Three and twelve-month analysis of the PROM-Q study: comparison of patient-reported outcome measures using the BREAST-Q questionnaire in pre- vs. sub-pectoral implant-based immediate breast reconstruction.

PURPOSE: Implant-based breast reconstruction (IBR) is being increasingly performed with implant placed above the pectoral muscle (pre-pectoral), instead of below the pectoral muscle (sub-pectoral). Currently, there is a lack of comparative data on clinical and patient-perceived outcomes between pre- vs. sub-pectoral IBR. We investigated whether this difference in surgical approach influenced clinical or patient-perceived outcomes. METHODS: This prospective non-randomised longitudinal cohort study (ClinicalTrials.gov identifier: NCT04842240) recruited patients undergoing immediate IBR at the Leeds Breast Unit (Sep 2019-Sep 2021). Data collection included patient characteristics and post-operative complications. Patient-Reported Outcome Measures were collected using the BREAST-Q questionnaire at baseline, 2 weeks, 3- and 12-months post-surgery. RESULTS: Seventy-eight patients underwent IBR (46 patients pre-pectoral; 59% vs. 32 patients sub-pectoral; 41%). Similar complication rates were observed (15.2% pre-pectoral vs. 9.4% sub-pectoral; p = 0.44). Overall implant loss rate was 3.8% (6.5% pre-pectoral vs. 0% sub-pectoral; p = 0.13). Respective median Breast-Q scores for pre- and sub-pectoral IBR at 3 months were: breast satisfaction (58 vs. 48; p = 0.01), psychosocial well-being (60 vs. 57; p = 0.9), physical well-being (68 vs. 76; p = 0.53), and Animation Q scores (73 vs. 76; p = 0.45). Respective Breast-Q scores at 12 months were: breast satisfaction (58 vs. 53; p = 0.3), psychosocial well-being (59 vs. 60; p = 0.9), physical well-being (68 vs. 78; p = 0.18), and Animation Q scores (69 vs. 73; p = 0.4). CONCLUSIONS: This study demonstrates equivalent clinical and patient-perceived outcomes between pre- and sub-pectoral IBR. The study findings can be utilised to aid informed decision making regarding either surgical option.

Embedding a novel screening programme for sexually transmitted infections (chlamydia and gonorrhoea) within an ambulatory emergency surgical assessment unit: an observational cohort study.

BACKGROUND: A number of females with pelvic inflammatory disease will present to general surgical services with non-specific abdominal pain. Screening for sexually transmitted infections (STI) as an underlying cause is not routinely offered. We therefore established an STI screening programme for young females presenting to a same day emergency ambulatory surgical clinic as part of the diagnostic pathway. Data outlining the incidence and prevalence of STIs as the underlying cause of lower abdominal pain were collected. METHODS: We conducted an observational cohort study. Self-collected vulvovaginal swabs for chlamydia and gonorrhoea were offered as part of a standardised diagnostic pathway for all females meeting inclusion criteria presenting with abdominal pain. Positive results were referred to our local sexual health team for treatment and contact tracing. RESULTS: The cohort comprised 297 eligible patients; 259 participated, 20 patients declined testing and 18 samples were rejected as inadequate in the laboratory. 5.4% of swab results were positive (2 gonorrhoea and 12 chlamydia). All patients with positive swabs had presented with lower abdominal pain and of these only 21% had a documented sexual history. CONCLUSION: Undiagnosed STIs are prevalent, with significant fertility and public health risks. Young females seeking medical assessment for abdominal pain provide an opportunistic screening cohort with a likely subset of patients presenting with abdominal pain as a direct result of an STI. Our results demonstrate a high incidence of positive tests, suggesting further training of surgeons to include a sexual history in assessment of females with abdominal pain is vital.

Just go with your body? A conversation analytic study of the transition from first to second stage of labor in UK midwife-led care.

BACKGROUND: The transition from first to second stage of labor is poorly understood. While the onset of second stage is defined by cervical measurement, dilation cannot be directly sensed or externally observed. Thus, uncertainty exists when women report pushing urges before dilation is confirmed. This study aimed to explore how sensations of pushing and uncertainty over progress are interactionally managed. METHODS: We audio/video recorded the labors of 37 women in two midwife-led units in England. Our analysis focused on a subset of 28 recordings that featured discussion of transition from first to second stage of labor. The interactions between midwives, laboring women and their birth partners were transcribed and analyzed using conversation analysis. RESULTS: We identified a 'pushing until proven otherwise' rule granting temporary, contingent authority to bodily urges to push while tracking progress over time. Specifically, midwives supported reported pushing sensations without insisting on examinations. Caution was occasionally expressed in distinguishing between irresistible and forced pushing. Across multiple contractions, midwives watched and waited for alignment of sensations with signs of descent. Where signs of progress were absent over time, examinations were treated as clinically indicated. DISCUSSION: Thus, a complex interplay of women's sensations and midwifery expertise produced care. Compared to past research, our analysis demonstrates increased validation of embodied experience in contemporary midwife-led practice. However, uncertainty still requires navigation through collaborative work. We evidence how this navigation is accomplished in real-time interactions.

Talking cervixes: How times materialise during the first stage of labour.

The clock occupies a prominent position in many feminist and midwifery critiques of the medicalisation of labour and birth. Concern has long focused on the production of standardised 'progress' during labour via the expectation that once in 'established' labour, birthing people's cervixes should dilate at a particular rate, measurable in centimetres and clock time. In this article we draw on 37 audio- or video-recordings of women labouring in two UK midwife-led units in NHS hospital settings to develop a more nuanced critique of the way in which times materialise during labour. Mobilising insights from literature that approaches time as relational we suggest that it is helpful to explore the making of times during labour as multiple, uncertain and open-ended. This moves analysis of time during labour and birth beyond concern with particular forms of time (such as the clock or the body) towards understanding how times are constituted through interactions (for example, between midwives, cervixes, clocks, people in labour and their birth partners), and what they do.

Sensory unpleasantness of very-high frequency sound and audible ultrasound.

Audible very-high frequency sound (VHFS) and ultrasound (US) have been rated more unpleasant than lower frequency sounds when presented to listeners at similar sensation levels (SLs). In this study, 17 participants rated the sensory unpleasantness of 14-, 16-, and 18-kHz tones and a 1-kHz reference tone. Tones were presented at equal subjective loudness levels for each individual, corresponding to levels of 10, 20, and 30 dB SL measured at 1 kHz. Participants were categorized as either "symptomatic" or "asymptomatic" based on self-reported previous symptoms that they attributed to exposure to VHFS/US. In both groups, subjective loudness increased more rapidly with sound pressure level for VHFS/US than for the 1-kHz reference tone, which is consistent with a reduced dynamic range at the higher frequencies. For loudness-matched tones, participants rated VHFS/US as more unpleasant than that for the 1-kHz reference. These results suggest that increased sensory unpleasantness and reduced dynamic range at high frequencies should be considered when designing or deploying equipment which emits VHFS/US that could be audible to exposed people.

My hearing explained for children: exploring use of this discussion tool in clinical practice.

OBJECTIVE: To explore the clinical use of 'My Hearing Explained for Children' (MHEfC) with children aged 8-11 years, from the perspectives of the child, parents and audiologist. DESIGN: A mixed methods randomised control trial. Participants completed evaluation questionnaires after their appointment. Statistical and thematic analyses were used to examine the rating scale and open response elements of the questionnaires respectively. STUDY SAMPLE: 45 families participated, 24 randomised to MHEfC and 21 to standard care. RESULTS: Use of MHEfC increased the appointment duration by 8.2 minutes (95% CI 4.1 to 14.2 minutes), which was acceptable to parents (96%) and audiologists (67%). It promoted conversation around 'behavioural and communication tactics', 'specific listening situations' and 'listening effort' at the expense of 'anatomy/physiology/aetiology'. MHEfC positively impacted the discussion of test results (54%); ease of finding joint solutions to problems (71%); and the nature of issues and management options discussed (54%). Parental satisfaction with discussion was high on both pathways, so some parents and audiologists questioned MHEfC necessity and recommended targeted use in future. CONCLUSIONS: MHEfC was acceptable to children (70%) and parents (86%). It successfully promoted child-centred topics of discussion and can positively impact discussion outcomes.

Imprecise recombinant viruses evolve via a fitness-driven, iterative process of polymerase template-switching events.

Recombination is a common feature of many positive-strand RNA viruses, playing an important role in virus evolution. However, to date, there is limited understanding of the mechanisms behind the process. Utilising in vitro assays, we have previously shown that the template-switching event of recombination is a random and ubiquitous process that often leads to recombinant viruses with imprecise genomes containing sequence duplications. Subsequently, a process termed resolution, that has yet to be mechanistically studied, removes these duplicated sequences resulting in a virus population of wild type length genomes. Using defined imprecise recombinant viruses together with Oxford Nanopore and Illumina high throughput next generation sequencing technologies we have investigated the process of resolution. We show that genome resolution involves subsequent rounds of template-switching recombination with viral fitness resulting in the survival of a small subset of recombinant genomes. This alters our previously held understanding that recombination and resolution are independent steps of the process, and instead demonstrates that viruses undergo frequent and continuous recombination events over a prolonged period until the fittest viruses, predominantly those with wild type length genomes, dominate the population.

Short-term risk prediction after major lower limb amputation: PERCEIVE study.

BACKGROUND: The accuracy with which healthcare professionals (HCPs) and risk prediction tools predict outcomes after major lower limb amputation (MLLA) is uncertain. The aim of this study was to evaluate the accuracy of predicting short-term (30 days after MLLA) mortality, morbidity, and revisional surgery. METHODS: The PERCEIVE (PrEdiction of Risk and Communication of outcomE following major lower limb amputation: a collaboratIVE) study was launched on 1 October 2020. It was an international multicentre study, including adults undergoing MLLA for complications of peripheral arterial disease and/or diabetes. Preoperative predictions of 30-day mortality, morbidity, and MLLA revision by surgeons and anaesthetists were recorded. Probabilities from relevant risk prediction tools were calculated. Evaluation of accuracy included measures of discrimination, calibration, and overall performance. RESULTS: Some 537 patients were included. HCPs had acceptable discrimination in predicting mortality (931 predictions; C-statistic 0.758) and MLLA revision (565 predictions; C-statistic 0.756), but were poor at predicting morbidity (980 predictions; C-statistic 0.616). They overpredicted the risk of all outcomes. All except three risk prediction tools had worse discrimination than HCPs for predicting mortality (C-statistics 0.789, 0.774, and 0.773); two of these significantly overestimated the risk compared with HCPs. SORT version 2 (the only tool incorporating HCP predictions) demonstrated better calibration and overall performance (Brier score 0.082) than HCPs. Tools predicting morbidity and MLLA revision had poor discrimination (C-statistics 0.520 and 0.679). CONCLUSION: Clinicians predicted mortality and MLLA revision well, but predicted morbidity poorly. They overestimated the risk of mortality, morbidity, and MLLA revision. Most short-term risk prediction tools had poorer discrimination or calibration than HCPs. The best method of predicting mortality was a statistical tool that incorporated HCP estimation.

The genomic landscape of response to EGFR blockade in colorectal cancer.

Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

An evaluation of the implementation of Safewards on an assessment and treatment unit for people with an intellectual disability.

This study evaluates the implementation of Safewards on an assessment and treatment unit (ATU) for people with an intellectual disability. There are no previous studies evaluating this model in this context and previous research has focused largely on acute mental health services. The 'Patient-Staff Conflict Shift Report' was used at baseline for 1 month and 1 year later, after all the interventions had been implemented, to evaluate the impact of Safewards. Significant reductions were found in conflict and containment measures used within the service after the implementation of Safewards. Staff who led on the interventions were also asked to give feedback on their experiences, the challenges they faced and how they would like to move forward. Safewards was generally seen as a positive approach by the team. Limitations of this study are highlighted and suggestions for future research are made.

Cancer-Associated Mutations in Endometriosis without Cancer.

BACKGROUND: Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS: We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS: Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS: We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

Nurse managed patient focused assessment and care: A grounded theory of qualified nurses in acute and critical care settings assessing the mental capacity of adult patients.

AIMS: To explore processes used by qualified nurses in assessing mental capacity of acutely and critically ill hospitalised adult patients. BACKGROUND: Mental capacity is the ability to understand, reason and make decisions. Acute and critical illness may impact upon the decision-making abilities of hospitalised adult patients but little is known about how qualified nurses across a range of acute settings assess the capacity of such patients in their care. DESIGN: A qualitative grounded theory approach informed by the Corbin and Strauss (Basics of Qualitative Research (Third Edition). London, UK: Sage, 2008) methodological pathway. METHODS: Data were collected through digitally recorded, semi-structured interviews to explore assessment of capacity processes used by 13 registered nurses employed in acute and critical care environments in a district general hospital in South Wales, UK. Data were analysed using iterative constant comparative processes leading to a core category and grounded theory. The study is presented in accordance with the COREQ checklist. RESULTS: Informal, intuitive, holistic nurse-led processes were used to assess the mental capacity of patients which combined processes for the assessment of their physiological and mental capacity status, recognising the need to support their rights, dignity and autonomy. The assessment of mental capacity was not a lone process but one that contributed to a cyclical process in which multi-professional assessment was necessary and ongoing, and in which qualified nurses had a co-ordinating role. This led to the development of the theory, Nurse Managed Patient Focused Assessment and Care. CONCLUSION: This theory provides a framework to explain processes and strategies used by qualified nurses in assessing mental capacity of, and caring for, adult patients with acute and/or critical illness. RELEVANCE TO CLINICAL PRACTICE: This framework may inform related clinical practice and can serve as a basis of an assessment tool in what has been identified as a fundamental role of the qualified nurse.

Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis-Pinnick Tandem Transformation.

A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).

Prevalence of spontaneous type I ECG pattern, syncope, and other risk markers in sudden cardiac arrest survivors with Brugada syndrome.

INTRODUCTION: A spontaneous type I electrocardiogram (ECG) pattern and/or unheralded syncope are conventionally used as risk markers for primary prevention of sudden cardiac arrest/death (SCA/SCD) in Brugada syndrome (BrS). In this study, we determine the prevalence of conventional and newer markers of risk in those with and without previous aborted SCA events. METHODS: All patients with BrS were identified at our institute. History of symptoms was obtained from medical tests or from interviews. Other markers of risk were also obtained, such as presence of (1) spontaneous type I pattern, (2) fractionated QRS (fQRS), (3) early repolarization (ER) pattern, (4) late potentials on signal-averaged ECG (SAECG), and (5) response to programmed electrical stimulation. RESULTS: In 133 patients with Bars, 10 (7%) patients (mean age = 39 ± 11 years; nine males) were identified with a previous ventricular fibrillation/ventricular tachycardia episode (n = 8) or requiring cardio-pulmonary resuscitation (n = 2). None of these patients had a prior history of syncope before their SCA event. Only two (20%) patients reported a history of palpitations or dizziness. None had apneic breathing and three (30%) patients had a family history of SCA. From their ECGs, a spontaneous pattern was only found in one (10%) of these patients. Further, 10% of patients had fQRS, 17% had late potentials on SAECG, 20% had deep S waves in lead I, and 10% had an ER pattern in the peripheral leads. No significant differences were observed in the non-SCA group. CONCLUSION: The majority of BrS patients with previous aborted SCA events did not have a spontaneous type I and/or prior history of syncope. Conventional and newer markers of risk appear to only have limited ability to predict SCA.

Public exposure to ultrasound and very high-frequency sound in air.

Recent work showing the presence of a new generation of ultrasound (US) sources in public places has reopened the debate about whether there are adverse effects of US on humans, and has identified weaknesses in standards and exposure guidelines. Systems that rely on very high-frequency sound (VHFS) and US include public-address voice-alarm (PAVA) systems (whose operational status is often monitored using tones at ∼20 kHz) and pest deterrents. In this study, sound pressure levels (SPLs) produced by 16 sources that were either publically available or installed in busy public spaces were measured. These sources were identified through a citizen science project, wherein members of the public were asked to provide smartphone recordings of VHFS/US sources. With measurements made in realistic listening positions, pest deterrents were found that produced levels of up to 100 dB SPL at ∼20 kHz, and a hand dryer was found to produce 84 dB SPL at 40 kHz. PAVA systems were found to emit lower levels of up to 76 dB SPL at ∼20 kHz. Pest deterrents measured breach recommended safe listening limits for public exposure for people who are nearby even for relatively short periods.

Effects of very high-frequency sound and ultrasound on humans. Part II: A double-blind randomized provocation study of inaudible 20-kHz ultrasound.

Some people have reported symptoms such as nausea, dizziness, and headaches that they attribute to ultrasound (US) emitted by devices in public places. The primary aim of the present study was to investigate whether inaudible US can provoke adverse symptoms compared to a sham presentation, under double-blind conditions. A second aim was to investigate whether the expectation of US being present could provoke adverse symptoms (a nocebo response). The US stimulus was a 20 kHz tone presented continuously for 20 min set to at least 15 dB below the participants' detection threshold, giving a typical sound pressure level (SPL) of 84 dB. No evidence that US provoked symptoms was found, but there was evidence of small nocebo effects. A case study on an individual with high self-reported sensitivity to US gave similar results. The present study did not reproduce the severe symptoms reported previously by some members of the public; this may be due to the SPL or duration of the stimulus, or strength of the nocebo stimulus. These findings cannot be used to predict outcomes from exposures to sounds that are audible to the individual in question, or to sounds with higher SPLs, longer durations, or different frequency content.

Effects of very high-frequency sound and ultrasound on humans. Part I: Adverse symptoms after exposure to audible very-high frequency sound.

Various adverse symptoms resulting from exposure to very high-frequency sound (VHFS) and ultrasound (US) have previously been reported. This study aimed to establish whether these symptoms are experienced under controlled laboratory conditions and are specific to VHFS/US. To do this, participants were exposed to VHFS/US (at frequencies between 13.5 and 20 kHz and sound pressure levels between 82 and 92 dB) and to a 1 kHz reference stimulus, both at 25 dB above their hearing threshold. The VHFS/US and reference stimuli were presented 4 times, each time for 3 min, during which participants performed a sustained attention task, rated their symptom severity, and had their galvanic skin response (GSR) measured to assess their level of anxiety. Prior to exposure, participants were assigned either to a symptomatic or an asymptomatic group, based on their prior history of symptoms that they attributed to VHFS/US. In both groups, overall discomfort ratings were higher in the VHFS/US condition than the reference condition. In the symptomatic group only, difficulty concentrating and annoyance were also rated higher in the VHFS/US than the reference condition. No difference between the two stimulus conditions was seen in performance on the attention task or on average GSRs for either group.

Measurements of ultrasonic deterrents and an acoustically branded hairdryer: Ambiguities in guideline compliance.

Acoustic radiation from three commercial pest deterrents and two hair dryers were measured in an anechoic chamber. The deterrents were chosen because the frequency range at which they emit the most energy is either in the very high-frequency sound band (11.2-17.8 kHz) or the ultrasound band (greater than 17.8 kHz). These are sources that may be heard by a subset of the general population, with the young typically having better high frequency sensitivity. A hairdryer reported to increase the frequency of the motor noise above the audible hearing range was compared with a standard hairdryer. The outputs of the deterrents are compared against six international regulations and guidelines for audible and ultrasound exposure. Multiple ambiguities in the application of these guidelines are discussed. These ambiguities could lead to a device being considered as in compliance despite unconventionally high levels. Even if a device measured here meets a guideline, actual exposures can exceed those taken here and may therefore breach guidelines if the listener is closer to the device or reflections increase the exposure level.

Activating STAT6 mutations in follicular lymphoma.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and cell-extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole-exome sequencing of 23 highly purified FL cases and 1 transformed FL case and expanded findings to a combined total of 114 FLs. We report recurrent mutations in the transcription factor STAT6 in 11% of FLs and identified the STAT6 amino acid residue 419 as a novel STAT6 mutation hotspot (p.419D/G, p.419D/A, and p.419D/H). FL-associated STAT6 mutations were activating, as evidenced by increased transactivation in HEK293T cell-based transfection/luciferase reporter assays, heightened interleukin-4 (IL-4) -induced activation of target genes in stable STAT6 transfected lymphoma cell lines, and elevated baseline expression levels of STAT6 target genes in primary FL B cells harboring mutant STAT6. Mechanistically, FL-associated STAT6 mutations facilitated nuclear residency of STAT6, independent of IL-4-induced STAT6-Y641 phosphorylation. Structural modeling of STAT6 based on the structure of the STAT1-DNA complex revealed that most FL-associated STAT6 mutants locate to the STAT6-DNA interface, potentially facilitating heightened interactions. The genetic and functional data combined strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis.