P = 0.03 corrected), as did severe patients for disgust (P = 0.04 corrected) and irritation (P < 0.01 corrected). In the whole cohort, these performances were associated with decreased episodic memory and anosmia, but not with depressive symptoms, anxiety or post-traumatic stress disorder. Neuroimaging revealed a positive contribution of functional connectivity, notably between the cerebellum and the default mode, somatosensory motor and salience/ventral attention networks. These results highlight the long-term consequences of SARS-Cov-2 infection on the limbic system at both the behavioural and neuroimaging levels.Alterations of the limbic system may be present in the chronic phase of SARS-CoV-2 infection. Our aim was to study the long-term impact of this disease on limbic system–related behaviour and its associated brain functional connectivity, according to the severity of respiratory symptoms in the acute phase. To this end, we investigated the multimodal emotion recognition abilities of 105 patients from the Geneva COVID-COG Cohort 223 days on average after SARS-CoV-2 infection (diagnosed between March 2020 and May 2021), dividing them into three groups  according to respiratory symptom severity in the acute phase. We used multiple regressions and partial least squares correlation analyses to investigate the relationships between emotion recognition, olfaction, cognition, neuropsychiatric symptoms and functional brain networks. Six to 9 months following SARS-CoV-2 infection, moderate patients exhibited poorer recognition abilities than mild patients for expressions of fear  for a scientific commentary on this article.See A. Matias-Guiu and Díez-Cirarda (  Matias-Guiu and Díez-Cirarda ,14 but to date, no study has sought to determine whether these results are driven by specific emotions. Neuroimaging studies in patients with COVID-19 have used a variety of methods, including fluorodeoxyglucose (18FDG) PET and MRI, to highlight hypometabolism or hypoconnectivity in cortical–subcortical brain regions and networks,15 many belonging to the limbic system, as well as alterations in the cerebellum.16 Moreover, a recent study highlighted a reduction in grey-matter thickness in the orbitofrontal cortex and parahippocampal gyrus, as well as tissue damage in regions that are functionally connected to the primary olfactory cortex—regions that are also known to form part of the limbic system.17 However, only a small number of studies have correlated cognitive and neuropsychiatric variables with functional neuroimaging data,18 and studies of emotion recognition abilities have so far focused solely on behavioural data.8 None have explored the relationships between multimodal emotion recognition and structural and functional neuroimaging data.Behavioural and neuroimaging data point to alterations of the limbic system in the chronic phase of COVID-19.19 and are well known to have an impact on emotion recognition abilities.20–24 To the best of our knowledge, no study has yet assessed the impact of relevant secondary neuropsychiatric variables on the recognition of individual multimodal emotions, as a function of the severity of respiratory symptoms in the acute phase. In this context, tasks assessing emotion processing abilities could be of interest. Only two studies have behaviourally assessed long-term emotion recognition abilities following SARS-CoV-2 infection, highlighting reduced performance in hospitalized versus non-hospitalized groups of patients.8 That said, these studies were carried out on overall scores and did not assess performances for individual emotions.Although previous results suggest that the virus directly (or more likely indirectly) attacks the CNS, and presumably the limbic system in particular, the potential effect of neuropsychiatric symptoms on long-term limbic-related functions has yet to be investigated. Many neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), anxiety and depressive symptoms, have been described following SARS-CoV-2 infection, as well as fatigue and sleep disturbances,25 The limbic circuits, involving the orbitofrontal cortex, insula and amygdala, inferior temporal lobe and subcortical regions, have historically been described as forming the neural base of emotional processes, as well as memory functions.27 Nevertheless, recent evidence suggests that there is not one limbic system, but several differentiated limbic systems for emotional processes, involving anterior structures of the limbic system, orbitofrontal cortex and amygdala in emotion processing, reward assessment and decision-making.28 Meanwhile, memory functions are underpinned by the hippocampus and the limbic structures to which it is connected, including the posterior cingulate cortex and the fornix–mammillary body–anterior thalamus–posterior cingulate circuit.28 Finally, these processes also seem to be underpinned by cerebellar structures, highlighting the close interaction between the limbic systems and the cerebellum.29According to recent models of emotions, particularly the process model of emotions, each emotion has distinct properties and involves five distinct functions .In this context, the present study was conducted to examine the impact of the severity of respiratory symptoms in the acute phase of COVID-19 on emotion recognition abilities 6–9 months post-infection (aim 1) and to explore the influence of secondary behavioural variables  (aim 2), as well as functional brain connectivity (aim 3). To this end, we assessed multimodal emotion recognition in 105 patients 223.07 ± 41.69 days following SARS-CoV-2 infection. We ran regression analyses to investigate the potential predictive value of neuropsychological functions sustained by the limbic system , neuropsychiatric manifestations  and olfactory performances. Finally, 45 of these 105 patients underwent functional MRI, and exploratory partial least squares correlation (PLSC) analyses were performed to identify associations between multimodal emotion recognition abilities and functional brain networks.30 For each patient, we carried out a medical file review, followed by a telephone call inviting the patient to take part in the study, if all the eligibility criteria were met. Exclusion criteria were a history of neurological issues, neuropsychiatric disorders, cancer, neurodevelopmental pathologies, pregnancy and age above 80 years.Data from 105 patients were extracted from the COVID-COG database of Geneva University Hospitals (HUG).The patients had all been diagnosed with SARS-CoV-2 infection between March 2020 and May 2021, either by positive PCR from a nasopharyngeal swab and/or by positive serology. Patients were included in the study 223.07 ± 41.69 days post-infection and divided into the following 3 groups: 24 patients who had been in ICU during the acute phase of the infection (severe), 39 patients who had been hospitalized but did not require mechanical ventilation (moderate) and 42 patients who had tested positive but had not been hospitalized (mild). During the screening–inclusion process, because of the limited number of patients who had been in ICU and who met our inclusion criteria, the mild and moderate groups were matched with the severe group for age, sociocultural level, gender and clinical variables (except for sleep apnoea and chronic kidney disease). All descriptive data are provided in All participants gave their written informed consent, and the study was approved by the cantonal ethics committee of Geneva (CCER-02186).30 as well as neuroimaging data13 from the COVID-COG project database.9For the purpose of the present study, we extracted olfactory, multimodal emotion recognition, memory and neuropsychiatric data,31), a validated multimodal emotion recognition task adapted from the full 83-item GERT. GERT-S is a performance-based test that measures individual differences in people’s ability to recognize others’ emotions expressed in the face, voice or body. During this task, participants watched 42 short video clips with sound (duration: 1–3 s), in which 14 different emotions extracted from the validated GEMEP database32 were displayed  a copy phase, which measures visuoconstructive function, and (ii) a recall phase, performed 3 and 20 min later , which measures the extent and quality of recall of the original figure from short- or long-term spatial memory. If patients failed to produce a copy of Rey’s figure, we did not administer the delayed recall,35 as the assessment of visual memory would otherwise have been biased by visuoconstructive deficits. For this reason, 11 patients did not perform the memory recall, but all patients were included in the other analyses.Verbal episodic memory was assessed with Grober and Buschke’s French-language 16-item Free and Delayed Recall Test (RL/RI-16).36We administered the validated Sniffin’ Sticks test battery, where participants must identify 16 odours. For each odour, they can choose between four possible answers.37 anxiety with the State-Trait Anxiety Inventory,37 apathy and its distinct subtypes with the Apathy Motivation Index,38 PTSD with the Posttraumatic Stress Disorder Checklist for DSM-5,39 manic symptoms with the Goldberg Mania Inventory,40 dissociative symptoms in the patient’s daily life with the Dissociative Experience Scale,41 current stress perception with the Perceived Stress Scale-14 items,42 emotion regulation with the Emotion Regulation Questionnaire43 and susceptibility to others’ emotions with the Emotion Contagion Scale.44All neuropsychiatric data were collected online  in the week preceding the neuropsychological assessment, via standardized and computerized questionnaires specially designed for the study. More specifically, depressive symptoms were assessed with the Beck Depression Inventory-Second edition,45 potential sleeping disorders with the Insomnia Severity Index46 and symptoms of sleepiness in daily life with the Epworth Sleepiness Scale.47Finally, fatigue was assessed with the French version of the Fatigue Impact Scale,n = 17; moderate, n = 19; severe, n = 9). Within this subset, no significant differences were found between the groups on either sociocultural level , handedness (one left-handed participant in both the mild and severe groups) or age , whereas gender ratios differed significantly, as there were no women in the severe group . In addition, no differences were observed on the intervals between infection and MRI  and between neuropsychological testing and MRI .Anatomical T1-weighted magnetization-prepared rapid acquisition gradient echo (T1w MPRAGE) and resting-state functional (rs-fMRI) MRI data were extracted from the COVID-COG dataset for 45 participants  were removed from the signal, a low-pass filter with a cut-off frequency of 0.15 Hz was applied, each fMRI volume was spatially smoothed with a Gaussian kernel , and frames with framewise displacement >0.7 mm were excluded.The image acquisition procedure is described elsewhere50 .Resting-state functional connectivity was computed as the Fisher-transformed Pearson’s correlation coefficient between the mean fMRI timecourses within 156 regions of interest associated with 19 resting-state networksP-values were corrected using the Bonferroni criterion. In addition, to establish baseline emotion recognition performances within our cohort, we compared the performances of our three groups of patients with that of healthy control participants from a previous study where the GERT-S was administered to a normative population (German-speaking part of Switzerland) in March 2020 (during lockdown).54 The raw scores were converted to standardized scores , in accordance with the guidelines of the Swiss Association of Neuropsychology.56First, we performed intergroup comparisons between the severe, moderate and mild groups on the GERT-S total score and subscores, using nonparametric Kruskal–Wallis analyses of variance and (if significant) Mann–Whitney U-tests. Bilateral Second, we performed forward stepwise multiple regressions on the significant emotion scores, adding verbal and visual episodic memory, neuropsychiatric, fatigue and olfactory scores as predictors. All the statistical analyses were run on TIBCO Statistica™ 14.0.0.57–60 The resulting latent components were defined as linear combinations of whole-brain functional connectivity patterns and GERT performances  with maximum covariances across patients and within each group. Additionally, the procedure was repeated separately for each group, to estimate the coherence of the group PLSC analysis. The significance of the multivariate correlations was assessed with permutation testing (1000 permutations) and the reliability of the features’ contributions (i.e. loadings) to the correlation components with bootstrapping (500 resamples). To control for the effect of memory processes on emotion recognition, we included the RL/RI 16-delayed free recall as a measure of verbal episodic memory, along with age, gender and sociocultural level as covariates. PLSC analyses were performed using the myPLS toolbox (https://github.com/danizoeller/myPLS).Third, to find associations between neuroimaging and behavioural data, we extracted multivariate components using a data-driven approach, performing exploratory group PLSC analysis on the whole cohort of patients.To probe for structural alterations that might be associated with the functional patterns we observed, we ran voxel-based morphometry analyses, by computing the proportions of white- and grey-matter voxels in the whole brain or within parcels of our custom fMRI atlas. We used analyses of covariance (ANCOVA) to assess statistical differences between the groups, with age, gender and sociocultural level as covariates.https://yareta.unige.ch/home, dataset DOI: 10.26037/yareta:56vcowyr7fdgxfikm5wycsc47a). The code for the PLSC analyses and figure generation is available in a GitHub repository (https://github.com/Cionkito/PLS-COVID_emotions).Nonsensitive COVID-COG data are available in open access on a dedicated platform   and severe  patients. This effect on the total score was mainly driven by performances for expressions of fear, irritation and disgust: mild patients performed better than moderate patients on fear expression recognition  and also performed better than severe patients on the recognition of expressions of irritation  and disgust .Results revealed a significant difference between the three groups  on the total emotion recognition score 6–9 months post-infection ( < 0.01) . More spWhen we compared the performances of our three patient groups with the performance of healthy control participants, we observed deficits for mild (9.52%), moderate (30.71%) and severe patients (45.83%) , sniff test (anosmia) , Rey figure-delayed recall 3′′ , RL/RI 16-sum of three free recalls  and RL/RI 16-immediate recall .For the GERT total score, the best fit was achieved using the following variables: RL/RI 16-delayed free recall  and RL/RI 16-delayed free recall .For the GERT fear score, the best fit was achieved using the Rey figure-delayed recall 3′′ , RL/RI 16-delayed free recall  and Fatigue Impact Scale  .For the GERT disgust score, the best fit was achieved using the RL/RI 16-delayed total recall , sniff test (anosmia)  and RL/RI 16-sum of three total recalls .For the GERT irritation score, the best fit was achieved using the RL/RI 16-delayed free recall (P = 0.004) (P = 0.021), and these did not survive false discovery rate correction  . This ex= 0.004) . The neu= 0.004) . The sam= 0.004) . Separatrrection . Even sorrection . Finallyrrection .first, to explore the impact of the severity of respiratory symptoms in the acute phase of COVID-19 on multimodal emotion recognition performances 6–9 months later; second, to determine whether memory, neuropsychiatric or olfactory variables are associated with these performances; and third, to identify the functional brain networks that are associated with them.The aim of the present study was 3-fold: 7 and in a previous study performed on the COVID-COG cohort.2 However, for the first time to our knowledge, our results revealed poorer scores not just across the board, but for specific emotions . These results support the hypothesis that the long-term neuropsychological effects of COVID-19 go beyond the well-known impact of hospitalization in ICU on cognitive functions, as attested by the performances displayed by the moderate group. However, this does not exclude an effect of conventional hospitalization.9 Thus, the ability to recognize emotions may be impaired following SARS-CoV-2 infection. Interestingly, using a transconnectome-based network diffusion model, Parsons et al.63 reported changes in thalamocortical connectivity in patients with COVID-19 that may have disrupted their regulation of consciousness and arousal, possibly affecting or interacting with emotion recognition.64With respect to the first aim, we observed that both moderate and severe patients had significantly lower emotion recognition scores than mild patients. This result on the total score is consistent with previous results obtained with a smaller cohort7 as well as short- and long-term memory impairment post-infection,11–13 have previously been described following SARS-CoV-2 infection,17 but we are the first to demonstrate associations between these disorders and emotion recognition. Given the overlapping brain substrates underlying memory, olfactory and emotion recognition mechanisms,65 notably via the insula, amygdala and hippocampus,67 our observation of these associations is particularly relevant and is probably consistent with the idea of limbic system alterations following SARS-CoV-2 infection. Interestingly, this hypothesis is partially corroborated by the neuroimaging findings of the present study and of previous studies in other neuroimaging modalities (e.g. FDG-PET).Regarding the second aim, multiple regression analyses revealed that the best predictors of multimodal emotion recognition were performances on verbal and visual episodic memory, as well as olfactory recognition abilities and self-reported physical fatigue. Surprisingly, neuropsychiatric symptoms, such as anxiety, depressive symptoms and PTSD, were not associated with emotion recognition abilities, despite showing high heterogeneity. Olfactory deficits ,13 and PET,68 and underline the involvement of the limbic system  following SARS-CoV-2 infection.1 Interestingly, limbic system alteration following viral infections has already been reported, with an increased number of enzymes involved in inflammatory responses within limbic system and associated brain structures, such as the hippocampus and basal ganglia.70Regarding the third aim, we found significant correlations between multimodal emotion recognition performances and functional connectivity patterns involving cortico–subcortical–cerebellar networks overlapping the so-called limbic system. Although we identified a positive correlation between emotion recognition scores and functional connectivity in the mild group, there was a negative correlation in the moderate group and no correlation in the severe group. Our interpretation is that moderate to severe symptoms in the acute phase may induce a compensatory response in the limbic system and lead to the patterns of altered functional connectivity that can be observed at 6–9 months post-infection. Whatever the underlying processes, which remain to be explored in future studies, these results are consistent with our behavioural results, as well as with previous observations in the literature for the long-term consequences of SARS-CoV-2 infection using both fMRIn = 9 patients) may explain the absence of significant correlations in the PLSC analyses. Nevertheless, the functional connectivity data of the severe patients were not particularly heterogeneous, compared with those of the mild and moderate groups .It is important to note that the present study had five limitations. First, the smaller number of patients in the severe group who agreed to undergo an MRI (e groups . Further13 This damage may not be solely explained by ICU effects (as attested by the performances displayed by the moderate group) nor by neuropsychiatric disorders that may arise from the pandemic context and/or personal history of infection such as anxiety, depressive symptoms or PTSD. In the light of the evidence provided in this study, interventions tailored to lessen cognitive impairment induced by SARS-CoV-2 infection could be developed.Taken together, the present results may provide further evidence of long-term damage by SARS-CoV-2 to the CNS and more specifically to the limbic system.fcad177_Supplementary_DataClick here for additional data file.


Monoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens.We selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes  from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen.Meta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit.RCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services. It has been nearly 50 years since Milstein and Kohler first described a method to produce monoclonal antibodies of desired specificity . The advFew people outside scientific circles are aware of the impact of Mab drugs. For example, Mab drugs have transformed certain cancers from being labeled a terminal disease to a chronic condition , 4. TheyMany studies have examined the health benefits and cost effectiveness of individual Mab drugs –9, but tJust how much Mab drugs add to the NHS budget can be seen from the case of adalimumab in 2018. Prescribed to more than 46,000 patients for serious conditions such as RA, inflammatory bowel disease, and psoriasis, adalimumab was the biggest NHS spend that year . With thOur aim was to determine whether systematic literature review (SLR) combined with meta-analysis followed by economic modeling can assess the impact across a range of different Mab drug regimens in different clinical settings. We report the results of a pilot study on five well-established Mab regimens where the follow-up data are sufficiently mature for analysis. This includes immune-checkpoint inhibitors for melanoma that have radically improved life survival , and adaConsidering that over fifty major conditions are currently treated with Mab drugs, we decided to focus this pilot study on two treatment groups that represent diverse conditions with proven benefits ranging from life-saving (melanoma) to life-enhancing (RA), each with enough cases to assess the real-world health and monetary impact. By selecting several Mab regimens for one of the conditions (melanoma), internal comparison was, in addition, possible.Our study includes two SLRs for melanoma and RA, each with a meta-analysis to determine the health benefit of each drug regimen under consideration (Prospero registration CRD42021261882). The meta-analyses results, along with other data in the literature, were used to populate two economic models estimating the net monetary benefit for each Mab. The five Mab regimens analyzed are listed in Systematic database searches for each Mab regimen were conducted to identify randomized controlled trials (RCTs) and real-world data (RWD) studies. Melanoma studies were only eligible where all participants had a diagnosis of metastatic cutaneous melanoma or unresectable locally advanced melanoma. Participants needed to receive either pembrolizumab, ipilimumab or nivolumab, or the ipi-nivo combination as first-line treatments. The following studies were deemed ineligible: Phase I and non-randomized Phase II studies, studies with <100 participants, single-center studies, and studies that did not include treatment-naïve participants. The primary outcome for RCTs was progression-free survival (PFS); the secondary outcomes were median overall survival (OS) and quality of life index (EQ-5D or EORTC-QLQ-C30). For observational studies, the primary outcome was survival rate and the secondary outcome was hospitalization rate (proxied from Grade III and Grade IV toxicities).Eligible RA studies included Phase III RCTs that compared adalimumab (40 mg subcutaneously every 2 weeks) with a placebo and captured data on Health Assessment Questionnaire-Disability Index outcomes  at drug initiation and 12-months post-initiation. Observational cohort studies were eligible where prospectively recruited adult RA patients were treated with adalimumab, and data on HAQ-DI outcomes at drug initiation and 12-months post-initiation were available. A comparator arm was non-essential for the inclusion of cohort studies. A stable background therapy with csDMARD was permissible for the inclusion in all studies. Extracted data included the following outcome measures at baseline and at 12- and 24-months post-adalimumab initiation: HAQ-DI Disease Activity Score-28 Joints (DAS28) and quality of life measures . The primary outcome measure was HAQ-DI at 12-months post-adalimumab initiation, relative to baseline. Secondary outcome measures were the change from baseline in HAQ-DI at 24-months post-adalimumab initiation; DAS-28 at 12- and 24-months post-adalimumab initiation; EQ-5D at 12- and 24-months post-adalimumab initiation; and SF-36/SF-12 at 12- and 24-months post-adalimumab initiation. For RCTs, comparison between the adalimumab and placebo study arms was made for the change from baseline in the above outcome measures.For melanoma, a random-effects model of network meta-analysis estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) for OS reported in RCTs. The analyses were based on the reported HRs between trial arms.I2. Publication bias was assessed using funnel plots. Meta-analyses for RCTs and RWD studies were conducted separately. Sensitivity analysis was performed to exclude those studies where heterogeneity between studies was considered high and to assess the impact on effect-size estimates.For RA, random-effects meta-analyses of aggregated study data were conducted where more than two RCTs and observational cohort studies reported on outcome measures. The heterogeneity assessment used p-value lower than 0.05 was considered statistically significant.Statistical analysis used R . A To estimate the total and net monetary benefits of Mabs, we developed separate Markov models for melanoma and RA . Markov The models required six input variables: (1) annual cost of Mab regimens and respective comparators; (2) utility value (UV) for each health state; (3) mortality; (4) probability of discontinuing Mab treatment; (5) patient population size in England; and (6) willingness to pay (WTP) .For melanoma, the mortality HRs for each Mab regimen relative to nivolumab was estimated by our SLR; the probability of death for nivolumab or the probabilities of transitioning to post-progression state for all Mabs were obtained from the follow-up of clinical trials. For RA, the probability of death followed that of England's life table, based on the assumption that RA has no effect on mortality. UVs were obtained from studies –15 identIn base-case analyses, the total and net monetary benefits were estimated for each Mab using the base-case (mean) values of all data. A positive net monetary benefit would suggest that the Mab is potentially cost-effective at the specified level of WTP; a negative net monetary benefit suggests that the Mab may not be cost-effective.The Mab regimen most recently recommended on July 2016 by NICE is ipi-nivo for melanoma . To compOne-way deterministic sensitivity analyses addressed whether the findings were sensitive to input variation, where the input value varied between the lower and upper limits, and the value of all other input variables was held constant. Included in the analyses were variations in the cost discount of Mabs , WTP  or SF-36 (n = 2) were too few to permit outcome analysis. Similarly, RCTs reporting HAQ-DI at 24 months (n = 1) or DAS28 at 24 months (n = 0) relative to baseline were too limited to permit outcome analysis. Sensitivity analysis after excluding studies from meta-analysis (based on the sample size and standard deviation) showed that our main conclusion was unaffected across the different analyses  or SF-36 (n = 2) were too few to permit meta-analysis of outcomes. Similarly, cohort studies reporting HAQ-DI at 24 months (n = 3) or DAS28 at 24 months (n = 3) relative to baseline were too scarce to permit meta-analysis of outcomes.In 11 eligible observational cohort studies of RA reporting HAQ-DI at baseline and 12 months, meta-analysis showed a weighted mean improvement in HAQ-DI of 0.51 (95% CIs: 0.35–0.68) at 12-month post-adalimumab initiation, relative to baseline . Of nineClinical benefits of adalimumab treatment, measured by functional impairment and disease activity, were therefore evident both in real-world and trial settings . HAQ-D1 and DAS28 were slightly higher at baseline in RCT than in RWD studies –S14. FunTo determine the total and net monetary benefits on health outcomes for the five Mab regimens from approval to 2020, we estimated that 81,387 patients with RA and 2,324 patients with melanoma would have started their respective Mab regimens since they became available in the NHS . Of thesSeparately, we calculated lifetime QALYs and costs of Mabs accrued per patient . Adalimutotal monetary benefits—adalimumab £7.4 billion , pembrolizumab £91M (n = 827), ipi-nivo £71M (n = 438), ipilimumab £46M (n = 967), and nivolumab £7M (n = 47). Since 2017, total monetary benefits were smaller—adalimumab £3 billion , pembrolizumab £84M (n = 810), ipi-nivo £65M (n = 405), nivolumab £55M (n = 37), and ipilimumab £47M (n = 98).Using the total number of patients from 2017, lifetime QALYs, and costs per patient, we calculated the total and net monetary benefits to NHS England since their availability . The larnet monetary benefit of £1.8 billion (£1 billion from 2017), ipi-nivo generated £ 11M (£10M from 2017), and nivolumab generated £5M (£4M from 2017). However, pembrolizumab (–£10M) and ipilimumab (–£26M since its availability and –£3M from 2017) generated negative net monetary benefits. For adalimumab, while more total monetary benefits were accrued before biosimilars became available in the NHS in 2019, net monetary benefits were higher once biosimilars became available.Accounting for the costs of Mabs, adalimumab generated a positive Sensitivity analyses determined how net monetary values varied at the lower and the upper limits of input variables . Mabs haThreshold analyses showed net monetary benefits for ipilimumab break-even with 35% discount from list price, and pembrolizumab at 11%, whereas ipi-nivo break-even at 20% cost increase and nivolumab at 3-fold cost increase . The HR Threshold analyses for adalimumab suggested the net monetary benefits would break-even at 58% cost increase from the list price (until 2018) or at 6.4-times cost increase from the reference price (since 2019), a HAQ-DI value of 1.36 (vs. 0.79 at base-case), UV of 0.54 for the discontinued-from-adalimumab state (vs. 0.62 at base-case), and 5.6% annual probability of discontinuing from adalimumab (vs. 10% at base-case), or at WTP of £ 16,241 per QALY gained .We have demonstrated that SLR combined with meta-analysis and subsequent health economic modeling can assess the impact across different Mab regimens used in different clinical contexts. Tested across five well-established Mab regimens in oncology and rheumatology where follow-up data were sufficiently mature for analysis, our data suggest the approach that may be suitable for applying more widely to other Mab regimens and indications. First, we observed a close agreement between the real-world health benefits and those anticipated from clinical trials. Second, we transformed these estimates of health benefits into a net monetary value for each Mab regimen by accounting for the perceived benefit over the comparator treatment, the number of patients receiving the treatment, actual drug costs, and WTP. While confirming the feasibility of this approach, the estimation of monetary return to the NHS depended on the accuracy of patient numbers and treatment costs for each Mab regimen, which presented a challenge to our analysis.Few published studies have directly compared RWD sets with RCT sets for the same Mab regimens. Rigorously selecting a total of 27 eligible prospective cohort studies and 26 pivotal trial studies for side-by-side analysis, we were able to compare the health benefits perceived by patients in clinical trial and post-licensing settings. Our analysis confirmed that the health measures (HAQ-DI for RA and OS for melanoma) estimated in pivotal trials represented the benefit a patient could expect to receive following the introduction of the regimen into clinical practice. The slightly lower estimate of health measures for the RWD was perhaps because the group of patients included more advanced cases than in a trial setting. This observation is nonetheless important because it suggests that we are largely getting the health benefits predicted at the point national recommendations were made.We developed a Markov model for each of the five regimens in melanoma and RA to accrue the lifetime QALYs and costs of Mabs and their comparators for all patients estimated to have received treatment since the Mabs became available in NHS England. In the five-year period from 2017, all Mabs accrued higher QALYs and costs per patient than their non-Mab comparators (ranging from £84M for pembrolizumab to £5M each for ipilimumab and nivolumab), with a total of £160M across the four Mab regimens. The net monetary benefits in England were positive for nivolumab and ipi-nivo but negative for pembrolizumab and ipilimumab because the lifetime cost of Mabs exceeded that of total monetary benefits. For RA, the additional QALYs from adalimumab compared to methotrexate translated to £3 billion (since 2017) and £12 billion net monetary benefit (since 2017), with the net benefit increasing since the availability of biosimilars in 2019.Net monetary benefits increased with higher price discounts, HRs of mortality (melanoma), lower probability of mortality (melanoma), higher UVs (melanoma), lower HAQ-DI (RA), and a higher WTP per QALY. Threshold analyses revealed the values of input variables at which the Mabs would give 0 net monetary benefit, i.e., the values at which the conclusion on cost-effectiveness would change, although not all threshold values were plausible .One important limitation was data access. We could not identify any appropriate data source for the actual patient-population size receiving the five Mab regimens in NHS England. Hence, we estimated the sizes based on reported incidence and prevalence data. However, we were unable to account for any fluctuations in the number of patients, e.g., adoption that may be slower early during its introduction or changes in patients diagnosed through the COVID pandemic. Furthermore, due to commercial confidentiality, we could not access the actual cost of Mabs borne by NHS England. Hence, the costs of Mabs in our estimations were based on list prices or reference prices, which we believe were higher than the actual cost. At list price, two of the five Mab regimens generated negative net monetary benefits; however, one-way sensitivity analyses revealed how the net monetary benefits would change with up to 10% discounts . We alsoAnother limitation was the scope of the cost data. Our estimations only accounted for the cost of Mab drugs and their administration. This assumes that the antibodies and their comparators do not differ in their downstream health-service usage, which may be plausible for melanoma due to its high mortality rate but less plausible for RA because it affects patients' quality of life and not just their mortality. This, coupled with the accrual of lifetime QALYs, suggests that the net monetary benefits are ceiling estimates. Our findings may also be sensitive to the comparators, both of which cost less than the Mab regimens.The fact that each drug was introduced at different times see  also posOther biosimilars are likely to be introduced in the future, which will have a bearing on the other drugs for melanoma in this study, which going forward will need to be factored into the treatment algorithms for that condition. New regulatory guidance issued by the UK's Medicine and Healthcare Regulatory Agency in 2021 will help accelerate the licensing of new biosimilars in the UK . PatentsDespite the limitations, our results have important implications for research practice and policy. Our results highlight the need for systematic data collection to assess the impact  of innovative treatments, such as Mabs on the NHS, particularly the number of treated patients and Mab drug costs. Prospective accrual of data from the time a Mab treatment is approved would avoid reliance on sporadic, retrospective, and incomplete dataset analysis. Our difficulty in accessing data during the current study strongly supports the case for an NHS-based system of data collection and analytics capturing all Mab treatments. Users would then derive the same benefits as for other comprehensive databases, e.g., the organ transplant database, which facilitates ongoing comparison of different practices across the NHS using standardized metrics to assess quality of life and transplant survival. Meaningful estimates of return of research investment would also incentivise publicly funded research on innovative (though costly) biological treatments such as Mab drugs.Multiple studies and meta-analyses have examined the utility of individual Mab drugs approved for treatment in the NHS. Few studies have considered the overall health and economic benefits of this genre of drugs, as well as how it compares to the predicted benefits from pivotal clinical trials.We show the relationship between clinical trials and real-world data on the outcome of different Mab treatments and diseases. Based on this information, we calculate the economic benefit to the NHS based on actual patient numbers. We illustrate how difficulties obtaining accurate information on patient numbers and Mab drug costs can distort the calculation of overall benefit.With an ever-increasing number of diseases benefiting from Mab therapies, our study emphasises the need for a systematic and comprehensive scheme for accurate data collection and analytics within the NHS. This will be useful to benchmark the overall value of Mab drugs and inform health strategy and equitable access. It is also a celebration of the underpinning science as it approaches its 50th year since first reported.The original contributions presented in the study are included in the article/KL: Conceptualization, Formal analysis, Investigation, Methodology, Writing—original draft. KN: Formal analysis, Methodology, Writing—original draft, Conceptualization, Data curation. SB: Data curation, Writing—original draft. MR: Conceptualization, Data curation, Formal analysis, Methodology, Writing—original draft. AB: Data curation, Writing—review & editing. AS: Data curation, Writing—review & editing. BC: Data curation, Writing—review & editing. KV: Data curation, Writing—review & editing. RM: Conceptualization, Data curation, Formal analysis, Methodology, Writing—original draft. AD: Conceptualization, Data curation, Formal analysis, Methodology, Writing—original draft. LM: Conceptualization, Funding acquisition, Project administration, Writing—original draft. SS: Conceptualization, Formal analysis, Funding acquisition, Methodology, Writing—original draft.


Escherichia coli (STEC) causes high frequencies of foodborne infections worldwide and has been linked to numerous outbreaks each year. Pulsed-field gel electrophoresis (PFGE) has been the gold standard for surveillance until the recent transition to whole-genome sequencing (WGS). To further understand the genetic diversity and relatedness of outbreak isolates, a retrospective analysis of 510 clinical STEC isolates was conducted. Among the 34 STEC serogroups represented, most (59.6%) belonged to the predominant six non-O157 serogroups. Core genome single nucleotide polymorphism (SNP) analysis differentiated clusters of isolates with similar PFGE patterns and multilocus sequence types (STs). One serogroup O26 outbreak strain and another non-typeable (NT) strain, for instance, were identical by PFGE and clustered together by MLST; however, both were distantly related in the SNP analysis. In contrast, six outbreak-associated serogroup O5 strains clustered with five ST-175 serogroup O5 isolates, which were not part of the same outbreak as determined by PFGE. The use of high-quality SNP analyses enhanced the discrimination of these O5 outbreak strains into a single cluster. In all, this study demonstrates how public health laboratories can more rapidly use WGS and phylogenetics to identify related strains during outbreak investigations while simultaneously uncovering important genetic attributes that can inform treatment practices.Shiga toxin-producing  Escherichia coli (STEC) is a Gram-negative foodborne pathogen that was estimated to cause ~265,000 infections, 3600 hospitalizations, and 30 deaths in the U.S. each year  due to incomplete sequencing of fliC.Over the four-year period, 34 typeable serogroups were identified, with serogroup O103 predominating  strains, while ST-66 strains representing serotype O157:H7  were also common. All O157 strains were classified as ST-66 except for two that were designated as novel STs (ST-1216).Among the 510 strains, PFGE detected 352 unique PFGE patterns following digestion with n = 1), ST-119 , ST-254 , ST-66 , and ST-175  were selected for the subsequent core genome analyses.Next, a Neighbor-joining tree was constructed using the seven MLST loci to determine the similarity between the clinical isolates and outbreak-associated isolates . The strstx1a-positive outbreak strains with matching PFGE patterns and outbreak codes despite having different O-antigens (serogroups) and H-antigens. One strain was classified as O26:H11, ST-106 (PNUSAE001586), whereas the other was a NT:H19 strain belonging to ST-254 (PNUSAE001592). Both strains were found on different branches in the MLST tree within subclades D and E, respectively, though these subclades grouped together with 90% bootstrapping  and O45:H2 (n = 61). Although most of these strains belonged to ST-119, strains representing STs 1220 and 1221 were also included. Despite having similar collection dates as well as identical PFGE patterns, outbreak codes, and eae and ehx alleles, the cgSNP analysis indicated the two stx1a-positive O103:H2 outbreak-associated strains, PNUSAE004161 and PNUSAE004654, were distinct  and 3 , which were distinct by PFGE, were grouped together within the same cgSNP cluster along with four non-outbreak strains. Within this cluster, the six ST-66-O3 outbreak strains were most closely related to each other, while the three ST-66-O2 outbreak strains were located on two different branches of the phylogeny. Such findings highlight the need to apply more discriminatory genomic approaches to better differentiate closely related strains.For the 98 STEC O157:H7 strains recovered between 2015 and 2018, 16 outbreak-associated strains were identified by PFGE. These strains were all classified as ST-66 but belonged to three different outbreaks. Since 82 additional ST-66 STEC O157:H7 strains were recovered during an overlapping time period, all 98 genomes were selected for inclusion in the cgSNP analysis. Unlike the MLST-based tree, the ST-66 strains could be differentiated into multiple clusters . The sixeae and ehx alleles, yet four of the strains had both the stx2a and stx2c genes as opposed to stx2c alone. The six strains also had identical banding patterns, though a shift in a single band was observed in outbreak strain PNUSAE013456. Importantly, all six outbreak strains and one non-outbreak strain differed by only 0–24 SNPs. Based on this level of similarity and the banding pattern, the non-outbreak strain PNUSAE007311 could have been classified as part of the original outbreak if the epidemiological data supported inclusion. However, it was isolated a year earlier than the rest of the outbreak strains and was therefore not classified as part of the same outbreak.Indeed, hqSNP analysis was applied to the subset of O157 ST-66 strains comprising the two different clusters containing the outbreak strains in the cgSNP phylogeny. The first analysis included the six outbreak 1 (ST-66-O1) strains plus nine other strains that were part of the same cgSNP cluster. Overlaying the PFGE data onto the hqSNP phylogeny showed that the banding patterns were highly similar for all of the strains in the cgSNP cluster . The sixstx2a and had identical eae and ehx alleles. Similar banding patterns were also observed for the nine outbreak strains, though strains belonging to the ST-66-O2 outbreak had a slight shift in the first band relative to strains from the ST-66-O3 outbreak. Outbreak strain PNUSAE005371 differed by additional SNPs but was recovered during the same time frame as the other two ST-66-O2 outbreak strains. Although the non-outbreak strain PNUSAE011462 was more similar to the ST-66-O2 outbreak strains with 0–3 SNP differences, it was recovered one year after the ST-66-O2 outbreak strains were detected and a year prior to the ST-66-O3 outbreak strains. The two most distantly related non-outbreak strains, PNUSAE000698 and PNUSAE020868, had similar PFGE patterns but failed to cluster with the known outbreak strains. Together, these findings indicate that the two O157 outbreaks were caused by the same strain. Since a year had passed between the two outbreaks, they were likely misclassified as distinct outbreaks; a continuous source was not investigated. In addition, two strains with missing and slightly distinct PFGE patterns were misclassified as non-outbreak strains. Hence, the use of WGS would have increased discriminatory power by identifying additional cases and linking all cases from both outbreak investigations together.Given the high degree of relatedness between the nine ST-66 O157:H7 strains from outbreaks 2 (ST-66-O2) and 3 (ST-66-O3) and four non-outbreak strains in the cgSNP analysis , a hqSNPn = 15) and O177:H25 (n = 2) and represented four STs; ST-175 predominated among the O5:H9 strains, though one was classified as ST-1210. Importantly, a cgSNP analysis demonstrated that all strains in subclade G were highly related despite having different serotypes and STs. In the cgSNP phylogeny, the six ST-175 O5:H9 outbreak-associated strains were grouped together with a set of nine non-outbreak strains in the phylogeny, whereas two strains were more distantly related  . Since tThe introduction of WGS into public health laboratories across the United States has improved surveillance efforts and enhanced our ability to detect enteric pathogens that may be epidemiologically linked or from a specific food source. Although the use of PFGE as the gold standard for surveillance promoted standardization across laboratories and enhanced national surveillance efforts ,40, it lSince WGS is still relatively new to public health laboratories, the reported molecular traits and serogroup distributions may not be representative of the true frequencies within a state or region. The prioritization and identification of certain serogroups may differ from the original implementation dates to the present. The recent sequencing trends for non-O157 and O157 STEC differ from what has been reported by the CDC through FoodNet, with a decrease in STEC O157 nationally but an increase in Michigan ,49. ThisSalmonella serovar Tennessee outbreak in peanut butter [Through this retrospective analysis of 509 STEC genomes from Michigan patients, we were able to compare how known outbreak strains were classified by WGS relative to MLST and PFGE. Notably, the WGS analyses identified some strains that should have been included in prior outbreak investigations but were misclassified by PFGE, as well as some genetically unrelated strains with similar PFGE banding patterns. The application of hqSNP analysis on a subset of isolates also promoted the identification of clusters with higher discriminatory power. For these analyses, we sought to create cutoffs based on SNP differences to detect clusters of related isolates and exclude isolates with slightly more SNP differences. These efforts led to the identification of putative outbreak strains with missing epidemiological links. For example, the analysis of O157 strains from the ST-66-O1 outbreak identified one highly similar strain that was isolated one year prior . Similart butter . ComparaAs was shown in our prior study , MLST grBecause MLST loci are easy to extract from genomes and the subsequent analyses are feasible for use in a public health setting, MLST represents an efficient way to initially identify clusters of related strains that can be interrogated further. The identification of clustered isolates with few SNP differences may initially suggest that the strains are related; however, an epidemiological investigation and additional analyses are still required to confirm the link between the strains and identify potential outbreak sources. The inclusion of other data, such as the type of antibiotic resistance genes and virulence genes, can also be informative during an investigation, particularly for strains with supporting epidemiological data. In this analysis, most of the outbreak-associated strains had identical virulence gene alleles. The same is true for the placement of strains with strong epidemiological linkages within a MLST tree versus a cgSNP-based phylogeny. To this point, we observed no discrepancies in the phylogenetic relationships among STEC recovered from a small number of cattle living on the same farm over an eight-week period . Since tXbaI restriction sites or drastically change the size of the fragments. Insertions and deletions of a few nucleotides are too minute to be accurately detected by gel electrophoresis [Linking WGS data to existing PFGE data is also helpful to identify discrepancies; such comparative studies are important for refining the WGS analytical methods to be used in outbreak investigations in the future. Strains with similar PFGE patterns that group together in different parts of the cgSNP and hqSNP phylogenies can occur because of mutations in the genome that do not affect the phoresis . At the phoresis . Hence, Collectively, our data further highlight the need for a transition to WGS to enhance outbreak surveillance activities and more accurately identify isolates that should be pursued in epidemiological investigations. Implementing WGS in public health laboratories will allow for more rapid characterization of foodborne pathogens and facilitate the extraction of genes encoding virulence factors, such as toxins and the O-antigen, as well as antibiotic resistance genes, to develop a preliminary assessment of virulence and susceptibilities. At the same time, the genetic relatedness of strains can be deduced to identify subsets of isolates for source tracking and downstream epidemiological investigations. Continued surveillance of STEC genomes in Michigan and elsewhere is needed as it will enhance our ability to rapidly monitor strain types in circulation and identify emergent types linked to clinical illness and more severe infections.


Patients with chronic kidney disease (CKD) are at increased risk for developing gout and having refractory disease. Gout flare prevention relies heavily on urate-lowering therapies such as allopurinol and febuxostat, but clinical decision making in patients with moderate-to-severe CKD is complicated by significant comorbidity and the scarcity of real-world cost-effectiveness studies.To compare total and disease-specific health care expenditures by line of therapy in allopurinol and febuxostat initiators after diagnosis with gout and moderate-to-severe CKD.A retrospective observational cohort study was conducted to compare mean monthly health care cost (in 2012 U.S. dollars) among gout patients with CKD (stage 3 or 4) who initiated allopurinol or febuxostat. The primary outcome was total mean monthly health care expenditures, and the secondary outcome was disease-specific  expenditures. Gout patients (ICD-9-CM 274.xx) aged ≥ 18 years with concurrent CKD (stage 3 or 4) were selected from the MarketScan databases (January 2009-June 2012) upon allopurinol or febuxostat initiation. Patients were followed until disenrollment, discontinuation of the qualifying study agent, or use of the alternate study agent. Patients initiating allopurinol were subsequently propensity score-matched (1:1) to patients initiating febuxostat. Five generalized linear models (GLMs) were developed, each controlling for propensity score, to identify the incremental costs  associated with febuxostat initiation in first-line  and second-line  settings.P = 0.809). GLM results suggest that first-line febuxostat users incurred significantly (P = 0.009) lower cost than allopurinol users , whereas second-line febuxostat initiators incurred significantly (P = 0.001) higher cost . Febuxostat initiators in both settings had significantly (P < 0.001) higher gout-specific cost, due to higher febuxostat acquisition cost. Increased gout-specific cost in the first-line febuxostat cohort was offset by significantly (P < 0.001) lower CVD ($288 vs. $459) and renal-related cost ($86 vs. $216). There were no significant differences in either renal or CVD costs (adjusted) between allopurinol initiators treated almost exclusively in the first-line setting and second-line febuxostat patients.Propensity score matching yielded 2 cohorts, each with 1,486 patients . Post-match, 74.6% of patients had stage 3 CKD; 82.9% had CVD; and 42.1% had diabetes. The post-match sample was well balanced on numerous comorbidities and medication exposures with the following exception: 50.0% of febuxo-stat initiators were treated in the second-line setting; that is, they had baseline exposure to allopurinol, whereas only 4.2% of allopurinol initiators had baseline exposure to febuxostat. Unadjusted mean monthly cost was $1,490 allopurinol and $1,525 febuxostat (Gout patients with concurrent CKD, initiating treatment with febuxostat in a first-line setting, incurred significantly less total cost than patients initiating allopurinol during the first exposure to each agent. Conversely, patients treated with second-line febuxostat following allopu-rinol incurred significantly higher total cost than patients initiating allopurinol. There was no significant difference in total cost between the agents across line of therapy. Although study findings suggest the potential for CVD and renal-related savings to offset febuxostat’s higher acquisition cost in gout patients with moderate-to-severe CKD, this is the first such retrospective evaluation. Future research is warranted to both demonstrate the durability of study findings and to better elucidate the mechanism by which associated cost offsets occur. What is already known about this subjectUrate-lowering therapies (ULTs) such as allopurinol and febuxo-stat are the mainstay of treatment for gout flare prevention, and clinical trial results suggest that febuxostat is as effective as allo-purinol in lowering serum uric acid levels.For patients with moderate-to-severe chronic kidney disease (CKD), management of gout is complicated by significant comorbidity and potential hypersensitivity reactions to allopurinol, resulting in suboptimal dosing of allopurinol for some CKD patients.Previous economic comparisons of allopurinol and febuxostat have compared overall patient populations in real-world settings, but no study has done so in a renally impaired population.What this study addsThis study is the first to employ real-world data to compare economic outcomes among gout patients with preexisting stage 3 or 4 CKD initiating allopurinol or febuxostat.This analysis, which employed propensity score matching to analyze a large administrative database, demonstrated that in the first-line setting, gout patients with concurrent CKD treated with febuxostat incurred significantly less total cost than patients treated with allopurinol, despite the higher drug acquisition cost of febuxostat.These findings suggest that quantifying the cost burden associated with ULT may be more complex than a simple comparison of drug acquisition cost alone.1 Gout prevalence is rising, in part due to an ever-increasing prevalence of comorbidities that promote hyperuricemia  and in part due to the extensive use of thiazide and loop diuretics for cardiovascular disease (CVD).4Gout, a metabolic disorder that causes acute, intermittent, and painful flares of arthritis in the joints of the foot, knee, hand, and wrist, occurs in some patients when there is a sudden onset of inflammation as a result of excess serum uric acid (sUA) in the blood (hyperuricemia) with deposition of crystals in tissue. It affects more than 3% of the U.S. adult population.5 Data from the Rochester Epidemiology Project suggest that the incidence of gout without diuretic exposure doubled in the United States between the 1970s and the 1990s.1 Studies have also described increased incidence of gout among populations with chronic renal failure1 and increased prevalence with successive stages of CKD.6 Among those with self-reported gout, 71% reported having CKD stage ≥ 2.7 CKD has also been shown to be an independent risk factor for more refractory gout.8The disease is more common in older adults, with an incidence of 8% in individuals aged 70-79 years compared with only 1.7% in those aged less than 50 years.16 with the annual direct burden of illness for new cases of acute gout among men in the United States estimated to be $27.4 million.10 Gout has also been shown to have a substantial impact on a patient’s health-related quality of life (HRQOL).19 Gout symptoms can cause significant discomfort, disruption, and disability with the patient’s HRQOL in the areas of sexual function, sleep, social life, emotional health, hobbies, and footwear.20 Both the physical and mental health consequences worsen as the frequency and severity of flares increase.21Numerous studies have demonstrated the substantial economic burden associated with gout,22 and a primary goal of treatment is to achieve a sUA level target of < 6 mg/dl.2 However, management of gout in renally impaired patients is multifaceted, as clinical decision making is complicated by significant additional comorbidity. Hypersensitivity reactions to allopurinol are more likely to occur in patients with renal impairment, for whom a reduced dose of allopurinol is recommended, although there is no precise dosing consensus.23 The failure of patients to reach target sUA and thus reduce gout flare risk has been associated with the appropriateness of allopurinol dosing, a low frequency of sUA measurements, and poor allopurinol compliance.24Gout flare prevention relies heavily on urate-lowering therapies (ULTs) such as allopurinol and febuxostat,27 However, some researchers have suggested that, given its comparatively high acquisition cost, use of this medication should be limited to patients with renal impairment, those intolerant to allopurinol, and those who do not achieve sUA targets on the maximum recommended dosage of allopurinol.29 However, few studies have compared the cost burden associated with specific gout therapies in real-world settings, and no study, to our knowledge, has done so in a renally impaired population.Clinical trial results suggest that febuxostat 80 mg per day is more effective than allopurinol 300 mg per day in lowering sUA levels.36The primary objective of this study was to estimate total and disease-specific cost among gout patients with preexisting stage 3 or 4 CKD who initiated allopurinol or febuxostat. The study hypothesis was that the higher acquisition cost of febuxostat would be offset by decreases in renal and CVD-specific costs due either to febuxostat’s greater clinical effectiveness in lowering uric acid levels or to the underdosing of allopurinol in renally impaired patients. This hypothesis presumes a causal relationship between hyperuricemia and CVD outcomes, for which there is a growing body of evidence.International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]) for gout (274.xx) on a nondiagnostic claim either before or within 30 days of initiating either agent. In addition, patients were required to have a diagnosis of stage 3 or 4 CKD (ICD-9-CM 585.3 or 585.4) on at least 1 nondiagnostic claim either before or within 30 days of ULT initiation. Furthermore, patients were required to have at least 12 months of continuous eligibility before ULT initiation, at least 31 days after initiation, and complete data availability for the duration of their study eligibility. Patients with end-stage renal disease or evidence of transplant, dialysis, non-skin-based malignancy, or HIV/AIDS in the 12 months preceding the index date; that is, baseline, were excluded from the study. Patients were allowed to contribute only the initial episode of treatment with each agent to the study. Patients were followed, within each episode, until disenroll-ment from MarketScan, discontinuation of the qualifying ULT (defined as a gap in therapy greater than 30 days), or use of the alternate study agent. The databases complied with all aspects of the Health Insurance Portability and Accountability Act of 1996, and the study data were de-identified and therefore exempt from institutional review board approval.The data source for this research was the MarketScan Commercial Claims and Medicare Supplemental/Coordination of Benefits databases. Patients were included in the analysis if they were aged ≥ 18 years and had at least 31 days of continuous therapy  with either allopurinol or febuxostat between January 1, 2009, and June 30, 2012. Patients were also required to have a diagnosis ; cardiovascular conditions and other comorbidities ; baseline medication exposure ; and CKD stage nearest index as a measure of renal disease severity. Measures of gout severity in the model included baseline evidence of tophi, number of baseline gout flares, using an algorithm published by Kim et al. (2013) to define gout flares,41 and medications used to treat gout flares . As a measure of resource intensivity, the model included baseline cost per patient per month. Post-match balance across study covari-ates was considered acceptable if the standardized difference between the 2 cohorts was < 10%,42 and traditional tests of significance  were > 0.05.Propensity score matchingThe primary study outcome was direct medical expenditure  as measured during each treatment episode. Secondary study outcomes included disease-specific cost per month. Gout-specific expenditure was defined as claims with a diagnosis of gout or any of the following gout-specific medications or services: allopurinol, colchicine, febuxostat, probenecid, glucocorticoids, prescription NSAIDs, sulfinpyrazone, intra-articular aspiration and/or injection, microscopic examination of specimen from musculoskeletal system/joint fluid, or uric acid measurement. Non-gout-specific expenditure was categorized into 4 mutually exclusive disease groups: renal, diabetes, cardiovascular, and other non-gout. The 4 non-gout disease groups were defined using a combination of ICD-9-CM diagnosis codes, specific medications, and/or medication classes . The “other non-gout” group was defined as the presence of any code that was not included in the definition of gout, renal, diabetes, or cardiovascular. The cost applied to each disease category was assigned proportionally based on the total number of diagnoses on the claim and the number of diagnoses associated with each disease group. A sensitivity analysis was conducted, which assigned cost solely based on the primary diagnosis.Multivariate analyses were employed because the propensity model could not adjust for the line of ULT treatment for the 2 cohorts. Five generalized linear models (GLMs) were developed, controlling for propensity score, to identify the incremental costs  associated with initiating febuxostat  in first- and second-line settings. Total, diabetes, cardiovascular, and renal-related costs were modeled with gamma distributions and log link; gout-specific cost was modeled with a gaussian distribution and identity link. Distributional assumptions were determined by the Park test. Goodness-of-fit was assessed using scaled deviance and scaled Pearson metrics. Two part models were employed if the proportion of patients with nonzero cost exceeded 5%.Among the 980,268 adults with a gout diagnosis in the MarketScan databases between January 1, 2009, and June 30, 2012, 37%  had a prescription for allopurinol or febuxostat. After applying the remaining study criteria, a total of 5,147 episodes in 4,941 patients were entered into the propensity model. The most common reasons for exclusion were no history of stage 3 or 4 CKD before allopurinol/febuxostat initiation, failure to meet continuous enrollment criteria, and prior use of allopurinol or febuxostat .There were notable differences in the pre-match sample at baseline. Febuxostat patients were younger and more likely to be male, to reside in the southern United States, to have commercial insurance, and to have a history of chronic liver disease and prior exposure to ARBs, antibiotics, or opiate analgesics/agonists. Moreover, febuxostat patients were more likely to have tophi documented on a medical claim, to have had more frequent gout flares, and to have had prior exposure to allopurinol; that is, to have been treated with febuxostat in a second-line setting. Accordingly, febuxostat patients were also more likely to have received colchicine, glucocorticoids, or probenecid before initiation.After propensity matching, the final post-match sample contained 1,486 episodes in each cohort. A total of 206 patients had an episode in both cohorts (6.9%). The post-match sample was well balanced on all covariates except prior exposure to the alternate agent . Fifty pP = 0.005) but were less likely to receive glucocorticoids (P = 0.025) than patients in the febuxostat cohort. During the follow-up period, 5.2% of allopurinol patients and 5.0% of febuxostat patients progressed to end-stage renal disease.Mean (SD) dose per day of allopurinol during follow-up was 183.4 (94.1) mg, with 25% of patients receiving a dosage of at least 260 mg. Mean (SD) dose per day of febuxostat during follow-up was 50.1 (17.8) mg, with 25% of patients receiving a dosage of at least 62 mg. Patients in the allopurinol cohort were significantly more likely to receive colchicine during follow-up , and they had fewer hospitalizations (P = 0.017). However, when hospitalized, febuxostat patients had significantly longer lengths of stay (P = 0.001). Unadjusted inpatient cost per month was lower (P = 0.465) in the febuxostat cohort ($397 vs. $489), but these gains were offset by significantly higher outpatient pharmacy cost in the febuxostat cohort (P < 0.0 01).Overall, febuxostat patients were significantly less likely to have had an emergency room visit (P < 0.001). Eighty percent of gout-specific cost in the febuxostat cohort was driven by gout-specific outpatient pharmacy cost , namely the cost of the comparator agents (Mean (SD) expenditure per month for gout-specific services was $243 ($265) and $87 ($389) in the febuxostat and allopu-rinol cohorts, respectively (r agents .P = 0.389). P = 0.065) fewer renal hospitalizations per month and significantly fewer repeat hospitalizations (P = 0.036), but significantly longer lengths of stay (P = 0.001). Febuxostat patients were also significantly (P = 0.002) less likely to have had renal-related emergency room visits and had significantly (P = 0.048) lower renal outpatient cost. Similarly, patients in the febuxostat cohort had significantly fewer cardiovascular hospitalizations per month (P = 0.022) and repeat hospitaliza-tions (P = 0.017), but longer lengths of stay (P < 0.001). The cost of cardiovascular-related office visits (P = 0.003) as well as over-all outpatient cardiovascular cost (P = 0.038) was significantly lower, unadjusted, in the febuxostat cohort.Mean (SD) expenditure per month for all non-gout-specific services, unadjusted, was $1,282  in the febuxostat cohort and $1,403  in the allopurinol cohort (P = 0.001) more total cost per patient per month than allopurinol users  treated primarily in the first-line setting. Conversely, febuxostat users treated in the first-line setting (n = 743) incurred significantly (P = 0.009) less total cost than allopurinol users treated almost exclusively (95.8%) in the same setting.Multivariate analysis was required because the post-match cohorts were not balanced in terms of line of ULT. GLM results  suggest P < 0.001) higher gout-specific cost, due almost entirely to higher febuxostat acquisition cost. Increased gout-specific expenditure in the first-line febuxostat cohort was offset by significantly lower cardiovascular and renal-related costs (P < 0.001) and marginally lower diabetes-related cost (P = 0.060). There were no significant differences in renal, cardiovascular, or diabetes-related costs between the allopurinol cohort and febuxostat patients treated in the second-line setting. Sensitivity analyses employing alternate distributional assumptions  in those models with ambiguous Park test coefficients were very similar to those produced in the gamma, log link models. Scaled deviance ranged from 1.0 to 1.3. Sensitivity analysis, which allocated cost based only on the primary diagnosis, shifted cost from disease-specific categories to “other” but did not otherwise alter study findings.Multivariate models also found that febuxostat users in both settings had significantly (P < 0.001), renal (P < 0.001), and diabetes-related (P = 0.060) costs. In addition, patients treated with second-line febuxostat following allo-purinol incurred significantly higher total cost than first-line allopurinol users (P = 0.001). This difference may be due to the presence of more aggressive disease from delayed effective ULT, given that these patients had previously failed treatment with allopurinol. Patients with concurrent gout and CKD represent a clinically complex and resource-intensive population requiring management of both gout- and non-gout-related conditions. Accordingly, the cost impact of the decision to treat with allopurinol or febuxostat is likely more complex than a comparison of ULT drug acquisition cost alone.To our knowledge, the current study is the first to compare economic outcomes among renally compromised gout patients in the year following initiation on the 2 most common ULTs, allopurinol and febuxostat. This study demonstrated that in the first-line setting, gout patients with concurrent CKD treated with febuxostat incurred significantly less total cost than patients treated with allopurinol, despite the higher drug acquisition cost of febuxostat. Higher gout-specific expenditure was offset by lower cardiovascular  reported total annual cost among gout patients ≥ 65 years at $14,734  and gout-specific cost at $876 ($73 per month).14 In a separate study, Wu et al. (2012) reported total cost among patients with 6 or more flares per year at $25,778  and gout-specific cost at $12,620 per year .15Total, all-cause, and gout-specific cost in patients with gout has been reported in several studies. In the current study, total cost per month  and gout-specific cost ($165) per month were slightly higher than results from studies conducted in a broad cross-section of patients,41 This study found that febuxostat initiators were highly comorbid, had twice the rate of CKD, and had greater use of medications and health care resources than those initiating allopurinol or colchicine. Febuxostat initiators also had the highest incidence of acute gout flares, which the authors acknowledge may be due to the tendency to treat more severe gout with febuxostat.Kim et al. described clinical characteristics and health care utilizations of gout patients in a large U.S. population-based cohort initiating allopurinol, febuxostat, or colchi-cine.28 concluded that second-line treatment with febuxostat 80 mg/120 mg is cost-effective following allopurinol 300 mg, even when accounting for mild-to-moderate renal impairment and titration of allopurinol. The Beard study differed from the current study with respect to the cost outcome , study design , and study population . Despite these differences, the current study came to the same conclusion as Beard et al.; first-line treatment with allopurinol results in lower gout-related costs. However, the Beard study did not examine cost impact beyond gout-related costs, whereas the current study demonstrated that the higher gout-related costs with first-line febuxostat were offset by significantly lower cardiovascular and renal-related costs in a real-world setting.In the United Kingdom, a cost-effectiveness study by Beard et al. (2014)44 recently published a Markov model of clinical trial data, comparing direct health care costs for febux-ostat and allopurinol from a U.S. payer’s perspective. Over a 5-year period, the expected treatment success for febuxostat was 72%, with an expected success rate of 42% for allopu-rinol. The authors found an incremental cost-effectiveness ratio of $6,322 (in 2014 U.S. dollars) per treatment success for febuxostat, leading the authors to conclude that febuxostat was cost-effective from a U.S. payer’s perspective. The Gandhi study differed from the present study with respect to study design  and study population . Jutkowitz et al. (2014) also used Markov modeling to assess the lifetime cost impact of 5 urate-lowering treatment strategies in a cross-section of gout patients.45 The authors concluded that allopurinol as a single therapy option is cost saving compared with no treatment, and that dose escalation of allopurinol-febuxostat sequential therapy is also cost-effective. Like the Gandhi study, this study used the literature to construct a theoretical model in a broad cross-section of patients. Neither of these models focused on the subset of patients with moderate-to-severe CKD.Gandhi et al. (2015)46 there remains a lack of consensus on the optimal management of gout patients with renal disease. In 2012, the American College of Rheumatology (ACR) released guidelines that included recommendations that CKD patients (stage 2-4) be considered candidates for ULT, with either allopurinol or febuxostat as the first-line agent.2 Although the ACR guidelines specify that allopurinol hypersensitivity syndrome can be minimized by dose titration in patients with renal impairment,2 these guidelines do not contain specific recommendations on use of ULTs in renally impaired patients.46 In contrast, other guidelines recommend only allopurinol as the first-line ULT, citing economic models in the United Kingdom that show the cost-effectiveness of febuxostat in the general population only in second-line set-tings.46 Choice of first-line ULT may also be influenced by the potential risk of cardiovascular events with use of febuxostat. According to guidance from the National Institute for Health and Care Excellence (NICE),47 febuxostat is not recommended for people with ischemic heart disease or congestive heart failure. The U.S. Food and Drug Administration (FDA) label48 includes a warning to monitor for signs of myocardial infarction and stroke.The results of the current study have important implications for the management of gout in a renally challenged population. Despite considerable evidence that gout is a disease with suboptimal management and low adherence to treatment,50 Systematic reviews have demonstrated significant relationships between gout or elevated sUA and incident coronary artery disease, CVD-related mortality,54 stroke incidence, and mortality.55 In addition, studies have suggested sUA as a strong independent prognostic factor in patients with heart failure57 and determined that a high-normal sUA level is associated with worse ejection fraction in heart failure patients, impaired stroke volume and cardiac output, cognitive function, and arterial stiffness in overall healthy adult-elderly subjects.58 Another recent meta-analysis demonstrated a linear association between sUA level and mortality: elevated sUA increased the risk of all-cause mortality  and cardiovascular mortality .59 In studies of urate-lowering medications, control of sUA was associated with a reduction in cardiovascular risk, but it is not known if this is due to direct effects of lowered sUA or to other benefits from these medications such as reduced oxidative stress and other pleio-tropic effects on the endothelium.39A growing number of clinicians have concluded that hyperuricemia is an independent cardiovascular risk fac-tor.60 In the current study, it is not clear why cardiovascular and renal-related costs were lower with febuxostat. Although we presume cost reductions reflect the favorable impact of lower sUA on cardiovascular events, unmeasured confounding may exist. Further studies are warranted to examine the relationship between cardiovascular events and use of febuxostat.This possibility underlines the importance of appropriate gout management, especially in patients with comorbid conditions. Although the present study did not analyze the impact of gout treatment on comorbid conditions clinically, the findings did show a beneficial impact of first-line febuxostat on the cost of cardiovascular and renal comorbid conditions. Although this finding seems to contradict the small numerically higher rate of cardiovascular thromboembolic events observed in patients treated with febuxostat in clinical trials (as noted in the FDA and NICE product guidance), it is important to note that this increased rate was not statistically significant and there is no evidence to date of a causal relationship between febuxostat and cardiovascular events.Although the current study was based on a sufficient sample of patients with gout and CKD, it is not a random sample and the sources of the data are worth reviewing. The MarketScan databases represent patients with either commercial or Medicare supplemental insurance. As such, study findings may not be generalizable to other populations such as the uninsured or patients with other coverage, such as Medicaid.These data are collected to facilitate reimbursement and as such do not contain all relevant socioeconomic and clinical data. Medical records were not available to supplement or validate CKD stage, comorbidity may have been underreported, measures of alcohol and tobacco use were absent, and sUA results were unavailable. Medication exposure may have been under- or overstated because prescription medications were presumed to be taken based on their pharmacy fill dates with coverage windows based on days supply. Moreover, sample size limitations prevented propensity matching the first-line and second-line treatment groups separately, primarily because of the limited use of allopurinol in a second-line setting. Postmatch multivariate modeling was used to address the residual imbalance.Finally, it is also conceivable that clinicians are cautious in using febuxostat in patients with existing CVD and therefore self-select patients with comparatively mild or stable disease. Similarly, it is conceivable that clinicians are also cautious in using allopurinol in patients with renal disease so that they self-select patients they perceive as having more stable disease. Although the current study used multiple methods to address such selection bias, some degree of unmeasured confounding may remain.Gout patients with concurrent CKD who initiated treatment with febuxostat in a first-line setting incurred significantly less total cost than patients initiating allopurinol during the first exposure to each agent. Conversely, patients treated with second-line febuxostat following allopurinol incurred significantly higher total cost than patients initiating allopurinol. There was no significant difference in total cost between the agents across line of therapy.Although study findings suggest the potential for cardiovascular- and renal-related savings to offset febuxostat’s higher acquisition in gout patients with moderate-to-severe CKD, this is the first such retrospective evaluation. Future research is warranted to both demonstrate the durability of study findings and to better elucidate the mechanism by which associated cost offsets occur.


Somatic symptom disorder (SSD) presents challenges to the healthcare system, including frequent medical visits, lack of symptom relief experienced by individuals with this condition, high associated medical costs, and patient dissatisfaction. This study examined the utility of a novel, low-barrier, brief cognitive behavioural therapy (CBT) group intervention for individuals with SSD.n = 30), each consisting of six weekly two-hour sessions, were facilitated at a large outpatient mental healthcare facility in Ontario, Canada. The final sample consisted of 13 individuals of whom 11 completed the treatment. Clinical outcome measures were administered pre-, mid- and post-group, including the Generalized Anxiety Disorder–7, Perceived Stress Scale–4, Pain Self-Efficacy Questionnaire, Pain Disability Index, Revised Illness Perception Questionnaire, and sections of the Patient Health Questionnaire. Six healthcare utilization metrics were collected from electronic medical records at six months pre- and post-group. Paired samples t-tests were used to examine pre- to post-group differences in participants’ somatic symptoms, psychological functioning, health, and degree of healthcare utilization.Participants were referred by their mental health providers or self-referral. Each participant underwent a telephone screen and in-person psychological and neuropsychological screen. Two cycles of the CBT-based group (d = 0.30). Further, we observed downward trends across participants’ pre- to post-group healthcare utilization, with small effect sizes observed for hospital admission (d = 0.36), days admitted to hospital (d = 0.47), and inpatient consults (d = 0.42). Differences between pre- and post-group measures of somatic symptom severity, psychological functioning, health, or healthcare utilization did not reach significance.When comparing pre- and post- group, we observed reductions in the mean scores for somatic symptom severity, depressive symptomatology, anxiety, perceived stress, and perceived disability related to pain. The change in depressive symptomatology yielded a small effect size (Current findings provide support for the potential effectiveness of an abbreviated CBT group for individuals with SSD in reducing psychiatric symptomatology. Further research is recommended, including randomized control trials, cost-benefit analyses, and comparisons between abbreviated versus longer-duration treatment programs for SSD.Not applicable. Somatic symptom disorder (SSD) is characterized by prominent physical symptoms that are associated with marked distress and impairment, including excessive thoughts, feelings, and behaviours relating to the physical disturbances . It is wSSD is a serious and debilitating disorder with wide-ranging adverse biopsychosocial underpinnings and implications. High levels of healthcare utilization are characteristic of this patient population and the frequency of these behaviours in SSD has been associated with adverse outcomes. Specifically, high healthcare utilization in SSD often leaves individuals vulnerable to incurring insurmountable healthcare expenses, as well as time spent seeking treatment alternatives that far exceed national averages in the United States . In factDespite the high prevalence rate of SSD and the robust correlation with adverse functional outcomes , the literature on interventions for the treatment and management of SSD remains underdeveloped. Consequently, adequate treatment for SSD continues to prove as a challenge for healthcare practitioners. While considerable strides have been made in attempting to develop evidence-based treatment approaches, recommendations, and protocols for the successful management of SSD, many of the interventions have significant limitations . AlthougRegarding psychotherapeutic intervention for the treatment of SSD, the bulk of research efforts have centered on exploring the utility of CBT and third wave CBT  interventions. Although there is emerging evidence to support the use of mindfulness therapy in SSD , this reThe current pilot study aimed to examine the utility of a brief six-session CBT group intervention focused on ameliorating somatic and comorbid psychiatric symptoms, and reducing healthcare utilization for individuals living with SSD in Ontario, Canada.The current pilot study was an uncontrolled analysis of a CBT-based group treatment for SSD designed to examine symptom reduction in response to treatment and clinical feasibility. Two groups were facilitated between May and December of 2019. The study was conducted at a large outpatient mental healthcare facility in Ontario, Canada, and was approved by the institution’s human research ethics committee.T score of 70, indicating that they did not endorse clinically significant symptoms of SSD at the outset of the group. The final sample consisted of 13 individuals  ranging from 32 to 69 years old , of whom 11 were treatment-completers  and 92% (n = 12) had been previously diagnosed with SSD  across two cycles of the intervention group. Eighteen of these individuals consented to the research study and were eligible to participate in the group, six people declined, four were ineligible for the group because they were not followed by a clinician at the mental healthcare facility (a requirement for group participation), and two were unable to be contacted after they were referred. Of the 18 people who participated in the group, 12 completed at least four out of six sessions and were considered treatment completers (33.3% drop out rate). Five participants were not included in data analysis as their scores on the somatic symptom scale of the Personality Assessment Inventory (PAI) were lower than a Of the 11 treatment-completers, the average age was 43.55 (ranged from 33 to 69). Eight were women , mid-group (session 3/4), and post-group (session 6) with the exception of the PAI, which was administered during the in-person screening appointment at baseline only.Personality Assessment Inventory (PAI). The PAI [ The PAI  is a wid The PAI , 43. ThePatient Health Questionnaire 9 (PHQ-9). Depressive symptoms were measured with the PHQ-9 , which is the 9-item depressive symptom module of the Patient Health Questionnaire (PHQ) [re (PHQ) . It is are (PHQ) .Generalized Anxiety Disorder 7 (GAD-7). Anxiety-related symptoms were measured using the GAD-7 [he GAD-7 , a 7-itehe GAD-7 .Patient Health Questionnaire 15 (PHQ-15). Somatization was measured with the 15-item somatic symptom module of the PHQ [ the PHQ , which a the PHQ , 48.Perceived Stress Scale 4 (PSS-4). Stress levels were measured with the 4-item PSS-4 [em PSS-4 , which mem PSS-4 , its brePain Self-Efficacy Questionnaire (PSEQ). The 10-item PSEQ [tem PSEQ  was usedtem PSEQ .Pain Disability Index (PDI). The 7-item PDI [item PDI  was useditem PDI .Revised Illness Perception Questionnaire (IPQ-R). The IPQ-R [he IPQ-R  is a 56-he IPQ-R .Healthcare utilization was assessed by deriving data from the electronic medical records of healthcare contacts during the six months prior to and following participation in the group. Information accessed included six different types of utilization, including: (i) total number of outpatient appointments (in-person or via videoconferencing), (ii) outpatient telephone encounters, (iii) emergency department presentations, (iv) hospital admissions, (v) days admitted to hospital, and (vi) inpatient consultations. Healthcare utilization information was collected from local and regional electronic medical records.The group intervention administered in this study was designed for individuals with SSD based on CBT principles, and by extrapolating components from the most promising findings in the non-pharmacological treatment-related findings in the SSD literature. The novel group intervention drew on CBT principles from a well-established body of literature and applied theoretical tenets in order to meet the clinical needs of this unique patient population in a real-world setting , 57. BasThis pilot study was conducted in a real-world clinical setting to meet the needs of referred psychiatric patients to a large outpatient mental health facility. Group facilitators included two fellows and an advanced graduate student in clinical and neuropsychology, all of whom were experienced in providing CBT. The fellows performed the initial screening evaluations and clinical interviews. The fellows and graduate student were supervised by a licensed Ph.D. level clinical psychologist and board-certified neuropsychologist.T ≥ 70; (n = 13), the number of comorbid psychiatric conditions experienced ranged from 0 to 4, with 62% of participants reporting at least one comorbidity (n = 8) and approximately 46% reporting two or more psychiatric comorbidities. The most prevalent comorbidities observed in the somatic sample were major depressive disorder/persistent depressive disorder  and generalized anxiety disorder . Baseline somatic symptom severity (PHQ-15) demonstrated significant moderate to strong positive correlations with pre-group levels of depression , anxiety , perceived disability related to pain , and perceived stress  , in which values ranged from 2 to 18 visits over the preceding 6 months. Although records indicated that approximately 31% of participants visited the ER in the 6 months prior to the group; the prevalence of the remainder of inpatient-related activities  in the sample was observed to be considerably smaller, comprising approximately 15% of participants (n = 2)  and those who opted to discontinue prematurely . Non-completers  reported significantly higher baseline levels of anxiety (GAD-7) than treatment completers , t(11) = -2.25, p = .05. Further, non-completers  reported significantly higher baseline levels of health concerns (PAI) than treatment completers , t(11) = − 2.41, p = .04. No other baseline psychological or health outcome measures demonstrated a significant difference between the two cohorts; however, notable trends included higher levels of conversion (PAI), somatization (PAI), somatic symptom severity (PHQ-15), depression (PHQ-9), and perceived stress (PSS-4) in non-completers. Treatment completers reported higher perceived disability related to pain (PDI), personal control (IPQ-R), and treatment control (IPQ-R) . The findings also demonstrated trends towards higher levels of personal control (IPQ-R) post-group. Some evidence for improvements in pain management self-efficacy were also observed; however, data on this measure was only available for a subset of participants (n = 8).Paired samples t-tests did not reveal significant differences pre- to post-group in participants’ experiences of somatic symptom severity and/or other associated psychiatric symptoms Table . Of noted = 0.36), days admitted to hospital (d = 0.47), and inpatient consults (d = 0.42). There was a total of three hospital admissions for two participants in the 6-month before the group, and one participant was admitted to hospital once in the 6-month following the group. The total number of days admitted to hospital across all participants was 53 days pre-group and one day post group. Pre-group there were a total of 7 inpatient consultations and post-group there was one.In a series of paired samples t-tests, downward trends were seen in the following mean healthcare utilization outcome metrics: outpatient visits, hospital admissions, days admitted to hospital, inpatient consults, and ER visits for group participants Table . There wFindings from this pilot study demonstrate promising trends, including the reduction of SSD symptoms and related symptomatology  associated with participation in a six-session CBT-based intervention group. The current study indicates that group participation may also have implications for reductions in healthcare utilization among individuals with SSD. Though many results in this study did not reach statistical significance due to the small sample size, we propose that the degree of reduction in symptoms and healthcare utilization behaviours observed in the current study are suggestive of clinically meaningful benefit. Indeed, the trends toward declines in hospitalizations and days admitted to hospital among our pilot group participants suggest that participation in group CBT may help to prevent the degree to which individuals with SSD utilize costly healthcare services. Specifically, there were a total of 3 hospitalizations and 53 days admitted to hospital across participants in the six months prior to the group. In contrast, only one participant was admitted to hospital for only one day post-group. Given that the average hospital admission in Ontario costs nearly $7000 , this inWhile previous research on group CBT for SSD typically included 8 to 13 sessions , 34–37, There is a high rate of treatment drop-out and reduced engagement among those with somatic complaints ; thus, iThis pilot study was conducted in an outpatient clinic in an effort to evaluate the clinical utility of including a CBT group for SSD among the clinical services that are offered. As a result, it is limited by a small sample size and lack of a control group. The sample was heterogeneous and included individuals with a variety of comorbidities, which is representative of the typical SSD population. There were many participant factors that were not controlled, such as medications and participation in other interventions. The group intervention was CBT-focused, with elements of third-wave CBT methods, including acceptance and commitment therapy and dialectical behavior therapy. While third-wave CBT approaches such as mindfulness and social skills training are conceptually relevant to the overarching treatment goals of individuals with SSD , the incGiven the inherent challenges associated with treating this disorder and the resultant limited resources available to treat individuals with SSD, we suggest that group CBT targeted for somatic symptoms should be considered in addition to treatment as usual . This pilot study suggests that CBT groups for SSD in outpatient settings holds promise, and justifies resources being allotted into further developing and extending the intervention program. Nonetheless, group CBT interventions for SSD continue to warrant further investigation to improve our understanding of best and most effective practices. Future research should implement a randomized controlled trial design with more stringent experimental controls and a larger sample size in order to more effectively evaluate the efficacy of the intervention in reducing symptoms and healthcare utilization. Authors would also recommend that future studies use a standard CBT approach for treating SSD, particularly if the intervention is brief and one of the goals is to generalize the results to the research literature. Additional elements could be added in the future, and researchers could examine whether adding elements from other modalities  benefit participant outcomes. Given the wide variability seen in healthcare utilization among those with SSD, future studies could investigate factors that contribute to healthcare utilization in this population and whether it would be prudent to target the intervention to those with higher healthcare utilization rates. Comprehensive information about healthcare usage would allow researchers to have a more fulsome picture of healthcare utilization, as many individuals with SSD access care across several disciplines. It will be important for future studies to compare the efficacy of abbreviated group treatments with their more traditional, longer counterparts and with individual therapy. A cost-benefit analysis would help to evaluate the net impact of a shorter, less expensive intervention that can be delivered to more people, considering the relatively high prevalence of SSD, high cost of healthcare utilization in this population, and current lack of access to treatment. Finally, more research is also needed to compare with other psychotherapeutic approaches for treating SSD as well as transdiagnostic factors contributing to somatization.The current study represents one of the few studies to date measuring both self-reported symptoms and healthcare utilization during a group CBT intervention for SSD. Symptom severity and healthcare usage are each important in SSD, given the complexity of the population. Findings of the study demonstrated a decrease in somatic and affective symptoms over the course of the group and a concomitant trend toward lower healthcare utilization in individuals who completed the treatment groups. Finally, the study revealed insights into the difficult nature of intervention in this population by highlighting that those individuals with lower perceived control and self-efficacy and higher overall symptom presentation were more likely to drop out of treatment. Given the significant burden of SSD on the individual  and society , moving towards a better collective understanding of SSD may hold significant implications toward better intervention approaches for individuals with somatic symptom disorders.