Mechanistic studies of the impact of chronic pain on brain, behaviour and cognition in a rodent model of chemically induced osteoarthritis

Chronic pain has been associated with changes in forebrain regions, including the hippocampus and prefrontal cortex, and impairments in cognitive functions associated with these forebrain regions, including impairments in memory and cognitive flexibility. Osteoarthritis (OA) is a major public health burden, and the main symptom of OA is chronic pain. The impact of OA pain on cognitive function is poorly understood. By combining methods from pain research and behavioural integrative neuroscience, in this PhD work, the impact of OA-like chronic knee pain on selected cognitive functions was investigated in a well-characterised rodent model. To investigate clinically relevant cognitive deficits associated with chronic pain caused by knee OA, in this study the rat monosodium iodoacetate (MIA) model was combined with translational tests of clinically relevant cognitive tests, including of hippocampus-dependent everyday type memory function, recognition memory and behavioural flexibility. Previous studies using this model of OA pain behaviour have used juvenile albino strains, which show comparatively poor performance in the cognitive tests. Therefore, the first objective was to transfer the MIA model to young adult Lister hooded (LH) rats, a pigmented strain, which is suitable for these cognitive tests (chapter 3). Pain behaviour and joint pathology phenotypes after a standard 1 mg dose of MIA were not robust in young adult LH rats or age and weight matched SD rats. By contrast, injection of 3mg of MIA caused robust pain behaviour, mainly changes in weight-bearing, accompanied by significant cartilage damage and synovitis. MIA-injected rats showed minor changes in locomotor activity with reduced rearing, which may reflect that they put less weight on their hind legs because of knee pain. This dose of MIA was therefore used throughout the thesis project. To longitudinally assess the impact of OA-related knee pain on hippocampus-dependent place memory, MIA LH rats were tested in the watermaze delayed-matching-to-place (DMP) test, which is highly hippocampus-dependent (chapter 4). There was no evidence of impaired hippocampal memory following induction of the MIA model. No performance parameter on the DMP task was affected by MIA injection up until day 93 after model induction. MIA injected rats showed robust pain behaviour (weight bearing asymmetry), slightly decreased rearing activity and features of knee joint pathology. In this chapter, MIA rats showed some evidence for mildly reduced prepulse inhibition (PPI) at high pulse intensities compared with saline control rats (although this was not replicated in chapter 5 when studied at a later time point following MIA injection). The impact of OA-like pain on recognition memory and behavioural flexibility was also evaluated in the MIA LH rats (chapter 5). This cohort of MIA injected LH rats was tested in the novel object recognition (NOR) test and in an automated set shifting task. Overall, there was no evidence of impaired recognition memory and behavioural flexibility after induction of chronic MIA up until day 59 after model induction. Other factors associated with chronic pain in humans may account for why humans experiencing chronic pain have memory impairments, such as the effects of treatment. To test this, the effects of chronic treatment with morphine (3mg/kg twice daily for 7 days) and subsequent withdrawal was evaluated (chapter 6). Pilot work showed that morphine treatment induced an initial antinociceptive effect in LH rats, followed by tolerance and the development of morphine-induced hyperalgesia. Then, to evaluate the potential impact of chronic morphine treatment on both rapid place learning and NOR memory, MIA-injected LH rats were treated with morphine for 10 days (3mg/kg twice daily) or received control injections and were tested on the watermaze DMP task during treatment and at withdrawal. In addition, they were assessed in the NOR test during morphine withdrawal. Morphine had analgesic effects with no evidence of morphine-induced hyperalgesia in the MIA LH rats. In both naïve and MIA LH rats, acute morphine injection promoted hyperactivity. There was no evidence that repeated morphine treatment induced any impairment in rapid place learning performance or recognition memory in MIA-injected rats. However, in this study, MIA-injected LH rats did not show significant object recognition memory 49 days after model induction, which limits the interpretation the lack of morphine effect, but indicates that MIA-induced pain may disrupt such memory at this stage. Overall, these findings suggest that hippocampus-dependent rapid place learning, NOR memory and behavioural flexibility are not affected by chronic OA-like knee pain in young adult male LH rats. Similarly, sustained treatment with morphine did not affect hippocampal and recognition memory in this model of OA-like knee pain. However, future investigation should be conducted in a wider age range and for longer periods after model induction to exclude the negative impacts of chronic OA pain in cognitive functions

Mechanistic studies of the impact of chronic pain on brain, behaviour and cognition in a rodent model of chemically induced osteoarthritis

Chronic pain has been associated with changes in forebrain regions, including the hippocampus and prefrontal cortex, and impairments in cognitive functions associated with these forebrain regions, including impairments in memory and cognitive flexibility. Osteoarthritis (OA) is a major public health burden, and the main symptom of OA is chronic pain. The impact of OA pain on cognitive function is poorly understood. By combining methods from pain research and behavioural integrative neuroscience, in this PhD work, the impact of OA-like chronic knee pain on selected cognitive functions was investigated in a well-characterised rodent model. To investigate clinically relevant cognitive deficits associated with chronic pain caused by knee OA, in this study the rat monosodium iodoacetate (MIA) model was combined with translational tests of clinically relevant cognitive tests, including of hippocampus-dependent everyday type memory function, recognition memory and behavioural flexibility. Previous studies using this model of OA pain behaviour have used juvenile albino strains, which show comparatively poor performance in the cognitive tests. Therefore, the first objective was to transfer the MIA model to young adult Lister hooded (LH) rats, a pigmented strain, which is suitable for these cognitive tests (chapter 3). Pain behaviour and joint pathology phenotypes after a standard 1 mg dose of MIA were not robust in young adult LH rats or age and weight matched SD rats. By contrast, injection of 3mg of MIA caused robust pain behaviour, mainly changes in weight-bearing, accompanied by significant cartilage damage and synovitis. MIA-injected rats showed minor changes in locomotor activity with reduced rearing, which may reflect that they put less weight on their hind legs because of knee pain. This dose of MIA was therefore used throughout the thesis project. To longitudinally assess the impact of OA-related knee pain on hippocampus-dependent place memory, MIA LH rats were tested in the watermaze delayed-matching-to-place (DMP) test, which is highly hippocampus-dependent (chapter 4). There was no evidence of impaired hippocampal memory following induction of the MIA model. No performance parameter on the DMP task was affected by MIA injection up until day 93 after model induction. MIA injected rats showed robust pain behaviour (weight bearing asymmetry), slightly decreased rearing activity and features of knee joint pathology. In this chapter, MIA rats showed some evidence for mildly reduced prepulse inhibition (PPI) at high pulse intensities compared with saline control rats (although this was not replicated in chapter 5 when studied at a later time point following MIA injection). The impact of OA-like pain on recognition memory and behavioural flexibility was also evaluated in the MIA LH rats (chapter 5). This cohort of MIA injected LH rats was tested in the novel object recognition (NOR) test and in an automated set shifting task. Overall, there was no evidence of impaired recognition memory and behavioural flexibility after induction of chronic MIA up until day 59 after model induction. Other factors associated with chronic pain in humans may account for why humans experiencing chronic pain have memory impairments, such as the effects of treatment. To test this, the effects of chronic treatment with morphine (3mg/kg twice daily for 7 days) and subsequent withdrawal was evaluated (chapter 6). Pilot work showed that morphine treatment induced an initial antinociceptive effect in LH rats, followed by tolerance and the development of morphine-induced hyperalgesia. Then, to evaluate the potential impact of chronic morphine treatment on both rapid place learning and NOR memory, MIA-injected LH rats were treated with morphine for 10 days (3mg/kg twice daily) or received control injections and were tested on the watermaze DMP task during treatment and at withdrawal. In addition, they were assessed in the NOR test during morphine withdrawal. Morphine had analgesic effects with no evidence of morphine-induced hyperalgesia in the MIA LH rats. In both naïve and MIA LH rats, acute morphine injection promoted hyperactivity. There was no evidence that repeated morphine treatment induced any impairment in rapid place learning performance or recognition memory in MIA-injected rats. However, in this study, MIA-injected LH rats did not show significant object recognition memory 49 days after model induction, which limits the interpretation the lack of morphine effect, but indicates that MIA-induced pain may disrupt such memory at this stage. Overall, these findings suggest that hippocampus-dependent rapid place learning, NOR memory and behavioural flexibility are not affected by chronic OA-like knee pain in young adult male LH rats. Similarly, sustained treatment with morphine did not affect hippocampal and recognition memory in this model of OA-like knee pain. However, future investigation should be conducted in a wider age range and for longer periods after model induction to exclude the negative impacts of chronic OA pain in cognitive functions

Anxiety enhances pain in a model of osteoarthritis and is associated with altered endogenous opioid function and reduced opioid analgesia

Introduction: Negative affect, including anxiety and depression, is prevalent in chronic pain states such as osteoarthritis (OA) and associated with greater use of opioid analgesics, potentially contributing to present and future opioid crises.Objectives: We tested the hypothesis that the interaction between anxiety, chronic pain, and opioid use results from altered endogenous opioid function.Methods: A genetic model of negative affect, the Wistar–Kyoto (WKY) rat, was combined with intra-articular injection of monosodium iodoacetate (MIA; 1 mg) to mimic clinical presentation. Effects of systemic morphine (0.5–3.5 mg·kg−1) on pain behaviour and spinal nociceptive neuronal activity were compared in WKY and normo-anxiety Wistar rats 3 weeks after MIA injection. Endogenous opioid function was probed by the blockade of opioid receptors (0.1–1 mg·kg−1 systemic naloxone), quantification of plasma β-endorphin, and expression and phosphorylation of spinal mu-opioid receptor (MOR).Results: Monosodium iodoacetate–treated WKY rats had enhanced OA-like pain, blunted morphine-induced analgesia, and greater mechanical hypersensitivity following systemic naloxone, compared with Wistar rats, and elevated plasma β-endorphin levels compared with saline-treated WKY controls. Increased MOR phosphorylation at the master site (serine residue 375) in the spinal cord dorsal horn of WKY rats with OA-like pain (P = 0.0312) indicated greater MOR desensitization.Conclusions: Reduced clinical analgesic efficacy of morphine was recapitulated in a model of high anxiety and OA-like pain, in which endogenous opioid tone was altered, and MOR function attenuated, in the absence of previous exogenous opioid ligand exposure. These findings shed new light on the mechanisms underlying the increased opioid analgesic use in high anxiety patients with chronic pain

RepeatsDB in 2021: Improved data and extended classification for protein tandem repeat structures

The RepeatsDB database (URL: https://repeatsdb.org/) provides annotations and classification for protein tandem repeat structures from the Protein Data Bank (PDB). Protein tandem repeats are ubiquitous in all branches of the tree of life. The accumulation of solved repeat structures provides new possibilities for classification and detection, but also increasing the need for annotation. Here we present RepeatsDB 3.0, which addresses these challenges and presents an extended classification scheme. The major conceptual change compared to the previous version is the hierarchical classification combining top levels based solely on structural similarity (Class > Topology > Fold) with two new levels (Clan > Family) requiring sequence similarity and describing repeat motifs in collaboration with Pfam. Data growth has been addressed with improved mechanisms for browsing the classification hierarchy. A new UniProt-centric view unifies the increasingly frequent annotation of structures from identical or similar sequences. This update of RepeatsDB aligns with our commitment to develop a resource that extracts, organizes and distributes specialized information on tandem repeat protein structures.Fil: Paladin, Lisanna. Università di Padova; ItaliaFil: Bevilacqua, Martina. Università di Padova; ItaliaFil: Errigo, Sara. Università di Padova; ItaliaFil: Piovesan, Damiano. Università di Padova; ItaliaFil: Mičetić, Ivan. Università di Padova; ItaliaFil: Necci, Marco. Università di Padova; ItaliaFil: Monzon, Alexander Miguel. Università di Padova; ItaliaFil: Fabre, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: López, José Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: Nilsson, Juliet Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas; ArgentinaFil: Ríos, Javier Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Lorenzano Menna, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Cabrera, Maia Diana Eliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: González Buitrón, Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Gonçalves Kulik, Mariane. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Fernández Alberti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Fornasari, Maria Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Parisi, Gustavo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Lagares, Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales. Departamento de Ciencias Biológicas; ArgentinaFil: Hirsh, Layla. Pontificia Universidad Católica de Perú; PerúFil: Andrade Navarro, Miguel A.. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Kajava, Andrey V. Centre National de la Recherche Scientifique; FranciaFil: Tosatto, Silvio C E. Università di Padova; Itali

Quantification of endogenous levels of IAA, IAAsp and IBA in micro-propagated shoots of hybrid chestnut pre-treated with IBA

Endogenous levels of indole-3-acetic acid (IAA), indole-3-acetylaspartic acid (IAAsp) and indole-3-butyric acid (IBA) were measured during the first 8 d of in vitro rooting of rootstock from the chestnut ‘M3’ hybrid by high performance liquid chromatography (HPLC). Rooting was induced either by dipping the basal ends of the shoots into a 4.92-mM IBA solution for 1 min or by sub-culturing the shoots on solid rooting medium supplemented with 14.8- μM IBA for 5 d. For root development, the induced shoots were transferred to auxin-free solid medium. Auxins were measured in the apical and basal parts of the shoots by means of HPLC. Endogenous levels of IAA and IAAsp were found to be greater in IBA-treated shoots than in control shoots. In extracts of the basal parts of the shoots, the concentration of free IAA showed a significant peak 2 d after either root inductive method and a subsequent gradual decrease for the remainder of the time course. The concentration of IAAsp peaked at day 6 in extracts of the basal parts of shoots induced with 14.8-μM IBA for 5 d, whereas shoots induced by dipping showed an initial increase until day 2 and then remained stable. In extracts from basal shoot portions induced by dipping, IBA concentration showed a transient peak at day 1 and a plateau between day 2 and 4, in contrast to the profile of shoots induced on auxin-containing medium, which showed a significant reduction between 4 and 6 d after transferred to auxin-free medium. All quantified auxins remained at a relatively low level, virtually constant, in extracts from apical shoot portions, as well as in extracts from control non-rooting shoots. In conclusion, the natural auxin IAA is the signal responsible for root induction, although it is driven by exogenous IBA independently of the adding conditions

Significance of glycolytic metabolism-related protein expression in colorectal cancer, lymph node and hepatic metastasis

Background: Colorectal cancer (CRC) is one of the most common malignancies and a leading cause of cancer death worldwide. Most cancer cells display high rates of glycolysis with production of lactic acid, which is then exported to the microenvironment by monocarboxylate transporters (MCTs). The main aim of this study was to evaluate the significance of MCT expression in a comprehensive series of primary CRC cases, lymph node and hepatic metastasis. Methods: Expressions of MCT1, MCT4, CD147 and GLUT1 were studied in human samples of CRC, lymph node and hepatic metastasis, by immunohistochemistry. Results: All proteins were overexpressed in primary CRC, lymph node and hepatic metastasis, when compared with non-neoplastic tissue, with exception of MCT1 in lymph node and hepatic metastasis. MCT1 and MCT4 expressions were associated with CD147 and GLUT1 in primary CRC. These markers were associated with clinical pathological features, reflecting the putative role of these metabolism-related proteins in the CRC setting. Conclusion: These findings provide additional evidence for the pivotal role of MCTs in CRC maintenance and progression, and support the use of MCTs as biomarkers and potential therapeutic targets in primary and metastatic CRC.This work was supported by the Fundação para a Ciência e a Tecnologia (FCT) grant ref. PTDC/SAU-FCF/104347/2008, under the scope of ‘Programa Operacional Temático Factores de Competitividade’ (COMPETE) of ‘Quadro Comunitário de Apoio III’ and co-financed by the Fundo Europeu De Desenvolvimento Regional (FEDER). Ricardo Amorim was recipient of the fellowship SFRH/BD/98002/2013, from Fundação para a Ciência e a Tecnologia (FCT Portugal).info:eu-repo/semantics/publishedVersio

MAMMALS IN PORTUGAL : A data set of terrestrial, volant, and marine mammal occurrences in P ortugal

Mammals are threatened worldwide, with 26% of all species being includedin the IUCN threatened categories. This overall pattern is primarily associatedwith habitat loss or degradation, and human persecution for terrestrial mam-mals, and pollution, open net fishing, climate change, and prey depletion formarine mammals. Mammals play a key role in maintaining ecosystems func-tionality and resilience, and therefore information on their distribution is cru-cial to delineate and support conservation actions. MAMMALS INPORTUGAL is a publicly available data set compiling unpublishedgeoreferenced occurrence records of 92 terrestrial, volant, and marine mam-mals in mainland Portugal and archipelagos of the Azores and Madeira thatincludes 105,026 data entries between 1873 and 2021 (72% of the data occur-ring in 2000 and 2021). The methods used to collect the data were: live obser-vations/captures (43%), sign surveys (35%), camera trapping (16%),bioacoustics surveys (4%) and radiotracking, and inquiries that represent lessthan 1% of the records. The data set includes 13 types of records: (1) burrowsjsoil moundsjtunnel, (2) capture, (3) colony, (4) dead animaljhairjskullsjjaws, (5) genetic confirmation, (6) inquiries, (7) observation of live animal (8),observation in shelters, (9) photo trappingjvideo, (10) predators dietjpelletsjpine cones/nuts, (11) scatjtrackjditch, (12) telemetry and (13) vocalizationjecholocation. The spatial uncertainty of most records ranges between 0 and100 m (76%). Rodentia (n=31,573) has the highest number of records followedby Chiroptera (n=18,857), Carnivora (n=18,594), Lagomorpha (n=17,496),Cetartiodactyla (n=11,568) and Eulipotyphla (n=7008). The data setincludes records of species classified by the IUCN as threatened(e.g.,Oryctolagus cuniculus[n=12,159],Monachus monachus[n=1,512],andLynx pardinus[n=197]). We believe that this data set may stimulate thepublication of other European countries data sets that would certainly contrib-ute to ecology and conservation-related research, and therefore assisting onthe development of more accurate and tailored conservation managementstrategies for each species. There are no copyright restrictions; please cite thisdata paper when the data are used in publications.info:eu-repo/semantics/publishedVersio

RepeatsDB in 2021: improved data and extended classification for protein tandem repeat structures

The RepeatsDB database (URL: https://repeatsdb.org/) provides annotations and classification for protein tandem repeat structures from the Protein Data Bank (PDB). Protein tandem repeats are ubiquitous in all branches of the tree of life. The accumulation of solved repeat structures provides new possibilities for classification and detection, but also increasing the need for annotation. Here we present RepeatsDB 3.0, which addresses these challenges and presents an extended classification scheme. The major conceptual change compared to the previous version is the hierarchical classification combining top levels based solely on structural similarity (Class > Topology > Fold) with two new levels (Clan > Family) requiring sequence similarity and describing repeat motifs in collaboration with Pfam. Data growth has been addressed with improved mechanisms for browsing the classification hierarchy. A new UniProt-centric view unifies the increasingly frequent annotation of structures from identical or similar sequences. This update of RepeatsDB aligns with our commitment to develop a resource that extracts, organizes and distributes specialized information on tandem repeat protein structures.Facultad de Ciencias ExactasInstituto de Biotecnologia y Biologia Molecula

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)

Purpose Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Non-AIDS-, non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.publishedVersio

Living with, managing and minimising treatment burden in long term conditions: a systematic review of qualitative research.

BACKGROUND: 'Treatment burden', defined as both the workload and impact of treatment regimens on function and well-being, has been associated with poor adherence and unfavourable outcomes. Previous research focused on treatment workload but our understanding of treatment impact is limited. This research aimed to systematically review qualitative research to identify: 1) what are the treatment generated disruptions experienced by patients across all chronic conditions and treatments? 2) what strategies do patients employ to minimise these treatment generated disruptions? METHODS AND FINDINGS: The search strategy centred on: treatment burden and qualitative methods. Medline, CINAHL, Embase, and PsychINFO were searched electronically from inception to Dec 2013. No language limitations were set. Teams of two reviewers independently conducted paper screening, data extraction, and data analysis. Data were analysed using framework synthesis informed by Cumulative Complexity Model. Eleven papers reporting data from 294 patients, across a range of conditions, age groups and nationalities were included. Treatment burdens were experienced as a series of disruptions: biographical disruptions involved loss of freedom and independence, restriction of meaningful activities, negative emotions and stigma; relational disruptions included strained family and social relationships and feeling isolated; and, biological disruptions involved physical side-effects. Patients employed "adaptive treatment work" and "rationalised non-adherence" to minimise treatment disruptions. Rationalised non-adherence was sanctioned by health professionals at end of life; at other times it was a "secret-act" which generated feelings of guilt and impacted on family and clinical relationships. CONCLUSIONS: Treatments generate negative emotions and physical side effects, strain relationships and affect identity. Patients minimise these disruptions through additional adaptive work and/or by non-adherence. This affects physical outcomes and care relationships. There is a need for clinicians to engage with patients in honest conversations about treatment disruptions and the 'adhere-ability' of recommended regimens. Patient-centred practice requires management plans which optimise outcomes and minimise disruptions