Reference Data for Diagnosis of Spondylolisthesis and Disc Space Narrowing Based on NHANES-II X-rays.

Robust reference data, representing a large and diverse population, are needed to objectively classify measurements of spondylolisthesis and disc space narrowing as normal or abnormal. The reference data should be open access to drive standardization across technology developers. The large collection of radiographs from the 2nd National Health and Nutrition Examination Survey was used to establish reference data. A pipeline of neural networks and coded logic was used to place landmarks on the corners of all vertebrae, and these landmarks were used to calculate multiple disc space metrics. Descriptive statistics for nine SPO and disc metrics were tabulated and used to identify normal discs, and data for only the normal discs were used to arrive at reference data. A spondylolisthesis index was developed that accounts for important variables. These reference data facilitate simplified and standardized reporting of multiple intervertebral disc metrics.

Definition of Normal Vertebral Morphometry Using NHANES-II Radiographs.

A robust definition of normal vertebral morphometry is required to confidently identify abnormalities such as fractures. The Second National Health and Nutrition Examination Survey (NHANES-II) collected a nationwide probability sample to document the health status of the United States. Over 10,000 lateral cervical spine and 7,000 lateral lumbar spine X-rays were collected. Demographic, anthropometric, health, and medical history data were also collected. The coordinates of the vertebral body corners were obtained for each lumbar and cervical vertebra using previously validated, automated technology consisting of a pipeline of neural networks and coded logic. These landmarks were used to calculate six vertebral body morphometry metrics. Descriptive statistics were generated and used to identify and trim outliers from the data. Descriptive statistics were tabulated using the trimmed data for use in quantifying deviation from average for each metric. The dependency of these metrics on sex, age, race, nation of origin, height, weight, and body mass index (BMI) was also assessed. There was low variation in vertebral morphometry after accounting for vertebrae (eg, L1, L2), and the R 2 was high for ANOVAs. Excluding outliers, age, sex, race, nation of origin, height, weight, and BMI were statistically significant for most of the variables, though the F-statistic was very small compared to that for vertebral level. Excluding all variables except vertebra changed the ANOVA R 2 very little. Reference data were generated that could be used to produce standardized metrics in units of SD from mean. This allows for easy identification of abnormalities resulting from vertebral fractures, atypical vertebral body morphometries, and other congenital or degenerative conditions. Standardized metrics also remove the effect of vertebral level, facilitating easy interpretation and enabling data for all vertebrae to be pooled in research studies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Tiled-ClickSeq for targeted sequencing of complete coronavirus genomes with simultaneous capture of RNA recombination and minority variants.

High-throughput genomics of SARS-CoV-2 is essential to characterize virus evolution and to identify adaptations that affect pathogenicity or transmission. While single-nucleotide variations (SNVs) are commonly considered as driving virus adaption, RNA recombination events that delete or insert nucleic acid sequences are also critical. Whole genome targeting sequencing of SARS-CoV-2 is typically achieved using pairs of primers to generate cDNA amplicons suitable for next-generation sequencing (NGS). However, paired-primer approaches impose constraints on where primers can be designed, how many amplicons are synthesized and requires multiple PCR reactions with non-overlapping primer pools. This imparts sensitivity to underlying SNVs and fails to resolve RNA recombination junctions that are not flanked by primer pairs. To address these limitations, we have designed an approach called 'Tiled-ClickSeq', which uses hundreds of tiled-primers spaced evenly along the virus genome in a single reverse-transcription reaction. The other end of the cDNA amplicon is generated by azido-nucleotides that stochastically terminate cDNA synthesis, removing the need for a paired-primer. A sequencing adaptor containing a Unique Molecular Identifier (UMI) is appended to the cDNA fragment using click-chemistry and a PCR reaction generates a final NGS library. Tiled-ClickSeq provides complete genome coverage, including the 5'UTR, at high depth and specificity to the virus on both Illumina and Nanopore NGS platforms. Here, we analyze multiple SARS-CoV-2 isolates and clinical samples to simultaneously characterize minority variants, sub-genomic mRNAs (sgmRNAs), structural variants (SVs) and D-RNAs. Tiled-ClickSeq therefore provides a convenient and robust platform for SARS-CoV-2 genomics that captures the full range of RNA species in a single, simple assay.

Tiled-ClickSeq for targeted sequencing of complete coronavirus genomes with simultaneous capture of RNA recombination and minority variants.

High-throughput genomics of SARS-CoV-2 is essential to characterize virus evolution and to identify adaptations that affect pathogenicity or transmission. While single-nucleotide variations (SNVs) are commonly considered as driving virus adaption, RNA recombination events that delete or insert nucleic acid sequences are also critical. Whole genome targeting sequencing of SARS-CoV-2 is typically achieved using pairs of primers to generate cDNA amplicons suitable for Next-Generation Sequencing (NGS). However, paired-primer approaches impose constraints on where primers can be designed, how many amplicons are synthesized and requires multiple PCR reactions with non-overlapping primer pools. This imparts sensitivity to underlying SNVs and fails to resolve RNA recombination junctions that are not flanked by primer pairs. To address these limitations, we have designed an approach called 'Tiled-ClickSeq', which uses hundreds of tiled-primers spaced evenly along the virus genome in a single reverse-transcription reaction. The other end of the cDNA amplicon is generated by azido-nucleotides that stochastically terminate cDNA synthesis, removing the need for a paired-primer. A sequencing adaptor containing a Unique Molecular Identifier (UMI) is appended to the cDNA fragment using click-chemistry and a PCR reaction generates a final NGS library. Tiled-ClickSeq provides complete genome coverage, including the 5'UTR, at high depth and specificity to the virus on both Illumina and Nanopore NGS platforms. Here, we analyze multiple SARS-CoV-2 isolates and clinical samples to simultaneously characterize minority variants, sub-genomic mRNAs (sgmRNAs), structural variants (SVs) and D-RNAs. Tiled-ClickSeq therefore provides a convenient and robust platform for SARS-CoV-2 genomics that captures the full range of RNA species in a single, simple assay.

Observational stepped-wedge analysis of a community health worker-led intervention for diabetes and hypertension in rural Mexico.

OBJECTIVES: There is emerging interest and data supporting the effectiveness of community health workers (CHWs) in non-communicable diseases (NCDs) in low/middle-income countries (LMICs). This study aimed to determine whether a CHW-led intervention targeting diabetes and hypertension could improve markers of clinical disease control in rural Mexico. DESIGN AND SETTING: A prospective observational stepped-wedge study was conducted across seven communities in rural Chiapas, Mexico from March 2014 to April 2018. PARTICIPANTS: 149 adults with hypertension and/or diabetes. INTERVENTION: This study was conducted in the context of the programmatic roll-out of an accompaniment-based CHW-led intervention designed to complement comprehensive primary care for adults with diabetes and/or hypertension. Implementation occurred sequentially at 3-month intervals with point-of-care data collected at baseline and every 3 months thereafter for 12 months following roll-out in all communities. OUTCOME MEASURES: Primary outcomes were glycated haemoglobin (HbA1c) and systolic blood pressure (SBP), overall and stratified by baseline disease control. We conducted an individual-level analysis using mixed effects regression, adjusting for time, cohort and clustering at the individual and community levels. RESULTS: Among patients with diabetes, the CHW-led intervention was associated with a decrease in HbA1c of 0.35%; however, CIs were wide (95% CI -0.90% to 0.20%). In patients with hypertension, there was a 4.7 mm Hg decrease in SBP (95% CI -8.9 to -0.6). In diabetic patients with HbA1c ≥9%, HbA1c decreased by 0.96% (95% CI -1.69% to -0.23%), and in patients with uncontrolled hypertension, SBP decreased by 10.2 mm Hg (95% CI -17.7 to -2.8). CONCLUSIONS: We found that a CHW-led intervention resulted in clinically meaningful improvement in disease markers for patients with diabetes and hypertension, most apparent among patients with hypertension and patients with uncontrolled disease at baseline. These findings suggest that CHWs can play a valuable role in supporting NCD management in LMICs. TRIAL REGISTRATION NUMBER: NCT02549495.

Community health workers improve disease control and medication adherence among patients with diabetes and/or hypertension in Chiapas, Mexico: an observational stepped-wedge study.

BACKGROUND: Non-communicable diseases (NCDs) contribute greatly to morbidity and mortality in low-income and middle-income countries (LMICs). Community health workers (CHWs) may improve disease control and medication adherence among patients with NCDs in LMICs, but data are lacking. We assessed the impact of a CHW-led intervention on disease control and adherence among patients with diabetes and/or hypertension in Chiapas, Mexico. METHODS: We conducted a prospective observational study among adult patients with diabetes and/or hypertension, in the context of a stepped-wedge roll-out of a CHW-led intervention. We measured self-reported adherence to medications, blood pressure and haemoglobin A1c at baseline and every 3 months, timed just prior to expansion of the intervention to a new community. We conducted individual-level mixed effects analyses of study data, adjusting for time and clustering by patient and community. FINDINGS: We analysed 108 patients. The CHW-led intervention was associated with a twofold increase in the odds of disease control (OR 2.04, 95% CI 1.15 to 3.62). It was also associated with optimal adherence assessed by 30-day recall (OR 1.86; 95% CI 1.15 to 3.02) and a positive self-assessment of adherence behaviour (OR 2.29; 95% CI 1.26 to 4.15), but not by 5-day recall. INTERPRETATION: A CHW-led adherence intervention was associated with disease control and adherence among adults with diabetes and/or hypertension. This study supports a role of CHWs in supplementing comprehensive primary care for patients with NCDs in LMICs. TRIAL REGISTRATION NUMBER: NCT02549495.

Ceftaroline Fosamil Use in 2 Pediatric Patients With Invasive Methicillin-Resistant Staphylococcus aureus Infections.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is one of the most common pathogens causing pediatric infections including skin and soft tissue infections, pyogenic arthritis, osteomyelitis, and septic shock. For decades, patients were treated with antibiotics such as vancomycin and clindamycin, but there is an increasing incidence of resistance to these traditional therapies. We describe 2 cases of patients with CA-MRSA invasive infections with bacteremia who experienced vancomycin therapy failure but who were successfully treated with ceftaroline fosamil. Case 1 involves an 8-year-old Hispanic male who was diagnosed with CA-MRSA bacteremia, thigh abscess, and osteomyelitis. The patient was admitted to the pediatric intensive care unit in septic shock. Case 2 involves an 8-year-old Caucasian male who was diagnosed with CA-MRSA sepsis, right arm abscess, and osteomyelitis. We were able to successfully treat both patients with CA-MRSA sepsis and invasive infection-who failed vancomycin therapy-with ceftaroline fosamil with no adverse efiects. Despite the positive outcome in both pediatric patients, clinical trials with ceftaroline fosamil are needed to further support its use in pediatric patients.

Asymmetric motion distribution between components of a mobile-core lumbar disc prosthesis: an explanation of unequal wear distribution in explanted CHARITÉ polyethylene cores.

BACKGROUND: The biconvex mobile core of the CHARITÉ lumbar disc prosthesis forms two joints (spherical bearings) with the metal end plates. We quantified the intra-prosthesis motion to test the hypothesis that the total prosthesis motion would not be equally distributed between the two bearings of implanted CHARITÉ discs, which might explain the unequal wear distribution reported in explanted cores. METHODS: The hypothesis was tested by studying the flexion-extension motion responses of (1) twenty-six monosegmental CHARITÉ III discs implanted in nineteen human cadaveric lumbar spines, and (2) twenty-one CHARITÉ III discs (fifteen monosegmental, six bisegmental) implanted in eighteen patients in other published clinical studies. Intra-prosthesis motions were quantified with use of a radiographic image analysis technique. RESULTS: Eighty-eight percent of the CHARITÉ discs implanted in cadaveric specimens exhibited larger motion at the superior bearing, with 54% demonstrating more than twice as much motion at the superior bearing as at the inferior bearing. The ratio of motion at the superior bearing to motion at the inferior bearing averaged 2.68 ± 1.84, which was significantly larger than 1.0 (p < 0.001). Ninety percent of prostheses implanted in patients showed larger motion at the superior bearing. The motion ratio averaged 2.39 ± 2.47 for monosegmental cases and 2.55 ± 2.66 for all cases; both ratios were significantly larger than 1.0 (p < 0.05). CONCLUSIONS: We found preferentially larger motion at the superior bearing of the CHARITÉ discs implanted in human cadaveric lumbar spines and in patients, regardless of the implanted level.

Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus.

BACKGROUND: Severe acute respiratory syndrome (SARS) emerged in China in 2002 and spread to other countries before brought under control. Because of a concern for reemergence or a deliberate release of the SARS coronavirus, vaccine development was initiated. Evaluations of an inactivated whole virus vaccine in ferrets and nonhuman primates and a virus-like-particle vaccine in mice induced protection against infection but challenged animals exhibited an immunopathologic-type lung disease. DESIGN: Four candidate vaccines for humans with or without alum adjuvant were evaluated in a mouse model of SARS, a VLP vaccine, the vaccine given to ferrets and NHP, another whole virus vaccine and an rDNA-produced S protein. Balb/c or C57BL/6 mice were vaccinated i.m. on day 0 and 28 and sacrificed for serum antibody measurements or challenged with live virus on day 56. On day 58, challenged mice were sacrificed and lungs obtained for virus and histopathology. RESULTS: All vaccines induced serum neutralizing antibody with increasing dosages and/or alum significantly increasing responses. Significant reductions of SARS-CoV two days after challenge was seen for all vaccines and prior live SARS-CoV. All mice exhibited histopathologic changes in lungs two days after challenge including all animals vaccinated (Balb/C and C57BL/6) or given live virus, influenza vaccine, or PBS suggesting infection occurred in all. Histopathology seen in animals given one of the SARS-CoV vaccines was uniformly a Th2-type immunopathology with prominent eosinophil infiltration, confirmed with special eosinophil stains. The pathologic changes seen in all control groups lacked the eosinophil prominence. CONCLUSIONS: These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.

Cotton rats and house sparrows as hosts for North and South American strains of eastern equine encephalitis virus.

Eastern equine encephalitis virus (EEEV; family Togaviridae, genus Alphavirus) is an arbovirus that causes severe disease in humans in North America and in equids throughout the Americas. The enzootic transmission cycle of EEEV in North America involves passerine birds and the ornithophilic mosquito vector, Culiseta melanura, in freshwater swamp habitats. However, the ecology of EEEV in South America is not well understood. Culex (Melanoconion) spp. mosquitoes are considered the principal vectors in Central and South America; however, a primary vertebrate host for EEEV in South America has not yet been identified. Therefore, to further assess the reservoir host potential of wild rodents and wild birds, we compared the infection dynamics of North American and South American EEEV in cotton rats (Sigmodon hispidus) and house sparrows (Passer domesticus). Our findings suggested that each species has the potential to serve as amplification hosts for North and South America EEEVs.

Placental malaria among HIV-infected and uninfected women receiving anti-folates in a high transmission area of Uganda.

BACKGROUND: HIV infection increases the risk of placental malaria, which is associated with poor maternal and infant outcomes. Recommendations in Uganda are for HIV-infected pregnant women to receive daily trimethoprim-sulphamethoxazole (TS) and HIV-uninfected women to receive intermittent sulphadoxine-pyrimethamine (SP). TS decreases the risk of malaria in HIV-infected adults and children but has not been evaluated among pregnant women. METHODS: This was a cross sectional study comparing the prevalence of placental malaria between HIV-infected women prescribed TS and HIV-uninfected women prescribed intermittent preventive therapy with sulphadoxine-pyrimethamine (IPT-SP) in a high malaria transmission area in Uganda. Placental blood was evaluated for malaria using smear and PCR. RESULTS: Placentas were obtained from 150 HIV-infected women on TS and 336 HIV-uninfected women on IPT-SP. The proportion of HIV-infected and HIV-uninfected women with placental malaria was 19% vs. 26% for those positive by PCR and 6% vs. 9% for those positive by smear, respectively. Among all infants, smear+ placental malaria was most predictive of low birth weight (LBW). Primigravidae were at higher risk than multigravidae of having placental malaria among HIV-uninfected, but not HIV-infected, women. Adjusting for gravidity, age, and season at the time of delivery, HIV-infected women on TS were not at increased risk for placental malaria compared to HIV-uninfected women on IPT-SP, regardless of the definition used. CONCLUSION: Prevalence of placental malaria was similar in HIV-infected women on TS and HIV-uninfected women on IPT-SP. Nonetheless, while nearly all of the women in this study were prescribed anti-folates, the overall risk of placental malaria and LBW was unacceptably high. The population attributable risk of placental malaria on LBW was substantial, suggesting that future interventions that further diminish the risk of placental malaria may have a considerable impact on the burden of LBW in this population.

Evaluation of the efficacy of a recombinant subunit West Nile vaccine in Syrian golden hamsters.

The efficacy of a recombinant subunit West Nile (WN) vaccine candidate was determined in a hamster model of encephalitis. Animals included young, aged, and immunocompromised animals in an effort to simulate key groups at risk of WN virus-induced disease. Groups of aged (12 month old), weanling, and adult hamsters rendered leukopenic after immunization were immunized subcutaneously with a WN virus recombinant envelope protein (WN-80E) with or without WN virus non-structural protein 1 (NS1) mixed with adjuvant or adjuvant alone. A challenge dose of wild-type WN virus was administered to produce 40-100% mortality in the control hamsters. The recombinant antigen preparations containing WN-80E with or without WN NS1 gave similar results. Hamsters in both groups had a strong antibody response after immunization, and none of the aged or weanling animals became ill or developed detectable viremia after challenge with WN virus at 2 weeks after booster vaccination. However, mortality among the control animals (administered adjuvant without antigen) at 2 weeks after booster challenge was 40-60%. In hamsters rendered leukopenic after immunization, survival rates up to 80% were observed, and a low-level viremia was detected in the vaccinated and challenged hamsters. The survival rate was significantly (P<0.05) higher in animals vaccinated with a higher dose of WN-80E than a lower dose. The addition of NS1 did not significantly affect survival after challenge. In contrast, all of the control animals that received adjuvant only developed a very high level of viremia, and the mortality rate was 100%. These findings indicate that the recombinant WN vaccines induced antibody in and afforded protection to young and aged hamsters and immunosuppressed hamsters.

Chimeric coronavirus-like particles carrying severe acute respiratory syndrome coronavirus (SCoV) S protein protect mice against challenge with SCoV.

We tested the efficacy of coronavirus-like particles (VLPs) for protecting mice against severe acute respiratory syndrome coronavirus (SCoV) infection. Coexpression of SCoV S protein and E, M and N proteins of mouse hepatitis virus in 293T or CHO cells resulted in the efficient production of chimeric VLPs carrying SCoV S protein. Balb/c mice inoculated with a mixture of chimeric VLPs and alum twice at an interval of four weeks were protected from SCoV challenge, as indicated by the absence of infectious virus in the lungs. The same groups of mice had high levels of SCoV-specific neutralizing antibodies, while mice in the negative control groups, which were not immunized with chimeric VLPs, failed to manifest neutralizing antibodies, suggesting that SCoV-specific neutralizing antibodies are important for the suppression of viral replication within the lungs. Despite some differences in the cellular composition of inflammatory infiltrates, we did not observe any overt lung pathology in the chimeric-VLP-treated mice, when compared to the negative control mice. Our results show that chimeric VLP can be an effective vaccine strategy against SCoV infection.

Efficacy of the antipoxvirus compound ST-246 for treatment of severe orthopoxvirus infection.

Efficacy of the new antipoxvirus compound ST-246 was evaluated as treatment of monkeypox (MPX) virus infection in a ground squirrel model of the disease. Ground squirrels were given a lethal dose of MPX virus and were then treated orally at various times post-inoculation (pi) with 100 mg/kg/day of ST-246. Morbidity and mortality, clinical laboratory results, viral load, and pathology of placebo and treatment groups were compared. All animals that started treatment with ST-246 on days 0, 1, 2, and 3 pi survived lethal challenge with MPX virus; 67% of animals treated on day 4 pi also survived. In contrast, 100% of the placebo group died. Most of the ST-246-treated animals showed no evidence of clinical disease or alteration of baseline clinical laboratory values and had minimal histopathologic changes. These results suggest that ST-246 is a promising candidate for early treatment of severe orthopoxvirus infection.

Comparative pathology of North American and central African strains of monkeypox virus in a ground squirrel model of the disease.

The first human cases of monkeypox (MPX) were recognized in central Africa in 1970. Since then, sporadic outbreaks of the disease have occurred in central and west Africa. In 2003, an outbreak of human MPX occurred in the United States after importation of infected rodents from west Africa. Clinical features of the 2003 outbreak were less severe than accounts of the disease among people in central Africa. The reasons for this observed difference are unknown. In this study, the clinical and pathologic characteristics of experimental infection with representative central African and North American MPX virus strains were compared in a ground squirrel model of the disease. The results indicate that the US 2003 virus, which phylogenetically is a member of the west African MPX virus clade, was less virulent than central African MPX virus strains.

Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor.

Animal models for severe acute respiratory syndrome (SARS) coronavirus infection of humans are needed to elucidate SARS pathogenesis and develop vaccines and antivirals. We developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. A transgenic lineage, designated AC70, was among the best characterized against SARS coronavirus infection, showing weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection. High virus titers were detected in the lungs and brains of transgene-positive (Tg+) mice on days 1 and 3 after infection. Inflammatory mediators were also detected in these tissues, coinciding with high levels of virus replication. Lower virus titers were also detected in other tissues, including blood. In contrast, infected transgene-negative (Tg-) mice survived without showing any clinical illness. Pathologic examination suggests that the extensive involvement of the central nervous system likely contributed to the death of Tg+ mice, even though viral pneumonia was present. Preliminary studies with mice of a second lineage, AC63, in which the transgene expression was considerably less abundant than that in the AC70 line, revealed that virus replication was largely restricted to the lungs but not the brain. Importantly, despite significant weight loss, infected Tg+ AC63 mice eventually recovered from the illness without any mortality. The severity of the disease that developed in these transgenic mice--AC70 in particular--makes these mouse models valuable not only for evaluating the efficacy of antivirals and vaccines, but also for studying SARS coronavirus pathogenesis.

Efficacy and durability of a recombinant subunit West Nile vaccine candidate in protecting hamsters from West Nile encephalitis.

The efficacy of a new recombinant subunit West Nile virus (WNV) vaccine candidate was determined in a hamster model of meningoencephalitis. Groups of hamsters were immunized subcutaneously with a WNV recombinant envelope protein (80E) with or without WNV non-structural protein 1 (NS1) mixed with adjuvant or adjuvant alone. At 2 weeks, 6 months, and 12 months after two immunizations at 4 week intervals with the respective immunogens, groups of animals were challenged via the intraperitoneal route with a virulent strain of WNV. The two recombinant antigen preparations gave similar results; hamsters in both groups had a strong antibody response following immunization, and none of the animals became ill or developed detectable viremia after challenge with WNV at 2 weeks or 6 months post-booster vaccination. In contrast, mortality among the control animals at 2 weeks post-booster challenge was 73%, and at 6 months post-booster, the mortality was 53% among the control animals. When challenged 12 months after the booster vaccination, a low level viremia was detected in some of the vaccinated hamsters, and one hamster became sick, but recovered. In contrast, all of the control animals that received adjuvant only developed a viremia, and the mortality rate was 77%. These results with the recombinant subunit WNV vaccine are very encouraging and warrant further animal studies to evaluate its potential use to protect humans against WNV disease.

Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus) III. Clinical laboratory values.

Using a recently described hamster model of yellow fever (YF), we compared the hematologic and clinical chemistry changes that occur in blood with the histopathologic alternations observed in liver and other organs. Inflammatory foci and necroapoptotic hepatocytes were first observed in the liver three days after YF infection. This was accompanied by a rapid increase in serum transaminase and bilirubin values, elevation of prothrombin times, thrombocytopenia, and leukocytosis. Maximum liver pathology was observed on the sixth and seventh days post-infection; this corresponded to the peak alternations in clinical chemistry and hematologic values. In surviving hamsters, regenerating hepatocytes began to appear on the eighth day post-infection; this was accompanied by a corresponding return to baseline levels of most of the aforementioned clinical laboratory values. The histopathologic and clinical laboratory findings in the hamster model were very similar to those observed in severe human cases of YF. These results provide further validation of the utility of the hamster model for studying the pathogenesis and treatment of YF.

Clinical laboratory, virologic, and pathologic changes in hamsters experimentally infected with Pirital virus (Arenaviridae): a rodent model of Lassa fever.

The clinical laboratory, virologic, and pathologic changes occurring in hamsters after infection with Pirital virus (Arenaviridae) are described. Pirital virus infection in the hamsters was characterized by high titered viremia, leukocytosis, coagulopathy, pulmonary hemorrhage and edema, hepatocellular and splenic necrosis, and marked elevation of serum transaminase levels. All of the animals died within 9 days. The clinical and histopathological findings in the Pirital virus-infected hamsters were very similar to those reported in severe human cases of Lassa fever, suggesting that this new animal model could serve as a low-cost and relatively safe alternative for studying the pathogenesis and therapy of Lassa fever.