Faculty Bibliography

BACKGROUND:Sexual transmission chains of Ebola virus (EBOV) have been verified and linked to EBOV RNA persistence in semen, post-recovery. The rate of semen persistence over time, including the average duration of persistence among Ebola virus disease (EVD) survivors, is not well known. This cohort study aimed to analyze population estimates of EBOV RNA persistence rates in semen over time, and associated risk factors in a population of survivors from Sierra Leone. METHODS AND FINDINGS/RESULTS:In this cohort study from May 2015 to April 2017 in Sierra Leone, recruitment was conducted in 2 phases; the first enrolled 100 male participants from the Western Area District in the capital of Freetown, and the second enrolled 120 men from the Western Area District and from Lungi, Port Loko District. Mean age of participants was 31 years. The men provided semen for testing, analyzed by quantitative reverse transcription PCR (qRT-PCR) for the presence of EBOV RNA. Follow-up occurred every 2 weeks until the endpoint, defined as 2 consecutive negative qRT-PCR results of semen specimen testing for EBOV RNA. Participants were matched with the Sierra Leone EVD case database to retrieve cycle threshold (Ct) values from the qRT-PCR analysis done in blood during acute disease. A purposive sampling strategy was used, and the included sample composition was compared to the national EVD survivor database to understand deviations from the general male survivor population. At 180 days (6 months) after Ebola treatment unit (ETU) discharge, the EBOV RNA semen positive rate was 75.4% (95% CI 66.9%-82.0%). The median persistence duration was 204 days, with 50% of men having cleared their semen of EBOV RNA after this time. At 270 days, persistence was 26.8% (95% CI 20.0%-34.2%), and at 360 days, 6.0% (95% CI 3.1%-10.2%). Longer persistence was significantly associated with severe acute disease, with probability of persistence in this population at 1 year at 10.1% (95% CI 4.6%-19.8%) compared to the probability approaching 0% for those with mild acute disease. Age showed a dose-response pattern, where the youngest men (≤25 years) were 3.17 (95% CI 1.60, 6.29) times more likely to be EBOV RNA negative in semen, and men aged 26-35 years were 1.85 (95% CI 1.04, 3.28) times more likely to be negative, than men aged >35 years. Among participants with both severe acute EVD and a higher age (>35 years), persistence remained above 20% (95% CI 6.0%-50.6%) at 1 year. Uptake of safe sex recommendations 3 months after ETU discharge was low among a third of survivors. The sample was largely representative of male survivors in Sierra Leone. A limitation of this study is the lack of knowledge about infectiousness. CONCLUSIONS:In this study we observed that EBOV RNA persistence in semen was a frequent phenomenon, with high population rates over time. This finding will inform forthcoming updated recommendations on risk reduction strategies relating to sexual transmission of EBOV. Our findings support implementation of a semen testing program as part of epidemic preparedness and response. Further, the results will enable planning of the magnitude of testing and targeted counseling needs over time.

Malaria is still one of the most devastating diseases worldwide, which is caused by infection of the genus Plasmodium. Liver stage is an essential early step of malaria parasite infection, and plasmodium replicates in parasitophorous vacuole (PV) of hepatocytes at this stage. Although encountering with hepatocyte autonomous immunity, exoerythrocytic forms (EEFs) in PV can still survive and successfully complete infection of hepatocytes. The underlying mechanism is largely unknown. Here, we show that sporozoite circumsporozoite protein (CSP) translocates from the parasitophorous vacuole into the hepatocyte cytoplasm to significantly inhibit the killing of exoerythrocytic forms (EEFs) by interferon-gamma (IFN-gamma). Nitric oxide were found to be indispensable for the resistance to IFN-gamma-mediated killing of EEFs by CSP. Attenuation of the IFN-gamma-mediated killing of EEFs by CSP is dependent on its ability to reduce the levels of ATGs in hepatocytes. The ATGs downregulation occurs through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that is upregulated by CSP when it translocates from the cytoplasm into the nucleus of hepatocytes via its NLS domain. Thus, we have revealed an unrecognized role of CSP in suppressing host autonomous immunity, and shed new light for a prophylaxis strategy against liver-stage infection

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.359.

Background/Purpose: Children with craniofacial dysostosis syndromes including Apert, Pfeiffer and Crouzon, may present with midface abnormalities but without major (calvarial) suture synostosis and head shape anomalies. This presentation is known as progressive postnatal craniosynostosis. Minor sutures/synchondroses are continuations of major calvarial sutures toward and within the skull base. Although skull base changes are associated with midface abnormalities, their role in major suture synostosis and calvarial shape anomalies are uncertain. We hypothesized that minor suture synostosis is present in infants with syndromic, progressive postnatal craniosynostosis, and underlie major suture synostosis. Methods/Description: We performed a multi-institutional review (CHOP and NYU) of infants (<1 year) with syndromic craniosynos-tosis and available CT scans. Major (metopic, sagittal, coronal, lambdoid) and minor suture/synchondrosis fusion was determined by two craniofacial surgeons and one radiologist using Mimics or Radiant software. Interrater-reliability scores were excellent between institutions (94.1%, kappa-0.821). Statistical assessments were performed using SPSS. Results: Seventy-three patients with 84 scans were included, with diagnoses of Crouzon, Pfeiffer, Apert, Antley-Bixler, Muenke, and Saethre-Chotzen syndromes. 13 scans lacked major suture synostosis; 10 of these had minor suture fusion present, and the remaining 3 had neither major nor minor suture synostosis. A diagnosis with an FGFR2 mutation was strongly associated with a lack of major suture fusion (OR 19.0, p=0.044). Examination of individual sutures revealed that minor suture fusion occurred significantly more often in the posterior branch of the coronal arch (OR 3.33, p<0.001), squamosal arch (OR 7.32, p<0.001) and posterior intraoccipital synchondroses (OR 15.84, p<0.001), among FGFR2 vs other patients. A strong temporal correlation between age at CT and suture fusion was identified for the metopic suture and 58% of minor sutures, but not in other major sutures. An analysis of those (n=9) with multiple scans revealed a pattern of minor suture fusion followed by increased minor and major suture synostosis. Four of these had no major suture synostosis initially, but progressed to increased minor suture fusion with or without major suture involvement. Over 84% of FGFR2-group patients had minor suture fusion, however 6 patients were identified with isolated major suture synostosis. This suggests that although minor suture fusion is common in these patients, it is not required for major suture synostosis. Conclusions: Perinatal, progressive, skull base suture/synchondrosis fusion occurs in most patients with FGFR2-related craniofacial dysostosis. Syndromic patients with patent calvarial sutures and findings consistent with increased intracranial pressure should be investigated for minor suture involvement. These data have important implications for the pathophysiology of skull growth and development in this select group of patients

AIM: To evaluate the performance of normalised apparent diffusion coefficient (ADC) values for prostate cancer assessment when performed by independent observers blinded to histopathology findings. MATERIALS AND METHODS: Fifty-eight patients undergoing 3 T phased-array coil magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI; maximal b-value 1000 s/mm2) before prostatectomy were included. Two radiologists independently evaluated the images, unaware of the histopathology findings. Regions of interest (ROIs) were drawn within areas showing visually low ADC within the peripheral zone (PZ) and transition zone (TZ) bilaterally. ROIs were also placed within regions in both lobes not suspicious for tumour, allowing computation of normalised ADC (nADC) ratios between suspicious and non-suspicious regions. The diagnostic performance of ADC and nADC were compared. RESULTS: For PZ tumour detection, ADC achieved significantly higher area under the receiver operating characteristic curve (AUC; p=0.026) and specificity (p=0.021) than nADC for reader 1, and significantly higher AUC (p=0.025) than nADC for reader 2. For TZ tumour detection, nADC achieved significantly higher specificity (p=0.003) and accuracy (p=0.004) than ADC for reader 2. For PZ Gleason score >3+3 tumour detection, ADC achieved significantly higher AUC (p=0.003) and specificity (p=0.005) than nADC for reader 1, and significantly higher AUC (p=0.023) than nADC for reader 2. For TZ Gleason score >3+3 tumour detection, ADC achieved significantly higher specificity (p=0.019) than nADC for reader 1. CONCLUSION: In contrast to prior studies performing unblinded evaluations, ADC was observed to outperform nADC overall for two independent observers blinded to the histopathology findings. Therefore, although strategies to improve the utility of ADC measurements in prostate cancer assessment merit continued investigation, caution is warranted when applying normalisation to improve diagnostic performance in clinical practice.

The microbiome is a new center of attention for studies on the pathogenesis of human disease by focusing on the alterations of all microorganisms living in a particular site or system of human body, referred as microbiota. Evidence suggests that microbiota could contribute to the pathogenesis of a number of chronic diseases, including cancers, both locally and remotely. Multiple mechanisms have been proposed and/or proven for the microbiota's role in tumorigenesis, such as via induction of chronic inflammation, genotoxicity, bacterium-mediated cell proliferation, and activation of procarcinogens. Emerging data suggest that indigenous microbiota in the urinary tract may play an important role in the tumorigenesis of urothelial carcinoma, similar to other tumors. Future studies are needed to adequately define the microbiota composition and correlate its change with urothelial carcinoma.