Nevin Manimala

Bioinformatics. 2022 Mar 10:btac152. doi: 10.1093/bioinformatics/btac152. Online ahead of print.

ABSTRACT

SUMMARY: The genetic architecture of complex traits can be influenced by both many common regulatory variants with small effect sizes and rare deleterious variants in coding regions with larger effect sizes. However, the two kinds of genetic contributions are typically analyzed independently. Here we present GenRisk, a python package for the computation and the integration of gene scores based on the burden of rare deleterious variants and common-variants based polygenic risk scores. The derived scores can be analyzed within GenRisk to perform association tests or to derive phenotype prediction models by testing multiple classification and regression approaches. GenRisk is compatible with VCF input file formats.

AVAILABILITY AND IMPLEMENTATION: GenRisk is an open source publicly available python package that can be downloaded or installed from Github (https://github.com/AldisiRana/GenRisk).

SUPPLEMENTARY INFORMATION: GenRisk documentation is available online at https://genrisk.readthedocs.io/en/latest/.

PMID:35266528 | DOI:10.1093/bioinformatics/btac152

Rheumatology (Oxford). 2022 Mar 10:keac150. doi: 10.1093/rheumatology/keac150. Online ahead of print.

ABSTRACT

OBJECTIVES: Secondary inefficacy with infusion reactions and anti-drug antibodies (2NDNR) occurs in 14% of SLE patients receiving repeated rituximab courses. We evaluated baseline clinical characteristics, efficacy and safety of obinutuzumab, a next-generation humanised type-2 anti-CD20 antibody licensed for haematological malignancies in SLE patients with 2NDNR to rituximab.

METHODS: We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2x1000mg infusions alongside methylprednisolone 100 mg.

RESULTS: All 9 patients included in the study received obinutuzumab with concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (p= 0.014) and total BILAG-2004 score from 21 to 2 (p= 0.009). Complement C3 and dsDNA titres improved significantly (both p= 0.04). Numerical, but not statistically significant improvements were seen in C4 levels. Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10mg/day), 5/8 had their dose reduced at 6 months. 4/9 patients were on 5 mg/day and were in Lupus Low Disease Activity State following obinutuzumab. After obinutuzumab, 6/9 patients with peripheral B cell data achieved complete depletion including 4/4 assessed with highly-sensitive assays. 1/9 obinutuzumab non-responder required cyclophosphamide therapy. 1 unvaccinated patient died from COVID-19.

CONCLUSIONS: Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. These patients have severe disease with few treatment options but given responsiveness to B cell depletion, switching to humanised type-2 anti-CD20 therapy is a logical approach.

PMID:35266512 | DOI:10.1093/rheumatology/keac150

Adv Nutr. 2022 Mar 10:nmac025. doi: 10.1093/advances/nmac025. Online ahead of print.

ABSTRACT

Kiwifruit have known positive effects on digestion. During clinical intervention trials using kiwifruit to improve constipation, upper gastrointestinal (GI) symptoms such as abdominal discomfort and pain, indigestion, and reflux were also alleviated. We aimed to evaluate the evidence for upper GI symptom relief by kiwifruit in clinical trials on participants with functional constipation (FC), irritable bowel syndrome with constipation (IBS-C), and healthy participants, and to elucidate which symptoms may be relieved and whether a difference exists between the effects of gold and green kiwifruit. We executed a systematic scoping review of three electronic databases from 1947 through January 2021 to identify clinical trials that reported effects of green or gold kiwifruit or kiwifruit compounds on upper GI symptoms as secondary outcomes in healthy participants or participants with FC or IBS-C. Studies were divided into those using the Gastrointestinal Symptom Rating Score (GSRS) and those using alternative measurement tools. GSRS outcomes were pooled and statistically analysed, non-GSRS outcomes were summarised. We identified 12 clinical trials with a total of 661 participants (124 control, 537 receiving intervention) providing evidence for symptom relief of upper GI symptoms by kiwifruit intake. Only 5 of the 12 clinical trials used the GSRS to assess upper GI symptom relief. We found good evidence that green kiwifruit may reduce abdominal discomfort and pain, and some evidence that kiwifruit consumption may attenuate indigestion. Pooled GSRS outcome analysis indicates an average reduction of -0.85 (95% CI [-1.1, -0.57], Z = 6.1) in abdominal pain scores and -0.33 (95% CI [-0.52, -0.15], Z = -3.5) in indigestion scores with habitual kiwifruit consumption. While the number of studies reporting on upper GI symptom relief with a comparable measurement is limited, there is consistent evidence for efficacy of kiwifruit on upper GI symptom relief. More research to strengthen the evidence is recommended.

PMID:35266507 | DOI:10.1093/advances/nmac025

Soft Matter. 2022 Mar 10. doi: 10.1039/d1sm01594j. Online ahead of print.

ABSTRACT

The sedimentation process in an active suspension is the result of the competition between gravity and the autonomous motion of particles. We carry out simulations of run-and-tumble squirmers that move in a fluid medium, focusing on the dependence of the non-equilibrium steady state on the swimming properties. We find that for large enough activity, the density profiles are no longer simple exponentials; we recover the numerical results through the introduction of a local effective temperature, suggesting that the breakdown of the Perrin-like exponential form is a collective effect due to fluid-mediated dynamic correlations among particles. We show that analogous concepts can also fit the case of active non-motile particles, for which we report the first study of this kind. Moreover, we provide evidence of scenarios where the solvent hydrodynamics induces non-local effects which require the full three-dimensional dynamics to be taken into account in order to understand sedimentation in active suspensions. Finally, analyzing the statistics of the orientations of microswimmers, the emergence of a height-dependent polar order in the system is discussed.

PMID:35266484 | DOI:10.1039/d1sm01594j

Soft Matter. 2022 Mar 10. doi: 10.1039/d1sm01451j. Online ahead of print.

ABSTRACT

Under applied shear strain, granular and amorphous materials deform via particle rearrangements, which can be small and localized or organized into system-spanning avalanches. While the statistical properties of avalanches under quasi-static shear are well-studied, the dynamics during avalanches is not. In numerical simulations of sheared soft spheres, we find that avalanches can be decomposed into bursts of localized deformations, which we identify using an extension of persistent homology methods. We also study the linear response of unstable systems during an avalanche, demonstrating that eigenvalue dynamics are highly complex during such events, and that the most unstable eigenvector is a poor predictor of avalanche dynamics. Instead, we modify existing tools that identify localized excitations in stable systems, and apply them to these unstable systems with non-positive definite Hessians, quantifying the evolution of such excitations during avalanches. We find that bursts of localized deformations in the avalanche almost always occur at localized excitations identified using the linear spectrum. These new tools will provide an improved framework for validating and extending mesoscale elastoplastic models that are commonly used to explain avalanche statistics in glasses and granular matter.

PMID:35266483 | DOI:10.1039/d1sm01451j

Lab Chip. 2022 Mar 10. doi: 10.1039/d1lc00878a. Online ahead of print.

ABSTRACT

Electrode-based impedance and electrochemical measurements can provide cell-biology information that is difficult to obtain using optical-microscopy techniques. Such electrical methods are non-invasive, label-free, and continuous, eliminating the need for fluorescence reporters and overcoming optical imaging’s throughput/temporal resolution limitations. Nonetheless, electrode-based techniques have not been heavily employed because devices typically contain few electrodes per well, resulting in noisy aggregate readouts. Complementary metal-oxide-semiconductor (CMOS) microelectrode arrays (MEAs) have sometimes been used for electrophysiological measurements with thousands of electrodes per well at sub-cellular pitches, but only basic impedance mappings of cell attachment have been performed outside of electrophysiology. Here, we report on new field-based impedance mapping and electrochemical mapping/patterning techniques to expand CMOS-MEA cell-biology applications. The methods enable accurate measurement of cell attachment, growth/wound healing, cell-cell adhesion, metabolic state, and redox properties with single-cell spatial resolution (20 μm electrode pitch). These measurements allow the quantification of adhesion and metabolic differences of cells expressing oncogenes versus wild-type controls. The multi-parametric, cell-population statistics captured by the chip-scale integrated device opens up new avenues for fully electronic high-throughput live-cell assays for phenotypic screening and drug discovery applications.

PMID:35266462 | DOI:10.1039/d1lc00878a

Drug Deliv. 2022 Dec;29(1):821-836. doi: 10.1080/10717544.2022.2048131.

ABSTRACT

This study aimed to illustrate the use of D-optimal mixture design (DOMD) for optimization of an enhancer containing Dapsone niosomal formula for acne topical treatment. Mixture components (MixCs) studied were: Span 20, Cholesterol, and Cremophor RH. Different responses were measured. Optimized formula (OF) was selected to minimize particle size and maximize absolute zeta potential and entrapment efficiency. Optimized formula gel (OF-gel) was prepared and characterized. OF-gel in vivo skin penetration using confocal laser scanning microscopy and activity against Cutibacterium acnes in acne mouse model were studied. Based on DOMD results analysis, adequate models were derived. Piepel and contour plots were plotted accordingly to explain how alteration in MixCs L-pseudo values affected studied responses and regions for different responses’ values. The OF had suitable predicted responses which were in good correlation with the actually measured ones. The OF-gel showed suitable characterization and in vivo skin penetration up to the dermis layer. In vivo acne mouse-model showed that OF-gel-treated group (OF-gel-T-gp) had significantly better recovery (healing) criteria than untreated (UT-gp) and Aknemycin^®-treated (A-T-gp) groups. This was evident in significantly higher reduction of inflammation percent observed in OF-gel-T-gp than both UT-gp and A-T-gp. Better healing in OF-gel-T-gp compared with other groups was also verified by histopathological examination. Moreover, OF-gel-T-gp and A-T-gp bacterial loads were non-significantly different from each other but significantly lower than UT-gp. Thus, DOMD was an adequate statistical tool for optimization of an appropriate enhancer containing Dapsone niosomal formula that proved to be promising for topical treatment of acne.

PMID:35266431 | DOI:10.1080/10717544.2022.2048131

J Health Soc Behav. 2022 Mar 10:221465221078313. doi: 10.1177/00221465221078313. Online ahead of print.

ABSTRACT

Postmortem diagnostic overshadowing-defined as inaccurately reporting a disability as the underlying cause of death-occurs for over half of adults with cerebral palsy. This practice obscures cause of death trends, reducing the effectiveness of efforts to reduce premature mortality among this marginalized health population. Using data from the National Vital Statistics System 2005 to 2017 U.S. Multiple Cause of Death files (N = 29,996), we identify factors (sociodemographic characteristics, aspects of the context and processing of death, and comorbidities) associated with the inaccurate reporting of cerebral palsy as the underlying cause of death. Results suggest that inaccurate reporting is associated with heightened contexts of clinical uncertainty, the false equivalence of disability and health, and potential racial-ethnic bias. Ending postmortem diagnostic overshadowing will require training on disability and health for those certifying death certificates and efforts to redress ableist death certification policies.

PMID:35266426 | DOI:10.1177/00221465221078313

Mult Scler. 2022 Mar 10:13524585221078825. doi: 10.1177/13524585221078825. Online ahead of print.

ABSTRACT

BACKGROUND: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide.

OBJECTIVES: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS.

METHODS: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events.

RESULTS: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population.

CONCLUSION: The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).

PMID:35266417 | DOI:10.1177/13524585221078825

J Comp Eff Res. 2022 Mar 10. doi: 10.2217/cer-2021-0245. Online ahead of print.

ABSTRACT

Aim: To examine the economic impact of lives lost due to the coronavirus pandemic across California and Los Angeles (LA) County. Patients & methods: Years of potential life lost (YPLL) and the value of statistical life (VSL) were calculated using mortality data from the California Department of Public Health, the LA County Department of Public Health and the Social Security Administration websites. Results: In California and LA County, the average YPLL per person were 14.3 and 14.7 and the VSLs were approximately US$219.9 billion and $82.7 billion, respectively. YPLL and VSL were greatest for Latinos aged 50-64. Conclusion: The economic burden of lives lost due to the coronavirus across California and LA County is substantial. Latinos aged 50-64 were most affected.

PMID:35266408 | DOI:10.2217/cer-2021-0245