Video-assisted thoracic surgery and robotic-assisted first-rib excision and thoracic outlet syndrome decompression.

Multiple surgical approaches have been used in the management of thoracic outlet syndrome. These approaches have traditionally been "open" approaches and have been associated with the inherent morbidities of an open approach, including a risk of injury to the neurovascular structures due to traction and trauma while resecting the first rib. In addition, there has been concern that recurrence of symptoms may be related to incomplete resection of the rib with conventional open techniques. With the advent of minimally invasive thoracic surgery, surgeons began to explore first-rib resection via a thoracoscopic approach. Unfortunately, the existing video-assisted thoracic surgery technology and equipment was not well suited to working in the apex of the chest. With the introduction and subsequent progress in robotic surgery and instrumentation, this dissection can be performed with all the advantages of robotics, but also with minimal traction and trauma to the neurovascular structures, and incorporates almost complete resection of the rib with minimal residual stump. Robotics has developed as a reliable, safe, and less invasive approach to first-rib resection, yielding excellent results while limiting the morbidity of the procedure.

Potassium rhythms couple the circadian clock to the cell cycle.

Circadian (~24 h) rhythms are a fundamental feature of life, and their disruption increases the risk of infectious diseases, metabolic disorders, and cancer1-6. Circadian rhythms couple to the cell cycle across eukaryotes7,8 but the underlying mechanism is unknown. We previously identified an evolutionarily conserved circadian oscillation in intracellular potassium concentration, [K+]i9,10. As critical events in the cell cycle are regulated by intracellular potassium11,12, an enticing hypothesis is that circadian rhythms in [K+]i form the basis of this coupling. We used a minimal model cell, the alga Ostreococcus tauri, to uncover the role of potassium in linking these two cycles. We found direct reciprocal feedback between [K+]i and circadian gene expression. Inhibition of proliferation by manipulating potassium rhythms was dependent on the phase of the circadian cycle. Furthermore, we observed a total inhibition of cell proliferation when circadian gene expression is inhibited. Strikingly, under these conditions a sudden enforced gradient of extracellular potassium was sufficient to induce a round of cell division. Finally, we provide evidence that interactions between potassium and circadian rhythms also influence proliferation in mammalian cells. These results establish circadian regulation of intracellular potassium levels as a primary factor coupling the cell- and circadian cycles across diverse organisms.

Timely Questions Emerging in Chronobiology: The Circadian Clock Keeps on Ticking.

Chronobiology investigations have revealed much about cellular and physiological clockworks but we are far from having a complete mechanistic understanding of the physiological and ecological implications. Here we present some unresolved questions in circadian biology research as posed by the editorial staff and guest contributors to the Journal of Circadian Rhythms. This collection of ideas is not meant to be comprehensive but does reveal the breadth of our observations on emerging trends in chronobiology and circadian biology. It is amazing what could be achieved with various expected innovations in technologies, techniques, and mathematical tools that are being developed. We fully expect strengthening mechanistic work will be linked to health care and environmental understandings of circadian function. Now that most clock genes are known, linking these to physiological, metabolic, and developmental traits requires investigations from the single molecule to the terrestrial ecological scales. Real answers are expected for these questions over the next decade. Where are the circadian clocks at a cellular level? How are clocks coupled cellularly to generate organism level outcomes? How do communities of circadian organisms rhythmically interact with each other? In what way does the natural genetic variation in populations sculpt community behaviors? How will methods development for circadian research be used in disparate academic and commercial endeavors? These and other questions make it a very exciting time to be working as a chronobiologist.

Axial Spondyloarthritis: Does Magnetic Resonance Imaging Classification Improve Report Interpretation.

OBJECTIVE: The interpretation of magnetic resonance imaging (MRI) reports is crucial for the diagnosis of axial spondyloarthritis, but the subjective nature of narrative reports can lead to varying interpretations. This study presents a validation of a novel MRI reporting system for the sacroiliac joint in clinical practice. METHODS: A historical review was conducted on 130 consecutive patients referred by 2 rheumatologists for initial MRI assessment of possible axial spondyloarthritis. The original MRI reports were interpreted by the rheumatologists and the radiologist who originally read the images and then categorized according to the novel system. Two musculoskeletal radiologists then reinterpreted the original MRI scans using the new system, and the resulting reports were interpreted and categorized by the same rheumatologists. The quality of the new framework was assessed by comparing the interpretations of both reports. RESULTS: Ninety-two patients met the study criteria. The rheumatologists disagreed on the categorization of the original MRI reports in 12% of cases. The rheumatologists and original radiologists disagreed on the categorization of the initial report in 23.4% of cases. In contrast, there was 100% agreement between the rheumatologists and radiologists on the categorization of the new MRI report. CONCLUSION: The new MRI categorization system significantly improved the agreement between the clinician and radiologist in report interpretation. The system provided a standard vocabulary for reporting, reduced variability in report interpretation, and may therefore improve clinical decision-making.

Lung-Mimetic Hydrofoam Sealant to Treat Pulmonary Air Leak.

Pulmonary air leak is the most common complication of lung surgery, contributing to post-operative morbidity in up to 60% of patients; yet, there is no reliable treatment. Available surgical sealants do not match the demanding deformation mechanics of lung tissue; and therefore, fail to seal air leak. To address this therapeutic gap, a sealant with structural and mechanical similarity to subpleural lung is designed, developed, and systematically evaluated. This "lung-mimetic" sealant is a hydrofoam material that has alveolar-like porous ultrastructure, lung-like viscoelastic properties (adhesive, compressive, tensile), and lung extracellular matrix-derived signals (matrikines) to support tissue repair. In biocompatibility testing, the lung-mimetic sealant shows minimal cytotoxicity and immunogenicity in vitro. Human primary monocytes exposed to sealant matrikines in vitro upregulate key genes (MARCO, PDGFB, VEGF) known to correlate with pleural wound healing and tissue repair in vivo. In rat and swine models of pulmonary air leak, this lung-mimetic sealant rapidly seals air leak and restores baseline lung mechanics. Altogether, these data indicate that the lung-mimetic sealant can effectively seal pulmonary air leak and promote a favorable cellular response in vitro.

Benefits and barriers to return to education and relationship to quality of life for people living with spinal cord injury: Results of a mixed methods study.

CONTEXT: There is limited research on return to education (RTE) after spinal cord injury (SCI). As a result, few programs exist to help people achieve this goal. OBJECTIVE: The primary objective was to investigate the barriers and facilitators to RTE, and the relationship between RTE and quality of life (QOL). The secondary objective was to examine the role of a Vocational Resource Facilitation (VRF) program on RTE. METHODS: A mixed methods approach with a semi-structured interview and online survey was used. Participants included 15 people with SCI with RTE goals who received VRF services at an acute inpatient rehabilitation hospital. Qualitative responses on the barriers, facilitators and perceived benefits of RTE were analyzed using a grounded theory strategy. RESULTS: Barriers to RTE included physical and mental health, transportation, time, environmental barriers, finances, lack of knowledge about available resources, and discrimination. Facilitators to RTE included the VRF program, social support, financial support, virtual learning, organizational support, and policy constructs. People who RTE after SCI reported better QOL, less depressed mood than those who did not, and were more likely to have returned to work. CONCLUSIONS: This study highlighted common barriers and facilitators to RTE, and potential areas of intervention. VRF is a potentially efficacious early intervention vocational rehabilitation approach that improves participation in education and employment for people with SCI. People who received VRF and achieved RTE may have better QOL outcomes and improved employability.

Propylene glycol inactivates respiratory viruses and prevents airborne transmission.

Viruses are vulnerable as they transmit between hosts, and we aimed to exploit this critical window. We found that the ubiquitous, safe, inexpensive and biodegradable small molecule propylene glycol (PG) has robust virucidal activity. Propylene glycol rapidly inactivates a broad range of viruses including influenza A, SARS-CoV-2 and rotavirus and reduces disease burden in mice when administered intranasally at concentrations commonly found in nasal sprays. Most critically, vaporised PG efficiently abolishes influenza A virus and SARS-CoV-2 infectivity within airborne droplets, potently preventing infection at levels well below those tolerated by mammals. We present PG vapour as a first-in-class non-toxic airborne virucide that can prevent transmission of existing and emergent viral pathogens, with clear and immediate implications for public health.

Macromolecular condensation buffers intracellular water potential.

Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive protein folding and macromolecular interactions1. Reciprocally, macromolecules restrict the movement of 'structured' water molecules within their hydration layers, reducing the available 'free' bulk solvent and therefore the total thermodynamic potential energy of water, or water potential. Here, within concentrated macromolecular solutions such as the cytosol, we found that modest changes in temperature greatly affect the water potential, and are counteracted by opposing changes in osmotic strength. This duality of temperature and osmotic strength enables simple manipulations of solvent thermodynamics to prevent cell death after extreme cold or heat shock. Physiologically, cells must sustain their activity against fluctuating temperature, pressure and osmotic strength, which impact water availability within seconds. Yet, established mechanisms of water homeostasis act over much slower timescales2,3; we therefore postulated the existence of a rapid compensatory response. We find that this function is performed by water potential-driven changes in macromolecular assembly, particularly biomolecular condensation of intrinsically disordered proteins. The formation and dissolution of biomolecular condensates liberates and captures free water, respectively, quickly counteracting thermal or osmotic perturbations of water potential, which is consequently robustly buffered in the cytoplasm. Our results indicate that biomolecular condensation constitutes an intrinsic biophysical feedback response that rapidly compensates for intracellular osmotic and thermal fluctuations. We suggest that preserving water availability within the concentrated cytosol is an overlooked evolutionary driver of protein (dis)order and function.

Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

Multiphase Veteran Engagement to Develop a Spinal Cord Injury Employment Survey.

BACKGROUND: Spinal cord injury is a condition that adversely impacts employment and economic stability. The Kessler Foundation National Employment and Disability Survey (KFNEDS) was developed to understand the experience of striving to work among persons with disabilities. However, this survey was not intended to capture the employment experiences of veterans living with spinal cord injury. The aim of this study was to engage veterans living with a spinal cord injury to adapt the KFNEDS for veterans living with this specific disability. OBJECTIVES: Describe the process and outcomes of actively engaging veterans living with spinal cord injury in the revision of the KFNEDS. METHODS: In this multiphase qualitative study, we used an iterative veteran-centered approach to engage veterans living with an SCI in all project phases. We consulted with a Veterans' hospital's Veteran Engagement Group and convened a study-specific Community Action Board to engage in a collaborative partnership with the research team. We recruited 17 veterans living with a spinal cord injury, employed or looking for employment since their spinal cord injury, to participate in focus groups and cognitive interviews that informed the adaptation of the KFNEDS-VS. RESULTS: A provisional version of the KFNEDS-VS included 37 survey questions in the following sections: Disability Screen, Employment Screen, Disability, Employment Overall, Looking for Work, At Work, and Workplace Accommodations and Supports. Revisions included wording changes for clarity, veteran and spinal cord injury-specific content that was missing from the questions or response options, and removal of irrelevant questions. CONCLUSIONS: Engaging veterans in multiple phases of the study lead to the development of a relevant survey that captures the lived experience of veterans seeking, obtaining, and maintaining employment following spinal cord injury.

Recognition of Children's Learning in Educational Research, Policy and Practice: Herbison Invited Lecture, NZARE Annual Conference 2022.

For Jean Herbison, learning in her early 20th century childhood world was relatively uncomplicated and predictable. Life was shaped by unambiguous family, faith and settler colonial prescriptions about how children should behave and what they should become. Approaching the centenary of her birth, children today must navigate a very different society of 'unlimited can'; an achievement society that generates a debilitating compulsion to self-improve (Byung Chul-Han). In this Herbison lecture, I offer a personal reflection on the contemporary 'triangle' of education research, policy and practice in Aotearoa New Zealand. Viewed as a culturally and historically specific 'form of life' (Rahel Jaeggi), I ask whether, over the last thirty five years, this triangle may have unwittingly contributed to a collective failure to give adequate recognition to children's learning. Despite our best intentions, have we simply reified students and in doing so alienated them from learning in all its complexities and dimensions (Knud Illeris)? More than mere acknowledgement of 'the other', recognition theory highlights the importance of socially developed qualities such as confidence, respect and esteem (Axel Honneth) to each child's capacity to develop meaningful relationships to or 'resonance' with an ever accelerating and uncontrollable world (Hartmut Rosa) and the people and communities in it. In practical terms, then, what can we draw on that is already immanent in our research, policy and practice triangle to transform children's institutionalised learning?

Contingent Electric Skin Shock: An Empirical or Ideological Issue?

Intractable self-injury, aggressive, and other destructive behaviors are real human conditions. Contingent electric skin shock (CESS) is a technology, based on behavior-analytic principles, used to ameliorate such behaviors. However, CESS has always been extraordinarily controversial. The Association for Behavior Analysis (ABAI), commissioned an independent Task Force to examine the issue. After a comprehensive review, the Task Force suggested the treatment should be available for use in select cases through a largely accurate report. Yet, ABAI adopted a position indicating CESS is never appropriate. On the issue of CESS, we are extremely concerned behavior analysis departed from the fundamental epistemology of positivism and is misleading nascent behavior analysts and consumers of behavioral technology. Destructive behaviors are extremely difficult to treat. In our commentary, we outline clarifications regarding aspects of the Task Force Report, proliferation of falsehoods by leaders in our field, and limitations to the standard of care in behavior analysis. We recommend using science to answer important questions instead of propagating false information at the expense of current and future clients with treatment refractory behaviors.

A phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors.

This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

Vitelline vascular remnant causing intestinal obstruction in a patient with TARP syndrome.

BACKGROUND: TARP syndrome, characterized by talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava, is an X-linked recessive condition caused by deleterious variants in RBM10. Vitelline vascular remnants (VVR) are a rare vitelline duct anomaly with approximately 26 cases previously reported. There are no previously reported cases of VVRs in patients with TARP syndrome. CASE: We present a male neonate diagnosed with TARP syndrome via trio whole exome sequencing who had classic features of this syndrome, although his course was additionally complicated by feeding intolerance with multiple episodes of abdominal distension. Serial imaging and contrast studies of the upper GI tract and small bowel demonstrated small bowel obstruction of unclear etiology. Given the poor prognosis associated with this condition, life-sustaining measures were withdrawn, and he passed away at 38 days of age. On autopsy, a VVR was unexpectedly identified with proximal bowel dilation, explaining his feeding intolerance. CONCLUSIONS: We highlight the importance of full post-mortem examination in understanding the complete spectrum of manifestations of genetic syndromes and provide a review of the literature.

Transfer Timing and the Length of Medication Weaning for Neonatal Opioid Withdrawal Syndrome.

OBJECTIVE: Many infants with neonatal opioid withdrawal syndrome (NOWS) from prenatal exposure to opioids require transfer to a pediatric inpatient unit for medication weaning. The purpose of this study is to assess the difference in the duration of medication weaning between infants transferred by day of life (DOL) 14 versus later (DOL 15 and after) to a tertiary care setting for pharmacological and nonpharmacological management of NOWS. METHODS: This single-site retrospective cohort study uses medical chart data from infants with NOWS transferred to specialized care between May 2016 and June 2021 (n = 87). The primary outcome is length of medication weaning, calculated as the number of days between transfer from the NICU to a tertiary care setting and the cessation of pharmacotherapy. RESULTS: The majority of the infants in this sample are transferred from acute to tertiary care after DOL 15 (62% versus 38% by DOL 14). The predicted number of days to wean is 14.2 among those infants transferred by DOL 14, whereas the duration of weaning is 6.6 days longer among the later transfer group (20.8 days), adjusting for key covariates. The duration of weaning is also prolonged among infants with greater NOWS symptom severity and with prenatal exposure to psychotropic medications. CONCLUSIONS: Delayed treatment prolongs NOWS symptoms and increases the burden on the health care system. Earlier referral from NICUs to pediatric inpatient units with environmental supports could reduce prolonged medication exposure and length of hospitalization for infants diagnosed with NOWS.