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Cell sorting and differential motion are key processes in the life cycle of Dictyostelium discoideum (Dd) and many other organisms. Here we develop a mathematical model and investigate the processes with computer simulations. The slug stage of Dd is modeled with ellipsoidal cells of two types which have viscoelastic properties. Using the force-based model we find that when the two cell types have different strengths of motive forces and or different degrees of directionality one cell type sorts to the front of the slug. These findings are consistent with previously published results using a different model formation. When one cell type is more directed than the other it will consistently sort to the front of the slug. Likewise, but less efficiently, when one cell type exerts greater motive forces than the other it will sort to the front of the slug. The most efficient and robust cell sorting due to differential motion is when both methods are employed.

Little is known about the impact of drug-resistance on clinical outcomes among patients with tuberculosis meningitis (TBM). A retrospective cohort study among patients treated for TBM in Tbilisi, Georgia. We performed medical chart abstraction to collect patient data. Long-term vital status was assessed using the Georgia National Death Registry. We utilized a Cox proportional-hazards model to evaluate the association of drug-resistance and mortality. Among 343 TBM suspects, 237 had a presentation consistent with TBM. Drug resistance was suspected (n = 5) or confirmed (n = 31) in 36 patients including 30 with multidrug- or rifampin-resistance and 6 with isoniazid-resistance. Thirty-four patients had HIV. The median follow-up time was 1331 days (IQR, 852-1767). Overall, 73 of 237 (30%) people died with 50 deaths occurring during and 23 after treatment. The proportion of death was higher among patients with drug-resistant vs. drug-susceptible disease (67% vs. 24%, p<0.001) and with HIV versus no HIV (59% vs 27%, p<0.001). Mortality was significantly higher in patients with drug-resistant TBM after 90 days of treatment (aHR = 7.2, CI95% [3.6-14.3], p < 0.001). Mortality was high among patients with drug-resistant TBM with many deaths occurring post treatment. More effective treatment options are urgently needed for drug-resistant TBM.

The diagnosis of incurable cancer can disrupt life stories, undermining meaning-making and challenging self-identity. People may therefore need to search for and create new stories about their lives that incorporate their diagnosis. Arts-based narrative interventions are being explored to support this existential process of narrative meaning-making. However, developing effective existential support may be limited by the lack of methods capable of investigating their impact. This study is the first to explore narrative meaning-making across time and a meaning-centred care intervention by longitudinally using ‘Rich Pictures’ (RPs) – hand-drawn visual narratives. We analysed repeated RPs about living with incurable cancer from thirty-eight participants in two studies: one incorporating an arts-based narrative intervention, and one without. RPs were compared across time and the two groups using an inductive, multi-level, and participatory analysis approach. Our findings highlighted six strategies variably used by participants to reconstruct their narratives over time: repeating, retaining, repurposing, reinforcing, reducing, and reassembling. Differences were found in the employment of these strategies between the two different studies, with arts-based intervention participants predominantly developing new ways of narrating and relating to cancer as a disruptive life event. We conclude that people living with incurable cancer employ a range of strategies in reconstructing their narratives. Arts-based interventions may support this existential process. The repeated use of RPs is a valuable method for investigating narrative meaning-making over time, across groups, and interventions, offering insights to evaluate and develop meaning-centred care in oncology.

WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50–70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis. We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test. From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47–87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23–66; 10/23) for Xpert and 43% (23–66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77–99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24–68]; 10/22; p=0·0010) or culture (45% [24–68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014). Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis. National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation.

We examine whether social data can be used to predict how members of Major League Baseball (MLB) and members of the National Basketball Association (NBA) transition between teams during their career. We find that incorporating social data into various machine learning algorithms substantially improves the algorithms’ ability to correctly determine these transitions in the NBA but only marginally in MLB. We also measure the extent to which player performance and team fitness data can be used to predict transitions between teams. This data, however, only slightly improves our predictions for players for both basketball and baseball players. We also consider whether social, performance, and team fitness data can be used to infer past transitions. Here we find that social data significantly improves our inference accuracy in both the NBA and MLB but player performance and team fitness data again does little to improve this score.

The Patient-Centered Outcomes Research Institute’s (PCORI) methodology standards for qualitative methods and mixed methods research help ensure that research studies are designed and conducted to generate the evidence needed to answer patients’ and clinicians’ questions about which methods work best, for whom, and under what circumstances. This set of standards focuses on factors pertinent to patient centered outcomes research, but it is also useful for providing guidance for other types of clinical research. The standards can be used to develop and evaluate proposals, conduct the research, and interpret findings. The standards were developed following a systematic process: survey the range of key methodological issues and potential standards, narrow inclusion to standards deemed most important, draft preliminary standards, solicit feedback from a content expert panel and the broader public, and use this feedback to develop final standards for review and adoption by PCORI’s board of governors. This article provides an example on how to apply the standards in the preparation of a research proposal.

Fluorescence Recovery After Photobleaching (FRAP) has been extensively used to understand molecular dynamics in cells. This technique when applied to soluble, globular molecules driven by diffusion is easily interpreted and well understood. However, the classical methods of analysis cannot be applied to anisotropic structures subjected to directed transport, such as cytoskeletal filaments or elongated organelles transported along microtubule tracks. A new mathematical approach is needed to analyze FRAP data in this context and determine what information can be obtain from such experiments. To address these questions, we analyze fluorescence intensity profile curves after photobleaching of fluorescently labelled intermediate filaments anterogradely transported along microtubules. We apply the analysis to intermediate filament data to determine information about the filament motion. Our analysis consists of deriving equations for fluorescence intensity profiles and developing a mathematical model for the motion of filaments and simulating the model. Two closed forms for profile curves were derived, one for filaments of constant length and one for filaments with constant velocity, and three types of simulation were carried out. In the first type of simulation, the filaments have random velocities which are constant for the duration of the simulation. In the second type, filaments have random velocities which instantaneously change at random times. In the third type, filaments have random velocities and exhibit pausing between velocity changes. Our analysis shows: the most important distribution governing the shape of the intensity profile curves obtained from filaments is the distribution of the filament velocity. Furthermore, filament length which is constant during the experiment, had little impact on intensity profile curves. Finally, gamma distributions for the filament velocity with pauses give the best fit to asymmetric fluorescence intensity profiles of intermediate filaments observed in FRAP experiments performed in polarized migrating astrocytes. Our analysis also shows that the majority of filaments are stationary. Overall, our data give new insight into the regulation of intermediate filament dynamics during cell migration.

Multiplexed hybridization probes are traditionally difficult to design with high sensitivity and specificity. Here Wu et al . present a method for fine, decoupled and on-the-fly tuning of probe behavior based on the stoichiometric formulation of a molecular competitor species. In silico –designed nucleic acid probes and primers often do not achieve favorable specificity and sensitivity tradeoffs on the first try, and iterative empirical sequence-based optimization is needed, particularly in multiplexed assays. We present a novel, on-the-fly method of tuning probe affinity and selectivity by adjusting the stoichiometry of auxiliary species, which allows for independent and decoupled adjustment of the hybridization yield for different probes in multiplexed assays. Using this method, we achieved near-continuous tuning of probe effective free energy. To demonstrate our approach, we enforced uniform capture efficiency of 31 DNA molecules (GC content, 0–100%), maximized the signal difference for 11 pairs of single-nucleotide variants and performed tunable hybrid capture of mRNA from total RNA. Using the Nanostring nCounter platform, we applied stoichiometric tuning to simultaneously adjust yields for a 24-plex assay, and we show multiplexed quantitation of RNA sequences and variants from formalin-fixed, paraffin-embedded samples.