Pathogen Paleogenetics and Late Antique Disease

To review existing data regarding late cytomegalovirus disease occurring after antiviral prophylaxis. There is a continued debate as to the respective merits of the preemptive and the prophylactic approach to prevent cytomegalovirus disease after transplantation. Arguably, by allowing some infection, the preemptive approach helps build immunity in contrast to prophylaxis, explaining the occurrence of late cytomegalovirus disease in the latter approach. No study comparing directly both approaches is large enough to definitely determine whether the preemptive approach leads to a faster development of immune response protective from late disease nor whether late disease is clinically different after prophylaxis compared to early cytomegalovirus diseases. While risk factors for late cytomegalovirus disease all point to a delay in mounting immune responses, there are no identified markers that would help predict the risk for late disease at the time of prophylaxis discontinuation. Various approaches to prevent late cytomegalovirus disease have been developed: prolonged prophylaxis, microbiological surveillance and preemptive treatment after prophylaxis discontinuation. Considering the identifying risk factors for late disease, it would also make sense to envision vaccinating cytomegalovirus-seronegative recipients. The best approach to prevent or manage late cytomegalovirus disease associated with cytomegalovirus prophylaxis remains to be defined.

There is no consensus on the most effective modality for the treatment of resectable esophageal adenocarcinomas (EAC). We theorized that treatment modality may influence survival differently depending on the stage of disease. A single-institution, retrospective examination of resectable EAC between 2000 and 2008 was performed. Resectable EAC were stratified into early disease (stage 2a or less) and late disease (stage 2b or more) based on pretreatment endoscopic ultrasound (EUS). Patients with T4, >N2, and/or distant disease were excluded. A total of 156 patients were included in this study. Most patients were white (97 %), male (83 %), and over 60 years of age (51 %). Patients with early disease on pretreatment EUS exhibited improved overall survival compared to patients with late disease (P < 0.001). Irrespective of treatment modality, there were no significant differences in overall 5-year survival for patients with early or late disease. Early and late disease patients whose disease responded to neoadjuvant chemotherapy (NAC) had significantly improved overall survival compared to nonresponsive disease (P < 0.05). The only negative independent predictors of overall 5-year survival were late stage disease on pretreatment EUS (hazard ratio 2.402, 95 % confidence interval 1.24-4.67, P = 0.01) and late stage disease on final pathological stage (hazard ratio 2.29, 95 % confidence interval 1.22-4.31, P = 0.01). Our data lack statistical power but reveal no difference in survival with the addition of neoadjuvant therapies to surgery for early or late resectable EAC. However, patients with disease that responded to NAC had improved outcomes at 5 years for both groups. Therefore, the prognosis for patients undergoing NAC may be optimized by immediate surgical resection if neoadjuvant therapies do not result in a dramatic clinical response.

The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eightyone consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5–9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26–60, median: 59 years). There was no association between the developemnt of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir. two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.

The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eighty-one consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5--9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26--60, median: 59 years). There was no association between the development of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir, two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.

Lyme disease can be classified using the terminology of syphilis. In this series of 95 cases from the upper midwest, early cases, defined as an illness of less than 2 months, were more likely to have lived in or recently visited a highly endemic area. Unlike late cases, early cases presented entirely in the nonwinter months (p less than .001). Early disease was further subdivided into primary and secondary disease. Ninety percent of primary and 43% of secondary cases had erythema migrans, while no late cases had active erythema migrans (p less than .001). Clinical manifestations of nonspecific inflammation, except for arthralgia, were more common in early than late disease (p less than .01). In secondary cases, monoarticular arthritis was slightly more common than polyarticular arthritis, with the reverse occurring in late disease (p less than .05). Indirect fluorescent antibody testing revealed a ratio of IgM to IgG antibodies to be helpful in distinguishing early from late disease. Antibacterial therapy in early, primary cases caused Jarisch-Herxheimer reaction 7% of the time. Despite longer and more frequent parenteral therapy, late Lyme disease frequently required retreatment, owing to poor clinical response (p less than .05).

Subjective health perception prioritizes psychological well-being over physical function in advanced ALS: A multigroup structural equation modeling analysis

Objectives:Femoroacetabular impingement (FAI) has been proposed as an etiologic factor in up to 50% of osteoarthritis hips (OA). Inflammation is thought to be one of the main initiators of hip OA, yet little is known about the location and progression of intraarticular inflammation in FAI hips. The aim of this study is to characterize inflammation and catabolic markers in the early and late stage of FAI hips in patients with symptomatic Cam FAI.Methods:Head-neck cartilage, acetabular cartilage, and synovial samples were obtained from 30 patients undergoing hip surgery. Fifteen patients had a diagnosis of symptomatic Cam FAI (early FAI-symptomatic FAI) and 15 presented with advanced OA secondary to Cam FAI (late FAI/secondary OA). Control cartilage samples were procured from the head-neck junction of 7 osteochondral fresh allografts from healthy young-adult donors (control). Radiographically, the α-angle was utilized to confirm hip impingement and Tönnis grade was used to define pre-OA (Tönnis grade 0-1) and advanced OA (Tönnis grade >2). Safranin O stained sections were used to assess cartilage degeneration using the Mankin score. Immunostaining of IL-1β, MMP-13, ADAMTS-4, type II collagen (COL2), and the NITEGE aggrecan neoepitote was performed to evaluate inflammation and catabolic markers. Quantification of immunopositive cells was performed and one-way analysis of variance with Tukey’s post hoc test was applied to analyze differences between groups.Results:Characteristics of the study participants are presented in Table 1. Cartilage from the impingement zone (head-neck and acetabulum) of hips with early and late FAI showed microscopic osteoarthritic degenerative changes. Compared to control, head-neck cartilage from early and late stage FAI hips highly expressed inflammatory and catabolic markers IL-1β (69.7±18.1, 72.5±13.2 vs 20.2±4.9), MMP-13 (79.6±12.6, 71.4±18.8 vs 25.3±9.5), ADAMTS-4 (83.9±12.2, 82.6±12.5 vs 24.3±11.1), NITEGE (89.7±7.7, 95.7±4.7 vs 39.8±20.5) (p<0.05). Expression for COL2 was similar among groups (93.6±3.9, 92.5±5.8 vs 95.4±6.4, p=0.4892). Finally, percent of immunopositive cells for IL-1β, MMP-13, ADAMTS-4, and ACAN were positively correlated with Mankin score (r=0.52-0.75; p<0.001). The percentage of immunopositive cells present in acetabular cartilage was similar in both early and late FAI (IL-1β: 83.3 ± 24.8, 80.7 ± 15.6, 80.9 ± 26.3, p = 0.9571; MMP-13: 94.3 ± 9.7, 85.2 ± 12.3, 93.3 ± 10.3, p = 0.0653; ADAMTS-4: 98.5 ± 2.3, 98.4 ± 3.4, 99.2 ± 3.0, p = 0.6997, COL2: 99.8 ± 0.7, 99.7 ± 1.1, 98.6 ± 3.6, p = 0.3830). Additionally, inflammatory and catabolic markers were secreted to the ECM (extracellular matrix) in late FAI but not in early FAI. (Figure 1) Synovitis was minimal in early FAI but severe in late FAI. The average synovitis score was lower in early FAI than late FAI (2.5 ± 1.7, 4.4 ± 1.6; p=0.0086). Lower IL-1β expression levels were noted in synovium from early FAI compared to late FAI (p=0.001).Conclusion:Osteoarthritic degenerative changes, inflammation and catabolic markers are evident in the cartilage from the head-neck and acetabulum (impingement zone) in patients with hip FAI morphology during early and late stage disease. In late disease, increase expression of these markers are also observed in the ECM. Severe synovitis, however, was only evident in late stage disease. This study defines joint specific location and timing of inflammation relative to the disease process, suggesting the impingement area is a potential mediator of inflammation and joint degeneration during disease progression.

Anti-thymocyte globulin (ATG) therapy is a risk factor for cytomegalovirus (CMV) disease in renal transplant (RTx) recipients and therefore antiviral prophylaxis is commonly used. We evaluated the outcome of our current policy of 90days of CMV prophylaxis in seropositive recipients given ATG and the risk factors for the occurrence of CMV disease after prophylaxis. We studied a retrospective cohort of 423 RTx (2010-2014) CMV-seropositive adults given ATG induction therapy. 54 (13%) patients developed CMV disease at a median of 163days after transplant, of which 29 (54%) had viral syndrome and 25 (46%) had invasive disease. Median prophylaxis time (94days) and immunosuppressive drugs were similar between groups (CMV vs no-CMV). Those with CMV disease had more deceased donors and higher donor age, lower lymphocyte count, and lower median eGFR at day 90. Multivariable logistic regression analysis at day 90 and 180 found that eGFR ≤40ml/min/1.73m2 (but not acute rejection) was associated with late CMV disease. In a separate validation cohort of 124 patients with 8% late CMV disease, eGFR ≤45 and lymphocyte count ≤800cells/mm3 at the end of prophylaxis remained predictive of late CMV disease occurrence. These data indicate that antiviral prophylaxis adequately prevented CMV in seropositive recipients given ATG, but late disease still occurred. Low eGFR and low lymphocyte count at the end of prophylaxis may help identify patients at higher risk of CMV disease.

Diagnosis and Treatment of Lyme Disease

Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation (HCT) in the Preemptive Therapy Era: Characteristics, Efficacy of PCR-Based Surveillance, and Impact on Mortality

Background:The GO-ALIVE study assessed efficacy and safety of intravenous golimumab (IV GLM) in patients (pts) with ankylosing spondylitis (AS).1,2Objectives:In this post hoc analysis, we assessed IV GLM efficacy and safety...

10 years of UK NEQAS digital morphology in haematology

Delayed hypersensitivity reactions (DTH) are lost with progression of HIV disease. This loss of DTH commonly occurs before the onset of opportunistic infections and is an independent predictor of disease progression. We wanted to determine whether patients in late HIV disease with a history of allergic contact dermatitis (ACD) to poison ivy continue to react to poison ivy. Twelve HIV+ patients with a past history of ACD to poison ivy were tested with an extract prepared from poison ivy leaves. All but 1 patient had CD4+ T cell counts < 200/microliters, and 5 patients had had an opportunistic infection. All 12 patients showed positive reactions ranging from mild erythema and infiltration to marked erythema with bulla formation. ACD is considered a variant of DTH, and as DTH results in a T helper 1 cytokine pattern. However, the antigen-specific effector cells in ACD may be more diverse than in DTH. This diversity could explain the continued reaction to some contact allergens in late disease and may be important in the use of contact allergens for immunotherapy.

There are conflicting reports regarding intercellular adhesion molecule-1 (ICAM-1) expression in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Expression of adhesion molecules ICAM-1, lymphocyte adhesion molecule-1 (LFA-1), vascular cell adhesion molecule (VCAM), and E-selectin was examined together with HLA-DR in 16 liver biopsy specimens showing PSC and 12 specimens showing PBC. These were compared with biopsy specimens showing large duct obstruction (n = 7), chronic active hepatitis (n = 4), alcoholic liver disease (n = 4), and normal liver histological results (n = 5). ICAM-1 was detected on biliary epithelium in five of seven PSC specimens of histological stage 3 or 4, but not in nine early PSC specimens or in specimens from disease controls. In PBC, ICAM-1 was positive on three of 12 cases, two stage 2, and one stage 3. Nine of 16 PSC specimens (three of nine early, six of seven late disease) and six of 10 PBC specimens (three early, three late disease) were positive for HLA-DR. LFA-1 stained infiltrating inflammatory cells in PSC, PBC, and disease controls. In conclusion, ICAM-1 expression on biliary epithelium in PSC occurs mainly in late stage disease and therefore may be secondary to previous events inducing inflammation rather than of primary pathogenic importance. ICAM-1 expression in PBC is less common and not clearly associated with a particular disorder. Previous reports of ICAM-1 prevalence may have been biased towards end stage, pre-transplantation biopsy specimens.

Delayed onset CMV disease in solid organ transplant recipients