Using neuroimaging in patients with REM sleep behaviour disorder, Barber  123I-ioflupane, which binds both serotonin and dopamine transporters. To investigate the relative roles of these neurotransmitters in prodromal parkinsonism, we imaged patients with idiopathic rapid eye movement sleep behaviour disorder, the majority of whom will develop a parkinsonian disorder in future. Forty-three patients underwent brain imaging with 123I-ioflupane single photon emission computed tomography and structural MRI. Apathy was quantified using the Lille Apathy Rating Scale. Other clinical parkinsonian features were assessed using standard measures. A negative correlation was observed between apathy severity and serotonergic 123I-ioflupane signal in the dorsal raphe nucleus . There was no significant correlation between apathy severity and basal ganglia dopaminergic signal, nor between dorsal raphe signal and other neuropsychiatric scores. This specific association between apathy and raphe 123I-ioflupane signal suggests that the serotonergic system might represent a target for the treatment of apathy.Apathy is a common and under-recognized disorder that often emerges in the prodromal phase of Parkinsonian diseases. The mechanism by which this occurs is not known, but recent evidence from patients with established Parkinson’s disease suggests that serotonergic dysfunction may play a role. The integrity of the raphe serotonergic system can be assessed alongside dopaminergic basal ganglia imaging using the radioligand  Apathy is a common and debilitating condition characterized by motivational deficits that impair emotional, social and behavioural function  project extensively to forebrain limbic regions implicated in the pathogenesis of apathy . The cha123I-ioflupane is commonly used in single photon emission computed tomography (SPECT) imaging in the investigation of parkinsonian disorders  .Comparisons of variables between apathetic and non-apathetic patients were made using an independent samples Access to the data that support the findings of this study may be requested by application to the Oxford Parkinson’s Disease Centre Data Access Committee. Initial enquiries can be made to the corresponding author.The mean age of patients was 65.1 years [standard deviation (SD) 7.60] and 42 patients were male. This high male to female ratio is representative of prevalent polysomnographically-diagnosed RBD  and 18 patients (42%) scored in the apathetic range of the LARS. Since apathy itself might be a marker of emerging Parkinsonism, we compared a number of other clinical variables according to apathy status to investigate whether apathetic patients had more extensive signs of prodromal disease . Postura123I-ioflupane signal in the DRN than non-apathetic patients , whereas the 123I-ioflupane signal did not differ in any other region of interest , indicating that greater apathy was associated with reduced serotonin signal . Signal in the dorsal raphe did not correlate with age .We next assessed the degree to which the relationship between DRN serotonin signal and apathy was dissociable from other parkinsonian symptoms. Of particular interest were comparisons with depression and cognitive impairment, respectively, as these syndromes exhibit considerable phenotypic overlap with apathy. 123I-ioflupane signal as the dependent variable and LARS, BDI and MOCA scores as predictors. Only LARS scores had a significant effect on dorsal raphe signal , whereas BDI scores  and MOCA scores  did not. Thus apathy, but not depression or cognitive function, appeared to be significantly and specifically associated with 123I-ioflupane signal in the DRN.To further dissociate the closely related neuropsychiatric features of apathy, depression and cognitive impairment, we used multiple linear regression, with dorsal raphe In this study, we demonstrate for the first time a relationship between serotonin loss in the DRN and clinical apathy in patients with RBD, a key population representing the prodromal phase of Parkinson’s disease and related alpha-synucleinopathies. Serotonergic dysfunction is associated with apathy early in Parkinson’s disease  can not only improve the symptoms of apathy, but also modulate objective measures of reward sensitivity, a key component of motivation for action (Our study has a number of notable strengths. Investigating patients with polysomnographically-proven RBD provides unparalleled enrichment for cases of prodromal parkinsonism. At this early stage, when neurodegeneration is largely confined to the brainstem, the confounding effects of more widespread degeneration involving other neurotransmitter systems is limited compared to established Parkinson’s disease patients.The CT-based attenuation correction that we used for SPECT/CT processing greatly enhanced the precision with which we could analyse brainstem structures. The accuracy of our brainstem nuclei measurements was further enhanced by the use of histologically derived regions of interest, giving us the best possible representations of their true anatomy.These methodological strengths help to address one of the main limitations of our study: that the nuclei studied are small and therefore close to the resolution of our SPECT imaging. A second limitation is the use of a relatively non-specific SPECT ligand, meaning that our assessment of the serotonergic system is limited to regions that do not contain significant numbers of dopamine transporters. Although the lack of a separate control group could be considered a limitation, the primary aim of our study was to explore the neural basis for the phenotypic heterogeneity that occurs amongst RBD patients, rather than to show how they differ from control subjects. It is interesting to note, however, that control subjects rarely exhibit apathy (In summary, we have shown that apathy is associated with serotonergic depletion in the dorsal raphe nucleus in patients with idiopathic RBD, suggesting that early degeneration in this area might underlie the development of apathy during the prodromal phase of Parkinson’s disease. The specific role of serotonin is evidenced by the fact that this relationship is dissociable from dopaminergic degeneration and other neuropsychiatric features, and should prompt investigation of serotonergic agents in the treatment of apathy, even in the absence of depression.Supplementary MaterialsClick here for additional data file.


Advanced age is one of the major determinants of frailty in patients with cancer-associated thrombosis. However, multiple other factors contribute to frailty in these patients. The identification of frailty in patients with cancer-associated thrombosis is critical as it influences the complexity of the anticoagulant treatment in this population at high risk of venous thromboembolism and bleeding. Factors that contribute to frailty in patients with cancer-associated thrombosis include age, type of cancer, comorbidities such as chronic kidney disease, poly-pharmacotherapy, treatment compliance, cognitive impairment, anemia, thrombocytopenia, mobility, nutritional status, Eastern Cooperative Oncology Group grade, risk of falls, and reduced life expectancy. In the absence of specific clinical studies current anticoagulant treatment guidelines for the management are not fully applicable to frail patients with cancer. The anticoagulant treatment should therefore benefit from a tailored approach based on an algorithm that takes into account the specificities of the malignant disease. According to the American Medical Association (AMA), the term “frailty” characterizes “the group of patients that presents the most complex and challenging problems to the physician and all health care professionals”, because they have a higher susceptibility to adverse outcomes such as mortality and institutionalization . In the Regarding the use of anticoagulants several situations at risk representing multiple challenges for the management of frail patients have been considered. They include chronic kidney disease (CKD), underweight or malnutrition, falls, cognitive impairment, multi-medication, pregnancy and cancer . All theThe identification of frailty in patients with cancer-associated thrombosis (CAT) is critical since malignancy is associated with multiple factors, making these patients highly vulnerable, especially in the context of venous thromboembolism. Anticoagulant treatment is quite complex since patients with cancer are at higher risk of a first venous thromboembolism (VTE), VTE recurrence, and bleeding compared to non-cancer patients . This inThere are no specific anticoagulant treatment guidelines for the management of elderly frail patients with cancer and their management rests on an interpretation of existing guidelines. The aim of this review was to identify main contributors to frailty in patients with cancer at risk of VTE and to discuss a decision-making algorithm for the management of the anticoagulant treatment in these patients.Patients with cancer are at higher risk of VTE compared to patients without cancer. The Khorana score is validated to predict the risk VTE in outpatients with cancer  Table 1Table 1. There is no validated scoring system to predict the risk of bleeding in frail patients with cancer receiving anticoagulant treatment. The American College of Chest Physicians (ACCP) has established a list of evidence-based risk factors for bleeding and estimated risk of major bleeding . Taking Very elderly patients were shown to be eligible for anticoagulant treatment with vitamin K antagonists (VKA) without an increased risk of bleeding . The incSeveral studies have documented the risk of bleeding in CAT patients treated with anticoagulants. The rate of major bleeding in cancer patients receiving anticoagulant treatment has been reported as between 4.1% and 12.4% ,15. Amonp = 0.013) . A . A 29]. Patients with recently diagnosed active cancer are at much higher risk of VTE recurrence and bleeding compared to patients with only a history of cancer . In thisVTE is one of the most frequent complications in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), with an incidence of 20–35% . The etiPrimary pharmacological prophylaxis of VTE with LMWH is indicated in patients with locally advanced or metastatic pancreatic cancer treated with systemic anticancer therapy and who have a low bleeding risk (grade 1B) ,35.Lung cancer is the most common malignancy worldwide and the leading cause of cancer-related death . It is aHematologic malignancies are mostly diagnosed in patients of older age , while aIn patients with multiple myeloma (MM) the International Myeloma Working Group (IMWG) used a simplified geriatric assessment (GA) tool based on age, co-morbidities, and activities of daily living (ADL). A score was developed that classifies patients as fit , intermediately fit , and frail  . The IMWIn patients with non-Hodgkin’s lymphoma (NHL), GAs utilizing age, ADL, co-morbidities, and geriatric syndromes were shown adequate to assess frailty and to identify patients fit for curative intent chemotherapy . ElderlyChronic kidney disease (CKD) is more frequent in cancer patients due to several factors such as dehydration or older age-related decrease in the glomerular filtration rate. Renal function may be further decreased by anti-cancer treatments such as cytotoxic drugs, tyrosine kinase inhibitors and androgen deprivation therapy ,52, and Hepatic function may be severely reduced as a result from organ metastasis or hepatotoxic side effects of anticancer treatmentCancer patients frequently suffer from infections leading to antibiotic or anti-mycotic treatments causing additional gastrointestinal side-effects such as vomiting, gastric atrophy or diarrhea. All these features must be taken into account since they have a direct implication on pharmacokinetics/pharmacodynamics relationship (PK/PD) properties of oral anticoagulants .Metabolic pathways involving cytochrome P450 3A4 (CYP 3A4) and P-glycoprotein (Pgp) must be taken into account in cancer patients as several cancer treatments and anticoagulants are metabolized through common pathways. Drug–drug interactions may modify anticoagulants pharmacodynamics and pharmacokinetics, resulting in an increase of either thrombotic or bleeding risks .The use of multiple concomitant treatments significantly increases the bleeding risk as shown in a trial in 18,201 patients with atrial fibrillation treated with anticoagulants .Compliance to the treatment is a challenge with the use of oral anticoagulants in patients with cancer. The key consequence of cognitive impairment is compromising the oral anticoagulant treatment compliance in outpatients who are not regularly monitored. Patients may forget to take their anticoagulants, leading to an increased thrombotic risk, or take the treatment repeatedly, as they forget the initial administration, leading to overdosing with increased bleeding risk. Cognitive impairment was shown to be associated with an increased risk of VTE and bleeding in patients with atrial fibrillation . Chen etThe bleeding risk is also increased because of chemotherapy-induced thrombocytopenia and hepatic or brain metastases. A previous episode of major bleeding in the last two months or the presence of intracranial or visceral tumor increases the risk of major bleeding  as does Conversely, thrombocytosis with platelet count >400,000/mL  or ≥350,Anemia poses a difficult challenge since cancer patients with anemia receiving anticoagulants were shown to have a higher rate of major bleeding compared to non-cancer patients  while apAnticoagulation is particularly complex in frail elderly patients who present with additional risk factors that affect both the efficacy and the safety of VTE or treatment. There is no formal guideline for the management and treatment of frail patients with CAT, as major clinical trials generally do not include elderly frail patients. The impact of frailty was analyzed in a literature review of 1204 hospitalized elderly patients (mean age of 85 ± 6) with atrial fibrillation (AF) showing that the use of anticoagulants was low in these patients, thus suggesting that frail elderly patients are less likely to receive oral anticoagulants .A decision-making algorithm has been developed for the use of anticoagulants in patients with AF . Given tData on the use of anticoagulants in frail patients with cancer are limited. Elderly represent a small proportion of patients included in large randomized-control trials (RCTs) comparing vitamin K antagonists (VKAs) to LMWH or comparing LMWH to direct oral anticoagulants (DOACs) for the long-term treatment or prophylaxis of CAT.In RCTs, LMWH was shown to be superior to VKA in reducing the incidence of VTE recurrence ,69,70,71As shown in Cognitive impairment in frail elderly patients may compromise treatment adherence with oral anticoagulants. Unless close patient monitoring is possible, injectable LMWH may be preferred to ensure treatment compliance.Frail patients with cancer treated with either VKA or DOAC are highly likely to experience pharmacokinetic drug–drug interactions due to the need for concomitant antineoplastic drugs, drugs to treat comorbidities, drugs to relieve symptoms from cancer, and drugs to treat cancer treatment-induced adverse events which are frequently either P-gp and CYP 3A4 inhibitors or inducers. Also, drug–drug interactions may be associated with decreased anticoagulation effects during the concomitant use of DOACs with anti-neoplastic drugs which are CYP 3A4 or P-gp inductors, while the bleeding risk may be increased with the concomitant use of DOACs and CYP 3A4 or P-gp inhibitors . MultiplThe anticoagulant treatment should be discussed and maintained as long it does not compromise the antineoplastic treatment.Even though trials suggest that DOACs are of comparable efficacy with respect to LMWH in preventing VTE recurrence, they are associated with an excess of bleeding in patients with cancer ,21,73. DIn case of renal impairment the accumulation of the anticoagulant effect should be avoided. Both LMWH and DOACs may be used in patients with CrCl >15 mL/min, with the exception of the DOAC dabigatran which should not be used in patients with CrCl <30 mL/min.The management of frail patients with cancer is extremely complex due to the lack of consensus in the definition of frailty, the paucity of evidence data based on clinical trials, and the absence of specific clinical guidelines.We have attempted to clarify the clinical context of these patients and to simplify the therapeutic decision-making with the development of the proposed decision tree .Besides advanced age, the most significant factors to be taken into account when assessing frailty patients with cancer are ECOG reflecting patient’s general condition , the type of cancer especially gastrointestinal (pancreas), lung, and multiple myeloma, and comorbidities. Poly-pharmacotherapy and cognitive impairment leading to drug–drug interactions and/or compromised treatment adherence, blood disorders, risk of falls, and reduced life expectancy must also be considered on a case by case approach. Frailty in patients with cancer results from the accumulation and overlapping of multiple factors which make this population highly vulnerable and the decision-making particularly complex for the clinician . The manThe identification and assessment of frailty in patients with CAT is therefore essential to optimize the anticoagulant treatment while maintaining quality of life. Managing anticoagulants in frail patients with CAT is highly complex and represents a major challenge as these patients are at high risk of bleeding due to the accumulation of bleeding risk factors. The anticoagulant treatment should minimize the bleeding risk while maintaining the antithrombotic efficacy and preserving the efficiency of antineoplastic drugs which may be altered by drug–drug interactions in the context of multiple therapies and co-morbidities. Given the multiple challenges related to the condition of frail patients with CAT, parenteral anticoagulation seems preferable to oral anticoagulation in patients receiving cytotoxic drugs with severe gastrointestinal and/or hematological side effects or suffering gastrointestinal malignancy. Treatment or prophylaxis of thromboembolic disease in frail patients with cancer therefore requires a carefully tailored approach. The complexity of frailty assessment in patients with CAT requires establishing scoring methods adapted to each specific situation to guide patient management.The development of a scoring system likely to predict both the VTE and bleeding risks to adjust anticoagulant treatment is warranted.


Background: Fitness to practise (FtP) impairment  can compromise patient safety, the profession’s reputation, and an individual’s career. In the United Kingdom (UK), various healthcare professionals’ FtP cases (documents about the panel hearing(s) and outcome(s) relating to the alleged FtP impairment) are publicly available, yet reviewing these to learn lessons may be time-consuming given the number of cases across the professions and amount of text in each. We aimed to demonstrate how machine learning facilitated the examination of such cases , involving UK dental, medical, nursing and pharmacy professionals. Methods: Cases dating from August 2017 to June 2019 were downloaded  and converted to text files. A topic analysis method  was employed for data analysis. Results: Identified topics were criminal offences; dishonesty (fraud and theft); drug possession/supply; English language; indemnity insurance; patient care (including incompetence) and personal behavior . The most frequently identified topic for dental, medical and nursing professions was patient care whereas for pharmacy, it was criminal offences. Conclusions: While commonalities exist, each has different priorities which professional and educational organizations should strive to address. The General Pharmaceutical Council  considers a pharmacy professional ‘fit to practise’ when they “can demonstrate the skills, knowledge, character and health required to do their job safely and effectively” . FitnessIn terms of previous research about FtP cases in the last ten years, Tiffin and colleagues 2017) conducted a national study predicting FtP events in international medical graduates ) and ascertained that the PLAB system  was a valid predictor of eventual censure (including a warning) . Humphre conducteTopic analysis facilitates the identification of recurrent themes or topics in text-rich datasets  given thto demonstrate how topic analysis could be employed for examining published FtP cases;to apply the NMF model to enable the identification of topics (themes);to determine the extent to which the topics affected the four professions.The aim of the research was to use topic analysis to examine UK FtP dental, medical, nursing and pharmacy cases to ascertain what lessons can be learnt. The objectives were as follows:From the findings of this research, it appears that topic analysis is an appropriate technique for examining published FtP cases as coherent topics were produced, enabling intelligent labelling assignment by the authors. The most frequently identified topic for the dental, medical and nursing professions was in relation to patient care whereas for pharmacy, it was criminal offences. While overlap in the nature of the cases exists for the four professions, each profession has different priorities which their professional and educational organizations should be informed about and strive to address.FtP cases were sourced from the websites of the four bodies representing each of the professions . For consistency across the four groups, cases from August 2017 to June 2019 were included. This specific time period was largely dictated based on the availability of the pharmacy cases. Only the last twelve months of FtP cases are publicly available on the GPhC website so initial downloads made during August 2018 (covering the time period August 2017 to August 2018) were supplemented with subsequent downloads in June 2019 (covered the time period August 2018 to June 2019). The publicly available data for the other three professions were downloaded in June 2019.The below text provides information about the nature of the data for each profession.Dental: Cases referred to one of the Practise Committees for a hearing . These cases relate to UK dentists and dental care professionals regulated by the GDC, including clinical dental technicians, dental hygienists, dental nurses, dental technicians, dental therapists, and orthodontic therapists.Medical: Cases involving UK medical practitioners (regulated by the GMC) that have been referred to the Medical Practitioners Tribunal Service (MPTS) for a hearing.Nursing: Cases referred to committee substantive hearing (CSH), committee substantive meeting (CSM), committee substantive order review hearing (CSORH) and committee substantive order review meeting (CSORM). These cases relate to nursing professionals regulated by the NMC i.e., UK nurses and midwives, and nursing associates (England).Pharmacy: Cases heard by the FtP committee  where a pharmacy professional’s FtP is alleged to be impaired. These cases relate to pharmacy technicians and pharmacists who are regulated by the GPhC.Removal of duplicate cases. Where the minutes of two or more hearings related to the same case identification number, the file with the largest size was retained on the basis that it provided the greatest descriptive detailRemoval of ‘boilerplate’ text  that appTokenization  Removal of all tokens not entirely comprised of alphabetic characters Removal of stop words  Removal of frequently appearing proper nouns including personally identifying names, and place namesThe conversion of text to lower caseThe downloaded PDF files were converted to text files using the R package pdftools (version 1.8) . To prepApplying these pre-processing steps was important as they reduce the computational effort required to extract results and hence increase the interpretability of the results (largely by removing words which are unlikely to provide any meaningful context). NB: Words may be filtered based on a pre-defined dictionary  but thisW, comprising of NC (the number of cases) rows and NW (the number of unique words) columns. The NMF process approximately decomposed the matrix CW into the product of two matrices CT (expressing cases in terms of topics) and TW (expressing topics in terms of words) such that CW ≈ CT TW. Critically, each of the derived matrices is of lower dimensionality. Matrix CT comprises NC rows and NT (number of topics) columns. The entry at row i, column j reveals a score representing the degree to which topic j features in case i. Matrix TW comprises NT rows and NW columns. The entry at row i, column j reveals a score representing the degree to which word j features in topic i. A key feature of NMF is that all elements of CT and TW are constrained to be non-negative so the presence of one topic is not assumed to reduce the prevalence of particular words. Following O’Callaghan et al. (2015), the approach of log-based term-frequency inverse-document-frequency was adopted [Initially, the FtP dataset was comprised of cases expressed in terms of words from which insights cannot readily be derived. The machine learning topic extraction process seeks to enable understanding by re-expressing the cases as topics which are readily interpretable by humans. The process began by expressing cases in terms of their word frequencies. The information was encoded as a matrix C adopted . The wor adopted . For refTwo measures were employed to guide the choice of the number of topics, namely coherence and entropy ,35,36. CW represents the topics through a series of scores indicating the prevalence of words. To interpret each topic, the words with the 10 highest scores were examined and manually assigned labels (topic titles) using the authors’ judgement where a coherent theme emerged. Unsurprisingly, many of the words forming topics related to the process of the FtP hearings themselves ; these topics were not included in the analysis. Matrix CT represents cases through a series of scores indicating the prevalence of topics. Thus, a case can relate to several topics with differing degrees of strength. To avoid associating cases to topics with which they were only weakly associated, only topics which had a normalized score above 10% were considered for each case. As a validation check, manual reviews were conducted on the complete pharmacy dataset to confirm that associated topic titles represented the nature of the FtP case.To make sense of the outputs of the NMF process, examination of the two aforementioned matrices was undertaken. Matrix TEthical approval was not sought for this work as the FtP cases under consideration were freely available via the internet . Moreover, only anonymized data is presented in this paper. Raw text files of the downloaded cases have not been provided as part of this paper since these are made publicly available by the respective regulatory organization, but for a limited time frame only.A total of 3320 FtP cases were included in the analysis.577 dental .481 medical 2199 nursing  and for the combined dataset . In this work, forty topics were chosen for individual profession analysis and one hundred for the simultaneous analysis across all professions.Criminal offencesDishonestyDrug possession/supplyEnglish languageIndemnity insurancePatient carePersonal behaviorAggressionAssaultCompetencyFraudSexual conductTerrorism-relatedTheftTrafficSubstance misuseOn some occasions, a second title was assigned to the group of words. For example, if there was enough unambiguous information in the word group about what the criminal offence(s) or personal behavior related to, this became the sub-title. Nine sub-titles were assigned, namely:In addition, word clouds provide a useful visualization that helps to both confirm and communicate the essence of each topic. By constructing word clouds using the top-50 scoring words per example topic, A comparison of topic prevalence across the four professions revealed that patient care issues were the most frequently identified for three of the four professions  but pharmacy differed by having the highest proportion relating to criminal offences. The most recent annual dental and nursing reports available (2017 data) showed that the majority of FtP hearings related to ‘failure to provide good quality care’ to patients ,37, whicWhile not the most frequently occurring topic for pharmacy, issues relating to patient care and incompetence still represented a large proportion of the identified topics for this profession. Potentially, there is under-reporting of such issues in an FtP context given the greater autonomy of community pharmacists than the other professions. Alternatively, it could be because they have traditionally held a limited clinical role in comparison to the other healthcare professions and hence have less chance of clinical incompetence or inadequate patient care being exposed. However, as the role of the pharmacist is evolving to be more clinical and less administrative, pharmacists must demonstrate that they have the necessary attributes to undertake these greater responsibilities safely and effectively. Of concern is a recent announcement (news) published by the Pharmacists’ Defence Association (PDA), a UK-based organization that provides assistance to pharmacists about professional indemnity, public liability and statutory liability claims. The news feature states that some doubts have been raised about pharmacists’ competence around diagnosis and prescribing. The PDA concludes by stating that “if pharmacists are expected to assume prescribing and diagnosing responsibilities within primary care, then similar levels of training and support should be provided that have been for doctors” .In addition, English language ability made up a small proportion of identified topics . Tiffin and colleagues (2017) found  tests) that international medical graduates working in the UK were more likely to be involved in the FtP process in comparison to home graduates . Donaldsn = 517) via a questionnaire study. Two behavioral elements were found, namely “overloading (taking on more work than one can comfortably manage) and risk taking (working at or beyond boundaries of safe practice).” The authors suggest that situational factors should be considered in tandem with personal factors when judging or remediating a person’s FtP [Criminal offence prevalence within pharmacy is concerning of itself, particularly when compared to the other professions, and carries reputational risk. This is something that the professional organization should further investigate. Potentially early interventions and support could help . While not related to criminal activity per se, a UK-based study involving pharmacists examined the association between job characteristics, well-being and behavior reflecting risky practice , although this does not explain why it was lowest among the nursing profession.The first limitation is the availability of the datasets. As previously mentioned, while regulatory organizations make FtP cases publicly available on their websites, they restrict the time frame that these are available for . Moreover, the pharmacy dataset (number of cases) was much smaller than the other professions’ datasets which means the findings should be interpreted with caution. Furthermore, a difficulty in topic analysis is the requirement to specify the number of topics. Choosing too few may lead to overly broad topics which cannot easily be classified, however, choosing too many may lead to overly narrow, spurious or infrequently discussed topics, from which no generalizable insights can be drawn.n = 3320 in total) were interrogated using NMF topic model analysis. It appears that topic analysis was an appropriate technique for examining such cases and the success of the NMF modelling was evident as coherent topics were produced, enabling intelligent labelling assignment by the authors. This approach could be considered for other pharmacy research involving interrogation of other text-rich documents such as medicine information leaflets.This paper has shown how UK FtP cases , drug possession/supply, patient care (including incompetence) and personal behavior . The most frequently identified topic for the dental, medical and nursing professions was in relation to patient care, whereas for pharmacy it was criminal offences. While overlap exists across the professions, each has different priorities which their professional and educational organizations should be informed about and strive to address.


Bacteriophages, or phages, are the viruses of bacteria. They are obligate intracellular parasites whose existence is fatefully coupled to the success and survival of the hosts they infect and kill. Known to be the most abundant biological entities on the planet, phages are pervasive to almost all microbial communities, in which they play central roles in moderating bacterial populations and mediating horizontal gene transfer. When phages propagate, they can sometimes encapsidate host bacterial DNA to form transducing particles. Transducing particles are ostensibly like mature phage particles, only they eject bacterial DNA instead of a viral genome when they infect other cells. The DNA can then recombine into the chromosome or replicate as a plasmid in the new host cell. This process of transferring bacterial DNA from one bacterium to another is known as genetic transduction.The genetic cargo carried in transducing particles can have very profound effects on the bacterial recipients. For example, genes that encode for antibiotic resistance or virulence factors can impart new capabilities and unlock new ecological niches, which can accelerate the emergence of new strains that are progressively more virulent and resistant to antibiotics. Although there are several mechanisms of horizontal gene transfer, phage transduction is often thought to be the major route by which bacteria acquire the genes that enable their rapid adaption to evolving environmental challenges.Historically, all phage-mediated gene transfer was thought to occur by one of two well-described mechanisms. Since their discovery in the 1950s, generalized and specialized transduction stood as the only mechanisms of phage transduction—until now. With the recent discovery of lateral transduction, there are now three modes of phage transduction. Here, in this short review, we will provide a brief overview of what is known and what is new in phage transduction. We will also discuss noncanonical examples of transduction in which pathogenicity islands exploit phages for horizontal gene transfer.pac or cos) utilized by the phage.Lysogenic bacteria are host cells that carry one or more prophages. Prophages are latent temperate phages that are most often stably integrated into the host bacterium’s genome, where they replicate passively as DNA during cell division. Phage development occurs in the lytic cycle following host cell infection or prophage induction from the lysogenic cycle . Transdupac or cos) and cleaves the DNA to begin processing the genome into phage heads [pac-type terminases make a nonspecific second cut to complete packaging [cos-type terminases require a second cos site to make the second cut [pac-type terminases advance down the viral DNA by headfuls or as the cos-type terminases advance by increments of cos site recognition so that multiple phage heads are filled from a single concatameric genome [For most phages, packaging of the viral genome occurs after DNA replication. One of the first steps in the lytic cycle is the episomal circularization of the viral genome. Once circularized, the genome undergoes several rounds of theta replication, followed by a switch to rolling circle replication that produces long head-to-tail concatamers , 2. Packge heads . When a ackaging , 5; by ccond cut . At thisc genome .Salmonella phage P22, was the first mechanism of phage-mediated gene transfer to be identified [Generalized transduction, discovered in entified . It is tentified , 10. Curpac-type phages such as P22, in which unfragmented chromosomal DNA serves as the substrate for packaging by the headful packaging mechanism. Here, phage terminases mistakenly recognize pseudo-pac sites (pac site homologs) in the host chromosomal or plasmid DNA and initiate packaging  of in situ DNA packaging, in situ theta replication creates multiple integrated genomes so that both in situ DNA packaging and phage maturation can proceed in parallel. As a result, staphylococcal phages naturally produce extremely high titers of lateral transducing particles concurrently with wild-type phage production.It has normally been assumed that prophages excise and circularize early after lysogenic induction, in following a standard excision–replication–packaging pathway. The sequence in which these events occur is thought to be critical because DNA packaging prior to excision would irreversibly compromise the viral genome by cleaving it in two. Remarkably, the phages of romosome . DNA pacS. aureus pathogenicity islands (SaPIs) are highly mobile genetic elements that carry genes for toxic shock toxin and other virulence factors [pac sites (instead of phage pac sites), enabling SaPIs to hijack the phage packaging machinery to encapsidate their own genomes into infective phage-derived particles that are transferred at extremely high frequencies, both intra- and intergenerically , island-mediated generalized transduction links the SaPIs to a much broader repertoire of virulence determinants than they can carry themselves.The SaPIs not only mediate their own transfer but also can independently direct the transfer of unlinked bacterial DNA that contains virulence genes . In a fal genome . HoweverWith the rise of superbug strains that are progressively more virulent and antibiotic resistant, the importance of understanding the drivers of bacterial evolution has never been so apparent. Now, with three modes of phage transduction, we are just beginning to appreciate that genetic transduction occurs on a scale that is far greater than we ever imagined. Remarkably, phage-mediated gene transfer may be just the tip of the iceberg when it comes to genetic transduction. The PICIs are a widely distributed family of mobile genetic elements that exploit phages for their own reproduction and transfer , 24. As In their predator–prey dynamic, phages exert a great influence over the existence of bacteria by killing and lysing them. However, the long-term survival of their host bacteria is also in the best interest of the phage, and that is best achieved by ensuring that their hosts adapt to fast-changing environments and challenges. In some instances, phages have even been reported to scavenge antibiotic resistance genes from competing neighboring cells for their host bacteria, in a process aptly termed autotransduction . In that


It has been a puzzle how decondensed interphase chromosomes remain essentially unknotted. The natural expectation is that in the presence of type II DNA topoisomerases that permit passages of double-stranded DNA regions through each other, all chromosomes should reach the state of topological equilibrium. The topological equilibrium in highly crowded interphase chromosomes forming chromosome territories would result in formation of highly knotted chromatin fibres. However, Chromosome Conformation Capture (3C) methods revealed that the decay of contact probabilities with the genomic distance in interphase chromosomes is practically the same as in the crumpled globule state that is formed when long polymers condense without formation of any knots. To remove knots from highly crowded chromatin, one would need an active process that should not only provide the energy to move the system from the state of topological equilibrium but also guide topoisomerase-mediated passages in such a way that knots would be efficiently unknotted instead of making the knots even more complex. We perform coarse-grained molecular dynamics simulations of the process of chromatin loop extrusion involving knotted and catenated chromatin fibres to check whether chromatin loop extrusion may be involved in active unknotting of chromatin fibres. Our simulations show that the process of chromatin loop extrusion is ideally suited to actively unknot, decatenate and demix chromatin fibres in interphase chromosomes. Type II DNA topoisomerases that pass DNA segments through each other are required to facilitate various DNA transactions and they are critically important for the segregation of freshly replicated DNA molecules ,2. HowevIndependent, strong argument for the active mechanism of unknotting and decatenation is provided by the fact that individual chromosomes in interphase cells form clearly defined chromosome territories . If chroThe paucity of knots in chromatin, in addition to avoiding problems created by tightened DNA knots, allows unimpeded decondensation of chromosomal regions where genes are expressed or where replication occurs ,14. HoweDescription of the model. Molecular dynamics simulations presented in K = 20 kBT) and their rest length was set to 1, they were rapidly shrinking, which resulted in the advancement of cohesin rings along embraced chromatin fibres. Once these spring-like bonds have shrunk to about their rest length, they were replaced with extended bonds connecting cohesin rings with next-neighbour beads positioned further along modelled chromatin fibres. Due to the tightness of cohesin rings and their excluded volume potential, as well as the excluded volume potential of beads forming chromatin fibres, the advancing cohesin rings were effectively pushing forward all encountered entanglements on modelled chromatin fibres. These entanglements were, however, free to untangle when they were pushed towards topologically associating domain (TAD) borders, where short sections of chains without excluded volume mimicked the presence of Top2B at TAD borders [K = 100 kBT) between two nonconsecutive beads. Once the two beads connected with that spring-like bond were brought close together, the spring-like bond was moved to bring together the next pair of beads, thus increasing the size of the formed loop with each move. borders . In the Voronoi space tessellation. The extent of mutual intermingling of separate chains was evaluated by using the Voronoi space tessellation approach [approach . Using tapproach . The visKnots identification. To determine and present the knot types formed after topological equilibration of 8 large rings, we entered xyz coordinates of each individual ring into Knoto-ID [Knoto-ID  to simplIt is now broadly accepted that topologically associating domains (TADs) in interphase chromosomes of mammalian cells are formed by chromatin loop extrusion mechanism ,31. DuriTo investigate whether chromatin loop extrusion can be involved in chromatin unknotting, we performed coarse-grained molecular dynamics simulations of chromatin loop extrusion involving knotted chromatin fibres see  and thusNext, we wanted to test what happens when a more complex knot forms on a chromatin fibre. Since complex torus knots can be formed as products of site-specific recombination , we inveSimulations presented in The simulations shown in Starting from this topologically very complex system composed of 8 knotted and catenated with each other rings that are in addition crowded see a, we iniExperimental studies of chromosomal territories revealed their limited intermingling ,39. It hIn our simulations presented in It needs to be stressed here that the mechanism of chromatin unknotting, decatenation, and demixing by chromatin loop extrusion is very much different from the mechanism of chromatin condensation needed for the formation of mitotic chromosomes. Chromatin condensation mediated by the action of condensin helps to disentangle sister chromatids from each other but this is due to effective shortening of chromatids changing them from long, thin, and floppy filaments that easily entangle with each other to short, thick, and rigid rods that are unable to entangle with each other ,41. In cIt is a popular saying that one cannot unscramble an egg. Apparently, the chromatin loop extrusion process can very well unscramble scrambled chromatin fibres forming neighbouring chromosome territories. Chromatin loop extrusion can also maintain chromosomes as essentially unknotted and uncatenated with each other even if some knotting and catenation events may occur between sequential rounds of chromatin loop extrusion. The rare knots observed in single cell Hi-C  are presAfter this work was completed, a very similar idea of chromatin loop extrusion involvement in chromatin unknotting and decatenation was proposed in a preprint by Orlandini et al. .


Interstitial cystitis (IC) or bladder pain syndrome (BPS) is considered a devastating condition of chronic nature  which caThe level of distress can be variable from abdominal tenderness to severe bladder spasm . The diaIn this article, we present an interesting and important etiology, which may justify some types of pain in interstitial cystitis.In historical medical manuscripts, Avicenna 980–1037 AD), the famous Iranian physician, described gas in the bladder as a possible cause of bladder pain and urinary tract symptoms , without infection and other urinary disorders. In this disorder excess moisture (Rotubat) and coldness in temperament of bladder, tissues weaken the bladder cells function which through incomplete metabolism leads to the production of gas trapped in these tissues . Accordi AD, the Al-Qanun fi Tibb have suggested a wide range of recommendation that includes regimental therapy along with numerous oral and topical medications such as figs and fragrant and solver oils like iris oil and saffron oil  if needed , 8. In tfron oil . Using wfron oil , 5.In conventional medicine first report of gas in the spine was in 1937 and this view has since been confirmed in a number of studies . MoreoveThere has been no previous article with direct suggestion of possibility of the gas as a cause of interstitial cystitis.


MC1R, which are associated with fair skin and red hair, are risk factors for melanoma. These polymorphisms lead to defective repair of UV-induced DNA damage and reduced melanin production due to defective cyclic AMP (cAMP) signaling [Cutaneous malignant melanoma arises from melanocytes, the pigment producing cells in the skin. Incidence of melanoma is increasing steadily during the past several decades. Melanoma is highly resistant to chemotherapy and patients with metastatic melanoma have a poor prognosis. Exposure to ultraviolet radiation (UV) from sunlight is the most common environmental risk factor for melanoma, although melanoma can occur in areas of the body not directly exposed to sun. Driver mutations in the mitogen-activated protein kinase (MAPK) pathway account for majority of melanomas . Additioignaling , 3.CA/Pten−/− mouse melanoma model, we showed that topical application of the cAMP inducer, forskolin (FSK), accelerated melanoma tumor development [in vitro with FSK stimulated their proliferation suggesting that cAMP signaling activation promotes melanoma tumor development and growth. Elevation of cAMP, however, inhibited the growth of metastatic melanoma cells indicating a dual role for cAMP signaling in melanoma.Cyclic AMP signaling is also know to play a role in MAPK pathway activation and in the development of resistance to MAPK inhibition . In melaelopment . SimilarThe effects of activation of cAMP signaling on the proliferation of melanoma cells were not associated with the activation of Protein Kinase A and the cAMP Responsive Element Binding Protein (CREB), the classical effectors of cAMP signaling . It is ain vivo [In the context of our data on anti-proliferative role of EPAC signaling in metastatic melanoma cells, it is interesting to note that EPAC has been reported to promote melanoma cell migration. These opposing roles of EPAC in proliferation and migration are consistent with the notion that proliferation is inhibited during tumor metastasis to favor an invasive phenotype. It has been documented that a similar phenotypic switch occurs in melanoma cell that converts them from a proliferative state to an invasive in vivo . Taken t


Nilotinib is a tyrosine kinase inhibitor used to treat patients with chronic myeloid leukemia (CML). This agent is also being studied in neurodegenerative disorders including Parkinson disease. Studies have shown that nilotinib may decrease the accumulation of parkin substrates and decrease the loss of dopaminergic cells. The use of nilotinib in neurologic disorders is relatively new, and little information about this use has been published. We report on a patient receiving nilotinib for CML. The patient had no previous neurologic deficits, and developed intermittent dystonic posturing of the left upper extremity and cognitive impairment after she began nilotinib treatment. The mechanisms behind this adverse effect are not clear; however, her symptoms began after nilotinib was introduced, decreased with dose reduction, stopped with its cessation, and re-emerged when the medication was restarted. To our knowledge, this is the first reported patient with neurologic symptoms secondary to nilotinib use. BCR-ABL. The BCR-ABL gene is also present in patients with Parkinson disease (PD) [Nilotinib is a tyrosine kinase inhibitor used to treat patients with chronic myeloid leukemia (CML) by deactivating the Philadelphia chromosome, which contains the fusion gene ase (PD) . Over-acA 38-year-old woman, with a history of CML, presented for evaluation of abnormal movements that began several months prior. Clinical examination showed speech difficulty, cognitive deficits, intermittent left upper extremity dystonic posturing  and head tilting to the left. The remainder of her neurologic examination was normal.She had been diagnosed with CML 3 years previously and was initially treated with imatinib, but she was later transitioned to nilotinib 300 mg twice a day because of lack of response to imatinib. Within a few weeks of starting nilotinib, her neurologic symptoms appeared. Months later, nilotinib was discontinued, and her neurologic symptoms resolved. She remained free from neurologic symptoms until nilotinib was restarted at a lower dose (150 mg twice daily), then the neurologic symptoms returned again after a few weeks. A further reduction of nilotinib dose to 150 mg once daily resulted in significant amelioration of her symptoms, and she remains this way clinically.Results from magnetic resonance imaging of the patient's brain with and without contrast, electroencephalography, a serum paraneoplastic panel, and cerebrospinal fluid analysis while she was on the higher dose of nilotinib  were normal. Neuropsychological testing, performed while the patient was on the higher dose of nilotinib, showed mild cognitive impairment with frontal lobe and executive function deficit. Results of FDG positron emission tomography (PET) when she was on the lower dose (150 mg twice daily) were also normal. Also noted were impairments in her semantic verbal fluency and verbal processing speed, and she exhibited intermittent dysarthric speech.This patient with CML had no previous neurologic deficits but developed neurologic symptoms after she began treatment with nilotinib. The mechanisms behind this adverse effect are not clear, but her symptoms began after medication was introduced, decreased with dose reduction, stopped with its cessation, and re-emerged when the medication was restarted.Nilotinib is a selective breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitor developed for CML patients who are resistant to treatment with imatinib , 2. NiloParkinson disease is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra neurons and accumulation of alpha synuclein protein. PD models have suggested that overactivation of c-Abl tyrosine kinase phosphorylation leads to loss of the ligase activity of parkin and thus leads to mitochondrial dysfunction and the accumulation of toxic substrates and synuclein –5. MousePagan et al.  conducteWhile our patient had no symptoms of parkinsonism, it is possible that parkin substrates had accumulated and could have led to functional modifications of her basal ganglia, leading to dystonia. However, it is also likely that she experienced a symptomatic effect of nilotinib due to altered central nervous system dopamine levels as suggested by Pagan et al. . At 150 Other rare neurologic adverse effects that have been reported with BCR-ABL inhibitors include rapidly progressive vasculopathy as well as dasatinib-associated reversible demyelinating peripheral polyneuropathy , 10. NilRegarding our patient's cognitive changes, we theorize that it is related to nilotinib, on the basis of the timing of her symptoms in correlation with medication and the dose-dependent correlation of her symptoms. It is possible that alteration of dopamine levels may play a role in changes in cognition or clearance of intraneuronal phosphorylated tau and alpha synuclein by nilotinib itself . As mentAnother limitation of this report is that nilotinib levels in the cerebrospinal fluid were not directly measured to provide a correlation with the patient's symptoms. In addition, no measurements of cerebrospinal fluid disease-related biomarkers such as alpha synuclein were taken.Nilotinib is currently used in CML patients to deactivate BCR-ABL kinase. In PD, nilotinib is thought to act by reducing harmful parkin substrates, thus preventing dopaminergic neuron cell loss. We report the first case known to demonstrate nilotinib causing intermittent dystonic posturing, dysarthric speech, and cognitive impairment in a neurologically normal patient. The pathophysiology underlying this adverse effect is most likely associated with disruption of the alternate protein kinases that are responsible for the proliferation and transduction of normal signals through the basal ganglia or by a direct effect on dopamine levels. As nilotinib is further studied for its usefulness in PD, we believe that its adverse effect profile and dosage should be carefully considered in a randomized, double-blind trial that includes a placebo group. This is important, as c-ABL inhibitors such as nilotinib may have a role in treating other neurodegenerative diseases, such as Alzheimer disease, and human tauopathies given c-ALB over-activation has been implicated in the pathogenesis of these neurodegenerative diseases .


Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer’s disease, Parkinson’s disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease. Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, particularly amongst young adults. Ten million individuals are affected by TBI annually, costing a staggering $9–10 billion/year . The ageIron homeostasis appears to be an important process in the pathobiology of TBI. Iron is essential for normal brain functioning where it acts as an essential cofactor for several enzymatic/cellular processes . HoweverIron is an important cofactor involved in a variety of bodily functions including cellular metabolism, energy production, cell growth and differentiation, and gene expression. It is primarily recognized for its ability to bind oxygen, contained within the hemoglobin complex, to transport oxygen throughout the body . Iron is3+) or soluble ferrous (Fe2+) state and is an active participant in electron transfer/redox reactions, which can drive oxidative stress-induced cellular toxicity  ultimately to reduce levels of iron in the body  and their receptors . The exptoxicity . Iron isroportin . In the roportin . The maithe body .3+) can enter through endothelial cells that line the BBB typically via endocytosis of transferrin/transferrin receptors and to a lesser extent either independently (non-transferrin bound iron) or as a low molecular weight complex  and pantothenate kinase-associated neurodegeneration (PKAN) . PatientIron dyshomeostasis appears to be a central factor in neurodegenerative conditions such as AD, PD, ALS, Huntington’s disease, and Friedreich’s ataxia . For dec3+) can cause the formation of neurofibrillary tangles by binding to aggregated hyperphosphorylated tau proteins and can also become reduced to its destructive redox-active form (free Fe2+) during the process  have an important role in the regulation and distribution of iron since they function to engulf and recycle damaged/dying cells and thereby release iron into the brain interstitial space . IntraceIn vitro studies reveal that iron can directly increase NFκB activity and stimulate pro-inflammatory cytokine production in microglia  can lead to neuronal damage not only due to oxidative stress and free radical formation but also through the promotion of pro-inflammatory mediators that further contributes to secondary damage in TBI. There is also the hypothesis that the inflammatory cells that migrate to the site of injury in TBI (or plaque regions in neurodegenerative diseases) are largely responsible for depositing iron . Hence, Iron deposits that accumulate in the brain can consist of both non-heme and heme iron sub-types. These features are more commonly observed in neurodegenerative conditions such as AD, although increasing evidence suggests that both these subtypes of iron are increased in the injured brain after TBI . Heme-boA feature seen in TBI as well as several neurodegenerative diseases is the formation of cerebral microhemorrhages. These have been observed at both the acute and chronic stages of TBI, in experimental models of single and repetitive TBI  as well The origin of brain iron deposits independent of heme-bound iron in TBI is not yet known although several hypotheses exist. Dysregulation of ceruloplasmin  can lead to an increase in free copper ions and a concomitant decrease in ferroxidase activity, thereby reducing clearance of iron from the CNS . Ceruloplasmin deficient mice subjected to TBI showed elevated brain iron levels and exacerbated infarct volume . TBI an. HO-1 isLiterature characterizing the metal profile and spatiotemporal distribution of iron is relatively sparse in TBI of varying injury severities and repetitive injuries, as well as ICH and stroke, in both clinical  progressively increase in the aging brain . Microgln = 40)  can predispose these individuals to the development of neurodegenerative diseases later in life or to post-traumatic epilepsy  . Howevern = 40) ; hence mn = 40) .This strategy of chelating iron has yet to be trialed in patients with TBI, or chronic traumatic encephalopathy (CTE) patients with repetitive head injury, nor has it been greatly explored in animal models of TBI. However, it remains a potential treatment option based on the few promising experimental TBI studies that have assessed the effect of iron chelators  in experimental models that will be described hereafter.3+ leading to Fe2+ oxidation  . They foSeveral key limitations of these studies exist, including the short period of treatment, limited outcome measures and only one recent study assessed brain pathology at one time-point. Hence, there is a great need for long-term sequential analysis for the use of iron chelators  in experimental TBI models, in which the influence of iron chelation on functional outcomes, pathology , other biochemical alterations and also inflammation are essential before moving into clinical trials.n = 21) showed improvement in oedema volume and hematoma absorption over a period of 30 days  inhibitor was shown to reduce iron deposition and result in a host of downstream benefits, including decreased neuronal degeneration and improved behavioral outcomes (motor and cognitive function) . Thus, fBrain iron accumulation is a common feature of most neurodegenerative/neurological conditions including TBI. It is increasingly becoming clear that iron plays a detrimental role in the pathogenesis of various neurodegenerative diseases, however, its relationship to TBI pathobiology still requires consolidation. Although iron chelation with deferoxamine has shown limited potential in experimental TBI models, using a chelator that can penetrate the BBB , with a known ability to lessen iron-induced neurotoxicity in ICH and neurodegenerative diseases, could prove to be superior than previously tested iron chelators in improving outcome after TBI. Whether a specified time-window for treatment is required  also needs to be addressed (as does the notion that a combination of iron and zinc-targeted treatments may have a synergistic benefit in TBI). Targeting both iron accumulation and subsequent oxidative damage and/or inflammation by proposed combined therapy  has not yet been assessed preclinically in TBI . This apMD and PA conceived and constructed the manuscript.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.


This paper revisits the dynamic causal modelling of fMRI timeseries by replacing the usual (Taylor) approximation to neuronal dynamics with a neural mass model of the canonical microcircuit. This provides a generative or dynamic causal model of laminar specific responses that can generate haemodynamic and electrophysiological measurements. In principle, this allows the fusion of haemodynamic and (event related or induced) electrophysiological responses. Furthermore, it enables Bayesian model comparison of competing hypotheses about physiologically plausible synaptic effects; for example, does attentional modulation act on superficial or deep pyramidal cells – or both? In this technical note, we describe the resulting dynamic causal model and provide an illustrative application to the attention to visual motion dataset used in previous papers. Our focus here is on how to answer long-standing questions in fMRI; for example, do haemodynamic responses reflect extrinsic (afferent) input from distant cortical regions, or do they reflect intrinsic (recurrent) neuronal activity? To what extent do inhibitory interneurons contribute to neurovascular coupling? What is the relationship between haemodynamic responses and the frequency of induced neuronal activity? This paper does not pretend to answer these questions; rather it shows how they can be addressed using neural mass models of fMRI timeseries. •This paper describes a DCM for fMRI based on neural mass models and canonical microcircuits.•This enables the (Bayesian) fusion of EEG and fMRI data.•That encompasses the formal modelling of neurovascular coupling.•Offers a surprising insight into the relationship between haemodynamic and electrophysiological responses. Over the past decade, dynamic causal modelling (DCM) has become the predominant way of characterising effective connectivity within networks of distributed neuronal responses , as measFirst, it allows one to specify hypotheses or models of distributed responses – as measured with fMRI – that are more physiologically grounded. For example, one can specify hierarchal architectures with distinct (laminar-specific) forward and backward connections. Furthermore, one can specify experimental effects in terms of changes in either extrinsic (between-region) or intrinsic (within-region) connectivity at the level of specific neuronal populations; e.g., superficial or deep pyramidal cells .Bayesian belief updating and properly accounts for the conditional dependencies between neuronal and haemodynamic parameters. The resulting multimodal Bayesian fusion provides a comprehensive characterisation of functional anatomy that exploits the temporal (electromagnetic) and spatial (fMRI) nature of different imaging modalities. We will illustrate multimodal fusion in a subsequent paper. In this paper, we consider the form of the DCM and provide some illustrative applications to show how far one can get using fMRI data alone.Second, it provides a framework within which to combine different modalities. Crucially, because the generative model used for MRI can also generate evoked or induced electromagnetic responses, one can use both modalities to inform the parameters of the same model. Furthermore, the form of fusion afforded by using the same  model frees one from the tyranny of having to acquire fMRI and electrophysiological data concurrently. In other words, one can first analyse EEG data using event related or induced responses to estimate the connectivity and synaptic parameters of a DCM. These posterior estimates then become prior probability distributions for a subsequent inversion, using fMRI data, to estimate regionally specific haemodynamic parameters. This is known as Third, having a physiologically informed neuronal and haemodynamic model means that one can, in principle, resolve outstanding questions about the nature of the BOLD response. For example, does the BOLD response reflect afferent presynaptic activity from distant (extrinsic) sources or does it report local activity mediated by recurrent (intrinsic) connectivity ? To whathttp://www.fil.ion.ucl.ac.uk/spm/).Our main aim in this paper is to show how such questions could be answered using the framework introduced below, rather than providing definitive answers to the aforementioned questions. Our illustrations are therefore restricted to the analysis of a single time series from a single subject . These dThis paper comprises four sections. The first introduces the neural mass model that constitutes the neuronal part of the DCM for fMRI. The second section illustrates its application to empirical data acquired during an ‘attention to visual motion’ paradigm. This section illustrates how biological questions about the synaptic mediation of attention can be posed at the level of specific neuronal populations; such as the contribution of superficial versus deep pyramidal cells to attentional effects in observed data. The third section turns to questions about haemodynamics; for instance whether BOLD responses are driven by extrinsic or intrinsic presynaptic activity – and whether inhibitory interneurons have a role to play. The final section considers the multimodal capabilities of the model by simulating the induced responses that would have been seen using local field potentials, based upon the parameters estimated from the fMRI data. This section focuses on the relationship between desynchronisation (and the expression of gamma activity) and BOLD responses disclosed by experimental changes in attention set. We conclude with a brief discussion of conclusions that can be drawn from this sort of modelling.model evidence for inferences about specific connections  models of observable responses, given a model of how neuronal activity causes measurements . This inversion generally uses standard Variational Laplace  procedurnections  and netwnections . The latUsually, dynamic causal models have a neuronal part that describes distributed neuronal activity with a greater or lesser degree of biological realism and a measurement part that converts neuronal activity into measurable observations. For fMRI, this involves specifying haemodynamic models, while for electromagnetic data it usually reduces to specifying a lead field or electrode gain. The separation into neuronal and measurement models is important, because it allows the same neuronal model to predict multiple modalities, using different measurement models. This means one can use multimodal data features to estimate the model's evidence and parameters. In this paper, the neuronal model is exactly the same model used in DCM for EEG (and MEG), while the haemodynamic model is exactly the same as has been used for fMRI over the past decade .There have been several advances in haemodynamic modelling that have been informed by different sorts of  fMRI data  – and thconvolution model  to known inter-and intralaminar connectivity . The anaIn brief, experimental and extrinsic input arrives at granular layer 4, targeting spiny stellate cells. These populations then project to superficial pyramidal cells, which project to deep pyramidal cells. In addition to this intrinsic feedforward pathway , there aPre-synaptic activity at each subpopulation is assumed to drive haemodynamic responses, through local collaterals innervating astrocytes, whose (endfeet) processes release vasodilatory signals . These sFrom our perspective, the important part of this model is the neurovascular coupling; namely, how neuronal activity induces a neurovascular signal; e.g., calcium transients in astrocytes . We haveClearly, there could be other neurovascular architectures; for example, each population could send signals to the local vasculature in proportion to its postsynaptic activity. Alternative mechanisms such as extra-synaptic communication could also be considered. Although we do not pursue this here, it would be an interesting exercise to adjudicate among different forms of neurovascular coupling  using BaA distributed network or graph is determined by between-node or extrinsic connectivity. The distinction between forward and backward connections defines the hierarchical relationships among cortical and subcortical systems – and has clear correlates in terms of laminar-specific origins and targets (please see above). This hierarchical aspect of the current DCM was missing from earlier variants based upon Taylor approximations. This is because earlier versions did not model laminar-specific neuronal dynamics. A matrices shown in the lower panel of A matrices.Here, we have selected three areas that showed a significant experimental effect  shown in the inset. These comprise an early visual source (V1) a motion sensitive area (V5 or MST) and an attentional area; the frontal eye fields (FEF). These three nodes are modelled as a simple hierarchy, where forward connections arise from superficial pyramidal cells and target spiny stellate cells in the granular layers of a higher level. In addition, we have modelled a (weak) connectivity to deep pyramidal cells. Backward connections arise from deep pyramidal cells and target inhibitory interneurons and superficial pyramidal cells in the level below. The laminar specificity of these extrinsic connections is specified quantitatively by the prior values of the parameters of adjacency or visual input, visual motion and attention to visual motion) drive or modulate neuronal responses. As usual, the driving effects of experimental inputs are determined by the parameters of a C matrix, directing experimental input to spiny stellate populations in each region. In this example, visual input, visual motion and attention drive responses in the early visual cortex, motion sensitive cortex and frontal eye fields respectively. Finally, we have to specify where experimental effects change intrinsic or extrinsic connectivity. For each experimental effect there are a pair of B matrices whose off-diagonal terms parameterise the change in the (forward or backward) adjacency matrix per-unit change in experimental input. The diagonal elements of the forward B matrix are used to model experimental modulation of intrinsic (recurrent or self-inhibition) of superficial pyramidal cells, while the diagonal elements of the backward B matrix encode condition specific changes in the self-inhibition of deep pyramidal cells. In this example, attention exerts a modulatory effect on both the self-inhibition of superficial and deep pyramidal cells in area (V5). This particular parameterisation allowed us to ask whether attentional modulation of superficial, deep or both pyramidal cell populations is necessary to explain the observed responses.In addition to specifying the extrinsic connectivity architecture, it is necessary to specify where experimental inputs  context sensitive changes in coupling. In other words, they model the dynamic effective connectivity, which characterises functional integration in the brain  whole body MRI system. Contiguous multi-slice images were acquired with a gradient echo-planar sequence . Four consecutive hundred-scan sessions were acquired, comprising a sequence of 10-scan blocks under five conditions. The first was a dummy condition to allow for magnetic saturation effects. In the second, The three potential causes of neuronal activity were encoded as box-car functions corresponding to the presence of a visual stimulus, motion in the visual field and attention. A standard whole brain SPM analysis then identified several regions showing a significant effect of visual input, motion and attention . This means the free parameters of a DCM are generally log-scaling parameters, where a value of zero means a scaling of exp(0)=100%. The variance of a Gaussian shrinkage prior therefore determines to what extent the scaling of a particular value can deviate from its prior log-scaling of zero. The prior variances in Neurobiologically, this is interesting because there are neuromodulatory synaptic processes that implicate both superficial and deep pyramidal cells. For example, cholinergic modulation of inhibitory interneurons is usually associated with the modulation of superficial (and deep) pyramidal cells through their interactions with inhibitory interneurons . ConversThe lower right panel shows the posterior probability over all models with and without each of the 12 parameters. These Bayesian parameter averages suggest that, in this instance, intrinsic inhibitory collaterals are the most important determinant of haemodynamic responses. Interestingly, these parameter estimates are both positive and negative. This suggests that (self-inhibiting) collaterals from the excitatory populations may target astrocytes to both increase and decrease local blood flow. Irrespective of the precise arrangements of axonal collaterals (or heterosynaptic facilitation), this sort of result highlights the key role of inhibitory interneurons not only in mediating synchronisation and excitability  – but alHaving said this, it is important to remember that this result should not be generalised. If one was really interested in the form of neurovascular coupling, one would use a much more informed model of laminar specific neuronal responses based upon extensive DCM studies using EEG. For example, one could use a DCM for cross spectral responses  in each In this section, we use the parameter estimates of the neuronal model to generate local field potential responses, to characterise the electrophysiological correlates of the observed BOLD responses. The resulting first-order kernel – mapping from experimental input to predicted electrophysiological responses – is what one would expect to see in response to a very brief stimulus. Under local linearity assumptions, one can use these kernels to predict induced responses that are generated by random fluctuations about the mean evoked response (modelled by the first-order kernel). This means that, given the spectral density of neuronal fluctuations, one can generate induced responses. These are illustrated on the right, in terms of autospectra (with and without observation noise in solid and dashed lines respectively) and the associated autocovariance function . The equations in The generation of predicted spectral or induced responses inherits the procedures used in DCM for cross spectral density . In brieThe electrophysiological responses show a similar profile; illustrating large offset and onset responses and then maintenance at their fixed point for each condition-specific profile of experimental input. The attentional modulation of the superficial and deep pyramidal cells in the motion sensitive area changes the connectivity and subsequent predictions of induced responses. These are consistent with alpha (at 10 Hz) desynchronization during attention that is accompanied by a marked increase in gamma activity (at 48 Hz) .The genesis of these induced responses is addressed in more detail in This paper has described a denouement of dynamic causal modelling for fMRI timeseries; in the sense that it combines neurophysiologically plausible models of neuronal processing and established haemodynamic models of fMRI signals. To briefly rehearse the advantages of this modelling, we note that the sorts of questions addressed by DCM for electromagnetic neurophysiology can now, in principle, be addressed to fMRI data.Perhaps the most important advantage has yet to be exploited; namely, the opportunity to use EEG or MEG data in conjunction with fMRI data to doubly inform parameter estimation and model selection at the level of neuronal architectures. A straightforward strategy suggests itself along the following lines: one first identifies the key regions engaged by an experimental paradigm using standard whole brain (SPM) analysis of fMRI data. Significantly activated regions can then be modelled as a neuronal network to explain evoked or induced electromagnetic responses (or both), using the location of activated regions as prior locations in DCM for ERP or cross spectral density responses. This modelling then provides precise or informative posterior densities over neuronal (effective connectivity and synaptic) parameters, which are passed as priors to a subsequent DCM of the fMRI data. The fMRI data supply informative constraints on the haemodynamic parameters; thereby providing a comprehensive characterisation of how non-invasive brain signals are generated. Note that this Bayesian data fusion does not rely upon concurrent EEG and fMRI. This enables the optimisation of both protocols that are linked through a common experimental manipulation. We hope to illustrate this approach elsewhere, using another (training) dataset based upon the viewing of familiar faces ; for whiA matrices, as opposed to a single A matrix in standard DCM. This follows from the fact that there is a distinction between forward and backward connections – and that within forward and backward connections there are two collateral streams. In practice, the user specifies allowable connections in two adjacency matrices, specifying whether a forward and backward connection exists. These prior specifications are then applied to both sorts of forward and backward connections respectively. Note that it is possible to have both forward and backward connections between a target and source region. These are often used to model lateral connections that have a less specific  laminar specificity  matrices is interpreted as allowing the modulation of the self inhibition of  pyramidal cells respectively. Other effects are easy to implement by simply changing the equations of motion (in spm_gen_fmri.m).Readers familiar with extant DCM for fMRI procedures will note that there are now four adjacency or cificity . SimilarDEMO_dcm_fmri_nnm.m) is available in the current version of the SPM software that reproduces the graphics in this paper. This routine shows how the core inversion routine (spm_dcm_fmri_nmm.m) is called and how to specify the requisite input arguments. In terms of numerics, the inversion of a typical timeseries takes about 16 s per iteration on a standard personal computer, where 32 iterations are usually required for convergence. One might ask how one can solve or integrate the neuronal equations of motion so quickly, over the long periods of time typically associated with an fMRI session. The computational efficiency follows from the fact that the neural mass model has a fixed point that is reached within a second or so, following any change in experimental or exogenous input. This means that the neuronal equations of motion only have to be solved for a brief period of time, following any change in experimental condition. Crucially, these changes are relatively infrequent in standard fMRI paradigms, from the point of view of neuronal dynamics that unfold over time scale of several hundred milliseconds. In block designs (of the sort used in this paper), one is effectively using an adiabatic approximation to neurodynamics. In other words, for the majority of the time, neuronal activity has attained steady-state, because neuronal dynamics are very fast  in relation to changes in input (every few seconds). As an alternative, fast GPU based integration of the differential equations could be adopted for paradigms with very frequent input changes  description of the procedures, a demo routine  in a reasonable amount of time. However, the current inversion scheme may take many hours with larger graphs – and may call for additional constraints that finesse the computational load; e.g., vice versa). We had always imagined that there was some systematic (unique or diffeomorphic) mapping between induced electrophysiological responses and concurrent fMRI signals (Perhaps the most interesting insight (at least for the authors) offered by the modelling in this paper pertains to the electrophysiological correlates of BOLD activity  mapping between induced and BOLD responses. To make this clear, A strong  conclusion is that the search for the spectral  correlates of haemodynamic responses is doomed to failure because electrophysiological responses do not cause haemodynamic responses and haemodynamic responses do not cause induced responses – both are caused by underlying neuronal activity. Perhaps, this should not be too surprising given the cautionary conclusion of studying endogenous brain activity as detected by surface EEG-combined fMRI: namely, "that one EEG feature can correlate with different fMRI activation maps and that a single resting state network may be associated with a variety of EEG patterns" . All of Bayesian fusion has been introduced to emphasise the implicit handshake between different modalities – that can only be realised with a common forward model that can generate the modalities in question.In summary, even in the absence of a one-to-one relationship between EEG and BOLD measurements, both modalities can still inform each other, if they provide complementary constraints on model parameters. An important example here is the ability of EEG to constrain posterior estimates of canonical microcircuitry, which increases the efficiency of estimating parameters that mediate neurovascular coupling using fMRI. This increase in efficiency rests upon resolving conditional dependencies among different sets of parameters, thereby exploiting the complementary nature of both modalities. Conversely, fMRI can provide very precise constraints on parameters that are difficult to estimate in EEG and MEG. Perhaps the most obvious are the locations of functionally specialised regions or nodes that constitute the DCM. These are specified implicitly by selecting volumes of interest in DCM for fMRI; however, source locations have to be estimated in EEG – and source reconstruction is a notoriously difficult aspect of the forward problem implicit in DCM for EEG. The term The ability to estimate microcircuitry and neurovascular parameters efficiently – and implicitly adjudicate among alternative models or hypotheses with greater precision – shifts the emphasis on the sorts of questions that one might ask. As with much of dynamic causal modelling, this shift is away from simply localising functionally differentiated responses and towards an understanding of functional integration – and how it is mediated at the synaptic level. The particular motivation for the current DCM was to answer questions about pharmacological effects that may be expressed on superficial versus deep pyramidal cells. However, one can imagine a host of interesting questions that pertain to laminar specific cortical architectures. And, more generally, the use of the fMRI to address the locus of experimental  effects on extrinsic (long-range) changes in connectivity relative to intrinsic (short-range) coupling – and whether these are mediated primarily by inhibitory or excitatory synaptic interactions.The usual limitations apply to this form of dynamic causal modelling. The most important thing to remember is that all models are wrong and there is no true model. In other words, the quality of a model – as assessed by Bayesian model comparison or reduction – depends upon the data at hand . This meThe authors have no disclosures or conflict of interest.


HPV related OPSCC has a distinct behavior and improved outcome. As immunotherapy has recently evolved into a new standard for advanced (SCCHN), trials for high-risk SCCHN have trended to encompass both HPV related and unrelated diseases. In this invited editorial, we question the wisdom of this approach and argue for the design of trials focused specifically on HPV related locally advanced oropharyngeal squamous cell carcinoma as a unique disease entity. Since the MACH meta-analysis and early phase III trials, the treatment of locally advanced SCCHN have relied on chemoradiotherapy . For morAs immunotherapy has recently evolved into a new standard for advanced HPV related and unrelated squamous cell carcinoma of the head and neck (SCCHN) , trials Even though the rationale for these approaches we believe is valid, the wisdom of encompassing both HPV related and unrelated disease is questionable. Assuming a similar outcome for diseases with different etiologies, presentations, pathologic and radiologic characteristics, degree of co-morbidities, clinical staging, and pattern of distant metastases we believe deserves a closer examination , 9. NoteECOG ACRIN EA3161 is a recently activated phase II/III trial examining the question of whether a maintenance approach with a single agent ICPI following definitive therapy would alter the progression-free survival (PFS) or overall survival (OS) for high-risk HPV related disease. As this study focuses on HPV related disease, it also avoids intensification of concurrent therapy and relies instead on abrogating the risk of distant metastases through a maintenance approach. We believe therefore EA3161 it uniquely positioned to answer an important question for a group of healthier patients with better prognosis yet equivalent risk of distant metastases.It is likely that adding ICPI to the backbone standard concurrent regimens will be proven effective for locally advanced SCCHN soon. The questions of whether intensification of concurrent therapy for the HPV related group is the correct approach and the degree to which this group will benefit from a maintenance ICPI, we believe will continue to linger for some time to come. EA3161 is poised to answer these questions.