Nevin Manimala

PLoS Comput Biol. 2021 Mar 8;17(3):e1008822. doi: 10.1371/journal.pcbi.1008822. Online ahead of print.

ABSTRACT

An intriguing fact long defying explanation is the observation of a universal exponential distribution of beneficial mutations in fitness effect for different microorganisms. To explain this effect, we use a population model including mutation, directional selection, linkage, and genetic drift. The multiple-mutation regime of adaptation at large population sizes (traveling wave regime) is considered. We demonstrate analytically and by simulation that, regardless of the inherent distribution of mutation fitness effect across genomic sites, an exponential distribution of fitness effects emerges in the long term. This result follows from the exponential statistics of the frequency of the less-fit alleles, f, that we predict to evolve, in the long term, for both polymorphic and monomorphic sites. We map the logarithmic slope of the distribution onto the previously derived fixation probability and demonstrate that it increases linearly in time. Our results demonstrate a striking difference between the distribution of fitness effects observed experimentally for naturally occurring mutations, and the “inherent” distribution obtained in a directed-mutagenesis experiment, which can have any shape depending on the organism. Based on these results, we develop a new method to measure the fitness effect of mutations for each variable residue using DNA sequences sampled from adapting populations. This new method is not sensitive to linkage effects and does not require the one-site model assumptions.

PMID:33684109 | DOI:10.1371/journal.pcbi.1008822

PLoS One. 2021 Mar 8;16(3):e0243517. doi: 10.1371/journal.pone.0243517. eCollection 2021.

ABSTRACT

Deuterium (D), the second most abundant isotope of hydrogen is present in natural waters at an approximate concentration of 145-155 ppm (ca. 1.5E-4 atom/atom). D is known to influence various biological processes due to its physical and chemical properties, which significantly differ from those of hydrogen. For example, increasing D-concentration to >1000-fold above its natural abundance has been shown to increase the frequency of genetic mutations in several species. An interesting deterministic hypothesis, formulated with the intent of explaining the mechanism of D-mutagenicity is based on the calculation that the theoretical probability of base pairs to comprise two adjacent D-bridges instead of H-bridges is 2.3E-8, which is equal to the mutation rate of certain species. To experimentally challenge this hypothesis, and to infer the mutagenicity of D present at natural concentrations, we investigated the effect of a nearly 100-fold reduction of D concentration on the bacterial mutation rate. Using fluctuation tests, we measured the mutation rate of three Escherichia coli genes (cycA, ackA and galK) in media containing D at either <2 ppm or 150 ppm concentrations. Out of 15 pair-wise fluctuation analyses, nine indicated a significant decrease, while three marked the significant increase of the mutation/culture value upon D-depletion. Overall, growth in D-depleted minimal medium led to a geometric mean of 0.663-fold (95% confidence interval: 0.483-0.911) change in the mutation rate. This falls nowhere near the expected 10,000-fold reduction, indicating that in our bacterial systems, the effect of D abundance on the formation of point mutations is not deterministic. In addition, the combined results did not display a statistically significant change in the mutation/culture value, the mutation rate or the mutant frequency upon D-depletion. The potential mutagenic effect of D present at natural concentrations on E. coli is therefore below the limit of detection using the indicated methods.

PMID:33684107 | DOI:10.1371/journal.pone.0243517

PLoS Comput Biol. 2021 Mar 8;17(3):e1008256. doi: 10.1371/journal.pcbi.1008256. Online ahead of print.

ABSTRACT

Modern spatial transcriptomics methods can target thousands of different types of RNA transcripts in a single slice of tissue. Many biological applications demand a high spatial density of transcripts relative to the imaging resolution, leading to partial mixing of transcript rolonies in many voxels; unfortunately, current analysis methods do not perform robustly in this highly-mixed setting. Here we develop a new analysis approach, BARcode DEmixing through Non-negative Spatial Regression (BarDensr): we start with a generative model of the physical process that leads to the observed image data and then apply sparse convex optimization methods to estimate the underlying (demixed) rolony densities. We apply BarDensr to simulated and real data and find that it achieves state of the art signal recovery, particularly in densely-labeled regions or data with low spatial resolution. Finally, BarDensr is fast and parallelizable. We provide open-source code as well as an implementation for the ‘NeuroCAAS’ cloud platform.

PMID:33684106 | DOI:10.1371/journal.pcbi.1008256

Anesth Analg. 2021 Mar 8. doi: 10.1213/ANE.0000000000005458. Online ahead of print.

ABSTRACT

BACKGROUND: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial.

METHODS: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI.

RESULTS: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes.

CONCLUSIONS: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.

PMID:33684086 | DOI:10.1213/ANE.0000000000005458

J Med Internet Res. 2021 Mar 5. doi: 10.2196/26718. Online ahead of print.

ABSTRACT

This article will provide a perspective on data sharing practices in the context of the novel coronavirus disease (COVID-19) pandemic. The scientific community has made several important inroads in the fight against COVID-19 and there are over 2,500 clinical trials registered globally. Within the rapidly changing pandemic, we are seeing a large number of trials conducted without results made available. It is likely that a plethora of trials have stopped early, not for statistical reasons, but due to lack of feasibility. Trials stopped early for feasibility are, by definition, statistically underpowered and thereby prone to inconclusive findings. Statistical power is not necessarily linear with total sample size and even small reductions in patient numbers or events can have a substantial impact. Given the profusion of clinical trials investigating identical or similar treatments across different geographical and clinical contexts, one must also consider that the likelihood of substantial numbers of false positive and negative trials emerging with the increasing number of trials, adding to public perceptions of uncertainty. Complicating this is the evolving nature of the pandemic, where baseline assumptions on control group risk factors used to develop sample size calculations are far more challenging than in well-documented diseases. The standard answer to these challenges during non-pandemic settings is to assess each trial for statistical power and risk-of-bias and then pool the reported aggregated results using meta-analytic approaches. This solution simply will not suffice for COVID-19. Even with random-effects meta-analysis models, it will be difficult to adjust for heterogeneity of different trials with aggregated reported data alone, especially given the absence of common data standards and outcome measures. To date, several groups have proposed structures and partnerships for data sharing. As COVID-19 has forced reconsideration of policies, processes, and interests, this is the time to advance scientific cooperation and shift the clinical research enterprise toward a data-sharing culture to maximize our response in the service of public health.

PMID:33684053 | DOI:10.2196/26718

IEEE J Biomed Health Inform. 2021 Mar 8;PP. doi: 10.1109/JBHI.2021.3064353. Online ahead of print.

ABSTRACT

Automatic quantification of the left ventricle (LV) from cardiac magnetic resonance (CMR) images plays an important role in making the diagnosis procedure efficient, reliable, and alleviating the laborious reading work for physicians. Considerable efforts have been devoted to LV quantification using different strategies that include segmentation-based (SG) methods and the recent direct regression (DR) methods. Although both SG and DR methods have obtained great success for the task, a systematic platform to benchmark them remains absent because of differences in label information during model learning. In this paper, we conducted an unbiased evaluation and comparison of cardiac LV quantification methods that were submitted to the Left Ventricle Quantification (LVQuan) challenge, which was held in conjunction with the Statistical Atlases and Computational Modeling of the Heart (STACOM) workshop at the MICCAI 2018. The challenge was targeted at the quantification of 1) areas of LV cavity and myocardium, 2) dimensions of the LV cavity, 3) regional wall thicknesses (RWT), and 4) the cardiac phase, from mid-ventricle short-axis CMR images. First, we constructed a public quantification dataset Cardiac-DIG with ground truth labels for both the myocardium mask and these quantification targets across the entire cardiac cycle. Then, the key techniques employed by each submission were described. Next, quantitative validation of these submissions were conducted with the constructed dataset. The evaluation results revealed that both SG and DR methods can offer good LV quantification performance, even though DR methods do not require densely labeled masks for supervision. Among the 12 submissions, the DR method LDAMT offered the best performance, with a mean estimation error of 301 mm^2 for the two areas, 2.15 mm for the cavity dimensions, 2.03 mm for RWTs, and a 9.5% error rate for the cardiac phase classification. Three of the SG methods also delivered comparable performances. Finally, we discussed the advantages and disadvantages of SG and DR methods, as well as the unsolved problems in automatic cardiac quantification for clinical practice applications.

PMID:33684050 | DOI:10.1109/JBHI.2021.3064353

IEEE Trans Neural Syst Rehabil Eng. 2021 Mar 8;PP. doi: 10.1109/TNSRE.2021.3064148. Online ahead of print.

ABSTRACT

Sensory abnormalities are experienced by 90 – 95% of individuals with Autism Spectrum Disorder (ASD), a developmental disorder that impacts at least 1 in 132 children worldwide. Virtual reality (VR) technologies can precisely present sensory stimuli and be integrated with human sensing technologies to automatically detect sensory responses, and thus has a potential to improve sensory assessment objectiveness and sensitivity, compared to traditional questionnaire-based methods. However, there is a lack of evidence to demonstrate this potential. Therefore, we designed and developed a preliminary sensory assessment VR system (SAVR) to objectively and precisely evaluate the visual and touch sensory processing differences between adolescents with ASD and their typically developing (TD) peers through game playing. A controlled experiment was conducted with 12 adolescents with ASD and 12 TD adolescents. Participants’ sensory pattern was assessed by SAVR and a widely used traditional questionnaire-the Adult/Adolescent Sensory Profile (AASP). We hypothesized that: 1) compared to AASP, SAVR can find more significant differences between the two participant groups, and 2) there are significant and strong correlations between the SAVR results and the AASP results. Statistical analyses of the experimental data supported the hypotheses. The implication and limitations of this preliminary exploration as well as future works are discussed.

PMID:33684040 | DOI:10.1109/TNSRE.2021.3064148

J Math Biol. 2021 Mar 8;82(4):30. doi: 10.1007/s00285-021-01573-7.

ABSTRACT

A game-theoretical model is constructed to capture the effect of imitation on the evolution of cooperation. This imitation describes the case where successful individuals are more likely to be imitated by newcomers who will employ their strategies and social networks. Two classical repeated strategies ‘always defect (ALLD)’ and ‘tit-for-tat (TFT)’ are adopted. Mathematical analyses are mainly conducted by the method of coalescence theory. Under the assumption of a large population size and weak selection, the results show that the evolution of cooperation is promoted in this dynamic network. As we observed that the critical benefit-to-cost ratio is smaller compared to that in well-mixed populations. The critical benefit-to-cost ratio approaches a specific value which depends on three parameters, the repeated rounds of the game, the effective strategy mutation rate, and the effective link mutation rate. Specifically, for a very high value of the effective link mutation rate, the critical benefit-to-cost ratio approaches 1. Remarkably, for a low value of the effective link mutation rate, by letting the effective strategy mutation is nearly equal to zero, the critical benefit-to-cost ratio approaches [Formula: see text] for the resulting highly connected networks, which allows TFT to be evolutionary stable. It illustrates that dominance of TFTs is associated with more connected networks. This research can enrich the theory of the coevolution of game strategy and network structure with dynamic imitation.

PMID:33683438 | DOI:10.1007/s00285-021-01573-7

Surg Endosc. 2021 Mar 8. doi: 10.1007/s00464-021-08366-5. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Laparoscopic liver resections (LLR) of bilobar colorectal liver metastases (CRLM) are challenging and the safety and long-term outcomes are unclear. In this study, the short- and long-term outcomes and recurrence patterns of one-stage LLR for bilobar CRLM were compared to single laparoscopic resection for CRLM.

METHODS: This single-center study consisted of all patients who underwent a parenchymal sparing LLR for CRLM between October 2011 and December 2018. Demographics, perioperative outcomes, short-term outcomes, oncologic outcomes and recurrence patterns were compared. Data were retrieved from a prospectively maintained database.

RESULTS: Thirty six patients underwent a LLR for bilobar CRLM and ninety patients underwent a single LLR. Demographics were similar among groups. More patients received neoadjuvant chemotherapy in the bilobar group (55.6% vs 34.4%, P = 0.03). There was no difference in conversion rate, R0 resection and transfusion rate. Blood loss and operative time were higher in the bilobar group (250 ml (IQR 150-450) vs 100 ml (IQR 50-250), P < 0.001 and 200 min (IQR 170-230) vs 130 min (IQR 100-165), P < 0.001) and hospital stay was longer (5 days (IQR 4-7) vs 4 days (IQR 3-6), P = 0.015). The bilobar group had more technically major resections (88.9% vs 56.7%, P < 0.001). Mortality was nil in both groups and major morbidity was similar (2.8% vs 3.3%, P = 1.0). There was no difference in recurrence pattern. Overall survival (OS) was similar (1 yr: 96% in both groups and 5 yr 76% vs 66%, P = 0.49), as was recurrence-free survival (RFS) (1 yr: 64% vs 73%, 3 yr: 38 vs 42%, 5 yr: 38% vs 28%, P = 0.62).

CONCLUSION: In experienced hands, LLR for bilobar CRLM can be performed safely with similar oncologic outcomes as patients who underwent a single LLR for CRLM.

PMID:33683435 | DOI:10.1007/s00464-021-08366-5

Graefes Arch Clin Exp Ophthalmol. 2021 Mar 8. doi: 10.1007/s00417-021-05144-w. Online ahead of print.

ABSTRACT

PURPOSE: Two-year post-operative outcomes of both deep sclerectomy (DS) and trabeculectomy surgery (Trab) augmented with Mitomycin C (MMC) at a single tertiary eye centre.

METHODS: Retrospective review of DS + MMC and trabeculectomy + MMC at a single centre between February 2015 and March 2018. Patients with a minimum of 12-month follow-up were included. Post-operative follow-up: day 1, week 1, months 1/3/6/12/18/24. Primary outcomes: changes in intraocular pressure (IOP) and changes in LogMAR visual acuity (BCVA) pre- and post-procedure.

SECONDARY OUTCOMES: changes in number of eye drops, number of follow-up clinic visits, post-operative complications and further surgical interventions. Complete success: IOP ≤ 21 mmHg off all IOP-lowering medications. Qualified success: IOP ≤ 21 mmHg on medication. Failure: IOP > 21 mmHg at 24 months or ≤ 5 mmHg on 2 consecutive follow-up visits after 3 months +/- additional incisional glaucoma surgery +/- loss of light perception. Statistical analysis performed using Microsoft Excel + SPSS.

RESULTS: 90 eyes: DS + MMC = 46 eyes, Trab + MMC = 44 eyes. DS + MMC v Trab + MMC: mean pre-op IOP = 19.57 mmHg v 18.89 mmHg, significantly reduced at all post-operative time-points for both groups (p < 0.001). Mean IOP reduction from baseline = 33.94% v 38.39%; > 30% IOP reduction = 54.35% v 68.18%. IOP ≤ 16 mmHg = 82.61% (38/46) v 95.46% (42/44), IOP ≤ 12 mmHg = 52.17% (24/46) v 72.72% (32/44). Complete success = 67.39% v 61.36%, qualified success = 26.09% v 29.55%, failure = 6.52% v 9.09%. Post-op BCVA: no statistically significant differences between two groups (p = 0.09). Mean pre-op drops v post-op drops = 2.98 v 0.38 (DS + MMC; p < 0.001); 2.68 v 0.39 (Trab + MMC; p < 0.001). Further surgical intervention = 13% v 29.55%. Mean number of post-op clinic visits DS + MMC v Trab + MMC = 10.09 v 13.02 (p = 0.005).

CONCLUSION: Both procedures achieve sustained intraocular pressure and drop reduction at 2 years post-op. DS + MMC has lower complication rates requiring less intervention and significantly fewer clinic visits, which may be an important factor for deciding surgical management of glaucoma patients in the era of Covid-19 to reduce patient/clinician exposure to the virus.

PMID:33683432 | DOI:10.1007/s00417-021-05144-w