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BACKGROUND: In the USA, nirmatrelvir/ritonavir is authorized for the treatment of mild-to-moderate COVID-19 in patients at least 12â years of age, at high risk for progression to severe COVID-19. OBJECTIVES: To estimate the impact of outpatient nirmatrelvir/ritonavir on COVID-19 hospitalization risk in a US healthcare system. METHODS: We conducted a cohort study using electronic health records among outpatients with a positive SARS-CoV-2 PCR test between January and August 2022. We evaluated the association of nirmatrelvir/ritonavir therapy with time to hospitalization by estimating adjusted HRs and assessed the impact of nirmatrelvir/ritonavir on predicted COVID-19 hospitalizations using machine-learning methods. RESULTS: Among 44â671 patients, 4948 (11%) received nirmatrelvir/ritonavir, and 201 (0.4%) were hospitalized within 28â days of COVID-19 diagnosis. Nirmatrelvir/ritonavir recipients were more likely to be older, white, vaccinated, have comorbidities and reside in areas with higher average socioeconomic status. The 28â day cumulative incidence of hospitalization was 0.06% (95% CI: 0.02%-0.17%) among nirmatrelvir/ritonavir recipients and 0.52% (95% CI: 0.46%-0.60%) among non-recipients. For nirmatrelvir/ritonavir versus no therapy, the age-adjusted HR was 0.08 (95% CI: 0.03-0.26); the fully adjusted HR was 0.16 (95% CI: 0.05-0.50). In the machine-learning model, the primary features reducing predicted hospitalization risk were nirmatrelvir/ritonavir, younger age, vaccination, female gender and residence in a higher socioeconomic status area. CONCLUSIONS: COVID-19 hospitalization risk was reduced by 84% among nirmatrelvir/ritonavir recipients in a large, diverse healthcare system during the Omicron wave. These results suggest that nirmatrelvir/ritonavir remained highly effective in a setting substantially different than the original clinical trials.
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COVID-19 , Lactamas , Leucina , Nitrilos , Pacientes Ambulatorios , Prolina , Humanos , Femenino , COVID-19/epidemiología , North Carolina , Prueba de COVID-19 , Estudios de Cohortes , Ritonavir/uso terapéutico , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19 , Hospitalización , Antivirales/uso terapéuticoRESUMEN
Undernutrition in children commonly disrupts the structure and function of the small intestinal microbial community, leading to enteropathies, compromised metabolic health, and impaired growth and development. The mechanisms by which diet and microbes mediate the balance between commensal and pathogenic intestinal flora remain elusive. In a murine model of undernutrition, we investigated the direct interactions Giardia lamblia, a prevalent small intestinal pathogen, on indigenous microbiota and specifically on Lactobacillus strains known for their mucosal and growth homeostatic properties. Our research reveals that Giardia colonization shifts the balance of lactic acid bacteria, causing a relative decrease in Lactobacillus spp . and an increase in Bifidobacterium spp . This alteration corresponds with a decrease in multiple indicators of mucosal and nutritional homeostasis. Additionally, protein-deficient conditions coupled with Giardia infection exacerbate the rise of primary bile acids and susceptibility to bile acid-induced intestinal barrier damage. In epithelial cell monolayers, Lactobacillus spp . mitigated bile acid-induced permeability, showing strain-dependent protective effects. In vivo, L. plantarum, either alone or within a Lactobacillus spp consortium, facilitated growth in protein-deficient mice, an effect attenuated by Giardia , despite not inhibiting Lactobacillus colonization. These results highlight Giardia's potential role as a disruptor of probiotic functional activity, underscoring the imperative for further research into the complex interactions between parasites and bacteria under conditions of nutritional deficiency.
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The ongoing COVID-19 pandemic has caused millions of deaths and the continued emergence of new variants suggests continued circulation in the human population. In the current time of vaccine availability and new therapeutic development, including antibody-based therapies, many questions about long-term immunity and protection remain uncertain. Identification of protective antibodies in individuals is often done using highly specialized and challenging assays such as functional neutralizing assays, which are not available in the clinical setting. Therefore, there is a great need for the development of rapid, clinically available assays that correlate with neutralizing antibody assays to identify individuals who may benefit from additional vaccination or specific COVID-19 therapies. In this report, we apply a novel semi-quantitative method to an established lateral flow assay (sqLFA) and analyze its ability to detect the presence functional neutralizing antibodies from the serum of COVID-19 recovered individuals. We found that the sqLFA has a strong positive correlation with neutralizing antibody levels. At lower assay cutoffs, the sqLFA is a highly sensitive assay to identify the presence of a range of neutralizing antibody levels. At higher cutoffs, it can detect higher levels of neutralizing antibody with high specificity. This sqLFA can be used both as a screening tool to identify individuals with any level of neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or as a more specific tool to identify those with high neutralizing antibody levels who may not benefit from antibody-based therapies or further vaccination.
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Giardia lamblia (Giardia) is among the most common intestinal pathogens in children in low- and middle-income countries (LMICs). Although Giardia associates with early-life linear growth restriction, mechanistic explanations for Giardia-associated growth impairments remain elusive. Unlike other intestinal pathogens associated with constrained linear growth that cause intestinal or systemic inflammation or both, Giardia seldom associates with chronic inflammation in these children. Here we leverage the MAL-ED longitudinal birth cohort and a model of Giardia mono-association in gnotobiotic and immunodeficient mice to propose an alternative pathogenesis of this parasite. In children, Giardia results in linear growth deficits and gut permeability that are dose-dependent and independent of intestinal markers of inflammation. The estimates of these findings vary between children in different MAL-ED sites. In a representative site, where Giardia associates with growth restriction, infected children demonstrate broad amino acid deficiencies, and overproduction of specific phenolic acids, byproducts of intestinal bacterial amino acid metabolism. Gnotobiotic mice require specific nutritional and environmental conditions to recapitulate these findings, and immunodeficient mice confirm a pathway independent of chronic T/B cell inflammation. Taken together, we propose a new paradigm that Giardia-mediated growth faltering is contingent upon a convergence of this intestinal protozoa with nutritional and intestinal bacterial factors.
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Giardiasis , Enfermedades Inflamatorias del Intestino , Ratones , Animales , Giardia , Giardiasis/parasitología , Nutrientes , Inflamación/complicaciones , AminoácidosRESUMEN
The global burden of infection from MDR organisms (MDROs) disproportionately affects children residing in low- and middle-income countries and those with increased healthcare exposure. These populations have high rates of malnutrition making them increasingly vulnerable to infection with intestinal-derived pathogens. Malnourished children experience increased incidence of intestinal carriage and invasive infection with intestinal-derived MDROs including ESBL- and carbapenemase-producing Enterobacterales. However, the relationship between malnutrition and MDRO infection remains to be clearly defined. Impairment in intestinal barrier function and innate and adaptive immunity in malnutrition increases the risk for infection with intestinal-derived pathogens, and there is an increasing appreciation of the role of the intestinal microbiota in this process. Current evidence from human studies and animal models suggests that diet and the intestinal microbiota influence each other to determine nutritional status, with important implications for infectious outcomes. These insights are crucial to developing microbiota-targeted strategies aimed at reversing the growing burden of MDRO infections in malnourished populations worldwide.
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Amidst the therapeutic void at the onset of the COVID-19 pandemic, a critical mass of scientific and clinical interest coalesced around COVID-19 convalescent plasma (CCP). To date, the CCP literature has focused largely on safety and efficacy outcomes, but little on implementation outcomes or experience. Expert opinion suggests that if CCP has a role in COVID-19 treatment, it is early in the disease course, and it must deliver a sufficiently high titer of neutralizing antibodies (nAb). Missing in the literature are comprehensive evaluations of how local CCP programs were implemented as part of pandemic preparedness and response, including considerations of the core components and personnel required to meet demand with adequately qualified CCP in a timely and sustained manner. To address this gap, we conducted an evaluation of a local CCP program at a large U.S. academic medical center, the University of North Carolina Medical Center (UNCMC), and patterned our evaluation around the dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to systematically describe key implementation-relevant metrics. We aligned our evaluation with program goals of reaching the target population with severe or critical COVID-19, integrating into the structure of the hospital-wide pandemic response, adapting to shifting landscapes, and sustaining the program over time during a compassionate use expanded access program (EAP) era and a randomized controlled trial (RCT) era. During the EAP era, the UNCMC CCP program was associated with faster CCP infusion after admission compared with contemporaneous affiliate hospitals without a local program: median 29.6 hours (interquartile range, IQR: 21.2-48.1) for the UNCMC CCP program versus 47.6 hours (IQR 32.6-71.6) for affiliate hospitals; (P<0.0001). Sixty-eight of 87 CCP recipients in the EAP (78.2%) received CCP containing the FDA recommended minimum nAb titer of ≥1:160. CCP delivery to hospitalized patients operated with equal efficiency regardless of receiving treatment via a RCT or a compassionate-use mechanism. It was found that in a highly resourced academic medical center, rapid implementation of a local CCP collection, treatment, and clinical trial program could be achieved through re-deployment of highly trained laboratory and clinical personnel. These data provide important pragmatic considerations critical for health systems considering the use of CCP as part of an integrated pandemic response.
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COVID-19 , Humanos , COVID-19/epidemiología , COVID-19/terapia , Centros Médicos Académicos , Plasma , Pandemias , Anticuerpos NeutralizantesAsunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Estudios Seroepidemiológicos , COVID-19/epidemiología , AnticuerposRESUMEN
COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for <10 days were eligible. Participants received either CCP with nAb titers of >1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray's P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher's P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507). IMPORTANCE In this study, in a high-risk population of patients admitted for COVID-19, we found an earlier time to hospital discharge among participants receiving CCP with nAb titers of >1:640 compared with participants receiving CCP with a lower nAb titer and no CCP-related AEs. The significance of our research is in identifying a dose response of CCP and clinical outcomes based on nAb titer. Although limited by a small study size, these findings support further study of high-nAb-titer CCP defined as >1:640 in the treatment of COVID-19.
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COVID-19 , SARS-CoV-2 , Adulto , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/terapia , Inmunización Pasiva/métodosRESUMEN
PURPOSE OF REVIEW: Giardia is a common intestinal parasite worldwide, and infection can be associated with clear, and sometimes persistent symptomatology. However, in children in high-prevalence settings, it is most often not associated with or is perhaps even protective against acute diarrhea. Nonetheless, recent longitudinal studies in high-prevalence settings increasingly identify an association with long-term outcomes that has been difficult to discern. RECENT FINDINGS: Recent studies have made progress in disentangling this apparent paradox. First, prospective, well characterized cohort studies have repeatedly identified associations between Giardia infection, gut function, and child growth. Second, experimental animal and in-vitro models have further characterized the biological plausibility that Giardia could impair intestinal function and subsequently child development through different pathways, depending upon biological and environmental factors. Finally, new work has shed light on the potential for Giardia conspiring with specific other gut microbes, which may explain discrepant findings in the literature, help guide future higher resolution analyses of this pathogen, and inform new opportunities for intervention. SUMMARY: Recent prospective studies have confirmed a high, if not universal, prevalence of persistent Giardia infections in low-and-middle income countries associated with child-growth shortfalls and altered gut permeability. However, the predominance of subclinical infections limits understanding of the true clinical impact of endemic pediatric giardiasis, and global disease burdens remain uncalculated. Integrating the role of Giardia in multipathogen enteropathies and how nutritional, microbial, metabolic, and pathogen-strain variables influence Giardia infection outcomes could sharpen delineations between pathogenic and potentially beneficial attributes of this enigmatic parasite.
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Giardiasis , Animales , Diarrea/epidemiología , Diarrea/etiología , Giardia , Giardiasis/complicaciones , Giardiasis/epidemiología , Giardiasis/parasitología , Humanos , Incidencia , Prevalencia , Estudios ProspectivosRESUMEN
AIM: To assess the rates of breast cancer detected in postoperative surveillance mammograms in women >70 Years and overall mortality in this age group. MATERIALS AND METHODS: Four hundred and ninety-eight patients were identified retrospectively from a database from a single large UK hospital. Patients were included in the study if they were female, aged >70 years at diagnosis of either invasive breast cancer or ductal carcinoma in situ (DCIS), had surgical treatment between 1 January 2010 and 31 December 2014, and no previous diagnosis of breast cancer. Statistical analysis was performed using Excel, using the X2 test, with p ≤ 0.05 considered statistically significant. RESULTS: The mean age of women included in this study was 77 years. The mean number of postoperative surveillance mammograms performed per patient was 4.2. In the 5-year follow-up, there was a local recurrence rate of 1.9% (n=6) and a contralateral breast cancer rate of 1% (n=6). The 5-year overall mortality rate was 17.7% (n=88), and the 5-year breast cancer-specific mortality rate was 7.2% (n=36). CONCLUSION: This study demonstrated low local recurrence and contralateral breast cancer rates during the 5-year follow-up period. Clear discussions therefore need to be held with older patients about the value of postoperative mammographic surveillance. Further research is required regarding patient opinion and experience to help develop more consistent guidelines.
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Neoplasias de la Mama , Supervivientes de Cáncer , Carcinoma Intraductal no Infiltrante , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Femenino , Humanos , Masculino , Mamografía , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patología , Estudios RetrospectivosRESUMEN
BackgroundCOVID-19 Convalescent Plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe SARS-CoV-2 infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAb) between different CCP donors. The present study was designed to evaluate nAb titer threshold for clinically effective CCP. MethodsWe conducted a double-blind, phase 2 study to evaluate the safety and effectiveness of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive on a SARS-CoV-2 nucleic acid amplification test and with symptoms for < 10 days were eligible. Participants received either CCP with nAb titers [≥]1:160-1:640 (standard titer group) or >1:640 (high titer group) in addition to standard of care treatments. Adverse events were contrasted by CCP titer. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. FindingsBetween August 28 and December 4, 2020, 316 participants were screened, 55 received CCP, with 41 and 14 receiving standard versus high titer CCP, respectively. Participants were a median of 61 years of age (IQR 52-67), 36% women, 25% Black and 33% Hispanic. Severe adverse events (SAE) ([≥] grade 3) occurred in 4 (29%) and 23 (56%) of participants in the high versus standard titer groups, respectively by day 28 (Risk Difference -0.28 [95% CI -0.56, 0.01]). There were no observed treatment-related AEs. By day 55, time to hospital discharge was shorter among participants receiving high versus standard titer, accounting for death as a competing event (hazard ratio 1.94 [95% CI 1.05, 3.58], Grays p=0.02). InterpretationIn this phase 2 trial in a high-risk population of patients admitted for Covid-19, we found earlier time to hospital discharge and lower occurrences of life-threatening SAEs among participants receiving CCP with nAb titers >1:640 compared with participants receiving CCP with lower nAb titer CCP. Though limited by a small study size these findings support further study of high-nAb titer CCP defined as >1:640 in the treatment of COVID-19. FundingThis clinical study was supported by the UNC Health Foundation and the North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund established and appropriated by the North Carolina General Assembly. The laboratory assays for neutralizing antibody titers and SARS-CoV-2 specific antibody-binding assays were partially supported by The NIH NCI/NIAID SeroNet Serocenter of Excellence Award U54 CA260543. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCOVID-19 Convalescent Plasma (CCP) has emergency use authorization from the FDA for early treatment of COVID-19 in either outpatient or inpatient settings. Evidence supporting the use of CCP for severe COVID-19 is mixed and still emerging. One major limitation in interpreting published clinical trials and the clinical role of CCP is incomplete understanding of necessary neutralizing antibody (nAb) titer for clinically effective CCP. Observational studies suggest that higher antibody-content CCP is more effective than lower antibody-content CCP, or that very low antibody-content CCP is harmful. We searched PubMed articles published between February 1, 2020, and April 15, 2022, using the terms "COVID-19", "convalescent plasma", "SARS-CoV-2", and "CCP" alone and in combination. Our search yielded 6,468 results which we filtered to 280 and 162 by selecting Clinical Trial and Randomized Controlled Trial article types, respectively. Among these, we identified 25 open-label or blinded efficacy or effectiveness studies in hospitalized patients that were relevant to our study. Preliminary reports show wide variability in the antibody content of CCP used in clinical trials, the assays used to define CCP antibody content, and the estimates of clinical outcomes following CCP therapy for hospitalized patients. Only one study deliberately infused CCP with nAb > 1:640. Post-hoc analyses of potent monoclonal antibody therapy in hospitalized patients in the UK showed survival benefit when monoclonal antibody was infused to patients who had not yet seroconverted by spike antibody ELISA, suggesting that if dosed appropriately, antibody-based therapies may have a role in improving outcomes of severe COVID-19. Added value of this studyThis phase 2 study showed that CCP with high nAb titer (>1:640) provided more rapid recovery to hospital discharge and fewer COVID-19 attributable AEs than CCP with nAb titer between the FDA-recommended minimum standard and 4-fold higher ([≥]1:160-1:640). The hazard ratio of time to hospital discharge from baseline through day 55, accounting for death as a competing event, contrasting patients receiving high versus standard CCP titer was 1.94 (95% CI 1.05-3.58). Adjusted hazard ratios of high versus standard titer CCP receipt for time to hospital discharge were consistent with the primary unadjusted findings. Mortality through 55 days was lower in the high titer group, but with a wide confidence interval that did not reach statistical significance. Implications of all available evidenceOur data that CCP with nAb >1:640 expedites recovery of patients admitted with COVID-19 compared with CCP with nAb [≥]1:160-1:640 suggests that a threshhold of nAb [≥]1:160 may be too low to define CCP as high titer. Analyses in larger CCP trials should consider full reporting of nAb in CCP units administered at individual study participant level, and specifically whether CCP contained nAb >1:640. Further investigation of CCP with nAb >1:640 is warranted given that raising the threshhold of nAb, or a correlative specific anti-spike antibody assay, used to qualify high titer CCP in clinical trials could inform policy guidance and clinical use of CCP.
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BACKGROUND: Poor pregnancy and birth outcomes are common in sub-Saharan Africa and have complex aetiologies. Sulfadoxine-pyrimethamine (SP), given for intermittent preventive therapy of malaria in pregnancy (IPTp), is one of few existing interventions that improves outcomes of both mother and baby despite widespread SP-resistant malaria. Compelling evidence exists that malaria-independent pathways contribute to this protective effect, but the exact sources of non anti-malarial protection remained unknown. We hypothesized that the beneficial effect of SP on birthweight is mediated by SP activity on maternal factors, including increased gestational weight gain and antibiotic activity on pathogens in the maternal gut. METHODS: Expectant mothers from a larger randomized control trial comparing the efficacy of IPTp-SP to IPTp with dihydroartemisinin-piperaquine (DP) were also enrolled in this sub-study study at their first antenatal care visit before commencement of IPTp (n = 105). Participants were followed monthly until delivery. Weights and mid-to-upper-arm circumferences (MUAC) were recorded. Monthly stool samples were collected and screened for five Escherichia coli pathotypes, Shigella spp., Vibrio cholerae, Salmonella, Campylobacter coli/jejuni, and three protozoa (Giardia spp., Entameba histolytica, and Cryptosporidium spp.) using previously validated molecular assays. FINDINGS: IPTp-SP vs. IPTP-DP was associated with higher maternal gestational weight gain (GWG) and nutritional indicators (MUAC and body-mass index, BMI). GWG was found to be a mediator of the birthweight and IPTp-SP relationship, as the birthweight of SP infants, but not DP infants, varied according to maternal GWG. The burden of maternal enteric infections was high. The three most commonly observed pathogens were enteroaggregative E. coli (EAEC), atypical enteropathogenic E.coli/enterohaemorrhagic E. coli (aEPEC/EHEC), and typical enteropathogenic E.coli (tEPEC). We found that SP reduced the prevalence of EAEC in a dose-dependent manner. After 3 or more doses, SP-recipients were 90% less likely to be infected with EAEC compared to DP-recipients (ORadj = 0.07, CI95 = 0.12, 0.39, p = 0.002). Compared to DP, this coincided with higher maternal gestational weight gain (GWG) and nutritional indicators (MUAC and body-mass index, BMI). The beneficial effect of SP on maternal GWG, MUAC and BMI, was lower if SP mothers had detectable EAEC, aEPEC/EHEC, tEPEC, and LT-ETEC at baseline. Maternal EAEC and tEPEC at baseline associated with lower birthweight for babies of both SP mothers and DP mothers. When comparing IPTp regimens, the positive effect of SP on birthweight compared to DP was only observed for infants of women who did not test positive for EAEC at baseline (adjusted mean birthweight difference SP vs. DP = 156.0 g, CI95 = -18.0 g, 336.9 g, p = 0.087), though confidence intervals crossed the null. INTERPRETATION: Our findings indicate that in pregnant Malawian women, IPTp-SP vs. IPTp-DP is consistently associated with higher MUAC, BMI, and GWG following the WHO-recommended regimen of at least 3 doses, but carriage of maternal gut pathogens before initiation of IPTp lessens this effect. Because GWG was a mediator of the association between birthweight and SP, we show that SP's previously proven positive effect on birthweight is by promoting maternal weight gain. Overall, our results present one plausible pathway SP exerts malaria-independent protection against poor birth outcomes in the context of its waning antimalarial activity and warrants further investigation. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Antimaláricos , Criptosporidiosis , Cryptosporidium , Ganancia de Peso Gestacional , Malaria , Complicaciones Parasitarias del Embarazo , Antimaláricos/uso terapéutico , Peso al Nacer , Combinación de Medicamentos , Escherichia coli , Femenino , Humanos , Lactante , Malaria/tratamiento farmacológico , Malaria/prevención & control , Embarazo , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Complicaciones Parasitarias del Embarazo/epidemiología , Complicaciones Parasitarias del Embarazo/prevención & control , Pirimetamina , SulfadoxinaRESUMEN
Serosurveillance is an important epidemiologic tool for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), used to estimate infection rates and the degree of population immunity. There is no general agreement on which antibody biomarker(s) should be used, especially with the rollout of vaccines globally. Here, we used random forest models to demonstrate that a single spike or receptor-binding domain (RBD) antibody was adequate for classifying prior infection, while a combination of two antibody biomarkers performed better than any single marker for estimating time-since-infection. Nucleocapsid antibodies performed worse than spike or RBD antibodies for classification, but can be useful for estimating time-since-infection, and in distinguishing infection-induced from vaccine-induced responses. Our analysis has the potential to inform the design of serosurveys for SARS-CoV-2, including decisions regarding a number of antibody biomarkers measured.
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Anticuerpos Antivirales/sangre , COVID-19/epidemiología , SARS-CoV-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Glicoproteína de la Espiga del Coronavirus/inmunología , Factores de TiempoRESUMEN
Acute Chagas disease reactivation (CDR) after cardiac transplantation is a well-known phenomenon in endemic countries of Central and South America and Mexico, but is rare outside of those countries. In this report, we describe a case of a 49-year-old male who presented 25 weeks after heart transplant with clinical features concerning for acute rejection, including malaise, anorexia, weight loss, and fever. His immunosuppression therapy included tacrolimus, mycophenolate, and prednisone. An endomyocardial biopsy revealed lymphocytic and eosinophilic inflammation, myocyte damage, and rare foci of intracellular organisms consistent with Trypanosoma cruzi amastigotes. The patient had no known history of Chagas disease. Upon additional questioning, the patient endorsed bites from reduviid bugs during childhood in El Salvador. Follow-up serum PCR testing was positive for T. cruzi DNA. Tests for other infectious organisms and donor specific antibodies were negative. This case illustrates the striking clinical and histologic similarities between acute cellular rejection and acute CDR with cardiac involvement in heart transplant patients, and thus emphasizes the importance of pre-transplant testing for Chagas in patients with epidemiologic risk factors.
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Cardiomiopatía Chagásica , Enfermedad de Chagas , Trasplante de Corazón , Trypanosoma cruzi , Aloinjertos , Biopsia , Cardiomiopatía Chagásica/diagnóstico , Enfermedad de Chagas/diagnóstico , Rechazo de Injerto/diagnóstico , Trasplante de Corazón/efectos adversos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Breast cancer management is evolving by the day and new discoveries is shifting the scale to more positive result mostly in developed countries and this is being reported and updated in the treatment guidelines to bridge the knowledge gaps and allow for global standardised management protocol. This study assessed the adherence to the breast cancer guideline use among oncologists in Nigeria, reviewing the commonly used guidelines, factors for the choice, effects on treatment and barriers to usage. METHODOLOGY: A proforma was sent by mail to the oncologist in Nigeria assessing their socio-demographic characteristics, knowledge of guidelines, use of guidelines, barriers to use of guidelines and benefits of guideline use and all the those that completed the survey within 1-month period were included in the study. RESULTS: A total of 109 oncologist responded to the survey with mean age of 42 years, mean year of oncology practice was 10 years. Sixty-four percent were consultants and 38% residents-in-training. All respondents were aware of breast cancer guidelines and 92.2% had used it in treatment decision making. The commonest used being National Comprehensive Cancer Network guideline in 87.4% and 82.6% had a choice guideline/institution adopted. The major reason for referring to a choice guideline by 66% of respondents was to gain access to evidence-based results and the major barrier to guideline use in 56% of cases was non compatibility with available resources. CONCLUSION: The study revealed high level of adherence to breast cancer guideline use among oncologists in Nigeria but there is need for more awareness about the locally developed ones like sub-Saharan adapted version and institutional based breast cancer treatment guidelines so as to address the barrier of disparities in target population and resources availability.
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The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2 months after infection or the reason for the discrepancy in COVID-19 disease and sex. Using convalescent-phase sera collected from 101 COVID-19-recovered individuals 21 to 212 days after symptom onset with 48 additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations of individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to 6 months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex and in individuals with cardiometabolic comorbidities. IMPORTANCE In this study, we found that neutralizing antibody responses in COVID-19-convalescent individuals vary in magnitude but are durable and correlate well with receptor binding domain (RBD) Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardiometabolic comorbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2 which supports the growing literature on sex discrepancies regarding COVID-19 disease morbidity and mortality, as well as functional neutralizing antibody responses to SARS-CoV-2.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Formación de Anticuerpos/inmunología , COVID-19/virología , Estudios de Cohortes , Femenino , Humanos , Inmunización Pasiva/métodos , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto JovenRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities.
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BACKGROUND: Outpatient diverticulitis is commonly treated with either a combination of metronidazole and a fluoroquinolone (metronidazole-with-fluoroquinolone) or amoxicillin-clavulanate alone. The U.S. Food and Drug Administration advised that fluoroquinolones be reserved for conditions with no alternative treatment options. The comparative effectiveness of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for diverticulitis is uncertain. OBJECTIVE: To determine the effectiveness and harms of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for outpatient diverticulitis. DESIGN: Active-comparator, new-user, retrospective cohort studies. SETTING: Nationwide population-based claims data on U.S. residents aged 18 to 64 years with private employer-sponsored insurance (2000 to 2018) or those aged 65 years or older with Medicare (2006 to 2015). PARTICIPANTS: Immunocompetent adults with diverticulitis in the outpatient setting. INTERVENTION: Metronidazole-with-fluoroquinolone or amoxicillin-clavulanate. MEASUREMENTS: 1-year risks for inpatient admission, urgent surgery, and Clostridioides difficile infection (CDI) and 3-year risk for elective surgery. RESULTS: In MarketScan (IBM Watson Health), new users of metronidazole-with-fluoroquinolone (n = 106 361) and amoxicillin-clavulanate (n = 13 160) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [95% CI, -0.3 to 0.6]), 1-year urgent surgery risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]), 3-year elective surgery risk (risk difference, 0.2 percentage points [CI, -0.3 to 0.7]), or 1-year CDI risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]) between groups. In Medicare, new users of metronidazole-with-fluoroquinolone (n = 17 639) and amoxicillin-clavulanate (n = 2709) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [CI, -0.7 to 0.9]), 1-year urgent surgery risk (risk difference, -0.2 percentage points [CI, -0.6 to 0.1]), or 3-year elective surgery risk (risk difference, -0.3 percentage points [CI, -1.1 to 0.4]) between groups. The 1-year CDI risk was higher for metronidazole-with-fluoroquinolone than for amoxicillin-clavulanate (risk difference, 0.6 percentage points [CI, 0.2 to 1.0]). LIMITATION: Residual confounding is possible, and not all harms associated with these antibiotics, most notably drug-induced liver injury, could be assessed. CONCLUSION: Treating diverticulitis in the outpatient setting with amoxicillin-clavulanate may reduce the risk for fluoroquinolone-related harms without adversely affecting diverticulitis-specific outcomes. PRIMARY FUNDING SOURCE: National Institutes of Health.