Nevin Manimala

Expert Opin Drug Discov. 2023 Nov 3:1-7. doi: 10.1080/17460441.2023.2277342. Online ahead of print.

ABSTRACT

INTRODUCTION: Modern drug discovery incorporates various tools and data, heralding the beginning of the data-driven drug design (DD) era. The distributions of chemical and physical data used for Artificial Intelligence (AI)/Machine Learning (ML) and to drive DD have thus become highly important to be understood and used effectively.

AREAS COVERED: The authors perform a comprehensive exploration of the statistical distributions driving the data-intensive era of drug discovery, including Benford’s Law in AI/ML-based DD.

EXPERT OPINION: As the relevance of data-driven discovery escalates, we anticipate meticulous scrutiny of datasets utilizing principles like Benford’s Law to enhance data integrity and guide efficient resource allocation and experimental planning. In this data-driven era of the pharmaceutical and medical industries, addressing critical aspects such as bias mitigation, algorithm effectiveness, data stewardship, effects, and fraud prevention are essential. Harnessing Benford’s Law and other distributions and statistical tests in DD provides a potent strategy to detect data anomalies, fill data gaps, and enhance dataset quality. Benford’s Law is a fast method for data integrity and quality of datasets, the backbone of AI/ML and other modeling approaches, proving very useful in the design process.

PMID:37921672 | DOI:10.1080/17460441.2023.2277342

Scand J Gastroenterol. 2023 Nov 3:1-9. doi: 10.1080/00365521.2023.2277663. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about the disease of early-onset cholangiocarcinoma (EOC). The primary objective of this study was to compare EOC with later-onset cholangiocarcinoma (LOC) concerning clinical features and survival prognosis.

METHODS: 19325 cholangiocarcinoma patients were extracted from 1975 to 2020 in the SEER database. Cox regression analysis and Kaplan-Meier survival curves were used for the evaluation of cause-specific survival (CSS) and overall survival (OS). To reduce confounding, we compared survival differences between the EOC and LOC groups using propensity score matching (PSM).

RESULTS: 4037 cholangiocarcinoma patients were included in the study, of which 274 were EOC and 3763 were LOC. Early-onset patients were more likely to be non-white, and intrahepatic cholangiocarcinoma. At diagnosis, patients had advanced AJCC stage, lymph node metastase and distant metastase. The EOC patients were more likely to receive surgery, radiotherapy, and chemotherapy than later-onset patients. Multifactorial COX analysis indicated that EOC patients had lower mortality risk than later-onset patients, and similar results were obtained after PSM; Kaplan-Meier survival curves corroborated that early-onset patients exhibited better OS than later-onset patients, and this survival advantage persisted after PSM. Further subgroup analysis following matching demonstrated that early-onset patients had better OS than later-onset patients in the surgical subgroup, while there were no statistically significant differences in the radiotherapy and chemotherapy subgroups.

CONCLUSION: The EOC patients typically exhibit an intrahepatic presentation and generally experience a more favorable prognosis. Surgery emerged as a critical treatment modality significantly influencing the overall prognosis of EOC.

PMID:37921657 | DOI:10.1080/00365521.2023.2277663

Toxicol Ind Health. 2023 Nov 3:7482337231210942. doi: 10.1177/07482337231210942. Online ahead of print.

ABSTRACT

This toxicology study was conducted to assess the impact of formaldehyde, a common air pollutant found in Chinese gymnasiums, on the brain function of athletes. In this research, a total of 24 Balb/c male mice of SPF-grade were divided into four groups, each consisting of six mice. The mice were exposed to formaldehyde at different concentrations, including 0 mg/m³, 0.5 mg/m³, 3.0 mg/m³, and 3.0 mg/m³ in combination with an injection of L-NMMA (N^G-monomethyl-L-arginine), which is a nitric oxide synthase antagonist. Following a one-week test period (8 h per day, over 7 days), measurements of biomarkers related to the nitric oxide (NO)/cGMP-cAMP signaling pathway were carried out on the experimental animals post-treatment. The study found that: (1) Exposure to formaldehyde can lead to brain cell apoptosis and neurotoxicity; (2) Additionally, formaldehyde exposure was found to alter the biomarkers of the NO/cGMP-cAMP signaling pathway, with some changes being statistically significant (p < 0.05 or p < 0.01); (3) The use of L-NMMA, an antagonist of the NO/cGMP-cAMP signaling pathway, was found to prevent these biomarker changes and had a protective effect on brain cells. The study suggests that the negative impact of formaldehyde on the brain function of mice is linked to the regulation of the NO/cGMP-cAMP signaling pathway.

PMID:37921628 | DOI:10.1177/07482337231210942

JBI Evid Synth. 2023 Nov 6. doi: 10.11124/JBIES-22-00057. Online ahead of print.

ABSTRACT

OBJECTIVE: The aim of this review is to evaluate the effectiveness of active compared with passive distraction-based interventions in relieving anxiety, fear, and pain in hospitalized preschool and school-age children during venous blood sampling.

INTRODUCTION: Venous blood sampling remains the most common procedure that causes anxiety, fear, and pain among the pediatric population. It is important that health care professionals relieve a child’s pain and the related emotions because untreated pain may have long-term effects on children’s growth and development. It is necessary to determine which interventions are effective in relieving these outcomes in preschool and school-age children during blood sampling.

INCLUSION CRITERIA: This review will include randomized controlled trials and quasi-experimental studies that include active and passive distraction-based interventions for relieving hospitalized preschool and school-age children’s anxiety, fear, and pain during venous blood sampling.

METHODS: CINAHL, PubMed, Scopus, and Cochrane Library databases will be searched for published studies. MedNar, Google Scholar, and PsycEXTRA databases will be searched for in-progress and unpublished studies. Two independent researchers will perform critical appraisal and data extraction using JBI methodology. Data describing randomized controlled trials and quasi-experimental studies will be pooled in a statistical meta-analysis. If statistical analysis is not possible, the findings will be reported narratively. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be used to assess certainty in the quality of evidence.

REVIEW REGISTRATION: PROSPERO CRD42023455617.

PMID:37921627 | DOI:10.11124/JBIES-22-00057

Plast Reconstr Surg. 2023 Nov 3. doi: 10.1097/PRS.0000000000011179. Online ahead of print.

ABSTRACT

BACKGROUND: Overhanging pannus may be detrimental to ambulation, urination, sexual function, and social well-being. Massive weight loss patients often have high residual body mass index (BMI) and comorbidities presenting a unique challenge in panniculectomy patient selection. This study aims to better characterize the role of BMI in post-operative complications following panniculectomy.

METHODS: A meta-analysis attempted to assess the impact of BMI on complications following panniculectomy. Cochrane Q and I 2 test statistics measured study heterogeneity, with subsequent random effects meta-regression investigating these results. After this, all panniculectomy patients in the National Surgical Quality Improvement Program (NSQIP) years 2007-2019, were analyzed. Univariate and multivariable tests assessed the relative role of BMI on 30-day postoperative complications.

RESULTS: Thirty-four studies satisfied inclusion criteria, revealing very high heterogeneity (Cochrane Q = 2453.3; I 2 = 99.1%), precluding further meta-analysis results. Receiver operator curves demonstrated BMI was a significant predictor of both all causes (area under the curve (AUC): 0.64, 95%CI:0.62-0.66) and wound complications (AUC:0.66, 95%CI:0.63-0.69). BMI remained significant following multivariable regression analyses. Restricted cubic spines demonstrated marginal increases in complication incidence above 33.2 and 35 for all-cause and wound complications respectively.

CONCLUSION: Reported literature regarding postoperative complications in panniculectomy patients is highly heterogeneous, and may limit evidence-based care. Complication incidence positively correlated with BMI, though ROC demonstrated its limitations as the sole predictive variable. Further, RSC demonstrated diminishing marginal predictive capacity of BMI for incremental increases in BMIs above 33.2-35 kg/m 2. These findings support a re-evaluation of the role of BMI cut-offs in panniculectomy patient selection.

PMID:37921622 | DOI:10.1097/PRS.0000000000011179

Int J Periodontics Restorative Dent. 2023 Nov 3;43(6):699-705. doi: 10.11607/prd.5534.

ABSTRACT

This study assessed the effectiveness and predictability of a readily available protocol to treat peri-implantitis utilizing mechanical debridement, chemical antiseptic surface detoxification, and osseous grafting. Nine patients (7 women, 2 men; mean age: 56.5 years) with 15 implants with peri-implantitis were included. Pocket probing depth (PPD), bleeding on probing (BOP), and standardized digital periapical radiographic measurements were taken. Surgical flaps were elevated, and the implant threads were cleaned with a plastic curette. Chemical decontamination was performed by scrubbing solutions of 0.25% sodium hypochlorite (NaClO) and 1.5% hydrogen peroxide (H2O2) around the exposed implant using cotton pellets. Bony defects were filled with a 50/50 mixture of bovine hydroxyapatite and nanocrystalline calcium sulfate (CaSO4). A porcine collagen membrane was placed over the grafted bony defect. Follow-up appointments were scheduled 1 week, 2 weeks, 3 months, 6 months, 9 months, and 1 year posttreatment. Clinical and radiographic parameters were assessed and compared. At baseline, PPD ranged from 5 to 7.5 mm (mean: 6 ± 0.7 mm). At 12 months, PPD ranged from 1.5 to 4.2 mm (mean: 2.5 ± 0.8 mm). The mean PPD reduction of 3.6 mm (59.2%) was statistically significant (P < .001). The number of bleeding sites around each test implant decreased significantly from 4 to 0.4 sites between baseline and 12 months (P < .001). Mean radiographic bone loss decreased from 4.8 ± 1.3 mm to 2.7 ± 1.2 mm (P < .001). The proposed method of mechanical decontamination, chemical detoxification, and bone regeneration is clinically effective and reproducible. Clinical peri-implant parameters and radiographic bone levels were improved and maintained their stability for 1 year using this peri-implantitis treatment protocol.

PMID:37921607 | DOI:10.11607/prd.5534

Clin Exp Immunol. 2023 Oct 31:uxad121. doi: 10.1093/cei/uxad121. Online ahead of print.

ABSTRACT

The adaptive and innate immune system is important in both initiating and preventing functional disorders during pregnancy, one of which is pre-eclampsia. The research aims to conduct the comparative quantification of selected subpopulations of peripheral blood immunoregulatory cells in pregnant women with pre-eclampsia in the third trimester. The marker receptors CD4, CD8, CD95, CD25, CD27, and the marker antigen HLA-DR were considered. The screening was performed by flow cytometry with dual phenotyping using phycoerythrin- and fluorescein-isothiocyanate-labeled monoclonal antibodies. Data processing consisted in calculating a likelihood value to assess the statistical significance of the difference between the samples. A statistically significant decrease in the subpopulation titer of T- and B-lymphocytes with marker receptors CD4, CD8, and CD19 was found in pre-eclampsia patients. In the CD4 carrier T-lymphocyte population, there was an increased expression of the CD25/CD95 activation and apoptosis markers. In the CD8 T-killer population, a decreased representation of the CD27/CD25/CD95 markers of differentiation, activation, and apoptosis was deterministic. The expression pattern of the major histocompatibility complex antigen HLA-DR did not change significantly in normality and pathology. The titer of peripheral natural killer cells carrying the CD56 marker increased in patients with various degrees of disease severity, while the number of CD16 natural killer remained at the level of the control group. The research results suggest that a change in the ratio of the above receptors is a diagnostic indicator for pre-eclampsia.

PMID:37921073 | DOI:10.1093/cei/uxad121

Int J Oncol. 2023 Dec;63(6):138. doi: 10.3892/ijo.2023.5586. Epub 2023 Nov 3.

ABSTRACT

The aim of the present study was to elucidate the role and downstream mechanism of long non‑coding RNA (lncRNA) metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) in the process of cervical cancer cell pyroptosis. The effect of inhibiting lncRNA MALAT1 on cervical cancer cells was determined using primary cells isolated from patients and U14 cervical tumor‑bearing nude mice. The level of lncRNA MALAT1 expression and cell viability were determined for relationship analysis. Pyroptosis was then investigated in HeLa cells with lncRNA MALAT1 knockdown or overexpression with or without lipopolysaccharide (LPS) treatment. Bioinformatics tools were used to identify downstream factors of lncRNA MALAT1, which were subsequently verified by gain‑ or loss‑of‑function analyses in the process of cervical cancer cell pyroptosis. It was observed that the level of lncRNA MALAT1 was markedly higher in cervical carcinoma cells compared with expression in paracarcinoma cells, and knockdown of lncRNA MALAT1 induced cervical cancer cell death through pyroptosis. By contrast, overexpression of lncRNA MALAT1 blocked LPS‑induced pyroptosis. These results, combined with bioinformatics statistical tools, demonstrated that the microRNA (miR)‑124/sirtuin 1 (SIRT1) axis may affect the progression of cervical cancer at least partly by mediating the effect of lncRNA MALAT1 on the pyroptosis of cervical cancer cells. In conclusion, the lncRNA MALAT1/miR‑124/SIRT1 regulatory axis in cervical cancer cells may mediate pyroptosis and may provide potential targets against the progression of cervical cancer.

PMID:37921054 | DOI:10.3892/ijo.2023.5586

Sports Biomech. 2023 Nov 3:1-23. doi: 10.1080/14763141.2023.2269543. Online ahead of print.

ABSTRACT

Eccentric quasi-isometrics (EQIs) are a novel, low-velocity resistance exercise technique that incorporates a holding isometric contraction to positional fatigue, followed by voluntary resistance of the resulting eccentric muscle action. As females are typically more fatigue resistant than males during isometric and low-velocity dynamic muscle actions, this study explored sex-differences in the muscle fatigue response to an EQI protocol. Twenty-five (n = 12 female) participants completed 4 unilateral EQI elbow flexions. Absolute and relative surface electromyography (sEMG) amplitude (iEMG, LE peak), mean power frequency (MPF), angular impulse (aIMP), and elbow angle were compared across repetitions and between sexes using discrete values and statistical parametric/non-parametric mapping. There were significant and substantial sex and repetition differences in absolute iEMG, MPF, and aIMP, however, males and females had statistically similar absolute aIMP by repetition 4. When expressed relatively, there were no significant sex-differences. Additionally, there were significant between repetition changes in sEMG amplitude and elbow angle with an increasing number of repetitions, largely in the first-two thirds of repetition time. The current study suggests that there are absolute, but not relative sex-differences in EQI induced muscle fatigue, and the effects across repetitions occur predominately in the first two-thirds of repetition time.

PMID:37921046 | DOI:10.1080/14763141.2023.2269543

Stat Med. 2023 Nov 3. doi: 10.1002/sim.9944. Online ahead of print.

ABSTRACT

Human microbiome research has gained increasing importance due to its critical roles in comprehending human health and disease. Within the realm of microbiome research, the data generated often involves operational taxonomic unit counts, which can frequently present challenges such as over-dispersion and zero-inflation. To address dispersion-related concerns, the generalized Poisson model offers a flexible solution, effectively handling data characterized by over-dispersion, equi-dispersion, and under-dispersion. Furthermore, the realm of zero-inflated generalized Poisson models provides a strategic avenue to simultaneously tackle both over-dispersion and zero-inflation. The phenomenon of zero-inflation frequently stems from the heterogeneous nature of study populations. It emerges when specific microbial taxa fail to thrive in the microbial community of certain subjects, consequently resulting in a consistent count of zeros for these individuals. This subset of subjects represents a latent class, where their zeros originate from the genuine absence of the microbial taxa. In this paper, we introduce a novel testing methodology designed to uncover such latent classes within generalized Poisson regression models. We establish a closed-form test statistic and deduce its asymptotic distribution based on estimating equations. To assess its efficacy, we conduct an extensive array of simulation studies, and further apply the test to detect latent classes in human gut microbiome data from the Bogalusa Heart Study.

PMID:37921025 | DOI:10.1002/sim.9944