species are a complex group of organisms considered to belong to the aerobic actinomycetes. Of the validly described species, many have been implicated as the cause of serious human infections, ...especially in immunocompromised patients. The genus has a complicated taxonomic history; this is especially true for
, the type species of the genus and previously the most frequently reported nocardial taxon from human specimens. We provide background on the current taxonomy of
, with a focus on clinically relevant species, and discuss the currently available methods used to accurately identify isolates to the species, complex, or group level.
Objective
To evaluate the efficacy and safety of eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of episodic migraine.
Methods
The ...PRevention Of Migraine via Intravenous ALD403 Safety and Efficacy-1 (PROMISE-1) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with episodic migraine were randomized to eptinezumab 30 mg, 100 mg, 300 mg, or placebo for up to four intravenous (IV) doses administered every 12 weeks. The primary endpoint was change from baseline in monthly migraine days (MMDs) over weeks 1–12.
Results
A total of 888 patients received treatment across 84 study sites. Mean MMDs at baseline was ∼8.6 across treatment groups. Eptinezumab 100 mg and 300 mg met the primary endpoint, significantly reducing MMDs across weeks 1–12 compared with placebo (30 mg, −4.0; 100 mg, −3.9, p = 0.0182; 300 mg, −4.3; placebo, −3.2, p = 0.0001). Treatment-emergent adverse events were reported by 58.4% (30 mg), 63.2% (100 mg), 57.6% (300 mg), and 59.5% (placebo) of patients. Treatment-emergent adverse events reported by ≥2% of eptinezumab-treated patients at an incidence greater than placebo included: upper respiratory tract infection (30 mg, 11.4%; 100 mg, 9.9%; 300 mg, 10.3%; placebo, 7.2%), and fatigue (30 mg, 2.3%; 100 mg, 3.6%; 300 mg, 3.6%; placebo, <1%).
Conclusion
Eptinezumab (100 mg or 300 mg) significantly reduced migraine frequency, was well tolerated, and had an acceptable safety profile when used for the preventive treatment of migraine in adults with episodic migraine.
ClinicalTrials.gov identifier: NCT02559895
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This multicenter study was designed to assess the accuracy and reproducibility of the Vitek MS v3.0 matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry system for ...identification of
and
species compared to DNA sequencing. A total of 963 clinical isolates representing 51 taxa were evaluated. In all, 663 isolates were correctly identified to the species level (69%), with another 231 (24%) correctly identified to the complex or group level. Fifty-five isolates (6%) could not be identified despite repeat testing. All of the tuberculous mycobacteria (45/45; 100%) and most of the nontuberculous mycobacteria (569/606; 94%) were correctly identified at least to the group or complex level. However, not all species or subspecies within the
,
, and
complexes and within the
and
groups could be differentiated. Among the 312
isolates tested, 236 (76%) were correctly identified to the species level, with an additional 44 (14%) correctly identified to the complex level. Species within the
and
complexes could not always be differentiated. Eleven percent of the isolates (103/963) underwent repeat testing in order to get a final result. Identification of a representative set of
and
species was highly reproducible, with 297 of 300 (99%) replicates correctly identified using multiple kit lots, instruments, analysts, and sites. These findings demonstrate that the system is robust and has utility for the routine identification of mycobacteria and
in clinical practice.
Although asexual reproduction via clonal propagation has been proposed as the principal reproductive mechanism across parasitic protozoa of the Leishmania genus, sexual recombination has long been ...suspected, based on hybrid marker profiles detected in field isolates from different geographical locations. The recent experimental demonstration of a sexual cycle in Leishmania within sand flies has confirmed the occurrence of hybridisation, but knowledge of the parasite life cycle in the wild still remains limited. Here, we use whole genome sequencing to investigate the frequency of sexual reproduction in Leishmania, by sequencing the genomes of 11 Leishmania infantum isolates from sand flies and 1 patient isolate in a focus of cutaneous leishmaniasis in the Çukurova province of southeast Turkey. This is the first genome-wide examination of a vector-isolated population of Leishmania parasites. A genome-wide pattern of patchy heterozygosity and SNP density was observed both within individual strains and across the whole group. Comparisons with other Leishmania donovani complex genome sequences suggest that these isolates are derived from a single cross of two diverse strains with subsequent recombination within the population. This interpretation is supported by a statistical model of the genomic variability for each strain compared to the L. infantum reference genome strain as well as genome-wide scans for recombination within the population. Further analysis of these heterozygous blocks indicates that the two parents were phylogenetically distinct. Patterns of linkage disequilibrium indicate that this population reproduced primarily clonally following the original hybridisation event, but that some recombination also occurred. This observation allowed us to estimate the relative rates of sexual and asexual reproduction within this population, to our knowledge the first quantitative estimate of these events during the Leishmania life cycle.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVETo evaluate the efficacy and safety of eptinezumab, a humanized anti–calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of chronic migraine (CM).
METHODSThe ...Prevention of Migraine via Intravenous ALD403 Safety and Efficacy–2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with CM were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12.
RESULTSAmong treated participants (n = 1,072), baseline mean number of MMDs was ≈16.1 across groups. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1 to 12 compared with placebo (placebo −5.6, 100 mg −7.7, p < 0.0001 vs placebo; 300 mg −8.2, p < 0.0001 vs placebo). Treatment-emergent adverse events (TEAEs) were reported by 43.5% (100 mg), 52.0% (300 mg), and 46.7% (placebo) of patients. Nasopharyngitis was the only TEAE reported for >2% of eptinezumab-treated patients at an incidence of >2% over placebo; it occurred in the 300 mg eptinezumab arm (eptinezumab 9.4%, placebo 6.0%).
CONCLUSIONIn patients with CM, eptinezumab 100 and 300 mg was associated with a significant reduction in MMDs from the day after IV administration through week 12, was well tolerated, and demonstrated an acceptable safety profile.
CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that for patients with CM, a single dose of eptinezumab reduces MMDs over 12 weeks of treatment.
CLINICALTRIALS.GOV IDENTIFIERNCT02974153.
Identification of nodal metastasis and tumor extranodal extension (ENE) is crucial for head and neck cancer management, but currently only can be diagnosed via postoperative pathology. Pretreatment, ...radiographic identification of ENE, in particular, has proven extremely difficult for clinicians, but would be greatly influential in guiding patient management. Here, we show that a deep learning convolutional neural network can be trained to identify nodal metastasis and ENE with excellent performance that surpasses what human clinicians have historically achieved. We trained a 3-dimensional convolutional neural network using a dataset of 2,875 CT-segmented lymph node samples with correlating pathology labels, cross-validated and fine-tuned on 124 samples, and conducted testing on a blinded test set of 131 samples. On the blinded test set, the model predicted ENE and nodal metastasis each with area under the receiver operating characteristic curve (AUC) of 0.91 (95%CI: 0.85-0.97). The model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
This review was designed to compile the currently available evidence on the prophylactic use of gabapentin in the head and neck cancer patient population.
Methods
A systematic search was ...conducted of PubMed, Web of Science, and Google Scholar to identify articles related to the use of prophylactic gabapentin in patients undergoing head and neck cancer therapy. Candidate studies were screened for inclusion and a subsequent bias assessment was conducted by multiple reviewers. Meta-analysis was conducted in cases in which the studies used compatible outcome measures.
Results
Ten studies were identified that met the inclusion criteria and were assessed for bias. Among the four small studies that examined pain prevention, 2 were positive and 2 were inconclusive. Three of the four studies examiniRDng opioid use noted less need for opioids in the treatment arm. Meta-analysis of the pertinent studies showed no difference in feeding tube placement (RD = 0.64%, 95%CI: (− 25.8%, 27.1%),
p
= 0.962) but substantially less weight loss among those in the treatment arm (
p
= 0.047).
Conclusion
Prophylactic gabapentin appears to be a promising treatment option for preventing pain, reducing opioids, and reducing weight loss in patients undergoing head and neck cancer therapy. However, the studies on the treatment to date are small and several have a substantial risk of bias.
Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is ...the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Sigma 1 receptor (S1R) is expressed in retinal ganglion cells (RGCs) and astrocytes, and its activation is neuroprotective. We evaluated the contribution of S1R within optic nerve head astrocytes ...(ONHAs) to growth and survival of RGCs in vitro.
Wild-type (WT) RGCs and WT or S1R knockout (S1R KO) ONHAs were cocultured for 2, 4, or 7 days. Total and maximal neurite length, neurite root, and extremity counts were measured. Cell death was measured using a TUNEL assay. Signal transducer and activator of transcription 3 phosphorylation levels were evaluated in ONHA-derived lysates by immunoblotting.
The coculture of WT RGCs with WT or S1R KO ONHAs increased the total and maximal neurite length. Neurite root and extremity counts increased at 4 and 7 days when WT RGCs were cocultured with WT or S1R KO ONHAs. At all timepoints, the total and maximal neurite length decreased for WT RGCs in coculture with S1R KO ONHAs compared with WT ONHAs. Root and extremity counts decreased for WT RGCs in coculture with S1R KO ONHAs compared with WT ONHAs at 2 and 7, but not 4 days. RGC apoptosis increased in S1R KO ONHA coculture and S1R KO-conditioned medium, compared with WT ONHA coculture or WT-conditioned medium. S1R KO ONHA-derived lysates showed decreased phosphorylated signal transducer and activator of transcription 3 levels compared with WT ONHA-derived lysates.
The absence of S1R within ONHAs has a deleterious effect on RGC neurite growth and RGC survival, reflected in analysis of WT RGC + S1R KO ONHA indirect cocultures. The data suggest that S1R may enhance ganglion cell survival via glia-mediated mechanisms.
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