Clinician Interruptions and Patient-Rated Clinician Empathy in Specialty Visits.

INTRODUCTION: Clinicians tend to interrupt patients when they are describing their problem, which may contribute to feeling unheard or misunderstood. Using transcripts of audio and video recordings from musculoskeletal (MSK) specialty visits, we asked what factors are associated with (1) Perceived clinician empathy, including the time a patient spends describing the problem and time to the first interruption, (2) duration of patient symptom description, and (3) duration between the end of greeting and first nonactive listening interruption. METHODS: We analyzed transcripts of 194 adult patients seeking MSK specialty care with a median age (Interquartile range [IQR]) of 47 (33 to 59) years. Participants completed postvisit measures of perceived clinician empathy, symptoms of depression, accommodation of pain, and health anxiety. A nonactive listening interruption was defined as the clinician unilaterally redirecting the topic of conversation. Factors associated with patient-rated clinician empathy, patient problem description duration, and time until the first nonactive listening interruption were sought in bivariate and multivariable analyses. RESULTS: The patient's narrative was interrupted at least one time in 144 visits (74%). The duration of each visit was a median of 12 minutes (IQR 9 to 16 minutes). The median time patients spent describing their symptoms was 139 seconds before the first interruption (IQR 84 to 225 seconds). The median duration between the end of the initial greeting and the first interruption was 60 seconds (IQR 30 to 103 seconds). Clinician interruption was associated with shorter duration of symptom description. Greater perceived clinician empathy was associated with greater accommodation of pain (regression coefficient [95% confidence interval] = 0.015 [0.0005-0.30]; P = 0.04). DISCUSSION: Clinician interruption was associated with shorter symptom presentation, but not with diminished perception of clinician empathy. Although active listening and avoidance of interruption are important communication tactics, other aspects of the patient-clinician relationship may have more effect on patient experience.

Does Addressing Mental Health During a Musculoskeletal Specialty Care Visit Affect Patient-rated Clinician Empathy?

BACKGROUND: Unhelpful thoughts and feelings of worry or despair about symptoms account for a notable amount of the variation in musculoskeletal symptom intensity. Specialists may be best positioned to diagnose these treatable aspects of musculoskeletal illness. Musculoskeletal specialists might be concerned that addressing mental health could offend the patient, and avoidance might delay mental health diagnosis and treatment. Evidence that conversations about mental health are not associated with diminished patient experience might increase specialist confidence in the timely diagnosis and initial motivation to treat unhelpful thoughts and feelings of worry or despair. QUESTIONS/PURPOSES: Using transcripts of videotaped and audiotaped specialty care visits in which at least one instance of patient language indicating an unhelpful thought about symptoms or feelings of worry or despair surfaced, we asked: (1) Is clinician discussion of mental health associated with lower patient-rated clinician empathy, accounting for other factors? (2) Are clinician discussions of mental health associated with patient demographics, patient mental health measures, or specific clinicians? METHODS: Using a database of transcripts of 212 patients that were audio or video recorded for prior studies, we identified 144 transcripts in which language reflecting either an unhelpful thought or feelings of distress (worry or despair) about symptoms was detected. These were labeled mental health opportunities. Patients were invited on days when the researcher making video or audio records was available, and people were invited based on the researcher's availability, the patient's cognitive ability, and whether the patient spoke English. Exclusions were not tracked in those original studies, but few patients declined. There were 80 women and 64 men, with a mean age of 45 ± 15 years. Participants completed measures of health anxiety, catastrophic thinking, symptoms of depression, and perceived clinician empathy. Factors associated with perceived clinician empathy and clinician discussion of mental health were sought in bivariate and multivariable analyses. RESULTS: Greater patient-rated clinician empathy was not associated with clinician initiation of a mental health discussion (regression coefficient 0.98 [95% confidence interval 0.89 to 1.1]; p = 0.65). A clinician-initiated mental health discussion was not associated with any factors. CONCLUSION: The observation that a clinician-initiated mental health discussion was not associated with diminished patient ratings of clinician empathy and was independent from other factors indicates that generally, discussion of mental health does not harm patient-clinician relationship. Musculoskeletal clinicians could be the first to notice disproportionate symptoms or misconceptions and distress about symptoms, and based on the evidence from this study, they can be confident about initiating a discussion about these mental health priorities to avoid delays in diagnosis and treatment. Future studies can address the impact of training clinicians to notice unhelpful thoughts and signs of distress and discuss them with compassion in a specialty care visit; other studies might evaluate the impact of timely diagnosis of opportunities for improvement in mental health on comfort, capability, and optimal stewardship of resources.

When Musculoskeletal Clinicians Respond to Empathetic Opportunities, do Patients Perceive Greater Empathy?

BACKGROUND: Patient use of verbal and nonverbal communication to signal what is most important to them can be considered empathetic opportunities. Orthopaedic surgeons may have mixed feelings toward empathetic opportunities, on one hand wanting the patient to know that they care, and on the other hand fearing offense, prolonged visit duration, or discussions for which they feel ill prepared. Evidence that action about empathetic opportunities does not harm the patient's experience or appreciably prolong the visit could increase the use of these communication tactics with potential for improved experience and outcomes of care. QUESTIONS/PURPOSES: Using transcripts from musculoskeletal specialty care visits in prior studies, we asked: (1) Are there factors, including clinician attentiveness to empathetic opportunities, associated with patient perception of clinician empathy? (2) Are there factors associated with the number of patient-initiated empathetic opportunities? (3) Are there factors associated with clinician acknowledgment of empathetic opportunities? (4) Are there factors associated with the frequency with which clinicians elicited empathetic opportunities? METHODS: This study was a retrospective, secondary analysis of transcripts from prior studies of audio and video recordings of patient visits with musculoskeletal specialists. Three trained observers identified empathetic opportunities in 80% (209 of 261) of transcripts of adult patient musculoskeletal specialty care visits, with any uncertainties or disagreements resolved by discussion and a final decision by the senior author. Patient statements considered consistent with empathetic opportunities included relation of emotion, expression of worries or concerns, description of loss of valued activities or loss of important roles or identities, relation of a troubling psychologic or social event, and elaboration on daily life. Clinician-initiated empathetic opportunities were considered clinician inquiries about these factors. Clinician acknowledgment of empathetic opportunities included encouragement, affirmation or reassurance, or supportive statements. Participants completed post-visit surveys of perceived clinician empathy, symptoms of depression, and health anxiety. Factors associated with perceived clinician empathy, number of empathetic opportunities, clinician responses to these opportunities, and the frequency with which clinicians elicited empathetic opportunities were sought in bivariate and multivariable analyses. RESULTS: After controlling for potentially confounding variables such as working status and pain self-efficacy scores in the multivariable analysis, no factors were associated with patient perception of clinician empathy, including attentiveness to empathetic opportunities. Patient-initiated empathetic opportunities were modestly associated with longer visit duration (correlation coefficient 0.037 [95% confidence interval 0.023 to 0.050]; p < 0.001). Clinician acknowledgment of empathetic opportunities was modestly associated with longer visit duration (correlation coefficient 0.06 [95% CI 0.03 to 0.09]; p < 0.001). Clinician-initiated empathetic opportunities were modestly associated with younger patient age (correlation coefficient -0.025 [95% CI -0.037 to -0.014]; p < 0.001) and strongly associated with one specific interviewing clinician as well as other clinicians (correlation coefficient -1.3 [95% CI -2.2 to -0.42]; p = 0.004 and -0.53 [95% CI -0.95 to -0.12]; p = 0.01). CONCLUSION: Musculoskeletal specialists can respond to empathic opportunities without harming efficiency, throughput, or patient experience. CLINICAL RELEVANCE: Given the evidence that patients prioritize feeling heard and understood, and evidence that a trusting patient-clinician relationship is protective and healthful, the results of this study can motivate specialists to train and practice effective communication tactics.

Tumor Infiltrating Lymphocytes Predict Survival in Solid Organ Transplant Recipients With Monomorphic Post-transplant Lymphoproliferative Disorders.

INTRODUCTION: The tumor microenvironment (TME) in post-transplant lymphoproliferative disorders (PTLDs) remains unexplored. Tumor infiltrating lymphocytes (TILs) are prognostic in other lymphomas. We assessed the prognostic impact of TILs in monomorphic B-cell PTLD. METHODS: TIL density (CD3+ cells/mm2) was determined by CD3 immunohistochemistry in archived diagnostic biopsies from patients diagnosed with monomorphic B-cell PTLD. RESULTS: Amongst monomorphic PTLDs (N = 107), low TIL-count was associated with inferior 2-year progression-free survival (PFS) (41% versus 86%, P = .003) and 2-year overall survival (OS) (52% versus 93%, P = .003) by Kaplan-Meier analysis. Low TIL-count was significant on Cox univariate regression for inferior PFS (HR 4.5, 95% CI 2.0-9.9, P < .001) and OS (HR 4.6, 95% CI 1.8-11.8, P < .001). Multivariate analysis with clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) and TIL-count showed significance for PFS (HR 3.3, 95% CI 1.3-8.3, P = .010) and a non-significant trend for OS (HR 2.6, 95% CI 0.9-7.3, P = .064). A composite score including TILs and clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) effectively stratified monomorphic PTLD patients by PFS and OS (2-year OS: low-risk 93%, intermediate-risk 61%, high-risk 23%, P < .001). CONCLUSIONS: The TME and TILs are prognostically relevant in monomorphic PTLD. Prognostic models including measures of the TME may improve risk stratification for patients with monomorphic PTLDs.

Failure of rituximab is associated with a poor outcome in diffuse large B cell lymphoma-type post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) may arise after solid organ transplantation, and the most common subtype resembles diffuse large B cell lymphoma (DLBCL). In DLBCL-type PTLD, the anti-CD20 antibody rituximab (R) may be combined with chemotherapy (R-CHOP) or use a strategy (R-primary; similar to the PTLD-1 clinical trial) consisting of induction with four weekly doses of R-alone, without any chemotherapy or sequential R-CHOP follow-up. Here we report on a multicentre retrospective cohort of solid organ transplant patients with DLBCL-type PTLD that were treated with R. In 168 adults, two-year overall survival (OS) was 63·7% [95% CI (confidence interval) 56·6-71·7%]. No difference in OS was observed, whether patients were treated with R-CHOP versus the R-primary strategy. In the 109 patients treated with R-primary, multivariate analysis found that baseline IPI score and the response to R-induction predicted OS. Patients who responded to R-induction had durable remissions without the addition of chemotherapy. Conversely, of the 46 patients who had stable or progressive disease after R-induction (R-failure), those who received R-CHOP had an only marginally improved outcome, with a two-year OS of 45% (23·1-65·3%) vs. no R-CHOP at 32% (14·7-49·8%). In real-world patients, R-failure and high IPI scores predict a poor outcome in DLBCL-type PTLD.

The Effect of Extended Continuous Positive Airway Pressure on Changes in Lung Volumes in Stable Premature Infants: A Randomized Controlled Trial.

OBJECTIVE: To compare changes in lung volumes, as measured by functional residual capacity (FRC), through to discharge in stable infants randomized to 2 weeks of extended continuous positive airway pressure CPAP (eCPAP) vs CPAP discontinuation (dCPAP). STUDY DESIGN: Infants born at ≤32 weeks of gestation requiring ≥24 hours of CPAP were randomized to 2 weeks of eCPAP vs dCPAP when meeting CPAP stability criteria. FRC was measured with the nitrogen washout technique. Infants were stratified by gestational age (<28 and ≥ 28 weeks) and twin gestation. A linear mixed-effects model was used to evaluate the change in FRC between the 2 groups. Data were analyzed blinded to treatment group allocation. RESULTS: Fifty infants were randomized with 6 excluded, for a total of 44 infants. Baseline characteristics were similar in the 2 groups. The infants randomized to eCPAP vs dCPAP had a greater increase in FRC from randomization through 2 weeks (12.6 mL vs 6.4 mL; adjusted 95% CI, 0.78-13.47; P = .03) and from randomization through discharge (27.2 mL vs 17.1 mL; adjusted 95% CI, 2.61-17.59; P = .01). CONCLUSIONS: Premature infants randomized to eCPAP had a significantly greater increase in FRC through discharge compared with those randomized to dCPAP. An increased change in FRC may lead to improved respiratory health. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02249143.

Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation.

BACKGROUND: The application of mesenchymal stromal cell (MSC)-based therapy during ex vivo lung perfusion (EVLP) could repair injured donor lungs before transplantation. The aim of this study was to determine the efficacy of MSC therapy performed during EVLP on ischemia-reperfusion injury using a pig lung transplant model. METHODS: Following 24 hours of cold storage, pig lungs were randomly assigned to 2 groups (n = 6 each), the control group without MSC vs the MSC group, where 5 × 106 cells/kg MSCs were delivered through the pulmonary artery during EVLP. After 12 hours of EVLP, followed by a 1-hour second cold preservation period, the left lung was transplanted and reperfused for 4 hours. RESULTS: EVLP perfusate hepatocyte growth factor (HGF) level at 12 hours was significantly elevated in the MSC group compared with the control and was associated with a significant decrease in cell death markers, cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, in the MSC group. The MSC group showed significantly lower interleukin (IL)-18 and interferon gamma levels and a significantly higher IL-4 level in lung tissue at 12 hours of EVLP than the control group. After transplantation, the MSC group showed a significant increase in lung tissue HGF level compared with the control group, associated with a significantly reduced lung tissue wet-to-dry weight ratio. Lung tissue tumor necrosis factor-α level and pathological acute lung injury score were significantly lower in the MSC group than the control group. CONCLUSIONS: The administration of MSCs ameliorated ischemic injury in donor lungs during EVLP and attenuated the subsequent ischemia-reperfusion injury after transplantation.

HDAC Inhibition for the Treatment of Epithelioid Sarcoma: Novel Cross Talk Between Epigenetic Components.

UNLABELLED: Epithelioid sarcoma is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it poses a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors (HDACi) exhibit marked antitumor effects in various malignancies. The studies here demonstrate that pan-HDAC inhibitors constitute novel therapeutics versus epithelioid sarcoma. Human ES cells (VAESBJ, HS-ES, Epi-544) were studied in preclinical models to evaluate HDACi effects. Immunoblot and RT-PCR were used to evaluate expression of acetylated tubulin, histones H3/H4, EZH2 upon HDACi. MTS and clonogenic assays were used to assess the impact of HDACi on cell growth. Cell culture assays were used to evaluate the impact of HDACi and EZH2-specific siRNA inhibition on cell-cycle progression and survival. Unbiased gene array analysis was used to identify the impact of HDACi on epithelioid sarcoma gene expression. Xenografts were used to evaluate epithelioid sarcoma tumor growth in response to HDACi. HDAC inhibition increased target protein acetylation and abrogated cell growth and colony formation in epithelioid sarcoma cells. HDACi induced G(2) cell-cycle arrest and marked apoptosis, and reduced tumor growth in xenograft models. HDACi induced widespread gene expression changes, and EZH2 was significantly downregulated. EZH2 knockdown resulted in abrogated cell growth in vitro. IMPLICATIONS: The current study suggests a clinical role for HDACi in human epithelioid sarcoma, which, when combined with EZH2 inhibitors, could serve as a novel therapeutic strategy for epithelioid sarcoma patients. Future investigations targeting specific HDAC isoforms along with EZH2 may potentially maximizing treatment efficacy.

CHOPER filters enable rare mutation detection in complex mutagenesis populations by next-generation sequencing.

Next-generation sequencing (NGS) has revolutionized genetics and enabled the accurate identification of many genetic variants across many genomes. However, detection of biologically important low-frequency variants within genetically heterogeneous populations remains challenging, because they are difficult to distinguish from intrinsic NGS sequencing error rates. Approaches to overcome these limitations are essential to detect rare mutations in large cohorts, virus or microbial populations, mitochondria heteroplasmy, and other heterogeneous mixtures such as tumors. Modifications in library preparation can overcome some of these limitations, but are experimentally challenging and restricted to skilled biologists. This paper describes a novel quality filtering and base pruning pipeline, called Complex Heterogeneous Overlapped Paired-End Reads (CHOPER), designed to detect sequence variants in a complex population with high sequence similarity derived from All-Codon-Scanning (ACS) mutagenesis. A novel fast alignment algorithm, designed for the specified application, has O(n) time complexity. CHOPER was applied to a p53 cancer mutant reactivation study derived from ACS mutagenesis. Relative to error filtering based on Phred quality scores, CHOPER improved accuracy by about 13% while discarding only half as many bases. These results are a step toward extending the power of NGS to the analysis of genetically heterogeneous populations.

A polymer-extracellular matrix composite with improved thromboresistance and recellularization properties.

Organ engineering using decellularized scaffolds is a potential long-term solution to donor organ shortage. However, this technology is severely limited by small vessel thrombosis due to incompletely recellularized vessels, resulting in exposure of extracellular matrix (ECM) components to platelets and clotting factors in flowing blood. To address this limitation, we designed a polymer-ECM composite and demonstrated its potential to reduce thrombosis and facilitate re-endothelialization in a vascular graft model. Rat aortas were decellularized using a sequential combination of weak detergents followed by a nuclease treatment that resulted in 96.5±1.3% DNA removal, while ECM components and mechanical properties were well maintained. A biodegradable and biocompatible elastomer poly(1,8 octanediol citrate) (POC, 1wt.%) was infused throughout the ECM at mild conditions (37°C and 45°C) and was functionalized with heparin using carbodiimide chemistry. The polymer-ECM composite significantly reduced platelet adhesion (67.4±8.2% and 82.7±9.6% reduction relative to untreated ECM using one of two processing temperatures, 37°C or 45°C, respectively); inhibited whole blood clotting (85.9±4.3% and 87.0±11.9% reduction relative to untreated ECM at 37°C or 45°C processing temperature, respectively); and supported endothelial cell-and to a lesser extent smooth muscle cell-adhesion in vitro. Taken together, this novel POC composite may provide a solution for thrombosis of small vessel conduits commonly seen in decellularized scaffolds used in tissue engineering applications.

Uterine leiomyosarcoma management, outcome, and associated molecular biomarkers: a single institution's experience.

BACKGROUND: Uterine leiomyosarcoma (ULMS) is an aggressive, rapidly progressive tumor lacking clinical and molecular predictors of outcome. METHODS: ULMS patients (n = 349) were classified by disease status at presentation to MDACC as having intra-abdominal (n = 157) or distant metastatic disease (n = 192). Patient, tumor, treatment, and outcome variables were retrospectively retrieved. Formalin-fixed, paraffin-embedded tumor and control tissues from these patients (n = 109) were assembled in a tissue microarray and evaluated for hormone receptors and markers of angiogenesis, cell-cycle progression and survival. Patient, tumor, and treatment variables were correlatively analyzed. RESULTS: The 5- and 10-year disease-specific survival (DSS) for the cohort was 42 and 27 %, respectively. Patients with primary intra-abdominal tumors had better outcomes than those with recurrent intraperitoneal tumors. Whites had a more favorable prognosis. In patients with intra-abdominal tumors, only mitotic count >10M/10HPF portended poorer prognosis. Patients with pulmonary metastasis had improved outcomes with "curative" metastasectomy. ULMS samples exhibited loss of ER and PR expression, overexpressed Ki-67, and altered p53, Rb, p16, cytoplasmic ß-catenin, EGFR, PDGFR-α, PDGFR-ß, and AXL levels. Metastatic tumors had increased VEGF, Ki-67, and survivin expression versus localized disease. Survivin and ß-catenin expression were associated with intraperitoneal recurrence; high bcl-2 expression predicted longer DSS. CONCLUSIONS: Analysis of both clinicopathologic factors and immunohistochemical biomarkers in ULMS identified several prognostic clinical and molecular factors, suggesting that further study may lead to improved ULMS understanding and treatment.

Long-term outcomes in patients with radiation-associated angiosarcomas of the breast following surgery and radiotherapy for breast cancer.

BACKGROUND: Radiation-associated angiosarcoma (RAAS) is a devastating disease occasionally observed in breast cancer patients treated with radiation. Due to its rarity, our knowledge-of disease risk factors, epidemiology, treatment, and outcome-is extremely limited. Therefore, we sought to identify clinicopathologic factors associated with local and distant recurrence and disease-specific survival (DSS). METHODS: Radiation-associated angiosarcoma was defined as pathologically confirmed breast or chest wall angiosarcoma arising within a previously irradiated field. A comprehensive search of our institutional tumor registry (1/1/93 through 2/28/11) was used to identify patients (n = 95 females). Patient, original tumor, RAAS treatment, and outcome variables were retrospectively retrieved and assembled into a database. RESULTS: The median follow-up for all RAAS patients was 10.3 (range, 2.4-31.8) years. The latency period following radiation exposure ranged from 1.4 to 26 (median, 7) years. One-year and 5-year DSS rates were 93.5 and 62.6 %, respectively. Reduced risk of local recurrence was observed in patients who received chemotherapy (P = 0.0003). In multivariable analysis, size was found to be an independent predictor of adverse outcome (P = 0.015). CONCLUSIONS: Our study demonstrates that RAAS exhibits high recurrence rates. It also highlights the need for well-designed, multicenter, clinical trials to inform the true utility of chemotherapy in this disease.

Ibn al-Nafis (1210-1288): the first description of the pulmonary circulation.

Ibn al-Nafis (1210-1288) was an Arab physician who contributed much to the advancement of medical knowledge and science in the 13th century. He was involved in jurisprudence, politics, and anatomical studies as well. Although a prominent ophthalmologist by training, today he is most recognized for his discovery of the lesser or pulmonary circulation. His was the first work to contradict the accepted teachings of Galen, which had existed since the 2nd century AD. His description included the observation that the wall of the septum is not porous either grossly or macroscopically as was believed by earlier scholars. Therefore, blood from the venous circulation had to be directed through the pulmonary artery ("venous artery") through the lungs to be "mixed with air" and drained back to the left side of the heart through the pulmonary vein ("arterial vein"). This discovery would lead to a change in the historical observations that the pulmonary circulation was discovered by European scientists in the 16th century and lead many to wonder if these scientists had access to Ibn al-Nafis' translated works. Ibn al-Nafis was devout to his work and to his religion, contributing much to the body of knowledge in anatomy and medicine as well as being a prominent and exceptional physician.