Last data update: Dec 02, 2024. (Total: 48272 publications since 2009)
Records 1-30 (of 40 Records) |
Query Trace: Martines RB[original query] |
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Bartonella quintana infection in kidney transplant recipients from donor experiencing homelessness, United States, 2022
Beeson AM , Rich SN , Russo ME , Bhatnagar J , Kumar RN , Ritter JM , Annambhotla P , Takeda MR , Kuhn KF , Pillai P , DeLeon-Carnes M , Scobell R , Ekambaram M , Finkel R , Reagan-Steiner S , Martines RB , Satoskar RS , Vranic GM , Mohammed R , Rivera GE , Cooper K , Abdelal H , Couturier MR , Bradley BT , Hinckley AF , Koehler JE , Mead PS , Kuehnert MJ , Ackelsberg J , Basavaraju SV , Marx GE . Emerg Infect Dis 2024 30 (12) 2467-2475 Bartonella quintana infection can cause severe disease that includes clinical manifestations such as endocarditis, chronic bacteremia, and vasoproliferative lesions of the skin and viscera. B. quintana bacteria is transmitted by the human body louse (Pediculus humanus corporis) and is associated with homelessness and limited access to hygienic services. We report B. quintana infection in 2 kidney transplant recipients in the United States from an organ donor who was experiencing homelessness. One infection manifested atypically, and the other was minimally symptomatic; with rapid detection, both recipients received timely treatment and recovered. B. quintana was identified retrospectively in an archived donor hematoma specimen, confirming the transmission link. Information about the organ donor's housing status was critical to this investigation. Evaluation for B. quintana infection should be considered for solid organ transplant recipients who receive organs from donors with a history of homelessness or of body lice infestation. |
Epidemiologic and genomic characterization of an outbreak of Rift Valley fever among humans and dairy cattle in northern Tanzania
Madut DB , Rubach MP , Allan KJ , Thomas KM , de Glanville WA , Halliday JEB , Costales C , Carugati M , Rolfe RJ , Bonnewell JP , Maze MJ , Mremi AR , Amsi PT , Kalengo NH , Lyamuya F , Kinabo GD , Mbwasi R , Kilonzo KG , Maro VP , Mmbaga BT , Lwezaula B , Mosha C , Marandu A , Kibona TJ , Zhu F , Chawla T , Chia WN , Anderson DE , Wang LF , Liu J , Houpt ER , Martines RB , Zaki SR , Leach A , Gibbons A , Chiang CF , Patel K , Klena JD , Cleaveland S , Crump JA . J Infect Dis 2024 BACKGROUND: A peri-urban outbreak of Rift Valley fever virus (RVFV) among dairy cattle from May through August 2018 in northern Tanzania was detected through testing samples from prospective livestock abortion surveillance. We sought to identify concurrent human infections, their phylogeny, and epidemiologic characteristics in a cohort of febrile patients enrolled from 2016-2019 at hospitals serving the epizootic area. METHODS: From September 2016 through May 2019, we conducted a prospective cohort study that enrolled febrile patients hospitalized at two hospitals in Moshi, Tanzania. Archived serum, plasma, or whole blood samples were retrospectively tested for RVFV by PCR. Human samples positive for RVFV were sequenced and compared to RVFV sequences obtained from cattle through a prospective livestock abortion study. Phylogenetic analysis was performed on complete RVFV genomes. RESULTS: Among 656 human participants, we detected RVFV RNA in four (0.6%), including one death with hepatic necrosis and other end-organ damage at autopsy. Humans infected with RVFV were enrolled from June through August 2018, and all resided in or near urban areas. Phylogenetic analysis of human and cattle RVFV sequences demonstrated that most clustered to lineage B, a lineage previously described in East Africa. A lineage E strain clustering with lineages in Angola was also identified in cattle. CONCLUSION: We provide evidence that an apparently small RVFV outbreak among dairy cattle in northern Tanzania was associated with concurrent severe and fatal infections among humans. Our findings highlight the unidentified scale and diversity of inter-epizootic RVFV transmission, including near and within an urban area. |
Clinicopathological discrepancies in the diagnoses of childhood causes of death in the CHAMPS network: An analysis of antemortem diagnostic inaccuracies
Leulseged H , Bethencourt C , Igunza KA , Akelo V , Onyango D , Omore R , Ogbuanu IU , Ameh S , Moseray A , Kowuor D , Bassey IA , El Arifeen S , Gurley ES , Hossain MZ , Rahman A , Alam M , Assefa N , Madrid L , Alemu A , Abdullahi YY , Kotloff KL , Sow SO , Tapia MD , Kourouma N , Sissoko S , Bassat Q , Varo R , Mandomando I , Carrilho C , Rakislova N , Fernandes F , Madhi S , Dangor Z , Mahtab S , Hale M , Baillie V , du Toit J , Madewell ZJ , Blau DM , Martines RB , Mutevedzi PC , Breiman RF , Whitney CG , Rees CA . BMJ Paediatr Open 2024 8 (1) INTRODUCTION: Determining aetiology of severe illness can be difficult, especially in settings with limited diagnostic resources, yet critical for providing life-saving care. Our objective was to describe the accuracy of antemortem clinical diagnoses in young children in high-mortality settings, compared with results of specific postmortem diagnoses obtained from Child Health and Mortality Prevention Surveillance (CHAMPS). METHODS: We analysed data collected during 2016-2022 from seven sites in Africa and South Asia. We compared antemortem clinical diagnoses from clinical records to a reference standard of postmortem diagnoses determined by expert panels at each site who reviewed the results of histopathological and microbiological testing of tissue, blood, and cerebrospinal fluid. We calculated test characteristics and 95% CIs of antemortem clinical diagnostic accuracy for the 10 most common causes of death. We classified diagnostic discrepancies as major and minor, per Goldman criteria later modified by Battle. RESULTS: CHAMPS enrolled 1454 deceased young children aged 1-59 months during the study period; 881 had available clinical records and were analysed. The median age at death was 11 months (IQR 4-21 months) and 47.3% (n=417) were female. We identified a clinicopathological discrepancy in 39.5% (n=348) of deaths; 82.3% of diagnostic errors were major. The sensitivity of clinician antemortem diagnosis ranged from 26% (95% CI 14.6% to 40.3%) for non-infectious respiratory diseases (eg, aspiration pneumonia, interstitial lung disease, etc) to 82.2% (95% CI 72.7% to 89.5%) for diarrhoeal diseases. Antemortem clinical diagnostic specificity ranged from 75.2% (95% CI 72.1% to 78.2%) for diarrhoeal diseases to 99.0% (95% CI 98.1% to 99.6%) for HIV. CONCLUSIONS: Antemortem clinical diagnostic errors were common for young children who died in areas with high childhood mortality rates. To further reduce childhood mortality in resource-limited settings, there is an urgent need to improve antemortem diagnostic capability through advances in the availability of diagnostic testing and clinical skills. |
A diagnostic algorithm for detection of leishmania spp. In human fresh and fixed tissue samples
Silva-Flannery LM , de Almeida ME , da Silva AJ , Bollweg BC , Fair PS , Ritter JM , Paddock CD , Martines RB , Zaki SR . Am J Trop Med Hyg 2024 Leishmaniasis is an important travel-related parasitic infection in the United States. Treatment regimens vary by Leishmania species and require an accurate diagnosis. The sensitivity and specificity of diagnostic methods depend on the type and condition of specimen analyzed. To identify the best algorithm for detection of parasites in fresh and fixed tissue samples, we evaluated parasite cultures, two PCR methods, and Leishmania immunohistochemistry (IHC) in samples received by the CDC from 2012 through 2019. The sensitivity and specificity of IHC assays were evaluated in fresh specimens tested. Diagnostic accuracy for formalin-fixed tissue was evaluated by using PCR-based methods and IHC. Of 100 suspected cases with fresh tissue available, Leishmania spp. infection was identified by PCR in 56% (56/100) of specimens; from these, 80% (45/56) were positive by parasite culture and 59% (33/56) by IHC. Of 420 possible cases where only fixed specimens were available, 58% (244/420) were positive by IHC and/or PCR. Of these, 96% (235/420) were positive by IHC and 84% (204/420) by PCR-based methods. Overall parasite detection using all methodologies was similar for fresh and formalin-fixed tissue specimens (56% versus 58%, respectively). Although PCR-based methods were superior for diagnosis of leishmaniasis and species identification in fresh samples, IHC in combination with PCR increased the accuracy for Leishmania spp. detection in fixed samples. In conclusion, PCR is the most effective method for detecting Leishmania infection in fresh tissue samples, whereas for formalin-fixed samples, IHC and PCR-based methods should be used in combination. |
Pathology and monkeypox virus localization in tissues from immunocompromised patients with severe or fatal mpox
Ritter JM , Martines RB , Bhatnagar J , Rao AK , Villalba JA , Silva-Flannery L , Lee E , Bullock HA , Hutson CL , Cederroth T , Harris CK , Hord K , Xu Y , Brown CA , Guccione JP , Miller M , Paddock CD , Reagan-Steiner S . J Infect Dis 2024 BACKGROUND: Pathology and monkeypox virus (MPXV) tissue tropism in severe and fatal human mpox is not thoroughly described but can help elucidate the disease pathogenesis and the role of coinfections in immunocompromised patients. METHODS: We analyzed biopsy and autopsy tissues from 22 patients with severe or fatal outcomes to characterize pathology and viral antigen and DNA distribution in tissues by immunohistochemistry and in situ hybridization. Tissue-based testing for coinfections was also performed. RESULTS: Mucocutaneous lesions showed necrotizing and proliferative epithelial changes. Deceased patients with autopsy tissues evaluated had digestive tract lesions, and half had systemic tissue necrosis with thrombotic vasculopathy in lymphoid tissues, lung, or other solid organs. Half also had bronchopneumonia, and one-third had acute lung injury. All cases had MPXV antigen and DNA detected in tissues. Coinfections were identified in 5/16 (31%) biopsy and 4/6 (67%) autopsy cases. DISCUSSION: Severe mpox in immunocompromised patients is characterized by extensive viral infection of tissues and viremic dissemination that can progress despite available therapeutics. Digestive tract and lung involvement are common and associated with prominent histopathological and clinical manifestations. Coinfections may complicate mpox diagnosis and treatment. Significant viral DNA (likely correlating to infectious virus) in tissues necessitates enhanced biosafety measures in healthcare and autopsy settings. |
Notes from the field: Severe bartonella quintana infections among persons experiencing unsheltered homelessness - New York City, January 2020-December 2022
Rich SN , Beeson A , Seifu L , Mitchell K , Wroblewski D , Juretschko S , Keller M , Gnanaprakasam R , Agladze M , Kodama R , Kupferman T , Bhatnagar J , Martines RB , Reagan-Steiner S , Slavinski S , Kuehnert MJ , Bergeron-Parent C , Corvese G , Marx GE , Ackelsberg J . MMWR Morb Mortal Wkly Rep 2023 72 (42) 1147-1148 Bartonella quintana infection is a vectorborne disease transmitted by the human body louse (1). In the United States, homelessness is the principal risk factor for B. quintana infection (2), likely attributable to limited access to hygiene facilities (1). This infection is not nationally notifiable in the United States, and its incidence is unknown. Acute B. quintana infection can cause fever, headache, and bone pain; severe manifestations include chronic bacteremia, bacillary angiomatosis, and infective endocarditis (3). Because the bacterium requires special conditions to grow in culture, standard blood cultures are usually negative (4). Diagnosis by serology is most common; however, cross-reactivity with other Bartonella species (e.g., B. henselae) can hamper interpretation. Molecular assays specific for B. quintana have been developed (5), but availability is limited to a few laboratories. Once diagnosed, infection can be cured by several weeks to months of antibiotic therapy. |
Rapid Development of Neutralizing and Diagnostic SARS-COV-2 Mouse Monoclonal Antibodies (preprint)
Chapman AP , Tang X , Lee JR , Chida A , Mercer K , Wharton RE , Kainulainen M , Harcourt JL , Martines RB , Schroeder M , Zhao L , Bryksin A , Zhou B , Bergeron E , Bollweg BC , Tamin A , Thornburg N , Wentworth DE , Petway D , Bagarozzi DA Jr , Finn MG , Goldstein JM . bioRxiv 2020 2020.10.13.338095 The need for high-affinity, SARS-CoV-2-specific monoclonal antibodies (mAbs) is critical in the face of the global COVID-19 pandemic, as such reagents can have important diagnostic, research, and therapeutic applications. Of greatest interest is the ~300 amino acid receptor binding domain (RBD) within the S1 subunit of the spike protein because of its key interaction with the human angiotensin converting enzyme 2 (hACE2) receptor present on many cell types, especially lung epithelial cells. We report here the development and functional characterization of 29 nanomolar-affinity mouse SARS-CoV-2 mAbs created by an accelerated immunization and hybridoma screening process. Differing functions, including binding of diverse protein epitopes, viral neutralization, impact on RBD-hACE2 binding, and immunohistochemical staining of infected lung tissue, were correlated with variable gene usage and sequence.Competing Interest StatementThe authors have declared no competing interest. |
Fatal case of heartland virus disease acquired in the Mid-Atlantic Region, United States
Liu S , Kannan S , Meeks M , Sanchez S , Girone KW , Broyhill JC , Martines RB , Bernick J , Flammia L , Murphy J , Hills SL , Burkhalter KL , Laven JJ , Gaines D , Hoffmann CJ . Emerg Infect Dis 2023 29 (5) 992-996 Heartland virus (HRTV) disease is an emerging tickborne illness in the midwestern and southern United States. We describe a reported fatal case of HRTV infection in the Maryland and Virginia region, states not widely recognized to have human HRTV disease cases. The range of HRTV could be expanding in the United States. |
Causes of death identified in neonates enrolled through Child Health and Mortality Prevention Surveillance (CHAMPS), December 2016 -December 2021
Mahtab S , Madhi SA , Baillie VL , Els T , Thwala BN , Onyango D , Tippet-Barr BA , Akelo V , Igunza KA , Omore R , Arifeen SE , Gurley ES , Alam M , Chowdhury AI , Rahman A , Bassat Q , Mandomando I , Ajanovic S , Sitoe A , Varo R , Sow SO , Kotloff KL , Badji H , Tapia MD , Traore CB , Ogbuanu IU , Bunn J , Luke R , Sannoh S , Swarray-Deen A , Assefa N , Scott JAG , Madrid L , Marami D , Fentaw S , Diaz MH , Martines RB , Breiman RF , Madewell ZJ , Blau DM , Whitney CG . PLOS Glob Public Health 2023 3 (3) e0001612 Each year, 2.4 million children die within their first month of life. Child Health and Mortality Prevention Surveillance (CHAMPS) established in 7 countries aims to generate accurate data on why such deaths occur and inform prevention strategies. Neonatal deaths that occurred between December 2016 and December 2021 were investigated with MITS within 24-72 hours of death. Testing included blood, cerebrospinal fluid and lung cultures, multi-pathogen PCR on blood, CSF, nasopharyngeal swabs and lung tissue, and histopathology examination of lung, liver and brain. Data collection included clinical record review and family interview using standardized verbal autopsy. The full set of data was reviewed by local experts using a standardized process (Determination of Cause of Death) to identify all relevant conditions leading to death (causal chain), per WHO recommendations. For analysis we stratified neonatal death into 24-hours of birth, early (1-<7 days) and late (7-<28 days) neonatal deaths. We analyzed 1458 deaths, 41% occurring within 24-hours, 41% early and 18% late neonatal deaths. Leading underlying causes of death were complications of intrapartum events (31%), complications of prematurity (28%), infections (17%), respiratory disorders (11%), and congenital malformations (8%). In addition to the underlying cause, 62% of deaths had additional conditions and 14% had ≥3 other conditions in the causal chain. The most common causes considering the whole causal chain were infection (40%), prematurity (32%) and respiratory distress syndrome (28%). Common maternal conditions linked to neonatal death were maternal hypertension (10%), labour and delivery complications (8%), multiple gestation (7%), placental complications (6%) obstructed labour and chorioamnionitis (5%, each). CHAMPS' findings showing the full causal chain of events that lead to death, in addition to maternal factors, highlights the complexities involved in each death along with the multiple opportunities for prevention. Highlighting improvements to prenatal and obstetric care and infection prevention are urgently needed in high-mortality settings. |
Melioidosis in cynomolgus macaques ( macaca fascicularis ) imported to the United States from Cambodia
Taetzsch SJ , Swaney EM , Gee JE , Hidalgo PM , Broussard KR , Martines RB , Blaney DD , Galland GG , Gulvik CA , Marston CK , Liu L , Elrod MG , DeLeon-Carnes M , Tyler RD , Bower WA , Bhatnager J , Brown CM , Pieracci EG , Weiner ZP . Comp Med 2022 72 (6) 394-402 Melioidosis, a potentially fatal infectious disease of humans and animals, including nonhuman primates (NHPs), is caused by the high-consequence pathogen Burkholderia pseudomallei. This environmental bacterium is found in the soil and water of tropical regions, such as Southeast Asia, where melioidosis is endemic. The global movement of humans and animals can introduce B. pseudomallei into nonendemic regions of the United States, where environmental conditions could allow establishment of the organism. Approximately 60% of NHPs imported into the United States originate in countries considered endemic for melioidosis. To prevent the introduction of infectious agents to the United States, the Centers for Disease Control and Prevention (CDC) requires newly imported NHPs to be quarantined for at least 31 d, during which time their health is closely monitored. Most diseases of public health concern that are transmissible from imported NHPs have relatively short incubation periods that fall within the 31-d quarantine period. However, animals infected with B. pseudomallei may appear healthy for months to years before showing signs of illness, during which time they can shed the organism into the environment. Melioidosis presents diagnostic challenges because it causes nonspecific clinical signs, serologic screening can produce unreliable results, and culture isolates are often misidentified on rapid commercial testing systems. Here, we present a case of melioidosis in a cynomolgus macaque (Macaca fascicularis) that developed a subcutaneous abscess after importation from Cambodia to the United States. The bacterial isolate from the abscess was initially misidentified on a commercial test. This case emphasizes the possibility of melioidosis in NHPs imported from endemic countries and its associated diagnostic challenges. If melioidosis is suspected, diagnostic samples and culture isolates should be submitted to a laboratory in the CDC Laboratory Response Network for conclusive identification and characterization of the pathogen. |
Probable vertical transmission of Alpha variant of concern (B.1.1.7) with evidence of SARS-CoV-2 infection in the syncytiotrophoblast, a case report.
Bullock HA , Fuchs E , Martines RB , Lush M , Bollweg B , Rutan A , Nelson A , Brisso M , Owusu-Ansah A , Sitzman C , Ketterl L , Timmons T , Lopez P , Mitchell E , McCutchen E , Figliomeni J , Iwen P , Uyeki TM , Reagan-Steiner S , Donahue M . Front Med (Lausanne) 2022 9 1099408 INTRODUCTION: Definitive vertical transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been rarely reported. We present a case of a third trimester pregnancy with fetal distress necessitating cesarean section that demonstrated maternal, placental, and infant infection with the SARS-CoV-2 Alpha variant/B.1.1.7. METHODS: CDC's Influenza SARS-CoV-2 Multiplex RT-PCR Assay was used to test for SARS-CoV-2 in a maternal NP swab, maternal plasma, infant NP swab, and formalin-fixed paraffin-embedded (FFPE) placental tissue specimens. Whole genome sequencing (WGS) was performed on maternal plasma, infant, and placental specimens to determine the SARS-CoV-2 genotype. Histopathological evaluation, SARS-CoV-2 immunohistochemistry testing (IHC), and electron microscopy (EM) analysis were performed on placenta, umbilical cord, and membrane FFPE blocks. RESULTS: All specimens tested positive for SARS-CoV-2 by RT-PCR. WGS further revealed identical SARS-CoV-2 sequences from clade 20I/501Y.V1 (lineage Alpha/B.1.1.7) in maternal plasma, infant, and placental specimens. Histopathologic evaluation of the placenta showed histiocytic and neutrophilic intervillositis with fibrin deposition and trophoblast necrosis with positive SARS-CoV-2 immunostaining in the syncytiotrophoblast and electron microscopy evidence of coronavirus. DISCUSSION: These findings suggest vertical transmission of SARS-CoV-2, supported by clinical course timing, identical SARS-CoV-2 genotypes from maternal, placental, and infant samples, and IHC and EM evidence of placental infection. However, determination of the timing or distinction between prepartum and peripartum SARS-CoV-2 transmission remains unclear. |
Welder's Anthrax: A Tale of 2 Cases.
Hendricks K , Martines RB , Bielamowicz H , Boyer AE , Long S , Byers P , Stoddard RA , Taylor K , Kolton CB , Gallegos-Candela M , Roberts C , DeLeon-Carnes M , Salzer J , Dawson P , Brown D , Templeton-LeBouf L , Maves RC , Gulvik C , Lonsway D , Barr JR , Bower WA , Hoffmaster A . Clin Infect Dis 2022 75 S354-s363 Bacillus anthracis has traditionally been considered the etiologic agent of anthrax. However, anthrax-like illness has been documented in welders and other metal workers infected with Bacillus cereus group spp. harboring pXO1 virulence genes that produce anthrax toxins. We present 2 recent cases of severe pneumonia in welders with B. cereus group infections and discuss potential risk factors for infection and treatment options, including antitoxin. |
Autopsy Histopathologic Cardiac Findings in Two Adolescents Following the Second COVID-19 Vaccine Dose.
Paddock CD , Reagan-Steiner S , Su JR , Oster ME , Martines RB , Bhatnagar J , Shimabukuro TT . Arch Pathol Lab Med 2022 146 (8) 921-923 To the Editor.We read with concern the manuscript by Gill et al1 that described autopsy findings for 2 adolescents who died after COVID-19 vaccination. The authors correctly stated that the Centers for Disease Control and Prevention (CDC) performed testing for SARS-CoV-2 and found no evidence of SARS-CoV-2 infection in autopsy tissues from the decedents. However, the authors did not include findings from far more thorough immunohistochemical and molecular testing performed by the CDC for each patient. We believe that all of the CDC's findings should be considered carefully, and that the omission of these data has important implications for the conclusions of this paper. |
Fatal human alphaherpesvirus 1 infection in free-ranging black-tufted marmosets in anthropized environments, Brazil, 2012-2019
Wilson TM , Ritter JM , Martines RB , Bullock HA , Fair P , Radford KW , Macedo IL , Sousa DER , Goncalves AAB , Romano AP , Passsos PHO , Ramos DG , Costa GRT , Cavalcante KRLJ , de Melo CB , Zaki SR , Castro MB . Emerg Infect Dis 2022 28(4) (4) 802-811 Human alphaherpesvirus 1 (HuAHV1) causes fatal neurologic infections in captive New World primates. To determine risks for interspecies transmission, we examined data for 13 free-ranging, black-tufted marmosets (Callithrix penicillata) that died of HuAHV1 infection and had been in close contact with humans in anthropized areas in Brazil during 2012-2019. We evaluated pathologic changes in the marmosets, localized virus and antigen, and assessed epidemiologic features. The main clinical findings were neurologic signs, necrotizing meningoencephalitis, and ulcerative glossitis; 1 animal had necrotizing hepatitis. Transmission electron microscopy revealed intranuclear herpetic inclusions, and immunostaining revealed HuAHV1 and herpesvirus particles in neurons, glial cells, tongue mucosal epithelium, and hepatocytes. PCR confirmed HuAHV1 infection. These findings illustrate how disruption of the One Health equilibrium in anthropized environments poses risks for interspecies virus transmission with potential spillover not only from animals to humans but also from humans to free-ranging nonhuman primates or other animals. Copyright © 2022 Centers for Disease Control and Prevention (CDC). All rights reserved. |
Detection of SARS-CoV-2 in Neonatal Autopsy Tissues and Placenta.
Reagan-Steiner S , Bhatnagar J , Martines RB , Milligan NS , Gisondo C , Williams FB , Lee E , Estetter L , Bullock H , Goldsmith CS , Fair P , Hand J , Richardson G , Woodworth KR , Oduyebo T , Galang RR , Phillips R , Belyaeva E , Yin XM , Meaney-Delman D , Uyeki TM , Roberts DJ , Zaki SR . Emerg Infect Dis 2022 28 (3) 510-517 Severe coronavirus disease in neonates is rare. We analyzed clinical, laboratory, and autopsy findings from a neonate in the United States who was delivered at 25 weeks of gestation and died 4 days after birth; the mother had asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and preeclampsia. We observed severe diffuse alveolar damage and localized SARS-CoV-2 by immunohistochemistry, in situ hybridization, and electron microscopy of the lungs of the neonate. We localized SARS-CoV-2 RNA in neonatal heart and liver vascular endothelium by using in situ hybridization and detected SARS-CoV-2 RNA in neonatal and placental tissues by using reverse transcription PCR. Subgenomic reverse transcription PCR suggested viral replication in lung/airway, heart, and liver. These findings indicate that in utero SARS-CoV-2 transmission contributed to this neonatal death. |
Histopathology and localization of SARS-CoV-2 and its host cell entry receptor ACE2 in tissues from naturally infected US-farmed mink (Neovison vison).
Ritter JM , Wilson TM , Gary JM , Seixas JN , Martines RB , Bhatnagar J , Bollweg BC , Lee E , Estetter L , Silva-Flannery L , Bullock HA , Towner JS , Cossaboom CM , Wendling NM , Amman BR , Harvey RR , Taylor D , Rettler H , Barton Behravesh C , Zaki SR . Vet Pathol 2022 59 (4) 3009858221079665 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory disease in mink similar to human COVID-19. We characterized the pathological findings in 72 mink from US farms with SARS-CoV-2 outbreaks, localized SARS-CoV-2 and its host cellular receptor angiotensin-converting enzyme 2 (ACE2) in mink respiratory tissues, and evaluated the utility of various test methods and specimens for SARS-CoV-2 detection in necropsy tissues. Of SARS-CoV-2-positive animals found dead, 74% had bronchiolitis and diffuse alveolar damage (DAD). Of euthanized SARS-CoV-2-positive animals, 72% had only mild interstitial pneumonia or minimal nonspecific lung changes (congestion, edema, macrophages); similar findings were seen in SARS-CoV-2-negative animals. Suppurative rhinitis, lymphocytic perivascular inflammation in the lungs, and lymphocytic infiltrates in other tissues were common in both SARS-CoV-2-positive and SARS-CoV-2-negative animals. In formalin-fixed paraffin-embedded (FFPE) upper respiratory tract (URT) specimens, conventional reverse transcription-polymerase chain reaction (cRT-PCR) was more sensitive than in situ hybridization (ISH) or immunohistochemistry (IHC) for detection of SARS-CoV-2. FFPE lung specimens yielded less detection of virus than FFPE URT specimens by all test methods. By IHC and ISH, virus localized extensively to epithelial cells in the nasal turbinates, and prominently within intact epithelium; olfactory mucosa was mostly spared. The SARS-CoV-2 receptor ACE2 was extensively detected by IHC within turbinate epithelium, with decreased detection in lower respiratory tract epithelium and alveolar macrophages. This study expands on the knowledge of the pathology and pathogenesis of natural SARS-CoV-2 infection in mink and supports their further investigation as a potential animal model of SARS-CoV-2 infection in humans. |
Effect of Time Since Death on Multipathogen Molecular Test Results of Postmortem Specimens Collected Using Minimally Invasive Tissue Sampling Techniques.
Dawa J , Walong E , Onyango C , Mathaiya J , Muturi P , Bunei M , Ochieng W , Barake W , Seixas JN , Mayieka L , Ochieng M , Omballa V , Lidechi S , Hunsperger E , Otieno NA , Ritter JM , Widdowson MA , Diaz MH , Winchell JM , Martines RB , Zaki SR , Chaves SS . Clin Infect Dis 2021 73 S360-s367 BACKGROUND: We used postmortem minimally invasive tissue sampling (MITS) to assess the effect of time since death on molecular detection of pathogens among respiratory illness-associated deaths. METHODS: Samples were collected from 20 deceased children (aged 1-59 months) hospitalized with respiratory illness from May 2018 through February 2019. Serial lung and/or liver and blood samples were collected using MITS starting soon after death and every 6 hours thereafter for up to 72 hours. Bodies were stored in the mortuary refrigerator for the duration of the study. All specimens were analyzed using customized multipathogen TaqMan® array cards (TACs). RESULTS: We identified a median of 3 pathogens in each child's lung tissue (range, 1-8; n = 20), 3 pathogens in each child's liver tissue (range, 1-4; n = 5), and 2 pathogens in each child's blood specimen (range, 0-4; n = 5). Pathogens were not consistently detected across all collection time points; there was no association between postmortem interval and the number of pathogens detected (P = .43) and no change in TAC cycle threshold value over time for pathogens detected in lung tissue. Human ribonucleoprotein values indicated that specimens collected were suitable for testing throughout the study period. CONCLUSIONS: Results suggest that lung, liver, and blood specimens can be collected using MITS procedures up to 4 days after death in adequately preserved bodies. However, inconsistent pathogen detection in samples needs careful consideration before drawing definitive conclusions on the etiologic causes of death. |
Building Global Capacity to Conduct Pathology-Based Postmortem Examination: Establishing a New Training Hub for Minimally Invasive Tissue Sampling
Paganelli CR , Parlberg L , Goco NJ , Ritter JM , Martines RB , Zaki SR , Walong E , Ochieng W , Inyangala D , Barake W , Wachiury C , Rakislova N , Marimon L , Ferrando M , Ordi J , McClure E . Clin Infect Dis 2021 73 S390-s395 BACKGROUND: Minimally invasive tissue sampling (MITS), an alternative to complete diagnostic autopsy, is a pathology-based postmortem examination that has been validated in low- and middle-income countries (LMICs) and can provide accurate cause of death information when used with other data. The MITS Surveillance Alliance was established in 2017 with the goal to expand MITS globally by increasing training capacity, accessibility, and availability in LMICs. Between January 2019 and May 2020, the MITS Surveillance Alliance convened a multidisciplinary team of technical advisors to attain this goal. METHODS: This article describes the process used to develop criteria and identify an optimal location for a MITS training hub, establish a cadre of LMIC-based trainers, refine standardized MITS sample collection protocols, develop a training program, and release a telepathology platform for quality assessment of MITS histological samples. RESULTS: Results include the creation of a training hub and curriculum, with a total of 9 pathologists and technicians trained as part of the training of the trainers. Those trainers trained 15 participants from seven MITS projects representing 6 LMICs trained in MITS sample collection. The 15 participants have gone on to train more than 50 project-level staff in MITS sample collection. CONCLUSIONS: Lessons learned include an appreciation for using an iterative process for establishing standardized procedures, creating opportunities for all stakeholders to deliver critical feedback, and highlighting the importance of complementing in-person trainings with ongoing technical assistance. |
Histopathology Is Key to Interpreting Multiplex Molecular Test Results From Postmortem Minimally Invasive Tissue Samples
Ritter JM , Seixas JN , Walong E , Dawa J , Onyango C , Pimenta FC , da Gloria Carvalho M , Silva-Flannery L , Jenkinson T , Howard K , Bhatnagar J , Diaz M , Winchell JM , Zaki SR , Chaves SS , Martines RB . Clin Infect Dis 2021 73 S351-s359 BACKGROUND: Minimally invasive tissue sampling (MITS) is an alternative to complete autopsy for determining causes of death. Multiplex molecular testing performed on MITS specimens poses challenges of interpretation, due to high sensitivity and indiscriminate detection of pathogenic, commensal, or contaminating microorganisms. METHODS: MITS was performed on 20 deceased children with respiratory illness, at 10 timepoints up to 88 hours postmortem. Samples were evaluated by multiplex molecular testing on fresh tissues by TaqMan® Array Card (TAC) and by histopathology, special stains, immunohistochemistry (IHC), and molecular testing (PCR) on formalin-fixed, paraffin-embedded (FFPE) tissues. Results were correlated to determine overall pathologic and etiologic diagnoses and to guide interpretation of TAC results. RESULTS: MITS specimens collected up to 3 days postmortem were adequate for histopathologic evaluation and testing. Seven different etiologic agents were detected by TAC in 10 cases. Three cases had etiologic agents detected by FFPE or other methods and not TAC; 2 were agents not present on TAC, and 2 were streptococci that may have been species other than those present on TAC. Result agreement was 43% for TAC and IHC or PCR, and 69% for IHC and PCR. Extraneous TAC results were common, especially when aspiration was present. CONCLUSIONS: TAC can be performed on MITS up to 3 days after death with refrigeration and provides a sensitive method for detection of pathogens but requires careful interpretation in the context of clinicoepidemiologic and histopathologic findings. Interpretation of all diagnostic tests in aggregate to establish overall case diagnoses maximizes the utility of TAC in MITS. |
Fatal Multisystem Inflammatory Syndrome in Adult after SARS-CoV-2 Natural Infection and COVID-19 Vaccination.
Grome HN , Threlkeld M , Threlkeld S , Newman C , Martines RB , Reagan-Steiner S , Whitt MA , Gomes-Solecki M , Nair N , Fill MM , Jones TF , Schaffner W , Dunn J . Emerg Infect Dis 2021 27 (11) 2914-2918 We describe a fatal case of multisystem inflammatory syndrome in an adult with onset 22 days after a second dose of mRNA coronavirus disease vaccine. Serologic and clinical findings indicated severe acute respiratory syndrome coronavirus 2 infection occurred before vaccination. The immunopathology of this syndrome, regardless of vaccination status, remains poorly understood. |
Pathology and One Health implications of fatal Leptospira interrogans infection in an urbanized, free-ranging, black-tufted marmoset (Callithrix penicillata) in Brazil
Wilson TM , Ritter JM , Martines RB , Fair P , Galloway R , Weiner Z , Zaki SR . Transbound Emerg Dis 2021 68 (6) 3207-3216 Leptospirosis is a zoonotic neglected disease of worldwide public health concern. Leptospira species can infect a wide range of wild and domestic mammals and can lead to a spectrum of disease, including severe and fatal forms. Herein, we report for the first time a fatal Leptospira interrogans infection in a free-ranging nonhuman primate (NHP), a black-tufted marmoset. Icterus, pulmonary hemorrhage, interstitial nephritis and hepatocellular dissociation were the main findings raising the suspicion of leptospirosis. Diagnostic confirmation was based on specific immunohistochemical and PCR assays for Leptospira species. Immunolocalization of leptospiral antigens and identification of pathogenic species (L. interrogans species) were important for better understanding the pathogenesis of disease. One Health related implications of free-ranging NHPs in anthropized areas and transmission dynamics of human and animal leptospirosis are discussed. This article is protected by copyright. All rights reserved. |
Intersecting Paths of Emerging and Reemerging Infectious Diseases.
Wilson TM , Paddock CD , Reagan-Steiner S , Bhatnagar J , Martines RB , Wiens AL , Madsen M , Komatsu KK , Venkat H , Zaki SR . Emerg Infect Dis 2021 27 (5) 1517-1519 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shares common clinicopathologic features with other severe pulmonary illnesses. Hantavirus pulmonary syndrome was diagnosed in 2 patients in Arizona, USA, suspected of dying from infection with SARS-CoV-2. Differential diagnoses and possible co-infections should be considered for cases of respiratory distress during the SARS-CoV-2 pandemic. |
Rapid development of neutralizing and diagnostic SARS-COV-2 mouse monoclonal antibodies.
Chapman AP , Tang X , Lee JR , Chida A , Mercer K , Wharton RE , Kainulainen M , Harcourt JL , Martines RB , Schroeder M , Zhao L , Bryksin A , Zhou B , Bergeron E , Bollweg BC , Tamin A , Thornburg N , Wentworth DE , Petway D , Bagarozzi DA Jr , Finn MG , Goldstein JM . Sci Rep 2021 11 (1) 9682 The need for high-affinity, SARS-CoV-2-specific monoclonal antibodies (mAbs) is critical in the face of the global COVID-19 pandemic, as such reagents can have important diagnostic, research, and therapeutic applications. Of greatest interest is the ~ 300 amino acid receptor binding domain (RBD) within the S1 subunit of the spike protein because of its key interaction with the human angiotensin converting enzyme 2 (hACE2) receptor present on many cell types, especially lung epithelial cells. We report here the development and functional characterization of 29 nM-affinity mouse SARS-CoV-2 mAbs created by an accelerated immunization and hybridoma screening process. Differing functions, including binding of diverse protein epitopes, viral neutralization, impact on RBD-hACE2 binding, and immunohistochemical staining of infected lung tissue, were correlated with variable gene usage and sequence. |
Difficulties in Differentiating Coronaviruses from Subcellular Structures in Human Tissues by Electron Microscopy.
Bullock HA , Goldsmith CS , Zaki SR , Martines RB , Miller SE . Emerg Infect Dis 2021 27 (4) 1023-1031 Efforts to combat the coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have placed a renewed focus on the use of transmission electron microscopy for identifying coronavirus in tissues. In attempts to attribute pathology of COVID-19 patients directly to tissue damage caused by SARS-CoV-2, investigators have inaccurately reported subcellular structures, including coated vesicles, multivesicular bodies, and vesiculating rough endoplasmic reticulum, as coronavirus particles. We describe morphologic features of coronavirus that distinguish it from subcellular structures, including particle size range (60-140 nm), intracellular particle location within membrane-bound vacuoles, and a nucleocapsid appearing in cross section as dense dots (6-12 nm) within the particles. In addition, although the characteristic spikes of coronaviruses may be visible on the virus surface, especially on extracellular particles, they are less evident in thin sections than in negative stain preparations. |
Evidence of SARS-CoV-2 Replication and Tropism in the Lungs, Airways and Vascular Endothelium of Patients with Fatal COVID-19: An Autopsy Case-Series.
Bhatnagar J , Gary J , Reagan-Steiner S , Estetter LB , Tong S , Tao Y , Denison AM , Lee E , DeLeon-Carnes M , Li Y , Uehara A , Paden CR , Leitgeb B , Uyeki TM , Martines RB , Ritter JM , Paddock CD , Shieh WJ , Zaki SR . J Infect Dis 2021 223 (5) 752-764 BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of SARS-CoV-2 tropism and replication in various tissues. METHODS: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case-patients (age range: 1 month to 84 years; COVID-19 confirmed n=21, suspected n=43) by SARS-CoV-2 RT-PCR. For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in-situ hybridization (ISH), subgenomic RNA RT-PCR, and whole genome sequencing. RESULTS: SARS-CoV-2 was identified by RT-PCR in 32 case-patients (confirmed n=21 and suspected n=11). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case-patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes and macrophages of lungs, epithelial cells of airways, and in endothelial cells and vessels wall of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. D614G variant was detected in 9 RT-PCR-positive case-patients. CONCLUSIONS: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes. |
Pathological findings in suspected cases of e-cigarette, or vaping, product use-associated lung injury (EVALI): a case series
Reagan-Steiner S , Gary J , Matkovic E , Ritter JM , Shieh WJ , Martines RB , Werner AK , Lynfield R , Holzbauer S , Bullock H , Denison AM , Bhatnagar J , Bollweg BC , Patel M , Evans ME , King BA , Rose DA , Baldwin GT , Jones CM , Krishnasamy V , Briss PA , Weissman DN , Meaney-Delman D , Zaki SR . Lancet Respir Med 2020 8 (12) 1219-1232 BACKGROUND: Since August, 2019, US public health officials have been investigating a national outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). A spectrum of histological patterns consistent with acute to subacute lung injury has been seen in biopsies; however, autopsy findings have not been systematically characterised. We describe the pathological findings in autopsy and biopsy tissues submitted to the US Centers for Disease Control and Prevention (CDC) for the evaluation of suspected EVALI. METHODS: Between Aug 1, 2019, and Nov 30, 2019, we examined lung biopsy (n=10 individuals) and autopsy (n=13 individuals) tissue samples received by the CDC, submitted by 16 US states, from individuals with: a history of e-cigarette, or vaping, product use; respiratory, gastrointestinal, or constitutional symptoms; and either pulmonary infiltrates or opacities on chest imaging, or sudden death from an undetermined cause. We also reviewed medical records, evaluated histopathology, and performed infectious disease testing when indicated by histopathology and clinical history. FINDINGS: 21 cases met surveillance case definitions for EVALI, with a further two cases of clinically suspected EVALI evaluated. All ten lung biopsies showed histological evidence of acute to subacute lung injury, including diffuse alveolar damage or organising pneumonia. These patterns were also seen in nine of 13 (69%) autopsy cases, most frequently diffuse alveolar damage (eight autopsies), but also acute and organising fibrinous pneumonia (one autopsy). Additional pulmonary pathology not necessarily consistent with EVALI was seen in the remaining autopsies, including bronchopneumonia, bronchoaspiration, and chronic interstitial lung disease. Three of the five autopsy cases with no evidence of, or a plausible alternative cause for acute lung injury, had been classified as confirmed or probable EVALI according to surveillance case definitions. INTERPRETATION: Acute to subacute lung injury patterns were seen in all ten biopsies and most autopsy lung tissues from individuals with suspected EVALI. Acute to subacute lung injury can have numerous causes; however, if it is identified in an individual with a history of e-cigarette, or vaping, product use, and no alternative cause is apparent, a diagnosis of EVALI should be strongly considered. A review of autopsy tissue pathology in suspected EVALI deaths can also identify alternative diagnoses, which can enhance the specificity of public health surveillance efforts. FUNDING: US Centers for Disease Control and Prevention. |
Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States.
Martines RB , Ritter JM , Matkovic E , Gary J , Bollweg BC , Bullock H , Goldsmith CS , Silva-Flannery L , Seixas JN , Reagan-Steiner S , Uyeki T , Denison A , Bhatnagar J , Shieh WJ , Zaki SR , Covid-Pathology Working Group . Emerg Infect Dis 2020 26 (9) 2005-2015 An ongoing pandemic of coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Characterization of the histopathology and cellular localization of SARS-CoV-2 in the tissues of patients with fatal COVID-19 is critical to further understand its pathogenesis and transmission and for public health prevention measures. We report clinicopathologic, immunohistochemical, and electron microscopic findings in tissues from 8 fatal laboratory-confirmed cases of SARS-CoV-2 infection in the United States. All cases except 1 were in residents of long-term care facilities. In these patients, SARS-CoV-2 infected epithelium of the upper and lower airways with diffuse alveolar damage as the predominant pulmonary pathology. SARS-CoV-2 was detectable by immunohistochemistry and electron microscopy in conducting airways, pneumocytes, alveolar macrophages, and a hilar lymph node but was not identified in other extrapulmonary tissues. Respiratory viral co-infections were identified in 3 cases; 3 cases had evidence of bacterial co-infection. |
Electron microscopy of SARS-CoV-2: a challenging task.
Goldsmith CS , Miller SE , Martines RB , Bullock HA , Zaki SR . Lancet 2020 395 (10238) e99 We read with interest the Correspondence by Zsuzsanna Varga and colleagues1 on the possible infection of endothelial cells by SARS-CoV-2 using electron microscopic (EM) images as evidence. However, we believe the EM images in the Correspondence do not show coronavirus particles but instead show cross-sections of the rough endoplasmic reticulum (RER). These spherical structures are surrounded by dark dots, which might have been interpreted as spikes on coronavirus particles but are instead ribosomes. The purported particles are free within the cytoplasm, whereas within a coronavirus-infected cell, accumulations of virus particles would be found in membrane-bound areas in the cisternae of the RER–Golgi area, where the spikes would be located on the inside of the cisternal space.2 In addition, cross-sections through the viral nucleocapsid are not seen in the interior of these structures as would be found with coronavirus particles (figure ). |
Potential of minimally invasive tissue sampling for attributing specific causes of childhood deaths in South Africa: A pilot, epidemiological study
Chawana R , Baillie V , Izu A , Solomon F , Bassat Q , Blau DM , Breiman RF , Hale M , Houpt ER , Lala SG , Martines RB , Mathunjwa A , Nzenze S , Pathirana J , Petersen KL , Raghunathan PL , Ritter JM , Wadula J , Zaki SR , Madhi SA . Clin Infect Dis 2019 69 S361-s373 BACKGROUND: Current estimates for causes of childhood deaths are mainly premised on modeling of vital registration and limited verbal autopsy data and generally only characterize the underlying cause of death (CoD). We investigated the potential of minimally invasive tissue sampling (MITS) for ascertaining the underlying and immediate CoD in children 1 month to 14 years of age. METHODS: MITS included postmortem tissue biopsies of brain, liver, and lung for histopathology examination; microbial culture of blood, cerebrospinal fluid (CSF), liver, and lung samples; and molecular microbial testing on blood, CSF, lung, and rectal swabs. Each case was individually adjudicated for underlying, antecedent, and immediate CoD by an international multidisciplinary team of medical experts and coded using the International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: An underlying CoD was determined for 99% of 127 cases, leading causes being congenital malformations (18.9%), complications of prematurity (14.2%), human immunodeficiency virus/AIDS (12.6%), diarrheal disease (8.7%), acute respiratory infections (7.9%), injuries (7.9%), and malignancies (7.1%). The main immediate CoD was pneumonia, sepsis, and diarrhea in 33.9%, 19.7%, and 10.2% of cases, respectively. Infection-related deaths were either an underlying or immediate CoD in 78.0% of cases. Community-acquired pneumonia deaths (n = 32) were attributed to respiratory syncytial virus (21.9%), Pneumocystis jirovecii (18.8%), cytomegalovirus (15.6%), Klebsiella pneumoniae (15.6%), and Streptococcus pneumoniae (12.5%). Seventy-one percent of 24 sepsis deaths were hospital-acquired, mainly due to Acinetobacter baumannii (47.1%) and K. pneumoniae (35.3%). Sixty-two percent of cases were malnourished. CONCLUSIONS: MITS, coupled with antemortem clinical information, provides detailed insight into causes of childhood deaths that could be informative for prioritization of strategies aimed at reducing under-5 mortality. |
An observational pilot study evaluating the utility of minimally invasive tissue sampling to determine the cause of stillbirths in South African women
Madhi SA , Pathirana J , Baillie V , Cutland C , Adam Y , Izu A , Bassat Q , Blau DM , Breiman RF , Hale M , Johnstone S , Martines RB , Mathunjwa A , Nzenze S , Ordi J , Raghunathan PL , Ritter JM , Solomon F , Wadula J , Zaki SR , Chawana R . Clin Infect Dis 2019 69 S342-s350 BACKGROUND: Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting. METHODS: This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths. RESULTS: A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%). CONCLUSIONS: In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause. |
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