Effect of Social Needs Case Management on Hospital Use Among Adult Medicaid Beneficiaries : A Randomized Study.

BACKGROUND: Case management programs assisting patients with social needs may improve health and avoid unnecessary health care use, but little is known about their effectiveness. OBJECTIVE: This large-scale study assessed the population-level impact of a case management program designed to address patients' social needs. DESIGN: Single-site randomized encouragement design with administrative enrollment from an eligible population and intention-to-treat analysis. Study participants were enrolled between August 2017 and December 2018 and followed for 1 year. (ClinicalTrials.gov: NCT04000074). SETTING: Contra Costa County, an economically and culturally diverse community in the San Francisco Bay Area. PARTICIPANTS: 57 972 randomized enrollments of adult Medicaid patients at elevated risk for health care use (top 15%) to the intervention or control group. INTERVENTION: Enrollees were offered 12 months of social needs case management, which provided more intensive services to patients with higher demonstrated needs. MEASUREMENTS: Medical use was measured via emergency department (ED) visits and inpatient admissions, some of which were classified as avoidable. RESULTS: Participants in the intervention group visited the ED at ratios of 0.96 (95% CI, 0.91 to 1.00) for all visits and 0.97 (CI, 0.92 to 1.03) for avoidable visits relative to the control group. The intervention group was hospitalized at ratios of 0.89 (CI, 0.81 to 0.98) for all admissions and 0.72 (CI, 0.55 to 0.88) for avoidable admissions. LIMITATIONS: Only 40% of the intervention group engaged with the program. The program was in continual development during the trial period. CONCLUSION: Although social needs case management programs may reduce health care use, these savings may not cover full program costs. More work is needed to identify ways to increase patient uptake and define characteristics of successful programs. PRIMARY FUNDING SOURCE: Contra Costa Health Services via the Medicaid waiver program.

Sequestration of Defenses against Predators Drives Specialized Host Plant Associations in Preadapted Milkweed Bugs (Heteroptera: Lygaeinae).

AbstractHost plant specialization across herbivorous insects varies dramatically, but while the molecular mechanisms of host plant adaptations are increasingly known, we often lack a comprehensive understanding of the selective forces that favor specialization. The milkweed bugs (Heteroptera: Lygaeinae) are ancestrally associated with plants of the Apocynaceae from which they commonly sequester cardiac glycosides for defense, facilitated by resistant Na+/K+-ATPases and adaptations for transport, storage, and discharge of toxins. Here, we show that three Lygaeinae species independently colonized four novel nonapocynaceous hosts that convergently produce cardiac glycosides. A fourth species shifted to a new source of toxins by tolerating and sequestering alkaloids from meadow saffron (Colchicum autumnale, Colchicaceae). Across three milkweed bug species tested, feeding on seeds containing toxins did not improve growth or speed of development and even impaired growth and development in two species, but sequestration mediated protection of milkweed bugs against two natural predators: lacewing larvae and passerine birds. We conclude that physiological preadaptations and convergent phytochemistry facilitated novel specialized host associations. Since toxic seeds did not improve growth but either impaired growth or, at most, had neutral effects, selection by predators on sequestration of defenses, rather than the exploitation of additional profitable dietary resources, can lead to obligatory specialized host associations in otherwise generalist insects.

Patient care in rapid-expansion intensive care units during the COVID-19 pandemic crisis.

BACKGROUND: The coronavirus-2019 (COVID-19) pandemic highlighted the unfortunate reality that many hospitals have insufficient intensive care unit (ICU) capacity to meet massive, unanticipated increases in demand. To drastically increase ICU capacity, NewYork-Presbyterian/Weill Cornell Medical Center modified its existing operating rooms and post-anaesthesia care units during the initial expansion phase to accommodate the surge of critically ill patients. METHODS: This retrospective chart review examined patient care in non-standard Expansion ICUs as compared to standard ICUs. We compared clinical data between the two settings to determine whether the expeditious development and deployment of critical care resources during an evolving medical crisis could provide appropriate care. RESULTS: Sixty-six patients were admitted to Expansion ICUs from March 1st to April 30th, 2020 and 343 were admitted to standard ICUs. Most patients were male (70%), White (30%), 45-64 years old (35%), non-smokers (73%), had hypertension (58%), and were hospitalized for a median of 40 days. For patients that died, there was no difference in treatment management, but the Expansion cohort had a higher median ICU length of stay (q = 0.037) and ventilatory length (q = 0.015). The cohorts had similar rates of discharge to home, but the Expansion ICU cohort had higher rates of discharge to a rehabilitation facility and overall lower mortality. CONCLUSIONS: We found no significantly worse outcomes for the Expansion ICU cohort compared to the standard ICU cohort at our institution during the COVID-19 pandemic, which demonstrates the feasibility of providing safe and effective care for patients in an Expansion ICU.

The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis.

Insulin-like growth factor 2 (IGF2), a developmentally regulated and maternally imprinted gene, is frequently overexpressed in pediatric cancers. Although loss of imprinting (LOI) at fetal promoters contributes to increased IGF2 in tumors, the magnitude of IGF2 expression suggests the involvement of additional regulatory mechanisms. A microRNA (miRNA) screen of primary Wilms' tumors identified specific overexpression of miR-483-5p, which is embedded within the IGF2 gene. Unexpectedly, the IGF2 mRNA itself is transcriptionally up-regulated by miR-483-5p. A nuclear pool of miR-483-5p binds directly to the 5' untranslated region (UTR) of fetal IGF2 mRNA, enhancing the association of the RNA helicase DHX9 to the IGF2 transcript and promoting IGF2 transcription. Ectopic expression of miR-483-5p in IGF2-dependent sarcoma cells is correlated with increased tumorigenesis in vivo. Together, these observations suggest a functional positive feedback loop of an intronic miRNA on transcription of its host gene.

A novel long non-coding RNA from NBL2 pericentromeric macrosatellite forms a perinucleolar aggregate structure in colon cancer.

Primate-specific NBL2 macrosatellite is hypomethylated in several types of tumors, yet the consequences of this DNA hypomethylation remain unknown. We show that NBL2 conserved repeats are close to the centromeres of most acrocentric chromosomes. NBL2 associates with the perinucleolar region and undergoes severe demethylation in a subset of colorectal cancer (CRC). Upon DNA hypomethylation and histone acetylation, NBL2 repeats are transcribed in tumor cell lines and primary CRCs. NBL2 monomers exhibit promoter activity, and are contained within novel, non-polyA antisense lncRNAs, which we designated TNBL (Tumor-associated NBL2 transcript). TNBL is stable throughout the mitotic cycle, and in interphase nuclei preferentially forms a perinucleolar aggregate in the proximity of a subset of NBL2 loci. TNBL aggregates interact with the SAM68 perinucleolar body in a mirror-image cancer specific perinucleolar structure. TNBL binds with high affinity to several proteins involved in nuclear functions and RNA metabolism, such as CELF1 and NPM1. Our data unveil novel DNA and RNA structural features of a non-coding macrosatellite frequently altered in cancer.

Targeting LINC00673 expression triggers cellular senescence in lung cancer.

Aberrant expression of noncoding RNAs plays a critical role during tumorigenesis. To uncover novel functions of long non-coding RNA (lncRNA) in lung adenocarcinoma, we used a microarray-based screen identifying LINC00673 with elevated expression in matched tumor versus normal tissue. We report that loss of LINC00673 is sufficient to trigger cellular senescence, a tumor suppressive mechanism associated with permanent cell cycle arrest, both in lung cancer and normal cells in a p53-dependent manner. LINC00673-depleted cells fail to efficiently transit from G1- to S-phase. Using a quantitative proteomics approach, we confirm the modulation of senescence-associated genes as a result of LINC00673 knockdown. In addition, we uncover that depletion of p53 in normal and tumor cells is sufficient to overcome LINC00673-mediated cell cycle arrest and cellular senescence. Furthermore, we report that overexpression of LINC00673 reduces p53 translation and contributes to the bypass of Ras-induced senescence. In summary, our findings highlight LINC00673 as a crucial regulator of proliferation and cellular senescence in lung cancer.

Long Noncoding RNAs in Lung Cancer.

Despite great progress in research and treatment options, lung cancer remains the leading cause of cancer-related deaths worldwide. Oncogenic driver mutations in protein-encoding genes were defined and allow for personalized therapies based on genetic diagnoses. Nonetheless, diagnosis of lung cancer mostly occurs at late stages, and chronic treatment is followed by a fast onset of chemoresistance. Hence, there is an urgent need for reliable biomarkers and alternative treatment options. With the era of whole genome and transcriptome sequencing technologies, long noncoding RNAs emerged as a novel class of versatile, functional RNA molecules. Although for most of them the mechanism of action remains to be defined, accumulating evidence confirms their involvement in various aspects of lung tumorigenesis. They are functional on the epigenetic, transcriptional, and posttranscriptional level and are regulators of pathophysiological key pathways including cell growth, apoptosis, and metastasis. Long noncoding RNAs are gaining increasing attention as potential biomarkers and a novel class of druggable molecules. It has become clear that we are only beginning to understand the complexity of tumorigenic processes. The clinical integration of long noncoding RNAs in terms of prognostic and predictive biomarker signatures and additional cancer targets could provide a chance to increase the therapeutic benefit. Here, we review the current knowledge about the expression, regulation, biological function, and clinical relevance of long noncoding RNAs in lung cancer.

Conformational rearrangements of RIG-I receptor on formation of a multiprotein:dsRNA assembly.

The retinoic acid inducible gene-I (RIG-I)-like family of receptors is positioned at the front line of our innate cellular defence system. RIG-I detects and binds to foreign duplex RNA in the cytoplasm of both immune and non-immune cells, and initiates the induction of type I interferons and pro-inflammatory cytokines. The mechanism of RIG-I activation by double-stranded RNA (dsRNA) involves a molecular rearrangement proposed to expose the N-terminal pair of caspase activation recruitment domains, enabling an interaction with interferon-beta promoter stimulator 1 (IPS-1) and thereby initiating downstream signalling. dsRNA is particularly stimulatory when longer than 20 bp, potentially through allowing binding of more than one RIG-I molecule. Here, we characterize full-length RIG-I and RIG-I subdomains combined with a stimulatory 29mer dsRNA using multi-angle light scattering and size-exclusion chromatography-coupled small-angle X-ray scattering, to build up a molecular model of RIG-I before and after the formation of a 2:1 protein:dsRNA assembly. We report the small-angle X-ray scattering-derived solution structure of the human apo-RIG-I and observe that on binding of RIG-I to dsRNA in a 2:1 ratio, the complex becomes highly extended and flexible. Hence, here we present the first model of the fully activated oligomeric RIG-I.

Adductor and Sciatic Peripheral Nerve Catheters for Schatzker VI Tibial Plateau Fracture: A Case Report.

Peripheral nerve blocks are typically avoided for high-speed tibial plateau fractures due to their ability to mask the paresthesias and pain associated with the feared complication of acute compartment syndrome (ACS). We present a case in which sciatic nerve and adductor canal catheters were placed utilizing low-volume infusions allowing for neurovascular assessment. These catheters served as a valuable portion of the multi-modal pain regimen in this patient with a Schatzker VI tibial plateau fracture.

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo.

IFN-γ has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-γ-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O(2) < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-γ are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-γ concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-γ under hypoxia was restricted to the urogenital serovars D and L(2), but was not observed with the ocular serovar A. Impaired effectiveness of IFN-γ on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-γ effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women.

Associations between Stressful Life Events and Increased Physical and Psychological Health Risks in Adolescents: A Longitudinal Study.

Stressful life events (SLEs) are understood as risk factors for mental and physical health problems, particularly in the vulnerable period of adolescence. Using a longitudinal approach, this study investigated associations between SLE and several negative health outcomes in adolescents. Moderating effects of sociodemographic factors were considered. We analyzed the data of a healthy adolescent sample from the LIFE Child study in Leipzig, Germany (n = 2024, aged 10-18 years). SLEs were measured by a questionnaire, addressing SLEs in the family and the social environment domain. Health-related quality of life (HrQoL), behavioral difficulties and BMI were compared before and after an SLE had occurred. Moderator effects of socioeconomic status (SES), age, and sex were investigated using linear regression models. All considered health parameters had, on average, deteriorated after the occurrence of an SLE in the social environment. Differences in HrQoL before and after an SLE were significantly stronger in girls. Higher SES functioned as a slight protective factor against decreased well-being after an SLE. The findings suggest that SLEs function as risk factors for mental and physical health disadvantages in adolescents. Prevention programs should seek to support adolescents in all age and SES groups affected by SLEs, with a specific focus on girls.

CD47 blockade enhances phagocytosis of cardiac cell debris by neutrophils.

CD47 is a cell surface protein controlling phagocytotic activity of innate immune cells. CD47 blockade was investigated as an immune checkpoint therapy in cancer treatment, enhancing phagocytosis of tumor cells by macrophages. Anti-CD47 treatment also reduced injury size during reperfused acute myocardial infarction (repAMI) by enhancing phagocytotic acitivity of macrophages. Little is known about the impact of CD47 blockade on neutrophils, representing the main portion of early infiltrating immune cells after repAMI. Therefore, we performed 45 min of cardiac ischemia followed by 24 h of reperfusion, observing a decreased cardiac injury size measured by triphenyl tetrazolium chloride (TTC) Evan's blue staining. We were able to detect this effect with an innovative three-dimensional method based on light sheet fluorescence microscopy (LSFM). This further allowed us a simultaneous analysis of neutrophil infiltration, showing an unaltered amount of injury-associated neutrophils with reduced cardiac injury volume from repAMI. This observation suggests modulated phagocytosis of cell debris by neutrophils. Therefore, we performed flow cytometry analysis, revealing an increased phagocytotic activity of neutrophils in vitro. These findings highlight that CD47 blockade also enhances phagocytosis of cardiac cell debris by neutrophils, which might be an additional protective effect of anti-CD47 treatment after repAMI.

Effects of Aspergillus spp. exogenous fibrolytic enzymes on in vitro fermentation of tropical forages.

BACKGROUND: Cellulose and hemicellulose are quantitatively the most important structural carbohydrates present in ruminant diets. Rumen micro-organisms produce enzymes that catalyse their hydrolysis, but the complex network formed by structural carbohydrates and lignin reduces their digestibility and restricts efficient utilisation of feeds by ruminants. This study aimed to produce two enzymatic extracts, apply them in ruminant diets to determine the best levels for ruminal digestibility and evaluate their effects on in vitro digestibility. RESULTS: In experiment 1 a two-stage in vitro technique was used to examine the effects of different enzymatic levels of Aspergillus japonicus and Aspergillus terricola on tropical forages. Enzyme addition had minor effects on corn silage at the highest enzymatic level. In experiment 2 an in vitro gas production (GP) technique was applied to determine apparent in vitro organic matter digestibility and metabolisable energy. The addition of enzymes in GP showed interesting results. Good data were obtained using sugar cane and Tifton-85 hay supplemented with extracts of A. japonicus and A. terricola respectively. CONCLUSION: Overall, the study suggests that addition of crude extracts containing exogenous fibrolytic enzymes to ruminant diets enhances the effective utilisation of ruminant feedstuffs such as forages.

Combined Spinal-Epidural for Loop Ileostomy in a Patient With End-Stage Amyotrophic Lateral Sclerosis: A Case Report.

Anesthesia can be a challenge for patients with amyotrophic lateral sclerosis (ALS). This progressive neurological disease is associated with a high risk of aspiration and postoperative ventilatory failure. Our patient was a 72-year-old man with ALS, quadriplegia, bulbar symptoms, dysphagia, and dysarthria who underwent palliative exploratory laparotomy and loop ileostomy creation. He received a single-shot spinal anesthetic at L4-L5 and a thoracic T11-12 epidural. He tolerated the procedure well with no perioperative pulmonary complications or worsening of his ALS. To reduce the risks of general anesthesia, we chose a neuraxial approach.

RNA meets disease in paradise.

Getting off the train in Jena-Paradies, 60 participants joined for the 12 (th) Young Scientist Meeting of the German Society for Cell Biology (DGZ) entitled "RNA & Disease". Excellent speakers from around the world, graduate students, postdocs and young group leaders enjoyed a meeting in a familiar atmosphere to exchange inspiring new data and vibrant scientific discussions about the fascinating history and exciting future of non-coding RNA research including microRNA, piRNA and long non-coding RNA as well as their function in cancer, diabetes and neurodegenerative diseases.

Shape, Size, and Internal Dynamics of Loosely Bound Colloidlike Ionic Clusters in Ternary Solvent Systems.

We characterize the influence of preferential solvation on the dynamic self-assembly process between small dianionic salts and a macrocyclic tetraimidazolium molecular box into highly defined, colloidlike ionic clusters in solution, called ionoids. Here, we substitute individual solvents in the established optimal ternary solvent mixture dimethyl sulfoxide (DMSO)/glycerol/water 50:43:7 (v/v/v), namely, DMSO through dimethyl formamide, glycerol through ethylene glycol and water through N-methylpropionamide, and such can characterize the changes in shape and size of the structures of loosely bound ionic clusters induced by the substitution of a specific solvent component. Using dynamic light scattering we associate size, shape, and initial durability of ionic clusters with solvent parameters like dynamic viscosity and relative permittivity to highlight the importance of solvent composition for the build-up of globular ionoids as well as anisotropic ionic clusters. To further analyze the solvation state of our dianionic building unit inside the initial ion cloud state, which later affects the self-assembly process of ionic clusters, we perform continuous wave (CW) electron paramagnetic resonance spectroscopy measurements at X-band (∼9.4 GHz) and Q-band (∼34 GHz) frequencies.

Prosody-Based Sound-Emotion Associations in Poetry.

Conveying emotions in spoken poetry may be based on a poem's semantic content and/or on emotional prosody, i.e., on acoustic features above single speech sounds. However, hypotheses of more direct sound-emotion relations in poetry, such as those based on the frequency of occurrence of certain phonemes, have not withstood empirical (re)testing. Therefore, we investigated sound-emotion associations based on prosodic features as a potential alternative route for the, at least partially, non-semantic expression and perception of emotions in poetry. We first conducted a pre-study designed to validate relevant parameters of joy- and sadness-supporting prosody in the recitation, i.e. acoustic production, of poetry. The parameters obtained thereof guided the experimental modification of recordings of German joyful and sad poems such that for each poem, three prosodic variants were constructed: one with a joy-supporting prosody, one with a sadness-supporting prosody, and a neutral variant. In the subsequent experiment, native German speakers and participants with no command of German rated the joyfulness and sadness of these three variants. This design allowed us to investigate the role of emotional prosody, operationalized in terms of sound-emotion parameters, both in combination with and dissociated from semantic access to the emotional content of the poems. The findings from our pre-study showed that the emotional content of poems (based on pre-classifications into joyful and sad) indeed predicted the prosodic features pitch and articulation rate. The subsequent perception experiment revealed that cues provided by joyful and sad prosody specifically affect non-German-speaking listeners' emotion ratings of the poems. Thus, the present investigation lends support to the hypothesis of prosody-based iconic relations between perceived emotion and sound qualia. At the same time, our findings also highlight that semantic access substantially decreases the role of cross-language sound-emotion associations and indicate that non-German-speaking participants may also use phonetic and prosodic cues other than the ones that were targeted and manipulated here.

Is oncoplastic surgery a contraindication for accelerated partial breast radiation using the interstitial multicatheter brachytherapy method?

PURPOSE: To evaluate accelerated partial breast irradiation (APBI) in patients after oncoplastic surgery for early breast cancer. METHODS AND MATERIALS: A retrospective analysis of 136 breasts of 134 patients, who received breast-conserving oncoplastic surgery for low-risk breast cancer between 2002 and 2010 in the Universities of Vienna and Luebeck followed by adjuvant APBI applying total doses of pulse dose rate of 50.4 Gy or high-dose rate (HDR) of 32 Gy over 4 days. Target volume definition was performed by the use of surgical-free margin data, related to intraoperatively fixed clip positions, pre- and postoperative imaging, and palpation. RESULTS: At the time of data acquisition, 131 of 134 patients were alive. The median follow-up time was 39 months (range, 4-106 months). After high-dose rate treatment, 3 of 89 patients showed systemic progress after a mean follow-up of 47 months (range, 19-75 months) and 2 patients had a different quadrant in-breast tumor after 27 and 35 months. One patient died 7 months after treatment of unknown causes. After pulse dose rate treatment, 1 of 45 patients had a local recurrence after 42 months and 1 patient died because of another cause after 13 months. We observed mild fibrosis in 27 breasts, telangiectasia in 6, hyperpigmentation in 14 cases, and keloid formation in 1. CONCLUSIONS: These preliminary results suggest the feasibility of multicatheter APBI after oncoplastic breast-conserving surgery in selected low-risk breast cancer patients; however, special attention to target volume definition is needed. Further prospective investigations with long follow-up are needed to define the real value of the procedure.