Protection from plague via single dose administration of antibody to neutralize the type I interferon response.

Yersinia pestis is a gram-negative bacterium and the causative agent for the plague. Yersinia spp . use effector proteins of the type III secretion system (T3SS) to skew the host immune response toward a bacterial advantage during infection. Previous work established that mice which lack the type I IFN receptor (IFNAR), exhibit resistance to pulmonary infection by Y. pestis . In this work, we addressed the efficacy of a single dose administration of neutralizing antibody to IFNAR (MAR1) as a preventive treatment for plague. We show that single dose administration of MAR1 provides protection from mortality due to secondary septicemic plague where it appears to reduce the production of serum TNFα during the disease phase. We further demonstrate that the T3SS effector protein YopJ is necessary for MAR1-induced protection, however IFNAR-dependent serum TNFα was observed independent of YopJ. We further define tissue-specific anti-bacterial roles of IFNAR that are blocked by YopJ activity indicating that YopJ and IFNAR work in parallel to promote disease. The combined data suggest that therapeutic targeting of IFNAR signaling may reduce the hyper-inflammatory response associated with plague.

Clinicopathological, genomic and immunological factors in colorectal cancer prognosis.

BACKGROUND: Numerous factors affect the prognosis of colorectal cancer (CRC), many of which have long been identified, such as patient demographics and the multidisciplinary team. In more recent years, molecular and immunological biomarkers have been shown to have a significant influence on patient outcomes. Whilst some of these biomarkers still require ongoing validation, if proven to be worthwhile they may change our understanding and future management of CRC. The aim of this review was to identify the key prognosticators of CRC, including new molecular and immunological biomarkers, and outline how these might fit into the whole wider context for patients. METHODS: Relevant references were identified through keyword searches of PubMed and Embase Ovid SP databases. RESULTS: In recent years there have been numerous studies outlining molecular markers of prognosis in CRC. In particular, the Immunoscore® has been shown to hold strong prognostic value. Other molecular biomarkers are useful in guiding treatment decisions, such as mutation testing of genes in the epidermal growth factor receptor pathway. However, epidemiological studies continue to show that patient demographics are fundamental in predicting outcomes. CONCLUSION: Current strategies for managing CRC are strongly dependent on clinicopathological staging, although molecular testing is increasingly being implemented into routine clinical practice. As immunological biomarkers are further validated, their testing may also become routine. To obtain clinically useful information from new biomarkers, it is important to implement them into a model that includes all underlying fundamental factors, as this will enable the best possible outcomes and deliver true precision medicine.

The effect of a multidisciplinary regional educational programme on the quality of colon cancer resection.

AIM: Mesocolic plane surgery with central vascular ligation produces an oncologically superior specimen following colon cancer resection and appears to be related to optimal outcomes. We aimed to assess whether a regional educational programme in optimal mesocolic surgery led to an improvement in the quality of specimens. METHOD: Following an educational programme in the Capital and Zealand areas of Denmark, 686 cases of primary colon cancer resected across six hospitals were assessed by grading the plane of surgery and undertaking tissue morphometry. These were compared to 263 specimens resected prior to the educational programme. RESULTS: Across the region, the mesocolic plane rate improved from 58% to 77% (P < 0.001). One hospital had previously implemented optimal surgery as standard prior to the educational programme and continued to produce a high rate of mesocolic plane specimens (68%) with a greater distance between the tumour and the high tie (median for all fresh cases: 113 vs 82 mm) and lymph node yield (33 vs 18) compared to the other hospitals. Three of the other hospitals showed a significant improvement in the plane of surgical resection. CONCLUSION: A multidisciplinary regional educational programme in optimal mesocolic surgery improved the oncological quality of colon cancer specimens as assessed by mesocolic planes; however, there was no significant effect on the amount of tissue resected centrally. Surgeons who attempt central vascular ligation continue to produce more radical specimens suggesting that such educational programmes alone are not sufficient to increase the amount of tissue resected around the tumour.

The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease. AIM: To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection. METHODS: Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded. RESULTS: A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001). CONCLUSIONS: In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.

Do directly acting antiviral agents for HCV increase the risk of hepatic decompensation and decline in renal function? Results from ERCHIVES.

BACKGROUND: Directly acting antiviral agents (DAA) have been associated with hepatic decompensation, especially in patients with pre-treatment cirrhosis, but this risk is not well defined. AIM: To determine the incidence of hepatic decompensation, liver transplantation, death and worsening renal function in patients treated with a Paritaprevir/ritonavir, Ombitasvir, Dasabuvir (PrOD), sofosbuvir/simeprevir or sofosbuvir/ledipasvir regimen. METHODS: We followed ERCHIVES participants treated with the above regimens for up to 12 weeks post-treatment. We excluded those with HIV, HBsAg+ and pre-existing diagnosis of hepatic decompensation and hepatocellular carcinoma. RESULTS: Of 3728 persons on PrOD, 1578 on sofosbuvir/simeprevir and 10 440 on sofosbuvir/ledipasvir, incidence rates (95% CI) of hepatic decompensation/1000 patient-years were 10.6 (5.89-17.36) for the PrOD, 32.4 (20.74-48.16) for the sofosbuvir/simeprevir and 13.0 (9.74-17.10) for the sofosbuvir/ledipasvir. Among those with baseline cirrhosis, these rates were 36.9 (19.1-64.5), 61.8 (38.2-94.5) and 41.1 (29.9-55.2) respectively, while among those without cirrhosis at baseline, these rates were 2.7 (0.6-8.0), 7.5 (1.5-21.8) and 2.7 (1.2-5.4). Advanced fibrosis was associated with increased risk of hepatic decompensation in all groups [HR (95% CI) per 0.5 unit increase in FIB-4 score: PrOD 1.11 (1.07-1.16); sofosbuvir/simeprevir 1.03 (1.01-1.05); sofosbuvir/ledipasvir 1.02 (1.01-1.03)]. There were no deaths. Proportion of persons with eGFR decrease >30 ml/min/1.73 m2 was higher among the PrOD group, but presence of cirrhosis did not appear to affect this. CONCLUSIONS: The incidence of hepatic decompensation in persons treated with PrOD, up to 12 weeks after completion of treatment, was comparable to those treated with sofosbuvir/ledipasvir regimen, and was lower than among those treated with a sofosbuvir/simeprevir regimen. Such risk was predominantly observed in those with pre-treatment cirrhosis.

Adding ribavirin to newer DAA regimens does not affect SVR rates in HCV genotype 1 infected persons: results from ERCHIVES.

BACKGROUND: Ribavirin is a key component of several hepatitis C virus (HCV) treatment regimens. However, its utility in combination with newer directly acting anti-viral agents regimens is unclear. AIM: To determine the SVR rates with paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimen ± ribavirin and compare this with sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens. METHODS: We used Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well-established national cohort of HCV-infected Veterans to identify HCV genotype 1 infected persons initiated on the above regimens. We excluded those with HIV coinfection, positive HBsAg and missing HCV RNA. RESULTS: We identified 1235 persons on PrOD (75.5% ribavirin), 1254 on sofosbuvir/simeprevir (16.9% ribavirin) and 4247 on sofosbuvir/ledipasvir (23.3% ribavirin). Among HCV genotype 1a infected persons, ribavirin was prescribed to 99.2% on PrOD, 18.2% on sofosbuvir/simeprevir and 23.3% on sofosbuvir/ledipasvir. The SVR rates ranged from 92.6% to 100% regardless of the treatment regimen, presence of cirrhosis or HCV subtype, except in PrOD group without ribavirin, HCV genotype 1a without cirrhosis (SVR 80%, N = 5). There were minor, clinically insignificant differences in SVR rates in those treated with or without ribavirin in each of the treatment groups, regardless of presence of cirrhosis at baseline. In multivariable logistic regression analysis, ribavirin use was not associated with achieving SVR in any group. CONCLUSIONS: In HCV genotype 1 infected persons, PrOD, sofosbuvir/simeprevir and sofosbuvir/ledipasvir regimens, are associated with high rates of SVR in actual clinical settings, which are comparable to clinical trials results (except PrOD genotype 1a with cirrhosis where the number was too small). The benefit of adding ribavirin to these regimens in the ERCHIVES treated cohort is not established.

Indication of non-thermal contribution to visible femtosecond laser-induced CO oxidation on Ru(0001).

We studied CO oxidation on Ru(0001) induced by 400 nm and 800 nm femtosecond laser pulses where we find a branching ratio between CO oxidation and desorption of 1:9 and 1:31, respectively, showing higher selectivity towards CO oxidation for the shorter wavelength excitation. Activation energies computed with density functional theory show discrepancies with values extracted from the experiments, indicating both a mixture between different adsorbed phases and importance of non-adiabatic effects on the effective barrier for oxidation. We simulated the reactions using kinetic modeling based on the two-temperature model of laser-induced energy transfer in the substrate combined with a friction model for the coupling to adsorbate vibrations. This model gives an overall good agreement with experiment except for the substantial difference in yield ratio between CO oxidation and desorption at 400 nm and 800 nm. However, including also the initial, non-thermal effect of electrons transiently excited into antibonding states of the O-Ru bond yielded good agreement with all experimental results.

Fulminant and fatal encephalitis caused by Acanthamoeba in a kidney transplant recipient: case report and literature review.

Acanthamoeba is the most common cause of granulomatous amebic encephalitis, a typically fatal condition that is classically described as indolent and slowly progressive. We report a case of Acanthamoeba encephalitis in a kidney transplant recipient that progressed to death within 3 days of symptom onset and was diagnosed at autopsy. We also review clinical characteristics, treatments, and outcomes of all published cases of Acanthamoeba encephalitis in solid organ transplant (SOT) recipients. Ten cases were identified, and the infection was fatal in 9 of these cases. In 6 patients, Acanthamoeba presented in a fulminant manner and death occurred within 2 weeks after the onset of neurologic symptoms. These acute presentations are likely related to immunodeficiencies associated with solid organ transplantation that result in an inability to control Acanthamoeba proliferation. Skin lesions may predate neurologic involvement and provide an opportunity for early diagnosis and treatment. Acanthamoeba is an under-recognized cause of encephalitis in SOT recipients and often presents in a fulminant manner in this population. Increased awareness of this disease and its clinical manifestations is essential to attain an early diagnosis and provide the best chance of cure.

The natural history of eosinophilic oesophagitis in the transition from childhood to adulthood.

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition affecting both children and adults. Little is known about the natural history of EoE in the transition from childhood into adulthood. AIM: To determine the prevalence of EoE symptoms and impact of EoE on quality of life among adults diagnosed with EoE during childhood. METHODS: This is a cross-sectional study of EoE patients from the Children's Hospital of Philadelphia EoE registry. Patients ≥18 years diagnosed with EoE during childhood were administered validated dysphagia [Mayo Dysphagia Questionnaire (MDQ)-30] and Quality of Life (PAGI-QOL) questionnaires. Ongoing EoE treatments were ascertained. RESULTS: A total of 140 EoE patients ≥18 years were identified; 53 completed all questions. Only 6 (11%) subjects had positive (n = 2) or indeterminate (n = 4) dysphagia scores. However, of 47 patients with negative scores, 18 (37%) reported ongoing difficulty swallowing. The mean PAGI-QOL score was 4.58/5. The dietary dimension score was 3.73/5. Current pharmacological EoE treatments were topical steroids (3/53) and interleukin-5 antagonists (3/53). Additionally, 26/53 (49%) were on PPI therapy and 40/53 (76%) were following allergy directed diets. CONCLUSIONS: The majority of young adults diagnosed with EoE during childhood continue to require pharmacological treatment and/or dietary modification for EoE. A substantial proportion of this population experiences ongoing swallowing difficulties that a standard dysphagia questionnaire fails to capture. Dietary quality of life, but not total quality of life, appears to be adversely affected. These data suggest that EoE diagnosed during childhood remains a significant medical issue during early adulthood, and that better EoE symptom measurement instruments are needed.

Integrated internist - addiction medicine - hepatology model for hepatitis C management for individuals on methadone maintenance.

Despite a high prevalence of hepatitis C virus (HCV) among drug users, HCV evaluation and treatment acceptance are extremely low among these patients when referred from drug treatment facilities for HCV management. We sought to increase HCV treatment effectiveness among patients from a methadone maintenance treatment program (MMTP) by maintaining continuity of care. We developed, instituted and retrospectively assessed the effectiveness of an integrated, co-localized care model in which an internist-addiction medicine specialist from MMTP was embedded in the hepatitis clinic. Methadone maintenance treatment program patients were referred, evaluated by the internist and hepatologist in hepatitis clinic and provided HCV treatment with integration between both sites. Of 401 evaluated patients, anti-HCV antibody was detected in 257, 86% of whom were older than 40 years. Hepatitis C virus RNA levels were measured in 222 patients, 65 of whom were aviremic. Of 157 patients with detectable HCV RNA, 125 were eligible for referral to the hepatitis clinic, 76 (61%) of whom accepted and adhered with the referral. Men engaged in MMTP <36 months were significantly less likely to be seen in hepatitis clinic than men in MMTP more than 36 months (odds ratio = 7.7; 95% confidence interval 2.6-22.9) or women. We evaluated liver histology in 63 patients, and 83% had moderate to advanced liver disease. Twenty-four patients initiated treatment with 19 completing and 13 (54%) achieving sustained response. In conclusion, integrated care between the MMTP and the hepatitis clinic improves adherence with HCV evaluation and treatment compared to standard referral practices.

Unintentional exposure of neonates to conventional radiography in the Neonatal Intensive Care Units.

OBJECTIVE: To evaluate the extent of unintentional exposure to X-rays performed during routine diagnostic procedures in the Neonatal Intensive Care Units (NICUs). STUDY DESIGN: During a 1-month period, 157 consecutive neonates from five level-III NICUs were recruited for this study. The mean birth weight was 1747+/-911 g (range: 564-4080 g), and gestational age was 31.6+/-3.6 weeks (range: 24-41 weeks). A total of 500 radiographs were performed including chest (68%), abdomen (17%) and combined chest and abdomen (15%). The average number of radiographs taken per infant was 4.2+/-3.6 (range: 1-21). Unintentional inclusion of body regions other than those ordered was determined by comparing the areas that should be included in the radiation field according to International recommendations, to those that appeared in the actual radiograph. RESULT: A comparison of the recommended borders to the actual boundaries of the radiographs taken show an additional exposure to radiation in all three procedures: 85% of chest radiographs also included the whole abdomen, 64% of abdomen radiographs included both thigh and upper chest and 62% of chest and abdomen radiograph included the thigh. (The range in all procedures was from ankle to upper head.) Between 2 and 20% of the relevant targeted body tissues were not included in the exposed fields resulting in missing data. The gonads of both sexes were exposed in 7% in all chest X-rays. Among male infants, the testes were exposed in 31% of plain abdomen radiographs and 34% of chest and abdomen radiographs. CONCLUSION: In the NICUs participating in the study, neonates are currently being exposed to X-ray radiation in nonrelevant body regions. Higher awareness and training of the medical teams and radiographers are required to minimize unnecessary exposure of newborns to ionizing radiation.

Combined immunocytochemistry and FISH: an improved method to study engraftment of accessory bone marrow stromal cells.

In aplastic anaemia (AA), correction of bone marrow (BM) stromal function may contribute to the outcome of bone marrow transplantation (BMT). Engraftment of BM stromal cells is rarely observed, but engraftment of accessory cells (macrophages and T cells) may be important. We have improved a method of combined immunocytochemistry and FISH described by van Tol et al. (1998) to define the cellular origin and time course of engraftment of BM stromal accessory cells after sex-mismatched BMT. Long-term bone marrow cultures were trypsinized and cytospin preparations stained by immunocytochemistry using monoclonal antibodies against specific cell lineages followed by FISH for X and Y chromosomes. Low level phase contrast microscopy was used to study staining of individual cells simultaneously with fluorescence microscopy to define chromosomal pattern. In controls, the combined procedure did not affect the intensity of APAAP staining or the accuracy of sex chromosome determination. In cultures from AA patients after sex-mismatched BMT, cell lineages could be identified and donor or recipient origin determined unequivocally. This procedure enabled us to examine the origin (host/donor) of different cell lineages with high confidence, in addition to producing images of the combined staining.

Correction of stromal cell defect after bone marrow transplantation in aplastic anaemia.

Defects in stromal cell function have been demonstrated in a number of aplastic anaemia (AA) patients. Here we have studied a patient with severe AA and abnormal stromal cell function who underwent bone marrow transplantation (BMT). The objective of this study was to investigate the timing and the mechanism of correction of the stromal defect after transplantation. The patient, a 25-year-old woman with severe AA, underwent BMT from her brother. BM was obtained from the patient on five occasions: 2 weeks pre BMT, and 3, 8, 16 and 21 months post BMT. Stromal cells were grown to confluence and recharged with purified CD34+ cells from normal donors. The support of such cells, as assessed by weekly colony-forming assay (CFU) of non-adherent cells, was compared with that of stromal layers grown from normal BM. A novel technique of combined fluorescence in situ hybridization (FISH) and immunocytochemistry was used to determine the origin of specific stromal cell types on cytospins of stroma post BMT. Stromal function was defective at 2 weeks pre BMT and at 3 months post BMT, but returned to normal at 8 and 16 months post BMT. At 21 months post BMT, stromal fibroblasts and endothelial cells were shown to be of recipient origin, and macrophages and T cells were of donor origin. We present here evidence in a case of severe AA for defective stromal function before BMT and delayed normalization of function after BMT. This correlated with engraftment of donor macrophages and T cells, but not fibroblasts and endothelial cells.

Childhood sexual trauma and psychosocial functioning in adults with schizophrenia.

OBJECTIVE: This study explored the association between sexual abuse in childhood and the severity of psychosocial deficits in adults with schizophrenia. METHODS: The Quality of Life Scale, which assesses current interpersonal and work function, and the NEO personality inventory, which assesses personality dimensions relevant to social functioning, were administered to 54 individuals who had been diagnosed as having schizophrenia. Nineteen of the individuals reported having been sexually abused as children, and 35 reported no history of abuse. RESULTS: A multiple analysis of variance indicated that there were differences between the group of individuals who had a history of sexual trauma and the group that did not. Subsequent univariate analysis of variance indicated that the individuals with a history of abuse had poorer current role functioning and fewer of the basic psychological building blocks necessary for sustaining intimacy. They also demonstrated higher levels of neuroticism, which is a measure of vulnerability to emotional turmoil. The two groups did not differ in frequency of interpersonal contacts or level of extroversion. CONCLUSIONS: Sexual abuse in childhood is associated with poorer psychosocial functioning in adults with schizophrenia.

Neurocognitive and symptom correlates of self-reported childhood sexual abuse in schizophrenia spectrum disorders.

This study examined whether self-reported childhood sexual abuse in schizophrenia spectrum disorders is linked with severity of neurocognitive deficits. The Wisconsin Card Sorting Test, California Verbal Learning Test, and select WAIS III subtests were administered to 15 participants with schizophrenia or schizoaffective disorder who had been sexually abused and to 28 participants with no abuse history. Controlling for age and premorbid IQ, a MANCOVA indicated there were group differences (f(9, 31) = 5.53, p < .001). Subsequent ANCOVA indicated that the sexual abuse group performed more poorly on tests of working memory and information processing speed. Childhood sexual abuse is associated with more severe working memory deficits in adults with schizophrenia spectrum disorders.

Neurocognitive correlates of helplessness, hopelessness, and well-being in schizophrenia.

Persons with schizophrenia are widely recognized to experience potent feelings of hopelessness, helplessness, and a fragile sense of well-being. Although these subjective experiences have been linked to positive symptoms, little is known about their relationship to neurocognition. Accordingly, this study examined the relationship of self-reports of hope, self-efficacy, and well-being to measures of neurocognition, symptoms, and coping among 49 persons with schizophrenia or schizoaffective disorder. Results suggest that poorer executive function, verbal memory, and a greater reliance on escape avoidance as a coping mechanism predicted significantly higher levels of hope and well being with multiple regressions accounting for 34% and 20% of the variance (p < .0001), respectively. Self-efficacy predicted lower levels of positive symptoms and greater preference for escape avoidance as a coping mechanism with a multiple repression accounting for 9% of the variance (p < .05). Results may suggest that higher levels of neurocognitive impairment and an avoidant coping style may shield some with schizophrenia from painful subjective experiences. Theoretical and practical implications for rehabilitation are discussed.

Self-Appraisal of Illness Questionnaire (SAIQ): relationship to researcher-rated insight and neuropsychological function in schizophrenia.

The Self-Appraisal of Illness Questionnaire (SAIQ) is a self-report instrument designed to assess attitudes toward mental illness among persons receiving psychiatric treatment. This instrument was developed for use in community settings, adapted closely from the Patient's Experience of Hospitalization questionnaire. In order to examine the validity of the SAIQ, a factor analysis was first conducted on the items of this instrument in a sample of 59 outpatients with schizophrenia or schizoaffective illness. Three factors emerged: Need for Treatment, Worry, and Presence/Outcome of Illness. Next, to examine the concurrent validity of these three SAIQ subscales, they were correlated with researcher rated insight scales and neuropsychological tests. Results indicated that the Need for Treatment and Presence/Outcome subscales were significantly correlated with both researcher-rated insight scales and with neuropsychological tests of executive functioning. The Worry subscale was not associated with either researcher-rated insight scales or neuropsychological tests. It was concluded that the Need for Treatment and Presence/Outcome subscales may be used in combination as a brief screening instrument for clients with schizophrenia receiving outpatient psychiatric treatment who may be at risk for treatment non-compliance due to a lack of insight into illness.