lung cancer was discussed in the context of perceived inevitability when reflecting on their general lung health and during completion of the symptom task when recalling friends/family with lung cancer. Beliefs about inevitability were often coupled with highly negative fearful and fatalistic beliefs about lung cancer, with no cure and eventual death. Such claims were evidenced by knowing a high proportion of friends and family who were diagnosed with lung cancer and often died. A few participants discussed that a cure for lung cancer involved luck or was ‘some miracle’ , reflecting a perceived lack of control over early diagnosis and treatment. Consequently, actual or anticipated medical help seeking for lung cancer symptoms was motivated by pain, or to seek a diagnosis and prognosis to notify family members. However, some participants anticipated refusal of treatment or would even contemplate suicide.We found differences in how participants with and without dependent family reported responding to symptoms of lung cancer. Female participants with dependent children or grandchildren discussed a motivation to visit the doctor with symptoms suggestive of lung cancer, in order to receive a prognosis to enable childcare arrangements after death. Women with dependent children who held more positive beliefs about lung cancer treatment reported the need to seek help for treatment to ‘stay healthy’ and prolong life. Participants with no dependent family were more likely to ignore lung cancer symptoms, or anticipate seeking medical help if in pain but refuse treatment.Participants discussed a sense of lack of entitlement to health services due to smoking habit, where respiratory-type symptoms of lung cancer were perceived as self-inflicted. For some, this was reinforced by an actual or expected ‘smoking lecture’ each time they sought help from healthcare professionals; the lecture made participants feel ostracised, particularly when smoking was used as a coping mechanism and contributed to not feeling worthy of seeking medical help. Some participants perceived that they may be treated differently by health professionals because they live in an area of deprivation, and discussed a potential power imbalance during consultations.Conversely, participants reported high criticism towards people who were perceived to waste, exploit and overuse NHS resources. They cited drug addicts, illegitimate benefits claimers, older people wanting social interaction and people with coughs and colds as over users of the health service. Such beliefs may reflect a downward comparison to other more stigmatised service users to legitimise their own help seeking. In order to be considered a model and non-problem patient, participants discussed legitimising their own help seeking by only consulting when absolutely necessary—and often after trying their ‘own cures’, that is, cough medicine from the pharmacist—to not burden the doctors. Infrequent attenders or ‘good service users’ discussed feeling a sense of superiority for being a model patient.Some participants disclosed traumatic events in their lives including physical and sexual abuse, leading to tobacco dependence and alcohol addiction. In addition, more than half of the sample described symptoms of depression and anxiety. Therefore, the reported relationship with their healthcare professional was important when considering whether to present with lung symptoms. Participants discussed the need to feel understood and not judged by their healthcare professional, with their personal history taken into account in the context of health behaviour such as smoking.Those who discussed feeling comfortable, safe and not judged by their chosen healthcare professional felt encouraged to present with symptoms. Some participants reported that they were prepared to wait up to three weeks for an appointment with their preferred healthcare professional to discuss worrisome and potentially serious symptoms that could indicate lung cancer. Many participants reported problems with maintaining continuity of care, highlighting problems with the stretched NHS.Two public focus groups were conducted in Wales and England. Most participants were female and former smokers, and all participants were diagnosed with a lung condition. Two professional focus groups were conducted in Wales. Most participants were female, and were medical professionals .Key themes discussed were: barriers to early lung cancer diagnosis, and preferences regarding the format and content of an intervention for the early detection of lung cancer. See The public and stakeholder focus groups confirmed our interview findings, where fear of wasting the doctor’s time with trivial symptoms and fear of being judged or lectured about smoking was perceived to deter medical help seeking for potential lung cancer symptoms. In addition, the health professional group supported our findings that patients with lung conditions tend to be preoccupied by chest infections. However, we found potential disparity between the patient-reported experience of the GP’s approach to smoking and the healthcare professional reported approach to smoking cessation. Healthcare professionals in Wales discussed new guidance that discourages health professionals from ‘lecturing’ patients, suggesting the patient-reported experience may be based on previous healthcare interactions, and they consequently anticipate a lecture. Alternatively, healthcare professionals may be unaware of new guidance, or not adhere to new guidance and consequently continue to ‘lecture’ patients about smoking.All groups discussed a preference for community based interventions, away from a traditional healthcare setting, for example, a community event, talk in a community venue or health check bus, similar to breast screening mobile units. The anonymous and relaxed nature of such an intervention meant that intervention participants would feel they were not wasting GP time; rather it would act as a signal that their attendance at the event was desired. Participants compared this with a visit to the doctor, where they discussed a feeling of wasting the GP’s time because they were not invited to attend. It was considered important that the intervention facilitator was knowledgeable or trained, non-judgemental, easy to talk to and approachable, highlighting the importance of relational aspects of a lung cancer intervention. Participants suggested a nurse, pharmacist, trained patient representative or community worker.The public groups requested more information about the symptoms of lung cancer. However, the healthcare professional groups felt that current lung cancer symptom information was too broad, leading to dismissal and potential avoidance of lung cancer information because people with smoking history or comorbid lung conditions experience most of the symptoms daily. To overcome this problem, the healthcare professionals groups discussed the need for more specific symptom information, emphasising changes to normal symptoms and coupled with information about risk factors for lung cancer.To modify negative beliefs about lung cancer, the health professionals groups suggested using positive stories to communicate messages about the importance of lung cancer early diagnosis and highlight the potential for survival outcomes with early stage detection.The inclusion of smoking cessation information in a lung cancer intervention was considered important by all groups. However, the manner in which smoking cessation could be approached was discussed as key to effective promotion of smoking cessation. Participants suggested highlighting the benefits of stopping smoking in a gentle and relaxed manner to encourage choice to quit.Our study was the first to explore the influences on lung cancer symptom presentation in high risk, highly deprived groups across three nations of the UK. Preferences for an intervention targeted at high-risk groups were ascertained through focus groups. We found evidence from the interviews and focus groups that individuals who are at high risk for lung cancer tend to be preoccupied by maintaining health in the short term. Prioritising the daily management of their lung condition led to avoiding consideration of long-term health problems such as lung cancer, to gain a sense of control over health in the context of difficult personal circumstances. Health beliefs were found to underpin behaviour in relation to medical help seeking, where perceptions of ‘inevitable but curable’ chest infections led to immediate help seeking. However, ‘inevitable but incurable’ lung cancer led to inaction when faced with potentially serious symptoms and anticipated refusal of treatment. Interview participants felt that the relationship with the healthcare professional was key when considering medical help seeking. The importance of the relational interaction between provider and patient was mirrored in the focus groups, where participants felt that a non-judgemental intervention facilitator was important. Multifaceted community-based interventions, away from the traditional healthcare setting, were preferred by participants.Previous empirical studies report prolonged lung cancer symptom presentation due to misattributionFear of being ineligible for treatment due to lifestyle has not been well described in studies with patients with lung cancer or those at high risk.We found that participants held seemingly contradictory views on their lung cancer susceptibility, reporting scepticism about the causal role of smoking in lung cancer alongside perceived inevitability of lung cancer. Beliefs about the link between smoking and lung cancer may reflect societal stigma towards smoking, where participants downplay the negative effects of smoking, possibly to legitimise medical help seeking for symptoms considered related to smoking. Perceived inevitability of lung cancer is likely to reflect high levels of exposure in social networks where there is high incidence and poor outcomes of lung cancer,A major strength of this study was the rigorous sampling procedure. We screened postcodes to ensure participants resided in the lowest quintile of deprivation, and measured multiple additional indicators of deprivation. Individual and area level indicators confirm that our sample was highly deprived, for instance, most were unemployed and seeking benefits, and rented social housing. In addition, we recruited participants with no previous diagnosis of lung cancer, without mention of lung cancer until discussed by participants during the interview, or at the end of the interview. These recruitment and interview procedures meant we were able to explore previous and anticipated lung cancer symptom presentation in those who were symptomatic or asymptomatic. This strategy was employed to overcome the methodological limitations associated with studying either retrospective or anticipated symptom presentation in isolationWith a comorbid lung condition and smoking history, those who are high risk for lung cancer will, in the main, be symptomatic. To avoid normalisation of symptoms, it is important to highlight the significance of changing and multiple symptoms. High-risk individuals should be empowered to seek timely medical help and made to feel welcome, not judged or blamed for their current or former lifestyle. For instance, interventions targeted at disadvantaged populations could be conducted outside of the traditional healthcare setting. Our findings highlight the importance of an intervention where participants would be invited to attend, as opposed to presenting to the GP surgery, in order to eliminate concerns about wasting GP time and legitimise their attendance. Community-based interventions have the potential to harness the relational aspects of help seeking, through interventions led by non-judgemental and welcoming facilitators. It is possible that previous mass media and social marketing lung cancer awareness interventions report low campaign reach to deprived groupsOver half of the current sample described mental health problems and/or difficult current or former life circumstances. Intervention developers and healthcare professionals in highly deprived communities should be aware of these wider social and contextual factors; they should receive training to recognise such circumstances and know how to appropriately signpost. Finally, we suggest that the current UK health system may encourage patients with a lung condition to focus on short-term management of their condition. GP prescribing of antibiotics and the use of rescue packs (prescribed antibiotics for storage at home in the event of an exacerbation) may inadvertently reinforce patients to detect and act on symptoms of a chest infection.The challenges of living in an area of deprivation with social exclusion issues, combined with fear of judgement by health professionals, contribute to avoidance and ignoring of lung cancer symptoms. Multi-faceted community based interventions are required to highlight lung cancer symptoms, the importance of early diagnosis and empower people who are at high risk for lung cancer to seek timely medical help.10.1136/bmjopen-2018-025902.supp3Supplementary file 310.1136/bmjopen-2018-025902.supp4Supplementary file 4


Whether persons with schizophrenia have a higher or lower incidence of cancer has been discussed for a long time. Due to the complex mechanisms and characteristics of different types of cancer, it is difficult to evaluate the exact relationship between cancers and schizophrenia without considering the type of tumor. Schizophrenia, a disabling mental illness that is now recognized as a neurodevelopmental disorder, is more correlated with brain tumors, such as glioma, than other types of tumors. Thus, we mainly focused on the relationship between schizophrenia and glioma morbidity. Glioma tumorigenesis and schizophrenia may share similar mechanisms; gene/pathway disruption would affect neurodevelopment and reduce the risk of glioma. The molecular defects of disrupted-in-schizophrenia-1 (DISC1), P53, brain-derived neurotrophic factor (BDNF) and C-X-C chemokine receptors type 4 (CXCR4) involved in schizophrenia pathogenesis might play opposite roles in glioma development. Many microRNAs (miRNAs) such as miR-183, miR-9, miR-137 and miR-126 expression change may be involved in the cross talk between glioma prevalence and schizophrenia. Finally, antipsychotic drugs may have antitumor effects. All these factors show that persons with schizophrenia have a decreased incidence of glioma; therefore, epidemiological investigation and studies comparing genetic and epigenetic aberrations involved in both of these complex diseases should be performed. These studies can provide more insightful knowledge about glioma and schizophrenia pathophysiology and help to determine the target/strategies for the prevention and treatment of the two diseases. Early in 1909 , a predisposing gene first found with its disruption by a balanced t  in a large Scottish family, is identified to be closely related to major mental illnesses such as schizophrenia and bipolar disorder  plays an important role in neuronal development including neurogenesis, synaptic transmission and consolidation  have been reported to overexpress in most cancers, including glioma  are small RNAs containing 20–23 nucleotides which regulate diverse biologic processes by inhibiting gene expression at the post-transcriptional level. Various studies have proved prominent roles of miRNAs in many physiological and pathological processes, and miRNAs could be a diagnostic and prognostic biomarker for various diseases such as cancer and CNS diseases including schizophrenia (Rao et al., Many studies have proved that antipsychotic drugs may have antitumor and radiosensitizing effects (Carney et al., Several pieces of evidence provided here indicate that there might be a negative correlation between glioma and schizophrenia (Eskandari et al., All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear editor Crocus sativus which is a precious plant cultivated in our country. We do believe that along with all other medicinal effects, saffron or its active constituents, primarily crocin and crocetin, could also have some clinical implications in the gynecology field. Historically and particularly in traditional Persian medicine, saffron has been regarded as an abortifacient agent . According to their results, Crocus sativus increased these contractions and showed spasmodic action on muscle fibers In the end, we congratulate Mokhtari-Zaer et al on their article and we appreciate the Avicenna Journal of Phytomedicine editorial board for their judicious concern on this topic. We hope to read well-controlled randomized clinical trials regarding the beneficiary effects of saffron in future.None.


Transcriptional regulation of cells in the immune system must be strictly controlled at multiple levels to ensure that a proper immune response is elicited only when required. Analysis in bulk, or ensemble of cells, provides a wealth of important information leading to a better understanding of the various molecular steps and mechanisms involved in regulating gene expression in immune cells. However, given the substantial heterogeneity of these cells, it is imperative now to decipher these mechanisms at a single cell level. Here I bring together several recent examples to review our understanding of transcriptional regulation of the immune system via single cell analysis and to further illustrate the immense power of such analyses to interrogate immune cell heterogeneity. Combight time –4. Colleght time , 6. HoweIn animal tissue, neighboring cells that are apparently identical turn out to exhibit important differences when significant depth of analysis was achieved via single cell techniques. Originally, single cell techniques were applied in situations where biological sample was limiting. But now, given the high throughput technologies that are at our disposal, profiling hundreds of thousands of heterogeneous cells within a population is possible with relative ease , 6. Within situ Hybridization, FISH), proteomics (with CyTOF and MIBI-TOF) and genomics  provide substantial hope that these additional methods reporting functional states of a cell would complement RNA-seq to identify novel cell types, and further analyze and assign function to these cells and tissues to perhaps reveal unchartered but promising therapeutic avenues (reviewed in 7).Despite significant technological advances, our understanding of the gene regulation in the immune system still remains incomplete because there is substantial heterogeneity in the cells constituting the system. Immune cells are diverse with respect to developmental stages, function and cell types  as well as location  in addition to circulating immune cells through peripheral blood and lymphatic systems , 6. MoreMemory B cells of the adaptive immune system are generated following pathogenic infection or vaccination so that they can respond against future infections . HoweverAs noted in the introduction, immune cells are found at multiple organs/tissues within the human body, raising the question of whether they behave in the same fashion at these discrete locations. Single cell analysis is making it possible to interrogate the identity and infer the function of immune cells found in disparate locations. For instance, although it has been known that immune cells are found in liver, the immunobiology of liver remains poorly understood. A new study mapped the cellular landscape of human liver using tissue dissociation techniques combined with functional assays and scRNA-seq . They idAnother recent study maps tissue resident macrophages in murine lung and identifies two subpopulations of interstitial macrophages via single cell transcriptomics . This stex vivo , the cells constituting the adaptive immune system are primarily composed of B and T lymphocytes . Howeverex vivo , 17. Insex vivo –18. DiscHeterogeneity in gene expression is important to elucidate because it might indicate the existence of new and yet unidentified subpopulations in such milieu. But, heterogeneity in gene expression profile could also provide novel insights into the function of a given gene or sets of genes , 19. ForAdditionally, the heterogeneity exhibited in scRNA-seq data could also be due to variability in the expression of a given gene in various cells. This in turn could depend on relative expression state of a given gene compared to other genes in the same signaling pathway , 19–21. To understand true transcriptional diversity in cells requires not only to determine total transcript levels but isoform levels as well . A compuImmune cells are characterized by surface expression of specific receptors, those that generally respond to signaling via engagement of cognate ligands for differentiation along particular lineages. However, due to high degree of heterogeneity in immune cell lineages, it remains to be determined whether there are sub-populations within a specific lineage that respond differentially  to ligands. To illustrate differential response of immune cells to specific ligands, Chea et al. used single cell analysis, which revealed that there is significant heterogeneity in response of fetal liver-derived ILC progenitors to Notch signaling . It is wWe now know that many patients do not respond to treatments because recent data shows that roughly 90% of drugs are only effective for < 50% of patients . The inein vitro assays with transcriptomics and functional assays, these studies demonstrate that the field of single cell analysis could move beyond descriptive analysis to providing mechanistic insights. Rothenberg and colleagues used a combination of scRNA-seq, in vitro differentiation assays along with flow cytometry and time-lapse live cell imaging to address lineage commitment mechanisms during T cell development (Bcl11b expression: (i) an early commitment step, where the locus becomes “poised” for expression, which is dependent on two T cell lineage-restricted transcription factors, TCF-1 and GATA-3, (ii) a more “permissive” step that is dependent on Notch signaling, and (iii) a third “amplitude-control” step to modulate Bcl11b gene expression, that requires another transcription factor, Runx1, already present from early precursor cells , they are likely to identify molecular targets and novel avenues appropriate for therapeutic interventions  is enabling us to decipher the genome architecture in distinct cell types at single cell resolution, which when combined with transcriptomic and proteomic data should provide mechanistic insights into cellular heterogeneity and differentiation . New andIt is worthwhile to ponder why no two cells in an animal could be identical. Raj and colleagues argue that in general, there are two reasons why any two cells might differ from each other and these might not be mutually exclusive . First, The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation, though no other collaboration, with the author.


The complex dynamics of biological systems is primarily driven by molecular interactions that underpin the regulatory networks of cells. These networks typically contain positive and negative feedback loops, which are responsible for switch-like and oscillatory dynamics, respectively. Many computing systems rely on switches and clocks as computational modules. While the combination of such modules in biological systems leads to a variety of dynamical behaviours, it is also driving development of new computing algorithms. Here we present a historical perspective on computation by biological systems, with a focus on switches and clocks, and discuss parallels between biology and computing. We also outline our vision for the future of biological computing. The similarity between the biological switch controlling mitotic entry and the approximate majority algorithm of distributed computing , of registers to hold intermediate results of iterative algorithms, and of coordination components that orchestrate the flow of information across registers and functional units. Coordination is most often achieved by clocks: at each tick data is frozen into registers, and between ticks data flows between registers through the functional units. This is the so called von Neumann architecture that, despite dramatic technology improvements and architectural refinements, has remained largely unchanged since the first electronic computers.Functional units compute Boolean and mathematical functions by combinational logic . We can easily find analogues of these in biology, like the function computed by the regulatory region of a single gene  are found both in biology and in computer engineering, it does not necessarily mean that these systems compute “in the same way”. In particular, coordination is achieved in fundamentally different ways in biological systems than in the von Neumann architecture. In biology, oscillators coordinate events only at the coarsest level of granularity, while fine-grained coordination is achieved by direct interaction between molecular components. In the central processing unit of computers, oscillators instead coordinate events at the finest grain, and do so at great cost. As a result, low-power devices tend to employ clock-free coordination strategies to save power. At the level of computer networks, though, coordination is achieved by message passing, because individual clocks can get out of step and network latency may vary. Many non-von Neumann models of computation have been studied in the area of distributed computing: these models resemble, and sometimes even technically coincide, with biochemical models  arise when at least two molecular species regulate each other’s activity Fig. . There aPositive FBLs (PFBLs) auto-enhance the production of the species involved in the loop. There are two subtypes of PFBL, pure positive or double-negative. Pure PFBLs contain only interactions of activation, while double-negative PFBLs, or antagonistic interactions, contain an even number of inhibitions (plus any number of activations). Fig. .relaxation oscillators produce characteristic fast switching in one direction, with slow switching in the other direction, producing triangular-like waveforms (Sel'Kov Feedback loops (FBLs) constitute a basic relationship between molecular species to construct complex behaviours and consequently are abundant in protein regulatory networks. FBLs can produce various dynamical behaviours, such as efficient switching and oscillations   as the computational substrate. The use of DNA for computation was first introduced by Adelman to solve an instance of the Hamiltonian path problem Adleman . It workApproximate Majority (AM) network, a system based on competing autocatalytic feedback loops  chemical reaction network that realizes a robust bistable switch is the ops Fig. a.Fig. 2Sn is the population size (number of agents). Moreover, the steady states are robust to large perturbations, and they are reached quickly even when starting from ambiguous configurations  that each agent can independently adopt ethylated, U(nmodified), or (A)cetylated  exactly the same as the set of trajectories of the simple network . In such a fashion it can be shown that various idealized cell cycle switches emulate AM . Nucleic acids are currently the molecules of choice for molecular programming, due to their high degree of programmability via Watson-Crick complementarity and their ability to directly interface with biological components, with potential applications in sensing, diagnosis and treatment of disease. A number of approaches have been proposed for implementing computation in nucleic acids. Here we will summarise two of the main ones—DNA Strand Displacement and PEN DNA Toolbox—and describe how they have been used to implement switches and clocks.Molecular Programming involves toehold. Various types of computation have been implemented experimentally using this approach, including elementary Boolean logic  toolbox is a set of modules that can be composed to implement molecular programs Fig. a and, asactivation module enables a short single-stranded DNA (ssDNA) signal deactivation module implements the reaction degradation module.An totoA bistable switch was one of the first circuits constructed using the PEN-DNA toolbox  (Tabor et al. integral control via negative feedback has been demonstrated in metabolic circuits (Briat and Khammash Put together, there is now real promise for designing cell colonies that control their own temporal dynamics and spatial positioning. This could be highly relevant to biologics production in bioreactors, where spatial heterogeneity in resources and cell density could lead to inefficiencies. The advantages of automatic control can be readily seen in more traditional control engineering applications, and consequently, there is now rising interest of implementing control algorithms in biological circuits (Del Vecchio et al. Despite the promise of synthetic biology, significant challenges remain for regulating biological behaviours with the insertion of designed networks of transcriptional components. One challenge relates to timescale: transcriptional control is slow, though is the dominant mode of regulation in synthetic biology applications to date. Control algorithms are sometimes inefficient in the face of delays, and so their success might depend on establishing faster modes of biological regulation. Here, molecular programming might provide a solution, as DNA-based circuits can be localized, speeding up their operation (Chatterjee et al. The extent to which spatiotemporal control can improve biotechnology applications is relatively unexplored. Therefore, more theoretical work is needed to establish the performance that can be achieved by algorithms based on chemistry and cellular communication, and therefore to understand the capability of synthetic multicellular platforms.As we increasingly rely on computing to process large datasets for everyday tasks at home and at work, power consumption will become a future limiting factor Council . In factIn this review we have highlighted how complex biomolecular networks make use of switches and oscillators to perform computation. The continued understanding of how this information processing is achieved at such high levels of robustness and low power requirements will require the concerted efforts of systems and synthetic biology in addition to leveraging tools from engineering and computer science. While it is unlikely that biological systems will ever replace silicon as our dominant computing platform, learning how they compute could have a significant impact on future computing architectures.


Primary health care providers identify and treat many patients who are at risk for or are already experiencing alcohol-related problems. Brief interventions—counseling delivered by primary care providers in the context of several standard office visits—can be a successful treatment approach for many of these patients. Numerous trials involving a variety of patient populations have indicated that brief interventions can reduce patients’ drinking levels, regardless of the patients’ ages and gender. In clinical practice, brief interventions can help reduce the drinking levels of nondependent drinkers who drink more than the recommended limits, facilitate therapy and abstinence in patients receiving pharmacotherapy, and enhance the effectiveness of assessment and treatment referral in patients who do not respond to brief interventions alone. Despite the evidence for their usefulness, however, brief interventions for alcohol-related problems have not yet been widely implemented in primary care settings. Most Americans consume alcohol at least occasionally, and results from the National Household Survey  suggest moderate, or low-risk, alcohol use is defined as consumption of no more than two standard drinks per day for men and no more than one standard drink per day for women and people over age 65. A standard drink is defined as one 12-ounce beer or wine cooler, one 5-ounce glass of wine, or 1.5 ounces of distilled spirits. Each of these standard drinks contains approximately 0.5 ounce, or 14 grams, of pure alcohol.According to guidelines published by the National Institute on Alcohol Abuse and Alcoholism in 1995, At-risk alcohol use is defined as consumption of more than 7 drinks per week or more than 3 drinks per occasion for women and more than 14 drinks per week or more than 4 drinks per occasion for men. A positive response to one or more questions on the four-item CAGE questionnaire (see footnote 1 below) also may indicate at-risk use. Problem alcohol use is defined as one or more positive responses to the CAGE questionnaire and evidence of alcohol-related medical or behavioral problems. Dependent use is defined as either three or four positive responses to the CAGE questionnaire and/or evidence of one or more symptoms of alcohol dependence .Many people who are at risk for, or who are already experiencing, alcohol-related social and medical problems do not consult alcoholism treatment specialists but receive their health care from a primary care provider. Consequently, primary care settings offer an important opportunity to identify and treat people with potential drinking problems. Epidemiological analyses underscore the notion that primary care settings are pivotal in helping people with alcohol-related problems. For example, a prevalence study conducted in primary care settings found that 20 percent of male patients and 10 percent of female patients who came to see their physicians met the criteria for at-risk, problem, or dependent alcohol use . FurtherOne treatment method that has proved to be effective in primary care settings is physician-delivered brief intervention . This arThe term “brief intervention” refers to a time-limited, patient-centered counseling strategy that focuses on changing patient behavior and increasing patient compliance with therapy. Although this article focuses on the use of brief intervention for changing alcohol use patterns, this approach is not unique to the treatment of alcohol problems. In fact, physicians and other health care professionals widely employ this technique to help patients change a variety of behaviors .In general, brief intervention consists of the following five essential steps . The goal of brief intervention with this population is to reduce alcohol use to low-risk levels, thereby minimizing the drinkers’ risk of developing alcohol-related social and medical problems. Thus, the aim of brief intervention for these drinkers is not so much abstinence as harm reduction. For example, in young men, total mortality and the relative riskA second clinical situation in which brief intervention may be useful is to facilitate medication compliance and abstinence in patients who are being treated with pharmacological therapies for alcohol dependence and coexisting psychiatric conditions, such as depression. Failure to continue taking their medication (i.e. noncompliance) is a major issue with these patients, a problem that brief intervention may ameliorate. For example, The third clinical situation in which brief intervention is beneficial involves alcohol-dependent patients or patients with alcohol-related problems who do not respond to this intervention alone. Although brief intervention by itself is not sufficient in these cases, it can help health care providers identify those patients and refer them to specialized treatment. Most patients who are referred for an assessment of their alcohol-related problems or for counseling either do not schedule an appointment or fail to keep the scheduled assessment . In the A variety of alcoholism treatment approaches exist, ranging from physician-delivered brief intervention to intensive inpatient therapy. Brief intervention is primarily based on motivational enhancement therapy. In addition, brief intervention uses many elements of 12-step-based methods and cognitive behavioral therapy. Nevertheless, brief intervention differs from these three types of interventions—which primarily are administered as long-term therapy—in two respects. First, brief intervention frequently is not aimed at achieving complete abstinence but focuses on harm reduction and on increasing the patient’s readiness to change his or her behavior. Second, the total number of visits during which brief intervention is delivered is limited.Several strategies can help clinicians achieve their goals in the limited time-frame available for brief intervention:The physician can emphasize specific medical problems related to a patient’s alcohol consumption to raise the patient’s awareness that alcohol use can lead to serious health problems.The clinician can provide the patient with a written contract (in the form of a prescription) that specifies goals for reducing drinking levels.In many cases, if the physician has had a long-term and trusting relationship with the patient, the physician can influence the patient to change his or her behavior.Many studies have demonstrated that brief intervention delivered in a primary care setting can be an effective way to help at-risk or problem drinkers change their drinking behavior, thereby ameliorating or preventing alcohol-related health and other problems. Nevertheless, brief intervention has not yet been widely implemented in primary care settings. Several factors contribute to this lack of implementation.First, health care settings today are complex systems involving numerous parties, including patients, health care providers, purchasers , and payers . All of these parties have specific and sometimes competing agendas. For example, health care providers are primarily interested in providing the most effective care to their patients , whereas purchasers and payers also are interested in cost containment. To enhance the implementation of brief intervention, health care purchasers and payers need to provide financial support and leadership. To achieve this goal, both purchasers and providers of health care insurance must realize that the prevention and treatment of alcohol problems will improve their clients’ health, thereby reducing both health care and social costs. Professional organizations must more actively work with payers and providers to allocate resources that accurately reflect the adverse effects of alcohol problems on the health care industry and on the health of the American people.Second, many clinicians do not receive adequate skills training in conducting brief intervention. Furthermore, clinicians often are not compensated or rewarded for conducting clinical activities related to the prevention and treatment of alcohol problems. Several steps can help remedy those barriers. For example, clinicians should attend training workshops on how to make brief intervention for alcohol problems an essential component of their regular clinical activities. The workshops should focus on skills-training activities, using role-play exercises and standardized patients . Quality improvement programs, which are being implemented throughout the health care system, also can provide a unique opportunity to change clinician practice behavior. Many of these programs currently do not cover alcoholism screening and intervention; however, the establishment of monitoring systems to examine alcohol use in patients being treated for hypertension, depression, or anxiety disorders could significantly change practice patterns. Such incentives as financial reimbursement, paid education time to attend training workshops, and quality-improvement peer review programs also may encourage clinicians to implement alcohol screening and intervention in their practices.Third, brief intervention may be particularly difficult to implement in clinic settings, which already must accommodate a wide range of clinical tasks and activities, such as routine physicals, treatment of acute medical problems , management of chronic conditions , and prevention programs . To implement and maintain alcohol screening and intervention in clinic settings, procedures must be developed to incorporate brief intervention into routine clinical care. Measures such as self-administered screening tests, incorporation of alcohol-related questions in the assessment of routine vital signs, and computerized reminder systems alerting clinicians to screen clients for alcohol problems can help identify patients who may benefit from brief intervention. Additional reminders  can be attached to the clients’ medical records or posted in another prominent location. Self-help booklets, alcohol consumption diary cards, lists of self-help group meetings , and referral information with telephone numbers and names of alcoholism treatment specialists can assist clinicians and clients in establishing followup plans and strategies.Fourth, the implementation of brief intervention often is prevented by the lack of integration of alcohol and other drug (AOD) treatment into primary care systems. Alcoholism treatment has historically occurred outside the traditional medical care system, and many alcoholism treatment programs are free standing and community based. Lack of communication between such specialized treatment programs and the client’s primary health care providers can have serious adverse effects on a patient’s long-term sobriety. For example, in contrast to other specialty referral systems , AOD treatment programs do not routinely send copies of the assessment, treatment plan, or discharge summary to the client’s health care provider. Similarly, AOD treatment specialists do not routinely call the client’s physician or therapist to coordinate and jointly develop long-term treatment plans. Concerns about patient confidentiality may prevent the free flow of information between the specialized treatment program and the primary health care provider. Clients with alcohol problems, however, deserve treatment providers who communicate and work together to provide coordinated, comprehensive care.Consequently, the integration of specialized alcoholism treatment into the general medical care system is an important component in enhancing the implementation of brief intervention. Two measures can facilitate an integrated treatment process of brief intervention and referral to specialized treatment:Alcoholism treatment programs should be located in close physical proximity to primary care offices, because physicians are more likely to refer clients to and communicate with a trusted colleague whose office is down the hall rather than make referrals to a stranger whose practice is located many miles away in a different system of care. Local proximity between primary care and specialized care providers also makes it easier for clients to accept and follow through with a referral.Communication between primary care and alcoholism treatment providers can be increased by encouraging primary health care providers to send referral letters to and request clinical updates from alcoholism treatment programs. Conversely, treatment programs should be encouraged to have their patients sign medical release forms that allow the programs to send assessments and treatment plans back to the primary health care provider. Such releases also allow primary care providers and alcoholism counselors to communicate directly by telephone to discuss treatment options. Ideally, primary care physicians and AOD treatment specialists should be members of one comprehensive medical care team.Brief interventions are counseling strategies that primary care physicians can deliver during routine office visits to help clients change their drinking behavior . Numerous studies have suggested that brief intervention can reduce alcohol consumption in a substantial number of at-risk or problem drinkers and can facilitate the referral of dependent drinkers into specialized alcoholism treatment. As a result, brief intervention can help prevent or ameliorate numerous alcohol-related medical and social problems and the associated costs. Despite the encouraging results regarding the effectiveness of brief intervention, however, such measures have not yet been widely incorporated into primary care practices. Factors contributing to this lack of implementation include the complexity of the health care system, inadequate physician training, and lack of integration of AOD treatment into general medical practice. Coordinated efforts of health care providers, purchasers, and payers can help remove these barriers, thereby ensuring that patients with alcohol-related problems receive the comprehensive care they need.


Furthering our understanding of how chemotherapy agents target the prepubertal testis will provide clarity to patients on the gonadotoxicity of different drugs and aid in the development of cytoprotective agents.Chemotherapy treatment is a mainstay of anticancer regimens, significantly contributing to the recent increase in childhood cancer survival rates. Conventional cancer therapy targets not only malignant but also healthy cells resulting in side effects including infertility. For prepubertal boys, there are currently no fertility preservation strategies in use, although several potential methods are under investigation. Most of the current knowledge in relation to prepubertal gonadotoxicity has been deduced from adult studies; however, the prepubertal testis is relatively quiescent in comparison to the adult. This review provides an overview of research to date in humans and animals describing chemotherapy-induced prepubertal gonadotoxicity, focusing on direct gonadal damage. Testicular damage is dependent upon the agent, dosage, administration schedule and age/pubertal status at time of treatment. The chemotherapy agents investigated so far target the germ cell population activating apoptotic pathways and may also impair Sertoli cell function. Due to use of combined chemotherapy agents for patients, the impact of individual drugs is hard to define, however, use of The admThe testis is responsible for producing mature spermatozoa along with the main male reproductive hormone, testosterone. During prepuberty, the testis was originally thought to be relatively inactive based on studies demonstrating few morphological changes and a lack of hormone production during this period . HoweverSRY (sex-determining region Y) gene, which drives production of the SOX9 (SRY-box 9) protein, Sertoli cells differentiate from precursors cells within the gonadal ridge and engulf the primordial germ cells which are now classified as gonocytes. This configuration results in the formation of seminiferous cords, which predominantly contain Sertoli cells with centrally located gonocytes. The Sertoli cells are key drivers in the differentiation and function of other cellular components of the testis including the Leydig cells and peritubular myoid cells  or pale  appearance. Adark spermatogonia are believed to represent the reserve stem cells with low mitotic activity, whilst the Apale cells are actively proliferating. Upon differentiation, the Apale spermatogonia differentiate to B spermatogonia, which can be observed from 4 to 5 years of age (single (As) spermatogonia actively proliferate to form two conjoined daughter cells known as Apaired (Apr) cells which continuously divide forming Aaligned  chains (reviewed in 3) decrease during the first 3 years of life followed by a gradual increase up to 6 to 7 years of age, plateauing up to age 11 when boys begin to enter puberty and numbers increase dramatically. The initial decrease may be a result of programmed cell death of the gonocytes that failed to migrate to the basement membrane earlier in development  and long-term analysis (6 to 10 years) following the cessation of cyclophosphamide treatment have shown that damage is often still observable in a dose- and time-dependent manner . PatientThe studies discussed above suggest that alkylating agents, in particular cyclophosphamide, can be detrimental to the prepubertal testis in a manner that can persist at least up to 10 years after the cessation of treatment. Since patients had received a combination of chemotherapy drugs, it is hard to determine the relative contributions of individual chemotherapeutic drugs to gonadal toxicity; in addition, results may have been influenced by the age/stage of pubertal development and each patient’s own sensitivity to chemotherapy treatments.in vivo or in vitro with the majority of studies focusing on germ cell effects. Work to date has looked specifically at alkylating agents, anthracyclines, topoisomerase inhibitors, vinca alkaloids and non-anthracycline antibiotic chemotherapy treatments.The use of animal models has the potential to provide a clearer picture of chemotherapy drug-induced gonadal toxicity in the prepubertal context, in comparison to our very limited ability to investigate this directly in humans. Research on animal models enables researchers to administer drugs through more regulated regimens and to compare results using animals, tissues or cells. The use of animal models also opens the possibility of determining which period of development is more sensitive to chemotherapy treatment, for example by comparing infancy to prepuberty. Additionally, such studies are likely to be invaluable in determining the underlying mechanisms by which the different chemotherapy drugs damage the prepubertal testis, information which should help in the subsequent development of protective strategies designed to directly block such damage. Despite their great potential, relatively few studies have been conducted in vitro, which could ultimately activate cell death pathways if not repaired by internal DNA repair systems  mouse testis (in vivo immediately following cisplatin treatment during early puberty (pnd 30–45) in the rat and after a 45-day recovery period  was not sufficient to kill all the SSCs, as some recovery was apparent. In addition to inhibition of topoisomerase II activity, doxorubicin has been shown to induce DNA damage in spermatogonia in vitro, which can result in cell death  has shown no such increase in levels of reactive oxygen species (ROS) before the onset of cytotoxicity  that reflect patient serum levels shows that this drug targets the proliferating germ cell population  inducing DNA damage that extends into telomere regions of chromosomes . This suggests that the germ cells were the primary cells targeted by doxorubicin, with loss/damage to the germ cells ultimately impacting Sertoli cells as a secondary effect , is thought to have multiple pharmacological effects through its antioxidant activity . R M’s work was undertaken in the MRC Centre for Reproductive Health funded by MRC Centre Grant MR/N022556/1, and C A was supported by Career Development PhD Scholarship in Biomedical Sciences funded by the Biomedical Sciences ZJU project. Thanks to Kathleen Duffin for comments on an earlier draft.


The combination of an aging population and a limited number of disaster responders reveals a need for trained laypeople who can implement interventions that facilitate recovery after traumatic events. Skills for Psychological Recovery (SPR) is an intervention that is designed to be implemented after use of Psychological First Aid with people who were exposed to a traumatic stressor. SPR uses a skills-building approach to promote self-efficacy, support resilience, strengthen social networks, and ameliorate the negative impact of traumatic life events. Strengthening social support is beneficial as research clearly demonstrates that destruction of communities and loss of informal social support networks produces long-term psychological distress for older adults. This presentation will demonstrate a SPR social support exercise with attendees, provide an overview of the other modules, and describe modifications for using SPR with older adults. During times of crisis, social support systems are critical to the psychological well-being of older adults.


Intraosseous (IO) needles are used in critically ill patients when it is not possible to quickly obtain venous access. While they allow for immediate access, IO infusions are associated with complications including fractures, infections, and compartment syndrome. We present a case where point-of-care ultrasound was used to quickly identify a malfunctioning IO needle that resulted in compartment syndrome of the lower extremity. Intraosseous (IO) needles are often used in high-acuity patients for whom having vascular access is essential. Malfunctioning IO needles may be associated with patient harm as there is decreased medication delivery and complications secondary to the IO placement, such as compartment syndrome. Further, identifying compartment syndrome may be difficult in critically ill patients who are unable to communicate and for whom serial compartment checks may not be possible or a priority due to competing medical priorities. For this reason, rapid identification of IO needle functionality is needed and can be achieved using point-of-care ultrasound (POCUS). POCUS use has been described as a tool to facilitate evaluation of an IO needle by looking for Doppler signals in the area surrounding the IO during infusions. POCUS can add to patient care and safety by identifying malfunctioning IO needles and potentially preventing complications. We present a case report in which POCUS aided in rapid recognition of IO needle malfunction and in the identification of compartment syndrome.A 63-year-old male was brought into the emergency department (ED) after being found unresponsive. Paramedics in the field noted that the patient was obtunded, with a Glasgow Coma Score of 3 and a blood sugar of 33 milligrams per deciliter (mg/dL). After multiple unsuccessful attempts were made to gain intravenous (IV) access, paramedics used the EZ-IO® to place a 45 mm IO needle into the left proximal tibiaand adminPOCUS was performed to evaluate the functionality of the IO needle. A high-frequency linear probe  with color Doppler was used to evaluate the area proximal and distal to the IO access in transverse (short) plane of the tibial bone. Color Doppler showed absence of flow in the IO space during injection of a small amount of normal saline, concerning for inappropriate IO needle placement . SubsequFifteen minutes after arrival to the ED, the patient’s left lower extremity was noted to be cool and mottled. Examination of the extremity showed firm compartments and decreased peripheral pulses concerning for compartment syndrome. The deep posterior compartment pressure was 85 mmHg. A radiograph showed that the IO needle had punctured both the anterior and posterior cortex of the tibia, extending 2 mm beyond the posterior cortex . The patWhat do we already know about this clinical entity?Intraosseous (IO) needle functionality can be assessed using point-of-care color Doppler ultrasound to evaluate for flow in the IO area during infusion through the IO needle.What makes this presentation of disease reportable?This is the first reported case in which ultrasound has helped to identify a malfunctioning IO needle and aided in the rapid recognition of a compartment syndrome.What is the major learning point?Just as radiographs are used to confirm proper placement of central venous catheters, ultrasound can be used to evaluate placement and functionality of IO needles.How might this improve emergency medicine practice?Point-of-care ultrasound can be used to improve patient safety by rapidly identifying malfunctioning IO needles and preventing complications such as compartment syndrome.IO needles are indicated in critically ill patients for whom peripheral venous access is not possible. Correct placement of the IO needle with the appropriate size needle are both essential to ensure proper function. IO needles may be placed in any large bone with palpable landmarks – usually the distal tibia, proximal tibia, distal femur, or proximal humerus. A 15-mm long needle (pink) is recommended for children (3 kg–39 kg), whereas a 25-mm long needle (blue) is recommended in adults. A 45-mm long needle (yellow) is considered the ideal length for humeral placement in patients with excessive soft tissue or musculature overlying the insertion site.IO access is considered a fast and effective alternative to peripheral and central lines in critically ill patients. This case, however, showcases a potential risk and complication of its use as well as the value of POCUS in mitigating these risks. The most common complications of IO needle insertion include insertion site infection, hematoma formation, extravasation of medications, and compartment syndrome.7POCUS is an adjunct that can be used to evaluate functionality of IO needles and ensure safety and efficacy of any medications that may be administered through this access site.Intraosseous needles are often placed in critically ill patients when lifesaving medications need to be administered emergently. A non-functioning or mispositioned IO needle can lead to inadequate medication administration as well as complications, as in our case. It is important to frequently check for signs of infiltration of medications from the IO needle as well as to re-evaluate the neurovascular status of the patient’s limb. In patients with altered mental status in whom a thorough neurovascular exam is difficult, or in an obese patient whose landmarks and compartments may be hard to evaluate, the clinical signs of compartment syndrome can be difficult to assess. By using POCUS to evaluate functionality of the IO needle immediately after placement, clinicians can rapidly confirm properly placed and functioning IO devices, ensuring adequate medication delivery in critically ill patients and potentially avoiding serious complications.Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.


Radiology has played an essential role in the diagnosis and treatment of many medicalconditions in the last three decades. The higher spatial resolution of modern computedtomography (CT) and magnetic resonance (MR) scanners has resulted in early detection ofdiseases, as well as providing an opportunity to understand and possibly change thenatural history of several neoplasms.(1). In many instances, such findings are not true neoplasmsand are not associated with any clinical morbidity but still generate high costs for thehealth care system, due to long-term follow-up and expensive diagnostic tests, as wellas causing anxiety for patients. For example, tiny pancreatic cysts are a very commonfinding on routine MR scans of the abdomen, especially when thin-sliceMR-cholangiopancreatography sequences are performed. The follow-up suggested by clinicaland surgical consensus is strict and seems overestimated(2). However, which of thosecysts will develop into a malignant neoplasm and how long that process takes are stillunanswered questions and create opportunities for future research. Incidentally detectedadrenal thickening and small adrenal masses are other examples of findings that maytrigger extensive clinical and laboratory work-ups, as well as requiring follow-upperiods of up to five years(3).The benefits of early detection have to be balanced against the large number ofincidental findings(4).We may have missed the essential nature of radiology and started "chasingghosts"(5).Our real purpose (telos in Aristotle's philosophy) should always be tosafeguard patient welfare, and care should be taken when reporting incidental findingsthat could potentially divert us from delivering the best patient care. Nevertheless, wedo realize that some incidental findings are truly important and are sometimes even moresignificant than the main clinical issue.The burden of health care costs is concerning worldwide, and there are opportunities toimprove patient care while reducing medical costs. When analyzing incidental findings,it is important to keep in mind our primary aim as radiologists, which is not chasingincidental findings but rather diagnosing disease or facilitating the diagnosticprocess(6).We need radiology to be more efficient and pragmatic, focusing on patient managementrather than "radiology by the book". Radiology reports should be focused less on thedifferential diagnosis and more on suggestions for the referring physician. It may bemore relevant to suggest a biopsy or even surveillance on a small renal mass than toguess the correct histology of the lesion. Third, quantitative imaging may also revealsome important value "hidden" in CT examinations ("opportunistic data"), such as theassessment of sarcopenia and abdominal fat(7-9), as well as the burden of abdominal aorta calcificationand cardiovascular risk(10). We can go even further, looking at bone density andthe risk of vertebral fracture(11), together with liver fat content, liver iron content,and even hepatic fibrosis(12-14). Finally, the use of artificial intelligence and bigdata may allow us to gather all relevant data even before the radiology report isissued, helping us deliver a more robust and meaningful report(15). If we do so, we may haverediscovered our telos.There are several opportunities for radiology to take the lead in this discussion. First,we should increase the added value of a radiology report, focusing on the clinicalquestions to be answered. Understanding the background of each patient may enable us toweight our reports regarding incidental findings. How important is a renal cyst in aterminal oncologic patient? Second, radiology committees may help to standardize imagingworkflow in several scenarios, and radiologists could act more as consultants than asreporters