To determine the burden of Salmonella infections in the United States, Foodborne Diseases Active Surveillance Network (FoodNet) investigators conducted population-based active surveillance for ...culture-confirmed Salmonella infections during 1996–1999 at FoodNet laboratories. In addition, all clinical microbiology FoodNet laboratories were surveyed to determine their practices for isolating Salmonella. Telephone interviews were also conducted among residents of the FoodNet sites to determine the proportion of persons with diarrheal illness who sought medical care and the proportion who submitted stool specimens for bacterial culture. Using our model, we estimated that there were 1.4 million nontyphoidal Salmonella infections in the United States, resulting in 168,000 physician office visits per year during 1996–1999. Including both culture-confirmed infections and those not confirmed by culture, we estimated that Salmonella infections resulted in 15,000 hospitalizations and 400 deaths annually. These estimates indicate that salmonellosis presents a major ongoing burden to public health.
Background: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective ...spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. Methods: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 × 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. Results: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. Conclusions: We demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates.
Background
Intralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or ...reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally.
Objective
We aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT.
Methods
One hundred and seventy‐three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21–59). The injections were ultrasound‐guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics.
Results
The results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections.
Conclusion
Based on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT.
Ultrasound‐guided ILIT holds promise for treatment of allergy. Correct positioning of the needle within the lymph node is critical for efficacy and safety, and practice correlate with improved needle visibility and more accurate ILIT injections. A guideline is proposed for effective ILIT. Abbreviations: ILIT, intralymphatic immunotherapy; LN, lymph node; SCIT, subcutaneous immunotherapy.
Allelic replacement mutants were constructed within arginine deiminase (arcA1 and arcA2) to assess the function of the arginine deiminase (ADI) pathway in organic acid resistance and biofilm ...formation of Staphylococcus epidermidis 1457. A growth-dependent acidification assay (pH ∼5.0 to ∼5.2) determined that strain 1457 devoid of arginine deiminase activity (1457 ΔADI) was significantly less viable than the wild type following depletion of glucose and in the presence of arginine. However, no difference in viability was noted for individual 1457 ΔarcA1 (native) or ΔarcA2 (arginine catabolic mobile element ACME-derived) mutants, suggesting that the native and ACME-derived ADIs are compensatory in S. epidermidis. Furthermore, flow cytometry and electron paramagnetic resonance spectroscopy results suggested that organic acid stress resulted in oxidative stress that could be partially rescued by the iron chelator dipyridyl. Collectively, these results suggest that formation of hydroxyl radicals is partially responsible for cell death via organic acid stress and that ADI-derived ammonia functions to counteract this acid stress. Finally, static biofilm assays determined that viability, ammonia synthesis, and pH were reduced in strain 1457 ΔADI following 120 h of growth in comparison to strain 1457 and the arcA1 and arcA2 single mutants. It is hypothesized that ammonia synthesis via the ADI pathway is important to reduce pH stress in specific microniches that contain high concentrations of organic acids.
Health information sources and the level of trust in a particular source may influence the subsequent adoption of advocated health behaviors. Information source preference and levels of trust are ...also likely to be influenced by sociodemographic (culture, age, gender) variables. Understanding these source-trust-behavior relationships across various national and cultural contexts is integral to improved health messaging. The present study identified the sources most frequently consulted to obtain information about COVID-19 during the pandemic's early stages in the United Arab Emirates (UAE). The study quantified levels of trust across an array of information sources, factoring in sociodemographic variables. Finally, the study explored the relationship between sociodemographic variables, levels of trust in information sources, and the adoption of COVID-19 related protective behaviors. Participants (
= 1585) were recruited during the first 2 weeks of April 2020 via announcements in the UAE media and through email networks. All participants completed a web-based survey presented in English or Arabic, as preferred. The most frequently consulted information sources were websites (health information websites), social media, government communications, and family and friends. The sources rated most trustworthy were: personal physicians, health care professionals, and government communications. There were differences in the use of sources and levels of trust according to age, gender, and education. The levels of trust in sources of information were associated with the adoption of protective behaviors, significantly so for citizens of the UAE. These findings may help inform the improvement of pandemic-related health messaging in multicultural contexts.
Rapid revascularization is highly effective for acute stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. We investigated the relationship between ...reperfusion and edema in patients from the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) and Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohorts. Reperfusion percentage was measured as the difference in perfusion-weighted imaging lesion volume between baseline and follow-up (day 3–5 for EPITHET; day 6–8 for MR RESCUE). Midline shift (MLS) and swelling volume were quantified on follow-up MRI. We found that reperfusion was associated with less MLS (EPITHET: Spearman ρ = −0.46; P < 0.001, and MR RESCUE: Spearman ρ = −0.49; P < 0.001) and lower swelling volume (EPITHET: Spearman ρ = −0.56; P < 0.001, and MR RESCUE: Spearman ρ = −0.27; P = 0.026). Multivariable analyses performed in EPITHET and MR RESCUE demonstrated that reperfusion independently predicted both less MLS (ß coefficient = −0.056; P = 0.025, and ß coefficient = −0.38; P = 0.028, respectively) and lower swelling volumes (ß coefficient = −4.7; P = 0.007, and ß coefficient = −10.7; P = 0.009, respectively), after adjusting for age, sex, NIHSS, admission glucose and follow-up lesion size. Taken together, our data suggest that even modest improvement in perfusion is associated with less brain edema in EPITHET and MR RESCUE.
In patients undergoing mechanical thrombectomy, achieving complete (Thrombolysis in Cerebral Infarction 3) rather than incomplete successful reperfusion (Thrombolysis in Cerebral Infarction 2b) is ...associated with better functional outcome. Despite technical improvements, incomplete reperfusion remains the final angiographic result in 40% of patients according to recent trials. As most incomplete reperfusions are caused by distal vessel occlusions, they are potentially amenable to rescue strategies. While observational data suggest a net benefit of up to 20% in functional independence of incomplete versus complete reperfusions, the net benefit of secondary improvement from Thrombolysis in Cerebral Infarction 2b to 3 reperfusion might differ due to lengthier procedures and delayed reperfusion. Current strategies to tackle distal vessel occlusions consist of distal (microcatheter) aspiration, small adjustable stent retrievers, and administration of intra-arterial thrombolytics. While there are promising reports evaluating those techniques, all available studies show relevant limitations in terms of selection bias, single-center design, or nonconsecutive patient inclusion. Besides an assessment of risks associated with rescue maneuvers, we advocate that the decision-making process should also include a consideration of potential outcomes if complete reperfusion would successfully be achieved. These include (1) a futile angiographic improvement (hypoperfused territory is already infarcted), (2) an unnecessary angiographic improvement (the patient would not have developed infarction if no rescue maneuver was performed), and (3) a successful rescue maneuver with clinical benefit. Currently there is paucity of data on how these scenarios can be predicted and the decision whether to treat or to stop in a patient with incomplete reperfusion involves many unknowns. To advance the status quo, we outline current knowledge gaps and avenues of potential research regarding this clinically important question.
Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or ...synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes—defined by 28 closely linked SNPs across 38.9 kb—that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.
We recently developed a model (PROCEED) that predicts the occurrence of persistent perfusion deficit (PPD) at 24 hours in patients with incomplete angiographic reperfusion after thrombectomy. This ...study aims to externally validate the PROCEED model using prospectively acquired multicenter data.BACKGROUND AND OBJECTIVESWe recently developed a model (PROCEED) that predicts the occurrence of persistent perfusion deficit (PPD) at 24 hours in patients with incomplete angiographic reperfusion after thrombectomy. This study aims to externally validate the PROCEED model using prospectively acquired multicenter data.Individual patient data for external validation were obtained from the Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection, Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke part 1 and 2 trials, and a prospective cohort of the Medical University of Graz. The model's primary outcome was the occurrence of PPD, defined as a focal, wedge-shaped perfusion delay on 24-hour follow-up perfusion imaging that corresponds to the capillary phase deficit on last angiographic series in patients with <Thrombolysis in Cerebral Infarction 3 reperfusion after thrombectomy. The model's performance was evaluated with discrimination, calibration accuracy, and clinical decision curves.METHODSIndividual patient data for external validation were obtained from the Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection, Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke part 1 and 2 trials, and a prospective cohort of the Medical University of Graz. The model's primary outcome was the occurrence of PPD, defined as a focal, wedge-shaped perfusion delay on 24-hour follow-up perfusion imaging that corresponds to the capillary phase deficit on last angiographic series in patients with <Thrombolysis in Cerebral Infarction 3 reperfusion after thrombectomy. The model's performance was evaluated with discrimination, calibration accuracy, and clinical decision curves.We included 371 patients (38% with PPD). The externally validated model had good discrimination (C-statistic 0.81, 95% CI 0.77-0.86) and adequate calibration (intercept 0.25, 95% CI 0.21-0.29 and slope 0.98, 95% CI 0.90-1.12). Across a wide range of probability thresholds (i.e., depending on the physicians' preferences on how the model should be used), the model shows net benefit on clinical decision curves, informing physicians on the likelihood of PPD. If a physician's attitude toward false-positive and false-negative ratings is equal, the model would reduce 13 in 100 unnecessary interventions by correctly predicting complete delayed reperfusion, without missing a patient with PPD.RESULTSWe included 371 patients (38% with PPD). The externally validated model had good discrimination (C-statistic 0.81, 95% CI 0.77-0.86) and adequate calibration (intercept 0.25, 95% CI 0.21-0.29 and slope 0.98, 95% CI 0.90-1.12). Across a wide range of probability thresholds (i.e., depending on the physicians' preferences on how the model should be used), the model shows net benefit on clinical decision curves, informing physicians on the likelihood of PPD. If a physician's attitude toward false-positive and false-negative ratings is equal, the model would reduce 13 in 100 unnecessary interventions by correctly predicting complete delayed reperfusion, without missing a patient with PPD.The externally validated model had adequate predictive accuracy and discrimination. Depending on the acceptable threshold probability, the model accurately predicts persistent incomplete reperfusion and may advise physicians whether additional reperfusion attempts should be performed.DISCUSSIONThe externally validated model had adequate predictive accuracy and discrimination. Depending on the acceptable threshold probability, the model accurately predicts persistent incomplete reperfusion and may advise physicians whether additional reperfusion attempts should be performed.
Environmental exposure to toxicants is a major risk factor for spontaneous preterm birth (PTB, <37 weeks). Toxicants and drugs administered to patients are metabolized primarily by the cytochrome ...P450 (CYP450) system. Along with the adult and fetal liver, the placenta, a critical feto-maternal interface organ, expresses CYP450 enzymes that metabolize these xenobiotics. However, the contribution of the fetal membranes, another tissue of the feto-maternal interface, to the expression of CYP450 enzymes and the detoxification of xenobiotics remains unknown.
This study characterized CYP450 expression and determined the functional activity of CYP450 enzymes in fetal membranes.
RNA sequencing (RNA-Seq) of placental and fetal membrane tissues and cells was done. Differential expressions of CYP450 genes were compared and validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) between the two tissues. The functional activity of major CYP450 enzymes was determined using a fluorophore-based enzymatic assay in the presence and absence of their corresponding inhibitors.
With the exception of genes that regulate cholesterol metabolism, the expression profile of CYP450 genes was similar between placental and fetal membranes tissues/cells. RT-qPCR analysis confirmed these findings with significant levels of mRNA for major CYP450 genes being detectable in amnion epithelial cells (AECs) and chorion trophoblasts cells (CTCs). Biochemical analyses revealed significant CYP450 enzymatic activities that were sensitive to specific inhibitors for both AECs and CTCs, suggesting that the genes were expressed as functional enzymes.
This is the first study to determine global expression of CYP450 enzymes in fetal membranes which may play a role in xenobiotic metabolism during pregnancy. Given that many women are exposed to environmental toxins or require medications during pregnancy, a better understanding of their role in metabolism is required to develop safer therapeutics and prevent adverse outcomes.
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•Exposure to drugs and toxicants a major risk factor for preterm birth•Global expression of CYP450 system not yet described in fetal membranes•Similar CYP450 expression profiles were seen in placenta and fetal membranes.•Major CYP450 enzymes were found to be functionally active in fetal membrane cells.•Fetal membranes could play a role in drug and toxicant metabolism during pregnancy.
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