Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy.

The development of humoral autoimmunity following organ transplantation is increasingly recognised, but of uncertain significance. We examine whether autoimmunity contributes independently to allograft rejection. In a MHC class II-mismatched murine model of chronic humoral rejection, we report that effector antinuclear autoantibody responses were initiated upon graft-versus-host allorecognition of recipient B cells by donor CD4 T-cells transferred within heart allografts. Consequently, grafts were rejected more rapidly, and with markedly augmented autoantibody responses, upon transplantation of hearts from donors previously primed against recipient. Nevertheless, rejection was dependent upon recipient T follicular helper (TFH) cell differentiation and provision of cognate (peptide-specific) help for maintenance as long-lived GC reactions, which diversified to encompass responses against vimentin autoantigen. Heart grafts transplanted into stable donor/recipient mixed haematopoietic chimeras, or from parental strain donors into F1 recipients (neither of which can trigger host adaptive alloimmune responses), nevertheless provoked GC autoimmunity and were rejected chronically, with rejection similarly dependent upon host TFH cell differentiation. Thus, autoantibody responses contribute independently of host adaptive alloimmunity to graft rejection, but require host TFH cell differentiation to maintain long-lived GC responses. The demonstration that one population of helper CD4 T-cells initiates humoral autoimmunity, but that a second population of TFH cells is required for its maintenance as a GC reaction, has important implications for how autoimmune-related phenomena manifest.

Thrombocytopenia and craniotomy for tumor: A National Surgical Quality Improvement Program analysis.

BACKGROUND: To the authors' knowledge, the current study is the first national analysis of the association between preoperative platelet count and outcomes after craniotomy. METHODS: Patients who underwent craniotomy for tumor were extracted from the prospective National Surgical Quality Improvement Program registry (2007-2014) and stratified by preoperative thrombocytopenia, defined as mild (125,000-149,000/µL), moderate (100,000-124,000/µL), severe (75,000-99,000/µL), or very severe (<75,000/µL). Cox proportional hazards analysis was used to evaluate the association between thrombocytopenia and 30-day mortality, and multivariable logistic regression with complications and unplanned reoperation. Covariates included patient age, sex, tumor histology, American Society of Anesthesiologists class, functional status, comorbidities, and surgical time. RESULTS: A total of 14,852 patients were included in the current study and thrombocytopenia was classified as mild in 4.4% (646 patients), moderate in 2.0% (290 patients), severe in 0.7% (105 patients), or very severe in 0.4% (66 patients) of patients. The adjusted hazard of 30-day death was significantly higher for patients with moderate (6.6%; hazard ratio [HR], 2.13 [95% confidence interval (95% CI), 1.30-3.49; P = 0.003]), severe (10.5%; HR, 2.33 [95% CI, 1.18-4.60; P = 0.02]), and very severe (10.6%; HR, 3.65 [95% CI, 1.71-7.82; P = 0.001]) thrombocytopenia, compared with patients without thrombocytopenia (2.9%), with an increased effect size noted with greater thrombocytopenia. Likewise, when the platelet count was evaluated continuously, a higher platelet count was associated with a lower hazard of 30-day mortality (HR, 0.987 [95% CI, 0.981-0.993; P<.001]), developing any complication (odds ratio, 0.985 [95% CI, 0.981-0.988; P<.001]), and reoperation (odds ratio, 0.990 [95% CI, 0.983-0.994; P = .003]). Unplanned reoperation was due to intracranial hemorrhage in 53.3% of patients with moderate thrombocytopenia. CONCLUSIONS: In this National Surgical Quality Improvement Program analysis, moderate and severe thrombocytopenia were associated with mortality and reoperation after craniotomy for tumor. Cancer 2016;122:1708-17. © 2016 American Cancer Society.

Pain management among Dominican patients with advanced osteoarthritis: a qualitative study.

BACKGROUND: Advanced osteoarthritis and total joint replacement (TJR) recovery are painful experiences and often prompt opioid use in developed countries. Physicians participating in the philanthropic medical mission Operation Walk Boston (OpWalk) to the Dominican Republic have observed that Dominican patients require substantially less opioid medication following TJR than US patients. We conducted a qualitative study to investigate approaches to pain management and expectations for postoperative recovery in patients with advanced arthritis undergoing TJR in the Dominican Republic. METHODS: We interviewed 20 patients before TJR about their pain coping mechanisms and expectations for postoperative pain management and recovery. Interviews were conducted in Spanish, translated, and analyzed in English using content analysis. RESULTS: Patients reported modest use of pain medications and limited knowledge of opioids, and many relied on non-pharmacologic therapies and family support to cope with pain. They held strong religious beliefs that offered them strength to cope with chronic arthritis pain and prepare for acute pain following surgery. Patients exhibited a great deal of trust in powerful others, expecting God and doctors to cure their pain through surgery. CONCLUSION: We note the importance of understanding a patient's individual pain coping mechanisms and identifying strategies to support these coping behaviors in pain management. Such an approach has the potential to reduce the burden of chronic arthritis pain while limiting reliance on opioids, particularly for patients who do not traditionally utilize powerful analgesics.

Length of hospital stay after craniotomy for tumor: a National Surgical Quality Improvement Program analysis.

OBJECT Although the length of hospital stay is often used as a measure of quality of care, data evaluating the predictors of extended hospital stay after craniotomy for tumor are limited. The goals of this study were to use multivariate regression to examine which preoperative characteristics and postoperative complications predict a prolonged hospital stay and to assess the impact of length of stay on unplanned hospital readmission. METHODS Data were extracted from the National Surgical Quality Improvement Program (NSQIP) database from 2007 to 2013. Patients who underwent craniotomy for resection of a brain tumor were included. Stratification was based on length of hospital stay, which was dichotomized by the upper quartile of the interquartile range (IQR) for the entire population. Covariates included patient age, sex, race, tumor histology, comorbidities, American Society of Anesthesiologists (ASA) class, functional status, preoperative laboratory values, preoperative neurological deficits, operative time, and postoperative complications. Multivariate logistic regression with forward prediction was used to evaluate independent predictors of extended hospitalization. Thereafter, hierarchical multivariate logistic regression assessed the impact of length of stay on unplanned readmission. RESULTS The study included 11,510 patients. The median hospital stay was 4 days (IQR 3-8 days), and 27.7% (n = 3185) had a hospital stay of at least 8 days. Independent predictors of extended hospital stay included age greater than 70 years (OR 1.53, 95% CI 1.28%-1.83%, p < 0.001); African American (OR 1.75, 95% CI 1.44%-2.14%, p < 0.001) and Hispanic (OR 1.68, 95% CI 1.36%-2.08%) race or ethnicity; ASA class 3 (OR 1.52, 95% CI 1.34%-1.73%) or 4-5 (OR 2.18, 95% CI 1.82%-2.62%) designation; partially (OR 1.94, 95% CI 1.61%-2.35%) or totally dependent (OR 3.30, 95% CI 1.95%-5.55%) functional status; insulin-dependent diabetes mellitus (OR 1.46, 95% CI 1.16%-1.84%); hematological comorbidities (OR 1.68, 95% CI 1.25%-2.24%); and preoperative hypoalbuminemia (OR 1.78, 95% CI 1.51%-2.09%, all p ≤ 0.009). Several postoperative complications were additional independent predictors of prolonged hospitalization including pulmonary emboli (OR 13.75, 95% CI 4.73%-39.99%), pneumonia (OR 5.40, 95% CI 2.89%-10.07%), and urinary tract infections (OR 11.87, 95% CI 7.09%-19.87%, all p < 0.001). The C-statistic of the model based on preoperative characteristics was 0.79, which increased to 0.83 after the addition of postoperative complications. A length of stay after craniotomy for tumor score was created based on preoperative factors significant in regression models, with a moderate correlation with length of stay (p = 0.43, p < 0.001). Extended hospital stay was not associated with differential odds of an unplanned hospital readmission (OR 0.97, 95% CI 0.89%-1.06%, p = 0.55). CONCLUSIONS In this NSQIP analysis that evaluated patients who underwent craniotomy for tumor, much of the variance in hospital stay was attributable to baseline patient characteristics, suggesting length of stay may be an imperfect proxy for quality. Additionally, longer hospitalizations were not found to be associated with differential rates of unplanned readmission.

Brainstem Injury in Pediatric Patients Receiving Posterior Fossa Photon Radiation.

PURPOSE: Brainstem necrosis is a rare, but dreaded complication of radiation therapy; however, data on the incidence of brainstem injury for tumors involving the posterior fossa in photon-treated patient cohorts are still needed. METHODS AND MATERIALS: Clinical characteristics and dosimetric parameters were recorded for 107 pediatric patients who received photon radiation for posterior fossa tumors without brainstem involvement from 2000 to 2016. Patients were excluded if they received a prescription dose <50.4 Gy, a brainstem maximum dose <50.4 Gy, or had fewer than 2 magnetic resonance imaging scans within 18 months after radiation. Post-radiation therapy magnetic resonance imaging findings were recorded, and brainstem toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5. RESULTS: The most common histologies were medulloblastoma (61.7%) and ependymoma (15.9%), and median age at diagnosis was 8.3 years (range, 0.8-20.7). Sixty-seven patients (62.6%) received craniospinal irradiation (median, 23.4 Gy; range, 18.0-39.6) as a component of their radiation therapy, and 39.3% and 40.2% of patients received an additional involved field or whole posterior fossa boost, respectively. Median prescribed dose was 55.8 Gy (range, 50.4-60.0). Median clinical and imaging follow-up were 4.7 years (range, 0.1-17.5) and 4.2 years (range, 0.1-17.3), respectively. No grade ≥2 toxicities were observed. The incidence of grade 1 brainstem necrosis was 1.9% (2 of 107). These patients were by definition asymptomatic and experienced resolution of imaging abnormality after 5.3 months and 2.1 years, respectively. CONCLUSIONS: Risk of brainstem necrosis was minimal in this multi-institutional study of pediatric patients treated with photon radiation therapy for tumors involving the posterior fossa with no cases of symptomatic brainstem injury, suggesting that brainstem injury risk is minimal in patients treated with photon therapy.

Body habitus, serum albumin, and the outcomes after craniotomy for tumor: a National Surgical Quality Improvement Program analysis.

OBJECTIVE Although there is a growing body of research highlighting the negative impact of obesity and malnutrition on surgical outcomes, few studies have evaluated these parameters in patients undergoing intracranial surgery. The goal of this study was to use a national registry to evaluate the association of body mass index (BMI) and hypoalbuminemia with 30-day outcomes after craniotomy for tumor. METHODS Adult patients who underwent craniotomy for tumor were extracted from the prospective National Surgical Quality Improvement Program registry. Patients were stratified by body habitus according to the WHO classification, as well as by preoperative hypoalbuminemia (< 3.5 g/dl). Multivariable logistic regression evaluated the association of body habitus and hypoalbuminemia with 30-day mortality, complications, and discharge disposition. Covariates included patient age, sex, race or ethnicity, tumor histology, American Society of Anesthesiology class, preoperative functional status, comorbidities (including hypertension and diabetes mellitus), and additional preoperative laboratory values. RESULTS Among the 11,510 patients included, 28.7% were classified as normal weight (BMI 18.5-24.9 kg/m2), 1.9% as underweight (BMI < 18.5 kg/m2), 33.4% as overweight (BMI 25.0-29.9 kg/m2), 19.1% as Class I obese (BMI 30.0-34.9 kg/m2), 8.3% as Class II obese (BMI 35.0-39.9 kg/m2), 5.5% as Class III obese (BMI ≥ 40.0 kg/m2), and 3.1% had missing BMI data. In multivariable regression models, body habitus was not associated with differential odds of mortality, postoperative stroke or coma, or a nonroutine hospital discharge. However, the adjusted odds of a major complication were significantly higher for Class I obese (OR 1.28, 99% CI 1.01-1.62; p = 0.008), Class II obese (OR 1.53, 99% CI 1.13-2.07; p < 0.001), and Class III obese (OR 1.67, 99% CI 1.19-2.36; p < 0.001) patients compared with those of normal weight; a dose-dependent effect was seen, with increased effect size with greater adiposity. The higher odds of major complications was primarily due to significantly increased odds of a venous thromboembolism in overweight and obese patients, as well as of a surgical site infection in those with Class II or III obesity. Additionally, 41.0% of patients had an albumin level ≥ 3.5 g/dl, 9.6% had hypoalbuminemia, and 49.4% had a missing albumin value. Hypoalbuminemia was associated with significantly higher odds of mortality (OR 1.91, 95% CI 1.41-2.60; p < 0.001) or a nonroutine hospital discharge (OR 1.46, 95% CI 1.21-1.76; p < 0.001). CONCLUSIONS In this National Surgical Quality Improvement Program analysis evaluating patients who underwent craniotomy for tumor, body habitus was not associated with differential mortality or neurological complications. However, obese patients had increased odds of a major perioperative complication, primarily due to higher rates of venous thromboembolic events and surgical site infections. Preoperative hypoalbuminemia was associated with increased odds of mortality and a nonroutine hospital discharge, suggesting that serum albumin may have utility in stratifying risk preoperatively in patients undergoing craniotomy.

Postoperative Pain Management Among Dominican and American Health-Care Providers: A Qualitative Analysis.

BACKGROUND: U.S. practitioners have prescribed opioid analgesics increasingly in recent years, contributing to what has been declared an opioid epidemic by the U.S. Centers for Disease Control and Prevention (CDC). Opioids are used frequently in the preoperative and postoperative periods for patients undergoing total joint replacement in developed countries, but cross-cultural comparisons of this practice are limited. An international medical mission such as Operation Walk Boston, which provides total joint replacement to financially vulnerable patients in the Dominican Republic, offers a unique opportunity to compare postoperative pain management approaches in a developed nation and a developing nation. METHODS: We interviewed American and Dominican surgeons and nurses (n = 22) during Operation Walk Boston 2015. We used a moderator's guide with open-ended questions to inquire about postoperative pain management and factors influencing prescribing practices. Interviews were recorded and transcripts were analyzed using content analysis. RESULTS: Providers highlighted differences in the patient-provider relationship, pain medication prescribing variability, and access to medications. Dominican surgeons emphasized adherence to standardized pain protocols and employed a paternalistic model of care, and American surgeons reported prescribing variability and described shared decision-making with patients. Dominican providers described limited availability of potent opioid preparations in the Dominican Republic, in contrast to American providers, who discussed opioid accessibility in the United States. CONCLUSIONS: Our findings suggest that cross-cultural comparisons provide insight into how opioid prescribing practices, approaches to the patient-provider relationship, and medication access inform distinct pain management strategies in American and Dominican surgical settings. Integrating lessons from cross-cultural pain management studies may yield more effective pain management strategies for surgical procedures performed in the United States and abroad.

Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium.

Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.