Cisplatin has been used as a chemotherapeutic agent to treat many different cancers. A well-known side effect of cisplatin is nephrotoxicity, which is the primary dose-limiting toxicity. Hydration in ...conjunction with appropriate diuresis can decrease the incidence of nephrotoxicity.
This article aims to identify best practices in supportive therapy for patients receiving cisplatin therapy.
A team was assembled to review research-based evidence and summarize recommendations to address appropriate hydration regimens and forced diuresis for patients receiving cisplatin chemotherapy.
After a systematic search of the literature, only one pediatric study was found. The remaining 22 research-based studies of adults were synthesized and critically appraised. Hydration is necessary to prevent nephrotoxicity with cisplatin administration. In addition, the administration of magnesium and mannitol may assist in maintaining renal function and reducing nephrotoxicity in adults receiving cisplatin. Additional research is needed to evaluate outcomes of these interventions in the pediatric population.
Antimicrobial therapy for sepsis has beneficial effects, but prolonged use fosters emergence of resistant microorganisms, increases cost, and secondary infections. We tested whether 3 days versus 5 ...days of antibiotics in the murine model of cecal ligation and puncture (CLP) negatively influences outcomes. Following CLP mice were randomized to receive the antibiotic imipenem-cilastatin (25mg/kg) in dextrose 5% in Lactated Ringer's solution every 12 hours for either three or five days. Serial monitoring over 28 days included body weight, temperature, pulse oximetry, and facial vein sampling for hematological analysis and glucose. A separate group of mice were euthanized on post-CLP day 5 to measure cytokines and peritoneal bacterial counts. The first study examined no antimicrobial therapy and demonstrated that antibiotics significantly improved survival compared to fluids only (p = 0.004). We next tested imipenem-cilastatin therapy for 3 days versus 5 days. Body weight, temperature, glucose, and pulse oximetry measurements remained generally consistent between both groups as did the hematological profile. Pro-inflammatory plasma cytokines were comparable between both groups for IL-6, IL-1β, MIP-2 and anti-inflammatory cytokines IL-10, and TNF SRI. At 5 days post-CLP, i.e. 2 days after the termination of antibiotics in the 3 day group, there were no differences in the number of peritoneal bacteria. Importantly, shortening the course of antibiotics by 40% (from 5 days to 3 days) did not decrease survival. Our results indicate that reducing the duration of broad-spectrum antibiotics in murine sepsis did not increase inflammation or mortality.
The Mars 2020 mission seeks to conduct a new scientific exploration on the surface of Mars. The
Perseverance
Rover will be sent to the surface of the Jezero Crater region to study its habitability, ...search for biosignatures of past life, acquire and cache samples for potential return, and prepare for possible human missions. To enable these objectives, an innovative Sampling and Caching Subsystem (SCS) has been developed and tested to allow the
Perseverance
Rover to acquire and cache rock core and regolith samples, prepare abraded rock surfaces, and support proximity science instruments.
The SCS consists of the Robotic Arm (RA), the Turret and Corer, and the Adaptive Caching Assembly (ACA). These elements reside and interact both inside and outside of the
Perseverance
Rover to enable surface interactions, sample transfer, and caching. The main body of the Turret consists of the Coring Drill (Corer) with a Launch Abrading Bit initially installed prior to launch. Mounted to the Turret main structure are two proximity science instruments, SHERLOC and PIXL, as well as the Gas Dust Removal Tool (gDRT) and the Facility Contact Sensor (FCS). These work together with the RA to provide the sample acquisition, abraded surface preparation, and proximity science functions. The ACA is a network of assemblies largely inside the front belly of the Rover, which combine to perform the sample handling and caching functions of the mission. The ACA primarily consists of the Bit Carousel, the Sample Handling Assembly (SHA), End Effector (EE), Sample Tubes and their Sample Tube Storage Assembly (STSA), Seals and their Dispenser, Volume, and Tube Assembly (DVT), the Sealing Station, the Vision Station, the Cover Parking Lot, and additional supporting hardware. These components attach to the Caching Component Mounting Deck (CCMD) that is integrated with the Rover interior. This work describes these major elements of the SCS, with an emphasis on the functionality required to perform the set of tasks and interactions required by the subsystem. Key considerations of contamination control and biological cleanliness throughout the development of these hardware elements are also discussed.
Additionally, aspects of testing and validating the functionality of the SCS are described. Early prototypes and tests matured the designs over several years and eventually led to the flight hardware and integrated testing in both Earth ambient and Mars-like environments. Multiple unique testbed venues were developed and used to enable testing from low-level mechanism operation through end-to-end sampling and caching interactions with the full subsystem and flight software. Various accomplishments from these testing efforts are highlighted. These past and ongoing tests support the successful preparations of the SCS on its pathway to operations on Mars.
Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read ...technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications.
This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols.
Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing.
This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology.
Genet Med18 12, 1282–1289.
Biomarkers are fundamental to basic and clinical research outcomes by reporting host responses and providing insight into disease pathophysiology. Measuring biomarkers with research-use ELISA kits is ...universal, yet lack of kit standardization and unexpected lot-to-lot variability presents analytic challenges for long-term projects. During an ongoing two-year project measuring plasma biomarkers in cancer patients, control concentrations for one biomarker (PF) decreased significantly after changes in ELISA kit lots. A comprehensive operations review pointed to standard curve shifts with the new kits, an analytic variable that jeopardized data already collected on hundreds of patient samples. After excluding other reasonable contributors to data variability, a computational solution was developed to provide a uniform platform for data analysis across multiple ELISA kit lots. The solution (ELISAtools) was developed within open-access R software in which variability between kits is treated as a batch effect. A defined best-fit Reference standard curve is modelled, a unique Shift factor "S" is calculated for every standard curve and data adjusted accordingly. The averaged S factors for PF ELISA kit lots #1-5 ranged from -0.086 to 0.735, and reduced control inter-assay variability from 62.4% to <9%, within quality control limits. S factors calculated for four other biomarkers provided a quantitative metric to monitor ELISAs over the 10 month study period for quality control purposes. Reproducible biomarker measurements are essential, particularly for long-term projects with valuable patient samples. Use of research-use ELISA kits is ubiquitous and judicious use of this computational solution maximizes biomarker reproducibility.
The paradigm of systemic inflammatory response syndrome-to-compensatory anti-inflammatory response syndrome transition implies that hyperinflammation triggers acute sepsis mortality, whereas ...hypoinflammation (release of anti-inflammatory cytokines) in late sepsis induces chronic deaths. However, the exact humoral inflammatory mechanisms attributable to sepsis outcomes remain elusive. In the first part of this study, we characterized the systemic dynamics of the chronic inflammation in dying (DIE) and surviving (SUR) mice suffering from cecal ligation and puncture sepsis (days 6-28). In the second part, we combined the current chronic and previous acute/chronic sepsis data to compare the outcome-dependent inflammatory signatures between these two phases. A composite cytokine score (CCS) was calculated to compare global inflammatory responses. Mice were never sacrificed but were sampled daily (20 μl) for blood. In the first part of the study, parameters from chronic DIE mice were clustered into the 72, 48, and 24 h before death time points and compared with SUR of the same post-cecal ligation and puncture day. Cytokine increases were mixed and never preceded chronic deaths earlier than 48 h (3- to 180-fold increase). CCS demonstrated simultaneous and similar upregulation of proinflammatory and anti-inflammatory compartments at 24 h before chronic death (DIE 80- and 50-fold higher versus SUR). In the second part of the study, cytokine ratios across sepsis phases/outcomes indicated steady proinflammatory versus anti-inflammatory balance. CCS showed the inflammatory response in chronic DIE was 5-fold lower than acute DIE mice, but identical to acute SUR. The systemic mixed anti-inflammatory response syndrome-like pattern (concurrent release of proinflammatory and anti-inflammatory cytokines) occurs irrespective of the sepsis phase, response magnitude, and/or outcome. Although different in magnitude, neither acute nor chronic septic mortality is associated with a predominating proinflammatory and/or anti-inflammatory signature in the blood.
•Functional outcomes >13 years after FDO (GMFCS I-II, III-IV) versus non-FDO I-II.•Hip rotation in gait improved approximately 14° for all three groups.•FDO I-II, non-FDO I-II had similar hip ...rotation in gait despite different anteversion.•No long-term differences in hip abductor moment, strength, repetitions, and most pain.•Functional improvements were maintained from short- to long-term in the FDO groups.
It is unknown how a femoral derotation osteotomy (FDO) during childhood affects functional outcomes in adulthood among individuals with bilateral cerebral palsy (CP).
How do long-term functional outcomes after an FDO compare to matched individuals who did not have an FDO? How do outcomes change over time?
We queried the gait laboratory database for individuals who underwent an external FDO in childhood and were currently ≥25 years old. Participants returned for a long-term analysis (gait, physical examination, functional tests, imaging, questionnaires). The matched non-FDO group included only individuals in Gross Motor Function Classification System levels I-II, yielding three groups (non-FDO I-II, FDO I-II, FDO III-IV).
Sixty-one adults (11 non-FDO, 34 FDO I-II, 16 FDO III-IV) returned 13–25 years after baseline (non-FDO) or surgery (FDO). The non-FDO and FDO I-II groups were matched at baseline on most variables, except the FDO group had weaker hip abductors. At long-term, groups were similar on gait variables (median long-term hip rotation primary outcome, non-FDO: −4°, FDO I-II: −4°, FDO III-IV: −5°), hip abduction test, fear of falling, and most pain measures despite anteversion being 29° greater in the non-FDO group. The FDO I-II group reported more falls than the non-FDO group. All groups improved on hip rotation, foot progression, and hip abductor strength. Speed and step length decreased/tended to decrease for all three groups. Hip abduction moment and gait deviation index did not change. Improvements in the FDO groups were maintained from short- to long-term.
These results challenge the notion that an FDO is necessary to correct mean stance hip rotation for higher functioning individuals since nearly identical results were achieved by adulthood in the non-FDO I-II group. However, an FDO provides improvement earlier and maintenance from short- to long-term. This should factor into the shared decision-making process.
Background: The Children's Oncology Group (COG) is the only National Cancer Institute–supported clinical trials organization focused exclusively on childhood and adolescent cancer research. The COG ...Nursing Discipline Committee has embedded the tenets of evidence-based practice (EBP) into clinical trials nursing in order to standardize the nursing care delivered to children enrolled on these trials. The COG nursing EBP initiative is aimed at developing evidence-based clinical resources and tools to provide guidance to clinicians regarding topics relevant to the provision of cancer treatment for patients enrolled on COG clinical trials from diagnosis through survivorship. A rigorous, evidence-based process designed to guide development of the evidence-based clinical tools and resources within the COG nursing discipline was developed and was implemented with the first nurse expert team beginning in 2012. Method: The standardized process included (a) selecting EBP projects and nursing expert teams (NETs), (b) providing leadership, mentoring, and championship for NETs; (c) approving clinical content developed through the NETs; and (d) providing guidance and oversight over planned dissemination of the COG EBP projects. Results: The COG Nursing EBP Subcommittee has developed 15 publications to date that include 90 authors. Eleven of these authors contributed to multiple publications. Discussion: On this 10th anniversary of the development of the EBP within the COG nursing discipline, we recognize its contributions to the professional growth of many of the discipline's members and to advances in nursing care for children enrolled in pediatric cancer clinical trials.
Assessments of lower limb torsion are ubiquitous in clinical gait analysis practice as pathologic lower limb rotational deformity may contribute to gait abnormalities, anterior knee pain, as well as ...other debilitating conditions. Understandably, the overall utility of any torsional assessment is dependent on the measurement method’s intrinsic accuracy, precision, and robustness to clinical interference factors. Recently, biplanar radiography (BPR) measurements of torsion have been shown to be both accurate and precise, but the robustness of BPR to potential interference factors is unknown.
How robust are BPR lower limb torsional assessments to six potential interference factors: amount of torsion, skeletal maturity, radiograph quality, prior osteotomy, presence of implants, and observer training background and experience?
In this retrospective cohort study, four observers of diverse backgrounds and experience generated digital 3D reconstructions of 44 lower limbs using BPR images obtained during standard of care visits (age range 7–35 years). From each reconstruction, four lower limb torsional parameters were computed: femoral torsion, femorotibial rotation, tibial torsion, and transmalleolar axis equivalent. The mean absolute deviation (MAD) of each torsional parameter – calculated across the four observers – was used as the measure of reliability and tested against all interference factors.
Results demonstrated that the average MAD was 2.1 degrees for femoral torsion, 3.0 degrees for transmalleolar axis equivalent, 3.8 degrees for femorotibial rotation, and 4.7 degrees for tibial torsion. None of the six potential interference factors were found to systematically influence BPR reliability across all four torsional parameters. Of the factors found to statistically influence one or more torsional parameter, none affected MAD values to a clinically meaningful extent.
In addition to being accurate and precise, BPR appears to be robust to several clinical factors relevant to children and young adults with or at risk for pathological lower limb torsion.
•Biplanar radiography produced reliable measurements of lower limb torsion.•Robustness was not systematically affected by any of the six interference factors.•Study utilized observers with diverse training background and experience.•Femoral anteversion and transmalleolar axis equivalent were the most reliable.
PDF
