Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis.

Progranulin (PGRN) is a glycoprotein implicated in several neurodegenerative diseases. It is highly expressed in microglia and macrophages and can be secreted or delivered to the lysosome compartment. PGRN comprises 7.5 granulin repeats and is processed into individual granulin peptides within the lysosome, but the functions of these peptides are largely unknown. Here, we identify CD68, a lysosome membrane protein mainly expressed in hematopoietic cells, as a binding partner of PGRN and PGRN-derived granulin E. Deletion analysis of CD68 showed that this interaction is mediated by the mucin-proline-rich domain of CD68. While CD68 deficiency does not affect the lysosomal localization of PGRN, it results in a specific decrease in the levels of granulin E but no other granulin peptides. On the other hand, the deficiency of PGRN, and its derivative granulin peptides, leads to a significant shift in the molecular weight of CD68, without altering CD68 localization within the cell. Our results support that granulin E and CD68 reciprocally regulate each other's protein homeostasis.

Magnetic Resonance Imaging Correlates of Multiple Sclerosis Immunopathological Patterns.

OBJECTIVE: Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. METHODS: We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). RESULTS: A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. INTERPRETATION: We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.

Respiratory gated multistatic PET reconstructions to delineate radiotherapy target volume in patients with mobile lung tumors.

BACKGROUND: PET-CT with 18F-FDG or other radiopharmaceuticals is a recommended tool to help the delineation of lung cancers candidate to radiotherapy. The motion artifacts caused by respiratory movements are reduced by 4D acquisitions. We introduced an extended reconstruction algorithm (multiple reconstruct register and average [multi-RRA]) which requires much shorter acquisition times than standard 4D PET-CT. Our aim was to evaluate the interest on multi-RRA images as an alternative of 3D and 4D PET-CT for the delineation of lung lesion. METHODS: PET acquisitions synchronized to the respiratory signal were obtained in 18 patients with mobile lung tumors. We compared the tumor volumes delineated on Multi-RRA images to 3D and 4D PET-CT, considering the 4D CT as a reference. The tumor volumes were delineated and compared with topologic similarity indexes (Dice, Jaccard and overlap). RESULTS: Twenty tumors were delineated. The volumes delineated with multi-RRA and 4D PET were not significantly different (mean difference of 0.2±0.7 mL). Comparison by pairs (Tukey-Kramer test) showed that 3D-PET volumes were significantly smaller than 4D-PET and multi-RRA volumes (P<0.001). Topologic similarity indexes with 4D-PET were slightly statistically higher with multi-RRA than with 3D-PET (Dice and Jaccard) or 4D-CT (Dice, Jaccard and Overlap). CONCLUSIONS: The tumor volumes delineated on multi-RRA are similar to the volumes obtained with 4D PET, with shorter acquisition time.

Targeted genotyping of circulating tumor DNA for classical Hodgkin lymphoma monitoring: a prospective study.

The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2). Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD-like [73.5%] and other regimens [5.2%, for elderly patients] were assessed in this non-interventional study. Median age of the patients was 33.5 years (range 20-86). Variants were identified in 42 (70%) patients. Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1 were found in 13.3%, 31.7%, 23.3%, 5%, 33.3%, 10%, 23.3%, 13.3% and 50% of patients, respectively. ctDNA concentration and genotype are correlated with clinical characteristics and presentation. Regarding early therapeutic response, 45 patients (83%, NA=6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1-3). Mean of DeltaSUVmax after C2 was -78.8%. We analyzed ctDNA after C2 for 54 patients (90%). ctDNA became rapidly undetectable in all cases after C2. Variant detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in association with PET. Clinical Trial reference: NCT02815137.

The added value of clinical radiopharmacists in nuclear medicine: The example of glomerular filtration rate assessment in kidney donors.

WHAT IS KNOWN AND OBJECTIVES: In Europe, the pharmaceutical supply of chromium-51 has been stopped. However, this isotope is necessary for the evaluation of glomerular filtration rates. It is possible to replace it with technetium-99m, but the validation of this change in the measurement method must be carried out. METHODS: A retrospective analysis of chromium-51 data from January 2018 to January 2019 was performed, followed by a study from January 2019 to January 2020 using the technetium tracer. The patients were different in the both study groups, and none had an eGFR below 50 mL min-1 . A cost analysis was performed. Patient exposure to ionizing radiation was studied for both methods. RESULTS AND DISCUSSION: Seventy-eight patients were included in the study. In total, 42 EDTA-51 Cr and 36 DTPA-99m Tc examinations were conducted and compared. There were no significant differences between the methods used to assess renal function (P = .351). The results of cost analysis and patient radiation exposure were in favour of DTPA-99m Tc examinations. WHAT IS NEW AND CONCLUSION: Within the limitations of a retrospective study of two patient cohorts, there was no significant difference between the results obtained with chromium-51 and technetium-99m tracers. In addition, with the use of DTPA-99m Tc, operating costs and patient exposure to ionizing radiation were reduced, and clinical activity was maintained for the patients' benefit. Radiopharmacists are able to react quickly to supply contingencies, reduce operating costs and maintain the quality of medical examinations.

Development and Validation of Early Warning Criteria to Identify Escalated Care Events in Neonatal Intensive Care Unit Patients.

OBJECTIVE: This study aimed to identify and validate the diagnostic utility of a set of clinical and laboratory criteria (early warning criteria [EWC]) that portend a clinical deterioration event (escalated care event [ECE]) in neonatal intensive care unit (NICU) patients. STUDY DESIGN: Using the RAND appropriateness method, we first established a consensus on seven ECE, that is, events that require additional monitoring, treatment, or stay in the NICU or that were associated with morbidity. We then established consensus on EWC that could portend an ECE from an initial set of 32 potential EWC items to a final set of 10 items. The occurrence and nonoccurrence of EWC and ECE were prospectively identified and tracked over 9 weeks. RESULTS: Among 170 NICU patients studied (2,502 patient-days), the frequency of an EWC was 53 per 1,000 patient-days. Of these patients, 41% had an EWC and 16% had an ECE. An EWC was followed by an ECE within 72 hours, 37% of the time, and within a median time interval of 113 minutes. The sensitivity, specificity, positive predictive values, and negative predictive values of EWC in identifying an ECE were 0.96, 0.69, 0.37, and 0.99, respectively. CONCLUSION: A simple bedside NICU-specific EWC identifies neonates likely to develop ECEs in the NICU.

Borderline Nerve Conduction Velocities for Median Neuropathy at the Carpal Tunnel.

PURPOSE: Patient knowledge of the frequency with which electrodiagnostic testing (EDx) for suspected median neuropathy at the carpal tunnel addresses nuance in the distinction between normal and abnormal neurophysiology might help them make an informed decision about whether or not to have this test. We reviewed a large set of consecutive EDx for possible carpal tunnel syndrome (CTS) and associated medical records to determine (1) the percentage of EDx measurements within 10% of threshold values; (2) discordance between clinician and EDx diagnosis of CTS using diagnostic performance characteristics; and (3) demographic and disease characteristics independently associated with EDx diagnosis of median neuropathy at the carpal tunnel. METHODS: We retrospectively reviewed nerve conduction study (NCS) results of 537 consecutive patients evaluated for possible idiopathic median neuropathy at the carpal tunnel. We measured the number of patients within 10% of 3 NCS diagnostic thresholds; the diagnostic performance characteristics comparing clinician and EDx diagnosis; and patient and disease characteristics associated with EDx diagnosis of CTS. RESULTS: The 3 NCS parameters were within 10% of the threshold for diagnosis of median neuropathy at the carpal tunnel in 2.6% to 33% of patients. Overall, 76% of EDx results were interpreted as median neuropathy at the carpal tunnel, 19% as normal, and 5% as another diagnosis (eg, cervical radiculopathy). Patients with normal EDx were significantly younger, more likely not to report paresthesias/numbness, more likely to have prior normal EDx, and less likely to have had a previous contralateral carpal tunnel release. CONCLUSIONS: This data set reflecting management strategies for suspected CTS at a large institution confirms inherent diagnostic uncertainty, relatively strong concordance between clinician and EDx diagnosis, and the importance of focusing on paresthesia rather than pain. These findings support the use of clinical prediction rules and may help inform a patient's decision regarding whether or not to have EDx. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

Effectiveness of training general practitioners to improve the implementation of brief stop-smoking advice in German primary care: study protocol of a pragmatic, 2-arm cluster randomised controlled trial (the ABCII trial).

BACKGROUND: The German clinical guideline on tobacco addiction recommends that general practitioners (GPs) provide brief stop-smoking advice to their patients according to the "5A" or the much briefer "ABC" method, but its implementation is insufficient. A lack of training is one barrier for GPs to provide such advice. Moreover, the respective effectiveness of a 5A or ABC training regarding subsequent delivery of stop-smoking advice has not been investigated. We developed a training for GPs according to both methods, and conducted a pilot study with process evaluation to optimize the trainings according to the needs of GPs. This study aims at evaluating the effectiveness of both trainings. METHODS: A pragmatic 2-arm cluster randomised controlled trial with a pre-post data collection will be conducted in 48 GP practices in North Rhine-Westphalia (Germany). GPs will be randomised to receive a 3.5-h-training in delivering either 5A or ABC, including peer coaching and intensive role plays with professional actors. The patient-reported primary outcome (receipt of GP advice to quit: yes/no) and secondary outcomes (recommendation rates of smoking cessation treatments, group comparison (5A versus ABC): receipt of GP advice to quit) will be collected in smoking patients routinely consulting their GP within 4 weeks prior, and 4 weeks following the training. Additional secondary outcomes will be collected at 4, 12 and 26 weeks following the consultation: use of cessation treatments during the last quit attempt (if so) since the GP consultation, and point-prevalence abstinence rates. The primary data analysis will be conducted using a mixed-effects logistic regression model with random effects for the cluster variable. DISCUSSION: If the training increases the rates of delivery of stop-smoking advice, it would offer a low-threshold strategy for the guideline implementation in German primary care. Should one method prove superior, a more specific guideline recommendation can be proposed. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00012786); registered on 22th August 2017, prior to the first patient in.

Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process.

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A1c (the conjugate acid of the Schiff base). Labile Hb A1c can then undergo slow, largely irreversible, formation of stable Hb A1c (the Amadori product). Stable Hb A1c is measured to assess diabetic progression after labile Hb A1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A1c and the slow rate of NEG.

Correction to: Tumor fragmentation estimated by volume surface ratio of tumors measured on 18F-FDG PET/CT is an independent prognostic factor of diffuse large B-cell lymphoma.

A unit error concerning the tumor volume surface ratio (TVSR) is present throughout the article. The unit reported is "cm" but is actually "mm".

Tumor fragmentation estimated by volume surface ratio of tumors measured on 18F-FDG PET/CT is an independent prognostic factor of diffuse large B-cell lymphoma.

INTRODUCTION: Our aim was to study the prognostic value of two new 18F-FDG PET biomarkers in diffuse large B-cell lymphoma (DLBCL). We examined the total tumor surface (TTS), describing the tumor-host interface, and the tumor volume surface ratio (TVSR), corresponding to the ratio between the total metabolic tumor volume (TMTV) and TTS, describing the tumor fragmentation. METHODS: We retrospectively included 215 patients with DLBCL. Patients underwent initial 18F-FDG PET/CT before R-CHOP (73%) or intensified R-CHOP (R-ACVBP) regimens (27%). The TMTV was measured using a fixed threshold value of 41% of SUVmax. To calculate TTS and TVSR, the surface was measured using an in-house software based on the marching cube algorithm. Spearman's rank correlation coefficient (ρ) was computed between TMTV, TTS, and TVSR, and ROC analysis was performed. Survival functions at 5 years were studied using a Kaplan-Meier method and uni/multivariate Cox analysis. RESULTS: TVSR was poorly correlated with TMTV (ρ = 0.5) and TTS (ρ = 0.26), while TTS was highly correlated with TMTV (ρ = 0.94) and was, therefore, excluded from the analysis. TMTV had the highest area under the ROC curve (0.711) and the best sensitivity (0.797), while TVSR had the best specificity (0.745). The optimal cut-off values to predict 5-year OS were 222 cm3 for TMTV and 6.0 mm for TVSR. Patients with high TMTV and TVSR had significantly worse prognosis in Kaplan-Meier and Cox univariate analysis. In a multivariate Cox analysis combining the International Prognostic Index (IPI), the type of chemotherapy, TMTV, and TVSR, all parameters were independent and significant prognostic factors (HR [95%CI]: IPI 1.4 [1.1-1.8], type of chemotherapy 4.5 [2.0-10.5], TMTV 2.8 [1.4-5.5], TVSR 2.1 [1.3-3.4]). A synergistic effect between TMTV and TVSR was observed in a Kaplan-Meier analysis combining the two parameters. CONCLUSIONS: TVSR measured on the initial 18F-FDG PET is an independent prognostic factor in DLBCL and has an additional prognostic value when combined with TMTV, IPI score and chemotherapy.

Predictive value of 18F-FDG PET/CT in adults with T-cell lymphoblastic lymphoma: post hoc analysis of results from the GRAALL-LYSA LLO3 trial.

PURPOSE: We examined whether FDG PET can be used to predict outcome in patients with lymphoblastic lymphoma (LL). METHODS: This was a retrospective post hoc analysis of data from the GRAAL-LYSA LL03 trial, in which the treatment of LL using an adapted paediatric-like acute lymphoblastic leukaemia protocol was evaluated. PET data acquired at baseline and after induction were analysed. Maximum standardized uptake values (SUVmax), total metabolic tumour volume and total lesion glycolysis were measured at baseline. The relative changes in SUVmax from baseline (ΔSUVmax) and the Deauville score were determined after induction. RESULTS: The population analysed comprised 36 patients with T-type LL. SUVmax using a cut-off value of ≤8.76 vs. >8.76 was predictive of 3-year event-free survival (31.6% vs. 80.4%; p = 0.013) and overall survival (35.0% vs. 83.7%; p = 0.028). ΔSUVmax using a cut-off value of ≤80% vs. >80% tended also to be predictive of 3-year event-free survival (40.0% vs. 76.0%; p = 0.054) and overall survival (49.2% vs. 85.6%; p = 0.085). Total metabolic tumour volume, baseline total lesion glycolysis and response according to the Deauville score were not predictive of outcome. CONCLUSIONS: A low initial SUVmax was predictive of worse outcomes in our series of patients with T-type LL. Although relatively few patients were included, the study also suggested that ΔSUVmax may be useful for predicting therapeutic efficacy.

Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma.

Classical Hodgkin lymphoma is one of the most common lymphomas and shares clinical and genetic features with primary mediastinal B-cell lymphoma. In this retrospective study, we analyzed the recurrent hotspot mutation of the exportin 1 (XPO1, p.E571K) gene, previously identified in primary mediastinal B-cell lymphoma, in biopsies and plasma circulating cell-free DNA from patients with classical Hodgkin lymphoma using a highly sensitive digital PCR technique. A total of 94 patients were included in the present study. This widely expressed XPO1 E571K mutation is present in one quarter of classical Hodgkin lymphoma patients (24.2%). Mutated and wild-type classical Hodgkin lymphomas were similar regarding the main clinical features. Patients with a detectable XPO1 mutation at the end of treatment displayed a tendency toward shorter progression-free survival, as compared to patients with undetectable mutation in plasma cell-free DNA (2-year progression-free survival: 57.1%, 95% confidence interval: 30.1-100% versus 2-year progression-free survival: 90.5%, 95% confidence interval: 78.8-100%, respectively, P=0.0601). To conclude, the detection of the XPO1 E571K mutation in biopsy and plasma cell-free DNA by digital PCR may be used as a novel biomarker in classical Hodgkin lymphoma for both diagnosis and minimal residual disease, and pinpoints a crucial role of XPO1 in classical Hodgkin lymphoma pathogenesis. The detection of somatic mutation in the plasma cell-free DNA of patients represents a major technological advance in the context of liquid biopsies and noninvasive management of classical Hodgkin lymphoma.

Interobserver Agreement of the Eaton-Glickel Classification for Trapeziometacarpal and Scaphotrapezial Arthrosis.

PURPOSE: To determine whether simplification of the Eaton-Glickel (E-G) classification of trapeziometacarpal (TMC) joint arthrosis (eliminating evaluation of the scaphotrapezial [ST] joint) and information about the patient's symptoms and examination influence interobserver reliability. We also tested the null hypotheses that no patient and/or surgeon factors affect radiographic rating of TMC joint arthrosis and that no surgeon factors affect the radiographic rating of ST joint arthrosis. METHODS: In an on-line survey, 92 hand surgeons rated TMC joint arthrosis and ST joint arthrosis separately on 30 radiographs (Robert, true lateral, and oblique views) according to the (modified) E-G classification. We randomly assigned 42 observers to review radiographs alone and also informed 50 of the patient's symptoms and examination. Information about symptoms and examination was randomized. Interobserver reliability was determined with the s* statistic. Because of the hierarchical data structure, cross-classified ordinal multilevel regression analyses were performed to identify factors associated with the severity of arthrosis. RESULTS: Shortening the E-G classification to the first 3 stages significantly improved the interobserver reliability, which approached substantial agreement. Providing clinical information to observers marginally improved interobserver reliability. Factors associated with a lower E-G stage for TMC joint arthrosis, among observers who rated the severity of TMC joint arthrosis based on radiographs and clinical information, included female surgeon, practice setting, supervising surgical trainees in the operating room, self-reported number of patients with TMC joint arthrosis typically treated annually, male patient, higher patient age, pain limiting daily activities, and shoulder sign. A self-reported larger number of patients with TMC joint arthrosis treated annually was the only variable associated with a higher modified E-G classification to rate ST joint arthrosis. CONCLUSIONS: Our findings suggest that simpler classifications that focus on a single anatomical area are reliable and that surgeon and patient factors can bias interpretation of objective pathophysiology such as radiographic findings. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

PET/CT before autologous stem cell transplantation predicts outcome in refractory/relapsed follicular lymphoma.

PURPOSE: Salvage of young patients with follicular lymphoma (FL) after R-CHOP includes salvage immunochemotherapy followed by autologous stem cell transplantation (ASCT). Previous studies dealing with relapsed Hodgkin lymphoma have shown the prognostic value of PET/CT prior to ASCT. METHODS: We retrospectively analysed 59 patients with refractory/relapsed FL after first-line R-CHOP who were chemosensitive (as evaluated by CT) to the salvage treatment and who proceeded to ASCT. The role of PET/CT in this setting to define chemosensitivity is not definitely established. So we focused on the prognostic value of PET/CT performed after salvage treatment, before ASCT. RESULTS: The estimated 3-year progression-free survival (PFS) and overall survival were 63.1% (50.9-78.3%) and 90.5% (82.8 - 98.8%), respectively, and did not differ significantly according to their Follicular Lymphoma International Prognostic Index at relapse, conditioning regimen, or type of salvage. PFS was significantly lower in PET/CT-positive patients, according to the International Harmonization Project revised response criteria, with a 3-year PFS of 45.5% (26.6 - 77.8%) versus 72.6% (58.5 - 90.0%; p = 0.039). To better refine prognosis, we applied two types of throsholds: a Deauville five-point scale positive threshold of ≥3 (3-year PFS of 74.9%, range 61.0 - 92.1% %, versus 42.8%, range 24.7 - 74.4%; p = 0.02), and a ≥70% ∆SUVmax threshold between presalvage and pre-ASCT PET/CT (3-year PFS of 72.4%, range 57.5 - 91.3% versus 13.3%, 2.2 - 81.7%; p < 10(-3)). The PET/CT findings before ASCT were independently correlated with PFS in our series. CONCLUSION: PET/CT negativity before ASCT is a desirable and achievable goal in the management of chemosensitive FL relapsing after first-line R-CHOP.

How prevalent are hazardous attitudes among orthopaedic surgeons?

BACKGROUND: So-called "hazardous attitudes" (macho, impulsive, antiauthority, resignation, invulnerable, and confident) were identified by the Federal Aviation Administration and the Canadian Air Transport Administration as contributing to road traffic incidents among college-aged drivers and felt to be useful for the prevention of aviation accidents. The concept of hazardous attitudes may also be useful in understanding adverse events in surgery, but it has not been widely studied. QUESTIONS/PURPOSES: We surveyed a cohort of orthopaedic surgeons to determine the following: (1) What is the prevalence of hazardous attitudes in a large cohort of orthopaedic surgeons? (2) Do practice setting and/or demographics influence variation in hazardous attitudes in our cohort of surgeons? (3) Do surgeons feel they work in a climate that promotes patient safety? METHODS: We asked the members of the Science of Variation Group-fully trained, practicing orthopaedic and trauma surgeons from around the world-to complete a questionnaire validated in college-aged drivers measuring six attitudes associated with a greater likelihood of collision and used by pilots to assess and teach aviation safety. We accepted this validation as applicable to surgeons and modified the questionnaire accordingly. We also asked them to complete the Modified Safety Climate Questionnaire, a questionnaire assessing the absence of a safety climate that is based on the patient safety cultures in healthcare organizations instrument. Three hundred sixty-four orthopaedic surgeons participated, representing a 47% response rate of those with correct email addresses who were invited. RESULTS: Thirty-eight percent (137 of 364 surgeons) had at least one score that would have been considered dangerously high in pilots (> 20), including 102 with dangerous levels of macho (28%) and 41 with dangerous levels of self-confidence (11%). After accounting for possible confounding variables, the variables most closely associated with a macho attitude deemed hazardous in pilots were supervision of surgical trainees in the operating room (p = 0.003); location of practice in Canada (p = 0.059), Europe (p = 0.021), and the United States (p = 0.005); and being an orthopaedic trauma surgeon (p = 0.046) (when compared with general orthopaedic surgeons), but accounted for only 5.3% of the variance (p < 0.001). On average, 19% of surgeon responses to the Modified Safety Climate Questionnaire implied absence of a safety climate. CONCLUSIONS: Hazardous attitudes are common among orthopaedic surgeons and relate in small part to demographics and practice setting. Future studies should further validate the measure of hazardous attitudes among surgeons and determine if they are associated with preventable adverse events. We agree with aviation safety experts that awareness of amelioration of such attitudes might improve safety in all complex, high-risk endeavors, including surgery-a line of thinking that merits additional research.

Medical services and associated costs vary widely among surgeons treating patients with hand osteoarthritis.

BACKGROUND: There are substantial variations in medical services that are difficult to explain based on differences in pathophysiology alone. The scale of variation and the number of people affected suggest substantial potential to lower healthcare costs with the reduction of practice variation. Our study assessed practice variation across three affiliated urban sites in one city in the United States and related healthcare costs following the diagnosis of hand osteoarthritis (OA) in patients. QUESTIONS/PURPOSES: (1) What are the factors associated with increased costs and surgery in the first year after diagnosis of hand OA? (2) How much practice variation exists among hand surgeons in terms of the number of patient visits, use of imaging tests, use of injections, occupational therapy use, and surgery? (3) What proportion of total cost is accounted for by patients who consult with an additional provider? METHODS: Patients receiving a new diagnosis of primary hand OA between January 1, 2007, and December 31, 2011, were identified from the research database of three affiliated urban hospitals in a single city in the United States. We included 2814 patients (69%, 1929 women) treated by six hand surgeons. We recorded all visits, imaging tests, injections, occupational therapy visits, and surgical procedures in the first year after that diagnosis. Costs were extracted from the Medicare Physician Fee Schedule. Reliability of the database was assessed by manual checking of 120 patient charts (4.3% of all data); reliability was determined to be 94% (113 of 120) for diagnoses, 97% (116 of 120) correct surgeon, 100% (120 of 120) second surgeon, 99% (278 of 282) visits, 99% (132 of 134) imaging procedures, 92% (11 of 12) injections, 95% (21 of 22) surgical procedures, and 85% (102 of 120) prescribing occupational therapy. RESULTS: Predictors of increased costs included younger patient age (regression coefficient [ß] -3.5, semipartial R(2) 0.0049, 95% confidence interval [CI] -5.4 to -1.7, p < 0.001), seeing a second surgeon (ß 283, semipartial R(2) 0.0095, 95% CI 176-391, p < 0.001), and specific surgeons (surgeon 1: ß -243, semipartial R(2) 0.026, 95% CI -298 to -188, p < 0.001; surgeon 2: ß -177, semipartial R(2) 0.0090, 95% CI -246 to -109, p < 0.001; surgeon 6: ß 124, semipartial R(2) 0.0050, 95% CI 59-189, p < 0.001) (adjusted R(2) = 0.056). Similarly, factors associated with increased surgical intervention included younger patient age (ß -0.0026, semipartial R(2) 0.0071, 95% CI -0.0037 to -0.0015, p < 0.001), male sex (ß 0.041, semipartial R(2) 0.0028, 95% CI -0.069 to -0.012, p = 0.005), seeing a second surgeon (ß 0.16, semipartial R(2) 0.0091, 95% CI 0.094-0.22, p < 0.001), and specific surgeons (surgeon 1: ß -0.14, semipartial R(2) 0.026, 95% CI -0.18 to -0.11, p < 0.001; surgeon 2: ß -0.13, semipartial R(2) 0.014, 95% CI -0.17 to -0.091, p < 0.001). There were large variations in the average number of visits (1.5-fold), imaging tests (threefold), use of injections (51-fold), occupational therapy (twofold), and surgery rates (sevenfold) among providers. One hundred twenty patients (4.3%) consulted a second surgeon within the first year after receiving the diagnosis of hand OA, which accounted for 8.1% (USD 68,826/USD 845,304) of the total costs. CONCLUSIONS: Patients who saw additional providers and who were of younger age incurred higher costs and a greater likelihood of undergoing surgery; the latter was also greater in male patients. Use of medical services and associated costs vary widely among providers treating patients with hand OA. Initiatives addressing practice variation-increased use of decision aids, for example-merit additional study. LEVEL OF EVIDENCE: Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Disability in patients with trapeziometacarpal joint arthrosis: incidental versus presenting diagnosis.

PURPOSE: To test the hypothesis that there is no difference in trapeziometacarpal (TMC) joint arthrosis-related symptoms and disability between patients seeking treatment for symptoms of TMC arthrosis and those with incidental TMC joint arthrosis. METHODS: We compared 64 patients presenting for care of TMC joint arthrosis with 64 with incidental TMC joint arthrosis. For both groups, the diagnosis was based on crepitation on examination. Bivariate and multivariate analyses assessed factors associated with symptoms and disability related to TMC joint arthrosis. RESULTS: In bivariate analysis, patients presenting for care of TMC joint arthrosis had significantly more symptoms and disability from TMC joint arthrosis than those with incidental TMC joint arthrosis. The best multivariate linear regression model for fewer TMC joint arthrosis-related symptoms and disability included patients with incidental TMC joint arthrosis, male sex, no other painful conditions, less catastrophic thinking, and fewer depressive symptoms and explained 74% of the variability. Having incidental TMC joint arthrosis (25%) and more adaptive coping strategies (less catastrophic thinking; 5%) were the most important contributors to fewer symptoms and less disability. CONCLUSIONS: Future studies are merited to determine whether training in better coping strategies (eg, less catastrophic thinking and fewer depressive symptoms) can decrease symptoms and disability in patients with TMC joint arthrosis. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III.

Relationships between pain misconceptions, disability, patients' goals and interpretation of information from hand therapists.

INTRODUCTION: Patient interpretation of advice from hand therapists may be related to nonadaptive pain thoughts (automatic, overprotective, unduly pessimistic statements triggered by nociception and exacerbated by psychological distress). PURPOSE OF THE STUDY: This study aimed to determine whether there were correlations between participants' hand therapy goals, interpretation of advice from hand therapists, nonadaptive pain thoughts, and upper extremity-specific disability. METHODS: One hundred and five participants completed questionnaires assessing nonadaptive pain thoughts, upper extremity-specific disability, lessons from hand therapists, and hand therapy goals. RESULTS: Nonadaptive pain thoughts correlated with disability and were bi-directionally related to participant goals and interpretation of advice from hand therapists. DISCUSSION: Patients' nonadapative pain thoughts and the words/concepts used by hand therapists are both important in recovery from upper extremity illness. CONCLUSIONS: Hand therapists should be mindful that nonadaptive pain thoughts are an important determinant of disability and that such thoughts can affect and be affected by their recommendations. LEVEL OF EVIDENCE: n/a.

Phase IB Study of Oral Selinexor in Combination with Rituximab and Platinum Chemotherapy in Patients with Relapsed/Refractory B-Cell Lymphoma-Final Analysis.

PURPOSE: Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma. PATIENTS AND METHODS: We conducted a phase 1b, dose-escalation, and expansion trial, which enrolled patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Patients received oral selinexor according to a 3 + 3 design in combination with rituximab and dexamethasone, high-dose cytarabine, oxaliplatine (DHAOX) or gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. RESULTS: A total of 39 patients were enrolled, 27 during the escalation phase and 12 during the expansion phase. Most patients had diffuse large B-cell lymphoma (DLBCL; 77%). Group R-DHAOX was prematurely closed to inclusion due to a recommendation from the French drug agency, independent of this trial. A recommended phase 2 dose (RP2D) of selinexor in association with R-GPD was established at 40 mg on days 1, 8, and 15 of each 21-day cycle. In a population of 18 patients treated at this dose of selinexor, the most frequent grade 3-4 adverse events were hematological. With this regimen, seven obtained a complete metabolic response and five a partial response. The median PFS was 5.8 months. CONCLUSIONS: Among the patients with R/R B-cell lymphoma, selinexor at a weekly dose of 40 mg with R-GDP is feasible for outpatients, with a generally acceptable safety profile.