"When I was Younger, My Story Belonged to Everyone Else": Co-production of Resources for Adults Living with Craniosynostosis.

OBJECTIVE: Despite growing recognition that congenital craniofacial conditions have lifelong implications, psychological support for adults is currently lacking. The aim of this project was to produce a series of short films about living with craniosynostosis in adulthood, alongside a psychoeducational booklet. DESIGN: The resources were developed using multiple focus groups and meetings attended by researchers, patient representatives, a leading charitable organisation, an award-winning film production company, clinicians, and other experts in the field. RESULTS: An online mixed-methods survey was developed based on prior work to request feedback on the acceptability and utility of the resources from the craniosynostosis community. While data collection to evaluate the resources is ongoing, preliminary results (n = 36) highlight an acceptability rating of 100%. CONCLUSIONS: The resources developed represent a step forward in addressing the unmet information and support needs of adults with craniosynostosis and highlight the benefits of co-production in research.

What is the relationship between collective memory and metacognition?

In this chapter we investigate whether we might learn more about the development of collective memory by examining its links with metacognition. Metacognition is the term given to the capacity that enables us to reflect on and judge our own cognitive abilities. For example, we have a global metacognitive belief in how good our memory is, as well as being able to evaluate how confident we are in completing a memory task at the local level. We use this capacity not only to judge our own cognitive ability but also to judge the cognitive ability of those with whom we interact. In fact, attention has recently been drawn to the social purpose of metacognition as the self- and other-reflective abilities it provides might be evolutionarily significant (e.g., Heyes et al., 2020). As collective memories are formed in part through social interactions with others and metacognition is likely to be necessary to facilitate these interactions, we examine the evidence for how these two processes relate. We will present evidence from the separate fields in Sections 2 and 3 of this chapter. In Section 4 we attempt to bring these separate fields together. In Section 5, we look at the case of aging, as there are changes both to memory processes and metacognition with advancing age. Finally, we sum up by suggesting priorities for future research.

Multicentre evaluation of two multiplex PCR platforms for the rapid microbiological investigation of nosocomial pneumonia in UK ICUs: the INHALE WP1 study.

BACKGROUND: Culture-based microbiological investigation of hospital-acquired or ventilator-associated pneumonia (HAP or VAP) is insensitive, with aetiological agents often unidentified. This can lead to excess antimicrobial treatment of patients with susceptible pathogens, while those with resistant bacteria are treated inadequately for prolonged periods. Using PCR to seek pathogens and their resistance genes directly from clinical samples may improve therapy and stewardship. METHODS: Surplus routine lower respiratory tract samples were collected from intensive care unit patients about to receive new or changed antibiotics for hospital-onset lower respiratory tract infections at 15 UK hospitals. Testing was performed using the BioFire FilmArray Pneumonia Panel (bioMérieux) and Unyvero Pneumonia Panel (Curetis). Concordance analysis compared machine and routine microbiology results, while Bayesian latent class (BLC) analysis estimated the sensitivity and specificity of each test, incorporating information from both PCR panels and routine microbiology. FINDINGS: In 652 eligible samples; PCR identified pathogens in considerably more samples compared with routine microbiology: 60.4% and 74.2% for Unyvero and FilmArray respectively vs 44.2% by routine microbiology. PCR tests also detected more pathogens per sample than routine microbiology. For common HAP/VAP pathogens, FilmArray had sensitivity of 91.7%-100.0% and specificity of 87.5%-99.5%; Unyvero had sensitivity of 50.0%-100.0%%, and specificity of 89.4%-99.0%. BLC analysis indicated that, compared with PCR, routine microbiology had low sensitivity, ranging from 27.0% to 69.4%. INTERPRETATION: Conventional and BLC analysis demonstrated that both platforms performed similarly and were considerably more sensitive than routine microbiology, detecting potential pathogens in patient samples reported as culture negative. The increased sensitivity of detection realised by PCR offers potential for improved antimicrobial prescribing.

INHALE: the impact of using FilmArray Pneumonia Panel molecular diagnostics for hospital-acquired and ventilator-associated pneumonia on antimicrobial stewardship and patient outcomes in UK Critical Care-study protocol for a multicentre randomised controlled trial.

BACKGROUND: Hospital-acquired and ventilator-associated pneumonias (HAP and VAP) are common in critical care and can be life-threatening. Rapid microbiological diagnostics, linked to an algorithm to translate their results into antibiotic choices, could simultaneously improve patient outcomes and antimicrobial stewardship. METHODS: The INHALE Randomised Controlled Trial is a multi-centre, parallel study exploring the potential of the BioFire FilmArray molecular diagnostic to guide antibiotic treatment of HAP/VAP in intensive care units (ICU); it identifies pathogens and key antibiotic resistance in around 90 min. The comparator is standard care whereby the patient receives empirical antibiotics until microbiological culture results become available, typically after 48-72 h. Adult and paediatric ICU patients are eligible if they are about to receive antibiotics for a suspected lower respiratory infection (including HAP/VAP) for the first time or a change in antibiotic because of a deteriorating clinical condition. Breathing spontaneously or intubated, they must have been hospitalised for 48 h or more. Patients are randomised 1:1 to receive either antibiotics guided by the FilmArray molecular diagnostic and its trial-based prescribing algorithm or standard care, meaning empirical antibiotics based on local policy, adapted subsequently based upon local microbiology culture results. Co-primary outcomes are (i) non-inferiority in clinical cure of pneumonia at 14 days post-randomisation and (ii) superiority in antimicrobial stewardship at 24 h post-randomisation (defined as % of patients on active and proportionate antibiotics). Secondary outcomes include further stewardship reviews; length of ICU stay; co-morbidity indicators, including septic shock, change in sequential organ failure assessment scores, and secondary pneumonias; ventilator-free days; adverse events over 21 days; all-cause mortality; and total antibiotic usage. Both cost-effectiveness of the molecular diagnostic-guided therapy and behavioural aspects determining antibiotic prescribing are being explored. A sample size of 552 will be required to detect clinically significant results with 90% power and 5% significance for the co-primary outcomes. DISCUSSION: This trial will test whether the potential merits of rapid molecular diagnostics for pathogen and resistance detection in HAP/VAP are realised in patient outcomes and/or improved antibiotic stewardship. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16483855 . Retrospectively registered on 15 July 2019.

Role of clinical psychology in UK hospices.

OBJECTIVE: The National Institute of Clinical Excellence (NICE) (2004) guidance recommends a tiered approach to psychological care within cancer care. This includes the provision of Clinical Psychologists to support other professionals to deliver high-quality psychological care at levels 1 and 2 and to provide direct input to patients experiencing high levels of distress at level 4. However, little is known about the role of Clinical Psychology within UK Hospices currently. A survey of Clinical Psychologists working in this area was undertaken to address this gap in knowledge. METHODS: We conducted an anonymous online survey of Clinical Psychologists working in Hospice organisations across the UK. Recruitment was completed via professional networking groups, social media and by contacting UK Hospice organisations. The survey included quantitative and qualitative items about professionals' experience, how their input is organised, their roles and activities and their views on the valuable and challenging aspects of working in this setting. RESULTS: Eighteen Clinical Psychologists responded and there was considerable variance in how their roles were organised. The tasks undertaken by most respondents were direct work with and consultation for hospice patients, and teaching and training staff. However, the findings demonstrated that Clinical Psychologists can undertake a wide range of tasks and draw on a range of therapeutic approaches including Cognitive Behavioural Therapy, Acceptance and Commitment Therapy and Compassion Focused Therapy, in their hospice work. CONCLUSION: Our results provide an overview of the role of Clinical Psychology in UK Hospices and demonstrate the contribution that Psychologists can make to this field.

Reward sensitivity predicts dopaminergic response in spatial neglect.

It has recently been revealed that spatial neglect can be modulated by motivational factors including anticipated monetary reward. A number of dopaminergic agents have been evaluated as treatments for neglect, but the results have been mixed, with no clear anatomical or cognitive predictors of dopaminergic responsiveness. Given that the effects of incentive motivation are mediated by dopaminergic pathways that are variably damaged in stroke, we tested the hypothesis that the modulatory influences of reward and dopaminergic drugs on neglect are themselves related. We employed a single-dose, double-blind, crossover design to compare the effects of Co-careldopa and placebo on a modified visual cancellation task in patients with neglect secondary to right hemisphere stroke. Whilst confirming that reward improved visual search in this group, we showed that dopaminergic stimulation only enhances visual search in the absence of reward. When patients were divided into REWARD-RESPONDERs and REWARD-NON-RESPONDERs, we found an interaction, such that only REWARD-NON-RESPONDERs showed a positive response to reward after receiving Co-careldopa, whereas REWARD-RESPONDERs were not influenced by drug. At a neuroanatomical level, responsiveness to incentive motivation was most associated with intact dorsal striatum. These findings suggest that dopaminergic modulation of neglect follows an 'inverted U' function, is dependent on integrity of the reward system, and can be measured as a behavioural response to anticipated reward.

Self-perspective in episodic memory after parietal damage and in healthy ageing.

Although there is strong support from functional imaging studies for lateral parietal lobe involvement in episodic memory, patients with damage to these regions do not appear to suffer from severe deficits in this cognitive domain. As such there has been no definitive explanation of this area's precise involvement. Here, we hypothesised that parietal regions play a crucial role in episodic memory - specifically in recollecting details from an egocentric perspective. In order to test this hypothesis systematically, we designed a novel experimental task utilising a head-mounted camera to record images from the participant's perspective, enabling us to evaluate the integrity of memory from the individual's own point of view. In the first study we examined patients with parietal damage and in a second study, using fMRI, we examined young and older healthy participants. Right-hemisphere patients with parietal damage were able to recall information accurately when recollecting what items had been present and where these items had been. However, patients were significantly impaired when attempting to judge from which perspective they had viewed the scenes. Critically, the patient group showed no evidence of impairment on standard tests of episodic and working memory. Examination of healthy participants in the second study utilised multi-voxel pattern analysis on neural activity during the recognition phase of a similar task. This revealed sensitivity to be highest around the angular gyrus of the lateral parietal cortex for our critical comparison - that is, when viewing stimuli that were the same as their egocentric view during encoding versus the identical scene but presented from an alternative angle. Our results provide important evidence that parietal cortex is directly involved in egocentric spatial perspective aspects of episodic memory and demonstrate for the first time a specific deficit in episodic memory in patients with right parietal damage.

Do evidence based interventions for chronic fatigue syndrome improve sleep? A systematic review and narrative synthesis.

Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are recommended evidence based treatments for chronic fatigue syndrome (CFS), with research supporting their effectiveness in reducing fatigue and functional impairment. However, little research has focussed on the effect of these treatments on sleep, despite high reported sleep disturbance in CFS. Using a narrative synthesis approach, we aimed to 1) systematically identify and summarise the current evidence for the effectiveness of CBT and GET in improving sleep; 2) consider factors influencing treatment effectiveness, including incorporation of sleep management techniques; and 3) consider the appropriateness of sleep outcome measures used within evaluations. Studies evaluating CBT and/or GET for CFS, and including a sleep outcome were eligible for inclusion. Eight studies were identified. We found that GET interventions can improve sleep but this effect is inconsistent across studies. For CBT the evidence is limited with only one of two evaluations demonstrating sleep-related improvements. We conclude from existing research that we know little about the effects of including sleep management components within CBT and GET interventions. We suggest that future research should explore the effectiveness of sleep components within interventions, and sleep specific interventions, using comprehensive outcome measures that fully capture the range of sleep difficulties experienced in CFS.

The effects of motivational reward on the pathological attentional blink following right hemisphere stroke.

Recent work has shown that attentional deficits following stroke can be modulated by motivational stimulation, particularly anticipated monetary reward. Here we examined the effects of anticipated reward on the pathological attentional blink (AB), an index of temporal selective attention, which is prolonged in patients with right hemisphere damage and a history of left neglect. We specifically compared the effects of reward versus feedback-without-reward on the AB in 17 patients. We found that the patients all manifested impaired performance compared to healthy controls and that reward modulated the pathological blink in the patient group, but only in the second experimental session. When the performance of patients whose neglect had recovered was compared with that of patients who had ongoing or persistent neglect, reward appeared to only influence the AB in the former. These results have implications for our understanding of motivation-attention interactions following right hemisphere stroke, and how they may impact upon recovery from spatial neglect.

Bed-sharing by breastfeeding mothers: who bed-shares and what is the relationship with breastfeeding duration?

AIM: To explore the link between breastfeeding duration and bed-sharing frequency among women reporting a prenatal intention to breastfeed. METHODS: About 870 participants in a randomised breastfeeding trial, recruited at mid-pregnancy, provided weekly snapshots of breastfeeding and bed-sharing behaviour for 26 weeks following birth. Strength of prenatal breastfeeding intent was recorded at recruitment using Likert-type scales. RESULTS: Outcomes were frequency of bed-sharing at home for at least one hour per week, and time to cessation of breastfeeding. There were insufficient data to classify bed-sharing pattern in 192/870 (22%) of mothers. Of the remainder, 44% (299/678) of participants 'rarely' or 'never' bed-shared, 28% (192/678) did so 'intermittently' and 28% (187/678) did so 'often'. These three groups did not differ significantly in marital status, income, infant gestational age, maternal age or delivery mode. Significantly, more participants who bed-shared 'often' reported strong prenatal breastfeeding intent (70% vs. 57% and 56% for 'intermittent' and 'rare' bed-share groups) and attached high prenatal importance to breastfeeding (95% vs. 87% and 82%). Significantly, more women who bed-shared frequently were breastfeeding at 6 months (p < 0.0001) than those who intermittently or rarely/never bed-shared. CONCLUSION: Women with strong motivation to breastfeed frequently bed-share. Given the complex relationship between bed-sharing and sudden infant death syndrome (SIDS) appropriate guidance balancing risk minimisation with support for breastfeeding mothers is crucial.

Subjective but Not Actigraphy-Defined Sleep Predicts Next-Day Fatigue in Chronic Fatigue Syndrome: A Prospective Daily Diary Study.

STUDY OBJECTIVES: This study aimed to (1) examine the relationship between subjective and actigraphy-defined sleep, and next-day fatigue in chronic fatigue syndrome (CFS); and (2) investigate the potential mediating role of negative mood on this relationship. We also sought to examine the effect of presleep arousal on perceptions of sleep. METHODS: Twenty-seven adults meeting the Oxford criteria for CFS and self-identifying as experiencing sleep difficulties were recruited to take part in a prospective daily diary study, enabling symptom capture in real time over a 6-day period. A paper diary was used to record nightly subjective sleep and presleep arousal. Mood and fatigue symptoms were rated four times each day. Actigraphy was employed to provide objective estimations of sleep duration and continuity. RESULTS: Multilevel modelling revealed that subjective sleep variables, namely sleep quality, efficiency, and perceiving sleep to be unrefreshing, predicted following-day fatigue levels, with poorer subjective sleep related to increased fatigue. Lower subjective sleep efficiency and perceiving sleep as unrefreshing predicted reduced variance in fatigue across the following day. Negative mood on waking partially mediated these relationships. Increased presleep cognitive and somatic arousal predicted self-reported poor sleep. Actigraphy-defined sleep, however, was not found to predict following-day fatigue. CONCLUSIONS: For the first time we show that nightly subjective sleep predicts next-day fatigue in CFS and identify important factors driving this relationship. Our data suggest that sleep specific interventions, targeting presleep arousal, perceptions of sleep and negative mood on waking, may improve fatigue in CFS.

Bone mineral density and inflammatory and bone biomarkers after darunavir-ritonavir combined with either raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults with HIV-1: a substudy of the NEAT001/ANRS143 randomised trial.

BACKGROUND: Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. METHODS: Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per µL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. FINDINGS: Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p<0.0001). Seven new fractures occurred during the trial (two in the NtRTI-sparing group and five in the standard group). INTERPRETATION: A raltegravir-based regimen was associated with significantly less loss of bone mineral density than a standard regimen containing tenofovir disoproxil fumarate, and might be a treatment option for patients at high risk of osteopenia or osteoporosis who are not suitable for NtRTIs such as abacavir or tenofovir alafenamide. FUNDING: The European Union Sixth Framework Programme, Inserm-ANRS, Ministerio de Sanidad y Asuntos Sociales de España, Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories.

Does Stroke Imaging Provide Insights into the Neural Basis of Cognition?

Since the advent of in vivo imaging, first with CT, and then MRI, structural neuroimaging in patients has been widely used as a tool to explore the neural correlates of a wide variety of cognitive functions. Findings from studies using this methodology have formed a core component of current accounts of cognition, but there are a number of problematic issues related to inferring cognitive functions from structural imaging data in stroke and more generally, lesion-based neuropsychology as a whole. This review addresses these concerns in the context of spatial neglect, a common disorder most frequently encountered following right hemisphere stroke. Recent literature, including attempts to address some of these questions, is discussed. Novel approaches and findings from related fields that may help to put stroke-based lesion mapping studies into perspective are reviewed, allowing critical but constructive evaluation of previous work in the field.

Preschool children's proto-episodic memory assessed by deferred imitation.

In two experiments, both employing deferred imitation, we studied the developmental origins of episodic memory in two- to three-year-old children by adopting a "minimalist" view of episodic memory based on its What-When-Where ("WWW": spatiotemporal plus semantic) content. We argued that the temporal element within spatiotemporal should be the order/simultaneity of the event elements, but that it is not clear whether the spatial content should be egocentric or allocentric. We also argued that episodic recollection should be configural (tending towards all-or-nothing recall of the WWW elements). Our first deferred imitation experiment, using a two-dimensional (2D) display, produced superior-to-chance performance after 2.5 years but no evidence of configural memory. Moreover, performance did not differ from that on a What-What-What control task. Our second deferred imitation study required the children to reproduce actions on an object in a room, thereby affording layout-based spatial cues. In this case, not only was there superior-to-chance performance after 2.5 years but memory was also configural at both ages. We discuss the importance of allocentric spatial cues in episodic recall in early proto-episodic memory and reflect on the possible role of hippocampal development in this process.

Harnessing motivation to alleviate neglect.

The syndrome of spatial neglect results from the combination of a number of deficits in attention, with patients demonstrating both spatially lateralized and non-lateralized impairments. Previous reports have hinted that there may be a motivational component to neglect and that modulating this might alleviate some of the debilitating symptoms. Additionally, recent work on the effects of reward on attention in healthy participants has revealed improvements across a number of paradigms. As the primary deficit in neglect has been associated with attention, this evidence for reward's effects is potentially important. However, until very recently there have been few empirical studies addressing this potential therapeutic avenue. Here we review the growing body of evidence that attentional impairments in neglect can be reduced by motivation, for example in the form of preferred music or anticipated monetary reward, and discuss the implications of this for treatments for these patients. Crucially these effects of positive motivation are not observed in all patients with neglect, suggesting that the consequences of motivation may relate to individual lesion anatomy. Given the key role of dopaminergic systems in motivational processes, we suggest that motivational stimulation might act as a surrogate for dopaminergic stimulation. In addition, we consider the relationship between clinical post stroke apathy and lack of response to motivation.

Could public restrooms be an environment for bacterial resistomes?

Antibiotic resistance in bacteria remains a major problem and environments that help to maintain such resistance, represent a significant problem to infection control in the community. Restrooms have always been regarded as potential sources of infectious diseases and we suggest they have the potential to sustain bacterial "resistomes". Recent studies have demonstrated the wide range of different bacterial phyla that can be found in non-healthcare restrooms. In our study we focused on the Staphylococci. These species are often skin contaminants on man and have been reported as common restroom isolates in recent molecular studies. We collected samples from 18 toilets sited in 4 different public buildings. Using MALDI-TOF-MS and other techniques, we identified a wide range of antibiotic resistant Staphylococci and other bacteria from our samples. We identified 19 different Staphylococcal species within our isolates and 37.8% of the isolates were drug resistant. We also identified different Staphylococcal species with the same antibiograms inhabiting the same restrooms. Bacterial "resistomes" are communities of bacteria often localised in specific areas and within these environments drug resistance determinants may be freely transferred. Our study shows that non-healthcare restrooms are a source of antibiotic resistant bacteria where a collection of antibiotic resistance genes in pathogenic and non-pathogenic bacteria could form a resistome containing a "nexus of genetic diversity"

Reward modulates spatial neglect.

BACKGROUND: Reward has been shown to affect attention in healthy individuals, but there have been no studies addressing whether reward influences attentional impairments in patients with focal brain damage. METHODS: Using two novel variants of a widely-used clinical cancellation task, we assessed whether reward modulated impaired attention in 10 individuals with left neglect secondary to right hemisphere stroke. RESULTS: Reward exposure significantly reduced neglect, as measured by total targets found, left-sided targets found and centre of cancellation, across the patient group. Lesion analysis showed that lack of response to reward was associated with damage to the ipsilateral striatum. CONCLUSIONS: This is the first experimental evidence that reward can modulate attentional impairments following brain damage. These results have significant implications for the development of behavioural and pharmacological therapies for patients with attentional disorders.

Dynamic attentional modulation of vision across space and time after right hemisphere stroke and in ageing.

INTRODUCTION: Attention modulates the availability of sensory information to conscious perception. In particular, there is evidence of pathological, spatial constriction of the effective field of vision in patients with right hemisphere damage when a central task exhausts available attentional capacity. In the current study we first examined whether this constriction might be modulated across both space and time in right hemisphere stroke patients without neglect. Then we tested healthy elderly people to determine whether non-pathological ageing also leads to spatiotemporal impairments of vision under conditions of high attention load. METHODS: Right hemisphere stroke patients completed a task at fixation while attempting to discriminate letters appearing in the periphery. Attentional load of the central task was modulated by increasing task difficulty. Peripheral letters appeared simultaneously with the central task or at different times (stimulus onset asynchronies, SOAs) after it. In a second study healthy elderly volunteers were tested with a modified version of this paradigm. RESULTS: Under conditions of high attention load right hemisphere stroke patients have a reduced effective visual field, over a significantly extended 'attentional blink', worse for items presented to their left. In the second study, older participants were unable to discriminate otherwise salient items across the visual field (left or right) when their attention capacity was loaded on the central task. This deficit extended temporally, with peripheral discrimination ability not returning to normal for up to 450 msec. CONCLUSIONS: Dynamically tying up attention resources on a task at fixation can have profound effects in patient populations and in normal ageing. These results demonstrate that items can escape conscious detection across space and time, and can thereby impact significantly on visual perception in these groups.

Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study.

New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.