Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 210 Records) |
Query Trace: Gupta N[original query] |
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Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of End Stage Kidney Disease in Diabetes.
Satake E , Saulnier PJ , Kobayashi H , Gupta MK , Looker HC , Wilson JM , Md Dom ZI , Ihara K , O'Neil K , Krolewski B , Pipino C , Pavkov ME , Nair V , Bitzer M , Niewczas MA , Kretzler M , Mauer M , Doria A , Najafian B , Kulkarni RN , Duffin KL , Pezzolesi MG , Kahn CR , Nelson RG , Krolewski AS . J Am Soc Nephrol 2021 32 (9) 2331-2351 BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition. |
Determining herd immunity thresholds for hepatitis A virus transmission to inform vaccination strategies among people who inject drugs in 16 U.S. States
Yang J , Lo NC , Dankwa EA , Donnelly CA , Gupta R , Montgomery MP , Weng MK , Martin NK . Clin Infect Dis 2024 78 (4) 976-982 BACKGROUND: Widespread outbreaks of person-to-person transmitted hepatitis A virus (HAV), particularly among people who inject drugs (PWID), continue across the United States and globally. However, the herd immunity threshold and vaccination coverage required to prevent outbreaks are unknown. We used surveillance data and dynamic modeling to estimate herd immunity thresholds among PWID in 16 US states. METHODS: We used a previously published dynamic model of HAV transmission calibrated to surveillance data from outbreaks involving PWID in 16 states. Using state-level calibrated models, we estimated the basic reproduction number (R0) and herd immunity threshold for PWID in each state. We performed a meta-analysis of herd immunity thresholds to determine the critical vaccination coverage required to prevent most HAV outbreaks among PWID. RESULTS: Estimates of R0 for HAV infection ranged from 2.2 (95% confidence interval [CI], 1.9-2.5) for North Carolina to 5.0 (95% CI, 4.5-5.6) for West Virginia. Corresponding herd immunity thresholds ranged from 55% (95% CI, 47%-61%) for North Carolina to 80% (95% CI, 78%-82%) for West Virginia. Based on the meta-analysis, we estimated a pooled herd immunity threshold of 64% (95% CI, 61%-68%; 90% prediction interval, 52%-76%) among PWID. Using the prediction interval upper bound (76%) and assuming 95% vaccine efficacy, we estimated that vaccination coverage of 80% could prevent most HAV outbreaks. CONCLUSIONS: Hepatitis A vaccination programs in the United States may need to achieve vaccination coverage of at least 80% among PWID in order to prevent most HAV outbreaks among this population. |
In vitro inflammation and toxicity assessment of pre- and post-incinerated organomodified nanoclays to macrophages using high-throughput screening approaches
Stueckle TA , Jensen J , Coyle JP , Derk R , Wagner A , Dinu CZ , Kornberg TG , Friend SA , Dozier A , Agarwal S , Gupta RK , Rojanasakul LW . Part Fibre Toxicol 2024 21 (1) 16 BACKGROUND: Organomodified nanoclays (ONC), two-dimensional montmorillonite with organic coatings, are increasingly used to improve nanocomposite properties. However, little is known about pulmonary health risks along the nanoclay life cycle even with increased evidence of airborne particulate exposures in occupational environments. Recently, oropharyngeal aspiration exposure to pre- and post-incinerated ONC in mice caused low grade, persistent lung inflammation with a pro-fibrotic signaling response with unknown mode(s) of action. We hypothesized that the organic coating presence and incineration status of nanoclays determine the inflammatory cytokine secretary profile and cytotoxic response of macrophages. To test this hypothesis differentiated human macrophages (THP-1) were acutely exposed (0-20 µg/cm(2)) to pristine, uncoated nanoclay (CloisNa), an ONC (Clois30B), their incinerated byproducts (I-CloisNa and I-Clois30B), and crystalline silica (CS) followed by cytotoxicity and inflammatory endpoints. Macrophages were co-exposed to lipopolysaccharide (LPS) or LPS-free medium to assess the role of priming the NF-κB pathway in macrophage response to nanoclay treatment. Data were compared to inflammatory responses in male C57Bl/6J mice following 30 and 300 µg/mouse aspiration exposure to the same particles. RESULTS: In LPS-free media, CloisNa exposure caused mitochondrial depolarization while Clois30B exposure caused reduced macrophage viability, greater cytotoxicity, and significant damage-associated molecular patterns (IL-1α and ATP) release compared to CloisNa and unexposed controls. LPS priming with low CloisNa doses caused elevated cathepsin B/Caspage-1/IL-1β release while higher doses resulted in apoptosis. Clois30B exposure caused dose-dependent THP-1 cell pyroptosis evidenced by Cathepsin B and IL-1β release and Gasdermin D cleavage. Incineration ablated the cytotoxic and inflammatory effects of Clois30B while I-CloisNa still retained some mild inflammatory potential. Comparative analyses suggested that in vitro macrophage cell viability, inflammasome endpoints, and pro-inflammatory cytokine profiles significantly correlated to mouse bronchioalveolar lavage inflammation metrics including inflammatory cell recruitment. CONCLUSIONS: Presence of organic coating and incineration status influenced inflammatory and cytotoxic responses following exposure to human macrophages. Clois30B, with a quaternary ammonium tallow coating, induced a robust cell membrane damage and pyroptosis effect which was eliminated after incineration. Conversely, incinerated nanoclay exposure primarily caused elevated inflammatory cytokine release from THP-1 cells. Collectively, pre-incinerated nanoclay displayed interaction with macrophage membrane components (molecular initiating event), increased pro-inflammatory mediators, and increased inflammatory cell recruitment (two key events) in the lung fibrosis adverse outcome pathway. |
Bartonella quintana Endocarditis: A Systematic Review of Individual Cases
Boodman C , Gupta N , Nelson CA , van Griensven J . Clin Infect Dis 2024 78 (3) 554-561 BACKGROUND: Bartonella quintana is a louse-borne bacterium that remains a neglected cause of endocarditis in low-resource settings. Our understanding of risk factors, clinical manifestations, and treatment of B. quintana endocarditis are biased by older studies from high-income countries. METHODS: We searched Pubmed Central, Medline, Scopus, Embase, EBSCO (CABI) Global Health, Web of Science and international trial registers for articles published before March 2023 with terms related to Bartonella quintana endocarditis. We included articles containing case-level information on B. quintana endocarditis and extracted data related to patient demographics, clinical features, diagnostic testing, treatment, and outcome. RESULTS: A total of 975 records were identified, of which 569 duplicates were removed prior to screening. In total, 84 articles were eligible for inclusion, describing a total of 167 cases. Infections were acquired in 40 different countries; 62 cases (37.1%) were acquired in low- and middle-income countries (LMICs). Disproportionately more female and pediatric patients were from LMICs. More patients presented with heart failure (n = 70/167 [41.9%]) than fever (n = 65/167 [38.9%]). Mean time from symptom onset to presentation was 5.1 months. Also, 25.7% of cases (n = 43/167) were associated with embolization, most commonly to the spleen and brain; 65.5% of antimicrobial regimens included doxycycline. The vast majority of cases underwent valve replacement surgery (n = 154/167, [98.0%]). Overall case fatality rate was 9.6% (n = 16/167). CONCLUSIONS: B. quintana endocarditis has a global distribution, and long delays between symptom onset and presentation frequently occur. Improved clinician education and diagnostic capacity are needed to screen at-risk populations and identify infection before endocarditis develops. |
A genetic locus in Elizabethkingia anophelis associated with elevated vancomycin resistance and multiple antibiotic reduced susceptibility
Johnson WL , Gupta SK , Maharjan S , Morgenstein RM , Nicholson AC , McQuiston JR , Gustafson JE . Antibiotics (Basel) 2024 13 (1) The Gram-negative Elizabethkingia express multiple antibiotic resistance and cause severe opportunistic infections. Vancomycin is commonly used to treat Gram-positive infections and has also been used to treat Elizabethkingia infections, even though Gram-negative organisms possess a vancomycin permeability barrier. Elizabethkingia anophelis appeared relatively vancomycin-susceptible and challenge with this drug led to morphological changes indicating cell lysis. In stark contrast, vancomycin growth challenge revealed that E. anophelis populations refractory to vancomycin emerged. In addition, E. anophelis vancomycin-selected mutants arose at high frequencies and demonstrated elevated vancomycin resistance and reduced susceptibility to other antimicrobials. All mutants possessed a SNP in a gene (vsr1 = vancomycin-susceptibility regulator 1) encoding a PadR family transcriptional regulator located in the putative operon vsr1-ORF551, which is conserved in other Elizabethkingia spp as well. This is the first report linking a padR homologue (vsr1) to antimicrobial resistance in a Gram-negative organism. We provide evidence to support that vsr1 acts as a negative regulator of vsr1-ORF551 and that vsr1-ORF551 upregulation is observed in vancomycin-selected mutants. Vancomycin-selected mutants also demonstrated reduced cell length indicating that cell wall synthesis is affected. ORF551 is a membrane-spanning protein with a small phage shock protein conserved domain. We hypothesize that since vancomycin-resistance is a function of membrane permeability in Gram-negative organisms, it is likely that the antimicrobial resistance mechanism in the vancomycin-selected mutants involves altered drug permeability. |
From cultivation to cancer: formation of N-nitrosamines and other carcinogens in smokeless tobacco and their mutagenic implications
Stanfill SB , Hecht SS , Joerger AC , González PJ , Maia LB , Rivas MG , Moura JJG , Gupta AK , Le Brun NE , Crack JC , Hainaut P , Sparacino-Watkins C , Tyx RE , Pillai SD , Zaatari GS , Henley SJ , Blount BC , Watson CH , Kaina B , Mehrotra R . Crit Rev Toxicol 2023 53 (10) 1-44 Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N′-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients. ©, This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law. |
Hepatic vitamin A concentrations and association with infectious causes of child death
Gupta PM , Madewell ZJ , Gannon BM , Grahn M , Akelo V , Onyango D , Mahtab S , Madhi SA , Giri J , Blau DM , Ramakrishnan U , Stein AD , Whitney CG , Young MF , Tanumihardjo SA , Suchdev PS . J Pediatr 2023 265 113816 OBJECTIVES: To assess postmortem vitamin A (VA) concentrations in children under 5 years of age and evaluate the association between vitamin A deficiency (VAD) and infectious causes of death (CoD). STUDY DESIGN: In this cross-sectional study from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network, liver biopsies collected within 72 hours of death were analyzed from 405 stillbirths and children under 5 years in Kenya and South Africa. Total liver vitamin A (VA) concentrations were quantified using ultra-performance liquid chromatography, and cutoffs of ≤0.1 μmol/g, >0.1 to <0.7 μmol/g, ≥0.7 to <1.0 μmol/g, and ≥1.0 μmol/g were used to define VAD, adequate VA status, high VA, and hypervitaminosis A, respectively. Causes of death (CoD) were determined by expert panel review. RESULTS: Among 366 liver samples with viable extraction, pooled prevalences of VAD, adequacy, high VA, and hypervitaminosis were 34.2%, 51.1%, 6.0%, and 8.7%, respectively. VAD was more common among neonates compared with stillbirths, infants, or children, and among those with low birthweight, underweight, or stunting (p<0.05). When adjusting for site, age, and sex, there was no significant association of VAD with increased infectious CoD (OR 1.9, 95%CI 0.9, 3.8, p=0.073). In stratified analyses, VA deficient boys, but not girls, had an increased risk of infectious CoD (OR 3.4, 95%CI 1.3, 10.3, p=0.013). CONCLUSIONS: Definitive post-mortem assessment of VA status identified both VAD and VA excess among children under 5 years of age in Kenya and South Africa. VAD in boys was associated with increased risk of infectious mortality. Our findings may inform a transition from universal VA supplementation to targeted strategies in certain countries. |
Preventable deaths during widespread community hepatitis A outbreaks - United States, 2016-2022
Hofmeister MG , Gupta N . MMWR Morb Mortal Wkly Rep 2023 72 (42) 1128-1133 Hepatitis A is acquired through the fecal-oral route and is preventable by a safe and effective vaccine. Although hepatitis A is generally mild and self-limited, serious complications, including death, can occur. Since 2016, widespread hepatitis A outbreaks have been reported in 37 U.S. states, primarily among persons who use drugs and those experiencing homelessness. Nearly twice as many hepatitis A-related deaths were reported during 2016-2022 compared with 2009-2015. CDC analyzed data from 27 hepatitis A outbreak-affected states* that contributed data during August 1, 2016-October 31, 2022, to characterize demographic, risk factor, clinical, and cause-of-death data among 315 outbreak-related hepatitis A deaths from those states. Hepatitis A was documented as an underlying or contributing cause of death on 60% of available death certificates. Outbreak-related deaths peaked in 2019, and then decreased annually through 2022. The median age at death was 55 years; most deaths occurred among males (73%) and non-Hispanic White persons (84%). Nearly two thirds (63%) of decedents had at least one documented indication for hepatitis A vaccination, including drug use (41%), homelessness (16%), or coinfection with hepatitis B (12%) or hepatitis C (31%); only 12 (4%) had evidence of previous hepatitis A vaccination. Increasing vaccination coverage among adults at increased risk for infection with hepatitis A virus or for severe disease from infection is critical to preventing future hepatitis A-related deaths. |
Impact of anthropometry training and feasibility of 3D imaging on anthropometry data quality among children under five years in a postmortem setting
Gupta PM , Sivalogan K , Oliech R , Alexander E , Klein J , Addo OY , Gethi D , Akelo V , Blau DM , Suchdev PS . PLoS One 2023 18 (9) e0292046 BACKGROUND: The Child Health and Mortality Prevention Surveillance Network (CHAMPS) identifies causes of under-5 mortality in high mortality countries. OBJECTIVE: To address challenges in postmortem nutritional assessment, we evaluated the impact of anthropometry training and the feasibility of 3D imaging on data quality within the CHAMPS Kenya site. DESIGN: Staff were trained using World Health Organization (WHO)-recommended manual anthropometry equipment and novel 3D imaging methods to collect postmortem measurements. Following training, 76 deceased children were measured in duplicate and were compared to measurements of 75 pre-training deceased children. Outcomes included measures of data quality (standard deviations of anthropometric indices and digit preference scores (DPS)), precision (absolute and relative technical errors of measurement, TEMs or rTEMs), and accuracy (Bland-Altman plots). WHO growth standards were used to produce anthropometric indices. Post-training surveys and in-depth interviews collected qualitative feedback on measurer experience with performing manual anthropometry and ease of using 3D imaging software. RESULTS: Manual anthropometry data quality improved after training, as indicated by DPS. Standard deviations of anthropometric indices exceeded limits for high data quality when using the WHO growth standards. Reliability of measurements post-training was high as indicated by rTEMs below 1.5%. 3D imaging was highly correlated with manual measurements; however, on average 3D scans overestimated length and head circumference by 1.61 cm and 2.27 cm, respectively. Site staff preferred manual anthropometry to 3D imaging, as the imaging technology required adequate lighting and additional considerations when performing the measurements. CONCLUSIONS: Manual anthropometry was feasible and reliable postmortem in the presence of rigor mortis. 3D imaging may be an accurate alternative to manual anthropometry, but technology adjustments are needed to ensure accuracy and usability. |
Recommendations on data sharing in HIV drug resistance research
Inzaule SC , Siedner MJ , Little SJ , Avila-Rios S , Ayitewala A , Bosch RJ , Calvez V , Ceccherini-Silberstein F , Charpentier C , Descamps D , Eshleman SH , Fokam J , Frenkel LM , Gupta RK , Ioannidis JPA , Kaleebu P , Kantor R , Kassaye SG , Kosakovsky Pond SL , Kouamou V , Kouyos RD , Kuritzkes DR , Lessells R , Marcelin AG , Mbuagbaw L , Minalga B , Ndembi N , Neher RA , Paredes R , Pillay D , Raizes EG , Rhee SY , Richman DD , Ruxrungtham K , Sabeti PC , Schapiro JM , Sirivichayakul S , Steegen K , Sugiura W , van Zyl GU , Vandamme AM , Wensing AMJ , Wertheim JO , Gunthard HF , Jordan MR , Shafer RW . PLoS Med 2023 20 (9) e1004293 Author summary • Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV. |
Bloodstream infections in neonates with central venous catheters in three tertiary neonatal intensive care units in Pune, India
Kartikeswar GAP , Parikh TB , Randive B , Kinikar A , Rajput UC , Valvi C , Vaidya U , Malwade S , Agarkhedkar S , Kadam A , Smith RM , Westercamp M , Schumacher C , Mave V , Robinson ML , Gupta A , Milstone AM , Manabe YC , Johnson J . J Neonatal Perinatal Med 2023 16 (3) 507-516 BACKGROUND: Neonates admitted to the neonatal intensive care unit (NICU) are at risk for healthcare-associated infections, including central line-associated bloodstream infections. We aimed to characterize the epidemiology of bloodstream infections among neonates with central venous catheters admitted to three Indian NICUs. METHODS: We conducted a prospective cohort study in three tertiary NICUs, from May 1, 2017 until July 31, 2019. All neonates admitted to the NICU were enrolled and followed until discharge, transfer, or death. Cases were defined as positive blood cultures in neonates with a central venous catheter in place for greater than 2 days or within 2 days of catheter removal. RESULTS: During the study period, 140 bloodstream infections were identified in 131 neonates with a central venous catheter. The bloodstream infection rate was 11.9 per 1000 central line-days. Gram-negative organisms predominated, with 38.6% of cases caused by Klebsiella spp. and 14.9% by Acinetobacter spp. Antimicrobial resistance was prevalent among Gram-negative isolates, with 86.9% resistant to third- or fourth-generation cephalosporins, 63.1% to aminoglycosides, 61.9% to fluoroquinolones, and 42.0% to carbapenems. Mortality and length of stay were greater in neonates with bloodstream infection than in neonates without bloodstream infection (unadjusted analysis, p < 0.001). CONCLUSIONS: We report a high bloodstream infection rate among neonates with central venous catheters admitted to three tertiary care NICUs in India. Action to improve infection prevention and control practices in the NICU is needed to reduce the morbidity and mortality associated with BSI in this high-risk population. |
Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes
Carey ME , Dyson ZA , Ingle DJ , Amir A , Aworh MK , Chattaway MA , Chew KL , Crump JA , Feasey NA , Howden BP , Keddy KH , Maes M , Parry CM , Van Puyvelde S , Webb HE , Afolayan AO , Alexander AP , Anandan S , Andrews JR , Ashton PM , Basnyat B , Bavdekar A , Bogoch II , Clemens JD , da Silva KE , De A , de Ligt J , Diaz Guevara PL , Dolecek C , Dutta S , Ehlers MM , Francois Watkins L , Garrett DO , Godbole G , Gordon MA , Greenhill AR , Griffin C , Gupta M , Hendriksen RS , Heyderman RS , Hooda Y , Hormazabal JC , Ikhimiukor OO , Iqbal J , Jacob JJ , Jenkins C , Jinka DR , John J , Kang G , Kanteh A , Kapil A , Karkey A , Kariuki S , Kingsley RA , Koshy RM , Lauer AC , Levine MM , Lingegowda RK , Luby SP , Mackenzie GA , Mashe T , Msefula C , Mutreja A , Nagaraj G , Nagaraj S , Nair S , Naseri TK , Nimarota-Brown S , Njamkepo E , Okeke IN , Perumal SPB , Pollard AJ , Pragasam AK , Qadri F , Qamar FN , Rahman SIA , Rambocus SD , Rasko DA , Ray P , Robins-Browne R , Rongsen-Chandola T , Rutanga JP , Saha SK , Saha S , Saigal K , Sajib MSI , Seidman JC , Shakya J , Shamanna V , Shastri J , Shrestha R , Sia S , Sikorski MJ , Singh A , Smith AM , Tagg KA , Tamrakar D , Tanmoy AM , Thomas M , Thomas MS , Thomsen R , Thomson NR , Tupua S , Vaidya K , Valcanis M , Veeraraghavan B , Weill FX , Wright J , Dougan G , Argimón S , Keane JA , Aanensen DM , Baker S , Holt KE . Elife 2023 12 BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]). | Salmonella Typhi (Typhi) is a type of bacteria that causes typhoid fever. More than 110,000 people die from this disease each year, predominantly in areas of sub-Saharan Africa and South Asia with limited access to safe water and sanitation. Clinicians use antibiotics to treat typhoid fever, but scientists worry that the spread of antimicrobial-resistant Typhi could render the drugs ineffective, leading to increased typhoid fever mortality. The World Health Organization has prequalified two vaccines that are highly effective in preventing typhoid fever and may also help limit the emergence and spread of resistant Typhi. In low resource settings, public health officials must make difficult trade-off decisions about which new vaccines to introduce into already crowded immunization schedules. Understanding the local burden of antimicrobial-resistant Typhi and how it is spreading could help inform their actions. The Global Typhoid Genomics Consortium analyzed 13,000 Typhi genomes from 110 countries to provide a global overview of genetic diversity and antimicrobial-resistant patterns. The analysis showed great genetic diversity of the different strains between countries and regions. For example, the H58 Typhi variant, which is often drug-resistant, has spread rapidly through Asia and Eastern and Southern Africa, but is less common in other regions. However, distinct strains of other drug-resistant Typhi have emerged in other parts of the world. Resistance to the antibiotic ciprofloxacin was widespread and accounted for over 85% of cases in South Africa. Around 70% of Typhi from Pakistan were extensively drug-resistant in 2020, but these hard-to-treat variants have not yet become established elsewhere. Variants that are resistant to both ciprofloxacin and ceftriaxone have been identified, and azithromycin resistance has also appeared in several different variants across South Asia. The Consortium’s analyses provide valuable insights into the global distribution and transmission patterns of drug-resistant Typhi. Limited genetic data were available fromseveral regions, but data from travel-associated cases helped fill some regional gaps. These findings may help serve as a starting point for collective sharing and analyses of genetic data to inform local public health action. Funders need to provide ongoing supportto help fill global surveillance data gaps. | eng |
Hepatitis C cascades: Data to inform hepatitis C elimination in the United States
Montgomery MP , Randall LM , Morrison M , Gupta N , Doshani M , Teshale E . Public Health Rep 2023 333549231193508 The United States has a goal to eliminate hepatitis C as a public health threat by 2030. To accomplish this goal, hepatitis C virus (HCV) care cascades (hereinafter, HCV cascades) can be used to measure progress toward HCV elimination and identify disparities in HCV testing and care. In this topical review of HCV cascades, we describe common definitions of cascade steps, review the application of HCV cascades in health care and public health settings, and discuss the strengths and limitations of data sources used. We use examples from the Massachusetts Department of Public Health as a case study to illustrate how multiple data sources can be leveraged to produce HCV cascades for public health purposes. HCV cascades in health care settings provide actionable data to improve health care quality and delivery of services in a single health system. In public health settings at jurisdictional and national levels, HCV cascades describe HCV diagnosis and treatment for populations, which can be challenging in the absence of a single data source containing complete, comprehensive, and timely data representing all steps of a cascade. Use of multiple data sources and strategies to improve interoperability of health care and public health data systems can advance the use of HCV cascades and speed progress toward HCV elimination. |
Systematic review of per person violence costs
Peterson C , Aslam MV , Rice KL , Gupta N , Kearns MC . Am J Prev Med 2023 INTRODUCTION: Data on the long-term and comprehensive cost of violence are essential for informed decision making on the future benefits of resources directed toward violence prevention. This review aimed to summarize original per person estimates of the attributable cost of interpersonal violence to support public health economic research and decision making. METHODS: In 2023, English-language peer-reviewed journal articles published 2000-2022 with high-income country focus reporting original per person average cost of violence estimates were identified using index terms in multiple databases. Study content including violence type (e.g., adverse childhood experiences, ACEs), timeline and payer cost perspective (e.g., hospitalization event-only health care payer cost), and associated per person cost estimates were summarized. Costs are 2022 USD. RESULTS: Per person cost estimates related to ACEs, community violence, sexual violence, intimate partner violence, homicide, firearm violence, youth violence, workplace violence, and bullying from 73 studies (majority U.S. focus) were summarized. For example, among 23 studies with ACEs focus, monetary estimates ranged from $390 for ACE-related annual health care out-of-pocket costs per U.S. adult with 3+ ACEs to $20.2m for the lifetime societal economic burden of a U.S. child maltreatment fatality. CONCLUSIONS: This review provides a descriptive summary of available per person cost of violence estimates. Results can help public health professionals describe the economic burden of violence, identify the best available estimate for a particular public health question, and address data gaps. Ultimately, understanding the long-term and comprehensive cost of violence is necessary to anticipate the economic benefits of prevention. |
Treated, hospital-onset Clostridiodes difficile infection: An evaluation of predictors and feasibility of benchmarking comparing 2 risk-adjusted models among 265 hospitals
Yu KC , Ye G , Edwards JR , Dantes R , Gupta V , Ai C , Betz K , Benin AL . Infect Control Hosp Epidemiol 2023 1-9 OBJECTIVES: To evaluate the incidence of a candidate definition of healthcare facility-onset, treated Clostridioides difficile (CD) infection (cHT-CDI) and to identify variables and best model fit of a risk-adjusted cHT-CDI metric using extractable electronic heath data. METHODS: We analyzed 9,134,276 admissions from 265 hospitals during 2015-2020. The cHT-CDI events were defined based on the first positive laboratory final identification of CD after day 3 of hospitalization, accompanied by use of a CD drug. The generalized linear model method via negative binomial regression was used to identify predictors. Standardized infection ratios (SIRs) were calculated based on 2 risk-adjusted models: a simple model using descriptive variables and a complex model using descriptive variables and CD testing practices. The performance of each model was compared against cHT-CDI unadjusted rates. RESULTS: The median rate of cHT-CDI events per 100 admissions was 0.134 (interquartile range, 0.023-0.243). Hospital variables associated with cHT-CDI included the following: higher community-onset CDI (CO-CDI) prevalence; highest-quartile length of stay; bed size; percentage of male patients; teaching hospitals; increased CD testing intensity; and CD testing prevalence. The complex model demonstrated better model performance and identified the most influential predictors: hospital-onset testing intensity and prevalence, CO-CDI rate, and community-onset testing intensity (negative correlation). Moreover, 78% of the hospitals ranked in the highest quartile based on raw rate shifted to lower percentiles when we applied the SIR from the complex model. CONCLUSIONS: Hospital descriptors, aggregate patient characteristics, CO-CDI burden, and clinical testing practices significantly influence incidence of cHT-CDI. Benchmarking a cHT-CDI metric is feasible and should include facility and clinical variables. |
Trends and opportunities: Hepatitis A virus infection, seroprevalence, and vaccination coverage-United States, 1976-2020
Hofmeister MG , Yin S , Nelson NP , Weng MK , Gupta N . Public Health Rep 2023 333549231184007 OBJECTIVES: The incidence of hepatitis A declined in the United States following the introduction of hepatitis A vaccines, before increasing in the setting of recent widespread outbreaks associated with person-to-person transmission. We describe the hepatitis A epidemiology in the United States, identify susceptible populations over time, and demonstrate the need for improved hepatitis A vaccination coverage, especially among adults at increased risk for hepatitis A. METHODS: We calculated the hepatitis A incidence rates for sociodemographic characteristics and percentages for risk factors and clinical outcomes for hepatitis A cases reported to the National Notifiable Diseases Surveillance System during 1990-2020. We generated nationally representative estimates and 95% CIs of hepatitis A seroprevalence during 1976-March 2020 and self-reported hepatitis A vaccination coverage during 1999-March 2020 for the noninstitutionalized civilian US population using data from the National Health and Nutrition Examination Survey. RESULTS: Overall, the rate per 100 000 population of reported cases of hepatitis A virus infection in the United States declined 17.3-fold, from 10.4 during 1990-1998 to 0.6 during 2007-2015, and then increased to 2.8 during 2016-2020. The overall hepatitis A seroprevalence in the United States increased from 38.2% (95% CI, 36.2%-40.1%) during 1976-1980 to 47.3% (95% CI, 45.4%-49.2%) during 2015-March 2020. The prevalence of self-reported hepatitis A vaccination coverage in the United States increased more than 2.5-fold, from 16.3% (95% CI, 15.0%-17.7%) during 1999-2006 to 41.9% (95% CI, 40.2%-43.7%) during 2015-March 2020. CONCLUSIONS: Hepatitis A epidemiology in the United States changed substantially during 1976-2020. Improved vaccination coverage, especially among adults recommended for vaccination by the Advisory Committee on Immunization Practices, is vital to stop current hepatitis A outbreaks associated with person-to-person transmission in the United States and prevent similar future recurrences. |
Hepatitis C virus-HIV coinfection in the United States among people who inject drugs: Data needed for ending dual epidemics
Moorman AC , Bixler D , Teshale EH , Hofmeister M , Roberts H , Chapin-Bardales J , Gupta N . Public Health Rep 2023 333549231181348 The overlapping epidemics of hepatitis C virus (HCV) and HIV infection stem from underlying behaviors and health disparities among disproportionately affected populations, especially people who inject drugs (PWID). Characterizing the prevalence of HCV-HIV coinfection offers improved data to address these underlying determinants of health. We performed a literature search for articles that describe US populations, were published during 2005-2021, and summarized evidence of the prevalence of HCV infection in recent HIV clusters and outbreaks among PWID. In population- and community-based studies, HCV antibody prevalence among PWID with HIV ranged from 10.7% to 71.4%, depending on the setting and study design. HCV-HIV coinfection ranged from 70% to 94% among 5 larger HIV clusters or outbreaks among PWID during 2014-2021; where characterized, HCV diagnosis preceded HIV detection by a median of 4 to 5 years. Robust modernized surveillance is needed to support and measure the progress of city, state, and national activities for ending the HIV epidemic and eliminating hepatitis C. Developing and leveraging surveillance systems can identify missed opportunities for prevention, evaluate care, and build capacity for outbreak investigation. In addition, improved data on injection drug use are crucial to inform efforts for improved HCV and HIV testing, prevention, and treatment in settings that serve PWID. By providing data in a wholistic, integrated manner, public health surveillance programs can support efforts to overcome inefficiencies of disease-specific silos, accelerate delivery of preventive and clinical services, and address the excess disease burden and health disparities associated with HCV-HIV coinfection. |
Estimated prevalence and awareness of hepatitis C virus infection among U.S. adults- National Health and Nutrition Examination Survey, January 2017-March 2020
Lewis KC , Barker LK , Jiles R , Gupta N . Clin Infect Dis 2023 77 (10) 1413-1415 During 2017-March 2020, approximately 2.2 million noninstitutionalized civilian U.S. adults had hepatitis C; one-third were unaware of their infection. Prevalence was substantially higher among persons who were uninsured or experiencing poverty. Unrestricted access to testing and curative treatment is urgently needed to reduce disparities and achieve 2030 elimination goals. |
Maternal colonization versus nosocomial transmission as the source of drug-resistant bloodstream infection in an Indian neonatal intensive care unit: A prospective cohort study
Robinson ML , Johnson J , Naik S , Patil S , Kulkarni R , Kinikar A , Dohe V , Mudshingkar S , Kagal A , Smith RM , Westercamp M , Randive B , Kadam A , Babiker A , Kulkarni V , Karyakarte R , Mave V , Gupta A , Milstone AM , Manabe YC . Clin Infect Dis 2023 77 S38-s45 BACKGROUND: Drug-resistant gram-negative (GN) pathogens are a common cause of neonatal sepsis in low- and middle-income countries. Identifying GN transmission patterns is vital to inform preventive efforts. METHODS: We conducted a prospective cohort study, 12 October 2018 to 31 October 2019 to describe the association of maternal and environmental GN colonization with bloodstream infection (BSI) among neonates admitted to a neonatal intensive care unit (NICU) in Western India. We assessed rectal and vaginal colonization in pregnant women presenting for delivery and colonization in neonates and the environment using culture-based methods. We also collected data on BSI for all NICU patients, including neonates born to unenrolled mothers. Organism identification, antibiotic susceptibility testing, and next-generation sequencing (NGS) were performed to compare BSI and related colonization isolates. RESULTS: Among 952 enrolled women who delivered, 257 neonates required NICU admission, and 24 (9.3%) developed BSI. Among mothers of neonates with GN BSI (n = 21), 10 (47.7%) had rectal, 5 (23.8%) had vaginal, and 10 (47.7%) had no colonization with resistant GN organisms. No maternal isolates matched the species and resistance pattern of associated neonatal BSI isolates. Thirty GN BSI were observed among neonates born to unenrolled mothers. Among 37 of 51 BSI with available NGS data, 21 (57%) showed a single nucleotide polymorphism distance of ≤5 to another BSI isolate. CONCLUSIONS: Prospective assessment of maternal GN colonization did not demonstrate linkage to neonatal BSI. Organism-relatedness among neonates with BSI suggests nosocomial spread, highlighting the importance of NICU infection prevention and control practices to reduce GN BSI. |
Development of a standardized, laboratory result-based hepatitis C virus clearance cascade for public health jurisdictions
Montgomery MP , Sizemore L , Wingate H , Thompson WW , Teshale E , Osinubi A , Doshani M , Nelson N , Gupta N , Wester C . Public Health Rep 2023 333549231170044 During 2013-2016, an estimated 2.4 million people in the United States were living with hepatitis C virus (HCV) infection.1 With the availability of curative treatment since 2013, the United States has established a goal of eliminating hepatitis C as a public health threat by 2030.2 HCV clearance cascades (hereinafter, HCV cascades) are an important tool to track progress toward elimination, across jurisdictions and at a national level, and to identify disparities in access to testing and treatment. HCV cascades are a sequence of steps that follow progression from testing and treatment to clearance and subsequent infection and can be used to inform public health interventions to facilitate progression along the cascade. | Many HCV cascades are developed in a single or regional health system in which both treatment and laboratory data are available. However, an important goal for health departments is to develop population-level cascades that capture data on HCV infection status for all people living in a jurisdiction who might seek care across various health settings. In the absence of treatment information, which is not always readily available in health department surveillance systems, HCV laboratory results can be used to develop HCV cascades. Here, we describe a standardized, laboratory result–based HCV cascade developed by the Centers for Disease Control and Prevention (CDC) as a guide for health departments (Figure 1, Supplemental Material). |
Experiences with COVID-19 case investigation and contact tracing: A qualitative analysis
DeLuca N , Caruso E , Gupta R , Kemmerer C , Coughlin R , Chan O , Vohra D , Oeltmann JE , Taylor MM , Moonan PK , Thorpe PG , Loosier PS , Haile G . SSM Qual Res Health 2023 3 100244 Case investigation and contact tracing (CI/CT) is a critical part of the public health response to COVID-19. Individuals' experiences with CI/CT for COVID-19 varied based on geographic location, changes in knowledge and guidelines, access to testing and vaccination, as well as demographic characteristics including age, race, ethnicity, income, and political ideology. In this paper, we explore the experiences and behaviors of adults with positive SARS-CoV-2 test results, or who were exposed to a person with COVID-19, to understand their knowledge, motivations, and facilitators and barriers to their actions. We conducted focus groups and one-on-one interviews with 94 cases and 90 contacts from across the United States. We found that participants were concerned about infecting or exposing others, which motivated them to isolate or quarantine, notify contacts, and get tested. Although most cases and contacts were not contacted by CI/CT professionals, those who were reported a positive experience and received helpful information. Many cases and contacts reported seeking information from family, friends, health care providers, as well as television news and Internet sources. Although participants reported similar perspectives and experiences across demographic characteristics, some highlighted inequities in receiving COVID-19 information and resources. |
Editorial: Ubiquitin and ubiquitin-like modifications in viral infection and innate immunity
Sparrer KMJ , Bergeron É , Gupta S . Front Immunol 2023 14 1148296 The Research Topic ‘ubiquitin and ubiquitin-like modifications in viral infection and innate immunity’ aimed to advance our knowledge and understanding of the regulation of innate immune signaling by ubiquitin and ubiquitin-like modifiers during infection, its interplay with viral proteins and the application of modern techniques to decode these interactions. Six original research papers, three mini-reviews, one review article, and one perspective article that covered various aspects of the Research Topic were eventually part of the collection. |
Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study
Smith J , Bansi-Matharu L , Cambiano V , Dimitrov D , Bershteyn A , van de Vijver D , Kripke K , Revill P , Boily MC , Meyer-Rath G , Taramusi I , Lundgren JD , van Oosterhout JJ , Kuritzkes D , Schaefer R , Siedner MJ , Schapiro J , Delany-Moretlwe S , Landovitz RJ , Flexner C , Jordan M , Venter F , Radebe M , Ripin D , Jenkins S , Resar D , Amole C , Shahmanesh M , Gupta RK , Raizes E , Johnson C , Inzaule S , Shafer R , Warren M , Stansfield S , Paredes R , Phillips AN . Lancet HIV 2023 10 (4) e254-e265 BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of $500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs $150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82% of setting-scenarios at the cost of $144 per year, in 52% at $264, and in 87% at $114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health. |
MaHPIC malaria systems biology data from Plasmodium cynomolgi sporozoite longitudinal infections in macaques.
DeBarry JD , Nural MV , Pakala SB , Nayak V , Warrenfeltz S , Humphrey J , Lapp SA , Cabrera-Mora M , Brito CFA , Jiang J , Saney CL , Hankus A , Stealey HM , DeBarry MB , Lackman N , Legall N , Lee K , Tang Y , Gupta A , Trippe ED , Bridger RR , Weatherly DB , Peterson MS , Jiang X , Tran V , Uppal K , Fonseca LL , Joyner CJ , Karpuzoglu E , Cordy RJ , Meyer EVS , Wells LL , Ory DS , Lee FE , Tirouvanziam R , Gutiérrez JB , Ibegbu C , Lamb TJ , Pohl J , Pruett ST , Jones DP , Styczynski MP , Voit EO , Moreno A , Galinski MR , Kissinger JC . Sci Data 2022 9 (1) 722 Plasmodium cynomolgi causes zoonotic malarial infections in Southeast Asia and this parasite species is important as a model for Plasmodium vivax and Plasmodium ovale. Each of these species produces hypnozoites in the liver, which can cause relapsing infections in the blood. Here we present methods and data generated from iterative longitudinal systems biology infection experiments designed and performed by the Malaria Host-Pathogen Interaction Center (MaHPIC) to delve deeper into the biology, pathogenesis, and immune responses of P. cynomolgi in the Macaca mulatta host. Infections were initiated by sporozoite inoculation. Blood and bone marrow samples were collected at defined timepoints for biological and computational experiments and integrative analyses revolving around primary illness, relapse illness, and subsequent disease and immune response patterns. Parasitological, clinical, haematological, immune response, and -omic datasets (transcriptomics, proteomics, metabolomics, and lipidomics) including metadata and computational results have been deposited in public repositories. The scope and depth of these datasets are unprecedented in studies of malaria, and they are projected to be a F.A.I.R., reliable data resource for decades. |
Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques
Dobard CW , Peet MM , Nishiura K , Holder A , Dinh C , Mitchell J , Khalil G , Pan Y , Singh ON , McCormick TJ , Agrahari V , Gupta P , Jonnalagadda S , Heneine W , Clark MR , García-Lerma JG , Doncel GF . EBioMedicine 2022 86 104361 BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. |
Deep sequencing of HIV-1 reveals extensive subtype variation and drug resistance after failure of first-line antiretroviral regimens in Nigeria.
ElBouzidi K , Datir RP , Kwaghe V , Roy S , Frampton D , Breuer J , Ogbanufe O , Murtala-Ibrahim F , Charurat M , Dakum P , Sabin CA , Ndembi N , Gupta RK . J Antimicrob Chemother 2022 77 (2) 474-482 BACKGROUND: Deep sequencing could improve understanding of HIV treatment failure and viral population dynamics. However, this tool is often inaccessible in low- and middle-income countries. OBJECTIVES: To determine the genetic patterns of resistance emerging in West African HIV-1 subtypes during first-line virological failure, and the implications for future antiretroviral options. PATIENTS AND METHODS: Participants were selected from a Nigerian cohort of people living with HIV who had failed first-line ART and subsequently switched to second-line therapy. Whole HIV-1 genome sequences were generated from first-line virological failure samples with Illumina MiSeq. Mutations detected at 2% frequency were analysed and compared by subtype. RESULTS: HIV-1 sequences were obtained from 101 participants (65% female, median age 30 years, median 32.9 months of nevirapine- or efavirenz-based ART). Thymidine analogue mutations (TAMs) were detected in 61%, other core NRTI mutations in 92% and NNRTI mutations in 99%. Minority variants (<20% frequency) comprised 18% of all mutations. K65R was more prevalent in CRF02_AG than G subtypes (33% versus 7%; P=0.002), and 3 TAMs were more common in G than CRF02_AG (52% versus 24%; P=0.004). Subtype G viruses also contained more RT cleavage site mutations. Cross-resistance to at least one of the newer NNRTIs, doravirine, etravirine or rilpivirine, was predicted in 81% of participants. CONCLUSIONS: Extensive drug resistance had accumulated in people with West African HIV-1 subtypes, prior to second-line ART. Deep sequencing significantly increased the detection of resistance-associated mutations. Caution should be used if considering newer-generation NNRTI agents in this setting. |
Two cases of monkeypox-associated encephalomyelitis - Colorado and the District of Columbia, July-August 2022
Pastula DM , Copeland MJ , Hannan MC , Rapaka S , Kitani T , Kleiner E , Showler A , Yuen C , Ferriman EM , House J , O'Brien S , Burakoff A , Gupta B , Money KM , Matthews E , Beckham JD , Chauhan L , Piquet AL , Kumar RN , Tornatore CS , Padgett K , O'Laughlin K , Mangla AT , Kumar PN , Tyler KL , O'Connor SM . MMWR Morb Mortal Wkly Rep 2022 71 (38) 1212-1215 Monkeypox virus (MPXV) is an orthopoxvirus in the Poxviridae family. The current multinational monkeypox outbreak has now spread to 96 countries that have not historically reported monkeypox, with most cases occurring among gay, bisexual, and other men who have sex with men (1,2). The first monkeypox case in the United States associated with this outbreak was identified in May 2022 in Massachusetts (1); monkeypox has now been reported in all 50 states, the District of Columbia (DC), and one U.S. territory. MPXV is transmitted by close contact with infected persons or animals; infection results in a febrile illness followed by a diffuse vesiculopustular rash and lymphadenopathy. However, illness in the MPXV current Clade II outbreak has differed: the febrile prodrome is frequently absent or mild, and the rash often involves genital, anal, or oral regions (3,4). Although neuroinvasive disease has been previously reported with MPXV infection (5,6), it appears to be rare. This report describes two cases of encephalomyelitis in patients with monkeypox disease that occurred during the current U.S. outbreak. Although neurologic complications of acute MPXV infections are rare, suspected cases should be reported to state, tribal, local, or territorial health departments to improve understanding of the range of clinical manifestations of and treatment options for MPXV infections during the current outbreak. |
Hospital-onset bacteremia and fungemia: An evaluation of predictors and feasibility of benchmarking comparing two risk-adjusted models among 267 hospitals
Yu KC , Ye G , Edwards JR , Gupta V , Benin AL , Ai C , Dantes R . Infect Control Hosp Epidemiol 2022 43 (10) 1-9 OBJECTIVES: To evaluate the prevalence of hospital-onset bacteremia and fungemia (HOB), identify hospital-level predictors, and to evaluate the feasibility of an HOB metric. METHODS: We analyzed 9,202,650 admissions from 267 hospitals during 2015-2020. An HOB event was defined as the first positive blood-culture pathogen on day 3 of admission or later. We used the generalized linear model method via negative binomial regression to identify variables and risk markers for HOB. Standardized infection ratios (SIRs) were calculated based on 2 risk-adjusted models: a simple model using descriptive variables and a complex model using descriptive variables plus additional measures of blood-culture testing practices. Performance of each model was compared against the unadjusted rate of HOB. RESULTS: Overall median rate of HOB per 100 admissions was 0.124 (interquartile range, 0.00-0.22). Facility-level predictors included bed size, sex, ICU admissions, community-onset (CO) blood culture testing intensity, and hospital-onset (HO) testing intensity, and prevalence (all P < .001). In the complex model, CO bacteremia prevalence, HO testing intensity, and HO testing prevalence were the predictors most associated with HOB. The complex model demonstrated better model performance; 55% of hospitals that ranked in the highest quartile based on their raw rate shifted to a lower quartile when the SIR from the complex model was applied. CONCLUSIONS: Hospital descriptors, aggregate patient characteristics, community bacteremia and/or fungemia burden, and clinical blood-culture testing practices influence rates of HOB. Benchmarking an HOB metric is feasible and should endeavor to include both facility and clinical variables. |
Ferrets as a model for tuberculosis transmission.
Gupta T , Somanna N , Rowe T , LaGatta M , Helms S , Owino SO , Jelesijevic T , Harvey S , Jacobs W , Voss T , Sakamoto K , Day C , Whalen C , Karls R , He B , Tompkins SM , Bakre A , Ross T , Quinn FD . Front Cell Infect Microbiol 2022 12 873416 Even with the COVID-19 pandemic, tuberculosis remains a leading cause of human death due to a single infectious agent. Until successfully treated, infected individuals may continue to transmit Mycobacterium tuberculosis bacilli to contacts. As with other respiratory pathogens, such as SARS-CoV-2, modeling the process of person-to-person transmission will inform efforts to develop vaccines and therapies that specifically impede disease transmission. The ferret (Mustela furo), a relatively inexpensive, small animal has been successfully employed to model transmissibility, pathogenicity, and tropism of influenza and other respiratory disease agents. Ferrets can become naturally infected with Mycobacterium bovis and are closely related to badgers, well known in Great Britain and elsewhere as a natural transmission vehicle for bovine tuberculosis. Herein, we report results of a study demonstrating that within 7 weeks of intratracheal infection with a high dose (>5 x 10(3) CFU) of M. tuberculosis bacilli, ferrets develop clinical signs and pathological features similar to acute disease reported in larger animals, and ferrets infected with very-high doses (>5 x 10(4) CFU) develop severe signs within two to four weeks, with loss of body weight as high as 30%. Natural transmission of this pathogen was also examined. Acutely-infected ferrets transmitted M. tuberculosis bacilli to co-housed naïve sentinels; most of the sentinels tested positive for M. tuberculosis in nasal washes, while several developed variable disease symptomologies similar to those reported for humans exposed to an active tuberculosis patient in a closed setting. Transmission was more efficient when the transmitting animal had a well-established acute infection. The findings support further assessment of this model system for tuberculosis transmission including the testing of prevention measures and vaccine efficacy. |
Health-care-associated bloodstream and urinary tract infections in a network of hospitals in India: a multicentre, hospital-based, prospective surveillance study
Mathur P , Malpiedi P , Walia K , Srikantiah P , Gupta S , Lohiya A , Chakrabarti A , Ray P , Biswal M , Taneja N , Rupali P , Balaji V , Rodrigues C , Lakshmi Nag V , Tak V , Venkatesh V , Mukhopadhyay C , Deotale V , Padmaja K , Wattal C , Bhattacharya S , Karuna T , Behera B , Singh S , Nath R , Ray R , Baveja S , Fomda BA , Sulochana Devi K , Das P , Khandelwal N , Verma P , Bhattacharyya P , Gaind R , Kapoor L , Gupta N , Sharma A , VanderEnde D , Siromany V , Laserson K , Guleria R . Lancet Glob Health 2022 10 (9) e1317-e1325 BACKGROUND: Health-care-associated infections (HAIs) cause significant morbidity and mortality globally, including in low-income and middle-income countries (LMICs). Networks of hospitals implementing standardised HAI surveillance can provide valuable data on HAI burden, and identify and monitor HAI prevention gaps. Hospitals in many LMICs use HAI case definitions developed for higher-resourced settings, which require human resources and laboratory and imaging tests that are often not available. METHODS: A network of 26 tertiary-level hospitals in India was created to implement HAI surveillance and prevention activities. Existing HAI case definitions were modified to facilitate standardised, resource-appropriate surveillance across hospitals. Hospitals identified health-care-associated bloodstream infections and urinary tract infections (UTIs) and reported clinical and microbiological data to the network for analysis. FINDINGS: 26 network hospitals reported 2622 health-care-associated bloodstream infections and 737 health-care-associated UTIs from 89 intensive care units (ICUs) between May 1, 2017, and Oct 31, 2018. Central line-associated bloodstream infection rates were highest in neonatal ICUs (>20 per 1000 central line days). Catheter-associated UTI rates were highest in paediatric medical ICUs (4·5 per 1000 urinary catheter days). Klebsiella spp (24·8%) were the most frequent organism in bloodstream infections and Candida spp (29·4%) in UTIs. Carbapenem resistance was common in Gram-negative infections, occurring in 72% of bloodstream infections and 76% of UTIs caused by Klebsiella spp, 77% of bloodstream infections and 76% of UTIs caused by Acinetobacter spp, and 64% of bloodstream infections and 72% of UTIs caused by Pseudomonas spp. INTERPRETATION: The first standardised HAI surveillance network in India has succeeded in implementing locally adapted and context-appropriate protocols consistently across hospitals and has been able to identify a large number of HAIs. Network data show high HAI and antimicrobial resistance rates in tertiary hospitals, showing the importance of implementing multimodal HAI prevention and antimicrobial resistance containment strategies. FUNDING: US Centers for Disease Control and Prevention cooperative agreement with All India Institute of Medical Sciences, New Delhi. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section. |
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