Persistence is key: Refining immunotherapy response prediction.

Tumor mutation burden (TMB) is a proven, but imperfect, immune checkpoint blockade (ICB) response-predictor. Recently in Nature Medicine, Niknafs et al. demonstrate that persistent mutation burden, a subset of TMB, is an improved metric to predict patient ICB therapy outcome.

Disease Modeling with 3D Cell-Based Assays Using a Novel Flowchip System and High-Content Imaging.

There is an increasing interest in using three-dimensional (3D) cell structures for modeling tumors, organs, and tissue to accelerate translational research. We describe here a novel automated organoid assay system (the Pu·MA System) combined with microfluidic-based flowchips that can facilitate 3D cell-based assays. The flowchip is composed of sample wells, which contain organoids, connected to additional multiple wells that can hold various assay reagents. Organoids are positioned in a protected chamber in sample wells, and fluids are exchanged from side reservoirs using pressure-driven flow. Media exchange, sample staining, wash steps, and other processes can be performed without disruption to or loss of 3D sample. The bottom of the sample chamber is thin, optically clear plastic compatible with high-content imaging (HCI). The whole system can be kept in an incubator, allowing long-term cellular assays to be performed. We present two examples of use of the system for biological research. In the first example, cytotoxicity effects of anticancer drugs were evaluated on HeLa and HepG2 spheroids using HCI and vascular endothelial growth factor expression. In the second application, the flowchip system was used for the functional evaluation of Ca2+ oscillations in neurospheroids. Neurospheres were incubated with neuroactive compounds, and neuronal activity was assessed using Ca2+-sensitive dyes and fast kinetic fluorescence imaging. This novel assay system using microfluidics enables automation of 3D cell-based cultures that mimic in vivo conditions, performs multidosing protocols and multiple media exchanges, provides gentle handling of spheroids and organoids, and allows a wide range of assay detection modalities.

Efficacy of Phase 1 of Life Goals Programme on symptom reduction and mood stability for bipolar disorder.

BACKGROUND: Life Goals Programme (LGP) was developed as a psychological intervention for bipolar disorder, with its structured 6-session psychoeducation phase (Phase 1) targeting understanding of the disorder, medication adherence, early warning signs, and coping with symptoms and triggers. The present study tested the efficacy of Phase 1 of the LGP on symptom recovery and moment-by-moment mood stability, as well as medication adherence and quality of life. METHODS: Adults with bipolar disorder were randomly allocated to the LGP condition (six weekly group sessions) or the waitlist condition (six weeks of standard care, followed by the same LGP intervention). Participants were assessed before and after treatment, and at 6-month follow up. Waitlist participants were additionally assessed at baseline. Assessment included a clinical interview (SCID, MADRS, YMRS, and HAM-A), self-reported questionnaires, and 6-day experience sampling assessment on a mobile device. RESULTS: 64 out-patients with bipolar disorder (44 Bipolar I and 20 Bipolar II subtypes) participated in this study. LGP was well received and attended. Following LGP, there were significant improvements in knowledge about illness and level of anxiety, which were of large effect sizes and sustained at 6-month follow-up. Experience sampling assessment revealed small but significant improvements in moment-by-moment mood stability. Improvement in medication adherence was significant at 6 months and was of a moderate-to-large effect size. Changes in anxiety and mood stability were significantly greater following LGP than standard care. LIMITATIONS: Our results warrant further testing against active control. CONCLUSIONS: There was a robust improvement in emotional regulation following the 6-week LGP.

Natural barriers: waterfall transit by small flying animals.

Waterfalls are conspicuous geomorphological features with heterogeneous structure, complex dynamics and multiphase flows. Swifts, dippers and starlings are well-known to nest behind waterfalls, and have been reported to fly through them. For smaller fliers, by contrast, waterfalls seem to represent impenetrable barriers, but associated physical constraints and the kinematic responses of volant animals during transit are unknown. Here, we describe the flight behaviour of hummingbirds (the sister group to the swifts) and of various insect taxa as they fly through an artificial sheet waterfall. We additionally launched plastic balls at different speeds at the waterfall so as to assess the inertial dependence of sheet penetration. Hummingbirds were able to penetrate the waterfall with reductions in both their translational speed, and stroke amplitude. The body tilted more vertically and exhibited greater rotations in roll, pitch and yaw, along with increases in tail spread and pitch. The much smaller plastic balls and some flies moving at speeds greater than 2.3 m s-1 and 1.6 m s-1, respectively, also overcame effects of surface tension and water momentum and passed through the waterfall; objects with lower momentum, by contrast, entered the sheet but then fell along with the moving water. Waterfalls can thus represent impenetrable physical barriers for small and slow animal fliers, and may also serve to exclude both predators and parasites from nests of some avian taxa.

Moment-to-moment interaction between affectivity and coping behaviours in bipolar disorder and the role of cognitive appraisals.

BACKGROUND: Individuals with bipolar disorder respond to affective symptoms with a range of coping behaviours, which may further maintain the symptoms. AIMS: To examine moment-to-moment dynamics between affective states and coping behaviours, and to evaluate the role of cognitive appraisals of internal states as moderators. METHOD: Forty-six individuals with bipolar disorder completed a clinical interview and an experience sampling assessment over 6 days. Time-lagged analyses were conducted by multilevel regression modelling. RESULTS: A total of 1807 momentary entries were analysed. Negative affect predicted an increase in rumination at the subsequent time point (ß = 0.21, s.e. = 0.08, P = 0.009, 95% CI 0.05-0.36), and vice versa (ß = 0.03, s.e. = 0.01, P = 0.009, 95% CI 0.01-0.05). Positive affect predicted an increase in adaptive coping (ß = 0.26, s.e. = 0.11, P = 0.018, 95% CI 0.04-0.47), and vice versa (ß = 0.02, s.e. = 0.01, P = 0.019, 95% CI 0.00-0.03). Positive affect also predicted a decrease in rumination (ß = -0.15, s.e. = 0.06, P = 0.014, 95% CI -0.26 to -0.03), and vice versa (ß = -0.03, s.e. = 0.01, P = 0.016, 95% CI -0.06 to -0.01). Extreme cognitive appraisals predicted stronger associations between affective states and coping behaviours. CONCLUSIONS: Feedback loops between affective states and coping behaviours were revealed in the daily life of individuals with bipolar disorder, which were moderated by extreme cognitive appraisals. DECLARATION OF INTEREST: None.

Normal sonographic renal length measurements in an Australian pediatric population.

BACKGROUND: Reference charts depicting normal growth are important for the sonographic assessment of the pediatric kidney. Limited charts are available for clinical use in an Australian population. OBJECTIVE: To retrospectively collate sonographic renal length measurements in a cohort of low-risk Australian children aged newborn to 16 years to produce a reference table and comparison with other published charts. MATERIALS AND METHODS: We identified consecutive pediatric patients who were at low risk for renal disease and had renal lengths measured. After exclusions, we included 941 renal lengths (male 490, female 451). We used linear regression to estimate the relationship of renal length with age, gender and side. We calculated percentile values of renal length according to age categories. RESULTS: No statistically significant differences in mean renal length were observed between males and females, or for left and right kidneys. We tabulated reference data and provide them in a reference chart (1-, 2.5-, 5-, 10-, 50-, 90-, 97.5- and 99-percentiles). CONCLUSION: We calculated new reference ranges for pediatric renal length using a larger cohort than previously published, from a population with diverse ethnicity.

The impact of bacteriophages on phyllosphere bacterial abundance and composition.

Interactions between bacteria and bacteriophage viruses (phages) are known to influence pathogen growth and virulence, microbial diversity and even biogeochemical cycling. Lytic phages in particular infect and lyse their host cells, and can therefore have significant effects on cell densities as well as competitive dynamics within microbial communities. Despite the known impacts of lytic phages on the ecology and evolution of bacteria in free-living communities, little is known about the role of lytic phages in host-associated microbiomes. We set out to characterize the impact of phages in the tomato phyllosphere, that is the bacteria associated with above-ground plant tissues, by transferring microbial communities from field-grown tomato plants to juvenile plants grown under mostly sterile conditions in either the presence or absence of their associated phage community. In three separate experiments, we found that the presence of phages affects overall bacterial abundance during colonization of new host plants. Furthermore, bacterial community analysis using 16S rRNA amplicon sequencing shows that phages significantly alter the relative abundance of dominant community members and can influence both within- and among-host diversity. These results underscore the importance of lytic phages in host-associated microbiomes and are relevant to microbiome transplantation approaches, as they suggest transferring nonbacterial components of the microbiome among hosts is likely to have a strong impact on growth of both the resident and colonizing microbiota.

CIG-P: Circular Interaction Graph for Proteomics.

BACKGROUND: A typical affinity purification coupled to mass spectrometry (AP-MS) experiment includes the purification of a target protein (bait) using an antibody and subsequent mass spectrometry analysis of all proteins co-purifying with the bait (aka prey proteins). Like any other systems biology approach, AP-MS experiments generate a lot of data and visualization has been challenging, especially when integrating AP-MS experiments with orthogonal datasets. RESULTS: We present Circular Interaction Graph for Proteomics (CIG-P), which generates circular diagrams for visually appealing final representation of AP-MS data. Through a Java based GUI, the user inputs experimental and reference data as file in csv format. The resulting circular representation can be manipulated live within the GUI before exporting the diagram as vector graphic in pdf format. The strength of CIG-P is the ability to integrate orthogonal datasets with each other, e.g. affinity purification data of kinase PRPF4B in relation to the functional components of the spliceosome. Further, various AP-MS experiments can be compared to each other. CONCLUSIONS: CIG-P aids to present AP-MS data to a wider audience and we envision that the tool finds other applications too, e.g. kinase - substrate relationships as a function of perturbation. CIG-P is available under: http://sourceforge.net/projects/cig-p/

Analysis of 30-day readmissions among neurosurgical patients: surgical complication avoidance as key to quality improvement.

UNLABELLED: OBJECT.: In terms of measuring quality of care and hospital performance, an outcome of increasing interest is the 30-day readmission rate. Recent health care policy making has highlighted the necessity of understanding the factors that influence readmission. To elucidate the rate, reason, and predictors of readmissions at a tertiary/quaternary neurosurgical service, the authors studied 30-day readmissions for the Department of Neurosurgery at two University of California, Los Angeles (UCLA), hospitals. METHODS: Over a 3-year period, the authors retrospectively identified adult and pediatric patients who had been discharged from the UCLA Medical Center after having undergone a major neurosurgical procedure and being readmitted within 30 days. Data were obtained on demographics, follow-up findings, diagnosis and reason for readmission, major operations performed, and length of stay during index admission and readmission. Reasons for readmission were broadly categorized into surgical, medical diagnosis/complication, problem associated with the original diagnosis, neurological decompensation, pain management, and miscellaneous. For further characterization, subgroup analysis and in-depth chart review were performed. RESULTS: Over the study period, 365 (6.9%) of 5569 patients were readmitted within 30 days. The most common diagnosis at index admission was brain tumor (102 patients), followed by CSF shunt malfunction (63 patients). The most common reason for readmission was surgical complication (50.1%). Among those with surgical complications, the largest subgroup consisted of patients with CSF shunt-related problems (77 patients). The second and third largest subgroups were surgical site infection and CSF leakage (41 and 31 patients, respectively). Medical diagnosis/complication was the second most frequent (27.9%) reason for readmission. CONCLUSIONS: Surgical complications seem to be a major reason for readmission at the neurosurgical practice studied. Results indicate that the outcomes that are amenable to and would have the greatest effect on quality improvement are CSF shunt-related complications, surgical site infections, and CSF leaks.

Subclinical early posttraumatic seizures detected by continuous EEG monitoring in a consecutive pediatric cohort.

PURPOSE: Traumatic brain injury (TBI) is an important cause of morbidity and mortality in children, and early posttraumatic seizures (EPTS) are a contributing factor to ongoing acute damage. Continuous video-EEG monitoring (cEEG) was utilized to assess the burden of clinical and electrographic EPTS. METHODS: Eighty-seven consecutive, unselected (mild - severe), acute TBI patients requiring pediatric intensive care unit (PICU) admission at two academic centers were monitored prospectively with cEEG per established clinical TBI protocols. Clinical and subclinical seizures and status epilepticus (SE, clinical and subclinical) were assessed for their relation to clinical risk factors and short-term outcome measures. KEY FINDINGS: Of all patients, 42.5% (37/87) had seizures. Younger age (p = 0.002) and injury mechanism (abusive head trauma - AHT, p < 0.001) were significant risk factors. Subclinical seizures occurred in 16.1% (14/87), while 6.9% (6/87) had only subclinical seizures. Risk factors for subclinical seizures included younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p < 0.001). SE occurred in 18.4% (16/87) with risk factors including younger age (p < 0.001), AHT (p < 0.001), and intraaxial bleed (p = 0.002). Subclinical SE was detected in 13.8% (12/87) with significant risk factors including younger age (p < 0.001), AHT (p = 0.001), and intraaxial bleed (p = 0.004). Subclinical seizures were associated with lower discharge King's Outcome Scale for Childhood Head Injury (KOSCHI) score (p = 0.002). SE and subclinical SE were associated with increased hospital length of stay (p = 0.017 and p = 0.041, respectively) and lower hospital discharge KOSCHI (p = 0.007 and p = 0.040, respectively). SIGNIFICANCE: cEEG monitoring significantly improves detection of seizures/SE and is the only way to detect subclinical seizures/SE. cEEG may be indicated after pediatric TBI, particularly in younger children, AHT cases, and those with intraaxial blood on computerized tomography (CT).