Nevin Manimala

Eur J Epidemiol. 2024 Feb 29. doi: 10.1007/s10654-024-01097-6. Online ahead of print.

ABSTRACT

Mendelian randomization may give biased causal estimates if the instrument affects the outcome not solely via the exposure of interest (violating the exclusion restriction assumption). We demonstrate use of a global randomization test as a falsification test for the exclusion restriction assumption. Using simulations, we explored the statistical power of the randomization test to detect an association between a genetic instrument and a covariate set due to (a) selection bias or (b) horizontal pleiotropy, compared to three approaches examining associations with individual covariates: (i) Bonferroni correction for the number of covariates, (ii) correction for the effective number of independent covariates, and (iii) an r² permutation-based approach. We conducted proof-of-principle analyses in UK Biobank, using CRP as the exposure and coronary heart disease (CHD) as the outcome. In simulations, power of the randomization test was higher than the other approaches for detecting selection bias when the correlation between the covariates was low (r² < 0.1), and at least as powerful as the other approaches across all simulated horizontal pleiotropy scenarios. In our applied example, we found strong evidence of selection bias using all approaches (e.g., global randomization test p < 0.002). We identified 51 of the 58 CRP genetic variants as horizontally pleiotropic, and estimated effects of CRP on CHD attenuated somewhat to the null when excluding these from the genetic risk score (OR = 0.96 [95% CI: 0.92, 1.00] versus 0.97 [95% CI: 0.90, 1.05] per 1-unit higher log CRP levels). The global randomization test can be a useful addition to the MR researcher’s toolkit.

PMID:38421485 | DOI:10.1007/s10654-024-01097-6

Ann Biomed Eng. 2024 Feb 29. doi: 10.1007/s10439-024-03455-7. Online ahead of print.

ABSTRACT

The distal semitendinosus tendon is commonly harvested for anterior cruciate ligament reconstruction, inducing substantial morbidity at the knee. The aim of this study was to probe how morphological changes of the semitendinosus muscle after harvest of its distal tendon for anterior cruciate ligament reconstruction affects knee flexion strength and whether the knee flexor synergists can compensate for the knee flexion weakness. Ten participants 8-18 months after anterior cruciate ligament reconstruction with an ipsilateral distal semitendinosus tendon autograft performed isometric knee flexion strength testing (15°, 45°, 60°, and 90°; 0° = knee extension) positioned prone on an isokinetic dynamometer. Morphological parameters extracted from magnetic resonance images were used to inform a musculoskeletal model. Knee flexion moments estimated by the model were then compared with those measured experimentally at each knee angle position. A statistically significant between-leg difference in experimentally-measured maximal isometric strength was found at 60° and 90°, but not 15° or 45°, of knee flexion. The musculoskeletal model matched the between-leg differences observed in experimental knee flexion moments at 15° and 45° but did not well estimate between-leg differences with a more flexed knee, particularly at 90°. Further, the knee flexor synergists could not physiologically compensate for weakness in deep knee flexion. These results suggest additional factors other than knee flexor muscle morphology play a role in knee flexion weakness following anterior cruciate ligament reconstruction with a distal semitendinosus tendon graft and thus more work at neural and microscopic levels is required for informing treatment and rehabilitation in this demographic.

PMID:38421479 | DOI:10.1007/s10439-024-03455-7

Arch Gynecol Obstet. 2024 Feb 29. doi: 10.1007/s00404-024-07387-4. Online ahead of print.

ABSTRACT

INTRODUCTION: Progesterone can be used instead of GnRH agonists and antagonists in order to avert a premature LH surge during controlled ovarian stimulation (COS) protocol. Nonetheless, there is limited knowledge regarding its utilization. Thus, this study compared the effects of progesterone and GnRH antagonists (GnRH-ant) on premature LH surges and assisted reproductive technology (ART) results in infertile women undergoing ART.

MATERIALS AND METHODS: In this clinical trial, the progesterone protocol (study group) and GnRH-ant protocol (control group) were tested in 300 infertile individuals undergoing IVF/ICSI. The main outcome was the number of oocytes retrieved. The secondary outcomes included premature LH rise/surge, the quantity of follicles measuring ≥ 10 and 14 mm, oocyte maturity and fertilization rate, the number of viable embryos, high-quality embryo rate and pregnancy outcomes.

RESULTS: The study group exhibited a statistically significant increase in the number of retrieved oocytes, follicles measuring 14 mm or greater, and viable embryos compared to the control group (P < 0.05). The study group also increased oocyte maturity, chemical pregnancy rate, and clinical pregnancy rate (P < 0.05). Both groups had similar mean serum LH, progesterone, and E2 levels on trigger day. The control group had more premature LH rise than the study group, although this difference was not statistically significant.

CONCLUSION: In conclusion, it can be stated that the progesterone protocol and the GnRH-ant protocol exhibit similar rates of sudden premature LH surge in infertile patients. However, it is important to note that the two regiments differ in their outcomes in ART.

TRIAL REGISTRATION: This study was retrospectively registered in the Iranian website ( www.irct.ir ) for clinical trials registration ( http://www.irct.ir : IRCT-ID: IRCT20201029049183N, 2020-11-27).

PMID:38421423 | DOI:10.1007/s00404-024-07387-4

Am J Hum Biol. 2024 Feb 29:e24055. doi: 10.1002/ajhb.24055. Online ahead of print.

ABSTRACT

INTRODUCTION: Although the primary function of a woman’s breast is milk synthesis, only a few studies have evaluated the relationship between breast size and human milk composition, showing equivocal results. This study aims to test if breast size during fully established lactation is related to energy density and content of macronutrients in human milk.

MATERIALS AND METHODS: Mothers of healthy, born-on-term infants at stage III of lactogenesis (N = 137) provided breast milk samples. Milk composition was analyzed using midinfrared transmission spectroscopy. The breast size index was calculated by dividing the breast by the circumference below the breast.

RESULTS: Stepwise forward linear regression showed a negative association between breast size index and lactose concentration in breast milk (β = -.242, p = .003). The final model, which includes breast size index, feeding frequency, and maternal energy intake together explained around 13% of the variance in breast milk lactose content (R² _adj = .126, p < .001). No statistically significant relationship was found between breast size index and milk’s energy density, protein, and fat content.

CONCLUSION: This is the first study that shows a negative relationship between breast size during fully established lactation and lactose concentration in milk in a large sample size. No relationship between other macronutrients and breast size indicates that large breast size is not necessary for adequate milk production; however, it may contribute to an altered lactose concentration.

PMID:38420902 | DOI:10.1002/ajhb.24055

J Infect Dis. 2024 Feb 29:jiae080. doi: 10.1093/infdis/jiae080. Online ahead of print.

ABSTRACT

BACKGROUND: Early risk assessment is needed to stratify Staphylococcus aureus infective endocarditis (SA-IE) risk among Staphylococcus aureus bacteraemia (SAB) patients to guide clinical management. The objective of this study is to develop a novel risk score independent of subjective clinical judgment and can be used early at the time of blood culture positivity.

METHODS: We conducted a retrospective big data analysis from territory-wide electronic data and included hospitalized patients with SAB between 2009 and 2019. We applied a random forest risk scoring model to select variables from an array of parameters, according to the statistical importance of each feature in predicting SA-IE outcome. The data was divided into derivation and validation cohorts. The areas under the curve of the receiver operating characteristic (AUCROC) were determined.

RESULTS: We identified 15,741 SAB patients, among them 4.18% had SA-IE. The AUCROC was 0.74 (95%CI 0.70-0.76), with a negative predictive value of 0.980 (95%CI 0.977-0.983). The four most discriminatory features were age, history of infective endocarditis, valvular heart disease, and being community-onset.

CONCLUSION: We developed a novel risk score with good performance as compared to existing scores and can be used at the time of SAB and prior to subjective clinical judgment.

PMID:38420871 | DOI:10.1093/infdis/jiae080

J Dent Educ. 2024 Feb 29. doi: 10.1002/jdd.13468. Online ahead of print.

ABSTRACT

PURPOSE/OBJECTIVES: This research aimed to identify factors that affect dental students’ attitudes toward participation in rural clinical outplacements (RCOP) in Australia, and to suggest strategies that will increase students’ desire to attend RCOP in the future.

METHODS: Dental students from the nine dental schools in Australia were invited to an online survey on their willingness to participate in an RCOP and the factors that influence this willingness. These factors were grouped into themes of education, personal and health, social, financial, and information-related.

RESULTS: The study had an estimated response rate of 10% with 202 responses. More than two-thirds (68%) of students were willing to participate in an RCOP. Students who grew up in a rural area were significantly more likely to be willing to attend an RCOP, compared to those from urban settings. Attitudes toward the anticipated educational experience of RCOP were positive, while factors related to finances and pre-existing information were of concern to students. Educational, personal/health-related, and social factors had significant impacts on participants’ willingness to attend RCOP.

CONCLUSION: Overall, despite students holding negative opinions on certain social and financial factors, their positive attitudes toward other factors outweighed these. Universities should aim to further promote the educational benefits of RCOP to improve students’ attitudes prior to attending RCOP. In-depth qualitative analysis is required to explore students’ concerns regarding RCOP and longitudinal research is warranted to monitor students’ attitudes toward RCOP and rural work over time.

PMID:38420864 | DOI:10.1002/jdd.13468

Front Biosci (Landmark Ed). 2024 Feb 6;29(2):66. doi: 10.31083/j.fbl2902066.

ABSTRACT

BACKGROUND: Gynecological malignancies, such as endometrial cancer (EC) and uterine cancer are prevalent. Increased Acyl-CoA synthetase long-chain family member 1 (ACSL1) activity may contribute to aberrant lipid metabolism, which is a potential factor that contributes to the pathogenesis of endometrial cancer. This study aimed to elucidate the potential molecular mechanisms by which ACSL1 is involved in lipid metabolism in endometrial cancer, providing valuable insights for targeted therapeutic strategies.

METHODS: Xenograft mouse models were used to assess the effect of ACSL1 on the regulation of endometrial cancer progression. ACSL1 protein levels were assessed via immunohistochemistry and immunoblotting analysis. To assess the migratory potential of Ishikawa cells, wound-healing and Transwell invasion assays were performed. Changes in lipids in serum samples from mice with endometrial cancer xenotransplants were examined in an untargeted lipidomic study that combined multivariate statistical methods with liquid chromatography‒mass spectrometry (LC/MS).

RESULTS: Patient sample and tissue microarray data suggested that higher ACSL1 expression is strongly associated with the malignant progression of EC. Overexpression of ACSL1 enhances fatty acid β-oxidation and 5′-adenylate triphosphate (ATP) generation in EC cells, promoting cell proliferation and migration. Lipidomic analysis revealed that significant changes were induced by ACSL1, including changes to 28 subclasses of lipids and a total of 24,332 distinct lipids that were detected in both positive and negative ion modes. Moreover, pathway analysis revealed the predominant association of these lipid modifications with the AMPK/CPT1C/ATP pathway and fatty acid β-oxidation.

CONCLUSIONS: This study indicates that ACSL1 regulates the AMPK/CPT1C/ATP pathway, which induces fatty acid β-oxidation, promotes proliferation and migration, and then leads to the malignant progression of EC.

PMID:38420815 | DOI:10.31083/j.fbl2902066

J Am Heart Assoc. 2024 Feb 29:e032011. doi: 10.1161/JAHA.123.032011. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies suggest an association between schizophrenia and stroke, but no studies have investigated stroke subtypes. We examined potential causal associations between schizophrenia and a range of atherosclerotic, embolic, and hemorrhagic stroke outcomes.

METHODS AND RESULTS: Two-sample Mendelian randomization analyses were conducted. The summary-level data (restricted to European ancestry) were obtained for schizophrenia and stroke: ischemic stroke, large-artery stroke, small-vessel stroke, cardioembolic stroke, and intracerebral hemorrhage. The associations between schizophrenia and each outcome were analyzed by an inverse variance weighting method primarily and Mendelian randomization Egger, weighted median, and weighted mode subsequently. The presence of pleiotropy was also tested by Cochran Q statistic, I² index, and Mendelian randomization Egger intercept with scatter and funnel plots. We found associations between schizophrenia and cardioembolic stroke (odds ratio [OR], 1.070 [95% CI, 1.023-1.119]) and intracerebral hemorrhage (OR, 1.089 [95% CI, 1.005-1.180]) using inverse variance weighting. Little evidence of associations with the other stroke subtypes was found. Different Mendelian randomization methods corroborated the association with cardioembolic stroke but not intracerebral hemorrhage.

CONCLUSIONS: We have provided evidence of a potentially causal association between schizophrenia and cardioembolic stroke. Our findings suggest that cardiac evaluation should be considered for those with schizophrenia.

PMID:38420769 | DOI:10.1161/JAHA.123.032011

J Am Heart Assoc. 2024 Feb 29:e032588. doi: 10.1161/JAHA.123.032588. Online ahead of print.

ABSTRACT

BACKGROUND: Resolvin D2 (RvD2) has been reported to protect against the development of atherosclerosis in animal models. The objective of this study was to examine the prospective association between plasma RvD2 and the risk of atherosclerotic cardiovascular disease (ASCVD) at the population level.

METHODS AND RESULTS: A cohort of 2633 community-dwelling individuals aged 35-60 years was followed for 8 years in this study. Adjusted hazard ratios and 95% CIs for ASCVD outcomes according to baseline RvD2 levels were calculated using Cox proportional hazards models. Mediation analysis was used to test the indirect effect of serum cholesterol indicators on the association between RvD2 and ASCVD probability. In total, 284 new cases of ASCVD were identified during follow-up. An inverted U-shaped association between natural log (ln)-transformed RvD2 and incident ASCVD was determined, and the threshold value for lnRvD2 was 3.87. Below the threshold, each unit increase in lnRvD2 was associated with a 2.05-fold increased risk of ASCVD (95% CI, 1.13-3.74; P=0.019). Above the threshold, each unit increase in lnRvD2 was associated with a 36% reduced risk of ASCVD (95% CI, 0.51-0.80; P<0.001). In addition, the association between RvD2 and ASCVD probability was partially mediated by high-density lipoprotein cholesterol (15.81%) when lnRvD2 <3.87, but by total cholesterol (30.23%) and low-density lipoprotein cholesterol (30.13%) when lnRvD2 ≥3.87.

CONCLUSIONS: Both lower and higher RvD2 levels are associated with a reduced risk of ASCVD, forming an inverted U-shaped relationship. Furthermore, this association is partially mediated by total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.

PMID:38420767 | DOI:10.1161/JAHA.123.032588

J Am Heart Assoc. 2024 Feb 29:e030613. doi: 10.1161/JAHA.123.030613. Online ahead of print.

ABSTRACT

BACKGROUND: Hypertension is the leading modifiable cardiovascular risk factor with recognized sex- and gender-based differences. We assessed the incorporation of sex and gender reporting in the antihypertensive medication literature informing hypertension guidelines.

METHODS AND RESULTS: Literature cited in the International Society of Hypertension (2020), European Society of Cardiology/European Society of Hypertension (2018), American College of Cardiology/American Heart Association (2017), Latin American Society of Hypertension (2017), Pan-African Society of Cardiology (2020), and Hypertension Canada (2020) guidelines was systematically reviewed. Observational studies, randomized controlled trials, and systematic reviews involving antihypertensive medications were included. Studies with participants of a single sex, guidelines, and commentaries were excluded. Data on study participation-to-prevalence ratio by sex, analysis of baseline demographics and study outcomes by sex, and stratification of adverse events by sex were extracted. Of 1659 unique citations, 331 studies met inclusion criteria. Of those, 81% reported the sex of participants, and 22% reported a male-to-female participation-to-prevalence ratio of 0.8 to 1.2. Three percent of studies stratified baseline characteristics by sex, and 20% considered sex during analysis through statistical adjustment or stratification. Although 32% of studies reported adverse events, only 0.6% stratified adverse events by sex. Most (58%) studies reporting sex/gender used sex and gender terms interchangeably.

CONCLUSIONS: Incorporation of sex- and gender-based considerations in study population, analysis, or reporting of results and adverse events is not common in the antihypertensive medication literature informing international hypertension guidelines. Greater attention to sex- and gender-based factors in research is required to optimally inform management of hypertension.

PMID:38420762 | DOI:10.1161/JAHA.123.030613