Nevin Manimala

bioRxiv. 2023 Nov 5:2023.11.03.565343. doi: 10.1101/2023.11.03.565343. Preprint.

ABSTRACT

Human induced pluripotent stem cell-derived sensory neurons (hiPSC-SNs) and human dorsal root ganglia (hDRG) neurons are popular tools in the field of pain research; however, few groups make use of both approaches. For screening and analgesic validation purposes, important characterizations can be determined of the similarities and differences between hDRG and hiPSC-SNs. This study focuses specifically on electrophysiology properties of hDRG in comparison to hiPSC-SNs. We also compared hDRG and hiPSC-SNs from both male and female donors to evaluate potential sex differences. We recorded neuronal size, rheobase, resting membrane potential, input resistance, and action potential waveform properties from 83 hiPSCs-SNs (2 donors) and 108 hDRG neurons (9 donors). We observed several statistically significant electrophysiological differences between hDRG and hiPSC-SNs, such as size, rheobase, input resistance, and several actional potential (AP) waveform properties. Correlation analysis also revealed many properties that were positively or negatively correlated, some of which were differentially correlated between hDRG and hiPSC-SNs. This study shows several differences between hDRG and hiPSC-SNs and allows better understanding of the advantages and disadvantages of both for use in pain research. We hope this study will be a valuable resource for pain researchers considering the use of these human in vitro systems for mechanistic studies and/or drug development projects.

PMID:37961669 | PMC:PMC10635102 | DOI:10.1101/2023.11.03.565343

Res Sq. 2023 Oct 27:rs.3.rs-3335211. doi: 10.21203/rs.3.rs-3335211/v1. Preprint.

ABSTRACT

Objective Pathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice.

DESIGN: A randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention.

SETTING: Preclinical laboratory study.

SAMPLE SIZE: Thirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)].

MEASUREMENTS: Measures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, blood samples were collected to assess blood beta-hydroxybutyrate levels.

STATISTICAL ANALYSIS: Two-way ANOVA mixed-effects analysis (time x diet) were performed to analyze grip, rotarod, MUNE, and muscle contractility data. Results Beta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η ² = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (time x diet, p = 0.0030), all limb grip strength (time x diet, p = 0.0523), and rotarod latency to fall (time x diet, p = 0.0021). Mice treated with the KD intervention also demonstrated significantly greater MUNE (time x diet, p = 0.0064), but no difference in muscle contractility (time x diet, p = 0.5836) or RNS (time x diet, p = 0.9871). Conclusion KD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

PMID:37961656 | PMC:PMC10635299 | DOI:10.21203/rs.3.rs-3335211/v1

bioRxiv. 2023 Oct 30:2023.10.25.563971. doi: 10.1101/2023.10.25.563971. Preprint.

ABSTRACT

Identifying reproducible and generalizable brain-phenotype associations is a central goal of neuroimaging. Consistent with this goal, prediction frameworks evaluate brain-phenotype models in unseen data. Most prediction studies train and evaluate a model in the same dataset. However, external validation, or the evaluation of a model in an external dataset, provides a better assessment of robustness and generalizability. Despite the promise of external validation and calls for its usage, the statistical power of such studies has yet to be investigated. In this work, we ran over 60 million simulations across several datasets, phenotypes, and sample sizes to better understand how the sizes of the training and external datasets affect statistical power. We found that prior external validation studies used sample sizes prone to low power, which may lead to false negatives and effect size inflation. Furthermore, increases in the external sample size led to increased simulated power directly following theoretical power curves, whereas changes in the training dataset size offset the simulated power curves. Finally, we compared the performance of a model within a dataset to the external performance. The within-dataset performance was typically within r=0.2 of the cross-dataset performance, which could help decide how to power future external validation studies. Overall, our results illustrate the importance of considering the sample sizes of both the training and external datasets when performing external validation.

PMID:37961654 | PMC:PMC10634903 | DOI:10.1101/2023.10.25.563971

bioRxiv. 2023 Nov 3:2023.03.16.533008. doi: 10.1101/2023.03.16.533008. Preprint.

ABSTRACT

Contingency tables, data represented as counts matrices, are ubiquitous across quantitative research and data-science applications. Existing statistical tests are insufficient however, as none are simultaneously computationally efficient and statistically valid for a finite number of observations. In this work, motivated by a recent application in reference-free genomic inference (1), we develop OASIS (Optimized Adaptive Statistic for Inferring Structure), a family of statistical tests for contingency tables. OASIS constructs a test-statistic which is linear in the normalized data matrix, providing closed form p-value bounds through classical concentration inequalities. In the process, OASIS provides a decomposition of the table, lending interpretability to its rejection of the null. We derive the asymptotic distribution of the OASIS test statistic, showing that these finitesample bounds correctly characterize the test statistic’s p-value up to a variance term. Experiments on genomic sequencing data highlight the power and interpretability of OASIS. The same method based on OASIS significance calls detects SARS-CoV-2 and Mycobacterium Tuberculosis strains de novo, which cannot be achieved with current approaches. We demonstrate in simulations that OASIS is robust to overdispersion, a common feature in genomic data like single cell RNA-sequencing, where under accepted noise models OASIS still provides good control of the false discovery rate, while Pearson’s X ² test consistently rejects the null. Additionally, we show on synthetic data that OASIS is more powerful than Pearson’s X ² test in certain regimes, including for some important two group alternatives, which we corroborate with approximate power calculations.

SIGNIFICANCE STATEMENT: Contingency tables are pervasive across quantitative research and data-science applications. Existing statistical tests fall short, however; none provide robust, computationally efficient inference and control Type I error. In this work, motivated by a recent advance in reference-free inference for genomics, we propose a family of tests on contingency tables called OASIS. OASIS utilizes a linear test-statistic, enabling the computation of closed form p-value bounds, as well as a standard asymptotic normality result. OASIS provides a partitioning of the table for rejected hypotheses, lending interpretability to its rejection of the null. In genomic applications, OASIS performs reference-free and metadata-free variant detection in SARS-CoV-2 and M. Tuberculosis, and demonstrates robust performance for single cell RNA-sequencing, all tasks without existing solutions.

PMID:37961606 | PMC:PMC10634974 | DOI:10.1101/2023.03.16.533008

bioRxiv. 2023 Nov 3:2023.11.01.565061. doi: 10.1101/2023.11.01.565061. Preprint.

ABSTRACT

Clark (2023) considers the similarity in socioeconomic status between relatives, drawing on records spanning four centuries in England. The paper adapts a classic quantitative genetics model in order to argue the fit of the model to the data suggests that: (1) variation in socioeconomic status is largely determined by additive genetic variation; (2) contemporary English people “remain correlated in outcomes with their lineage relatives in exactly the same way as in preindustrial England”; and (3) social mobility has remained static over this time period due to strong assortative mating on a “social genotype.” These conclusions are based on a misconstrual of model parameters, which conflates genetic and non-genetic transmission (e.g. of wealth) within families. As we show, there is strong confounding of genetic and non-genetic sources of similarity in these data. Inconsistent with claims (2) and (3), we show that familial correlations in status are variable-generally decreasing-through the time period analyzed. Lastly, we find that statistical artifacts substantially bias estimates of familial correlations in the paper. Overall, Clark (2023) provides no information about the relative contribution of genetic and non-genetic factors to social status.

PMID:37961599 | PMC:PMC10635045 | DOI:10.1101/2023.11.01.565061

medRxiv. 2023 Oct 24:2023.10.23.23297381. doi: 10.1101/2023.10.23.23297381. Preprint.

ABSTRACT

Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or “time controls” born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen’s d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.

PMID:37961592 | PMC:PMC10635168 | DOI:10.1101/2023.10.23.23297381

J Rural Health. 2023 Nov 13. doi: 10.1111/jrh.12811. Online ahead of print.

ABSTRACT

PURPOSE: Our goal was to compare locations of COVID-19 vaccine provision in urban and rural communities over the course of the pandemic.

METHODS: We used the Iowa Immunization Registry Information System (IRIS) to identify the organizations providing COVID-19 vaccines (eg, pharmacies, public health departments, and medical providers). Proportions of first-dose vaccines by organization type and patient census-based statistical area were generated. We calculated Chi-square tests to assess differences among metropolitan, micropolitan, and noncore communities.

FINDINGS: IRIS data revealed that 64% (n = 2,043,251) of Iowans received their first COVID-19 vaccine between December 14, 2020, and December 31, 2022. For metropolitan-dwelling individuals, most first doses were administered at pharmacies (53%), with similar trends observed for micropolitan (49%) and noncore (42%) individuals. The second most common location for metropolitan individuals was medical practices (17%); public health clinics and departments were the second most common provider for micropolitan (26%) and noncore (33%) individuals. These trends shifted over time. In December 2020, hospitals were the most common vaccine provider for everyone, but by December 2022, medical providers were the most common source for metropolitan individuals, and pharmacies were most common for micropolitan and noncore individuals.

CONCLUSIONS: Trends in the type of vaccine provider differentiated metropolitan residents from micropolitan and noncore residents. For the latter groups, local public health departments played a more significant role. Across all groups, pharmacists emerged as a critical vaccine provider. Our findings can be used to plan for seasonal vaccine campaigns as well as potential future mass vaccination campaigns.

PMID:37957524 | DOI:10.1111/jrh.12811

Odontology. 2023 Nov 13. doi: 10.1007/s10266-023-00870-5. Online ahead of print.

ABSTRACT

This study aims to evaluate the number of roots and root canal morphology types of maxillary premolars in relation to a patient’s gender and age in an Iraqi population using two classification systems. Cone beam computed tomography (CBCT) scans of 1116 maxillary premolars from 385 patients were evaluated for the number of roots and root canal morphology types according to Vertucci’s classification and Ahmed et al. classification systems. Differences in the number of roots and root canal morphology types with regard to tooth type, patients’ gender and age groups were evaluated and the degree of bilateral symmetry was determined. Chi-squared test was used for statistical analysis. About 51.1% of the 1st premolars were double rooted. The majority (87.9%) of the 2nd premolars were single rooted. The three-rooted form presented in only 1.2% and 0.7% of the 1st and 2nd premolars, respectively. Vertucci Type IV (Ahmed et al. code ²MaxP B¹P¹) and Vertucci Type I (Ahmed et al. code ¹MaxP¹) were the most common canal morphology types in the 1st and 2nd premolars, respectively. Females showed a lower number of roots and a higher prevalence of Vertucci Type I configuration (P < 0.05). Younger age groups showed a higher prevalence of Vertucci Type I configuration (P < 0.05). Bilateral symmetry was seen in more than half of the maxillary premolars. There is a considerable variation in the number of roots and root canal configurations of maxillary premolars in the studied Iraqi population, with a significant difference by gender and age groups. Ahmed et al. classification provided more accurate presentation of the root and canal anatomy in maxillary premolars compared to Vertucci’s classification.

PMID:37957521 | DOI:10.1007/s10266-023-00870-5

Inflammopharmacology. 2023 Nov 13. doi: 10.1007/s10787-023-01338-2. Online ahead of print.

ABSTRACT

BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes. The synthetic drugs available in the market have side effects and limitations for diabetic patients, the vast majority of whom are in the upper age group. In this regard, based on Persian medicinal sources, Nigella sativa (N. sativa) has proved to have beneficial effects on neuropathic pain and neurological disorders. In this study, the effect of N. sativa is investigated topically in patients with diabetic neuropathy.

METHODS: This study was performed as a double-blind clinical trial on 120 neuropathic patients. The patients were divided into three groups. The first group received a topical N. sativa product as an ointment, the second group was given a topical placebo, and the third received 300 mg gabapentin capsules. The blindness was done in first and second groups. Diabetic neuropathy was assessed before the study using the Michigan Neuropathy Screening Instrument (MNSI). In addition, neuropathy symptoms were evaluated after the trial using the MNSI questionnaire.

RESULTS: The data were elicited from the patients’ answers to a number of questions in the Michigan questionnaire. There were statistically significant differences between the group that received the topical N. sativa product and the other two groups in terms of legs and feet numbness (p value = 0.001), burning pain in feet or legs (p value = 0.001), muscle cramps in feet or legs (p value = 0.001), prickling fleeing in feet or legs (p value = 0.001), hurting of the skin when the bed covers touch it (p value = 0.005), aggravated symptoms at night (p value = 0.001) and hurting feelings in the legs when walking (p value = 0.032). However, the three studied groups were not statistically different in distinguishing hot water from cold water.

CONCLUSION: According to the results of this study, the topical use of N. sativa, compared to the current drugs, has acceptable improving effects on diabetic neuropathic patients.

PMID:37957516 | DOI:10.1007/s10787-023-01338-2

Reprod Sci. 2023 Nov 13. doi: 10.1007/s43032-023-01385-8. Online ahead of print.

ABSTRACT

The aim of this study was to investigate if variation in endometrial thickness affects clinical pregnancy and live birth rates among patients undergoing single euploid embryo transfer (SET). A retrospective review of IVF cycles performed at a single private fertility institution between 2015 and 2020 was performed. Patients with normal uterine anatomy undergoing their first SET of a euploid embryo undergoing their first cycle at the center were included, for a total of 796 cycles. Endometrial thickness was measured by transvaginal ultrasound following 10-14 days of estradiol exposure. Specific infertility diagnoses did not significantly impact endometrial lining thickness with means across diagnoses ranging from 9.3 to 11.0 mm. Endometrial thickness was grouped into five categories: < 8 mm, 8-10 mm, 10-13 mm, 13-15 mm, and ≥ 15 mm. Using 8-10 mm as the reference group, the odds ratio of live birth was 0.5, 1.22, 1.05, and 1.05 for < 8 mm, 10-13 mm, 13-15 mm, and ≥ 15 mm groups, respectively. Risk of first trimester miscarriage was equivalent across groups. There was a trend toward an increased rate of biochemical pregnancies in patients with a < 8 mm and ≥ 15 mm endometrium; however, this was not statistically significant. The clinical pregnancy and live birth rate were lowest in patients with < 8-mm endometrial thickness. For single euploid embryo transfers, an endometrial lining greater than or equal to 8 mm confers optimal live birth rates following a medicated FET cycle. These data confirm the findings of prior studies in fresh embryo transfers without the confounders of supraphysiologic ovarian hormone concentrations and genetically untested embryos.

PMID:37957470 | DOI:10.1007/s43032-023-01385-8