A Systematic Review of Safety and Immunogenicity of Influenza Vaccination Strategies in Solid Organ Transplant Recipients

Immunogenicity from seasonal inactivated influenza vaccine (IIV) remains suboptimal in solid organ transplant recipients (SOTRs). We conducted a systematic review that compared the safety and immunogenicity of nonstandard influenza vaccination strategies with single-dose IIV in SOTRs. Booster doses and possibly high-dose (HD) influenza vaccination strategies seem to hold promise for improving vaccination immunogenicity in SOTRs. Administration of intradermal and MF59-adjuvanted trivalent IIV (IIV3) did not improve vaccine immunogenicity compared with single-dose intramuscular IIV. Alternative vaccine strategies were generally well tolerated; SOTRs who received HD, intradermal or adjuvanted IIV3 had a higher frequency of infection site reactions, while systemic adverse events were more frequent in SOTRs who received HD IIV3. Allograft rejection rates were similar in both groups. SOTRs should continue to receive standard-dose IIV annually in accordance with current recommendations, pending future studies to determine the optimal timing, frequency, and dosage of IIV using the booster-dose strategy

Successful Diagnosis of Intestinal Mycobacterium avium Complex Infection in a Kidney Transplant Recipient Using Nasogastric Aspirate Culture: A Case Report

Intestinal Mycobacterium avium complex (MAC) infections are rare and can be challenging to diagnose. We describe a case of intestinal MAC infection in a kidney transplant recipient with 5 months of unexplained weight loss and abdominal pain who developed intestinal obstruction. Esophagoduodenoscopy with biopsies was performed but was nondiagnostic. Intestinal MAC was diagnosed via nasogastric aspirate culture results. The patient's symptoms rapidly improved after initiation of appropriate treatment, but he later died of aspiration pneumonia and candidemia

Predictors of persistent diarrhea in norovirus enteritis after solid organ transplantation

Solid organ transplant (SOT) recipients may develop protracted diarrheal illness from norovirus. We performed a retrospective chart review between January 2010 and April 2014 to identify predictors of persistent diarrhea in transplant recipients with norovirus enteritis. A total of 152 SOT recipients with mean age of 31.5 years (SD 23.1) were included: 43.4% male, 34.2% pediatric patients. Allograft types were abdominal 136 (89.5%) (kidney [39.5%], liver-small bowel [23%], other [27%]) and thoracic 16 (10.5%). The median time to diagnosis of first norovirus enteritis episode from date of transplantation was 1.7 (0.3-5.3) years. At time of presentation, diarrhea was present in 141 (93%). Thirty percent had persistent diarrhea at 2 weeks. Hospitalization was required for treatment in 121 (80%) of episodes with the mean length of stay of 10±15.2 days. Most (91%) infections were due to norovirus genogroup II, and gastrointestinal coinfections were seen in 23 (19%) norovirus enteritis episodes. Nausea at time of diagnosis (P=.002) and cytomegalovirus (CMV) infection in the preceding 90 days (P=.036) were identified as independent risk factors for persistent diarrhea using univariate and multivariable logistic regression. Our study shows that nausea on presentation and prior CMV infection were associated with persistent diarrhea in patients with norovirus enteritis

Clinical presentation and outcomes of norovirus infection in intestinal allograft compared to native intestine

Background: No data are available on clinical manifestations and course of norovirus gastroenteritis (NVE) in intestinal allograft (from intestinal and multivisceral transplant recipients, ITR) compared to native intestine (from other allograft recipients, nITR). Methods: This was a retrospective study of solid organ transplant recipients with NVE at two centers from January 1, 2010 to April 1, 2014. Chi-square, t-test, linear and logistic regression analyses were done to compare NVE in ITR vs nITR patients. Results: The ITR (45 patients) were compared to nITR (107 patients). ITR were younger (odds ratio [OR]=0.90; P<.0001), less likely to receive anti-lymphocyte induction therapy (OR=0.15; P<.0001), and had shorter time from transplant to NVE (OR=0.99; P=.008). On presentation ITR had less frequent nausea (OR=0.11; P<.0001) or vomiting (OR=0.36; P=.01), higher white blood cell count (OR=1.09; P=.001), and higher glomerular filtration rate (OR=1.02; P<.0001). ITR were less likely to receive anti-motility agents (OR=9.6; P<.0001). ITR were more likely to stay longer on intravenous (IV) fluids (OR=1.18; P<.0001); have recurrent NVE (OR=4.25; P<.0001); have longer hospital stay (OR=1.07; P<.0001); develop acute rejection (OR=5.1; P=.006); and have lower overall survival (OR=0.28; P=.006). Conclusions: Compared to nITR, the ITR with NVE were significantly younger, had less nausea and vomiting at presentation, received less anti-motility agents, required more IV fluids, and had longer hospital stay. A trend was seen for lower survival with NVE in ITR

Vancomycin-resistant Enterococcal Bloodstream Infections in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancies: Impact of Daptomycin MICs of 3 to 4 mg/L

Purpose Case reports of treatment failure with standard-dose daptomycin (6 mg/kg) have recently surfaced in vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) episodes with daptomycin MICs of 3 to 4 mg/L. The clinical implications of daptomycin MICs of 3 to 4 mg/L in VRE BSIs have not been elucidated. Methods We performed a single institutional retrospective analysis of adult stem cell transplant recipients and patients with hematologic malignancies diagnosed with VRE BSI from 2006 to 2014 and compared outcomes between those with daptomycin MICs of 3 to 4 mg/L those with 2 mg/L, as determined by Etest. Findings Forty-two daptomycin-treated VRE BSI episodes, all due to Enterococcus faecium were identified; 19 episodes with daptomycin MICs of 3 to 4 mg/L and 23 episodes with a daptomycin MIC of 2 mg/L. Patients in the higher daptomycin MIC group were more likely to be male, to be stem cell transplant recipients, and to have received high-dose daptomycin treatment (>6 mg/kg). In unadjusted analyses, microbiological failure in the daptomycin MICs 3 to 4 mg/L versus 2 mg/L groups (odds ratio = 1.79, 95% CI, 0.52–6.11; P = 0.35), the median duration of bacteremia (4 days in daptomycin MICs 3–4 mg/L vs 3 days in daptomycin MIC 2 mg/L; P = 0.18) and all-cause 30-day mortality (21% in daptomycin MICs 3–4 mg/L vs 35% in daptomycin MIC 2 mg/L group; P = 0.49) were not different. In adjusted analyses, the association between higher Pitt bacteremia scores and all-cause 30-day mortality was statistically significant (P = 0.0006), whereas the association between daptomycin MICs of 3 to 4 mg/L and all-cause 30-day mortality approached statistical significance (P = 0.06). Implications Duration of bacteremia and microbiological failure rates did not differ by daptomycin MICs in VRE BSI episodes in our patients, composed of adult stem cell transplant recipients and patients with hematologic malignancies. There was a nonsignificant trend in multivariable analysis suggesting that all-cause 30-day mortality was lower in patients whose VRE bloodstream isolates were with daptomycin MICs of 3 to 4 mg/L

Increasing rates of fluoroquinolone resistance in escherichia coli isolated from the blood and urine of patients with hematologic malignancies and stem cell transplant recipients

Fluoroquinolone (FQ) antibiotics have been shown to reduce mortality and the number of febrile episodes when used as prophylaxis during neutropenia. Prior studies suggest that prophylaxis may result in increasing rates of FQ resistance. Fluoroquinolone non-susceptibility trends in Escherichia coli isolated from blood and urine cultures were evaluated over a 16-year period during which prophylaxis was initiated in patients with hematologic malignancies and stem cell transplants. Non-susceptibility rates increased after the introduction of prophylaxis, with yearly non-susceptibility rates rising from 30%–33% to 40%–88% in blood isolates. The high rates of non-susceptibility now observed raise concerns about the continued efficacy of FQ prophylaxis. This concern exists particularly in those patients undergoing stem cell transplants where the total FQ non-susceptibility rates over the study period were 82.3%. Further evaluation of the effect of FQ prophylaxis on antibiotic resistance and its efficacy in the setting of increased rates of resistance is warranted

New Phenolic Constituents from the Fruit Juice of Phyllanthus emblica

Six new phenolic constituents, L-malic acid 2-O- (1), mucic acid 2-O- (5), mucic acid 1, 4-lactone 2-O- (6), 5-O- (8), 3-O- (10), and 3, 5-di-O- (11) gallates, were isolated from the fruit juice of Phyllanthus emblica together with their methyl esters (2-4, 7, 9), and their structures were determined by spectral and chemical methods. Compounds 5, 6, and 8, the major phenolic constituents of the juice, were present as an equilibrium mixture in aqueous solution

Fibulin-3 is necessary to prevent cardiac rupture following myocardial infarction

Published online: 11 September 2023Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.Lucy A. Murtha, Sean A. Hardy, Nishani S. Mabotuwana, Mark J. Bigland, Taleah Bailey, Kalyan Raguram, Saifei Liu, Doan T. Ngo, Aaron L. Sverdlov, Tamara Tomin, Ruth Birner, Gruenberger, Robert D. Hume, Siiri E. Iismaa, David T. Humphreys, Ralph Patrick, James J. H. Chong, Randall J. Lee, Richard P. Harvey, Robert M. Graham, Peter P. Rainer and Andrew J. Boyl

Self-emulsifying therapeutic system: a potential approach for delivery of lipophilic drugs

Self-emulsifying therapeutic system (SETs) provide an effective and intelligent solution to the various issues related to the formulation of hydrophobic drugs with limited solubility in gastrointestinal fluid. Although the potential utility of SETs is well known, only in recent years has a mechanistic understanding of the impact of these systems on drug disposition emerged. These in situ emulsion-forming systems have a high stability when incorporated in various dosage forms. SETs are being looked upon as systems which can overcome the problems associated with delivery of poorly water soluble drugs. An in-depth knowledge about lipids and surfactants that can contribute to these systems, criterion for their selection and the proportion in which they can be used, represent some crucial factors determining the in vivo performance of these systems. This article presents a comprehensive account of various types of self-emulsifying formulations with emphasis on their composition and examples of currently marketed preparations.O sistema terapêutico auto-emulsionante (SETs) fornece solução eficaz e inteligente para os vários problemas relativos à formulação de fármacos hidrofóbicos com solubilidade limitada no fluido gastrintestinal. Embora a utilidade potencial dos SETs seja bem conhecida, só recentemente se compreendeu, mecanisticamente,o impacto desses sistemas na disposição de fármacos. Estes sistemas de formação de emulsão in situ têm alta estabilidade, quando incorporados em várias formas de dosagem. Os SETs têm sido considerados como sistemas que podem resolver problemas associados à liberação de fármacos pouco solúveis em água. O conhecimento profundo dos lipídios e tensoativos que podem ser utilizados para estes sistemas e o critério para a sua seleção e proporção na qual eles são utilizados são alguns dos fatores cruciais que determinam o desempenho do sistema in vivo. Este artigo apresenta o relato abrangente de vários tipos de formulações auto-emulsificantes, com ênfase em sua composição e exemplos das preparações que são correntemente comercializadas

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation