Calibration of MAJIS (Moons And Jupiter Imaging Spectrometer). II. Spatial calibration.

MAJIS, Moons and Jupiter Imaging Spectrometer, is one of the scientific payloads aboard European Space Agency's Jupiter Icy Moons Explorer mission. This instrument underwent a comprehensive characterization and calibration campaign before integration on the spacecraft. In this work, we report on the measurements of the instrumental spatial responses, including the slit and pixel functions, the knife edge function, the ensquared energy, and the keystone aberration. The measurements were repeated in several positions of the field of view and within the range of MAJIS temperatures during science observations. The goal was to characterize the instrument's response under a wide set of conditions and at different visible-infrared wavelengths. The experimental setups employed to perform calibrations are described in detail, and the methodology applied to derive the instrumental spatial responses is discussed. After launch, minor changes in the instrument response and the coalignment between the two spectral channels were identified by comparing on-ground data with the first in-flight data returned by MAJIS.

Calibration of MAJIS (Moons And Jupiter Imaging Spectrometer). III. Spectral calibration.

The Moons And Jupiter Imaging Spectrometer (MAJIS) is the visible and near-infrared imaging spectrometer onboard the European Space Agency (ESA)'s Jupiter Icy Moons Explorer mission. Before its integration into the spacecraft, the instrument undergoes an extensive ground calibration to establish its baseline performances. This process prepares the imaging spectrometer for flight operations by characterizing the behavior of the instrument under various operative conditions and uncovering instrumental distortions that may depend on instrumental commands. Two steps of the on-ground calibration campaigns were held at the instrument level to produce the data. Additional in-flight measurements have recently been obtained after launch during the Near-Earth Commissioning Phase. In this article, we present the analyses of these datasets, focusing on the characterization of the spectral performances. First, we describe and analyze the spectral calibration datasets obtained using both monochromatic sources and polychromatic sources coupled with solid and gas samples. Then, we derive the spectral sampling and the spectral response function over the entire field of view. These spectral characteristics are quantified for various operational parameters of MAJIS, such as temperature and spectral binning. The derived on-ground performances are then compared with in-flight measurements obtained after launch and presented in the framework of the MAJIS performance requirements.

Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in children: guidance from the American Academy of Sleep Medicine.

The American Academy of Sleep Medicine commissioned a task force of clinical experts in pediatric sleep medicine to review published literature on performing the Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test for diagnosis and management of central disorders of hypersomnolence among children and adolescents. This paper follows a format similar to that of the paper "Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine" that was published in 2021. Since there is insufficient evidence to specify a recommended protocol for the Maintenance of Wakefulness Test in children and adolescents, this paper focuses only on the MSLT protocol. This protocol paper provides guidance to health care providers who order, sleep specialists who interpret, and technical staff who administer the MSLT to pediatric patients. Similar to the adult protocol paper, this document provides guidance based on pediatric expert consensus and evidence-based data when available. Topics include patient preparation, evaluation of medication and substance use, sleep needs before testing, scheduling considerations, optimal test conditions for youth, and documentation. Specific changes recommended for pediatric MSLT protocols include (1) provision of a minimum of 7 hours of sleep (with a minimum 8-hour recording time) on polysomnography the night before the MSLT, ideally meeting age-based needs; (2) use of clinical judgment to guide the need for sleep-disordered breathing treatments before polysomnography-MSLT testing; and (3) shared patient-health care provider decision-making regarding modifications in the protocol for children and adolescents with neurodevelopmental/neurological disorders, young age, and/or delayed sleep phase. CITATION: Maski KP, Amos LB, Carter JC, Koch EE, Kazmi U, Rosen CL. Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in children: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 2024;20(4):631-641.

Clinical, economic, and humanistic burden of community acquired pneumonia in Europe: a systematic literature review.

BACKGROUND: Community-acquired pneumonia (CAP) is an infectious lung inflammation contracted outside the hospital. CAP is a leading cause of death among young children, elderly, and immunocompromised persons. Incidence can reach 14 cases/1,000 adults. Up to 50% of cases require inpatient hospitalization. Mortality is 0.7/1,000 cases or 4 million deaths per year. We sought to summarize multi-dimensional burden of CAP for selected European countries. METHODS: We conducted a systematic literature review of literature published from 2011 to 2021 whereby we sought information pertaining to the epidemiologic, clinical, economic, and humanistic burden of CAP. Findings were summarized descriptively. RESULTS: CAP incidence in Europe is variable, with the highest burden among those of advanced age and with chronic comorbidities. Etiology is primarily bacterial infection with Streptococcus pneumoniae being the most frequently implicated. Direct medical costs are primarily attributable to inpatient stay, which is exacerbated among high-risk populations. Higher mortality rates are associated with increasing age, the need for inpatient hospitalization, and antibiotic resistance. CONCLUSIONS: A better understanding of CAP is needed, specifically the economic and quality of life burden on patients and caregivers. We recommend further assessments using population-level and real-world data employing consistent disease definitions.

Short Sequence Aligner Benchmarking for Chromatin Research.

Much of today's molecular science revolves around next-generation sequencing. Frequently, the first step in analyzing such data is aligning sequencing reads to a reference genome. This step is often taken for granted, but any analysis downstream of the alignment will be affected by the aligner's ability to correctly map sequences. In most cases, for research into chromatin structure and nucleosome positioning, ATAC-seq, ChIP-seq, and MNase-seq experiments use short read lengths. How well aligners manage these reads is critical. Most aligner programs will output mapped reads and unmapped reads. However, from a biological point of view, reads will fall into one of three categories: correctly mapped, incorrectly mapped, and unmapped. While increased sequencing depth can often compensate for unmapped reads, incorrectly and correctly mapped reads appear algorithmically identical but can produce biologically significant alterations in the results. For this reason, we are benchmarking various alignment programs to determine their propensity to incorrectly map short reads. As short-read alignment is an important step in ATAC-seq, ChIP-seq, and MNase-seq experiments, caution should be taken in mapping reads to ensure that the most accurate conclusions can be made from the data generated. Our analysis is intended to help investigators new to the field pick the alignment program best suited for their experimental conditions. In general, the aligners we tested performed well. BWA, Bowtie2, and Chromap were all exceptionally accurate, and we recommend using them. Furthermore, we show that longer read lengths do in fact lead to more accurate mappings.

Cost-effectiveness of terlipressin for hepatorenal syndrome: the United States hospital perspective.

BACKGROUND: Hepatorenal syndrome (HRS) is characterized by severely reduced renal perfusion that precipitates rapid morbidity and mortality. Terlipressin is the only US Food and Drug Administration-approved treatment to improve kidney function for adults with HRS with a rapid reduction in kidney function. Prior to the approval of terlipressin, unapproved vasoconstrictive agents used in HRS treatment were octreotide/midodrine and norepinephrine with albumin. METHODS: A cohort decision-tree model representing a US hospital perspective assessed the clinical outcomes and direct medical costs (based primarily on hospital charges) of treating HRS with terlipressin + albumin (ALB) versus midodrine/octreotide (MID/OCT)+ALB, or norepinephrine (NorEp)+ALB. Treatment efficacy was defined by clinical response (complete/HRS reversal, partial, or no response) based on change of serum creatinine derived from published clinical trial reports. The proportions of patients with complete response were: terlipressin + ALB (36.2%), NorEp + ALB (19.1%), and MID/OCT + ALB (3.1%). Model outcomes included utilization of HRS-related healthcare resources (hospital and intensive care, outpatient and emergency department, dialysis, and transplantations), adverse events, and HRS-related mortality. Outcomes were assessed for the initial hospitalization in the base case and at 30, 60, and 90 days post-discharge. RESULTS: Total costs incurred over the initial hospitalization with terlipressin + ALB were lower vs NorEp + ALB, primarily due to higher ICU costs with NorEp + ALB ($7,433 vs $61,897). TER + ALB was associated with higher total costs vs MID/OCT + ALB due to higher pharmacy costs with terlipressin + ALB. The cost per complete response achieved of terlipressin + ALB ($451,605) was half that of NorEp + ALB ($930,571) and one-tenth that of MID/OCT + ALB ($4,942,123). CONCLUSIONS: HRS patients treated with terlipressin experienced better clinical outcomes and a lower cost per treatment response vs other unapproved treatments. ICU days and pharmacy costs were key cost drivers distinguishing the treatment groups. These outcomes suggest that terlipressin is cost-effective on the basis of total cost per response achieved.

Hepatorenal syndrome (HRS) is a rare and sudden life-threatening complication of the liver. Patients with HRS should receive immediate treatment with a drug that narrows blood vessels known as a vasoconstrictor. Terlipressin is the most common vasoconstrictor used for patients with HRS. Other common vasoconstrictors are midodrine with octreotide and norepinephrine. This study aimed to compare the cost of terlipressin with those of midodrine with octreotide and norepinephrine while also considering how well each of them worked to reverse HRS. This was done using an economic model. This economic model assessed the costs of the vasoconstrictor drugs and the costs of treating HRS, including costs attributable to drug acquisition, adverse events, organ transplantation, dialysis, and institutional encounters (i.e. hospitalization, ICU, emergency department, and outpatient visits). The magnitude of these costs depends on how well each drug reversed HRS. Based on inputs derived from their respective clinical trials, 36% of patients who were given terlipressin had a complete response (HRS was reversed), 19% of patients who were given norepinephrine had a complete response, and 3% of patients who were given midodrine with octreotide had a complete response. The total cost per patient was approximately $163,481 for terlipressin, $177,298 for norepinephrine, and $155,030 for midodrine with octreotide. When the costs were evaluated against how well the drugs worked to reverse HRS, the lowest cost per HRS reversal was $451,605 when treated with terlipressin. The cost per reversal for norepinephrine was $930,571 and for midodrine with octreotide was $4,942,123. These results show that terlipressin works well and is more cost-effective for US hospitals compared with the other unapproved treatment options for HRS with rapid reduction in kidney function.

False positive urine amphetamine immunoassay due to solriamfetol.

Solriamfetol is a schedule IV-controlled substance used to treat excessive daytime sleepiness resulting from narcolepsy or obstructive sleep apnea. We present a patient prescribed solriamfetol who tested positive for amphetamines on a routine urinary toxicology screen despite patient denial of illicit drug use, raising the possibility of a false positive amphetamine screen. Spiking studies were performed on negative urine, and different concentrations of solriamfetol drug on 2 different amphetamine assays: the commonly used Beckman Emit® II Plus Amphetamines Assay, and the Citrine™ Triple Quad™ MS/MS Systems. The Beckman yielded positive results for amphetamines at solriamfetol concentrations of 200 µg/mL and 2000 µg/mL and negative results at 0.2 µg/mL and 2 µg/mL. However, the Citrine™ Triple Quad™ MS/MS Systems was negative at all concentrations. The Beckman Emit® II Plus Amphetamine Assay gave false positive results for amphetamines due to solriamfetol drug usage, a finding of relevance to prescribers of solriamfetol.

Manipulating chromatin architecture in C. elegans.

BACKGROUND: Nucleosome-mediated chromatin compaction has a direct effect on the accessibility of trans-acting activators and repressors to DNA targets and serves as a primary regulatory agent of genetic expression. Understanding the nature and dynamics of chromatin is fundamental to elucidating the mechanisms and factors that epigenetically regulate gene expression. Previous work has shown that there are three types of canonical sequences that strongly regulate nucleosome positioning and thus chromatin accessibility: putative nucleosome-positioning elements, putative nucleosome-repelling sequences, and homopolymeric runs of A/T. It is postulated that these elements can be used to remodel chromatin in C. elegans. Here we show the utility of such elements in vivo, and the extreme efficacy of a newly discovered repelling sequence, PRS-322. RESULTS: In this work, we show that it is possible to manipulate nucleosome positioning in C. elegans solely using canonical and putative positioning sequences. We have not only tested previously described sequences such as the Widom 601, but also have tested additional nucleosome-positioning sequences: the Trifonov sequence, putative repelling sequence-322 (PRS-322), and various homopolymeric runs of A and T nucleotides. CONCLUSIONS: Using each of these types of putative nucleosome-positioning sequences, we demonstrate their ability to alter the nucleosome profile in C. elegans as evidenced by altered nucleosome occupancy and positioning in vivo. Additionally, we show the effect that PRS-322 has on nucleosome-repelling and chromatin remodeling.

Negative Ulnar Variance Lessens DRUJ Instability After DRUJ Disruption: A Biomechanical Analysis.

BACKGROUND: The purpose of this study was to perform a biomechanical investigation on the effect of ulnar variance (UV) on the stability of the distal radioulnar joint (DRUJ) prior to and after DRUJ sectioning. METHODS: Ten cadaveric forearm specimens were included in the study and baseline UV was assessed radiographically. Radial motion relative to the ulna was evaluated using Intel real sense cameras and a custom developed program. The forearms were dissected, and a radial osteotomy was performed. Using a custom-made plate, radial stability was assessed with an UV of + 4, 0, and -4 mm by measuring the maximum and minimum radial position relative to the ulna during a simulated Shuck test. The volar radioulnar ligaments and triangular fibrocartilage complex (TFCC) were then sectioned, and testing was repeated at each UV state. RESULTS: Sectioning significantly increased radial translation at neutral (P = .008), +4 mm UV (P = .008), and -4 mm UV (P = .018). There were no significant differences in translation between the 3 UV groups with the DRUJ intact (P = .124). The ulnar negative (-4 mm) state had significantly lower translation compared to the positive (+4 mm) (P < .001) and the neutral (0 mm) (P = .026) UV states. There were no significant differences between the positive and neutral UV groups with the DRUJ sectioned. CONCLUSIONS: Fixating the radius in -4 mm of ulnar negativity significantly decreased radial translation after sectioning the volar radioulnar ligament and TFCC. Ulnar variance had no effect on stability with an intact DRUJ. STUDY TYPE: Biomechanical Study.

Efficacy of expansion pharyngoplasty and hypoglossal nerve stimulation in treating sleep apnea.

OBJECTIVE: We investigated whether a palatal conversion procedure combined with a second-stage hypoglossal nerve stimulator (HGNS) insertion can be beneficial for those patients who have a complete concentric velopharyngeal collapse and may initially not meet the criteria for use of HGNS. METHODS: A retrospective chart review included all patients who underwent a planned multi-level sleep surgery including expansion sphincter pharyngoplasty (ESP) followed by HGNS. All patients had a complete concentric collapse (CCC) of the velopharynx (VP) on pre-intervention drug-induced sleep endoscopy (DISE) and were initially not a candidate for HGNS. These patients then underwent ESP followed by a DISE to confirm elimination of the CCC of the VP. They then went on to HGNS implantation several months later followed by a sleep study. RESULTS: A total of 20 patients were identified and included in the retrospective chart analysis. All patients who underwent ESP successfully converted their VP from CCC to an anterior-posterior collapse pattern and thus met inclusion criteria for HGNS. After the HGNS was implanted, patients showed a significant reduction of the mean AHI from 53.9 before ESP to 8.2 after ESP and HGNS and a decrease in the Epworth Sleep Score (ESS) from a mean of 13.3 to 5.7. CONCLUSION: ESP can be effective in eliminating the CCC of the VP thus making patients become HGNS candidates. In selected OSA patients, who have multilevel upper airway obstruction with complete concentric VP collapse, the combination of ESP and HGNS insertion should be considered as a planned 2-staged approach.

Calibration and performances of the MicrOmega instrument for the characterization of asteroid Ryugu returned samples.

MicrOmega, a miniaturized near-infrared hyperspectral microscope, has been selected to characterize in the laboratory the samples returned from Ryugu by the Hayabusa2 mission. MicrOmega has been delivered to the Extraterrestrial Samples Curation Center of the Japanese Aerospace eXploration Agency at the Institute of Space and Astronautical Science in July 2020 and then mounted and calibrated to be ready for the analyses of the samples returned to Earth on December 6, 2020. MicrOmega was designed to analyze the returned samples within a field of view of 5 × 5 mm2 and a spatial sampling of 22.5 µm. It acquires 3D near-infrared hyperspectral image-cubes by imaging the sample with monochromatic images sequentially covering the 0.99-3.65 µm spectral range, with a typical spectral sampling of 20 cm-1. This paper reports the calibration processes performed to extract scientific data from these MicrOmega image-cubes. The determination of the instrumental response and the spectral calibration is detailed. We meet or exceed the goals of achieving an accuracy of ∼20% for the absolute reflectance level, 1% for the relative wavelength-to-wavelength reflectance, and <5 nm for the peak position of the detected absorption features. For the nominal measurements of Ryugu samples with MicrOmega/Curation, the instrument performance also reaches a signal-to-noise ratio of >100 over the entire spectral range. By characterizing the entire collection of the returned samples at the microscopic scale, MicrOmega/Curation offers the potential to provide unprecedented insights into the composition and history of their asteroid parent body.

Budget Impact and Cost-Effectiveness of Intravenous Meloxicam to Treat Moderate-Severe Postoperative Pain.

INTRODUCTION: This study assesses the budget impact and cost-effectiveness of intravenous meloxicam (MIV) to treat moderate-severe acute postoperative pain in adults. METHODS: A two-part Markov cohort model captured the pharmacoeconomic impact of MIV versus non-opioid intravenous analgesics (acetaminophen, ibuprofen, ketorolac) among a hypothetical adult cohort undergoing selected inpatient procedures and experiencing moderate-severe acute postoperative pain: Part 1 (postoperative hour 0 to discharge, cycled hourly), health states were defined by pain level. Pain transition rates, adverse event probabilities, and concomitant opioid utilization were derived from a network meta-analysis. Part 2 (discharge to week 52, cycled weekly), health states were defined by the presence/absence of pain-related readmission and opioid use disorder as determined by literature-based inputs relating to pain control outcomes. Healthcare utilization and direct medical costs were derived from an administrative claims database analysis. Primary outcomes were the incremental cost per member per month (PMPM) and cost per quality-adjusted life year (QALY) gained. Scenario, univariate, and probabilistic sensitivity analyses were conducted. The model assumed a private payer perspective in the USA (no discounting, 2019 US$). RESULTS: Modeled outcomes indicated MIV was associated with lower accumulated postoperative pain, fewer adverse events, and less opioid utilization for most procedures and comparators, with longer-term outcomes also generally favoring MIV. The budget impact of MIV was - $0.028 PMPM. From a cost-effectiveness perspective, MIV had lower costs and better outcomes for all comparisons except against ketorolac in orthopedic procedures where the former was cost-effective but not cost saving ($95,925/QALY). Scenario and sensitivity analyses indicated that modeled outcomes were robust to alternative inputs and underlying input uncertainty. Differences in direct medical costs were driven by reduced costs attributable to length of stay and opioid-related adverse drug events. CONCLUSION: MIV was associated with modeled clinical and economic benefits compared to commonly used non-opioid intravenous analgesics.

Cardiorespiratory management of Duchenne muscular dystrophy: emerging therapies, neuromuscular genetics, and new clinical challenges.

The life-limiting complications of Duchenne muscular dystrophy (DMD) include loss of lung function and progressive cardiomyopathy; when patients are treated with assisted ventilation, cardiac function becomes the main determinant of survival. Therapy for DMD is changing rapidly, with the emergence of new genetic and molecular therapeutic options, the proliferation of which has fostered the perception that DMD is a potentially curable disease. However, data for respiratory and cardiac outcomes are scarce and available evidence is not uniformly positive. Patients who share a dystrophin (DMD) genotype can have highly divergent cardiorespiratory phenotypes; genetic modifiers of DMD gene expression are a probable cause of respiratory and cardiac phenotypic variability and discordance. In this Personal View, we provide an overview of new and emerging DMD therapies, highlighting the limitations of current research and considering strategies to incorporate cardiorespiratory assessments into clinical trials. We explore how genetic modifiers could be used to predict cardiorespiratory natural history and how manipulation of such modifiers might represent a promising therapeutic strategy. Finally, we examine the changing role of respiratory physicians, cardiologists, and intensive care clinicians on the frontline of a challenging new clinical landscape.

Assessing the value of orphan drugs using conventional cost-effectiveness analysis: Is it fit for purpose?

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward.

Multi-modality machine learning predicting Parkinson's disease.

Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available.

Thyrotoxic periodic paralysis (TPP): assessment in the emergency department.

A male patient aged in his early twenties presented to the emergency department (ED) with quadriparesis. He was ordinarily fit and well and had exercised and eaten a carbohydrate rich meal the evening before. His point-of-care venous blood sample on arrival to the ED showed hypokalaemia of 1.6 mmol/L. (normal range=3.5-5.0 mmol/L). He was put on a cardiac monitor and started on an intravenous infusion of potassium chloride. With the benefit of hindsight, his male sex, particular features in his history and his initial ECG all pointed to a differential diagnosis of thyrotoxic periodic paralysis (TPP), although a differential diagnosis of a first attack of familial hypokalaemic paralysis was considered. As urgent thyroid function tests were sent promptly, there was minimal delay in reaching a diagnosis of TPP and promptly starting propranolol as a safe and more effective means of reversing TPP, followed by definitive treatment with carbimazole.

Pharmacogenomic alerts: Developing guidance for use by healthcare professionals.

AIMS: For diseases with a genetic cause, genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age, it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. METHODS: The Professional Record Standards Body commissioned by NHS England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. RESULTS: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. CONCLUSION: Ensuring pharmacogenetics information is available to make safer use of medicines will require a major effort, of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and at the right times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing.