Severe papilloedema with vision loss secondary to Guillain-Barré syndrome.

We discuss a patient who presented with bilateral VI and VII cranial nerve palsies, symmetric upper and lower limb weakness and areflexia, 2 weeks following an flu-like illness. At presentation, there was no papilloedema, and her visual function was normal. Cerebrospinal fluid analysis and electrophysiology supported the diagnosis of Guillain-Barré Syndrome (GBS). She received intravenous immunoglobulins. She subsequently developed headaches and vision loss. Funduscopy demonstrated severe papilloedema with visual acuity of 6/18 right eye, 6/12 left eye with bitemporal visual field depression. Lumbar puncture revealed elevated opening pressure with high protein and normal cell count. She received acetazolamide. There was resolution of papilloedema and normal visual function at 3 months. Of note, the patient's body mass index was 17 kg/m2Our case highlights the rare occurrence of papilloedema in GBS, reiterating the importance of performing funduscopy on patients with any neurological diagnosis. Early detection and prompt management of papilloedema can prevent permanent vision loss.

Outcomes of 45 µm gelatin stent surgery over 24-month follow-up.

BACKGROUND: The main objectives of this study were to determine whether known risk factors for trabeculectomy failure similarly influence gelatin stent outcomes and to identify surgical factors which may optimise success. METHODS: A retrospective, observational study was conducted at a single centre in Perth, Western Australia over 24 months. Two-hundred and sixty-two eyes of 207 patients underwent XEN-45 stent surgery with various forms of glaucoma. Surgical and postoperative data on subjects undergoing XEN-45 stent surgery was collated. Intraocular pressure (IOP) reduction success was determined using three criteria: 1; IOP <18 mm Hg, 2: IOP <15 mm Hg and 3: >25% IOP reduction from baseline. Kaplan-Meier, mixed effects Cox Proportional hazard model and Chi-Square test were used to measure survival of functioning stents. RESULTS: The success rates at a maximum of 2 years after surgery by criteria 1, 2 and 3 were 61.3%, 26.2% and 28.9% in primary open angle glaucoma (n = 243), 18.8%, 16.9%, 21.4% in angle closure glaucoma (n = 11), 0%, 0%, 66.7% in congenital glaucoma (n = 5) and 0% in uveitic glaucoma (n = 3). No significant reduction in success was found in those eyes that had prior ocular surgery (all p > 0.07). CONCLUSIONS: Prior cataract or trabeculectomy surgery does not appear to adversely affect gelatin stent outcomes over 2 years follow up. Gelatin stent surgery appears to have less IOP reduction effect compared to trabeculectomy at 2 years.

Acceptability of reproductive goals assessment in public mental health care.

OBJECTIVE: To assess patient and provider perspectives on the acceptability of reproductive goals assessment in public mental health clinics and inform potential tailoring for these settings. DATA SOURCES AND STUDY SETTING: Primary qualitative data from patients and providers at four clinics in an urban public mental health system serving individuals with chronic mental illness (collected November 2020-October 2021). STUDY DESIGN: This was an exploratory qualitative study with patients (English-speaking women of reproductive age, primarily Black or Latina) and mental health providers (psychiatrists, psychotherapists, case managers, nurses). We examined the acceptability of reproductive goals assessment within mental health care and obtained feedback on two reproductive goals assessment conversation guides: PATH (Pregnancy Attitudes, Timing, and How Important is Pregnancy Prevention) and OKQ (One Key Question). DATA COLLECTION: We conducted semi-structured telephone interviews with 22 patients and 36 providers. We used rapid qualitative analysis to summarize interview transcripts and identified themes using matrix analysis. PRINCIPAL FINDINGS: Perceptions of reproductive goals assessment were generally positive. Providers said the conversation guides would "open the door" to important discussions, support a better understanding of patients' goals, and facilitate medication counseling and planning. A minority of patients expressed discomfort or ambivalence; several suggested providers ask permission or allow patients to raise the topic. Additional themes included the need for framing to provide context for these personal questions, the need to build rapport before asking them, and the challenge of balancing competing priorities. Many participants found both PATH and OKQ prompts acceptable; some preferred the "conversational" and "open-ended" PATH phrasing. CONCLUSIONS: Participants perceived reproductive goals assessment as a promising practice in mental health care with unique functions in this setting. Areas of discomfort highlight the sensitivity of these topics for some women with chronic mental illness and suggest opportunities to tailor language, framing, and provider training to support effective and appropriate implementation.

Optical diffraction tomography and image reconstruction to measure host cell alterations caused by divergent Plasmodium species.

Malaria is a life-threatening infectious disease caused by parasites of the genus Plasmodium. Understanding the biological features of various parasite forms is important for the optical diagnosis and defining pathological states, which are often constrained by the lack of ambient visualization approaches. Here, we employ a label-free tomographic technique to visualize the host red blood cell (RBC) remodeling process and quantify changes in biochemical properties arising from parasitization. Through this, we provide a quantitative body of information pertaining to the influence of host cell environment on growth, survival, and replication of P. falciparum and P. vivax in their respective host cells: mature erythrocytes and young reticulocytes. These exquisite three-dimensional measurements of infected red cells demonstrats the potential of evolving 3D imaging to advance our understanding of Plasmodium biology and host-parasite interactions.

Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model.

In recent decades, chimeric antigen receptor (CAR)-engineered immune effector cells have demonstrated promising antileukemic activity. Nevertheless, their efficacy remains unsatisfactory on solid cancers, plausibly due to the influence of tumor microenvironments (TME). In a novel mouse cancer model with a humanized immune system, tumor-infiltrating immunosuppressive leukocytes and exhausted programmed death protein-1 (PD-1)high T cells were found, which better mimic patient TME, allowing the screening and assessment of immune therapeutics. Particularly, membrane-bound programmed death ligand 1 (PD-L1) level was elevated on a tumor cell surface, which serves as an attractive target for natural killer (NK) cell-mediated therapy. Hematopoietic stem cell-derived CAR-NK (CAR pNK) cells targeting the PD-L1 showed enhanced in vitro and in vivo anti-solid tumor function. The CAR pNK cells and nivolumab resulted in a synergistic anti-solid tumor response. Together, our study highlights a robust platform to develop and evaluate the antitumor efficacy and safety of previously unexplored therapeutic regimens.

What is Noise Sensitivity?

Background: Noise sensitivity moderates the association between environmental noise exposure and annoyance and health outcomes. Methods: In normally hearing adults, we measured noise sensitivity in three ways: using the noise sensitivity questionnaire, a 3-point self-rating, and the loudness discomfort level (LDL; mean reported discomfort level for tone bursts). We then presented recordings of a 15-second 80 dBLAeq aeroplane overflight and participants rated the annoyance and loudness they experienced. Results: The three measures of noise sensitivity were not well correlated with each other, and only the overall LDL was associated with the ratings of loudness and annoyance in response to the aeroplane sounds. Conclusions: This implies that our current measures of noise sensitivity may only capture parts of the underlying construct, and therefore underestimate effects due to it on the association between environmental noise and annoyance and health outcomes. We developed a theoretical model to describe the set of factors that may influence a person's sensitivity to noise and propose that interaction between the systems described is the basis for noise sensitivity. This paradigm alters the focus of noise research from the annoyance caused by the sound, to the sensitization to noise that may occur as a result of the interplay of many factors. We hope that our model will allow research to explore the sensitizing factors for noise more easily and systematically.

Plasmodium cynomolgi Berok Growth Inhibition Assay by Thiol-reactive Probe Based Flow Cytometric Measurement.

The relapsing malaria species, Plasmodium vivax, is the most widely distributed and difficult-to-treat cause of human malaria. The merozoites of P. vivax preferentially invade ephemeral human CD71+ reticulocytes (nascent reticulocytes), thereby limiting the development of a robust continuous culture in vitro. Fortunately, P. vivax's sister species, P. cynomolgi Berok, can be cultured continuously, providing the ability to screen novel therapeutics drug and vaccine candidates in a reliable and high-throughput manner. Based on well-established growth inhibition activity (GIA) assays against P. falciparum and P. knowlesi, this protocol adopts the current flow cytometry assay methodology and investigates P. vivax inhibitory antibodies using the P. cynomolgi Berok invasion model based on the thiol-reactivity and DNA abundance of viable parasites in macaque erythrocytes. Established GIA assays screen antibodies at either a single concentration or high/low dose concentrations to provide quick insights for prioritizing potential antibodies capable of specifically interrupting parasite ligand and host receptor binding with minimal concentrations. Hence, this protocol expands on the existing GIA assay by using serially diluted antibodies and generating a dose-response curve to better quantify the inhibitory efficacy amongst selected vaccine candidates.

Sonographic abnormalities in pregnancies conceived following IVF with and without preimplantation genetic testing for aneuploidy (PGT-A).

PURPOSE: To report the rate of fetal anomalies detected on anatomy ultrasound in pregnant patients who underwent IVF with preimplantation genetic testing for aneuploidy (PGT-A) compared to patients who conceived following IVF with unscreened embryos and age-matched patients with natural conceptions. METHODS: Retrospective cohort study at a single maternal-fetal medicine practice. Patients with singleton pregnancies who had a mid-trimester anatomy ultrasound between January 2017 and December 2018 were screened for inclusion. A total of 712 patients who conceived after IVF with or without PGT-A were age-matched with natural conception controls. The primary outcome was the rate of fetal and placental anomalies detected on mid-trimester anatomical survey. Secondary outcomes included the rates of abnormal nuchal translucency (NT), second trimester serum analytes, non-invasive prenatal testing (NIPT), and invasive diagnostic testing. RESULT(S): There were no differences in the rate of fetal anomalies in patients who underwent IVF with PGT-A compared to patients who conceived following IVF with unscreened embryos and age-matched patients with natural conceptions. Rate of abnormal NT, high-risk NIPT, and abnormal invasive diagnostic testing were also similar. Patients who conceived after IVF with or without PGT-A had higher rates of abnormal placental ultrasound findings and abnormal second trimester serum analytes compared to natural conception controls. CONCLUSION: The use of PGT-A was not associated with a difference in risk of fetal anomaly detection on a mid-trimester anatomical survey. The results of this study highlight the importance of improved patient counseling regarding the limitations of PGT-A, and of providing standard prenatal care for pregnancies conceived through ART, regardless of whether PGT-A was performed.

A Chimeric Plasmodium vivax Merozoite Surface Protein Antibody Recognizes and Blocks Erythrocytic P. cynomolgi Berok Merozoites In Vitro.

Research on erythrocytic Plasmodium vivax merozoite antigens is critical for identifying potential vaccine candidates in reducing P. vivax disease. However, many P. vivax studies are constrained by its inability to undergo long-term culture in vitro Conserved across all Plasmodium spp., merozoite surface proteins are essential for invasion into erythrocytes and highly expressed on erythrocytic merozoites, thus making it an ideal vaccine candidate. In clinical trials, the P. vivax merozoite surface protein 1 (PvMSP1-19) vaccine candidate alone has shown to have limited immunogenicity in patients; hence, we incorporate the highly conserved and immunogenic C terminus of both P. vivax merozoite surface protein 8 (PvMSP8) and PvMSP1-19 to develop a multicomponent chimeric protein rPvMSP8+1 for immunization of mice. The resulted chimeric rPvMSP8+1 antibody was shown to recognize native protein MSP8 and MSP1-19 of mature P. vivax schizonts. In the immunized mice, an elevated antibody response was observed in the rPvMSP8+1-immunized group compared to that immunized with single-antigen components. In addition, we examined the growth inhibition of these antibodies against Plasmodium cynomolgi (Berok strain) parasites, which is phylogenetically close to P. vivax and sustains long-term culture in vitro Similarly, the chimeric anti-rPvMSP8+1 antibodies recognize P. cynomolgi MSP8 and MSP1-19 on mature schizonts and showed strong inhibition in vitro via growth inhibition assay. This study provides support for a new multiantigen-based paradigm rPvMSP8+1 to explore potential chimeric vaccine candidates against P. vivax malaria using sister species P. cynomolgi.

Spontaneous extrusion of a dexamethasone intravitreal implant (Ozurdex).

A 59-year-old man with diabetic macular oedema was treated with a dexamethasone intravitreal implant (Ozurdex) to his right eye. Immediately after injection, the implant was noted to have extruded into the perilimbal subconjunctival space. The remnants of the implant were expeditiously removed the following day to avoid corneal decompensation and permanent corneal oedema. Endothelial decompensation secondary to the migration of dexamethasone implants into the subconjunctival space or anterior chamber is a recognised complication of Ozurdex injection. The patient recovered well postoperatively with no further complications. He was planned for a new Ozurdex implant 1 month later.

Genetic diversity and neutral selection in Plasmodium vivax erythrocyte binding protein correlates with patient antigenicity.

Plasmodium vivax is the most widespread and difficult to treat cause of human malaria. The development of vaccines against the blood stages of P. vivax remains a key objective for the control and elimination of vivax malaria. Erythrocyte binding-like (EBL) protein family members such as Duffy binding protein (PvDBP) are of critical importance to erythrocyte invasion and have been the major target for vivax malaria vaccine development. In this study, we focus on another member of EBL protein family, P. vivax erythrocyte binding protein (PvEBP). PvEBP was first identified in Cambodian (C127) field isolates and has subsequently been showed its preferences for binding reticulocytes which is directly inhibited by antibodies. We analysed PvEBP sequence from 316 vivax clinical isolates from eight countries including China (n = 4), Ethiopia (n = 24), Malaysia (n = 53), Myanmar (n = 10), Papua New Guinea (n = 16), Republic of Korea (n = 10), Thailand (n = 174), and Vietnam (n = 25). PvEBP gene exhibited four different phenotypic clusters based on the insertion/deletion (indels) variation. PvEBP-RII (179-479 aa.) showed highest polymorphism similar to other EBL family proteins in various Plasmodium species. Whereas even though PvEBP-RIII-V (480-690 aa.) was the most conserved domain, that showed strong neutral selection pressure for gene purifying with significant population expansion. Antigenicity of both of PvEBP-RII (16.1%) and PvEBP-RIII-V (21.5%) domains were comparatively lower than other P. vivax antigen which expected antigens associated with merozoite invasion. Total IgG recognition level of PvEBP-RII was stronger than PvEBP-RIII-V domain, whereas total IgG inducing level was stronger in PvEBP-RIII-V domain. These results suggest that PvEBP-RII is mainly recognized by natural IgG for innate protection, whereas PvEBP-RIII-V stimulates IgG production activity by B-cell for acquired immunity. Overall, the low antigenicity of both regions in patients with vivax malaria likely reflects genetic polymorphism for strong positive selection in PvEBP-RII and purifying selection in PvEBP-RIII-V domain. These observations pose challenging questions to the selection of EBP and point out the importance of immune pressure and polymorphism required for inclusion of PvEBP as a vaccine candidate.

Evaluation of the Proximity of Singaporean Children's Dietary Habits to Food-Based Dietary Guidelines.

Dietary habits in children may not only impact current health status but could also shape future, lifelong dietary choices. Dietary intake data in Singaporean children are limited. The current study aimed to define the overall diet quality of Singaporean children using an existing cross-sectional dataset and to consider how demographic factors (i.e., body mass index (BMI) status, ethnicity, age, and sex) were associated with these scores. Existing, cross-sectional dietary data (n = 561 children aged 6-12 years, collected in 2014-2015) from duplicate 24-h recalls were assessed for diet quality using an index based on the Singaporean Health Promotion Board dietary guidelines. Total diet quality scores were calculated from ten different components (frequencies of rice and alternatives, whole grains, fruits, vegetables, meat and alternatives, dairy and alternatives, total fat, saturated fat, sodium intake, and added sugars). Association with demographic factors and BMI category was evaluated by one-way multivariate ANOVA (MANOVA) tests, with Bonferroni post hoc analyses. Median (interquartile range) total diet quality scores were 65.4 (57.1-73.0). Median scores for whole grains (0.0, 0.0-33.4), fruits (24.1, 0.0-65.3), vegetables (36.5, 10.4-89.8), and sodium (58.4, 0.0-100.0) intake were frequently sub-optimal. Children of Malay ethnic origin had statistically lower total diet quality scores ((55.3, 47.5-60.3) vs. other ethnic groups (combined median 65.4 (57.1, 73.0); p < 0.001). These findings highlight the need for continuing efforts to improve dietary intake in young Singaporeans and for longitudinal dietary monitoring in this group.

Robust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages.

The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax, the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi, a macaque-infecting species phylogenetically close to P. vivax, was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax. We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti-P. vivax drug discovery efforts.

Hepatic spheroids used as an in vitro model to study malaria relapse.

Hypnozoites are the liver stage non-dividing form of the malaria parasite that are responsible for relapse and acts as a natural reservoir for human malaria Plasmodium vivax and P. ovale as well as a phylogenetically related simian malaria P. cynomolgi. Our understanding of hypnozoite biology remains limited due to the technical challenge of requiring the use of primary hepatocytes and the lack of robust and predictive in vitro models. In this study, we developed a malaria liver stage model using 3D spheroid-cultured primary hepatocytes. The infection of primary hepatocytes in suspension led to increased infectivity of both P. cynomolgi and P. vivax infections. We demonstrated that this hepatic spheroid model was capable of maintaining long term viability, hepatocyte specific functions and cell polarity which enhanced permissiveness and thus, permitting for the complete development of both P. cynomolgi and P. vivax liver stage parasites in the infected spheroids. The model described here was able to capture the full liver stage cycle starting with sporozoites and ending in the release of hepatic merozoites capable of invading simian erythrocytes in vitro. Finally, we showed that this system can be used for compound screening to discriminate between causal prophylactic and cidal antimalarials activity in vitro for relapsing malaria.

Reducing the number of invalid surgical consents in the day surgery unit.

AIM: To reduce the number of invalid surgical consents in the Singapore National Eye Centre Day Surgery Unit over a period of 6 months. METHODOLOGY: A multidisciplinary team involving doctors, nurses, day surgery unit, operating theatre, listing and clinical audit staff looked into the listing process and the root causes of the high number of invalid consents. A Pareto chart detailing the top causes of invalid consents was drawn, and with a prioritisation matrix, feasible yet effective changes were identified and effected. Plan-Do-Study-Act (PDSA) cycles included moving consent checks upstream, getting invalid consents amended on the same day, sending emails to raise awareness on invalid consents and posters in clinics to emphasise the correct way to fill up consent forms. RESULT: There has been a progressive downtrend in the monthly mean percentage of invalid consents since the introduction of PDSA cycles. There was a significant reduction in the mean rate of rejected consents from the preintervention phase of 15.2% to the postintervention phase of 11.3%, shown with a Z score of 6.56 (P<0.05). Sustainability was also demonstrated with multiple consecutive points below the median of 14.5% on the postimplementation phase of the run chart, with estimated time-efficiency savings of USD$19 738.50 annually. CONCLUSION: Errors in the workplace can be reduced with a concerted effort from multiple stakeholders. It is important to have a thorough look at processes with concerned parties, so that different perspectives and skill sets can be harnessed to determine and implement feasible and effective interventions.

Helmet use in bicycles and non-motorised wheeled recreational vehicles in children.

AIM: Injuries involving non-motorised wheeled recreational vehicles (NMWRV) and bicycles are a common cause for hospitalisation in children. Studies show that helmet use whilst bicycle riding can decrease mortality and morbidity due to head injury. However, there remains an important proportion of children who are non-helmet users (NHU). This study aims to investigate helmet use and attitudes and injury patterns in children presenting with trauma after riding bicycles and other NMWRVs. METHODS: A prospective cohort study was undertaken over 8 months of children aged 0-16 years, who presented with injury secondary to bicycle or NMWRV to the emergency department of two tertiary paediatric centres. Demographics, incident, injury severity and attitudes towards helmet use were compared between helmet users and NHU. RESULTS: A total of 342 children were included - 41% (n = 139) scooter riders, 39% (n = 133) bicyclists, 18% (n = 61) skateboarders and 2% (n = 9) in-line skaters. Of those interviewed (n = 161), 58% (n = 93) wore a helmet, with children riding bicycles significantly more likely to be helmeted than NMWRV (75 vs. 48%, P = 0.01). NHU were more likely to be admitted to hospital (P = 0.05) and to sustain a major head injury (P = 0.009). The main influence on helmet use was parental rules. The biggest factor influencing non-helmet use was perceived low levels of danger. CONCLUSIONS: Despite legislation mandating this, helmet use is not universal in cyclists, particularly younger riders. Even fewer NMWRV riders use them. To promote helmet use, a multifaceted approach aimed at altering community norms and individual behaviours and attitudes is required.

Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants.

Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1-null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL/6J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.

Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi.

Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date, only a single case of naturally acquired P cynomolgi has been found in humans. In this study, we show that whereas P cynomolgi merozoites invade monkey red blood cells indiscriminately in vitro, in humans, they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234). This likely contributes to the paucity of detectable zoonotic cynomolgi malaria. We further describe postinvasion morphologic and rheologic alterations in P cynomolgi-infected human reticulocytes that are strikingly similar to those observed for P vivax These observations stress the value of P cynomolgi as a model in the development of blood stage vaccines against vivax malaria.

Hmga2 is dispensable for cutaneous squamous cell carcinoma.

Hmga2 functions as a chromatin-associated factor during development, but is not expressed in most adult tissues. Expression of Hmga2 in adult tissues has been associated with a variety of human cancers. Numerous studies have implicated Hmga2 in epithelial-to-mesenchymal transition (EMT) and cancer progression through gain of function studies, but it is unclear whether Hgma2 is necessary for EMT, tumor formation or tumor progression. We deleted Hmga2 in two mouse models of squamous cell carcinoma and found this gene to be dispensable. In fact, EMT, tumor initiation and progression all appeared to be mostly unaffected by the absence of Hmga2. Tumors lacking the ability to induce Hmga2 proceeded to initiate cutaneous spindle cell and squamous cell carcinomas with all the typical pathological and molecular hallmarks of these cancers.

Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection.

OBJECTIVE: HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. DESIGN: Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg(-/-) (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated. RESULTS: In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment. CONCLUSIONS: The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.