Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme ...disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.
Two stochastic weather simulation models (USCLIMATE and CLIGEN) were compared for their performance in replicating observed precipitation, temperature, and solar radiation variables at six locations ...in the United States. Statistical tests of significance were performed on means and standard deviations of a variety of standard and derived daily weather variables over monthly and annual time periods. Model replication of extreme events also was evaluated. In general, mean monthly and annual values were well replicated by both models, but variance replication of temperature and solar radiation were found superior in USCLIMATE. Extreme-value replication, especially over short (24-h) time intervals, was highly a function of climatic element, location, and time of year but, in general, was judged only fair in both models. Suggestions for model improvement and enhancement are given, as are suggestions for model applications.
Nowadays, progress in the determination of three‐dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment ...of modern high‐speed, high‐resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high‐performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability. There is also an issue of long‐term data maintenance and availability of structure‐solution projects as the links between experimental observations and the final results deposited in the PDB. In this article, CCP4 Cloud, a new front‐end of the CCP4 software suite, is presented which mitigates these effects by providing an online, cloud‐based environment for crystallographic computation. CCP4 Cloud was developed for the efficient delivery of computing power, database services and seamless integration with web resources. It provides a rich graphical user interface that allows project sharing and long‐term storage for structure‐solution projects, and can be linked to data‐producing facilities. The system is distributed with the CCP4 software suite version 7.1 and higher, and an online publicly available instance of CCP4 Cloud is provided by CCP4.
The paper describes CCP4 Cloud, an online system for macromolecular structure determination based on the CCP4 software suite.
Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, ...notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described.
Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays.
After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs.
RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.
Since 1998, cyclic mortality events in common eiders (Somateria mollissima), numbering in the hundreds to thousands of dead birds, have been documented along the coast of Cape Cod, MA, USA. Although ...longitudinal disease investigations have uncovered potential contributing factors responsible for these outbreaks, detecting a primary etiological agent has proven enigmatic. Here, we identify a novel orthomyxovirus, tentatively named Wellfleet Bay virus (WFBV), as a potential causative agent of these outbreaks. Genomic analysis of WFBV revealed that it is most closely related to members of the Quaranjavirus genus within the family Orthomyxoviridae. Similar to other members of the genus, WFBV contains an alphabaculovirus gp64-like glycoprotein that was demonstrated to have fusion activity; this also tentatively suggests that ticks (and/or insects) may vector the virus in nature. However, in addition to the six RNA segments encoding the prototypical structural proteins identified in other quaranjaviruses, a previously unknown RNA segment (segment 7) encoding a novel protein designated VP7 was discovered in WFBV. Although WFBV shows low to moderate levels of sequence similarity to Quaranfil virus and Johnston Atoll virus, the original members of the Quaranjavirus genus, additional antigenic and genetic analyses demonstrated that it is closely related to the recently identified Cygnet River virus (CyRV) from South Australia, suggesting that WFBV and CyRV may be geographic variants of the same virus. Although the identification of WFBV in part may resolve the enigma of these mass mortality events, the details of the ecology and epidemiology of the virus remain to be determined.
The emergence or reemergence of viral pathogens resulting in large-scale outbreaks of disease in humans and/or animals is one of the most important challenges facing biomedicine. For example, understanding how orthomyxoviruses such as novel influenza A virus reassortants and/or mutants emerge to cause epidemic or pandemic disease is at the forefront of current global health concerns. Here, we describe the emergence of a novel orthomyxovirus, Wellfleet Bay virus (WFBV), which has been associated with cyclic large-scale bird die-offs in the northeastern United States. This initial characterization study provides a foundation for further research into the evolution, epidemiology, and ecology of newly emerging orthomyxoviruses, such as WFBV, and their potential impacts on animal and/or human health.
ABSTRACT
We report the discovery and characterization of a transiting warm sub-Neptune planet around the nearby bright (V = 8.75 mag, K = 7.15 mag) solar twin HD 183579, delivered by the Transiting ...Exoplanet Survey Satellite (TESS). The host star is located 56.8 ± 0.1 pc away with a radius of R* = 0.97 ± 0.02 R⊙ and a mass of M* = 1.03 ± 0.05 M⊙. We confirm the planetary nature by combining space and ground-based photometry, spectroscopy, and imaging. We find that HD 183579b (TOI-1055b) has a radius of Rp = 3.53 ± 0.13 R⊕ on a 17.47 d orbit with a mass of Mp = 11.2 ± 5.4 M⊕ (3σ mass upper limit of 27.4 M⊕). HD 183579b is the fifth brightest known sub-Neptune planet system in the sky, making it an excellent target for future studies of the interior structure and atmospheric properties. By performing a line-by-line differential analysis using the high-resolution and signal-to-noise ratio HARPS spectra, we find that HD 183579 joins the typical solar twin sample, without a statistically significant refractory element depletion.
Nowadays, progress in the determination of three-dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment ...of modern high-speed, high-resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high-performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability. There is also an issue of long-term data maintenance and availability of structure-solution projects as the links between experimental observations and the final results deposited in the PDB. In this article,
CCP
4 Cloud, a new front-end of the
CCP
4 software suite, is presented which mitigates these effects by providing an online, cloud-based environment for crystallographic computation.
CCP
4 Cloud was developed for the efficient delivery of computing power, database services and seamless integration with web resources. It provides a rich graphical user interface that allows project sharing and long-term storage for structure-solution projects, and can be linked to data-producing facilities. The system is distributed with the
CCP
4 software suite version 7.1 and higher, and an online publicly available instance of
CCP
4 Cloud is provided by CCP4.
Women with refractory urgency urinary incontinence (ie, unresponsive to behavioral and pharmacological interventions) are treated with onabotulinumtoxinA or sacral neuromodulation.
The objective of ...the study was to compare treatment efficacy and adverse events in women <65 and ≥65 years old treated with onabotulinumtoxinA or sacral neuromodulation.
This study was a planned secondary analysis of a multicenter, randomized trial that enrolled community-dwelling women with refractory urgency urinary incontinence to onabotulinumtoxinA or sacral neuromodulation treatments. The primary outcome was a change in mean daily urgency urinary incontinence episodes on a bladder diary over 6 months. Secondary outcomes included ≥75% urgency urinary incontinence episode reduction, change in symptom severity/quality of life, treatment satisfaction, and treatment-related adverse events.
Both age groups experienced improvement in mean urgency urinary incontinence episodes per day following each treatment. There was no evidence that mean daily urgency urinary incontinence episode reduction differed between age groups for onabotulinumtoxinA (adjusted coefficient, –0.127, 95% confidence interval, –1.233 to 0.979; P = .821) or sacral neuromodulation (adjusted coefficient, –0.698, 95% confidence interval, –1.832 to 0.437; P = .227). Among those treated with onabotulinumtoxinA, women <65 years had 3.3-fold greater odds of ≥75% resolution than women ≥65 years (95% confidence interval, 1.56 –7.02). Women <65 years had a greater reduction in Overactive Bladder Questionnaire Short Form symptom bother scores compared with women ≥65 years by 7.49 points (95% confidence interval, –3.23 to –11.74), regardless of treatment group. There was no difference between quality of life improvement by age. Women ≥65 years had more urinary tract infections following onabotulinumtoxinA and sacral neuromodulation (odds ratio, 1.9, 95% confidence interval, 1.2–3.3). There was no evidence of age differences in sacral neuromodulation revision/removal or catheterization following onabotulinumtoxinA treatment.
Younger women experienced greater absolute continence, symptom improvement, and fewer urinary tract infections; both older and younger women had beneficial urgency urinary incontinence episode reduction, similar rates of other treatment adverse events, and improved quality of life.
To examine how frequently Breast Imaging Reporting and Data System (BI-RADS) mammographic screening assessments were associated with expected clinical management recommendations.
Seven Breast Cancer ...Surveillance Consortium mammography registries recorded screening assessments and recommendations in 1997 to identify the proportion of women in each BI-RADS category. The first screening assessment for a woman without cancer or a prior mammogram within 9 months was associated with its independently recorded recommendation.
Among 292,795 women, screening assessments included 269,022 (91.9%) with a "negative" or "benign finding," and 267,103 (99.3%) of these women were recommended for normal interval follow-up. Among 11,861 (4.1%) women with screening assessments of "probably benign finding," 4,782 (40.3%) were recommended for short interval follow-up as expected on the basis of the BI-RADS, but a high proportion (36.9%) were recommended for additional imaging. Among 1,625 (0.6%) women with "suspicious abnormality," most were recommended for biopsy (48.7%) or clinical examination and/or surgical consult (9.0%), but many were recommended for additional imaging (38.7%). Among 243 (0.1%) women with screening assessments "highly suggestive of malignancy," a majority were recommended for biopsy (73.3%) or clinical examination and/or surgical consult (18.1%) consistent with BI-RADS, but some were recommended for additional imaging (6.6%).
BI-RADS assessments and management recommendations are consistent for negative and benign assessments, but inconsistencies were found in assessments and recommendations for mammographic abnormalities.
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