Comparative mitochondrial genomics in Nematoda reveal astonishing variation in compositional biases and substitution rates indicative of multi-level selection.

BACKGROUND: Nematodes are the most abundant and diverse metazoans on Earth, and are known to significantly affect ecosystem functioning. A better understanding of their biology and ecology, including potential adaptations to diverse habitats and lifestyles, is key to understanding their response to global change scenarios. Mitochondrial genomes offer high species level characterization, low cost of sequencing, and an ease of data handling that can provide insights into nematode evolutionary pressures. RESULTS: Generally, nematode mitochondrial genomes exhibited similar structural characteristics (e.g., gene size and GC content), but displayed remarkable variability around these general patterns. Compositional strand biases showed strong codon position specific G skews and relationships with nematode life traits (especially parasitic feeding habits) equal to or greater than with predicted phylogeny. On average, nematode mitochondrial genomes showed low non-synonymous substitution rates, but also high clade specific deviations from these means. Despite the presence of significant mutational saturation, non-synonymous (dN) and synonymous (dS) substitution rates could still be significantly explained by feeding habit and/or habitat. Low ratios of dN:dS rates, particularly associated with the parasitic lifestyles, suggested the presence of strong purifying selection. CONCLUSIONS: Nematode mitochondrial genomes demonstrated a capacity to accumulate diversity in composition, structure, and content while still maintaining functional genes. Moreover, they demonstrated a capacity for rapid evolutionary change pointing to a potential interaction between multi-level selection pressures and rapid evolution. In conclusion, this study helps establish a background for our understanding of the potential evolutionary pressures shaping nematode mitochondrial genomes, while outlining likely routes of future inquiry.

Entanglement Assisted Probe of the Non-Markovian to Markovian Transition in Open Quantum System Dynamics.

We utilize a superconducting qubit processor to experimentally probe non-Markovian dynamics of an entangled qubit pair. We prepare an entangled state between two qubits and monitor the evolution of entanglement over time as one of the qubits interacts with a small quantum environment consisting of an auxiliary transmon qubit coupled to its readout cavity. We observe the collapse and revival of the entanglement as a signature of quantum memory effects in the environment. We then engineer the non-Markovianity of the environment by populating its readout cavity with thermal photons to show a transition from non-Markovian to Markovian dynamics, ultimately reaching a regime where the quantum Zeno effect creates a decoherence-free subspace that effectively stabilizes the entanglement between the qubits.

Orthopedic surgery in Palau-Current capacity, needs, and future directions.

BACKGROUND: Palau, an island nation in Micronesia, is a medically underserved area with a shortage of specialty care services. Orthopedic diagnoses in Palau remain among the three most common reasons for costly off-island medical referral. The purpose of this study was to assess Palau's current orthopedic surgery capacity and needs to inform interventions to build capacity to improve care access and quality. METHODS: Orthopedic needs and capacity assessment tools developed by global surgical outreach experts were utilized to gather information and prompt discussions with a broad range of Palau's most knowledgeable stakeholders (n = 6). Results were reported descriptively. RESULTS: Finance, community impact, governance, and professional development were the lowest-scored domains from the Capacity Assessment Tool for orthopedic surgery (CAT-os), indicating substantial opportunity to build within these domains. According to administrators (n = 3), governance and finance were the greatest capacity-building priorities, followed by professional development and partnership. Belau National Hospital (BNH) had adequate surgical infrastructure. Skin grafting, soft tissue excision/resection, infection management, and amputation were the most commonly selected procedures by stakeholders reporting orthopedic needs. CONCLUSIONS: This study utilizes a framework for orthopedic capacity-building in Palau which may inform partnership between Palau's healthcare system and orthopedic global outreach organizations with the goal of improving the quality, safety, and value of the care delivered. This demonstration of benchmarking, implementation planning, and subsequent re-evaluation lays the foundation for the understanding of capacity-building and may be applied to other medically underserved areas globally to improve access to high-quality orthopedic care.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Poly(dimethylsiloxane) as a room-temperature solid solvent for photophysics and photochemistry.

Medium viscosity strongly affects the dynamics of solvated species and can drastically alter the deactivation pathways of their excited states. This study demonstrates the utility of poly(dimethylsiloxane) (PDMS) as a room-temperature solid-state medium for optical spectroscopy. As a thermoset elastic polymer, PDMS is transparent in the near ultraviolet, visible, and near infrared spectral regions. It is easy to mould into any shape, forming surfaces with a pronounced smoothness. While PDMS is broadly used for the fabrication of microfluidic devices, it swells in organic solvents, presenting severe limitations for the utility of such devices for applications employing non-aqueous fluids. Nevertheless, this swelling is reversible, which proves immensely beneficial for loading samples into the PDMS solid matrix. Transferring molecular-rotor dyes (used for staining prokaryotic cells and amyloid proteins) from non-viscous solvents into PDMS induces orders-of-magnitude enhancement of their fluorescence quantum yield and excited-state lifetimes, providing mechanistic insights about their deactivation pathways. These findings demonstrate the unexplored potential of PDMS as a solid solvent for optical applications.

Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

Enhancing Faculty Development Through Compiled Verbal Feedback on Clinical Teaching From Trainees.

OBJECTIVE: Feedback from fellows-in-training (FITs) is important for faculty development and to enrich clinical teaching. We sought to evaluate the effectiveness of traditional online evaluations and a novel compiled verbal feedback mechanism. METHODS: An annual feedback system was implemented in our rheumatology division in which FITs provided verbal feedback on all faculty to a facilitator who compiled, deidentified, and shared the feedback with individual faculty members. FITs also completed standard online annual evaluations of faculty. FITs and faculty completed surveys assessing the perceived effectiveness and confidentiality of each feedback mechanism. RESULTS: Thirteen of 15 eligible faculty and all 4 eligible FITs completed both surveys. Responses by FITs and faculty regarding the quality of online evaluations were generally unfavorable or neutral. Faculty responses regarding compiled verbal feedback were more favorable in all questions and significantly more favorable with respect to the feedback's ability to explain strengths (54% favorable for online evaluations vs 100% for compiled verbal feedback), the feedback's specificity (0% vs 54%), and the feedback's actionable nature (15% vs 62%). All FITs' responses regarding quality of compiled verbal feedback were favorable. FITs had concerns regarding confidentiality with both online evaluations (0% favorable) and compiled verbal feedback (25% favorable), though FITs had less concern for future faculty interactions with compiled verbal feedback (100% favorable) than with online evaluations (0% favorable). CONCLUSION: Compiled verbal feedback by FITs produced more actionable and effective feedback for faculty, with less concerns regarding future faculty interactions compared with traditional online evaluations. Further study of this method across different programs and institutions is warranted.

Complications Have Not Improved With Newer Generation Robots.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The purpose of this study was to see whether upgrades in newer generation robots improve safety and clinical outcomes following spine surgery. METHODS: All patients undergoing robotic-assisted spine surgery with the Mazor X Stealth EditionTM (Medtronic, Minneapolis, MN) from 2019 to 2022 at a combined orthopedic and neurosurgical spine service were retrospectively reviewed. Robot related complications were recorded. RESULTS: 264 consecutive patients (54.1% female; age at time of surgery 63.5 ± 15.3 years) operated on by 14 surgeons were analyzed. The average number of instrumented levels with robotics was 4.2 ± 2.7, while the average number of instrumented screws with robotics was 8.3 ± 5.3. There was a nearly 50/50 split between an open and minimally invasive approach. Six patients (2.2%) had robot related complications. Three patients had temporary nerve root injuries from misplaced screws that required reoperation, one patient had a permanent motor deficit from the tap damaging the L1 and L2 nerve roots, one patient had a durotomy from a misplaced screw that required laminectomy and intra-operative repair, and one patient had a temporary sensory L5 nerve root injury from a drill. Half of these complications (3/6) were due to a reference frame error. In total, four patients (1.5%) required reoperation to fix 10 misplaced screws. CONCLUSION: Despite newer generation robots, robot related complications are not decreasing. As half the robot related complications result from reference frame errors, this is an opportunity for improvement.

Multivalent, asymmetric IL-2-Fc fusions show enhanced selectivity for regulatory T cells.

The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (Treg) cells. IL-2 receptors consist of combinations of α, ß, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively Treg-selective, high-affinity receptor while reducing binding to the less selective, low-affinity receptor. However, we found that refining the designs to focus on targeting the high-affinity receptor through avidity effects is key to optimizing Treg selectivity. We profiled the dynamics and dose dependency of signaling responses in primary human immune cells induced by engineered fusions composed of either wild-type IL-2 or mutant forms with altered affinity, valency, and fusion to the antibody Fc region for stability. Treg selectivity and signaling response variations were explained by a model of multivalent binding and dimer-enhanced avidity-a combined measure of the strength, number, and conformation of interaction sites-from which we designed tetravalent IL-2-Fc fusions that had greater Treg selectivity in culture than do current designs. Biasing avidity toward IL2Rα with an asymmetrical multivalent design consisting of one α/ß chain-binding and one α chain-binding mutant further enhanced Treg selectivity. Comparative analysis revealed that IL2Rα was the optimal cell surface target for Treg selectivity, indicating that avidity for IL2Rα may be the optimal route to producing IL-2 variants that selectively target Tregs.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

Canadian healthcare workers' mental health and health behaviours during the COVID-19 pandemic: results from nine representative samples between April 2020 and February 2022.

OBJECTIVE: In the context of COVID-19, Canadian healthcare workers (HCWs) worked long hours, both to respond to the pandemic and to compensate for colleagues who were not able to work due to infection and burnout. This may have had detrimental effects on HCWs' mental health, as well as engagement in health-promoting behaviours. This study aimed to identify changes in mental health outcomes and health behaviours experienced by Canadian HCWs throughout the COVID-19 pandemic. METHODS: Nine representative samples (Ntotal = 1615 HCWs) completed the iCARE survey using an online polling firm between April 2020 (Time 1) and February 2022 (Time 9). Participants were asked about the psychological effects of COVID-19 (e.g., feeling anxious) and about changes in their health behaviours (e.g., alcohol use, physical activity). RESULTS: A majority of the HCWs identified as female (65%), were younger than 44 years old (66%), and had a university degree (55%). Female HCWs were more likely than male HCWs to report feeling anxious (OR = 2.68 [1.75, 4.12]), depressed (OR = 1.63 [1.02, 2.59]), and irritable (OR = 1.61 [1.08, 2.40]) throughout the first two years of the pandemic. Female HCWs were more likely than their male counterparts to report eating more unhealthy diets (OR = 1.54 [1.02, 2.31]). Significant differences were also revealed by age, education level, income, parental status, health status, and over time. CONCLUSION: Results demonstrate that the impacts of COVID-19 on HCWs' mental health and health behaviours were significant, and varied by sociodemographic characteristics (e.g., sex, age, income).

RéSUMé: OBJECTIF: Dans le contexte de la COVID-19, les travailleurs de la santé canadiens ont travaillé de longues heures, à la fois pour répondre à la pandémie et pour compenser pour les collègues qui n'étaient pas en mesure de travailler en raison d'infection et d'épuisement professionnel. Cela a pu générer un important impact sur leur santé mentale, ainsi que sur leurs engagements dans des comportements favorables à la santé. MéTHODES: Neuf échantillons représentatifs (Ntotal = 1 615 travailleurs de la santé) ont répondu à l'enquête iCARE par l'intermédiaire d'une compagnie de sondage en ligne entre avril 2020 (temps 1) et février 2022 (temps 9). Les participants ont été interrogés sur les effets psychologiques de la COVID-19 (p.ex., le sentiment d'anxiété) et sur les changements dans leurs comportements de santé (p.ex., la consommation d'alcool, l'activité physique). RéSULTATS: La majorité des travailleurs de santé répondants sont des femmes (65 %), ont moins de 44 ans (66 %) et ont un diplôme universitaire (55 %). Les femmes travailleuses de la santé étaient plus susceptibles de se sentir anxieuses (OR = 2,68 [1,75, 4,12]), déprimées (OR = 1,63 [1,02, 2,59) et irritables (OR = 1,61 [1,08, 2,40]) que les hommes au cours des deux premières années de la pandémie. Les femmes travailleuses de la santé étaient plus susceptibles d'avoir une alimentation plus malsaine (OR = 1,54 [1,02, 2,31]) que leurs homologues masculins. Des différences significatives ont également été révélées selon l'âge, le niveau d'éducation, le revenu, le statut parental, l'état de santé et à travers le temps. CONCLUSION: Les résultats démontrent que les impacts de COVID-19 sur la santé mentale et les comportements de santé des travailleurs de santé sont significatifs, mais varient selon les caractéristiques sociodémographiques (p.ex., le sexe, l'âge, le revenu).

An Atypical Presentation of Early Periprosthetic Infection After Cervical Disc Arthroplasty: A Case Report.

CASE: A 22-year-old woman with Klippel-Feil syndrome who underwent cervical disc arthroplasty (CDA) presented 3 months postoperatively with worsening neck pain and radiculopathy. Work-up was negative for infection, but single-photon emission computed tomography revealed increased metabolic activity in the vertebral body below the implant. During revision, the implant was grossly loose and multiple cultures grew Cutibacterium acnes. She was treated with an antibiotic course and conversion to anterior fusion without recurrence. CONCLUSION: This report highlights the rare presentation of an early periprosthetic infection after CDA caused by C. acnes.

Steroid sparing in vasculitis: Myth or reality?

Glucocorticoids are the cornerstone of therapy for all forms of vasculitis. However, glucocorticoid treatment carries with it the risk of glucocorticoid toxicity. Recent research efforts in vasculitis have emphasized investigation into strategies that reduce glucocorticoid exposure. These strategies include the adoption of rapid-acting steroid-sparing agents, reduced-dose glucocorticoid induction regimens, the early introduction of steroid-sparing agents for maintenance therapy, and the extension of maintenance therapy to minimize glucocorticoid exposure associated with disease relapse. These are critical advances to move us toward the goal of glucocorticoid-free treatment of vasculitis. The evidence supporting each of these strategies and directions for future research are explored.

Ear, Nose, and Throat Manifestations of Vasculitis and Other Systemic Autoimmune Diseases: Otologic, Sinus, and Airway.

Auricular, nasal, and laryngeal manifestations occur frequently in rheumatic diseases. Inflammatory ear, nose, and throat (ENT) processes often result in organ damage and have profound effects on quality of life. Herein, we review the otologic, nasal, and laryngeal involvement of rheumatic diseases, focusing on their clinical presentation and diagnosis. ENT manifestations generally respond to treatment of the systemic disease, which is outside the scope of this review; however, adjunctive topical and surgical treatment approaches, as well as treatment of idiopathic inflammatory ENT manifestations will be reviewed.

Myeloproliferative neoplasms - blurring the lines between cancer and chronic inflammatory disorder.

Myeloproliferative Neoplasm (MPN) is a group of chronic blood cancers that arise from a hematopoietic stem cell (HSC) clone with somatic mutations causing constitutive activation of myeloid cytokine receptor signaling. In addition to elevated blood cell counts, MPN typically presents with increased inflammatory signaling and inflammation symptoms. Therefore, while being a clonally derived neoplasm, MPN has much in common with chronic non-cancerous inflammatory conditions, such as rheumatoid arthritis, lupus, and many more. MPN and chronic inflammatory disease (CID) share similar chronicity, symptoms, dependency on the immune system, environmental triggers, and treatments. Overall, we will highlight the similarities between an MPN and CID. We highlight that while MPN is classified as a cancer, its behavior is more aligned to that of a chronic inflammatory disease. We propose that MPN should inhabit a fluid/spectrum between auto-inflammatory disease and cancer.

18S-NemaBase: Curated 18S rRNA Database of Nematode Sequences.

Nematodes are the most abundant and diverse animals on the planet but lack representation in biodiversity research. This presents a problem for studying nematode diversity, particularly when molecular tools (i.e., barcoding and metabarcoding) rely on well-populated and curated reference databases, which are absent for nematodes. To improve molecular identification and the assessment of nematode diversity, we created and curated an 18S rRNA database specific to nematodes (18S-NemaBase) using sequences sourced from the most recent publicly available 18S rRNA SILVA v138 database. As part of the curation process, taxonomic strings were standardized to contain a fixed number of taxonomic ranks relevant to nematology and updated for the most recent accepted nematode classifications. In addition, apparent erroneous sequences were removed. To test the efficacy and accuracy of 18S-NemaBase, we compared it to an older but also curated SILVA v111 and the newest SILVA v138 by assigning taxonomies and analyzing the diversity of a nematode dataset from the Western Nebraska Sandhills. We showed that 18S-NemaBase provided more accurate taxonomic assignments and diversity assessments than either version of SILVA, with a much easier workflow and no need for manual corrections. Additionally, observed diversity further improved when 18S-NemaBase was supplemented with reference sequences from nematodes present in the study site. Although the 18S-NemaBase is a step in the right direction, a concerted effort to increase the number of high-quality, accessible, full-length nematode reference sequences is more important now than ever.