Nevin Manimala

Biotechnol Prog. 2023 Nov 24:e3413. doi: 10.1002/btpr.3413. Online ahead of print.

ABSTRACT

13C-Metabolic Flux Analysis (13C-MFA) and Flux Balance Analysis (FBA) are widely used to investigate the operation of biochemical networks in both biological and biotechnological research. Both methods use metabolic reaction network models of metabolism operating at steady state so that reaction rates (fluxes) and the levels of metabolic intermediates are constrained to be invariant. They provide estimated (MFA) or predicted (FBA) values of the fluxes through the network in vivo, which cannot be measured directly. These fluxes can shed light on basic biology and have been successfully used to inform metabolic engineering strategies. Several approaches have been taken to test the reliability of estimates and predictions from constraint-based methods and to compare alternative model architectures. Despite advances in other areas of the statistical evaluation of metabolic models, such as the quantification of flux estimate uncertainty, validation and model selection methods have been underappreciated and underexplored. We review the history and state-of-the-art in constraint-based metabolic model validation and model selection. Applications and limitations of the χ² -test of goodness-of-fit, the most widely used quantitative validation and selection approach in 13C-MFA, are discussed, and complementary and alternative forms of validation and selection are proposed. A combined model validation and selection framework for 13C-MFA incorporating metabolite pool size information that leverages new developments in the field is presented and advocated for. Finally, we discuss how adopting robust validation and selection procedures can enhance confidence in constraint-based modeling as a whole and ultimately facilitate more widespread use of FBA in biotechnology.

PMID:37997613 | DOI:10.1002/btpr.3413

Int J Digit Earth. 2023;16(1):130-157. doi: 10.1080/17538947.2022.2161652. Epub 2023 Jan 3.

ABSTRACT

Geospatial social media (GSM) data has been increasingly used in public health due to its rich, timely, and accessible spatial information, particularly in infectious disease research. This review synthesized 86 research articles that use GSM data in infectious diseases published between December 2013 and March 2022. These articles cover 12 infectious disease types ranging from respiratory infectious diseases to sexually transmitted diseases with spatial levels varying from the neighborhood, county, state, and country. We categorized these studies into three major infectious disease research domains: surveillance, explanation, and prediction. With the assistance of advanced statistical and spatial methods, GSM data has been widely and deeply applied to these domains, particularly in surveillance and explanation domains. We further identified four knowledge gaps in terms of contextual information use, application scopes, spatiotemporal dimension, and data limitations and proposed innovation opportunities for future research. Our findings will contribute to a better understanding of using GSM data in infectious diseases studies and provide insights into strategies for using GSM data more effectively in future research.

PMID:37997607 | PMC:PMC10664840 | DOI:10.1080/17538947.2022.2161652

Stat Theory Relat Fields. 2023;7(2):159-163. doi: 10.1080/24754269.2023.2205802. Epub 2023 Apr 28.

ABSTRACT

To improve precision of estimation and power of testing hypothesis for an unconditional treatment effect in randomized clinical trials with binary outcomes, researchers and regulatory agencies recommend using g-computation as a reliable method of covariate adjustment. However, the practical application of g-computation is hindered by the lack of an explicit robust variance formula that can be used for different unconditional treatment effects of interest. To fill this gap, we provide explicit and robust variance estimators for g-computation estimators and demonstrate through simulations that the variance estimators can be reliably applied in practice.

PMID:37997606 | PMC:PMC10665030 | DOI:10.1080/24754269.2023.2205802

F1000Res. 2022 Jul 18;11:798. doi: 10.12688/f1000research.122108.1. eCollection 2022.

ABSTRACT

Background: Polymer infiltrated ceramic networks, or hybrid ceramics, are a combination of infiltrating polymerizable organic monomers into a pre-sintered porous ceramic matrix. In addition to having good mechanical properties, the polymer infiltrated ceramic network must comply with the possibility of adequate bonding to the resinous cement. The surface conditioning of this hybrid material must be carefully considered due to its organic composition and ceramic network. The purpose of this research is to evaluate the effect of hydrofluoric acid and a self-etching ceramic primer, under two different application times, on the bond strength of a polymer infiltrated ceramic network. Methods: Blocks of a polymer infiltrated ceramic network were cut to obtain sheets, and these were randomized into five groups. For the group termed AAS, airborne-particle abrasion with Al ₂O ₃ (aluminum oxide) of 50µm was used. For groups HF2 and HF6, hydrofluoric acid was used for 20 and 60 seconds respectively, and for the groups MB2 and MB6, a self-etch ceramic primer was applied for 20 and 60 seconds respectively. A silane was applied to the groups AAS, HF2, and HF6 after the treatment. After 24-hour storage in distilled water, a micro-shear bond strength test was performed using a universal mechanical testing machine. All samples were evaluated in a stereomicroscope at 40x and 50x to determine the type of failure. Results: The highest and lowest values of bond strength were reported by groups MB6 and AAS, respectively. Groups HF2, HF6, MB6, and MB2 did not report statistically significant differences. The predominant failure pattern was a mixed failure. Conclusions: With the limitations of the present investigation, the treatments of self-etching ceramic primer and hydrofluoric acid followed by silane were reported to be statistically equal at 20 and 60 seconds.

PMID:37997604 | PMC:PMC10665602 | DOI:10.12688/f1000research.122108.1

J Orthop. 2023 Nov 4;46:150-155. doi: 10.1016/j.jor.2023.10.035. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Shoulder arthroplasty is a successful procedure that provides pain relief and improvements in function and range of motion. Anatomic and reverse shoulder arthroplasty are both effective procedures, and their indications continue to expand. We look at the outcomes of revision reverse total shoulder arthroplasty and compare it to the outcomes of primary reverse and anatomic total shoulder arthroplasty.

METHODS: We identified patients undergoing total shoulder arthroplasty at our institution between the years of 2010 and 2020. Data was prospectively collected and retrospectively reviewed for post-operative range of motion and strength in patients with revision surgery and compared to controls. Measurements were collected preoperatively and postoperatively including range of motion and strength in the affected and unaffected shoulder. We collected patient reported outcome measures in person and via phone to identify subjective outcomes of total shoulder arthroplasty. Average final follow-up was 5.27 years.

RESULTS: Our total patient sample was split between three groups: those with primary anatomic arthroplasty those who underwent primary reverse arthroplasty, and those who were revised to a reverse shoulder arthroplasty. All three groups had significant improvements in abduction and forward elevation from their pre-operative baseline to two years follow-up. Primary reverse had a significant improvement over revision reverse in abduction at one year follow-up. For all other range of motion measurements, there was no statistically significant difference at 2 years between primary and revision reverse shoulder arthroplasty. Patient reported outcomes had a significant increase from pre-op to most recent follow-up in all three groups.

CONCLUSION: Overall, our data suggest there is an improvement in outcomes with both primary and revision surgeries, and that results after revision reverse total shoulder arthroplasty may be comparable to primary reverse total shoulder arthroplasty.

PMID:37997602 | PMC:PMC10663749 | DOI:10.1016/j.jor.2023.10.035

J Comput Graph Stat. 2023;32(3):1036-1045. doi: 10.1080/10618600.2022.2141752. Epub 2022 Nov 30.

ABSTRACT

Individualized treatment effect lies at the heart of precision medicine. Interpretable individualized treatment rules (ITRs) are desirable for clinicians or policymakers due to their intuitive appeal and transparency. The gold-standard approach to estimating the ITRs is randomized experiments, where subjects are randomized to different treatment groups and the confounding bias is minimized to the extent possible. However, experimental studies are limited in external validity because of their selection restrictions, and therefore the underlying study population is not representative of the target real-world population. Conventional learning methods of optimal interpretable ITRs for a target population based only on experimental data are biased. On the other hand, real-world data (RWD) are becoming popular and provide a representative sample of the target population. To learn the generalizable optimal interpretable ITRs, we propose an integrative transfer learning method based on weighting schemes to calibrate the covariate distribution of the experiment to that of the RWD. Theoretically, we establish the risk consistency for the proposed ITR estimator. Empirically, we evaluate the finite-sample performance of the transfer learner through simulations and apply it to a real data application of a job training program.

PMID:37997592 | PMC:PMC10664843 | DOI:10.1080/10618600.2022.2141752

AEM Educ Train. 2023 Nov 22;7(6):e10908. doi: 10.1002/aet2.10908. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Cultural sensitivity (CS) training is vital to pediatric emergency medicine (PEM) curricula. This study aimed to explore CS in Yale PEM fellows and emergency medicine (EM) residents at Indus Hospital and Health Network (IHHN) in Pakistan through distance simulation activities.

METHODS: This mixed-methods analysis of an educational intervention was conducted at Yale University in collaboration with IHHN. We approached seven U.S. PEM fellows and 22 Pakistani EM residents. We performed a baseline CS assessment using the Clinical Cultural Competency Questionnaire (CCCQ). Afterward, the U.S. PEM fellows facilitated the Pakistani EM residents through six distance simulation sessions. Qualitative data were collected through online focus groups. The CCCQ was analyzed using descriptive statistics, and content analysis was used to analyze the data from the focus groups.

RESULTS: Seven U.S. PEM fellows and 18 of 22 Pakistani EM residents responded to the CCCQ at the beginning of the module. The mean (±SD) CCCQ domain scores for the U.S. PEM fellows versus the Pakistani EM residents were 2.56 (±0.37) versus 2.87 (±0.72) for knowledge, 3.02 (±0.41) versus 3.33 (±0.71) for skill, 2.86 (±0.32) versus 3.17 (±0.73) for encounter/situation, and 3.80 (±0.30) versus 3.47 (±0.47) for attitude (each out of 5 points). Our qualitative data analysis showed that intercultural interactions were valuable. There is a common language of medicine among the U.S. PEM fellows and Pakistani EM residents. The data also highlighted a power distance between the facilitators and learners, as the United States was seen as the standard of “how to practice PEM.” The challenges identified were time differences, cultural practices such as prayer times, the internet, and technology. The use of local language during debriefing was perceived to enhance engagement.

CONCLUSION: The distance simulation involving U.S. PEM fellows and Pakistani EM residents was an effective approach in assessing various aspects of intercultural education, such as language barriers, technical challenges, and religious considerations.

PMID:37997591 | PMC:PMC10664395 | DOI:10.1002/aet2.10908

AEM Educ Train. 2023 Nov 22;7(6):e10917. doi: 10.1002/aet2.10917. eCollection 2023 Dec.

ABSTRACT

OBJECTIVES: Cricothyrotomy is a high-stakes emergency procedure. Because the procedure is rare, simulation is often used to train residents. The Accreditation Council for Graduate Medical Education (ACGME) requires performance of three cricothyrotomies during residency, but the optimal number of training repetitions is unknown. Additional repetitions beyond three could increase proficiency, though it is unknown whether there is a threshold beyond which there is no benefit to additional repetition. The objective of this study was to establish a minimum number of simulated cricothyrotomy attempts beyond which additional attempts did not increase proficiency.

METHODS: This was a prospective, observational study conducted over 3 years at the simulation center of an academic emergency medicine residency program. Participants were residents participating in a cricothyrotomy training as part of a longitudinal airway curriculum course. The primary outcome was time to successful completion of the procedure as first-year residents. Secondary outcomes included time to completion as second- and third-year residents. Procedure times were plotted as a function of attempt number. Data were analyzed using descriptive statistics, repeated-measures analysis of variance, and correlation analysis. Preprocedure surveys collected further data regarding procedure experience, confidence, and comfort.

RESULTS: Sixty-nine first-year residents participated in the study. Steady improvement in time to completion was seen through the first six attempts (from a mean of 75 to 41 sec), after which no further significant improvement was found. Second- and third-year residents initially demonstrated slower performance than first-year residents but rapidly improved to surpass their first-year performance. Resident mean times at five attempts were faster with each year of residency (first-year 48 sec, second-year 30 sec, third-year 24 sec). There was no statistically significant correlation between confidence and time to complete the procedure.

CONCLUSIONS: Additional repetition beyond the ACGME-endorsed three cricothyrotomy attempts may help increase proficiency. Periodic retraining may be important to maintain skills.

PMID:37997589 | PMC:PMC10664393 | DOI:10.1002/aet2.10917

J Transl Med. 2023 Nov 24;21(1):847. doi: 10.1186/s12967-023-04737-9.

ABSTRACT

BACKGROUND: In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm’s canal (SC) is a hybrid vascular and lymphatic vessel that mediates aqueous humour drainage from the anterior ocular chamber. Animal studies support the importance of SC endothelial angiopoietin-TEK signalling, and more recently TIE1 signalling, in maintaining normal IOP. However, human genetic support for a causal role of TIE1 and TEK signalling in lowering IOP is currently lacking.

METHODS: GWAS summary statistics were obtained for plasma soluble TIE1 (sTIE1) protein levels (N = 35,559), soluble TEK (sTEK) protein levels (N = 35,559), IOP (N = 139,555) and POAG (N_cases = 16,677, N_controls = 199,580). Mendelian randomization (MR) was performed to estimate the association of genetically proxied TIE1 and TEK protein levels with IOP and POAG liability. Where significant MR estimates were obtained, genetic colocalization was performed to assess the probability of a shared causal variant (PP_shared) versus distinct (PP_distinct) causal variants underlying TIE1/TEK signalling and the outcome. Publicly available single-nucleus RNA-sequencing data were leveraged to investigate differential expression of TIE1 and TEK in the human ocular anterior segment.

RESULTS: Increased genetically proxied TIE1 signalling and TEK signalling associated with a reduction in IOP (- 0.21 mmHg per SD increase in sTIE1, 95% CI = – 0.09 to – 0.33 mmHg, P = 6.57 × 10^-4, and – 0.14 mmHg per SD decrease in sTEK, 95% CI = – 0.03 to – 0.25 mmHg, P = 0.011), but not with POAG liability. Colocalization analysis found that the probability of a shared causal variant was greater for TIE1 and IOP than for TEK and IOP (PP_shared/(PP_distinct + PP_shared) = 0.98 for TIE1 and 0.30 for TEK). In the anterior segment, TIE1 and TEK were preferentially expressed in SC, lymphatic, and vascular endothelium.

CONCLUSIONS: This study provides novel human genetic support for a causal role of both TIE1 and TEK signalling in regulating IOP. Here, combined evidence from cis-MR and colocalization analyses provide stronger support for TIE1 than TEK as a potential IOP-lowering therapeutic target.

PMID:37996923 | DOI:10.1186/s12967-023-04737-9

BMC Med Educ. 2023 Nov 23;23(1):897. doi: 10.1186/s12909-023-04861-6.

ABSTRACT

OBJECTIVES: Abdominal palpation is an essential examination to diagnose various digestive system diseases. This study aimed to develop an objective and standardized test based on abdominal palpation simulators, and establish a credible pass/fail standard of basic competency.

METHODS: Two tests were designed using the newly developed Jucheng abdominal palpation simulator (test 1) and the AbSim simulator (test 2), respectively. Validity evidence for both tests was gathered according to Messick’s contemporary framework by using experts to define test content and then administering the tests in a highly standardized way to participants of different experience. Different simulator setups modified by the built-in software were selected from hepatomegaly, splenomegaly, positive McBurney’s sign plus rebound tenderness, gallbladder tenderness (Murphy’s sign), pancreas tenderness, and a normal setup without pathologies, with six sets used in test 1 and five sets used in test 2. Different novices and experienced were included in the tests, and test 1 was also administered to an intermediate group. Scores and test time were collected and analyzed statistically.

RESULTS: The internal consistency reliability of test 1 and test 2 showed low Cronbach’s alphas of 0.35 and -0.41, respectively. Cronbach’s alpha for palpation time across cases were 0.65 for test 1 and 0.76 for test 2. There was no statistical difference in total time spent and total scores among the three groups in test 1 (P-values (ANOVA) were 0.53 and 0.35 respectively), nor between novices and experienced groups in test 2 (P-values (t-test) were 0.13 and 1.0 respectively). It was not relevant to try to establish pass/fail standards due to the low reliability and lack of discriminatory ability of the tests.

CONCLUSIONS: It was not possible to measure abdominal palpation skills in a valid way using either of the two standardized, simulation-based tests in our study. Assessment of the patient’s abdomen using palpation is a challenging clinical skill that is difficult to simulate as it highly relies on tactile sensations and adequate responsiveness from the patients.

PMID:37996904 | DOI:10.1186/s12909-023-04861-6