Predictors of Nonsentinel Lymph Node Metastasis in Cutaneous Melanoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Although completion lymph node dissection (CLND) is not routinely performed for a positive sentinel lymph node (SLN) anymore, adjuvant therapy depends on the risk factors available from SLN biopsy, including the risk of nonsentinel node metastases (NSNM). A systematic review and meta-analysis was performed in an attempt to identify risk factors that could be used to predict the risk of NSNM. MATERIALS AND METHODS: Medline, Web of Science, Embase, and Cochrane were searched for articles discussing predictive factors for NSNM. PRISMA guidelines were followed, and RevMan software was used to calculate pooled odds ratios (OR) using the Mantel-Haenszel test. RESULTS: Fifty publications were suitable for additional analysis. The clinical and primary tumor factors that were consistently identified as risk factors for NSNMs were: age >50, T stage 3 or 4, Clark level IV/V, ulceration, microsatellitosis, lymphovascular invasion, nodular histology, and extremity versus trunk primary tumor location. SLN factors that predicted NSNMs were >1 positive SLN, SLN micrometastatic tumor burden, diameter >2 mm, extracapsular extension, nonsubcapsular location (Dewar), and Rotterdam > 1 mm or ≥ 0.1 mm. CONCLUSIONS: The findings in this study support that many clinical and pathologic risk factors that can be assessed with SLN biopsy alone can be used to predict the risk of NSNMs. The factors identified in this review should be evaluated in clinical prediction models to predict the risk of NSNMS, a prediction that may be used to select patients for adjuvant therapy in high-risk melanoma.

IP3R-mediated intra-axonal Ca2+ release contributes to secondary axonal degeneration following contusive spinal cord injury.

Secondary axonal loss contributes to the persistent functional disability following trauma. Consequently, preserving axons following spinal cord injury (SCI) is a major therapeutic goal to improve neurological outcome; however, the complex molecular mechanisms that mediate secondary axonal degeneration remain unclear. We previously showed that IP3R-mediated Ca2+ release contributes to axonal dieback and axonal loss following an ex vivo laser-induced SCI. Nevertheless, targeting IP3R in a clinically relevant in vivo model of SCI and determining its contribution to secondary axonal degeneration has yet to be explored. Here we used intravital two-photon excitation microscopy to assess the role of IP3R in secondary axonal degeneration in real-time after a contusive-SCI in vivo. To visualize Ca2+ changes specifically in spinal axons over time, adult 6-8 week-old triple transgenic Avil-Cre:Ai9:Ai95 (sensory neuron-specific expression of tdTomato and the genetic calcium indicator GCaMP6f) mice were subjected to a mild (30 kdyn) T12 contusive-SCI and received delayed treatment with the IP3R blocker 2-APB (100 µM, intrathecal delivery at 3, and 24 h following injury) or vehicle control. To determine the IP3R subtype involved, we knocked-down IP3R3 using capped phosphodiester oligonucleotides. Delayed treatment with 2-APB significantly reduced axonal spheroids, increased axonal survival, and reduced intra-axonal Ca2+ accumulation within dorsal column axons at 24 h following SCI in vivo. Additionally, knockdown of IP3R3 yielded increased axon survival 24 h post-SCI. These results suggest that IP3R-mediated Ca2+ release contributes to secondary axonal degeneration in vivo following SCI.

Thalamic mediation of hypoxic respiratory depression in lambs.

Immaturity of respiratory controllers in preterm infants dispose to recurrent apnea and oxygen deprivation. Accompanying reductions in brain oxygen tensions evoke respiratory depression, potentially exacerbating hypoxemia. Central respiratory depression during moderate hypoxia is revealed in the ventilatory decline following initial augmentation. This study determined whether the thalamic parafascicular nuclear (Pf) complex involved in adult nociception and sensorimotor regulation (Bentivoglio M, Balerecia G, Kruger L. Prog Brain Res 87: 53-80, 1991) also becomes a postnatal controller of hypoxic ventilatory decline. Respiratory responses to moderate isocapnic hypoxia were studied in conscious lambs. Hypoxic ventilatory decline was compared with peak augmentation. Pf and/or adjacent thalamic structures were destroyed by the neuron-specific toxin ibotenic acid (IB). IB lesions involving the thalamic Pf abolished hypoxic ventilatory decline. Lesions of adjacent thalamic nuclei that spared Pf and control injections of vehicle failed to blunt hypoxic respiratory depression. Our findings reveal that the thalamic Pf region is a critical controller of hypoxic ventilatory depression and thus a key target for exploring molecular concomitants of forebrain pathways regulating hypoxic ventilatory depression in early development.

Fetal breathing movements and changes at birth.

The fetus, which develops within a fluid-filled amniotic sac, relies on the placenta for respiratory gas exchange rather than the lungs. While not involved in fetal oxygenation, fetal breathing movements (FBM) nevertheless have an important role in lung growth and in development of respiratory muscles and neural regulation. FBM are regulated differently in many respects than postnatal respiration, which results from the unique intrauterine environment. Prominent distinctions of FBM include its episodic nature and apnea-sensitivity to hypoxia. The latter characteristic is the basis for using FBM in the assessment of fetuses at risk for hypoxic injury. At birth, the transition to continuous postnatal respiration involves a fall in temperature, gaseous distention of the lungs, activation of the Hering-Breuer reflexes, and functional connectivity of afferent O2 chemoreceptor activity with respiratory motoneurons and arousal centers. Importantly, exposure to drugs or adverse conditions in utero not only can change patterns of FBM but also can lead to epigenetic dysregulation in postnatal respiration. Such changes, can blunt respiratory and arousal defenses against hypoxic challenges in sleep. Thus, fetal hypoxia and/or drug exposure may in later life dispose sleeping infants, children, and adults to hypertension, diabetes mellitus, brain injury, and sudden death.

Training of Family Medicine residents in the first year of the COVID-19 pandemic.

Background: The immediate impact of the pandemic on resident training has been well documented. As the pandemic and its effects persisted beyond what was initially predicted, this study aimed to assess the impact of the pandemic on the training of family medicine (FM) residents a year after it began and to assess the burnout residents experienced during this period. Methods: The survey was conducted between January 18 and February 18, 2021. Participation was solicited via an email sent to the program directors throughout the US, who were asked to circulate the survey among their residents. The questionnaire was divided into sections to assess the impact of the pandemic on clinical training, didactics, and preparedness for the next phase in the career. In addition, the burnout experienced was assessed using the Copenhagen Burnout Inventory. Results: 227 responses were analyzed. 83% (n = 186) of respondents felt that the pandemic had a negative impact on their training and 63% (n = 141) felt that the pandemic had a negative impact on didactics. 50% (n = 44) of the third-year residents thought that they would be able to meet the graduation requirement for outpatient encounters. 41% (n = 36) of the third-year residents felt less prepared for the next step in their careers. 119 respondents met the cutoff threshold for personal burnout, 134 for work-related burnout, and 65 for client-related burnout. Conclusion: Residency training is difficult with high reported rates of burnout before the COVID-19 pandemic. This study reinforces the evidence that the pandemic made both mental well-being and adequate training more difficult for FM residents across the country.

The Effectiveness of Direct Supervision by an Attending Compared To a Senior Resident on Quality of Supervision of Novice Anesthesiology Residents: A Randomized Study.

Background: New trainees are directly supervised by either an attending physician or a senior resident under indirect supervision from an attending physician. The main objective was to evaluate which type of direct supervision (attending vs. senior resident) would result in better quality of supervision to novice residents during their first month of training. Methods: Novice anesthesiology residents were randomized to receive direct supervision by an attending anesthesiologist or a senior resident during their introduction month of intraoperative anesthesia. The primary outcome was a validated instrument to evaluate supervision performance of the instructor. The secondary outcome was a validated anxiety scale. Results: The overall mean supervision score across the study days was greater in the residents who were directly supervised by attendings, mean (standard error [SE]) of 3.88 ± 0.03 compared with direct supervision by a senior resident, mean (SE) of 3.77 ± 0.03 a mean difference of 0.11 (95% confidence interval [CI], 0.05-0.16), P = .0012. Five of 9 individual items on the supervision survey were significantly greater in the group directly supervised by attendings compared with residents. There was no difference between groups regarding anxiety scores. In contrast, there was a mild association between supervision scores and Spielberger State-Trait Anxiety Inventory-6 anxiety scores, correlation coefficient = 0.23 (95% CI, 0.08-0.39), P < .0035. Conclusions: We detected better supervision scores when novice anesthesiology residents were directly supervised by attendings when compared with senior residents. Nevertheless, direct supervision by senior residents still provided supervision scores consistent with a safe supervision practice.

Inhibiting Calcium Release from Ryanodine Receptors Protects Axons after Spinal Cord Injury.

Ryanodine receptors (RyRs) mediate calcium release from calcium stores and have been implicated in axonal degeneration. Here, we use an intravital imaging approach to determine axonal fate after spinal cord injury (SCI) in real-time and assess the efficacy of ryanodine receptor inhibition as a potential therapeutic approach to prevent intra-axonal calcium-mediated axonal degeneration. Adult 6-8 week old Thy1YFP transgenic mice that express YFP in axons, as well as triple transgenic Avil-Cre:Ai9:Ai95 mice that express the genetically-encoded calcium indicator GCaMP6f in tdTomato positive axons, were used to visualize axons and calcium changes in axons, respectively. Mice received a mild SCI at the T12 level of the spinal cord. Ryanodine, a RyR antagonist, was given at a concentration of 50 µM intrathecally within 15 min of SCI or delayed 3 h after injury and compared with vehicle-treated mice. RyR inhibition within 15 min of SCI significantly reduced axonal spheroid formation from 1 h to 24 h after SCI and increased axonal survival compared with vehicle controls. Delayed ryanodine treatment increased axonal survival and reduced intra-axonal calcium levels at 24 h after SCI but had no effect on axonal spheroid formation. Together, our results support a role for RyR in secondary axonal degeneration.

Pediatric Allergy: An Overview.

Allergy is a broad topic encompassing common clinical allergic diseases, asthma, and complex immunodeficiencies. In this article, the authors discuss the most common allergic diseases and anaphylaxis and briefly review the current knowledge and management of food allergies, allergic rhinitis, otitis media, sinusitis, chronic cough, atopic dermatitis, urticarial and angioedema, contact dermatitis, allergic ophthalmopathy, drug allergy, latex allergy, and insect sting. Because the prevalence of allergic disorders continues to increase, it is increasingly important for physicians to stay up to date on most recent evidence-based diagnosis and management of allergic disorders.

Repeat intravital imaging of the murine spinal cord reveals degenerative and reparative responses of spinal axons in real-time following a contusive SCI.

Spinal cord injury (SCI) induces a secondary degenerative response that causes the loss of spared axons and worsens neurological outcome. The complex molecular mechanisms that mediate secondary axonal degeneration remain poorly understood. To further our understanding of secondary axonal degeneration following SCI, we assessed the spatiotemporal dynamics of axonal spheroid and terminal bulb formation following a contusive SCI in real-time in vivo. Adult 6-8 week old Thy1YFP transgenic mice underwent a T12 laminectomy for acute imaging sessions or were implanted with a custom spinal cord imaging chamber for chronic imaging of the spinal cord. Two-photon excitation time-lapse microscopy was performed prior to a mild contusion SCI (30 kilodyne, IH Impactor) and at 1-4 h and 1-14 days post-SCI. We quantified the number of axonal spheroids, their size and distribution, the number of endbulbs, and axonal survival from 1 h to 14 days post-SCI. Our data reveal that the majority of axons underwent swelling and axonal spheroid formation acutely after SCI resulting in the loss of ~70% of axons by 1 day after injury. In agreement, the number of axonal spheroids rapidly increased at 1 h after SCI and remained significantly elevated up to 14 days after SCI. Furthermore, the distribution of axonal spheroids spread mediolaterally over time indicative of delayed secondary degenerative processes. In contrast, axonal endbulbs were relatively sparse and their numbers peaked at 1 day after injury. Intriguingly, axonal survival significantly increased at 7 and 14 days compared to 3 days after SCI revealing a potential endogenous axonal repair process that mirrors the known spontaneous functional recovery after SCI. In support, ~43% of tracked axonal spheroids resolved over the course of observation revealing their dynamic nature. Furthermore, axonal spheroids and endbulbs accumulated mitochondria and excessive tubulin polyglutamylation suggestive of disrupted axonal transport as a shared mechanism. Collectively, this study provides important insight into both degenerative and recoverable responses of axons following contusive SCI in real-time. Understanding how axons spontaneously recover after SCI will be an important avenue for future SCI research and may help guide future clinical trials.

Pathogen- and Danger-Associated Molecular Patterns and the Cytokine Response in Sepsis.

The sepsis syndrome is a systemic host inflammatory response accompanied by organ dysfunction in response to invading microbial pathogens. The host recognizes both danger and pathogens through its pattern recognition receptors on immune cells. These receptors bind to pathogen- (PAMP) and danger- (DAMP) associated molecular patterns derived from microbes and host tissues, respectively. These processes set in motion a cascade of events in host cells and tissue, which activate multiple cytokines that serve as activators of the host inflammatory response as well as eventually lead to resolution of the response if the host recovers. The following article describes some of these DAMPs and PAMPs, and how they activate pathways that activate the host cytokine immune response to injury and infection.