Development of Drugs for Nontuberculous Mycobacterial Disease:Clinicians’ Interpretation of a US Food and Drug Administration Workshop

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop

Bronchiectasis insanity:Doing the same thing over and over again and expecting different results?

Bronchiectasis is an increasingly common disease with a significant impact on quality of life and morbidity of affected patients. It is also a very heterogeneous disease with numerous different underlying etiologies and presentations. Most treatments for bronchiectasis are based on low-quality evidence; consequently, no treatments have been approved by the US Food and Drug Administration or the European Medicines Agency for the treatment of bronchiectasis. The last several years have seen numerous clinical trials in which the investigational agent, thought to hold great promise, did not demonstrate a clinically or statistically significant benefit. This commentary will review the likely reasons for these disappointing results and a potential approach that may have a greater likelihood of defining evidence-based treatment for bronchiectasis

Stage- and Gender-Specific Proteomic Analysis of Brugia malayi Excretory-Secretory Products

To succeed in infection, parasites must have ways to reach the host, penetrate its tissues and escape its defense systems. As they are not necessarily fatal, most helminth parasites remain viable within their host for many years, exerting a strong influence over the host immune function. Many of these functions are performed by products that are released from the parasite. We exploited the remarkable sensitivity of modern proteomics tools together with the availability of a sequenced genome to identify and compare the proteins released in vitro by adult males, adult females and the microfilariae of the filarial nematode Brugia malayi. This parasite is one of the etiological agents of lymphatic filariasis, a disease that poses continuing and significant threats to human health. The different forms of the parasite inhabit different compartments in the mammalian host. We found that the set of proteins released by each form is unique; they must reflect particular developmental processes and different strategies for evasion of host responses. The identification of these proteins will allow us to illuminate the biology of secretory processes in this organism and to establish a path for developing an understanding of how these parasite proteins function in immune evasion events

Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol

Abstract Background The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work. Methods Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum. Discussion SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients. Trial registration NCT03331991 . Registered on November 6, 2017.https://deepblue.lib.umich.edu/bitstream/2027.42/146186/1/12879_2018_Article_3444.pd

Toll-Like Receptor 3 and Suppressor of Cytokine Signaling Proteins Regulate CXCR4 and CXCR7 Expression in Bone Marrow-Derived Human Multipotent Stromal Cells

The use of bone marrow-derived human multipotent stromal cells (hMSC) in cell-based therapies has dramatically increased in recent years, as researchers have exploited the ability of these cells to migrate to sites of tissue injury, inflammation, and tumors. Our group established that hMSC respond to "danger" signals--by-products of damaged, infected or inflamed tissues--via activation of Toll-like receptors (TLRs). However, little is known regarding downstream signaling mediated by TLRs in hMSC.We demonstrate that TLR3 stimulation activates a Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 1 pathway, and increases expression of suppressor of cytokine signaling (SOCS) 1 and SOCS3 in hMSC. Our studies suggest that each of these SOCS plays a distinct role in negatively regulating TLR3 and JAK/STAT signaling. TLR3-mediated interferon regulatory factor 1 (IRF1) expression was inhibited by SOCS3 overexpression in hMSC while SOCS1 overexpression reduced STAT1 activation. Furthermore, our study is the first to demonstrate that when TLR3 is activated in hMSC, expression of CXCR4 and CXCR7 is downregulated. SOCS3 overexpression inhibited internalization of both CXCR4 and CXCR7 following TLR3 stimulation. In contrast, SOCS1 overexpression only inhibited CXCR7 internalization.These results demonstrate that SOCS1 and SOCS3 each play a functionally distinct role in modulating TLR3, JAK/STAT, and CXCR4/CXCR7 signaling in hMSC and shed further light on the way hMSC respond to danger signals

Channel initiation in the semiarid Colorado Front Range

2010 Summer.Includes bibliographic references (pages 53-55).Covers not scanned.Print version deaccessioned 2022.The channel head, defined as the upstream boundary of concentrated water flow and sediment transport between definable banks, represents the transition from hillslope processes to fluvial processes. The ability to delineate the location along a slope at which channels initiate is important for understanding hydrologic and geomorphic processes governing headwater streams. Studies demonstrating an inverse relationship between either contributing drainage area (A) and local valley slope {6) or basin length (L) and 6 for channel heads come primarily from regions with humid climates. Seventy-eight channel heads were mapped in the headwaters of the Cache la Poudre River and the North St. Vrain Creek in the semiarid Colorado Front Range. Multiple field sites were chosen along both rivers to account for variability due to aspect and elevation. Surface topographic parameters were measured in the field and analyzed to test the hypothesis that surface processes control channel initiation in this region. Although simple linear regressions indicate a poor inverse relationship between A and L and no relationship between L and (9, multiple regressions indicate that surface topographic parameters explain over half the variability in the location of channel heads. This suggests that surface processes exert an influence on channel initiation, but do not explain as much of the variability as observed in previous studies from wetter regions. A threshold of erosion necessary to initiate a channel was observed at approximately 10,000 for .4, although values as high as 600,000 were mapped for some channel heads. Variation within the study area correlated with elevation, which is a proxy for differences in volume and type of precipitation; sites at lower elevation with less precipitation, but more intense convective rainfall, tend to have smaller contributing area and basin length. Aspect did not influence surface topographic parameters. Field-mapped channel head locations plot at or downslope from the inflection point of a regional slope-area curve generated from 10 m DEMs, although some extend well downslope. Most actual drainage areas for channel initiation are thus an order of magnitude larger, and plot in a significantly different portion of the slope-area graph, than would result from the widespread practice of assuming channel heads are located at the gradient reversal in such curves