RESUMEN
Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.
Asunto(s)
Lisofosfatidilcolinas/metabolismo , Malaria/parasitología , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/metabolismo , Animales , Femenino , Humanos , Malaria/inmunología , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos C57BL , Plasmodium berghei/fisiología , ReproducciónRESUMEN
The pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding parasite-induced intestinal injury and changes in the human intestinal microbiota composition in patients with Plasmodium falciparum malaria. During the blood stage of P. falciparum infection, infected red blood cells adhere to the vascular endothelium, leading to widespread microcirculatory obstruction in critical tissues, including the splanchnic vasculature. This process may cause intestinal injury and gut leakage. Epidemiological studies indicate higher rates of concurrent bacteraemia in severe malaria cases. Furthermore, severe malaria patients exhibit alterations in the composition and diversity of the intestinal microbiota, although the exact contribution to pathophysiology remains unclear. Mouse studies have demonstrated that the gut microbiota composition can impact susceptibility to Plasmodium infections. In patients with severe malaria, the microbiota shows an enrichment of pathobionts, including pathogens that are known to cause concomitant bloodstream infections. Microbial metabolites have also been detected in the plasma of severe malaria patients, potentially contributing to metabolic acidosis and other clinical complications. However, establishing causal relationships requires intervention studies targeting the gut microbiota.
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Microbioma Gastrointestinal , Enfermedades Intestinales , Malaria Falciparum , Malaria , Humanos , Animales , Ratones , Microcirculación , Malaria Falciparum/parasitología , Malaria/parasitología , Plasmodium falciparum/fisiologíaRESUMEN
During May-July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the organism from 4 patients and phylogenetic analysis with worldwide representative P. vivax genomes indicated probable single parasite introduction from Central/South America.
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Malaria Vivax , Filogenia , Plasmodium vivax , Humanos , Malaria Vivax/epidemiología , Malaria Vivax/parasitología , Malaria Vivax/diagnóstico , Florida/epidemiología , Plasmodium vivax/genética , Masculino , Secuenciación Completa del Genoma , Femenino , Adulto , Persona de Mediana EdadRESUMEN
Ivermectin, a broad-spectrum anti-parasitic drug, has been proposed as a novel vector control tool to reduce malaria transmission by mass drug administration. Ivermectin and some metabolites have mosquito-lethal effect, reducing Anopheles mosquito survival. Ivermectin inhibits liver stage development in a rodent malaria model, but no inhibition was observed in a primate malaria model or in a human malaria challenge trial. In the liver, cytochrome P450 3A4 and 3A5 enzymes metabolize ivermectin, which may impact drug efficacy. Thus, understanding ivermectin metabolism and assessing this impact on Plasmodium liver stage development is critical. Using primary human hepatocytes (PHHs), we characterized ivermectin metabolism and evaluated the efficacy of ivermectin and its primary metabolites M1 (3â³-O-demethyl ivermectin) and M3 (4-hydroxymethyl ivermectin) against Plasmodium falciparum liver stages. Two different modes of ivermectin exposure were evaluated: prophylactic mode (days 0-3 post-infection) and curative mode (days 3-5 post-infection). We used two different PHH donors and modes to determine the inhibitory concentration (IC50) of ivermectin, M1, M3, and the known anti-malarial drug pyrimethamine, with IC50 values ranging from 1.391 to 14.44, 9.95-23.71, 4.767-8.384, and 0.9073-5.416 µM, respectively. In our PHH model, ivermectin and metabolites M1 and M3 demonstrated inhibitory activity against P. falciparum liver stages in curative treatment mode (days 3-5) and marginal activity in prophylactic treatment mode (days 0-3). Ivermectin had improved efficacy when co-administered with ketoconazole, a specific inhibitor of cytochrome P450 3A4 enzyme. Further studies should be performed to examine ivermectin liver stage efficacy when co-administered with CYP3A4 inhibitors and anti-malarial drugs to understand the pharmacokinetic and pharmacodynamic drug-drug interactions that enhance efficacy against human malaria parasites in vitro.
Asunto(s)
Hepatocitos , Ivermectina , Plasmodium falciparum , Ivermectina/farmacología , Hepatocitos/parasitología , Hepatocitos/efectos de los fármacos , Humanos , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Citocromo P-450 CYP3A/metabolismo , Antimaláricos/farmacología , Hígado/parasitología , Hígado/efectos de los fármacos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Animales , Células Cultivadas , Anopheles/parasitología , Anopheles/efectos de los fármacosRESUMEN
We report the results of a first-in-human phase 1 clinical study to evaluate TRL1068, a native human monoclonal antibody that disrupts bacterial biofilms with broad-spectrum activity against both Gram-positive and Gram-negative species. The study population consisted of patients with chronic periprosthetic joint infections (PJIs) of the knee or hip, including both monomicrobial and polymicrobial infections, that are highly resistant to antibiotics due to biofilm formation. TRL1068 was administered via a single pre-surgical intravenous infusion in three sequentially ascending dose groups (6, 15, and 30 mg/kg). Concomitant perioperative antibiotics were pathogen-targeted as prescribed by the treating physician. In this double-blinded study, 4 patients were randomized to receive placebo and 11 patients to receive TRL1068 on day 1, as well as targeted antibiotics for 7 days prior to the scheduled removal of the infected implant and placement of an antibiotic-eluting spacer as the first stage of the standard of care two-stage exchange arthroplasty. No adverse events attributable to TRL1068 were reported. TRL1068 serum half-life was 15-18 days. At day 8, the concentration in synovial fluid was approximately 60% of the blood level and thus at least 15-fold above the threshold for biofilm-disrupting activity in vitro. Explanted prostheses were sonicated to release adherent bacteria for culture, with elimination of the implant bacteria observed in 3 of the 11 patients who received TRL1068, which compares favorably to prior PJI treatments. None of the patients who received TRL1068 had a relapse of the original infection by the end of the study (day 169). CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04763759.
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Antibacterianos , Anticuerpos Monoclonales , Biopelículas , Infecciones Relacionadas con Prótesis , Humanos , Biopelículas/efectos de los fármacos , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/microbiología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Método Doble Ciego , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacologíaRESUMEN
CRISPR/Cas9 technology applied to Plasmodium falciparum offers the potential to greatly improve gene editing, but such expectations including large DNA fragment knock-ins and sequential gene editing have remained unfulfilled. Here, we achieved a major advance in addressing this challenge, especially for creating large DNA fragment knock-ins and sequential editing, by modifying our suicide-rescue-based system that has already been demonstrated to be highly efficient for conventional gene editing. This improved approach was confirmed to mediate efficient knock-ins of DNA fragments up to 6.3 kb, to produce "marker-free" genetically engineered parasites and to show potential for sequential gene editing. This represents an important advancement in establishing platforms for large-scale genome editing, which might gain a better understanding of gene function for the most lethal cause of malaria and contribute to adjusting synthetic biology strategies to live parasite malaria vaccine development. Site-directed knock-in of large DNA fragments is highly efficient using suicide-rescue-based CRISPR/Cas9 system, and sequential gene insertion is feasible but further confirmation is still needed.
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Edición Génica , Malaria , Humanos , Sistemas CRISPR-Cas , Plasmodium falciparum/genética , ADN , Malaria/genéticaRESUMEN
AIM: To examine the impact of increased hepatic glucose production (HGP) on the decrease in plasma glucose concentration caused by empagliflozin in individuals living with diabetes and in nondiabetic individuals. METHODS: A total of 36 individuals living with diabetes and 34 nondiabetic individuals were randomized to receive, in double-blind fashion, empagliflozin or matching placebo in a 2:1 treatment ratio. Following an overnight fast, HGP was measured with 3-3 H-glucose infusion before, at the start of, and 3 months after therapy with empagliflozin. RESULTS: On Day 1 of empagliflozin administration, the increase in urinary glucose excretion (UGE) in individuals with normal glucose tolerance was smaller than in those with impaired glucose tolerance and those living with diabetes, and was accompanied by an increase in HGP in all three groups. The amount of glucose returned to the systemic circulation as a result of the increase in HGP was smaller than that excreted by the kidney during the first 3 h after empagliflozin administration, resulting in a decrease in fasting plasma glucose (FPG) concentration. After 3 h, the increase in HGP was in excess of UGE, leading to a small increase in plasma glucose concentration, which reached a new steady state. After 12 weeks, the amount of glucose returned to the circulation due to the empagliflozin-induced increase in HGP was comparable with that excreted by the kidney in all three groups. CONCLUSION: The balance between UGE and increase in HGP immediately after sodium-glucose cotransporter-2 (SGLT2) inhibition determined the magnitude of decrease in FPG and the new steady state which was achieved. After 12 weeks, the increase in HGP caused by empagliflozin closely matched the amount of glucose excreted by the kidneys; thus, FPG level remained stable despite the continuous urinary excretion of glucose caused by SGLT2 inhibition.
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Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Compuestos de Bencidrilo/uso terapéutico , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Glucósidos , Hipoglucemiantes , Transportador 2 de Sodio-Glucosa , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
OBJECTIVE: We evaluate the clinical feasibility of a portable, low-field magnetic resonance imaging (MRI) system for prostate cancer (PCa) biopsy. METHODS: A retrospective analysis of men who underwent a 12-core systematic transrectal ultrasound-guided prostate biopsy (SB) and a low-field MRI guided transperineal targeted biopsy (MRI-TB). Comparison of the detection of clinically significant PCa (csPCa) (Gleason Grade [GG] ≥ 2) by SB and low field MRI-TB, stratified by Prostate Imaging Reporting & Data System (PI-RADS) score, prostate volume, and prostate serum antigen (PSA) was performed. RESULTS: A total of 39 men underwent both the MRI-TB and SB biopsy. Median (interquartile range [IQR]) age was 69.0 (61.5-73) years, body mass index (BMI) was 28.9 kg/m2 (25.3-34.3), prostate volume was 46.5 cc (32-72.7), and PSA was 9.5 ng/ml (5.5-13.2). The majority (64.4%) of patients had PI-RADS ≥ 4 lesions and 25% of lesions were anterior on pre-biopsy MRII. Cancer detection rate (CDR) was greatest when combining SB and MRI-TB (64.1%). MRI-TB detected 74.3% (29/39) cancers. Of which, 53.8% (21/39) were csPCa while SB detected 42.5% (17/39) csPCa (p = 0.21). In 32.5% (13/39) of cases, MRI-TB upstaged the final diagnosis, compared to 15% (6/39) of cases in which SB upstaged the final diagnosis (p = 0.11). CONCLUSION: Low-field MRI-TB is clinically feasible. Although future studies on the accuracy of MRI-TB system are needed, the initial CDR is comparable to those seen with fusion-based prostate biopsies. A transperineal and targeted approach may be beneficial in patients with higher BMI and anterior lesions.
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Próstata , Neoplasias de la Próstata , Masculino , Humanos , Anciano , Próstata/diagnóstico por imagen , Próstata/patología , Imagen por Resonancia Magnética/métodos , Neoplasias de la Próstata/patología , Antígeno Prostático Específico , Estudios Retrospectivos , Estudios de Factibilidad , Estudios Prospectivos , Biopsia Guiada por Imagen/métodosRESUMEN
BACKGROUND: Plasma levels of angiopoietin-like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels. METHODS: ANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjects received 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp. RESULTS: Subjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p < 0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p < 0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose-dependent increase in plasma ANGPTL8 concentration. During the 2-step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline. CONCLUSIONS: In response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.
Asunto(s)
Intolerancia a la Glucosa , Hiperinsulinismo , Resistencia a la Insulina , Hormonas Peptídicas , Estado Prediabético , Humanos , Glucemia/metabolismo , Intolerancia a la Glucosa/metabolismo , Proteína 8 Similar a la Angiopoyetina , Insulina/metabolismo , Glucosa/metabolismo , Ayuno , Ingestión de Alimentos , Insulina Regular Humana , Nutrientes , Resistencia a la Insulina/fisiologíaRESUMEN
BACKGROUND: Knowledge of the diversity of invasion ligands in malaria parasites in endemic regions is essential to understand how natural selection influences genetic diversity of these ligands and their feasibility as possible targets for future vaccine development. In this study the diversity of four genes for merozoite invasion ligands was studied in Ecuadorian isolates of Plasmodium vivax. METHODS: Eighty-eight samples from P. vivax infected individuals from the Coast and Amazon region of Ecuador were obtained between 2012 and 2015. The merozoite invasion genes pvmsp-1-19, pvdbpII, pvrbp1a-2 and pvama1 were amplified, sequenced, and compared to the Sal-1 strain. Polymorphisms were mapped and genetic relationships between haplotypes were determined. RESULTS: Only one nonsynonymous polymorphism was detected in pvmsp-1-19, while 44 nonsynonymous polymorphisms were detected in pvdbpII, 56 in pvrbp1a-2 and 33 in pvama1. While haplotypes appeared to be more related within each area of study and there was less relationship between parasites of the coastal and Amazon regions of the country, diversification processes were observed in the two Amazon regions. The highest haplotypic diversity for most genes occurred in the East Amazon of the country. The high diversity observed in Ecuadorian samples is closer to Brazilian and Venezuelan isolates, but lower than reported in other endemic regions. In addition, departure from neutrality was observed in Ecuadorian pvama1. Polymorphisms for pvdbpII and pvama1 were associated to B-cell epitopes. CONCLUSIONS: pvdbpII and pvama1 genetic diversity found in Ecuadorian P. vivax was very similar to that encountered in other malaria endemic countries with varying transmission levels and segregated by geographic region. The highest diversity of P. vivax invasion genes in Ecuador was found in the Amazonian region. Although selection appeared to have small effect on pvdbpII and pvrbp1a-2, pvama1 was influenced by significant balancing selection.
Asunto(s)
Malaria Vivax , Plasmodium vivax , Humanos , Ecuador , Antígenos de Protozoos/genética , Proteínas Protozoarias/genética , Reticulocitos , Ligandos , Malaria Vivax/epidemiología , Polimorfismo Genético , Selección Genética , Variación GenéticaRESUMEN
BACKGROUND: Acquired functional inhibitory antibodies are one of several humoral immune mechanisms used to neutralize foreign pathogens. In vitro bioassays are useful tools for quantifying antibody-mediated inhibition and evaluating anti-parasite immune antibodies. However, a gap remains in understanding of how antibody-mediated inhibition in vitro translates to inhibition in vivo. In this study, two well-characterized transgenic Plasmodium berghei parasite lines, PbmCh-luc and Pb-PfCSP(r), and murine monoclonal antibodies (mAbs) specific to P. berghei and Plasmodium falciparum circumsporozoite protein (CSP), 3D11 and 2A10, respectively, were used to evaluate antibody-mediated inhibition of parasite development in both in vitro and in vivo functional assays. METHODS: IC50 values of mAbs were determined using an established inhibition of liver-stage development assay (ILSDA). For the in vivo inhibition assay, mice were passively immunized by transfer of the mAbs and subsequently challenged with 5.0 × 103 sporozoites via tail vein injection. The infection burden in both assays was quantified by luminescence and qRT-PCR of P. berghei 18S rRNA normalized to host GAPDH. RESULTS: The IC50 values quantified by relative luminescence of mAbs 3D11 and 2A10 were 0.396 µg/ml and 0.093 µg/ml, respectively, against transgenic lines in vitro. Using the highest (> 90%) inhibitory antibody concentrations in a passive transfer, an IC50 of 233.8 µg/ml and 181.5 µg/ml for mAbs 3D11 and 2A10, respectively, was observed in vivo. At 25 µg (250 µg/ml), the 2A10 antibody significantly inhibited liver burden in mice compared to control. Additionally, qRT-PCR of P. berghei 18S rRNA served as a secondary validation of liver burden quantification. CONCLUSIONS: Results from both experimental models, ILSDA and in vivo challenge, demonstrated that increased concentrations of the homologous anti-CSP repeat mAbs increased parasite inhibition. However, differences in antibody IC50 values between parasite lines did not allow a direct correlation between the inhibition of sporozoite invasion in vitro by ILSDA and the inhibition of mouse liver stage burden. Further studies are needed to establish the conditions for confident predictions for the in vitro ILSDA to be a predictor of in vivo outcomes using this model system.
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Anticuerpos Monoclonales , Vacunas contra la Malaria , Ratones , Animales , Plasmodium berghei/genética , Plasmodium falciparum/genética , ARN Ribosómico 18S , Proteínas Protozoarias/genética , Animales Modificados Genéticamente , Anticuerpos AntiprotozoariosRESUMEN
PURPOSE: The collection and use of patient reported outcomes (PROs) in care-based child health research raises challenging ethical and logistical questions. This paper offers an analysis of two questions related to PROs in child health research: (1) Is it ethically obligatory, desirable or preferable to share PRO data collected for research with children, families, and health care providers? And if so, (2) What are the characteristics of a model best suited to guide the collection, monitoring, and sharing of these data? METHODS: A multidisciplinary team of researchers, providers, patient and family partners, and ethicists examined the literature and identified a need for focus on PRO sharing in pediatric care-based research. We constructed and analyzed three models for managing pediatric PRO data in care-based research, drawing on ethical principles, logistics, and opportunities to engage with children and families. RESULTS: We argue that it is preferable to share pediatric PRO data with providers, but to manage expectations and balance the risks and benefits of research, this requires a justifiable data sharing model. We argue that a successful PRO data sharing model will allow children and families to have access to and control over their own PRO data and be engaged in decision-making around how PROs collected for research may be integrated into care, but require support from providers. CONCLUSION: We propose a PRO data sharing model that can be used across diverse research settings and contributes to improved transparency, communication, and patient-centered care and research.
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Salud Infantil , Calidad de Vida , Niño , Humanos , Calidad de Vida/psicología , Difusión de la Información , Comunicación , Medición de Resultados Informados por el PacienteRESUMEN
INTRODUCTION: In trauma care, pelvic fractures contribute to morbidity and mortality. Since men and women have different pelvic structures and hormonal milieu, we studied if these gender differences affect clinical outcomes after pelvic fractures. METHODS: Using the 2016 American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) database, we stratified 24,425 patients with pelvic fractures by gender. Male and female patients were analyzed for differences in comorbidities, mechanism of injury, complications, and other clinical parameters. RESULTS: Female patients were older (p < 0.001) and had more comorbidities (p < 0.001), such as bleeding disorder, congestive heart failure, chronic obstructive pulmonary disorder, dementia, chronic renal failure, diabetes mellitus, and hypertension. Although female patients were sicker before sustaining pelvic fractures, male patients had higher rates of post-trauma complications (p < 0.001), such as acute kidney injury, deep vein thrombosis, unplanned admission to the intensive care unit (ICU), and unplanned return to the operating room (OR). Multivariate logistic regression further supports this as male gender was independently associated with a 26.1% higher risk of developing at least one complication (p < 0.001), despite having a higher average Injury Severity Score (ISS) (21.91 ± 0.09 versus 20.71 ± 0.11, p < 0.001). Interestingly, male patients also had a longer hospital length of stay than female patients (13.36 ± 0.12 days versus 11.8 2± 0.14 days, p < 0.001). CONCLUSION: Even though female patients were older and had more pre-existing comorbidities, male patients developed more complications and had longer hospital stays. Trial registration number Not a clinical trial.
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Fracturas Óseas , Huesos Pélvicos , Humanos , Masculino , Femenino , Estudios Retrospectivos , Fracturas Óseas/cirugía , Huesos Pélvicos/lesiones , Hospitalización , Comorbilidad , Tiempo de Internación , Puntaje de Gravedad del TraumatismoRESUMEN
Fibroblast growth factor 21 (FGF21) is increased acutely by carbohydrate ingestion and is elevated in patients with type 2 diabetes (T2D). However, the physiological significance of increased FGF21 in humans remains largely unknown. We examined whether FGF21 contributed to the metabolic improvements observed following treatment of patients with T2D with either triple (metformin/pioglitazone/exenatide) or conventional (metformin/insulin/glipizide) therapy for 3 yr. Forty-six patients with T2D were randomized to receive either triple or conventional therapy to maintain HbA1c < 6.5%. A 2-h 75-g oral glucose tolerance test (OGTT) was performed at baseline and following 3 years of treatment to assess glucose tolerance, insulin sensitivity, and ß-cell function. Plasma total and bioactive FGF21 levels were quantitated before and during the OGTT at both visits. Patients in both treatment arms experienced significant improvements in glucose control, but insulin sensitivity and ß-cell function were markedly increased after triple therapy. At baseline, FGF21 levels were regulated acutely during the OGTT in both groups. After treatment, fasting total and bioactive FGF21 levels were significantly reduced in patients receiving triple therapy, but there was a relative increase in the proportion of bioactive FGF21 compared with that observed in conventionally treated subjects. Relative to baseline studies, triple therapy treatment also significantly modified FGF21 levels in response to a glucose load. These changes in circulating FGF21 were correlated with markers of improved glucose control and insulin sensitivity. Alterations in the plasma FGF21 profile may contribute to the beneficial metabolic effects of pioglitazone and exenatide in human patients with T2D.NEW & NOTEWORTHY In patients with T2D treated with a combination of metformin/pioglitazone/exenatide (triple therapy), we observed reduced total and bioactive plasma FGF21 levels and a relative increase in the proportion of circulating bioactive FGF21 compared with that in patients treated with metformin and sequential addition of glipizide and basal insulin glargine (conventional therapy). These data suggest that FGF21 may contribute, at least in part, to the glycemic benefits observed following combination therapy in patients with T2D.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Metformina , Tiazolidinedionas , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Exenatida , Factores de Crecimiento de Fibroblastos , Glipizida , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Péptidos , Pioglitazona , PonzoñasRESUMEN
OBJECTIVE: Contemporary data on the natural history of large abdominal aortic aneurysms (AAAs) in patients undergoing delayed or no repair are lacking. In this study, we examine the impact of large AAA size on the incidence of rupture and mortality. METHODS: From a prospectively maintained aneurysm surveillance registry, patients with an unrepaired, large AAA (≥5.5 cm in men and ≥5.0 cm in women) at baseline (ie, index imaging) or who progressed to a large size from 2003 to 2017 were included, with follow-up through March 2020. Outcomes of interest obtained by manual chart review included rupture (confirmed by imaging/autopsy), probable rupture (timing/findings consistent with rupture without more likely cause of death), repair, reasons for either no or delayed (>1 year after diagnosis of large AAA) repair and total mortality. Cumulative incidence of rupture was calculated using a nonparametric cumulative incidence function, accounting for the competing events of death and aneurysm repair and was stratified by patient sex. RESULTS: Of the 3248 eligible patients (mean age, 83.6 ± 9.1 years; 71.2% male; 78.1% white; and 32.0% current smokers), 1423 (43.8%) had large AAAs at index imaging, and 1825 progressed to large AAAs during the follow-up period, with a mean time to qualifying size of 4.3 ± 3.4 years. In total, 2215 (68%) patients underwent repair, of which 332 were delayed >1 year; 1033 (32%) did not undergo repair. The most common reasons for delayed repair were discrepancy in AAA measurement between surgeon and radiologist (34%) and comorbidity (20%), whereas the most common reasons for no repair were patient preference (48%) and comorbidity (30%). Among patients with delayed repair (mean time to repair, 2.6 ± 1.8 years), nine (2.7%) developed symptomatic aneurysms, and an additional 11 (3.3%) ruptured. Of patients with no repair, 94 (9.1%) ruptured. The 3-year cumulative incidence of rupture was 3.4% for initial AAA size 5.0 to 5.4 cm (women only), 2.2% for 5.5 to 6.0 cm, 6.0% for 6.1 to 7.0 cm, and 18.4% for >7.0 cm. Women with AAA size 6.1 to 7.0 cm had a 3-year cumulative incidence of rupture of 12.8% (95% confidence interval, 7.5%-19.6%) compared with 4.5% (95% confidence interval, 3.0%-6.5%) in men (P = .002). CONCLUSIONS: In this large cohort of AAA registry patients over 17 years, annual rupture rates for large AAAs were lower than previously reported, with possible increased risk in women. Further analyses are ongoing to identify those at increased risk for aneurysm rupture and may provide targeted surveillance regimens and improve patient counseling.
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Aneurisma de la Aorta Abdominal/cirugía , Rotura de la Aorta/epidemiología , Implantación de Prótesis Vascular/estadística & datos numéricos , Tiempo de Tratamiento/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Aorta Abdominal/diagnóstico por imagen , Aorta Abdominal/patología , Aorta Abdominal/cirugía , Aneurisma de la Aorta Abdominal/complicaciones , Aneurisma de la Aorta Abdominal/diagnóstico , Rotura de la Aorta/etiología , Rotura de la Aorta/prevención & control , Consejo , Progresión de la Enfermedad , Femenino , Humanos , Incidencia , Masculino , Estudios Prospectivos , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Data on race-and-ethnicity that are needed to measure health equity are often limited or missing. The importance of first name and sex in predicting race-and-ethnicity is not well understood. OBJECTIVE: The objective of this study was to compare the contribution of first-name information to the accuracy of basic and more complex racial-and-ethnic imputations that incorporate surname information. RESEARCH DESIGN: We imputed race-and-ethnicity in a sample of Medicare beneficiaries under 2 scenarios: (1) with only sparse predictors (name, address, sex) and (2) with a rich set (adding limited administrative race-and-ethnicity, demographics, and insurance). SUBJECTS: A total of 284,627 Medicare beneficiaries who completed the 2014 Medicare Consumer Assessment of Healthcare Providers and Systems survey and reported race-and-ethnicity were included. RESULTS: Hispanic, non-Hispanic Asian/Pacific Islander, and non-Hispanic White racial-and-ethnic imputations are more accurate for males than females under both sparse-predictor and rich-predictor scenarios; adding first-name information increases accuracy more for females than males. In contrast, imputations of non-Hispanic Black race-and-ethnicity are similarly accurate for females and males, and first names increase accuracy equally for each sex in both sparse-predictor and rich-predictor scenarios. For all 4 racial-and-ethnic groups, incorporating first-name information improves prediction accuracy more under the sparse-predictor scenario than under the rich-predictor scenario. CONCLUSION: First-name information contributes more to the accuracy of racial-and-ethnic imputations in a sparse-predictor scenario than in a rich-predictor scenario and generally narrows sex gaps in accuracy of imputations.
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Etnicidad , Medicare , Anciano , Población Negra , Femenino , Hispánicos o Latinos , Humanos , Masculino , Encuestas y Cuestionarios , Estados UnidosRESUMEN
AIM: To examine the efficacy of glucose-lowering medications in subgroups of patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Cluster analysis was performed in participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study and the Qatar study using age, body mass index (BMI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-ß). Participants also underwent an oral glucose tolerance test with measurement of plasma glucose, insulin and C-peptide concentrations to derive independent measures of insulin secretion and insulin sensitivity. The response to glucose-lowering therapies (change in HbA1c) was measured in each participant cluster for 3 years. RESULTS: Three distinct and comparable clusters/groups of T2DM patients were identified in both the EDICT and Qatar studies. Participants in Group 1 had the highest HbA1c and manifested severe insulin deficiency. Participants in Group 3 had comparable insulin sensitivity to those in Group 1 but better beta-cell function and better glucose control. Participants in Group 2 had the highest BMI with severe insulin resistance accompanied by marked hyperinsulinaemia, which was primarily attributable to decreased insulin clearance. Unexpectedly, participants in Group 1 had better response to combination therapy with pioglitazone plus exenatide than with insulin therapy or metformin sequentially followed by glipizide and basal insulin, while participants in Group 2 responded equally well to both therapies despite very severe insulin resistance. CONCLUSION: Distinct metabolic phenotypes characterize different T2DM clusters and differential responses to glucose-lowering therapies. Participants with severe insulin deficiency respond better to agents that preserve beta-cell function, while, surprisingly, patients with severe insulin resistance did not respond favourably to insulin sensitizers.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/uso terapéutico , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Qatar/epidemiologíaRESUMEN
AIM: To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin â glipizide â glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes. METHODS: Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. RESULTS: At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. CONCLUSIONS: At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.
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Diabetes Mellitus Tipo 2 , Metformina , Enfermedad del Hígado Graso no Alcohólico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Exenatida , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/epidemiología , Metformina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pioglitazona/uso terapéutico , PrevalenciaRESUMEN
Malaria, caused by the parasite Plasmodium falciparum, continues to threaten much of the world's population, and there is a pressing need for expanding treatment options. Natural products have been a vital source of such drugs, and here we report seven new highly N-methylated linear peptides, friomaramide B (2) and shagamides A-F (3-8) from the marine sponge Inflatella coelosphaeroides, collected in Antarctic waters, which demonstrate activity against three strains of blood-stage P. falciparum. The planar structures of these metabolites were solved by interpreting NMR data, as well as HRESIMS/MS fragmentation patterns, while Marfey's analysis was used to establish the configurations of the amino acids. Reisolation of the previously reported compound friomaramide A (1) allowed us to revise its structure. The panel of isolated compounds allowed establishing structure/activity relationships and provided information for future structure optimization for this class of P. falciparum inhibitory metabolites.
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Plasmodium falciparum , Poríferos , Animales , Poríferos/química , Regiones Antárticas , Péptidos/química , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body's systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3ß, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1ß, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3ß (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1ß, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.