Citations

Abstract A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Abstract Aims Increases in left ventricular filling pressure are a fundamental haemodynamic abnormality in heart failure with preserved ejection fraction (HFpEF). However, very little is known regarding how elevated filling pressures cause pulmonary abnormalities or symptoms of dyspnoea. We sought to determine the relationships between simultaneously measured central haemodynamics, symptoms, and lung ventilatory and gas exchange abnormalities during exercise in HFpEF. Methods and results Subjects with invasively-proven HFpEF (n = 50) and non-cardiac causes of dyspnoea (controls, n = 24) underwent cardiac catheterization at rest and during exercise with simultaneous expired gas analysis. During submaximal (20 W) exercise, subjects with HFpEF displayed higher pulmonary capillary wedge pressures (PCWP) and pulmonary artery pressures, higher Borg perceived dyspnoea scores, and increased ventilatory drive and respiratory rate. At peak exercise, ventilation reserve was reduced in HFpEF compared with controls, with greater dead space ventilation (higher VD/VT). Increasing exercise PCWP was directly correlated with higher perceived dyspnoea scores, lower peak exercise capacity, greater ventilatory drive, worse New York Heart Association (NYHA) functional class, and impaired pulmonary ventilation reserve. Conclusion This study provides the first evidence linking altered exercise haemodynamics to pulmonary abnormalities and symptoms of dyspnoea in patients with HFpEF. Further study is required to identify the mechanisms by which haemodynamic derangements affect lung function and symptoms and to test novel therapies targeting exercise haemodynamics in HFpEF.

Background: The purpose of this study was to report our long-term outcomes following reconstruction of the forearm interosseous membrane (IOM) with bone-patellar tendon-bone (BPTB) graft for treatment of chronic Essex-Lopresti injuries. Methods: We identified 33 patients who underwent IOM reconstruction with BPTB graft for chronic Essex-Lopresti injuries over a 20-year treatment interval. Twenty male and 13 female patients, with a mean age of 42.1 years (range, 19 to 73 years) and a minimum follow-up interval of 5 years, were included. Preinjury clinical examination and radiographic measurements were obtained from records for comparison with prospectively collected data. Additional functional outcome data collected postoperatively included QuickDASH (an abbreviated version of the Disabilities of the Arm, Shoulder and Hand [DASH]), modified Mayo wrist (MMW), and Broberg-Morrey elbow function scores. Results: IOM reconstruction was performed at a mean interval (and standard deviation) of 44.9 ± 60.0 months (range, 6.4 to 208 months) from the time of the initial injury. At a mean follow-up of 10.9 ± 4.4 years (range, 5.5 to 24.2 years), significant improvements were observed in mean elbow flexion-extension arc (+13° [95% confidence interval (CI), 4° to 22°]; p = 0.005), wrist flexion-extension arc (+19° [95% CI, 4° to 34°]; p = 0.016), forearm pronation-supination (+23° [95% CI, 8° to 39°]; p = 0.004), and grip strength (+25% of that of the contralateral side [95% CI, 18% to 32% of contralateral side]; p < 0.001). Improvements in ulnar variance were sustained over the long term from +3.9 mm (95% CI, 3.2 to 4.6 mm) preoperatively to −1.6 mm (95% CI, −2.3 to −0.9 mm) immediately postoperatively and −1.1 mm (95% CI, −1.8 to −0.4 mm) at the time of the final follow-up (p < 0.001). The mean QuickDASH, MMW, and Broberg-Morrey scores were 29.8 (range, 5 to 61), 82.7 (range, 60 to 100), and 91.6 (range, 64 to 100), respectively. Conclusions: IOM reconstruction with a BPTB graft is an effective treatment option for chronic Essex-Lopresti injuries, with satisfactory clinical and functional outcomes over the long term. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Objective To evaluate biochemical recurrence ( BCR ) patterns amongst men undergoing radical prostatectomy ( RP ) with specimens having negative ( NSM ), positive ( PSM ), and close surgical margins ( CSM ) from the Shared Equal Access Regional Cancer Hospital ( SEARCH ) cohort, as PSM after RP are a significant predictor of biochemical failure and possible disease progression, with CSM representing a diagnostic challenge for surgeons. Patients and Methods Men undergoing RP between 1988 and 2015 with known final pathological margin status were evaluated. The cohort was divided into three groups based on margin status; NSM , PSM , and CSM . CSM were defined by distance of tumour ≤1 mm from the surgical margin. BCR was defined as a prostate‐specific antigen ( PSA ) level of >0.2 ng/mL, two values at 0.2 ng/mL, or secondary treatment for an elevated PSA level. Predictors of BCR , metastases, and mortality were analysed using Cox proportional hazard models. Results Of 5515 men in the SEARCH database, 4337 (79%) men met criteria for inclusion in the analysis. Of these, 2063 (48%) had NSM , 1902 (44%) had PSM , and 372 (8%) had CSM . On multivariable analysis, relative to NSM , men with CSM had a higher risk of BCR (hazard ratio [ HR ] 1.51, 95% confidence interval [ CI ] 1.25–1.82; P < 0.001) but a decreased risk of BCR when compared to those men with PSM ( HR 2.09, 95% CI 1.86–2.36; P < 0.001). Metastases, prostate cancer‐specific mortality and all‐cause mortality did not differ based on margin status alone. Conclusions Management of men with CSM is a diagnostic challenge, with a disease course that is not entirely benign. The evaluation of other known risk factors probably provides greater prognostic value for these men and may ultimately better select those who may benefit from adjuvant therapy.

Elderly seasonal migrators share time between homes in different states, presenting challenges for care coordination and patient attribution methods. Medicare has prioritized alternative payment models, putting health care providers at risk for quality and value of services delivered to their attributed patients, regardless of the location of care. Little research is available to guide providers and payers on the service use of seasonal migrators. The authors use claims data on fee-for-service (FFS) Medicare beneficiaries' locations throughout the year to (1) identify seasonal migrators and (2) describe the care they receive in each seasonal home, focusing on primary care and emergency department (ED) visits and the relationships between the two. In all, 5.5% of the Medicare aged FFS population were identified as seasonal migrators, with 4.1% following the traditional snowbird pattern of migration, spending warm months in the north and cold months in the south. Migrators had higher rates of ED visits and primary care treatable (PCT) ED visits than the nonmigratory groups, controlling for location, age, race, sex, Medicaid status, season, and comorbidities. They also had more visits with specialist physicians, more days with outpatient services, and more days seeing a physician in any setting. Having local primary care strongly reduced rates of both PCT ED visits and total ED visits for all migration categories, with the greatest reduction seen in PCT ED visits by migrators (local primary care was associated with a 58% reduction in PCT ED visits by snowbirds and a 65% reduction in PCT ED visits by other migrators).

Abstract Electronic medical records (EMRs) have gained widespread use in clinical practice and by default serve as a large patient database with potential for use in clinical research. Although there remains significant interest in leveraging EMRs for research purposes, extraction of data has proven to be complex and with insufficient accuracy. We describe the limitations of an EMR in our attempt to conduct a seemingly simple study aimed at validating variables identified in the PRECiSE 3, a 7-year open label safety and efficacy study of certolizumab pegol in Crohn’s disease that identified clinical factors that predicted both short- and long-term efficacy. A multicenter, retrospective cohort study from 8 academic and large community practices was performed, and data were collected from each respective EMR. Significant challenges with reliable capture of key data elements were encountered, and overall a screen fail rate of 91.8% across all sites was seen. We describe these challenges and potential future directions to work together to advance accuracy and implementation of the use of EMRs in inflammatory bowel disease.

Purpose: Patients with Fuchs endothelial corneal dystrophy (FECD) often notice poor vision in the morning that improves as the day progresses. In this study, we determined changes in corneal optical properties associated with induced corneal edema. Methods: Twenty-three phakic eyes (23 participants) with FECD (grades 1–6, modified Krachmer scale) and 8 normal eyes (8 participants) were examined by Scheimpflug photography. Central corneal thickness, high-order aberrations from anterior and posterior corneal surfaces, and backscatter from the anterior, mid-, and posterior cornea were determined from the Scheimpflug images. A low-oxygen permeable contact lens was placed on the eye, and eyes were closed for 2 hours, after which the lens was removed and Scheimpflug photography was repeated for up to 5 hours to determine changes in backscatter and high-order aberrations. Results: Corneas swelled by 10% [95% confidence interval (CI), 9–10]. Backscatter from the anterior cornea increased by 416 scatter units (SU, 95% CI, 344–488; P < 0.001), independent of the presence and severity of FECD. Recovery of anterior backscatter was slower in advanced FECD (81 SU/h, 95% CI, 60–120) compared with normal (123 SU/h, 95% CI, 95–150; P = 0.019). Anterior and posterior corneal high-order aberrations, and mid and posterior backscatter, did not increase with induced swelling. Conclusions: Inducing corneal edema increases anterior corneal backscatter but not high-order aberrations. Subjective poor vision in the morning in FECD is probably caused by scattered light rather than by high-order aberrations, suggesting that these patients experience more disability glare than decreased visual acuity.