Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.

Distinct RPA functions promote eukaryotic DNA replication initiation and elongation.

Replication protein A (RPA) binds single-stranded DNA (ssDNA) and serves critical functions in eukaryotic DNA replication, the DNA damage response, and DNA repair. During DNA replication, RPA is required for extended origin DNA unwinding and DNA synthesis. To determine the requirements for RPA during these processes, we tested ssDNA-binding proteins (SSBs) from different domains of life in reconstituted Saccharomyces cerevisiae origin unwinding and DNA replication reactions. Interestingly, Escherichia coli SSB, but not T4 bacteriophage Gp32, fully substitutes for RPA in promoting origin DNA unwinding. Using RPA mutants, we demonstrated that specific ssDNA-binding properties of RPA are required for origin unwinding but that its protein-interaction domains are dispensable. In contrast, we found that each of these auxiliary RPA domains have distinct functions at the eukaryotic replication fork. The Rfa1 OB-F domain negatively regulates lagging-strand synthesis, while the Rfa2 winged-helix domain stimulates nascent strand initiation. Together, our findings reveal a requirement for specific modes of ssDNA binding in the transition to extensive origin DNA unwinding and identify RPA domains that differentially impact replication fork function.

The influence of peer non-suicidal self-harm on young adults' urges to self-harm: experimental study.

OBJECTIVE: To test the hypothesis that exposure to peer self-harm induces adolescents' urges to self-harm and that this is influenced by individual suggestibility. METHODS: We recruited 97 UK-based adults aged 18-25 years with a recent history of self-harm, measuring baseline suggestibility (Resistance to Peer Influence; RPI) and perceived ability to control urges to self-harm (using an adapted item from the Self-Efficacy to Resist Suicidal Action scale; SEASA) before and after two self-harm vignettes featuring named peers from the participant's social network (to simulate exposure to peer non-suicidal self-harm) and after a wash-out exposure. We used paired t-tests to compare mean SEASA scores pre- and post-exposure, and linear regression to test for an association between RPI and change in SEASA scores pre- and post-exposure. RESULTS: Perceived ability to control urges to self-harm was significantly reduced following exposure to peer self-harm (t(96) = 4.02, p < 0.001, mean difference = 0.61; 95% CI = 0.31, 0.91), but was not significantly different from baseline after exposure to a wash-out. We found no association between suggestibility and change in urges to self-harm after exposure to peer self-harm. CONCLUSION: Our findings support social influences on self-harm in a sample of young adults, regardless of their individual degree of suggestibility.

10 Simple Rules for a Supportive Lab Environment.

The transition to principal investigator (PI), or lab leader, can be challenging, partially due to the need to fulfil new managerial and leadership responsibilities. One key aspect of this role, which is often not explicitly discussed, is creating a supportive lab environment. Here, we present ten simple rules to guide the new PI in the development of their own positive and thriving lab atmosphere. These rules were written and voted on collaboratively, by the students and mentees of Professor Mark Stokes, who inspired this piece.

Threat of shock promotes passive avoidance, but not active avoidance.

Anxiety and stress are adaptive responses to threat that promote harm avoidance. In particular, prior work has shown that anxiety induced in humans using threat of unpredictable shock promotes behavioral inhibition in the face of harm. This is consistent with the idea that anxiety promotes passive avoidance-that is, withholding approach actions that could lead to harm. However, harm can also be avoided through active avoidance, where a (withdrawal) action is taken to avoid harm. Here, we provide the first direct within-study comparison of the effects of threat of shock on active and passive avoidance. We operationalize passive avoidance as withholding a button press response in the face of negative outcomes, and active avoidance as lifting/releasing a button press in the face of negative outcomes. We explore the impact of threat of unpredictable shock on the learning of these behavioral responses (alongside matched responses to rewards) within a single cognitive task. We predicted that threat of shock would promote both active and passive avoidance, and that this would be driven by increased reliance on Pavlovian bias, as parameterized within reinforcement-learning models. Consistent with our predictions, we provide evidence that threat of shock promotes passive avoidance as conceptualized by our task. However, inconsistent with predictions, we found no evidence that threat of shock promoted active avoidance, nor evidence of elevated Pavlovian bias in any condition. One hypothetical framework with which to understand these findings is that anxiety promotes passive over active harm avoidance strategies in order to conserve energy while avoiding harm.

The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK's population-based haematological malignancy research network 2004-2018.

OBJECTIVES: A retrospective population-based study to determine the incidence and prevalence of patients with the rare blood disease paroxysmal nocturnal haemoglobinuria (PNH). METHODS: All patients were identified by flow cytometric detection of blood cells deficient in glycosylphosphatidylinositol (GPI) linked proteins at a single diagnostic reference laboratory that serves the Yorkshire based, Haematological Malignancy Research Network (HMRN) with a population of 3.8 million. RESULTS: One hundred and ninety-seven patients with detectable PNH clones at a level of >0.01% in at least two lineages of cells (neutrophils, monocytes and/or red cells) were identified over a 15-year period (2004-2018). Of these, 88% had aplastic anaemia (AA), 8% classical PNH and 3% myelodysplastic syndrome. The overall incidence rate was estimated at 0.35 cases per 100 000 people per year. This equates to 220 cases newly diagnosed in the United Kingdom each year. The overall prevalence rate was 3.81 per 100 000, this equates to an estimated 2400 prevalent cases in the UK. The overall and relative 5-year survival rates were 72% and 82.7%, respectively. CONCLUSIONS: This study showed that classical haemolytic PNH is a rare disease and represents only a small proportion overall of patients with detectable PNH cells, the majority of which have aplastic anaemia.

The translational neural circuitry of anxiety.

Anxiety is an adaptive response that promotes harm avoidance, but at the same time excessive anxiety constitutes the most common psychiatric complaint. Moreover, current treatments for anxiety-both psychological and pharmacological-hover at around 50% recovery rates. Improving treatment outcomes is nevertheless difficult, in part because contemporary interventions were developed without an understanding of the underlying neurobiological mechanisms that they modulate. Recent advances in experimental models of anxiety in humans, such as threat of unpredictable shock, have, however, enabled us to start translating the wealth of mechanistic animal work on defensive behaviour into humans. In this article, we discuss the distinction between fear and anxiety, before reviewing translational research on the neural circuitry of anxiety in animal models and how it relates to human neuroimaging studies across both healthy and clinical populations. We highlight the roles of subcortical regions (and their subunits) such as the bed nucleus of the stria terminalis, the amgydala, and the hippocampus, as well as their connectivity to cortical regions such as dorsal medial and lateral prefrontal/cingulate cortex and insula in maintaining anxiety responding. We discuss how this circuitry might be modulated by current treatments before finally highlighting areas for future research that might ultimately improve treatment outcomes for this common and debilitating transdiagnostic symptom.

BRD4 inhibitors block telomere elongation.

Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.

Distinct Mechanisms for Distractor Suppression and Target Facilitation.

It is well established that preparatory attention improves processing of task-relevant stimuli. Although it is often more important to ignore task-irrelevant stimuli, comparatively little is known about preparatory attentional mechanisms for inhibiting expected distractions. Here, we establish that distractor inhibition is not under the same top-down control as target facilitation. Using a variant of the Posner paradigm, participants were cued to either the location of a target stimulus, the location of a distractor, or were provided no predictive information. In Experiment 1, we found that participants were able to use target-relevant cues to facilitate target processing in both blocked and flexible conditions, but distractor cueing was only effective in the blocked version of the task. In Experiment 2, we replicate these findings in a larger sample and leveraged the additional statistical power to perform individual differences analyses to tease apart potential underlying mechanisms. We found no evidence for a correlation between these two types of benefit, suggesting that flexible target cueing and distractor suppression depend on distinct cognitive mechanisms. In Experiment 3, we use EEG to show that preparatory distractor suppression is associated with a diminished P1, but we found no evidence to suggest that this effect was mediated by top-down control of oscillatory activity in the alpha band (8-12 Hz). We conclude that flexible top-down mechanisms of cognitive control are specialized for target-related attention, whereas distractor suppression only emerges when the predictive information can be derived directly from experience. This is consistent with a predictive coding model of expectation suppression. SIGNIFICANCE STATEMENT: If you were told to ignore a white bear, you might find it quite difficult. Holding something in working memory is thought to automatically facilitate feature processing, even if doing so is detrimental to the current task. Despite this paradox, it is often assumed that distractor suppression is controlled via similar top-down mechanisms of attention that prepare brain areas for target enhancement. In particular, low-frequency oscillations in visual cortex appear especially well suited for gating task-irrelevant information. We describe the results of a series of studies exploring distractor suppression and challenge this popular notion. We draw on behavioral and EEG evidence to show that selective distractor suppression operates via an alternative mechanism, such as expectation suppression within a predictive coding framework.

Editorial: What is computational psychopathology, and why do we need it?

Computational Psychopathology is an emerging discipline, which is based around the theoretical and mechanistic focus of explanatory psychopathology and computational psychiatry, and reflects the general move in psychiatric research away from whole disorders to component symptoms or transdiagnostic processes. In this Editorial, we present a brief summary of these disciplines and how they combine together to form a 'Computational Psychopathology', and present a brief possible taxonomy. We highlight the papers that form part of this Special Issue, along with their place in our putative taxonomy. We conclude this Editorial by highlighting the benefits of a Computational Psychopathology for research into mental health.

Eating disorder symptoms and control-seeking behavior.

OBJECTIVE: Eating disorders (EDs) are a heterogenous group of disorders characterized by disturbed eating patterns. Links have been made between ED symptoms and control-seeking behaviors, which may cause relief from distress. However, whether direct behavioral measures of control-seeking behavior correlate with ED symptoms has not been directly tested. Additionally, existing paradigms may conflate control-seeking behavior with uncertainty-reducing behavior. METHOD: A general population sample of 183 participants completed part in an online behavioral task, in which participants rolled a die in order to obtain/avoid a set of numbers. Prior to each roll, participants could choose to change arbitrary features of the task (such as the color of their die) or view additional information (such as the current trial number). Selecting these Control Options could cost participants points or not (Cost/No-Cost conditions). Each participant completed all four conditions, each with 15 trials, followed by a series of questionnaires, including the Eating Attitudes Test-26 (EAT-26), the Intolerance of Uncertainty Scale, and the Obsessive-Compulsive Inventory-Revised (OCI-R). RESULTS: A Spearman's rank test indicated no significant correlation between total EAT-26 score and total number of Control Options selected, with only elevated scores on a measure of obsessions and compulsivity (OCI-R) correlating with the total number of Control Options selected (rs  = .155, p = .036). DISCUSSION: In our novel paradigm, we find no relationship between EAT-26 score and control-seeking. However, we do find some evidence that this behavior may be present in other disorders that often coincide with ED diagnosis, which may indicate that transdiagnostic factors such as compulsivity are important to control-seeking.

Catastrophizing and Risk-Taking.

Background: Catastrophizing, when an individual overestimates the probability of a severe negative outcome, is related to various aspects of mental ill-health. Here, we further characterize catastrophizing by investigating the extent to which self-reported catastrophizing is associated with risk-taking, using an online behavioural task and computational modelling. Methods: We performed two online studies: a pilot study (n = 69) and a main study (n = 263). In the pilot study, participants performed the Balloon Analogue Risk Task (BART), alongside two other tasks (reported in the Supplement), and completed mental health questionnaires. Based on the findings from the pilot, we explored risk-taking in more detail in the main study using two versions of the Balloon Analogue Risk task (BART), with either a high or low cost for bursting the balloon. Results: In the main study, there was a significant negative relationship between self-report catastrophizing scores and risk-taking in the low (but not high) cost version of the BART. Computational modelling of the BART task revealed no relationship between any parameter and Catastrophizing scores in either version of the task. Conclusions: We show that increased self-reported catastrophizing may be associated with reduced behavioural measures of risk-taking, but were unable to identify a computational correlate of this effect.

Adaptive learning from outcome contingencies in eating-disorder risk groups.

Eating disorders are characterised by altered eating patterns alongside overvaluation of body weight or shape, and have relatively low rates of successful treatment and recovery. Notably, cognitive inflexibility has been implicated in both the development and maintenance of eating disorders, and understanding the reasons for this inflexibility might indicate avenues for treatment development. We therefore investigate one potential cause of this inflexibility: an inability to adjust learning when outcome contingencies change. We recruited (n = 82) three groups of participants: those who had recovered from anorexia nervosa (RA), those who had high levels of eating disorder symptoms but no formal diagnosis (EA), and control participants (HC). They performed a reinforcement learning task (alongside eye-tracking) in which the volatility of wins and losses was independently manipulated. We predicted that both the RA and EA groups would adjust their learning rates less than the control participants. Unexpectedly, the RA group showed elevated adjustment of learning rates for both win and loss outcomes compared to control participants. The RA group also showed increased pupil dilation to stable wins and reduced pupil dilation to stable losses. Their learning rate adjustment was associated with the difference between their pupil dilation to volatile vs. stable wins. In conclusion, we find evidence that learning rate adjustment is unexpectedly higher in those who have recovered from anorexia nervosa, indicating that the relationship between eating disorders and cognitive inflexibility may be complex. Given our findings, investigation of noradrenergic agents may be valuable in the field of eating disorders.

Reinforcement Learning in Patients With Mood and Anxiety Disorders vs Control Individuals: A Systematic Review and Meta-analysis.

IMPORTANCE: Computational psychiatry studies have investigated how reinforcement learning may be different in individuals with mood and anxiety disorders compared with control individuals, but results are inconsistent. OBJECTIVE: To assess whether there are consistent differences in reinforcement-learning parameters between patients with depression or anxiety and control individuals. DATA SOURCES: Web of Knowledge, PubMed, Embase, and Google Scholar searches were performed between November 15, 2019, and December 6, 2019, and repeated on December 3, 2020, and February 23, 2021, with keywords (reinforcement learning) AND (computational OR model) AND (depression OR anxiety OR mood). STUDY SELECTION: Studies were included if they fit reinforcement-learning models to human choice data from a cognitive task with rewards or punishments, had a case-control design including participants with mood and/or anxiety disorders and healthy control individuals, and included sufficient information about all parameters in the models. DATA EXTRACTION AND SYNTHESIS: Articles were assessed for inclusion according to MOOSE guidelines. Participant-level parameters were extracted from included articles, and a conventional meta-analysis was performed using a random-effects model. Subsequently, these parameters were used to simulate choice performance for each participant on benchmarking tasks in a simulation meta-analysis. Models were fitted, parameters were extracted using bayesian model averaging, and differences between patients and control individuals were examined. Overall effect sizes across analytic strategies were inspected. MAIN OUTCOMES AND MEASURES: The primary outcomes were estimated reinforcement-learning parameters (learning rate, inverse temperature, reward learning rate, and punishment learning rate). RESULTS: A total of 27 articles were included (3085 participants, 1242 of whom had depression and/or anxiety). In the conventional meta-analysis, patients showed lower inverse temperature than control individuals (standardized mean difference [SMD], -0.215; 95% CI, -0.354 to -0.077), although no parameters were common across all studies, limiting the ability to infer differences. In the simulation meta-analysis, patients showed greater punishment learning rates (SMD, 0.107; 95% CI, 0.107 to 0.108) and slightly lower reward learning rates (SMD, -0.021; 95% CI, -0.022 to -0.020) relative to control individuals. The simulation meta-analysis showed no meaningful difference in inverse temperature between patients and control individuals (SMD, 0.003; 95% CI, 0.002 to 0.004). CONCLUSIONS AND RELEVANCE: The simulation meta-analytic approach introduced in this article for inferring meta-group differences from heterogeneous computational psychiatry studies indicated elevated punishment learning rates in patients compared with control individuals. This difference may promote and uphold negative affective bias symptoms and hence constitute a potential mechanistic treatment target for mood and anxiety disorders.

Effectiveness of SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on DMARDs: as determined by antibody and T cell responses.

OBJECTIVES: To assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs). METHODS: This prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive antibody response was defined as sera IgG binding to ≥1 antigen. Those that remained seronegative after first vaccination were retested 4 weeks after second vaccination; and if still seronegative after vaccination three. A T cell response was defined an ELISpot count of ≥7 interferon (IFN)γ-positive cells when exposed to spike antigens. Type I IFN activity was determined using the luminex multiplex assay IFN score. RESULTS: After vaccine one, in patients without prior SARS-CoV-2 exposure, 37/83 (45%) developed vaccine-specific antibody responses, 44/83 (53%) vaccine-specific T cell responses and 64/83 (77%) developed either antibody or T cell responses. Reduced seroconversion was seen with abatacept, rituximab (RTX) and those on concomitant methotrexate (MTX) compared to 100% for healthy controls (p<0.001). Better seroconversion occurred with anti-tumour necrosis factor (TNF) versus RTX (p=0.012) and with age ≤50 (p=0.012). Pre-vaccine SARS-CoV-2 exposure was associated with higher quantitative seroconversion (≥3 antibodies) (p<0.001). In the subgroup of non-seroconverters, a second vaccination produced seroconversion in 54% (19/35), and after a third in 20% (2/10). IFN score analysis showed no change post-vaccine. CONCLUSION: Patients with RA on DMARDs have reduced vaccine responses, particularly on certain DMARDs, with improvement on subsequent vaccinations but with approximately 10% still seronegative after three doses.

The Importance of Common Currency Tasks in Translational Psychiatry.

PURPOSE OF REVIEW: Common currency tasks are tasks that investigate the same phenomenon in different species. In this review, we discuss how to ensure the translational validity of common currency tasks, summarise their benefits, present recent research in this area and offer future directions and recommendations. RECENT FINDINGS: We discuss the strengths and limitations of three specific examples where common currency tasks have added to our understanding of psychiatric constructs-affective bias, reversal learning and goal-based decision making. SUMMARY: Overall, common currency tasks offer the potential to improve drug discovery in psychiatry. We recommend that researchers prioritise construct validity above face validity when designing common currency tasks and suggest that the evidence for construct validity is summarised in papers presenting research in this area.

The development and psychometric properties of a self-report Catastrophizing Questionnaire.

Catastrophizing is a cognitive process that can be defined as predicting the worst possible outcome. It has been shown to be related to psychiatric diagnoses such as depression and anxiety, yet there are no self-report questionnaires specifically measuring it outside the context of pain research. Here, we therefore develop a novel, comprehensive self-report measure of general catastrophizing. We performed five online studies (total n = 734), in which we created and refined a Catastrophizing Questionnaire, and used a factor analytic approach to understand its underlying structure. We also assessed convergent and discriminant validity, and analysed test-retest reliability. Furthermore, we tested the ability of Catastrophizing Questionnaire scores to predict relevant clinical variables over and above other questionnaires. Finally, we also developed a four-item short version of this questionnaire. We found that our questionnaire is best fit by a single underlying factor, and shows convergent and discriminant validity. Exploratory factor analyses indicated that catastrophizing is independent from other related constructs, including anxiety and worry. Moreover, we demonstrate incremental validity for this questionnaire in predicting diagnostic and medication status. Finally, we demonstrate that our Catastrophizing Questionnaire has good test-retest reliability (intraclass correlation coefficient = 0.77, p < 0.001). Critically, we can now, for the first time, obtain detailed self-report data on catastrophizing.

A review of the treatment landscape in paroxysmal nocturnal haemoglobinuria: where are we now and where are we going?

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-orphan disease, which until 15 years ago had limited treatment options. Eculizumab, a monoclonal antibody that inhibits C5 in the terminal complement cascade, has revolutionised treatment for this disease, near normalising life expectancy and improving quality of life for patients. The treatment landscape of PNH is now evolving, with ravulizumab a second longer acting intravenous C5 inhibitor now licenced by the FDA and EMA. With different therapeutic targets in the complement cascade and difference modalities of treatment, including subcutaneous, oral and intravenous therapies being developed, increasing independence for patients and reducing healthcare requirements. This review discusses the current and future therapies for PNH. Lay summary: Review of current and future treatments for patients with Paroxysmal Nocturnal Haemoglobinuria What is Paroxysmal Nocturnal Haemoglobinuria? Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease. It arises from PNH stem cells in the bone marrow. In a normal bone marrow these are inactive; however, if there has been a problem in the bone marrow, the PNH stem cells can expand and make PNH red blood cells, white blood cells and platelets. The problem with these cells is that they lack the cell surface markers that usually protect them. Red blood cells are broken down in the circulation rather than the spleen, which gives rise to PNH symptoms such as abdominal pain, difficulty swallowing, erectile dysfunction and red or black urine (known as haemoglobinuria). The white blood cells and platelets are 'stickier' increasing the risk of blood clots. Previously life expectancy was reduced as there were limited treatment options available. What was the aim of this review? To provide an overview of current and future treatment options for PNH Which treatments are available? • Eculizumab is an treatment given through a vein (intravenous) every week for 5 weeks then every 2 weeks after this, and has been available for 13 years, improving life expectancy to near normal.• Ravulizumab is a newer intravenous treatment similar to eculizumab but is given every 8 weeks instead of every 2 weeks. In clinical studies it was comparable with eculizumab.• Future Treatments - There is new research looking at different methods of treatment delivery, including injections under the skin (subcutaneous) that patients can give themselves, treatments taken by mouth (oral) or a combination of an intravenous and oral treatment for those patients who are not optimally controlled on eculizumab or ravulizumab. What does this mean? PNH is now treatable. For years, the only drug available was eculizumab, but now different targets and drug trials are available. Ravulizumab is currently the only second licenced product available, in USA and Europe, there are other medications active in clinical trials. Why is this important? The benefit for patients, from treatment every 2 weeks to every 8 weeks is likely to be improved further with the development of these new treatments, providing patients with improved disease control and independence.As we move into an era of more patient-friendly treatment options, the PNH community both physicians and patients look forward to new developments as discussed in this article.