CRLF3 plays a key role in the final stage of platelet genesis and is a potential therapeutic target for thrombocythemia.

The process of platelet production has so far been understood to be a 2-stage process: megakaryocyte maturation from hematopoietic stem cells followed by proplatelet formation, with each phase regulating the peripheral blood platelet count. Proplatelet formation releases into the bloodstream beads-on-a-string preplatelets, which undergo fission into mature platelets. For the first time, we show that preplatelet maturation is a third, tightly regulated, critical process akin to cytokinesis that regulates platelet count. We show that deficiency in cytokine receptor-like factor 3 (CRLF3) in mice leads to an isolated and sustained 25% to 48% reduction in the platelet count without any effect on other blood cell lineages. We show that Crlf3-/- preplatelets have increased microtubule stability, possibly because of increased microtubule glutamylation via the interaction of CRLF3 with key members of the Hippo pathway. Using a mouse model of JAK2 V617F essential thrombocythemia, we show that a lack of CRLF3 leads to long-term lineage-specific normalization of the platelet count. We thereby postulate that targeting CRLF3 has therapeutic potential for treatment of thrombocythemia.

Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission.

OBJECTIVES: We investigated whether soluble immune checkpoints (sICPs) predict treatment resistance, relapse and infections in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). METHODS: Plasma sICP concentrations from available samples obtained during conduct of the RAVE trial were measured by immunoabsorbent assays from patients with either proteinase 3 (PR3) or myeloperoxidase (MPO)-ANCA vasculitis and were correlated with clinical outcomes, a set of biomarkers and available flow cytometry analyses focusing on T cell subsets. Log-rank test was used to evaluate survival benefits, and optimal cut-off values of the marker molecules were calculated using Yeldons J. RESULTS: Analysis of 189 plasma samples at baseline revealed higher concentrations of sTim-3, sCD27, sLag-3, sPD-1 and sPD-L2 in patients with MPO-ANCA vasculitis (n=62) as compared with PR3-ANCA vasculitis (n=127). Among patients receiving rituximab induction therapy (n=95), the combination of lower soluble (s)Lag-3 (<90 pg/mL) and higher sCD27 (>3000 pg/mL) predicted therapy failure. Twenty-four out of 73 patients (32.9%) in the rituximab arm reaching remission at 6 months relapsed during follow-up. In this subgroup, high baseline values of sTim-3 (>1200 pg/mL), sCD27 (>1250 pg/mL) and sBTLA (>1000 pg/mL) were associated with both sustained remission and infectious complications. These findings could not be replicated in 94 patients randomised to receive cyclophosphamide/azathioprine. CONCLUSIONS: Patients with AAV treated with rituximab achieved remission less frequently when concentrations of sLag-3 were low and concentrations of sCD27 were high. Higher concentrations of sTim-3, sCD27 and sBTLA at baseline predicted relapse in patients treated with rituximab. These results require confirmation but may contribute to a personalised treatment approach of AAV.

The Impact of Global Collaboration on the Academic Focus of the West African College of Surgeons: Are Worldwide Efforts Aligning with Local Priorities?

BACKGROUND: Global collaboration has the potential to induce a shift in research focus away from the priorities of those in low- and low-middle-income countries (LICs and LMICs). This study quantified international collaboration among surgery publications by Fellows of the West African College of Surgeons (WACS) and investigated if collaboration with upper-middle-income and high-income countries (UMICs and HICs) decreases the homophily of research focus. METHODS: Publications by WACS surgery Fellows from 1960 to 2019 were characterized as local WACS publications, collaborative publications without UMIC/HIC participation, or collaborative publications with UMIC/HIC participation. Research topics were determined for each publication, and topic percentages were compared between collaboration groups. RESULTS: We analyzed 5065 publications. Most (3690 publications, 73%) were local WACS publications, while 742 (15%) were collaborative publications with UMIC/HIC participation and 633 (12%) were collaborative publications without UMIC/HIC participation. UMIC/HIC collaborations contributed to 49% of the increase (378 out of 766 publications) from 2000 to 2019. Topic homophily was significantly lower between local WACS publications and collaborations with UMIC/HIC participation (differed in nine research topics) than it was between local WACS publications and collaborations without UMIC/HIC participation (differed in two research topics). CONCLUSIONS: Publications without international collaboration comprise most WACS research, but the rate of UMIC/HIC collaborations is rapidly increasing. We found that UMIC/HIC collaborations decreased the homophily of topic focus in WACS publications, indicating that global collaborations need to have greater emphasis on the priorities of those in LICs and LMICs.

LC-MS/MS Analysis of the Formation and Loss of DNA Adducts in Rats Exposed to Vinyl Acetate Monomer through Inhalation.

Formation of DNA adducts is a key event during carcinogenesis. DNA adducts, if not repaired properly, can lead to mutations and cancer. DNA adducts have been frequently used as biomarkers to evaluate chemical exposure. Vinyl acetate monomer (VAM) is widely used in the manufacture of various industrial polymers. Previous studies have documented that VAM induced nasal tumors in rodents exposed to high exposure levels of VAM. VAM is metabolized by carboxylesterase to acetaldehyde (AA), which subsequently results in DNA adducts. However, AA is also an endogenous metabolite in living cells, which impedes accurate assessment of the contribution of VAM exposure under the substantial endogenous background. To address this challenge, we exposed rats to stable isotope labeled [13C2]-VAM at 50, 200, and 400 ppm through inhalation for 6 h, followed by DNA adduct analysis in nasal respiratory and olfactory epithelia with highly sensitive mass spectrometry. Our results show that exogenous N2-ethyl-dG adducts were present in all rats exposed to [13C2]-VAM, with over 2-fold higher DNA adducts in nasal respiratory epithelium than olfactory epithelium. Our data also show that N2-ethyl-dG is a more sensitive biomarker to assess VAM exposure than 1,N2-propano-dG adducts. Moreover, a very low amount of exogenous N2-ethyl-dG adducts were detected in peripheral blood mononuclear cell samples of exposed rats, suggesting that only an extremely small percentage of [13C2]-VAM or its metabolite may enter into systemic circulation to potentially damage tissues beyond nasal epithelium. Furthermore, exogenous N2-ethyl-dG DNA adducts undergo rapid repair or spontaneous loss in nasal epithelium of exposed rats. Taken together, the results presented herein provide novel quantitative data and lay the foundation for future studies to improve risk assessment of VAM.

Epithelial Alteration Associated With Recovery From Laryngeal Squamous Metaplasia in Rats: Kinetics of Recovery From a Test Item-Related Change.

Squamous metaplasia is a nonspecific adaptive response to chronic irritation in the larynx and is often diagnosed as a test item-related change in rat inhalation studies. Investigating scientists are frequently asked to assess the adversity of laryngeal squamous metaplasia and to interpret its relevance to human risk. One factor in predicting relevance to human risk is the kinetics (degree and speed) of recovery following the cessation of exposure to the test item. Most reports describing recovery from squamous metaplasia in the rat larynx discuss the more severe end of the spectrum of metaplastic change (moderate to severe) and include relatively long (6 weeks or more) recovery periods. We conducted 2 studies to evaluate the toxicity and recovery from any potential effects of 4-(Chloro-2-methylphenoxy) butyric (MCPB) acid, a herbicide, when administered by inhalation to young male Sprague Dawley rats for 3 to 4 weeks. The studies resulted in minimal to moderate laryngeal squamous metaplasia for which we describe the kinetics of recovery over 1 to 4 weeks. We found that the microscopic change epithelial alteration, which is normally considered to be a precursor in the development of squamous metaplasia, can occur as a transitional stage between squamous and normal epithelium during recovery.

Systematic Generation of the Dunham Coefficients Using Symbolic Mathematics Software.

The Dunham coefficients are an indispensable part of the analysis of the ro-vibrational spectrum of a diatomic molecule. They provide a direct connection between the ro-vibrational states observed and the interatomic potential that must exist in the molecule. One may deduce the interatomic potential from the spectrum or, alternatively, predict the spectrum from a theoretically generated interatomic potential. The coefficients result from a mathematical analysis of the Schrödinger equation for such a system. Dunham's derivation relied on the WKB approximation and, as such, was subject to the associated limitations. In this paper, the quantum condition is derived without any reliance on the WKB approximation, using only principles of complex analysis. This sidesteps the need for introducing an approximate function to join solutions and suggests that the expansion has a more fundamental basis. Also in this paper, a mathematical algorithm for generating the Dunham coefficients is elaborated in detail. Careful attention is paid to keeping these coefficients accurate to a specified order in the smallness parameter, τe = Be/ωe. This algorithm is intended to be presented in a way that makes it amenable to incorporation into computer code and points where the efficiency can be improved are indicated. Coefficients have been generated and presented in the literature through the years. The current paper presents the coefficients explicitly to tenth order in the smallness parameter, far more than have been generated in any previous work.

Postoperative Delirium is Associated With Prolonged Head and Neck Resection and Reconstruction Surgery: An Institutional Study.

PURPOSE: Delirium is a recognized complication of surgery. It has a deleterious effect on a patient's postoperative recovery and well-being. The purpose of this study was to estimate the frequency and identify the risk factors for the development of postoperative delirium (POD) in a cohort of patients who underwent extensive head and neck surgery (HNS) of greater than five hours duration. MATERIALS AND METHODS: The authors undertook a retrospective cohort study of patients who underwent HNS of greater than five hours duration. The primary predictor variables comprised a set of risk factors (sociodemographic, disease-specific, duration of surgery, and duration of inpatient stay) that were thought to be associated with the development of POD. The primary outcome variable was the development of POD. Descriptive, bivariate, and multivariate statistical analysis was undertaken, and significance was set at P < .05. RESULTS: One hundred and seventy patients were included in the study. There were 124 males and 46 females. Forty patients (23.53%) developed POD: 30 documented and 10 inferred. The mean age of the POD cohort was 65 years (SD 13), with a median age of 69 years. The occurrence of POD was statistically related to increased age, mental health status, American Society of Anesthesiologists (ASA) score, and drug dependence (either illicit or prescription). POD and operative duration were statistically associated. POD and length of stay were not statistically associated. CONCLUSION: Delirium did occur postoperatively in 23.53% of our patients who underwent extensive and prolonged HNS. POD may go unrecognized by treating teams. As POD has a deleterious effect on the cognitive function, it is important to identify and aggressively treat episodes of POD that occur during a patient's postoperative recovery.

Improving screening for physical impairments and access to early physiotherapy after neck dissection surgery: a translational controlled trial.

PURPOSE: Lack of routine screening for a range of physical impairments that can result after neck dissection (ND) may hinder physiotherapy referral and treatment. The purpose of this study was to implement an intervention that targeted both physiotherapists and surgeons to increase their post-operative physical screening of ND patients and in turn improve physiotherapy referral rates. METHODS: The authors undertook a translational controlled pilot study, conducted over a 12-month period that utilised three tertiary hospital sites. The target groups were physiotherapists at one intervention site and surgeons at the other intervention site, with the third hospital acting as a control site and receiving usual care. The intervention included a physiotherapy brochure and a clinical pathway for screening, to promote early identification and prompt referral of patients with a physical impairment. The primary outcome variables were screening and referral rates between sites at the study end-point. RESULTS: Logistic regression analyses were conducted on n = 174 to assess differences in screening and referral rates between sites. Patients at the intervention site that targeted physiotherapists had four times the odds of being screened for shoulder dysfunction compared to the control site (p = 0.0002), and three times the odds of being referred to physiotherapy (0.0039). There were no statistically significant differences in the odds of patients being screened for shoulder dysfunction or referred to physiotherapy at the intervention site that targeted surgeons. CONCLUSION: The translational intervention undertaken by physiotherapists resulted in significantly greater screening and referral rates of post-operative ND patients for physiotherapy.

Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America.

OBJECTIVES: To develop and replicate, using data-driven methods, a novel classification system in Takayasu's arteritis based on distribution of arterial lesions. METHODS: Patients were included from four international cohorts at major academic centres: India (Christian Medical College Vellore); North America (National Institutes of Health, Vasculitis Clinical Research Consortium and Cleveland Clinic Foundation). All patients underwent whole-body angiography of the aorta and branch vessels, with categorization of arterial damage (stenosis, occlusion or aneurysm) in 13 territories. K-means cluster analysis was performed to identify subgroups of patients based on pattern of angiographic involvement. Cluster groups were identified in the Indian cohort and independently replicated in the North American cohorts. RESULTS: A total of 806 patients with Takayasu's arteritis from India (n = 581) and North America (n = 225) were included. Three distinct clusters defined by arterial damage were identified in the Indian cohort and replicated in each of the North American cohorts. Patients in cluster one had significantly more disease in the abdominal aorta, renal and mesenteric arteries (P < 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P < 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P < 0.01). Demographics, clinical symptoms and clinical outcomes differed by cluster. CONCLUSION: This large study in Takayasu's arteritis identified and replicated three novel subsets of patients based on patterns of arterial damage. Angiographic-based disease classification requires validation by demonstrating potential aetiological or prognostic implications.

The Efficacy and Safety of Transversus Abdominis Plane Blocks After Open Cholecystectomy in Low- and Middle-Income Countries.

BACKGROUND: Postoperative pain management is challenging in low- and middle-income countries (LMICs). This study assesses the safety and efficacy of transversus abdominis plane (TAP) blocks as an adjunct for postoperative pain control after an open cholecystectomy in LMICs during short-term surgical missions (STSMs). TAP block is a regional anesthesia technique that has been shown to be effective in providing supplementary analgesia to the anterolateral wall post abdominal surgery. METHODS: A retrospective chart review of patients undergoing open cholecystectomy during STSMs was performed. STSMs took place in Guatemala, the Philippines, and Peru from 2009 to 2019. Measured outcomes including pain scores, presence of postoperative nausea or vomiting, and opioid consumption were compared between TAP block and non-TAP block groups. RESULTS: Of the 48 patients analyzed, 28 underwent TAP block (58%). Non-TAP block patients received, on average, 8 mg of oral morphine equivalents more than the TAP patients (P = 0.035). No significant difference was noted in pain scores, which were taken immediately after surgery, 2 h after surgery, and at multiple times between these time points to calculate an average. Of the patients who received a TAP block, 11% reported nausea or vomiting compared with 45% in the standard group (P < 0.01). There were no reported procedure-related complications. CONCLUSIONS: TAP blocks are safe and effective adjuncts for postoperative pain management on STSMs to LMICs. Additional studies are needed to investigate the potential advantages and disadvantages of more widespread use of TAP blocks in LMICs.

Face Transplantation for Granulomatosis With Polyangiitis (Wegener Granulomatosis): Technical Considerations, Immunological Aspects, and 3-Year Posttransplant Outcome.

BACKGROUND: We report new data for a rare face transplant performed 3 years ago. Granulomatosis with polyangiitis (GPA) (Wegener) is a severe autoimmune necrotizing vasculitis and parenchymal inflammatory disease that can affect any organ including those of the craniofacial region. Skin involvement manifests as malignant pyoderma. This account (1) highlights the technical details of face transplantation for this unique indication, (2) reports the 3-year posttransplant outcome, and (3) describes relevant immunological aspects. METHODS: A Le Fort III near-total face and near-total scalp transplant was performed after extensive trauma and subsequent bone and soft tissue infection in a patient with GPA. Incisions were planned along facial aesthetic subunits. The vascular pedicle comprised the facial and superficial temporal arteries bilaterally. The functioning left eye was preserved and fitted into the donor tissues. RESULTS: The procedure took 21 hours, and transfusion was limited to 4 units of packed red cells. Early medical and surgical complications were successfully treated. At 3 years, acceptable aesthetic outcome was achieved with adequate color match and scalp hair growth. The patient has recovered light touch, temperature, and 2-point discrimination and has evidence of symmetric cheek elevation albeit with limited eyelid and frontalis function. GPA relapse did not occur. Four acute rejections were fully reversed. CONCLUSIONS: This case represents a new underlying disease (trauma + GPA) leading to face transplantation and a unique clinical scenario where allografting was indicated for potentially life-threatening and sight-preserving reasons and not for mere functional and aesthetic concerns. Despite complexity, 3-year clinical outcome is encouraging, and the patient is no longer at risk for dural exposure, meningitis, and related morbidity.

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

Evaluation of damage in giant cell arteritis.

Objectives: To evaluate damage and variables associated with damage in GCA. Methods: Patients with GCA enrolled in a prospective, multicentre, longitudinal study were included. Per-protocol assessments were made with the Vasculitis Damage Index and the Large-Vessel Vasculitis Index of Damage. Results: The study included 204 patients: 156 women (76%), mean age at diagnosis 71.3 years (s.d. 8.3), mean follow-up of 3.5 years (s.d. 1.9). One or more damage item was present in 54% at baseline and 79% at the last follow-up on the Vasculitis Damage Index, and 60% at baseline and 82% at the last follow-up on the Large-Vessel Vasculitis Index of Damage. The most frequently observed damage items were large-artery complications (29% cohort) and ocular (22%). Among 117 patients with new damage, most new items were ocular (63 patients), cardiac/vascular (48) and musculoskeletal (34). Of these, treatment-associated items were frequently observed, including cataracts (46 patients), osteoporosis (22) and weight gain (22). Disease-associated new damage included ischaemic optic neuropathy (3 patients), limb claudication (13), arterial occlusions (10) and damage requiring vascular intervention (10). In univariate analysis, the risk of damage increased 22% for every additional year of disease duration [odds ratio (OR) 1.22 (95% CI 1.04, 1.45)]. In 94 patients enrolled within ⩽90 days of diagnosis of GCA, the risk of new damage at the last follow-up decreased 30% for each additional relapse [OR 0.70 (95% CI 0.51, 0.97)]. Conclusions: Large-artery complications and ocular manifestations are the most commonly occurring items of damage in GCA. Most new damage is associated with treatment. These findings emphasize the cumulative burden of disease in GCA.

Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis.

Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results: RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion: Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.

Does microbial colonisation of a neck drain predispose to surgical site infection: clean vs clean-contaminated procedures.

PURPOSE: The study was designed to assess the difference in microbiological colonisation and growth that may occur in drains, in the setting of clean-contaminated compared to clean head and neck surgery. METHODS: A prospective observational cohort study was performed. Surgical drain tips upon removal were sent for bacterial culture and the culture results were compared between clean-contaminated and clean procedures using mixed effects logistic regression. In all statistical analyses, a priori, p < 0.05 (two-tailed) was calculated to indicate statistical significance. RESULTS: One hundred and ten drains were examined in both clean-contaminated and clean procedures. Drains from clean-contaminated procedures had a significantly longer time in situ (11 vs 5 days, p < 0.001). Overall, significant evidence was seen for an association between procedure type and drain growth rates: 68% of clean-contaminated procedures; and 45% of clean procedures. Although not statistically significant, there was an increase in normal skin flora contaminated drains in clean-contaminated procedures (41 vs 25%). Rates of pathogenic skin organisms (15 vs 16%) and pathogenic oropharyngeal organisms (2.9 vs 0%) were similar for clean-contaminated vs clean procedure patients. CONCLUSION: This preliminary study demonstrated a higher rate of microbial contamination of neck drains that were placed during procedures that involved continuity with the upper aero-digestive tract and neck. Retrograde migration of skin flora along the drain is common but of no clinical significance. Similar rates of pathogenic microbial growth have been demonstrated thus far. However, selection of nosocomial pathogens due to extended antibiotic prophylaxis may pose a risk for infection. LEVEL OF EVIDENCE: 1b.

Interstitial Immunostaining and Renal Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.

BACKGROUND: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy. METHODS: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined. RESULTS: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group. CONCLUSIONS: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed.

IgA antibodies to myeloperoxidase in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVES: To determine the prevalence of anti-myeloperoxidase (MPO) antibodies of IgA (IgA anti-MPO) isotype in patients with eosinophilic granulomatosis with polyangiitis (EGPA), and the association of the IgA antibodies with IgG anti-MPO and with disease activity. METHODS: Serum samples from patients with EGPA followed in a multicenter longitudinal cohort were tested by ELISA for the presence of IgA anti-MPO and IgG anti-MPO antibodies. Sera from 87 healthy controls were used to define a positive test. Sera from 168 patients with EGPA (298 samples) were tested. Frequencies of positive testing for IgA anti-MPO were compared between patients with active EGPA, patients in remission, and controls. RESULTS: IgA anti-MPO was detected in 10 of 168 (6%) patients with EGPA (11 of 298 serum samples) compared to 1 of 87 (1%) healthy controls (p=0.10). All 11 samples testing positive for IgA anti-MPO also tested positive for IgG anti-MPO. Ninety samples tested positive for IgG anti-MPO but negative for IgA. Samples taken during active EGPA were positive for IgA anti-MPO in 6/72 cases (8%), compared to 5/226 (2%) during remission (p=0.03). Among samples taken during moderate or high disease activity, 5/41 were positive (12%, p=0.01 compared to remission). CONCLUSIONS: Although IgA anti-MPO antibodies are detectable in some patients with EGPA and may be detectable more frequently during active disease, their presence seems unlikely to provide information beyond what is obtained from conventional IgG anti-MPO.

Does Preoperative Diplopia Determine the Incidence of Postoperative Diplopia After Repair of Orbital Floor Fracture? An Institutional Review.

PURPOSE: The purpose of our study was to investigate whether the occurrence of preoperative diplopia determines the incidence of postoperative diplopia after orbital floor repair. MATERIALS AND METHODS: We undertook a retrospective cohort study with a review of the records of 126 consecutive patients who had undergone repair of an orbital floor fracture under the maxillofacial surgery service at John Hunter Hospital (Newcastle, NSW, Australia). The primary predictor variables were a number of demographic, etiologic, and operative factors that might influence the occurrence of diplopia. The secondary outcome variable was diplopia. A descriptive statistical analysis was used to assess each of these variables and their potential relationship to the occurrence of diplopia. RESULTS: Of the 126 patients included in our study, 84 (66.6%) were treated for diplopia and 42 (33.3%) for dystopia. We found that orbital exploration and repair, when undertaken to manage diplopia, can resolve (75%), improve (7.14%), stabilize (7.14%), or worsen (10.71%) diplopia. In contrast, orbital surgery to manage or prevent dystopia can, in our experience, induce diplopia in 9.52% of patients. At the 95% confidence interval, age was the only variable shown to be significantly associated with diplopia (P = .039). We found that the presence of preoperative diplopia is causally statistically associated with postoperative diplopia at the 90% confidence interval (P = .063). CONCLUSIONS: Diplopia is a common occurrence that results from orbital floor fracture. It can resolve, persist (improve, remain stable, or worsen), or be induced after repair of such an injury. In addition to the known myogenic cause (entrapment) of diplopia, both trauma and surgical manipulation have been shown to have the capacity to compromise ocular motor nerve function and possibly result in the development of neurogenic causes of diplopia. It has also been noted that several intraorbital adherence syndromes can potentially contribute to the development of diplopia. This is an area that requires further research.

Outcome of Head and Neck Cancer Patients Who Did Not Receive Curative-Intent Treatment.

PURPOSE: There exists a subgroup of patients with head and neck cancer (HNC) who neither warrant nor request curative-intent treatment and who progress to a terminal-care paradigm. The purpose of this study was to determine the frequency of and reasons for an HNC terminal-care referral and the time to and place of death for such patients. MATERIALS AND METHODS: The authors undertook a retrospective cohort study of all attendees with HNC who had undergone multidisciplinary team (MDT) assessment at the Calvary Mater Hospital (Newcastle, Australia) from January 2013 through December 2014. The primary predictor variables were a heterogeneous set of factors grouped together into logical demographic (age and gender) and clinicopathologic (tumor histology, site, and stage) categories and the reason for referral to terminal care. The secondary outcome variables were survival and place of death. A descriptive statistical analysis was undertaken and survival data were graphically displayed as Kaplan-Meier estimates. RESULTS: Of the 412 attendees with HNC who underwent MDT assessment, 74 (18%) were identified as having been immediately referred for terminal care. Their median survival was 6 months (95% confidence interval, 4.75-7.50). The most common reason for referral for terminal care was tumor extent. The most common place of death recorded for the group was a hospice facility. CONCLUSION: This study serves as a timely reminder that when curative-intent HNC treatment options have been exhausted, dialog and action need to be directed to transitioning the patient to a terminal-care management paradigm.

Giant Cell Arteritis.

This issue provides a clinical overview of giant cell arteritis, focusing on diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.