A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank.

BACKGROUND: Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. METHODS: A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. RESULTS: We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). CONCLUSIONS: We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

Primary peritoneal clear cell carcinoma arising in the setting of abdominal wall Endometriosis: A case report and review of the literature.

•Primary peritoneal clear cell carcinoma can arise from endometriotic implants within the abdomen and pelvis.•Immunohistochemistry can be used to confirm primary disease site. Endometriotic origin can be inferred based on clinical history and intraoperative findings suggestive of endometriosis.•While no standardized treatment exists, consideration should be given to cytoreductive surgery with adjuvant chemotherapy. Adjuvant radiation can also be considered for local control.

Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity.

Plasma cell responses are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify anti-tumor immune responses through antibody production; yet B cells in patients and tumor-bearing mice often fail to support this effector function. We identify dysregulated transcriptional program in B cells that disrupts differentiation of naive B cells into anti-tumor plasma cells. The signaling network contributing to this dysfunction is driven by interleukin (IL) 35 stimulation of a STAT3-PAX5 complex that upregulates the transcriptional regulator BCL6 in naive B cells. Transient inhibition of BCL6 in tumor-educated naive B cells is sufficient to reverse the dysfunction in B cell differentiation, stimulating the intra-tumoral accumulation of plasma cells and effector T cells and rendering pancreatic tumors sensitive to anti-programmed cell death protein 1 (PD-1) blockade. Our findings argue that B cell effector dysfunction in cancer can be due to an active systemic suppression program that can be targeted to synergize with T cell-directed immunotherapy.

Robust temporal pumping in a magneto-mechanical topological insulator.

The transport of energy through 1-dimensional (1D) waveguiding channels can be affected by sub-wavelength disorder, resulting in undesirable localization and backscattering phenomena. However, quantized disorder-resilient transport is observable in the edge currents of 2-dimensional (2D) topological band insulators with broken time-reversal symmetry. Topological pumps are able to reduce this higher-dimensional topological insulator phenomena to lower dimensionality by utilizing a pumping parameter (either space or time) as an artificial dimension. Here we demonstrate a temporal topological pump that produces on-demand, robust transport of mechanical energy using a 1D magneto-mechanical metamaterial. We experimentally demonstrate that the system is uniquely resilient to defects occurring in both space and time. Our findings open a path towards exploration of higher-dimensional topological physics with time as a synthetic dimension.

Enhancing the patient and family experience during pediatric sleep studies.

STUDY OBJECTIVES: Pediatric polysomnography can result in suboptimal patient and provider (physician and advanced practice provider) experiences. We embarked on a project aimed at increasing the proportion of maximal satisfaction survey scores by a minimum of 10% in 1 year without adding personnel or major expenses. METHODS: We used a Six Sigma framework, define, measure, analyze, improve, and control (DMAIC), to conduct our analysis. For measurement, we designed a project-specific survey that was given to caregivers of children who underwent PSG in February 2018 and repeated the survey after interventions in February 2019. Lean and Six Sigma quality improvement tools were used to define important processes that influence patient satisfaction, including: supplier, input, process, output, customer, and requirements (SIPOC-R); journey mapping; 1-2-4-All brainstorming; and views solicited from our center's Patient and Family Advisory Council. We analyzed the relationships between identified processes and outcomes using usual descriptive statistics. We prioritized interventions using a Kano model and a quality function deployment (QFD) technique to rank priorities for interventions. Multiple opportunities to improve patient and family satisfaction before, during, and after a pediatric polysomnography were identified. Many were simple, one-step interventions and were implemented simultaneously. For those that required substantial training and/or scheduling changes, pilots were performed and plan, do, study, act (PDSA) cycles were used to check effectiveness. RESULTS: After implementation, top box scores rose 20%, from 51% (n = 47) in 2018 to 71% (n = 50) in 2019. CONCLUSIONS: Various quality improvement techniques employed in business, engineering, and manufacturing were used to identify and address areas of improvement in the pediatric polysomnography experience.

B cell-Derived IL35 Drives STAT3-Dependent CD8+ T-cell Exclusion in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.

Effect of shifting costs to patients on specialty evaluation for sleep disorders.

OBJECTIVE: To determine whether the introduction of out-of-pocket expenses to medical center employees would lead to decreased use of sleep disorder services. PATIENTS AND METHODS: We retrospectively analyzed and compared the clinical and medical accounting data from visits by Mayo Clinic employees to the Sleep Disorders Center from January 1 to March 31, 2003, with that of January 1 to March 31, 2004, le, before and after a January 2004 increase in co-payments for evaluation and testing. RESULTS: The total number of new patients evaluated in the first quarters of 2003 and 2004 was similar (113 vs 119; P = .37). Snoring, restless legs symptoms, hypertension, atrial fibrillation, and prior overnight oximetry testing were more prevalent in 2004 than in 2003 (P = .05, P = .01, P < .001, P = .003, P = .02, respectively). In contrast, insomnia and parasomnia complaints were less common in 2004 (P < .001). The mean apnea-hypopnea index, minimum oxygen saturation, and percentage of time with oxygen saturation less than 90% were all more severe in 2004 (P = .01, P = .001, P < .001, respectively). Sleep-related breathing disorders were more commonly diagnosed in 2004 (83.2% vs 67.2%; P = .02), whereas the diagnoses of nonbreathing disorders declined. CONCLUSION: The insurance policy changes that resulted in larger employee co-payments shifted the spectrum of diagnoses seen at the Sleep Disorders Center toward more symptomatic patients, with more associated comorbidities, and patients who had more severe sleep-related breathing disorders. Total utilization did not decrease.

Neurophysiology of sleep and wakefulness.

Wakefulness, NREM sleep, and REM sleep are three distinct states of existence. Each state has characteristic behavioral and physiologic patterns,and each has specific neurophysiologic mechanisms associated with its generation and control. Structures in the brainstem use various neurotransmitters to influence higher brain structures in the midbrain and cortex. The ARAS provides cholinergic, noradrenergic, and glutaminergic stimulation to the thalamus, hypothalamus, and basal forebrain resulting in cholinergic and glutaminergic excitation of the cortex. An active cortex that exhibits a characteristic pattern of desynchronized EEG manifests wakefulness. Various factors affect the need and timing of sleep onset. These factors influence the nucleus tractus solitarius, causing its noradrenergic projections to midbrain and forebrain structures to inhibit activity in the ARAS, resulting inactivation of inhibitory GABAergic thalamocortical projections to the cor-tex. During a state of decreased activation, the cortex exhibits a pattern of synchronized EEG. Transition between NREM sleep and REM sleep is controlled by noradrenergic neurons in the loci coeruleus and serotoninergic neurons in the raphe called REM-off cells and cholinergic neurons in the nucleus reticularis pontis oralis called REM-on cells. Other brain structures are involved in generation and control of REM sleep-related phenomena, such as eye movement and muscle atonia. During wakefulness, there is increased sympathetic tone and decreased parasympathetic tone that maintains most organ systems in a state of action or readiness. During NREM sleep, there is decreased sympathetic tone and increased parasympathetic activity that creates a state of reduced activity. REM sleep is characterized by increased parasympathetic activity and variable sympathetic activity associated with increased activation of certain brain functions. The states of wakefulness and sleep are characterized as stages that are defined by stereotypical EEG, EMG, and EOG patterns. Wakefulness stage has an EEG pattern predominated by the alpha rhythm. With onset of stage 1 sleep, the alpha rhythm attenuates, and an EEG pattern of relatively low voltage and mixed frequency is seen. Progression to stage 2 sleep is defined by the appearance of sleep spindles or K-complexes. Further progression into the deepest sleep stages 3 and 4 is defined by the occurrence of high-amplitude, low-frequency EEG activity. The progression of sleep stages occurs in cycles of 60 to 120 minutes throughout the sleep period. Various circadian environmental and ontologic factors affect the pattern of sleep stage occurrence.

Requisite role for Nck adaptors in cardiovascular development, endothelial-to-mesenchymal transition, and directed cell migration.

Development of the cardiovascular system is critically dependent on the ability of endothelial cells (ECs) to reorganize their intracellular actin architecture to facilitate migration, adhesion, and morphogenesis. Nck family cytoskeletal adaptors function as key mediators of actin dynamics in numerous cell types, though their role in EC biology remains largely unexplored. Here, we demonstrate an essential requirement for Nck within ECs. Mouse embryos lacking endothelial Nck1/2 expression develop extensive angiogenic defects that result in lethality at about embryonic day 10. Mutant embryos show immature vascular networks, with decreased vessel branching, aberrant perivascular cell recruitment, and reduced cardiac trabeculation. Strikingly, embryos deficient in endothelial Nck also fail to undergo the endothelial-to-mesenchymal transition (EnMT) required for cardiac valve morphogenesis, with loss of Nck disrupting expression of major EnMT markers, as well as suppressing mesenchymal outgrowth. Furthermore, we show that Nck-null ECs are unable to migrate downstream of vascular endothelial growth factor and angiopoietin-1, and they exhibit profound perturbations in cytoskeletal patterning, with disorganized cellular projections, impaired focal adhesion turnover, and disrupted actin-based signaling. Our collective findings thereby reveal a crucial role for Nck as a master regulator within the endothelium to control actin cytoskeleton organization, vascular network remodeling, and EnMT during cardiovascular development.

Pupillometry in clinically sleepy patients.

OBJECTIVES: Investigators have suggested using pupillometry to assess alertness in hypersomnolent patients. In this study we assessed hypersomnolent patients and normal volunteers by using pupillometry and examined the usefulness of this technique for the diagnosis of pathologic sleepiness in individual patients. METHODS: Forty-nine patients were examined by pupillometry and their sleepiness was assessed by using the multiple sleep latency test (MSLT). Thirty-three normal well-rested volunteers were also examined by pupillometry. The patients were classified as having 'mild', 'moderate', or 'severe' sleepiness, based on their mean MSLT sleep latency. Several dynamic variables of pupil diameter were calculated from the pupillograms and correlated with the mean MSLT sleep latency, and were compared between severity groups of patients and the well-rested normal subjects. RESULTS: All but two pupillometric variables were significantly correlated with sleep latency. All except the same two pupillometric variables of the sleepiest group were significantly different from those of normal subjects. However, only 51% of patients with mean sleep latencies less than 10 min and 35% of patients with mean sleep latencies of less than 5 min could be correctly identified by pupillometry. CONCLUSIONS: Pupillometry is clearly associated with differences in alertness between groups of patients. However, pupillometric assessment cannot substitute for the MSLT in most cases.

History of the development of sleep medicine in the United States.

Sleep Medicine has only recently been recognized as a specialty of medicine. Its development is based on an increasing amount of knowledge concerning the physiology of sleep, circadian biology and the pathophysiology of sleep disorders. This review chronicles the major advances in sleep science over the past 70 years and the development of the primary organizations responsible for the emergence of Sleep Medicine as a specialty, sleep disorders as a public health concern and sleep science as an important area of research.