Emerging antibiotics for community-acquired pneumonia.

Introduction: Community-acquired pneumonia is the most common infection leading to hospitalization and death in all age groups, especially in elderly populations. Increasing antibiotic resistance among the common bacterial pathogens associated with community-acquired pneumonia, especially Streptococcus pneumoniae and staphylococci, has made its empirical treatment increasingly problematic, highlighting the need for effective antibiotic therapy.Areas covered: We searched PubMed and ClinicalTrials.gov for English-language reports of phase III clinical trials conducted between 2000 and 2019 concerning the antibiotic treatment of community-acquired pneumonia. We provide a summary of the latest approved drugs for this indication and highlight emerging drugs with a potential indication.Expert opinion: Ceftaroline (a new cephalosporine) and omadacycline (a cycline alternative), either parenterally or orally, are the only two new antibiotics to have been approved by the FDA for the treatment of community-acquired pneumonia in the last five years. Among the antimicrobials in development, Lefamulin (the first pleuromutilin), is currently in phase III development. Among the known antibiotic classes, solithromycin (a macrolide), nemonoxacin (a quinolone), and delafloxacin and zabofloxacin (both fluoroquinolones), have been studied in phase II and III in clinical trials. The availability of these new antibiotics may offer opportunities to improve the empirical treatment for community-acquired pneumonia.

Mechanical stress through growth on stiffer substrates impacts animal health and longevity in C. elegans.

Mechanical stress is a measure of internal resistance exhibited by a body or material when external forces, such as compression, tension, bending, etc. are applied. The study of mechanical stress on health and aging is a continuously growing field, as major changes to the extracellular matrix and cell-to-cell adhesions can result in dramatic changes to tissue stiffness during aging and diseased conditions. For example, during normal aging, many tissues including the ovaries, skin, blood vessels, and heart exhibit increased stiffness, which can result in a significant reduction in function of that organ. As such, numerous model systems have recently emerged to study the impact of mechanical and physical stress on cell and tissue health, including cell-culture conditions with matrigels and other surfaces that alter substrate stiffness and ex vivo tissue models that can apply stress directly to organs like muscle or tendons. Here, we sought to develop a novel method in an in vivo, model organism setting to study the impact of mechanical stress on aging, by increasing substrate stiffness in solid agar medium of C. elegans. To our surprise, we found shockingly limited impact of growth of C. elegans on stiffer substrates, including limited effects on cellular health, gene expression, organismal health, stress resilience, and longevity. Overall, our studies reveal that altering substrate stiffness of growth medium for C. elegans have only mild impact on animal health and longevity; however, these impacts were not nominal and open up important considerations for C. elegans biologists in standardizing agar medium choice for experimental assays.

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin function and life span.

The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energyconsuming network with dynamic properties to shape the structure and function of the cell. Proper actin function is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis. Deterioration of these processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton. However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well-understood. Here, we performed a multipronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo Caenorhabditis elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator of actin function and longevity. Overexpression of bet-1 preserves actin function at late age and promotes life span and healthspan in C. elegans. These beneficial effects are mediated through actin preservation by the transcriptional regulator function of BET-1. Together, our discovery assigns a key role for BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.

Investigating impacts of marine sponge derived mycothiazole and its acetylated derivative on mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), a widely used ETC complex I inhibitor, these two molecules showed cytotoxicity to cancer cells but strikingly demonstrate a lack of toxicity to non-cancer cells, a highly beneficial feature in the development of anti-cancer therapeutics. Furthermore, in vivo experiments with these small molecules utilizing C.elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. Interestingly, we also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilize the transcription factors ATFS-1 and HSF-1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF-1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

Surveying Low-Cost Methods to Measure Lifespan and Healthspan in Caenorhabditis elegans.

The discovery and development of Caenorhabditis elegans as a model organism was influential in biology, particularly in the field of aging. Many historical and contemporary studies have identified thousands of lifespan-altering paradigms, including genetic mutations, transgenic gene expression, and hormesis, a beneficial, low-grade exposure to stress. With its many advantages, including a short lifespan, easy and low-cost maintenance, and fully sequenced genome with homology to almost two-thirds of all human genes, C. elegans has quickly been adopted as an outstanding model for stress and aging biology. Here, several standardized methods are surveyed for measuring lifespan and healthspan that can be easily adapted into almost any research environment, especially those with limited equipment and funds. The incredible utility of C. elegans is featured, highlighting the capacity to perform powerful genetic analyses in aging biology without the necessity of extensive infrastructure. Finally, the limitations of each analysis and alternative approaches are discussed for consideration.

Prevalencia e implicaciones pronósticas de los trastornos del sueño en la insuficiencia cardiaca crónica / Prevalence and prognostic implications of sleep disorders in patients with chronic heart failure

Objetivos. Evaluar la prevalencia e implicaciones pronosticas de los trastornos del sueño en pacientes con insuficiencia cardiaca crónica atendidos en una unidad de Insuficiencia Cardiaca hospitalaria. Método. Se realizó un estudio observacional, descriptivo y prospectivo. Ámbito: Unidad de Insuficiencia Cardiaca del Hospital de la Santa Creu i Sant Pau. Participantes: pacientes atendidos por primera vez en la Unidad entre abril de 2014 y noviembre de 2014. Variables: se realizó una evaluación de los trastornos del sueño mediante el cuestionario Insomnia Severity Index8,9 modificado. Se obtuvieron datos sociodemográficos, clínicos y farmacológicos de la historia clínica del paciente. Se evaluó la aparición de eventos adversos en el seguimiento (hospitalización por insuficiencia cardiaca o muerte de causa cardiovascular). Análisis: las variables cualitativas se describieron en forma de porcentajes y las cuantitativas en forma de media y desviaciones estándares. Resultados. La muestra total fue de 68 pacientes con una media de edad de 68 ± 12 años; un 59 % de los pacientes fueron varones. La etiología de la insuficiencia cardiaca fue en un 37 % de causa no isquémica, en un 40 % de causa isquémica, en el 10 % valvular y en un 13 % de otras etiologías. Los trastornos del sueño estaban presentes en el 48.5 % del total de la muestra (33 pacientes). Los pacientes con trastornos del sueño presentaron mayor incidencia de efectos adversos cardiovasculares en el seguimiento (21 % frente a 0 %; p < 0.05). Conclusiones. La prevalencia de los trastornos del sueño es alta en pacientes con insuficiencia cardiaca y se asocia a un peor pronóstico clínico (AU)

Objectives. To evaluate the prevalence and prognostic implications of sleep disorders in patients with chronic heart failure treated in a hospital’s Heart Failure Unit. Method. An observational, descriptive and prospective study. The study was carried out in Hospital de la Santa Creu i Sant Pau Heart Failure Unit, Barcelona. Participants consisted of patients arriving to the Unit for the first time between April and November 2014. An assessment of sleeping disorders was performed using the modified questionnaire Insomnia Severity Index8,9. Patient’s sociodemographic, clinical and pharmacological data was obtained from their medical history. Adverse events during follow-up, (hospitalization due to heart failure and/or cardiovascular death), were assessed. In the analysis, qualitative variables were described as percentages and quantitative variables as mean and standard deviations. Results. The total sample consisted of 68 patients with a mean age of 68 ± 12 years. 59 % of patients were male. The etiological cause of heart failure was: in 37 % of the cases non-ischemic, 40 % ischemic, 10 % valvular and 13 % presented other etiologies. Sleep disorders were present in 48.5 % of the total sample (33 patients). Patients with sleep disorders had a higher incidence of cardiovascular adverse effects during the follow-up: 21 % vs 0 %; p <0.05. Conclusions. The prevalence of sleep disorders is high in patients with heart failure and is associated with a worse clinical prognosis (AU)