Improving recovery after bowel cancer surgery: mixed methods feasibility study of a co-produced information intervention (Recover Together).

AIM: Recovery after surgery for colorectal cancer is a complex process, involving numerous physiological, emotional, social and economic challenges. Good information is a key factor for enabling patients to recover well, but there is a paucity of evidence to guide how this should be done. A new information intervention (Recover Together) comprising a booklet, an online video and an inpatient goal board has been developed. This study explores its feasibility, as well as the feasibility of key study methods, during its first use in the United Kingdom National Health Service (NHS). METHODS: This is a mixed methods, multi-centre, feasibility study of a complex intervention. A total of 105 participants undergoing oncological colorectal surgery will be recruited across three to four study sites in the UK. Participants will receive each component of the Recover Together intervention at defined timepoints before and during hospital admission. A series of patient-centred outcome instruments will be administered in hospital and during follow-up at 30 days and 6 months. Outcomes of feasibility will comprise the time taken to establish the intervention at participating sites, assessments of intervention fidelity and acceptability, as well as return rates of key clinical outcome instruments. The mixed methods design will comprise interviews and focus groups with patients and health professionals, non-participant observation in ward areas and clinics, user-specific video analytics and daily photographs of the goal boards. DISCUSSION: The findings of this study will provide a feasibility assessment of the Recover Together intervention when used for the first time in NHS practice. If shown to be feasible, this will guide the development of a future definitive study to explore the clinical and cost effectiveness of the Recover Together intervention to improve recovery after surgery. CLINICAL TRIALS REGISTRATION: ISRCTN62430915.

Acceptability of automatic referrals to supportive and palliative care by patients living with advanced lung cancer: qualitative interviews and a co-design process.

PURPOSE: Timely access to supportive and palliative care (PC) remains a challenge. A proposed solution is to trigger an automatic referral process to PC by pre-determined clinical criteria. This study sought to co-design with patients and providers an automatic PC referral process for patients newly diagnosed with stage IV lung cancer. METHODS: In Step 1 of this work, nine one on one phone interviews were conducted with advanced lung cancer patients on their perspectives on the acceptability of phone contact by a specialist PC provider triggered by an automatic referral process. Interviews were thematically analysed. Step 2: Patient advisors, healthcare providers (oncologists, nurses from oncology and PC, clinical social worker, psychologist), and researchers were invited to join a working group to provide input on the development and implementation of the automatic referral process. The group met biweekly (virtually) over the course of six months. RESULTS: From interviews, the concept of an automatic referral process was perceived to be acceptable and beneficial for patients. Participants emphasized the need for timely support, access to peer and community resources. Using these findings, the co-design working group identified eligibility criteria for identifying newly diagnosed stage IV lung cancer patients using the cancer centre electronic health record, co-developed a telephone script for specialist PC providers, handouts on supportive care, and interview and survey guides for evaluating the implemented automatic process. CONCLUSION: A co-design process ensures stakeholders are involved in program development and implementation from the very beginning, to make outputs relevant and acceptable for stage IV lung cancer patients.

Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications.

Crohn's disease (CD) has been traditionally viewed as a chronic inflammatory disease that cause gut wall thickening and complications, including fistulas, by mechanisms not understood. By focusing on Parabacteroides distasonis (presumed modern succinate-producing commensal probiotic), recovered from intestinal microfistulous tracts (cavernous fistulous micropathologies CavFT proposed as intermediate between 'mucosal fissures' and 'fistulas') in two patients that required surgery to remove CD-damaged ilea, we demonstrate that such isolates exert pathogenic/pathobiont roles in mouse models of CD. Our isolates are clonally-related; potentially emerging as transmissible in the community and mice; proinflammatory and adapted to the ileum of germ-free mice prone to CD-like ileitis (SAMP1/YitFc) but not healthy mice (C57BL/6J), and cytotoxic/ATP-depleting to HoxB8-immortalized bone marrow derived myeloid cells from SAMP1/YitFc mice when concurrently exposed to succinate and extracts from CavFT-derived E. coli , but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange with Bacteroides fragilis -BGF539, evidence of international presence in primarily human metagenome databases, these CavFT Pdis isolates could represent to a new opportunistic Parabacteroides species, or subspecies (' cavitamuralis' ) adapted to microfistulous niches in CD.

Increasing access to palliative care for patients with advanced cancer of African and Latin American descent: a patient-oriented community-based study protocol.

BACKGROUND: Cancer disparities are a major public health concern in Canada, affecting racialized communities of Latin American and African descent, among others. This is evident in lower screening rates, lower access to curative, and palliative-intent treatments, higher rates of late cancer diagnoses and lower survival rates than the general Canadian population. We will develop an Access to Palliative Care Strategy informed by health equity and patient-oriented research principles to accelerate care improvements for patients with advanced cancer of African and Latin American descent. METHODS: This is a community-based participatory research study that will take place in two Canadian provinces. Patients and community members representatives have been engaged as partners in the planning and design of the study. We have formed a patient advisory council (PAC) with patient partners to guide the development of the Access to Palliative Care Strategy for people of African and Latin American descent. We will engage100 participants consisting of advanced cancer patients, families, and community members of African and Latin American descent, and health care providers. We will conduct in-depth interviews to delineate participants' experiences of access to palliative care. We will explore the intersections of race, gender, socioeconomic status, language barriers, and other social categorizations to elucidate their role in diverse access experiences. These findings will inform the development of an action plan to increase access to palliative care that is tailored to our study population. We will then organize conversation series to examine together with community partners and healthcare providers the appropriateness, effectiveness, risks, requirements, and convenience of the strategy. At the end of the study, we will hold knowledge exchange gatherings to share findings with the community. DISCUSSION: This study will improve our understanding of how patients with advanced cancer from racialized communities in Canada access palliative care. Elements to address gaps in access to palliative care and reduce inequities in these communities will be identified. Based on the study findings a strategy to increase access to palliative care for this population will be developed. This study will inform ways to improve access to palliative care for racialized communities in other parts of Canada and globally.

A single-center, single-blinded, randomized, parallel-group, non-inferiority trial to compare the efficacy of a 22-gauge needle versus a 15 blade to perform an Achilles tendon tenotomy in 244 clubfeet-study protocol.

BACKGROUND: Achilles tendon tenotomy is an integral part of the Ponseti method, aimed at correcting residual equinus and lack of dorsiflexion after correction of the adductus deformity in clubfoot. Percutaneous tenotomy using a number 15 scalpel blade is considered the gold standard, resulting in excellent results with minimal complications. The use of a large-bore needle to perform Achilles tendon tenotomies has been described in literature, but a large-scale randomized controlled trial is currently lacking. In this trial, we aim to show the non-inferiority of the needle tenotomy technique compared to the gold standard blade tenotomy technique. METHODS: We will randomize 244 feet into group A: needle tenotomy or group B: blade tenotomy. Randomization will be done using a block randomization with random block sizes and applying a 1:1 allocation to achieve an intervention and control group of the exact same size. Children will be evaluated at 3 weeks and 3 months post-tenotomy for primary and secondary clinical outcomes. The primary clinical outcome will be the range of dorsiflexion obtained the secondary clinical outcomes will be frequency of minor and major complications and Pirani score. The non-inferiority margin was set at 4°, and thus, the null hypothesis of inferiority of the needle technique will be rejected if the mean difference between both techniques is less than 4°. The statistical analysis will use a multi-level mixed effects linear regression model for the primary outcomes and a multi-level mixed effects logistic regression model for the secondary clinical outcomes. The physician performing the evaluations post-tenotomy will be the only one blinded to group allocation. TRIAL REGISTRATION: This trial was registered prospectively with ClinicalTrials.gov registration number: NCT04897100 on 21 May 2021.

Patient & Caregiver Experiences: Qualitative Study Comparison Before and After Implementation of Early Palliative Care for Advanced Colorectal Cancer.

BACKGROUND: The Palliative Care Early and Systematic (PaCES) program implemented an early palliative care pathway for advanced colorectal cancer patients in January 2019, to increase specialist palliative care consultation and palliative homecare referrals more than three months before death. This study aimed to understand the experience of patients with advanced colorectal cancer and family caregivers who received early palliative care supports from a specialist palliative care nurse and compared those experiences with participants who experienced standard oncology care prior to implementation of early palliative care. METHODS: This was a qualitative and patient-oriented study. We conducted semi-structured telephone interviews with two cohorts of patients with advanced colorectal cancer before and after implementation of an early palliative care pathway. We conducted a thematic analysis of the transcripts guided by a Person-Centred Care Framework. RESULTS: Seven patients living with advanced colorectal cancer and five family caregivers who received early palliative care supports expressed that visits from their early palliative care nurse was helpful, improved their understanding of palliative care, and improved their care. Four main themes shaped their experience of early palliative care: care coordination, perception of palliative care & advance care planning, coping with advanced cancer, and patient and family engagement. These findings were compared with experiences of 15 patients and seven caregivers prior to pathway implementation. CONCLUSION: An early palliative care pathway can improve advanced cancer care, and improve understanding and acceptance of early palliative care. This work was conducted in the context of colorectal cancer but may have relevance for the care of other advanced cancers.

The Weissella Genus: Clinically Treatable Bacteria with Antimicrobial/Probiotic Effects on Inflammation and Cancer.

Weissella is a genus earlier considered a member of the family Leuconostocaceae, which was reclassified into the family Lactobacillaceae in 1993. Recently, there have been studies emphasizing the probiotic and anti-inflammatory potential of various species of Weissella, of which W. confusa and W. cibaria are the most representative. Other species within this genus include: W. paramesenteroides, W. viridescens, W. halotolerans, W. minor, W. kandleri, W. soli, W. ghanensis, W. hellenica, W. thailandensis, W. fabalis, W. cryptocerci, W. koreensis, W. beninensis, W. fabaria, W. oryzae, W. ceti, W. uvarum, W. bombi, W. sagaensis, W. kimchi, W. muntiaci, W. jogaejeotgali, W. coleopterorum, W. hanii, W. salipiscis, and W. diestrammenae. Weissella confusa, W. paramesenteroides, W. koreensis, and W. cibaria are among the few species that have been isolated from human samples, although the identification of these and other species is possible using metagenomics, as we have shown for inflammatory bowel disease (IBD) and healthy controls. We were able to isolate Weissella in gut-associated bacteria (post 24 h food deprivation and laxatives). Other sources of isolation include fermented food, soil, and skin/gut/saliva of insects/animals. With the potential for hospital and industrial applications, there is a concern about possible infections. Herein, we present the current applications of Weissella on its antimicrobial and anti-inflammatory mechanistic effects, the predisposing factors (e.g., vancomycin) for pathogenicity in humans, and the antimicrobials used in patients. To address the medical concerns, we examined 28 case reports focused on W. confusa and found that 78.5% of infections were bacteremia (of which 7 were fatal; 1 for lack of treatment), 8 were associated with underlying malignancies, and 8 with gastrointestinal procedures/diseases of which 2 were Crohn's disease patients. In cases of a successful resolution, commonly administered antibiotics included: cephalosporin, ampicillin, piperacillin-tazobactam, and daptomycin. Despite reports of Weissella-related infections, the evolving mechanistic findings suggest that Weissella are clinically treatable bacteria with emerging antimicrobial and probiotic benefits ranging from oral health, skin care, obesity, and inflammatory diseases to cancer.

Volumetric changes of the parotid gland during IMRT based on mid-treatment imaging: implications for parotid stem cell sparing strategies in head and neck cancer.

BACKGROUND: To evaluate the change in parotid glands at mid-treatment during IMRT and the association between radiation dose to the parotid gland stem cell (PGSC) region and patient-reported xerostomia for patients with head and neck cancer (HNC). MATERIAL AND METHODS: Patients who were treated from 2006-2012 at our institution with patient-reported xerostomia outcomes available at least 9 months following RT were included. PG and PGSC regions were delineated and the dose was estimated from the treatment plan dose distribution, using contours from pre- and mid-treatment CT scans. The association between radiation dose and volumetric changes was assessed using linear regression. Univariable logistic regression, logistic dose-response curves, and receiver operating characteristics (ROC) were used to examine the relationship between radiation dose and patient-reported xerostomia. RESULTS: Sixty-three patients were included, most treated with 70 Gy in 33 fractions; 34 patients had mid-treatment CT scans. Both contralateral and ipsilateral PGs had considerable volume reduction from baseline to mid-treatment (25% and 27%, respectively, both p < .001), significantly associated with mean PG dose (-0.44%/Gy, p = .008 and -0.54%/Gy, p < .001, respectively). There was a > 5 Gy difference in mean PG and PGSC dose for 8/34 patients at mid-treatment, with 6/8 (75%) reporting severe xerostomia. Xerostomia prediction based on whole PG or PGSC region dose showed similar performance (ROC AUC 0.754 and 0.749, respectively). The corresponding dose-response models also predicted similar risk of patient-reported xerostomia with mean dose to the contralateral PG (32.5%) or PGSC region (31.4%) at the 20 Gy QUANTEC-recommended sparing level. CONCLUSIONS: The radiation dose to the PGSC region did not show stronger association with patient-reported xerostomia compared to that of whole PG, possibly due to considerable anatomical changes identified at mid-treatment. This shift in the size and position of the PG warrants adaptive planning strategies to evaluate the true benefit of parotid stem cell sparing.

Assessing Impact: Implementing an Opioid Prescription Protocol in Otolaryngology.

OBJECTIVE: A lack of guidance for pain control after otolaryngology surgery can lead to overprescription of opioids. We implemented a postoperative site-specific opioid prescription protocol and analyzed the impact on opioid prescriptions. METHODS: This is a retrospective cohort study. A postoperative opioid prescription protocol was implemented within our otolaryngology department at a tertiary academic medical center on January 1, 2020. Retrospective chart review was completed for all patients undergoing otolaryngology surgery from November 1, 2019, to February 29, 2020 (2 months before and after initiation of intervention; n = 1070). The primary outcome was change in the amount of opioid prescribed for the preintervention and postintervention cohorts. Unplanned contact related to pain and opioid refills were tracked to assess pain control. RESULTS: A total of 940 cases were included; adult and pediatric data were analyzed separately. There were 489 pediatric cases, 250 preintervention and 239 postintervention. There was a significant decrease in the amount of opioid prescribed per pediatric patient in the postintervention cohort (2.7 versus 0.32 morphine milligram equivalents, P = 0.02), and 99% of patients were not prescribed opioids at all. There was no significant change in unplanned contact, and no refills were required. There were 451 adult cases, 200 preintervention and 251 postintervention. There was no statistically significant decrease in the amount of opioid prescribed per adult patient (56.8 versus 51.7 morphine milligram equivalents, P = 0.23). There was no significant increase in unplanned contact or refills. CONCLUSIONS: A postoperative opioid prescribing protocol can reduce the amount of opioid prescribed without increasing unplanned contact or opioid refills.

Use of Predictive Modeling to Tailor Molecular Testing Utilization for Thyroid Nodules.

OBJECTIVE: Various risk stratification systems for cytologically indeterminate thyroid nodules are available. However, malignancy risk assessment data, such as ultrasound features, are not always used when the decision is to order molecular testing or not. Our aim was to investigate the utility of molecular testing after incorporating an algorithm with ultrasound-based risk of malignancy (ROM) estimation. STUDY DESIGN: Diagnostic/prognostic study. SETTING: Single-institution urban tertiary care center. METHODS: We performed a single-institution retrospective chart review of all thyroid nodules that had undergone molecular testing. A web-based Malignancy Risk Estimation System for Thyroid Nodules was utilized with ultrasound findings to stratify malignancy risk according to the Korean Thyroid Imaging Reporting and Data System (TI-RADS), French TI-RADS, American Association of Clinical Endocrinology guideline, and American Thyroid Association guideline. A novel algorithm for utilizing molecular testing at our institution was developed with the Korean TI-RADS and with recommendations from the American Thyroid Association and National Comprehensive Cancer Network. RESULTS: The Korean TI-RADS performed best in our population (area under the curve = 0.83). A positive molecular test result had a positive association with a higher ROM according to all 4 models (P < .05). Use of our algorithm prior to molecular testing would have prevented 38% of benign/low-ROM negative nodules (n = 28) from being tested. CONCLUSION: In patients with indeterminate thyroid nodules, an algorithm built on pre- and posttest probability to guide molecular testing might reduce unnecessary testing of benign and low-risk nodules.

Can the negative pressures found in obstructive sleep apnea and Eustachian tube dysfunction be related?

OBJECTIVE: The association between obstructive sleep apnea (OSA) and Eustachian tube dysfunction (ETD) is well known. When both exist in a single pediatric patient, one of the expected culprits is adenoid enlargement. We hypothesize, in contrast, that the negative pharyngeal pressure found in OSA may be transmitted to the middle ear as negative middle ear pressure (MEP), which subsequently results in pathology. The objective of this study was to determine whether the degree of OSA and MEP are associated while using MEP as a quantifiable measurement of ETD. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic center (Jan 2000-Jan 2018). SUBJECTS AND METHODS: The relationship between apnea-hypopnea index (AHI) and MEP was examined. A non-anatomic model was utilized to support causality. RESULTS: Thirty-four pediatric patients and twenty-three adult patients were included in the analysis. REM AHI showed a moderate negative correlation with MEP in children (r = -0.265), and a weak positive correlation with MEP in adults (r = 0.171). Children with an AHI in the severe OSA category had a more negative mean MEP than those in the mild category (p = 0.36). Adults with an AHI in the severe OSA category had a more positive mean MEP than those in the mild category (p = 0.11). CONCLUSION: In children, increasing severity of OSA is associated with a negative MEP, suggesting that negative pressure associated with OSA may be transmitted to the middle ear. In adults, increasing severity of OSA is associated with a more positive MEP.

Patient and caregiver experiences with advanced cancer care: a qualitative study informing the development of an early palliative care pathway.

BACKGROUND: Palliative care is an approach that improves the quality of life of patients and families facing challenges associated with life-threatening illness. In order to effectively deliver palliative care, patient and caregiver priorities need to be incorporated in advanced cancer care. AIM: This study identified experiences of patients living with advanced colorectal cancer and their caregivers to inform the development of an early palliative care pathway. DESIGN: Qualitative patient-oriented study. SETTINGS/PARTICIPANTS: Patients receiving care at two cancer centres were interviewed using semistructured telephone interviews to explore their experiences with cancer care services received prior to a new developed pathway. Interviews were transcribed verbatim, and the data were thematically analysed. RESULTS: From our study, we identified gaps in advanced cancer care that would benefit from an early palliative approach to care. 15 patients and 7 caregivers from Edmonton and Calgary were interviewed over the phone. Participants identified the following gaps in advanced cancer care: poor communication of diagnosis, lack of communication between healthcare providers, role and involvement of the family physician, lack of understanding of palliative care and advance care planning. CONCLUSIONS: Early palliative approaches to care should consider consistent and routine delivery of palliative care information, collaborations among different disciplines such as oncology, primary care and palliative care, and engagement of patients and family caregivers in the development of care pathways.

In Situ Simulation to Assess Pediatric Tracheostomy Care Safety: A Novel Multicenter Quality Improvement Program.

OBJECTIVES: Our objectives were (1) to use in situ simulation to assess the clinical environment and identify latent safety threats (LSTs) related to the management of pediatric tracheostomy patients and (2) to analyze the effects of systems interventions and team factors on LSTs and simulation performance. METHODS: A multicenter, prospective study to assess LSTs related to pediatric tracheostomy care management was conducted in emergency departments (EDs) and intensive care units (ICUs). LSTs were identified through equipment checklists and in situ simulations via structured debriefs and blinded ratings of team performance. The research team and unit champions developed action plans with interventions to address each LST. Reassessment by equipment checklists and in situ simulations was repeated after 6 to 9 months. RESULTS: Forty-one LSTs were identified over 21 simulations, 24 in the preintervention group and 17 in the postintervention group. These included LSTs in access to equipment (ie, availability of suction catheters, lack of awareness of the location of tracheostomy tubes) and clinical knowledge gaps. Mean equipment checklist scores improved from 76% to 87%. Twenty-one unique teams (65 participants) participated in the simulations. The average simulation score was 6.19 out of 16 points. DISCUSSION: In situ simulation is feasible and effective as an assessment tool to identify latent safety threats and thus measure the system-level performance of a clinical care environment. IMPLICATIONS FOR PRACTICE: In situ simulation can be used to identify and reassess latent safety threats related to pediatric tracheostomy management and thereby support quality improvement and educational initiatives.

Origin of Locoregional Recurrences After Definitive Intensity-modulated Radiation Therapy (IMRT) for Laryngeal Cancer Determined Based on Follow-up PET/CT Imaging.

PURPOSE: The aim of our study was to report on patterns of failure using detailed information from follow-up positron emission tomography-computed tomography (PET/CT) scans for patients with laryngeal squamous cell carcinoma (SCCA) treated with definitive radiation therapy using intensity-modulated radiation therapy (IMRT). METHODS: One hundred and sixty-eight patients with laryngeal SCCA treated with definitive IMRT using a simultaneous integrated boost were included. The point of recurrence origin on follow-up PET/CT was determined using two separate data-driven methods. The first method, the mathematical epicenter point of origin (POEpi), calculated the mathematical focal epicenter point for which the maximum distance to the surface of the surrounding volume was smaller than for any other point. The second method, maximum standardized uptake value point of origin (POMax), calculated the voxel with maximum standardized uptake value (SUV) uptake within the recurrence volume. The failure pattern was then determined by whether the point of recurrence origin fell within the low, intermediate, or high-risk target volumes in the original treatment planning CT. RESULTS: Thirty-five primary/nodal recurrences in 33 patients were included in the analysis. In the POEpi method, 94% (33/35) of all recurrences originated either within the high-risk gross tumor volume (GTVHigh-risk) or within an average of 0.9 ± 1.3 mm from it. In the POMax method, 91% (32/35) of all recurrences originated either within the GTVHigh-risk or within an average of 1.8 ± 1.7 mm from it. There were no recurrences outside the low-risk planning target volume (PTVLow-risk) for the POEpi method but there was one for the POMax method, which was 19.8 mm away from the edge of the gross tumor volume receiving 70 Gy (GTV70). Increasing distance between the two different origin points was strongly correlated with the size of the recurrence volume. CONCLUSION: The majority of recurrences for laryngeal cancer patients treated with definitive IMRT originated from within the high-dose treatment region. This can have implications for reducing clinical target volumes while using a risk-adaptive treatment approach to both constrain dose to critical areas and further escalate the dose to the gross tumor to improve locoregional control rates.

Catalytic performance of bis(imino)pyridine Fe/Co complexes toward ethylene polymerization by 2D-/3D-QSPR modeling.

The two-dimensional and three-dimensional quantitative structure-property relationship (2D- and 3D-QSPR) approaches are applied to investigate the catalytic performance for a total data set of 55 bis(imino)pryridine iron and cobalt complexes, including the catalytic activity, molecular weight, and melting temperature of the product. The obtained models for the catalytic performance of interest exhibit good results by both 2D- and 3D-QSPR modeling, meanwhile higher predictive and validation powers observed in the 3D type. The modeling results indicate that the bulky substituents on ortho-position of the singular side phenyl ring and positive charge on para-position of the phenyl ring within the ligand are favorable to catalytic activity, while unfavorable to the molecular weight of product. Based on the obtained QSPR models, four new complexes are designed and predicted with good catalytic activity and very high molecular weight, which are in good agreement with our recent experimental report. © 2019 Wiley Periodicals, Inc.

Catalytic Activities of Bis(pentamethylene)pyridyl(Fe/Co) Complex Analogues in Ethylene Polymerization by Modeling Method.

The catalytic activities of α,α'-bisimino-2,3:5,6-bis(pentamethylene)pyridyl(Fe/Co) chloride analogue complexes are quantitatively investigated by the multiple linear regression analysis (MLRA) method. From the point of view of the electronic and steric effects, seven structural descriptors are selected and calculated, including the Hammett constant ( F), effective net charge ( Qeff), energy difference (Δ E), HOMO-LUMO energy gap (Δε1, Δε2), open cone angle (θ), and bite angle (ß). In order to get better model, the fitting analyses are carried out by using the combinations of four, three, two, and single descriptors. The calculation results show quite good correlation results. By using two descriptors ( Qeff, ß), the catalytic activities for both the Fe and Co complexes individually and also the variation between Fe and Co (Fe-Co) analogue system can be well predicted with correlation coefficient values over 0.934. It is found that the effective net charge ( Qeff) plays the dominant role in determining the catalytic activities for Fe and Co complexes. Furthermore, the lower values of catalytic activities in Co complexes are mainly attributed to the decreasing values of Qeff.

B-cell biology and related therapies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. The immunologic events triggering the onset and progression of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis has been brought to the fore in the last several years. The breakdown of B-cell tolerance is likely a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Antibody-dependent and -independent mechanisms of B cells are important in SLE. Thus, autoantibodies contribute to autoimmunity by multiple mechanisms including immune complex mediated type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including interferon alpha, tumor necrosis factor, and interleukin 1. Recent data have highlighted the critical role of toll-like receptors as a link between the innate and adaptive immune system in SLE immunopathogenesis. Given the large body of evidence implicating abnormalities in the B-cell compartment in SLE, there has been a therapeutic focus on developing interventions that target the B-cell compartment. Several different approaches to targeting B cells have been used, including B-cell depletion with monoclonal antibodies against B-cell-specific molecules, induction of negative signaling in B cells, and blocking B-cell survival and activation factors. Overall, therapies targeting B cells are beginning to show promise in the treatment of SLE and continue to elucidate the diverse roles of B cells in this complex disease.