Strong Causal Association Research Articles

Circulating levels of micronutrients and risk of osteomyelitis: a Mendelian randomization study.

Few observational studies have investigated the effect of micronutrients on osteomyelitis, and these findings are limited by confounding and conflicting results. Therefore, we conducted Mendelian randomization (MR) analyses to evaluate the association between blood levels of eight micronutrients (copper, selenium, zinc, vitamin B12, vitamin C, and vitamin D, vitamin B6, vitamin E) and the risk of osteomyelitis. We performed the two-sample and multivariable Mendelian randomization (MVMR) to investigate causation, where instrument variables for the predictor (micronutrients) were derived from the summary data of micronutrients from independent cohorts of European ancestry. The outcome instrumental variables were used from the summary data of European-ancestry individuals (n = 486,484). The threshold of statistical significance was set at p < 0.00625. We found a significant causal association that elevated zinc heightens the risk of developing osteomyelitis in European ancestry individuals OR = 1.23 [95% confidence interval (CI) [1.07, 1.43]; p = 4.26E-03]. Similarly, vitamin B6 showed a similar significant causal effect on osteomyelitis as a risk factor OR = 2.78 (95% CI [1.34, 5.76]; p = 6.04E-03; in the secondary analysis). Post-hoc analysis suggested this result (vitamin B6). However, the multivariable Mendelian randomization (MVMR) provides evidence against the causal association between zinc and osteomyelitis OR = 0.98(95% CI [-0.11, 0.07]; p = 7.20E-1). After searching in PhenoScanner, no SNP with confounding factors was found in the analysis of vitamin B6. There was no evidence of a reverse causal impact of osteomyelitis on zinc and vitamin B6. This study supported a strong causal association between vitamin B6 and osteomyelitis while reporting a dubious causal association between zinc and osteomyelitis.

Critical Reflections on the Usefulness of eConnect to a Sample of Child and Youth Care Workers in South Africa

ABSTRACT In South Africa, most children in care have been removed from homes characterized by violence, abuse, poverty, and neglect, with many of these children often exposed to multiple traumatic events. Research points to a strong causal association between child trauma and attachment difficulties. Poor attachment increases children’s risk for a range of externalizing behaviors, with related negative consequences for the child in both the short and long term. Addressing attachment difficulties of children who have experienced disrupted care is therefore vital. This paper reflects critically on the usefulness of eConnect, a trauma informed and attachment-based programme in such cases. It reports the interview-facilitated insights of 11 child and youth care workers (CYCW) from a care facility in Johannesburg, South Africa, who completed the eConnect programme in 2021. The first interviews were conducted in the last eConnect session (2021); follow-up interviews were done in 2022. The resulting insights allow evaluation of the contextual fit of eConnect for CYCW in SA and understanding of which programme aspects had enduring uptake. They nudge continued sensitivity to situational and cultural dynamics to optimize programme efficacy and best enable care workers.

Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study.

Previous studies have reported controversial relationships between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS). This study aims to demonstrate the causal effect between VEGF and IS using Mendelian randomization (MR). Summary statistics data from two large-scale genome-wide association studies (GWAS) for 16,112 patients with measured VEGF levels and 40,585 patients with IS were downloaded from public databases and included in this study. A published calculator was adopted for MR power calculation. The primary outcome was any ischemic stroke, and the secondary outcomes were large-artery stroke, cardioembolic stroke, and small-vessel stroke. We used the inverse variance-weighted (IVW) method for primary analysis, supplemented by MR-Egger regression and the weighted median method. Nine SNPs were included to represent serum VEGF levels. The IVW method revealed no strong causal association between VEGF and any ischemic stroke (odds ratio [OR] 1.01, 95%CI 0.99-1.04, p = 0.39), cardioembolic stroke (OR 1.04, 95%CI 0.97-1.12, p = 0.28), large-artery stroke (OR 1.02, 95%CI 0.95-1.09, p = 0.62), and small-vessel stroke (OR 0.98, 95%CI 0.91-1.04, p = 0.46). These findings remained robust in sensitivity analyses. MR-Egger regression suggested no horizontal pleiotropy. This Mendelian randomization study found no relationship between genetically predisposed serum VEGF levels and risks of IS or its subtypes.

Causal association of obesity with epigenetic aging and telomere length: a bidirectional mendelian randomization study

BackgroundIn observational studies, there exists an association between obesity and epigenetic age as well as telomere length. However, varying and partially conflicting outcomes have notably arisen from distinct studies on this topic. In the present study, two-way Mendelian randomization was used to identify potential causal associations between obesity and epigenetic age and telomeres.MethodsA genome-wide association study was conducted using data from individuals of European ancestry to investigate bidirectional Mendelian randomization (MR) regarding the causal relationships between obesity, as indicated by three obesity indicators (body mass index or BMI, waist circumference adjusted for BMI or WCadjBMI, and waist-to-hip ratio adjusted for BMI or WHRadjBMI), and four epigenetic age measures (HannumAge, HorvathAge, GrimAge, PhenoAge), as well as telomere length. To assess these causal associations, various statistical methods were employed, including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode. To address the issue of multiple testing, we applied the Bonferroni correction. These methods were used to determine whether there is a causal link between obesity and epigenetic age, as well as telomere length, and to explore potential bidirectional relationships. Forest plots and scatter plots were generated to show causal associations between exposures and outcomes. For a comprehensive visualization of the results, leave-one-out sensitivity analysis plots, individual SNP-based forest plots for MR analysis, and funnel plots were included in the presentation of the results.ResultsA strong causal association was identified between obesity and accelerated HannumAge, GrimAge, PhenoAge and telomere length shrinkage. The causal relationship between WCadjBMI and PhenoAge acceleration (OR: 2.099, 95%CI: 1.248—3.531, p = 0.005) was the strongest among them. However, only the p-values for the causal associations of obesity with GrimAge, PhenoAge, and telomere length met the criteria after correction using the Bonferroni multiple test. In the reverse MR analysis, there were statistically significant causal associations between HorvathAge, PhenoAge and GrimAge and BMI, but these associations exhibited lower effect sizes, as indicated by their Odds Ratios (ORs). Notably, sensitivity analysis revealed the robustness of the study results.ConclusionsThe present findings reveal a causal relationship between obesity and the acceleration of epigenetic aging as well as the reduction of telomere length, offering valuable insights for further scientific investigations aimed at developing strategies to mitigate the aging process in humans.

Univariable and multivariable Mendelian randomization study identified the key role of gut microbiota in immunotherapeutic toxicity

BackgroundIn cancer patients receiving immune checkpoint inhibitors (ICIs), there is emerging evidence suggesting a correlation between gut microbiota and immune-related adverse events (irAEs). However, the exact roles of gut microbiota and the causal associations are yet to be clarified.MethodsTo investigate this, we first conducted a univariable bi-directional two-sample Mendelian randomization (MR) analysis. Instrumental variables (IVs) for gut microbiota were retrieved from the MiBioGen consortium (18,340 participants). GWAS summary data for irAEs were gathered from an ICIs-treated cohort with 1,751 cancer patients. Various MR analysis methods, including inverse variance weighted (IVW), MR PRESSO, maximum likelihood (ML), weighted median, weighted mode, and cML–MA–BIC, were used. Furthermore, multivariable MR (MVMR) analysis was performed to account for possible influencing instrumental variables.ResultsOur analysis identified fourteen gut bacterial taxa that were causally associated with irAEs. Notably, Lachnospiraceae was strongly associated with an increased risk of both high-grade and all-grade irAEs, even after accounting for the effect of BMI in the MVMR analysis. Akkermansia, Verrucomicrobiaceae, and Anaerostipes were found to exert protective roles in high-grade irAEs. However, Ruminiclostridium6, Coprococcus3, Collinsella, and Eubacterium (fissicatena group) were associated with a higher risk of developing high-grade irAEs. RuminococcaceaeUCG004, and DefluviitaleaceaeUCG011 were protective against all-grade irAEs, whereas Porphyromonadaceae, Roseburia, Eubacterium (brachy group), and Peptococcus were associated with an increased risk of all-grade irAEs.ConclusionsOur analysis highlights a strong causal association between Lachnospiraceae and irAEs, along with some other gut microbial taxa. These findings provide potential modifiable targets for managing irAEs and warrant further investigation.

Long term outcomes in the critically ill: Investigating the association between frailty and survival. LONG a SWARM regional observational study

Background: Frailty is common and is present in up to 30% of patients admitted to the ICU. We do not yet understand the true impact of ICU admission on this population, certainly in terms of longer-term outcomes. Method: Random selection of patients admitted to each general ICU within the SWARM network between October 1st 2012 and January 31st 2013. To be eligible, patients had to be over the age of 18 and admitted to the ICU with either a medical diagnosis or following emergency gastrointestinal/vascular surgery. Results: 1888 patients were eligible for random selection. 560 patients were selected for the final analysis. Three hundred and eighteen patients had an estimated frailty score between 1 and 3 (classified as not frail, 56.8%), whilst 112 had a score of 4 (classified as vulnerable, 20%) and 130 patients had a score of between 5 and 7 (classified as frail, 23.2%). The median survival for patients with an estimated frailty score of four (vulnerable) was lower than those with an estimated score of 5 or greater (331.5 vs 594 days, p &lt; 0.0001). One-year survival was 79% (75, 84), whilst 5-year survival was 69% (65, 75). Hazard ratios for ‘vulnerable’ and ‘frail’ sub-groups were estimated as 2.6 and 2.4 respectively. Conclusion: There is significant evidence to suggest a strong causal association between frailty and survival after ICU admission. ‘Vulnerable’ status may well be associated with similar effect on long-term survival to that of ‘frailty’.

Causal relationship between plasma metabolites and carpal tunnel syndrome risk: evidence from a mendelian randomization study.

Carpal tunnel syndrome (CTS) is a common symptom of nerve compression and a leading cause of pain and hand dysfunction. However, the underlying biological mechanisms are not fully understood. The aim of this study was to reveal the causal effect of circulating metabolites on susceptibility to CTS. We employed various Mendelian randomization (MR) methods, including Inverse Variance Weighted, MR-Egger, Weighted Median, Simple Mode, and Weighted Model, to examine the association between 1,400 metabolites and the risk of developing CTS. We obtained Single-nucleotide polymorphisms (SNPs) associated with 1,400 metabolites from the Canadian Longitudinal Study on Aging (CLSA) cohort. CTS data was derived from the FinnGen consortium, which included 11,208 cases and 1,95,047 controls of European ancestry. The results of the two-sample MR study indicated an association between 77 metabolites (metabolite ratios) and CTS. After false discovery rate (FDR) correction, a strong causal association between glucuronate levels (odd ratio (OR) [95% CI]: 0.98 [0.97-0.99], p FDR = 0.002), adenosine 5'-monophosphate (AMP) to phosphate ratio (OR [95% CI]:0.58 [0.45-0.74], p FDR = 0.009), cysteinylglycine disulfide levels (OR [95% CI]: 0.85 [0.78-0.92], p FDR = 0.047) and CTS was finally identified. In summary, the results of this study suggest that the identified glucuronate, the ratio of AMP to phosphate, and cysteinylglycine disulfide levels can be considered as metabolic biomarkers for CTS screening and prevention in future clinical practice, as well as candidate molecules for future mechanism exploration and drug target selection.

Both clinically informed and brain region agnostic approaches identify neuroimaging derived phenotypes associated with genetically regulated gene expression of late‐onset Alzheimer’s disease genes

AbstractBackgroundGenetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regions associated with late‐onset AD (LOAD) via gene expression.MethodThis study contained brain region‐agnostic and region‐informed approaches. Both approaches utilized a set of 25 genes causally associated with LOAD in our previous cross‐tissue transcriptome‐wide association studies (TWAS) (Chen et al., 2021) to identify LOAD‐associated GReX‐mediated NIDPs. We leveraged the UK Biobank (UKBB) neuroimaging TWAS resource to provide GReX‐mediated NIDP information. Region‐agnostic: We assessed associations between GReX of LOAD genes and T1‐derived cortical and subcortical grey matter NIDPs from the UKBB neuroimaging TWAS. Region‐informed: We identified a set of AD‐associated cortical grey matter NIDPs from diagnosed AD patients (Westman et al., 2013). Next, we subset the UKBB neuroimaging TWAS data to those describing associations between GReX of LOAD genes and the selected AD NIDPs.A Benjamini‐Hochberg FDR p‐value threshold of 0.05 was used to establish statistical significance, and causal inference testing on associations between GReX of LOAD genes and NIDPs was conducted by implementing MR‐JTI in both approaches.Result Region‐agnostic: This approach found associations between GReX of 8 LOAD‐associated genes and 14 NIDPs (Figure 1). The most significant association is the GreX of ZNF296 and the right pars opercularis of the inferior frontal cortex, which replicated across 16 different tissues. Region‐informed: A single highly significant causal association between the GReX of PSMC3 and the ventral diencephalon was identified and replicated in gene expression models of 3 different bansal ganglia‐derived tissue models.ConclusionOur study shows the highly significant causal association between the GReX of ZNF296 and the right pars opercularis on LOAD through the region‐agnostic approach and the strong causal association between the GReX of PSMC3 and the ventral diencephalon on LOAD in AD‐associated region‐informed analyses. Our methodologies provide opportunities to explore brain regions associated with LOAD that are mediated by GReX of AD‐associated genes illuminating the impact of LOAD‐associated genes on gene expression and brain physiology.

Mendelian randomization study of gastroesophageal reflux disease and major depression.

This study systematically investigated the causal relationship between gastroesophageal reflux disease (GERD) and major depression (MD). Single-nucleotide polymorphisms (SNPs) associated with disorders of interest were screened via the genome-wide association study (GWAS) enrolling individuals of European descent. Summary-level data for GERD and MD were extracted from the UK Biobank. The inverse-variance-weighted (IVW) method was utilized as the primary analysis. Sensitivity analyses were performed using the MR-Egger method, the Maximum likelihood method, the MR-pleiotropy residual sum outlier (MR-PRESSO) method, and MR-robust adjusted profile score (MR-RAPS) method. MR-Egger regression, heterogeneity tests, pleiotropy tests, and leave-one-out tests were also performed to analyze sensitivity. The MR Steiger test was used to verify the directionality of the exposure to the outcome. An available website tool (https://shiny.cnsgenomics.com/mRnd/) was used to calculate the statistical power of MR analysis. Meta-analysis was applied to test MD's average genetically predicted effect on GERD. Our MR study showed a bidirectional causal association between MD and GERD. Regarding MD to GERD, there was a positive association between them; the ORs were 1.500 (95% CI = 1.320-1.704; P = 4.91E-10) and 2.058 (95% CI = 1.868-2.267; P = 2.20E-48) in the IVW method, respectively. In addition, the meta-analysis also showed a strong positive causal association between MD and GERD. When exposure and outcome were reversed, genetic predisposition to GERD was significantly associated with the overall Risk of advanced MD (ieu-a-1187, OR = 1.982, 95% CI = 1.694-2.319, P = 1.41E-17; ieu-b-102, OR = 1.612, 95% CI = 1.530-2.700, P = 1.15E-70). Our study provides 100% power to detect the causal effect of MD on GERD and vice versa. Genetically predicted MD was positively associated with higher GERD risk, and vice versa. Our study reminds clinicians to pay attention to screening for GERD when diagnosing and treating MD and vice versa. Moreover, there may be positive feedback between MD and GERD when treating and preventing one disorder may benefit the treatment and prevention of the other.

Comparison of Guillain-Barre Syndrome Cases during and Prior to the COVID-19 Pandemic: A Multicentric Study.

Guillain-Barre syndrome (GBS) is one of the most common neurological manifestations associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Although data for a strong causal association is lacking, anecdotal reports, case series and systematic reviews linking the two have emerged in the literature. This prompted us to compare the clinical features, electrophysiology, and outcomes of GBS cases presenting during the pandemic with cases reported during a similar time period prior to the pandemic. Prospective data of GBS cases diagnosed as per the National Institute of Neurological Disorders and Stroke (NINDS) criteria was collected for a 6-month period (July-December 2021) at three tertiary care teaching hospitals during the coronavirus pandemic and compared with retrospective records-based data of cases prior to the pandemic (January-July 2019). A total of 40 cases were included in the cases, out of which 17 were in the prepandemic and 23 in the postpandemic period. A total of three cases temporally related to coronavirus disease 2019 (COVID-19) infection and four cases following COVID-19 vaccination were seen in the pandemic cohort. The clinical features, electrophysiological features, and outcomes were comparable during both periods. A slightly higher rate of in-hospital complications and single mortality was reported in the postpandemic period. The number of GBS hospital admissions, clinical presentation, electrodiagnostic features, and short-term outcomes did not differ significantly between the prepandemic and postpandemic periods; a slightly higher incidence of in-hospital complications was observed during the pandemic period. How to cite this article: Panicker P, R D, V AG, et al. Comparison of Guillain-Barre Syndrome Cases during and Prior to the COVID-19 Pandemic: A Multicentric Study. J Assoc Physicians India 2023;71(9):69-71.

The impacts on informal financing strategy of small and micro enterprises by interest rate risks and public health emergencies

Informal finance is a crucial financing method for small and micro enterprises (SMEs) in most developing countries. Interest rate risks (IRS) should be a vital component of SMEs' informal finance strategies (IFS), and public health emergencies (as COVID-19) is likely to modify IFS due to increased liquidity risks for SMEs. This article examines the relationship between IRS and IFS and its moderated effects by COVID-19. The study develops a structural equation model of SMEs' IFS to investigate SMEs' IFS, the causal relationship between IRS and SMEs' IFS, mediator effects of SMEs' corporate financial status and regional financial and economic conditions, and moderating effects of SMEs' variables. The empirical data is from Wenzhou, China, distributed between 2016 and 2021. The study concludes that IFS will continue to be a financing technique for Chinese SMEs, even if it may have a deterrent effect due to COVID-19. Additionally, there is a strong positive causal association between IFS and SMEs' IRS, as well as moderator and mediator effects. Recommendations for government policy include clarifying the connection between SMEs' IFS and influencing variables, providing scientific and methodical analysis tools for evaluating factors impacting SMEs' IFS, and encouraging the optimization and upgrading of SMEs' IFS.

Maternal septicemia caused by Streptococcus mitis: a possible link between intra-amniotic infection and periodontitis. Case report and literature review

BackgroundIntra-amniotic infection has a strong causal association with spontaneous preterm birth and preterm prelabor rupture of membranes (PPROM). The most common route of intra-amniotic infection is the ascending pathway in which microorganisms from the vagina gain access to the amniotic cavity. Distant microorganisms such as those from the oral cavity have been reported in intra-amniotic infection through hematogenous spreading.Case presentationA 31-year-old gravida 1, para 0 Thai woman at 33+6 weeks’ gestation presented with leakage of vaginal fluid and irregular uterine contraction. She developed fever at 4 h after admission and was later diagnosed with acute chorioamnionitis. A Cesarean section was performed to terminate pregnancy. In addition to a blood culture, the cultures of amniotic fluid, vaginal and chorioamniotic membrane swabs were positive for Streptococcus mitis with identical susceptibility profiles. After the delivery and antibiotic prescription, oral examination showed dental caries and chronic periodontitis.ConclusionsThis is the first case report demonstrating maternal septicemia and intra-amniotic infection caused by S. mitis which might be attributed to periodontitis in women presenting with preterm PROM. We highlighted the association of periodontal disease and preterm labor/PROM syndrome. Oral cavity examination should be included in the prenatal care to ensure good dental hygiene.

Prediction of insulin therapy in women with gestational diabetes: a systematic review and meta-analysis of observational studies.

To identify antenatal risk factors that may predict the need for insulin treatment upon diagnosis of gestational diabetes (GDM), that is, to identify the specific characteristics of women diagnosed with GDM who did not achieve good glycemic control through lifestyle modifications. We performed a comprehensive literature search in PubMed, Science Direct, Ebsco, and Scielo for studies evaluating the associations between antenatal factors and the need for insulin treatment published until January 28th, 2021. Random-effects models were used to estimate risk ratios and their 95% confidence interval. The quality of studies was assessed using the Newcastle-Ottawa Scale. Random-effects models were used to estimate outcomes, and effects reported as risk ratio and their 95% confidence interval. The systematic review and meta-analysis were registered in the International Prospective Register of Systematic Reviews. Eighteen observational studies were selected, reporting 14,951 women with GDM of whom 5,371 received insulin treatment. There were statistically significant associations between the need for insulin treatment and BMI≥30 (RR:2.2; 95%CI: 1.44-3.41), family history of type2 diabetes mellitus (RR:1.74; 95%CI: 1.56-1.93), prior personal history of GDM (RR:2.10; 95%CI: 1.56-2.82), glycated hemoglobin value at GDM diagnosis (RR:2.12; 95%CI: 1.77-2.54), and basal glycemia obtained in the diagnostic curve (RR: 1.2; 95%CI: 1.12-1.28). Nulliparity and maternal age were not determinants factor. There was moderate-to-high heterogeneity among the included studies. the strong causal association between BMI≥30, family history of type 2 diabetes mellitus, prior history of GDM and glycosylated hemoglobin with the need for insulin treatment was revealed.

Histone demethylase KDM5A enhances cell proliferation, induces EMT in lung adenocarcinoma cells, and have a strong causal association with paclitaxel resistance

Recent reports suggest that histone demethylase KDM5A emerges as a new player in the development of drug resistance and thus increases the challenges of chemotherapy. Here, we explore the role of KDM5A in cell proliferation, epithelial-mesenchymal transition (EMT)and its causal association with paclitaxel resistance in lung adenocarcinoma. Paclitaxel-resistant lung adenocarcinoma PTX-Calu-3 cells showed significantly higher IC50 value (7±0.176 µM) upon paclitaxel treatment than lung adenocarcinoma SK-LI-1 (3.6±0.005 nM), Calu-3 (4.3±0.015 nM), and A549 (4.5±0.106 nM) cells. We found that expression of KDM5A and P-glycoprotein (P-gp), which plays a critical role in the development of paclitaxel resistance, were significantly higher in PTX-Calu-3 cells compared to SK-LI-1, Calu-3, and A549 cells.. We observed a significant increase in the expression of mesenchymal markers N-cadherin and vimentin, and a concomitant decrease in expression of E-cadherin and α-catenin in PTX-Calu-3 compared to SK-LI-1, Calu-3, and A549 lung cancer cell lines. Transwell Boyden chamber and wound healing assays further demonstrated that a significantly higher number of PTX-Calu-3 cells were invasive and motile compared to SK-LI-1, Calu-3, and A549 cells, thus supporting the role of KDM5A in metastasis-associated processes. Additionally, a significantly higher expression of KDM5A was observed in lung adenocarcinoma patients' samples compared with adjacent normal tissues as well as in PTX-Calu-3 cells compared toSK-LI-1, Calu-3, and A549 cells, as shown both with histochemistry and real time-polymerase chain reaction (RT-PCR). In summary, these results suggest that KDM5A plays a key role in lung adenocarcinoma by promoting proliferation, EMT, and drug resistance to paclitaxel treatment.

Association of smoking status and recurrence of non-muscle invasive bladder cancer among patients managed with blue light cystoscopy

PurposeSmoking has a strong causal association with bladder cancer but the relationship with recurrence is not well established. We sought to assess the association of smoking status on recurrence of non-muscle invasive bladder cancer (NMIBC) in a contemporary cohort of patients with predominantly high-risk, recurrent NMIBC managed with photodynamic enhanced cystoscopy. Materials and methodsWe performed a retrospective study of patients with NMIBC included in a multi-institutional registry. Our primary exposure of interest was smoking status. Our primary outcome was first recurrence of NMIBC. Kaplan-Meier analysis was used to calculate recurrence free probabilities and Cox proportional hazards regression was used to evaluate the impact of smoking status on recurrence free survival. ResultsOur analytic cohort included 723 adults with bladder cancer, 11.5% with primary NMIBC and 88.5% with recurrent NMIBC. The majority of patients were white, male, and had high-risk NMIBC (72.6%). 52.6% of included patients were former smokers and 12.7% were current smokers. During the three-year study period, there was a NMIBC recurrence in 259 of the 723 patients (35.8%). The 1- and 3-year probability of recurrence was 19% and 44%, respectively. The grade and stage of recurrences were 28.9% LG Ta, 34.4% HG Ta, 15.8% pure CIS, 0.3% LG T1, 15.4% HG T1, and 5.4% unknown. After adjustment for a priori clinical and demographic factors, smoking status had no significant association with recurrence. ConclusionSmoking status was not significantly association with recurrence in a study of patients with predominantly high-risk recurrent NMIBC managed with photodynamic enhanced cystoscopy.

Comprehensive Investigation of Circulating Biomarkers and Their Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events.

Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood. We performed multivariable-adjusted regressions and 2-sample Mendelian randomization analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451 933 participants of the UK Biobank. After multiple-testing correction (alpha=1.3×10-4), we found a total of 15, 9, 21, 22, 26, 24, and 26 biomarkers strongly associated with coronary artery disease, ischemic stroke, atrial fibrillation, type 2 diabetes, systolic blood pressure, body mass index, and waist-to-hip ratio; respectively. The Mendelian randomization analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with type 2 diabetes and coronary artery disease. Particularly interesting findings included a protective role of IGF-1 (insulin-like growth factor 1) in systolic blood pressure, and the strong causal association of lipoprotein(a) in coronary artery disease development (β, -0.13; per SD change in exposure and outcome and odds ratio, 1.28; P=2.6×10-4 and P=7.4×10-35, respectively). In addition, our results indicated a causal role of increased ALT (alanine aminotransferase) in the development of type 2 diabetes and hypertension (odds ratio, 1.59 and β, 0.06, per SD change in exposure and outcome; P=4.8×10-11 and P=6.0×10-5). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease. We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies.

The Effect of Remittances on Crime in India

Abstract There is a well-established literature that finds a strong causal association between remittance flows and economic growth and poverty. Owing to the poverty-alleviating and income-generating effects of remittances, it may theoretically reduce crime by increasing the opportunity cost of committing crime. This paper studies the effects of remittance receipts on crime outcomes in India. The identification strategy, exploits the variation in rainfall as an instrument for remittance receipts. The results suggest that remittance receipts have a negative effect on violent crimes and a positive effect on nonviolent crimes. Since remittance flows mean that more economic resources are available, remittances provide an incentive for certain crimes that thrive in the presence of economic resources. Therefore, an important implication of this result is that as remittance receipts increase income and welfare, there is a diverse effect on the costs and benefits of different types of crimes. It may result in unfavorable outcomes in the form of increases in certain nonviolent crimes.

ASSOCIATION OF HIGH RISK HUMAN PAPILLOMA VIRUS (HPV-16/18) WITH P16 PROTEIN IN ORAL PREMALIGNANT LESIONS AND ORAL SQUAMOUS CELL CARCINOMA

Background: Oral cancer is a major problem globally. The strong causal association with tobacco, prevalent in Pakistan makes it imperative to know the role of molecular events in oral oncogenesis. We aim to evaluate high risk HPV 16/18 and p16 in oral premalignant lesions (OPL) and oral squamous cell carcinoma (OSCC). We further analyze the association between high risk human papilloma virus (HR-HPV16/18) and p16 in OPL and OSCC. Methods: A total of 100 OSCC and 50 OPL cases were included. Demographic data along with habitual exposure to smoked and chewable tobacco, betel and gutka etc., was noted. We evaluated p16 in OPL and OSCC by immunohistochemistry, HPV was detected by polymerase chain reaction. Data was entered and analyzed using SPSS 21. Chi square and Fisher exact were applied to determine the association of HPV and p16 with different variables. Results: Out of 50 OPL, 14% were positive and 86% were negative for p16 whereas out of 100 OSCC, 18% were positive and 82% were negative. Out of 50 OPL, HPV was detected in 6% whereas out of 100 OSCC, 15% were positive. Highly significant co expression of HPV with p16 was observed in all 15 (100%) HPV positive OSCC cases (p = 0.001). However, 3 out of 18 cases, which showed p16 expression, did not show HPV infection. Conclusion: Role of p16 as a surrogate marker for HPV in OSCC can be supported in the present study. Moreover a Chemical carcinogen like tobacco is considered as major associative risk factor with p16 and HPV in concert.

Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End-Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach.

BackgroundCirculating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association.Methods and ResultsPlasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New‐onset hypertension was recorded in 1206 participants during a median follow‐up of 10.7 years. Baseline total bilirubin was approximately log‐linearly associated with hypertension risk. Age‐ and sex‐adjusted hazard ratio for hypertension per 1‐SD increase in loge total bilirubin was 0.86 (0.81–0.92; P<0.001), which was attenuated to 0.94 (0.88–0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high‐sensitivity C‐reactive protein (0.94; 0.88–1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels—rs6742078—was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure.ConclusionsThe weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.

Pathogenesis of Zika Virus-Associated Embryopathy.

A strong causal association has become evident between Zika virus (ZIKV) infection during pregnancy and the occurrence of fetal growth restriction, microcephaly and eye defects. Circumstantial evidence is presented in this paper in support of the hypothesis that these effects, as well as the Guillain-Barré syndrome, are due to an endogenous form of hypervitaminosis A resulting from ZIKV infection-induced damage to the liver and the spillage of stored vitamin A compounds (“retinoids”) into the maternal and fetal circulation in toxic concentrations. Retinoids are mainly stored in the liver (about 80%) and are essential for numerous biological functions. In higher concentration, retinoids are potentially cytotoxic, pro-oxidant, mutagenic and teratogenic, especially if sudden shifts occur in their bodily distribution. Although liver involvement has not been mentioned specifically in recent reports, conventional liver enzyme tests underestimate the true extent of liver dysfunction. The proposed model could be tested by comparing retinoid concentration and expression profiles in microcephalic newborns of ZIKV-infected mothers and nonmicrocephalic newborn controls, and by correlating these profiles with measures of clinical severity.