Little Evidence Of Heterogeneity Research Articles

Impact of SGLT2 inhibitors on lower limb complications: a mendelian randomization perspective.

While Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in managing diabetes and reducing cardiovascular risk, concerns about their association with lower limb complications, including, osteomyelitis, ulcers, and peripheral artery disease (PAD), persist. This study employs Mendelian Randomization (MR) to assess the causal relationship between SGLT2 inhibitors and these lower limb safety outcomes. A two-sample drug-target MR approach was used, complemented by a one-sample MR and genetic association analysis. Six SNPs were selected as instrumental variables to proxy the effect of SGLT2 inhibition. Primary outcomes were major limb safety outcomes, including osteomyelitis, lower limb ulcers, PAD, and cellulitis. The primary analytical method was the generalized inverse variance-weighted (IVW) approach, along with several sensitivity analyses. The MR analysis indicated no significant causal association between genetically proxied SGLT2 inhibition and most of the studied lower limb safety outcomes. However, a significant association with PAD was observed, necessitating careful interpretation due to discrepancies between IVW and MR-Egger results. Sensitivity analyses supported these findings, showing little evidence of heterogeneity or directional pleiotropy. This study suggests that SGLT2 inhibitors may not be significantly associated with an increased risk of most lower limb safety outcomes, including osteomyelitis, lower limb ulcers, and cellulitis, in patients with type 2 diabetes. However, the complex relationship with PAD highlights the need for further research. These findings contribute to the understanding of the safety profile of SGLT2 inhibitors, supporting their continued use in diabetes management while underlining the importance of continuous safety monitoring.

Cyber versus Brick and Mortar: Achievement, Attainment, and Postsecondary Outcomes in Pennsylvania Charter High Schools

Abstract The charter school sector has expanded beyond brick-and-mortar schools to cyber schools, where enrollment grew almost tenfold between 2015 and 2020. While a large literature documents the effects of charter schools on test scores, fewer studies explore impacts on attainment or postsecondary outcomes and there is almost no work exploring the consequences of cyber charter enrollment for these outcomes. In this paper, I examine the impacts of Pennsylvania's charter high schools on student attendance, achievement, graduation, and postsecondary enrollment, distinguishing the impacts of brick-and-mortar from cyber schools. I find that brick-and-mortar charters have no or positive effects across outcomes, and that effects are concentrated in urban districts and among Black and economically disadvantaged students. By contrast, attending a cyber charter is associated with almost universally worse outcomes, with little evidence of heterogeneity. Students who enroll in a cyber charter at the beginning of ninth grade are 9.5 percentage points (pp) less likely to graduate, 16.8 pp less likely to enroll in college, and 15.2 pp less likely to persist in a postsecondary institution beyond one semester. These results suggest that additional regulation and oversight of cyber charter schools is warranted and also bring into question the efficacy of online education.

Prospective associations of leucocyte subtypes and obesity with the risk of developing cutaneous malignant melanoma in the UK Biobank cohort

BackgroundObesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear.MethodsWe examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis.ResultsDuring a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888–0.971; per one standard deviation increase; SD = 0.144*109/L women; SD = 0.169*109/L men), specifically in older participants (HR = 0.906; 95%CI: 0.862–0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824–0.939), or with BMI ≥ 25 kg/m2 (HR = 0.895; 95%CI: 0.837–0.958 for overweight; HR = 0.923; 95%CI: 0.848–1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702–0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867–0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078–1.222; SD = 4.04 kg/m2). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time.ConclusionsMonocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance.

N–6 fatty acid biomarkers and incident atrial fibrillation: an individual participant-level pooled analysis of 11 international prospective studies

BackgroundThe presence of atrial fibrillation (AF) is associated with an over 2-fold increased risk of stroke, heart failure, and cardiovascular mortality. Long chain n–6 PUFAs have been suggested to have a variety of beneficial biologic effects that may reduce AF development; however, prior studies evaluating this relationship are limited. ObjectivesWe prospectively evaluated the association between circulating levels of linoleic acid (LA) and arachidonic acid (AA) with incident AF. MethodsWe used participant-level data from a global consortium of 11 prospective cohort studies with measurements of LA and AA in adults (aged ≥18 y). Participating studies conducted de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcomes, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. ResultsAmong 41,335 participants, 6173 incident cases of AF were ascertained, with median follow-up time of 14 y. In multivariable analysis, per interquintile range (difference between the 10th and 90th percentiles for each fatty acid), circulating n–6 levels were not associated with incident AF. For LA, the hazard ratio per interquintile range was 0.96 (95% confidence interval [CI]: 0.89, 1.04), and for AA, 1.02 (95% CI: 0.94, 1.10), with little evidence of heterogeneity between cohorts. Associations were similarly nonsignificant across subgroups of age, race, and biomarker fraction. ConclusionsBiomarkers of n–6 fatty acids including LA and AA are not associated with incident AF. These findings suggest that overall effects of n–6 PUFAs on influencing AF development are neutral.

Modifiers of COVID-19 vaccine efficacy: Results from four COVID-19 prevention network efficacy trials

Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802.

Abstract 5227: Cross-trait genome-wide association meta-analyses of clonal hematopoiesis and solid tumor risk

Abstract Clonal hematopoiesis (CH) is an age-related phenomenon where hematopoietic stem cells and their progeny acquire specific somatic mutations in a small, well-defined set of leukemogenic genes conferring them with fitness advantage leading to clonal proliferation. Mosaic chromosomal alterations (mCAs) are somatic structural variants that are manifestations of genomic instability and a sign of CH when they occur in blood. The recent availability of large-scale cohorts with blood exome sequence and genotype data has powered genome-wide association studies (GWAS) investigating the germline genetic contribution to CH and mCA risk. However, phenotypes of somatic mutation acquisition in driver genes, clonal selection and expansion, and chromosomal mosaicism are processes that are not confined to blood and contribute to neoplastic transformation across tissue types. GWAS of solid tumor susceptibility have so far identified hundreds of germline variants associated with cancer risk and it is likely that a subset of these variants contributes to solid tumor risk by affecting these somatic phenotypes in the corresponding tissues of origin and that some of the variants exert these somatic effects across tissues. We aimed to identify this subset of solid tumor risk variants by undertaking fixed effects inverse-variance weighted meta-analyses combining breast, prostate, ovarian, and endometrial cancer GWAS (total n = 237,483 cases/317,006 controls; no UK Biobank samples included) with UK Biobank-based CH (10,203 “cases”/173,918 controls) and mCA (66,011 “cases”/378,188 controls) risk GWAS in pairs where each pair involved one solid tumor type and one of either CH or mCA (for example, breast cancer and mCA constituted a pair). These analyses collectively identified 61 independent (r2<0.05) lead variants at combined cross-trait genome-wide significance (P<5 × 10−8) across 22 genomic loci where each lead variant was associated with each trait individually at P<10−3, had the same direction of allelic effect across traits, and little evidence of heterogeneity in effect (I2<40%). New loci (>1 Mb away from previously reported risk loci for a given trait) counts were: 14 new loci in the context of mCA risk, 6 new loci for CH risk, 2 for breast cancer risk, and one each for prostate, ovarian, and endometrial cancer risks. In silico functional annotation of these loci suggested lead variant-target genes that could be assigned to the discrete pathways of mitotic spindle assembly (INCENP, CENPN, ZWILCH, MAD1L1), p53 signaling (TP53, MDM4, SPI1), DNA damage repair (ATM, RAD51C, CHEK2, USP28, PARP8), and myeloid oncogenesis (WT1, HOXA9, L3MBTL3). Our novel approach combining the latest and largest blood somatic genomic trait GWAS with large-scale solid tumor risk GWAS thus yielded clear mechanistic insights into the shared inherited genetic basis of solid tumor risk and somatic genomic traits. Citation Format: Victoria Gray, George Richenberg, Pedro Quirós, Matthew Freedman, Paul Pharoah, Simon Gayther, Michelle Jones, George Vassiliou, Kate Lawrenson, Siddhartha Kar. Cross-trait genome-wide association meta-analyses of clonal hematopoiesis and solid tumor risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5227.

Intravenous iron in patients with heart failure and iron deficiency: an updated meta-analysis.

For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF. We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61-0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53-0.99; p=0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70-1.05; p=0.14) and all-cause mortality (OR 0.93, 95% CI 0.78-1.12; p=0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49-0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74-1.30) (heterogeneity p=0.07). In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.

Screen time and the risk of metabolic syndrome among children and adolescents: A systematic review and dose-response meta-analysis

AimsThe metabolic syndrome (MetS) and its consequences are one of the main public health challenges worldwide. We conducted a systematic review and dose-response meta-analysis of studies that examined the association between screen time and the MetS among children and adolescents. Data synthesisA systematic search was conducted using electronic databases, including PubMed, Scopus, ProQuest, and Cochrane Library, for studies published from 1963 up to 2 May 2022. In this systematic review and meta-analysis, observational studies with cross-sectional, case-control, and cohort design evaluating the association between screen time and MetS were included. Random effects models and linear and nonlinear dose-response meta-analyses were used to pool study results. ResultsSeven studies were included in the meta-analysis. The summary OR of MetS among children and adolescents for the highest vs. lowest time of screen time was 1.64 (95% CI: 1.32–2.03, with little evidence of heterogeneity, I2 = 9.3%, P-heterogeneity = 0.35, n = 7 studies) and 1.64 (95% CI: 1.27–2.12, I2 = 27.7%, n = 6) for cross-sectional studies. Results persisted across several additional subgroup analyses. There was a linear positive association between screen time and the risk of MetS (P dose-response <0.0001; P nonlinearity = 0.64) with an OR of 1.29 (95% CI: 1.12–1.46) per 2 h/day increment in screen time. ConclusionThe current dose-response meta-analysis suggested that increased screen time is associated with an increased risk of MetS among children and adolescents. Public health strategies may target unhealthy screen-based related behaviors to halt the development of MetS among children and adolescents.

Over Diagnosed or Over Looked? The Effect of Age at Time of School Entry on Students Receiving Special Education Services

There is growing evidence that school starting age impacts children's likelihood of receiving special education services, but less is known about variations in this effect. Using a regression discontinuity design, I found that the youngest students in a kindergarten cohort are 40% more likely ( p &lt; .001) to be placed in special education than are the oldest students, and that this effect persists through eighth grade. I found little evidence of heterogeneity by gender, race, or socioeconomic status, but some suggestive evidence that the effect is particularly great for White boys in early grades and for Black girls in the later elementary grades. I also found exploratory evidence that this effect is largest in schools with kindergarten cohorts that vary widely in age. These findings add new evidence to support policies to reduce age-induced bias in early special education placements, particularly those that address variation in this effect across students and schools.

LIFE SATISFACTION CHANGES AND ADAPTATION IN THE COVID-19 PANDEMIC: EVIDENCE FROM SINGAPORE

We provide novel evidence on how COVID-19 affected overall life satisfaction using a monthly longitudinal survey of middle-aged and older Singaporeans. We study how the subjective well-being of individuals evolves over the course of 18 months including the outbreak of the pandemic, the implementation of the lockdown and the spike of cases due to the delta variant in a country where COVID-19 is controlled in a sustained manner. Using an event-study design framework, we find large declines in overall life satisfaction in the lead-up to and following the lockdown. Fifteen months after the outbreak of the pandemic, and 13 months out from the end of lockdown, individuals have nearly, though not fully, adapted to living with the virus. We find greater negative well-being impacts of COVID-19 among individuals who report a drop in household income during the COVID-19 outbreak compared to those who do not report any income loss. However, we find little evidence of heterogeneity in the dynamics of the recovery in well-being by individuals’ underlying health status, marital status and education. On personality types, people who are high in neuroticism experience larger dips in well-being during the lockdown, and adapt to living with COVID-19 at a slower rate.

Application of diffusion-weighted whole-body MRI for response monitoring in multiple myeloma after chemotherapy: a systematic review and meta-analysis.

Myeloma Response Assessment and Diagnosis System recently published provides a framework for the standardised interpretation of DW-WBMRI in response assessment of multiple myeloma (MM) based on expert opinion. However, there is a lack of meta-analysis providing higher-level evidence to support the recommendations. In addition, some disagreement exists in the literature regarding the effect of timing and lesion subtypes on apparent diffusion coefficient (ADC) value changes post-treatment. Medline, Cochrane and Embase were searched from inception to 20th July 2021, using terms reflecting multiple myeloma and DW-WBMRI. Using PRISMA reporting guidelines, data were extracted by two investigators. Quality was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2 method. Of the 74 papers screened, 10 studies were included comprising 259 patients (127 males and 102 females) and 1744 reported lesions. Responders showed a significant absolute ADC change of 0.21×10-3mm/s2 (95% CI, 0.01-0.41) with little evidence of heterogeneity (Cochran Q, p = 0.12, I2 = 45%) or publication bias (p = 0.737). Non-responders did not show a significant absolute difference in ADC (0.06 ×10-3mm/s2, 95% CI, -0.07 to 0.19). A percentage ADC increase of 34.78% (95% CI, 10.75-58.81) was observed in responders. Meta-regression showed an inverse trend between ADC increases and time since chemotherapy initiation which did not reach statistical significance (R2 = 20.46, p = 0.282). This meta-analysis supports the use of the DW-WBMRI as an imaging biomarker for response assessment. More evidence is needed to further characterise ADC changes by lesion subtypes over time. • In multiple myeloma patients who received chemotherapy, responders have a significant absolute increase in ADC values that is not seen in non-responders. • A 35% increase in ADC from baseline values is found to classify response post-induction chemotherapy which corroborates with expert opinion from the Myeloma Response Assessment and Diagnosis System. • More evidence is needed to further characterise ADC changes by lesion subtypes over time after induction of therapy.

Diabetes mellitus as a risk factor for chemotherapy-induced peripheral neuropathy: a meta-analysis

BackgroundTo identify the association between diabetes mellitus (DM) and the risk of chemotherapy-induced peripheral neuropathy (CIPN) through a systematic review and meta-analysis.MethodsAn electronic literature search was conducted in PubMed, Embase, Web of Science, the Wanfang database, the VIP Journals database (CQVIP), the China National Knowledge Infrastructure (CNKI) database, and the China Biology Medicine database (Sinomed) between January 2010 and January 2021. Articles were included if they investigated CIPN and DM. Stata 15.1 was used to analyze the data.ResultsWe examined 8923 cancer patients from 25 studies comprising 9 cohort studies and 16 case–control studies. Meta-analysis showed that there was a statistically significant positive correlation between DM and CIPN (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.38–1.85, P < 0.001). Egger’s test (P = 0.824) showed no evidence of publication bias. The positive associations did not significant differ by study type, study quality, evaluation instrument, and type of antineoplastic drug. Omission of any single study had little effect on the combined risk estimate. Little evidence of heterogeneity was observed.ConclusionThis meta-analysis provides evidence of a significant positive association between DM and risk of CIPN. Furthermore, a more detailed evaluation is warranted for cancer patients with diabetes when they are treated with antineoplastic drugs that have the potential to cause peripheral neuropathy.

Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts

Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults. We used prospective cohort design to complete time-to-event analyses. We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n=103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks. Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week. Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.

The Effects of Career and Technical Education: Evidence from the Connecticut Technical High School System

We examine the effect of admission to 16 stand-alone technical high schools within the Connecticut Technical High School System (CTHSS) on student educational and labor market outcomes. To identify the causal effect of admission on student outcomes, we exploit the fact that CTHSS utilizes a score-based admissions system and identify the effect of admission using a regression discontinuity approach. We find that male students attending one of the technical high schools are approximately 10 percentage points more likely to graduate from high school and 8 percentage points less likely to attend college, although there is some evidence that the negative effects on college attendance fade over time. We also find that male students attending a technical high school have quarterly earnings that are approximately 31% higher. Analyses of potential mechanisms behind these results reveal that male students that attend a technical high school have higher 9th grade attendance rates and higher 10th grade test scores. We find little evidence that attending a technical high school affects the educational or labor outcomes of women. These effects appear relatively broad based across different types of students in that we find little evidence of heterogeneity in these effects over student attributes like race and ethnicity, free lunch eligibility or residence in a poor, central city school district. However, when distinguishing between students based on the Career and Technical Education (CTE) offerings of the high school that these students likely would have attended, we find that the effects of admission to a CTHSS school are noticeably larger when the counterfactual high school has less CTE offerings.

Are Trustworthiness and Legitimacy \u2018Hard to Win, Easy to Lose\u2019? A Longitudinal Test of the Asymmetry Thesis of Police-Citizen Contact

ObjectivesTest the asymmetry thesis of police-citizen contact that police trustworthiness and legitimacy are affected more by negative than by positive experiences of interactions with legal agents by analyzing changes in attitudes towards the police after an encounter with the police. Test whether prior attitudes moderate the impact of contact on changes in attitudes towards the police.MethodsA two-wave panel survey of a nationally representative sample of Australian adults measured people’s beliefs about police trustworthiness (procedural fairness and effectiveness), their duty to obey the police, their contact with the police between the two waves, and their evaluation of those encounters in terms of process and outcome. Analysis is carried out using autoregressive structural equation modeling and latent moderated structural models.ResultsThe association between both process and outcome evaluation of police-citizen encounters and changes in attitudes towards the police is asymmetrical for trust in police effectiveness, symmetrical for trust in procedural fairness, and asymmetrical (in the opposite direction expected) for duty to obey the police. Little evidence of heterogeneity in the association between encounters and trust in procedural fairness and duty to obey, but prior levels of perceived effectiveness moderate the association between outcome evaluation and changes in trust in police effectiveness.ConclusionsThe association between police-citizen encounters and attitudes towards the police may not be as asymmetrical as previously thought, particularly for changes in trust in procedural fairness and legitimacy. Policy implications include considering public-police interactions as ‘teachable moments’ and potential sources for enhancing police trustworthiness and legitimacy.

Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors

The addition of daratumumab to backbone multiple myeloma (MM) regimens is associated with improved response rates and progression-free survival (PFS). Whether improved outcomes are also associated with this regimen among patients with cytogenetically defined high-risk MM (HRMM) remains unclear. To measure PFS associated with adding daratumumab to backbone MM regimens among patients with HRMM. For this systematic review and meta-analysis, MEDLINE, Embase, PubMed, Scopus, Web of Science Core Collection, Cochrane Library, clinical trials registries, and meeting libraries were searched from inception to January 2, 2020, using terms reflecting multiple myeloma and daratumumab. Included studies were phase 3 randomized clinical trials that compared backbone MM regimens with the same regimen plus daratumumab in newly diagnosed or relapsed or refractory MM, such that the only difference between the intervention and control groups was use of daratumumab and reported outcomes by cytogenetic risk. High-risk MM was defined as the presence of t(4;14), t(14;16), or del(17p). Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 investigators independently extracted study data, with disagreements resolved by a third investigator. Quality was assessed by the Cochrane risk-of-bias method. Data on effectiveness were extracted using hazard ratios (HRs) for PFS. Relative log-HRs were pooled using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the Cochran Q and the I2 statistic. Of 5194 studies screened, 6 phase 3 trials were eligible, including 3 trials for newly diagnosed MM (2528 patients; 358 with HRMM) and 3 trials for relapsed or refractory MM (1533 patients; 222 with HRMM). Among patients with newly diagnosed HRMM, the addition of daratumumab to backbone regimens was associated with improved PFS (pooled HR, 0.67; 95% CI, 0.47-0.95; P = .02), with little evidence of heterogeneity (Cochran Q, P = .77; I2 = 0%). Similar results were seen among patients with relapsed or refractory HRMM (pooled HR, 0.45; 95% CI, 0.30-0.67; P < .001), again with little evidence of heterogeneity (Cochran Q, P = .63; I2 = 0%). This study suggests that incorporating daratumumab to backbone regimens may be associated with improved PFS among patients with newly diagnosed HRMM or relapsed or refractory HRMM.

Growth-Mindset Interventions at Scale: Experimental Evidence From Argentina

This is one of the first evaluations of a “growth-mindset” intervention at scale in a developing country. I randomly assigned 202 public secondary schools in Salta, Argentina, to a treatment group in which Grade 12 students were asked to read about the malleability of intelligence, write a letter to a classmate, and post their letters in their classroom, or to a control group. The intervention was implemented as intended. Yet, I find no evidence that it affected students’ propensity to find tasks less intimidating, school climate, school performance, achievement, or post-secondary plans. I rule out small effects and find little evidence of heterogeneity. This study suggests that the intervention may be more challenging to replicate and scale than anticipated.

Effects of strawberry intervention on cardiovascular risk factors: a meta-analysis of randomised controlled trials.

We conducted a meta-analysis of randomised controlled trials (RCT) to examine the effects of strawberry interventions on cardiovascular risk factors. We searched multiple databases including PubMed, Web of Science and Scopus to identify eligible studies published before 19 May 2019. The endpoints were blood pressure, total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, TAG, fasting blood glucose, endothelial function and inflammatory factors. Pooled analyses were performed using random- or fixed-effects models according to a heterogeneity test. We also conducted sub-group analyses by baseline endpoint levels. We included eleven RCT in this meta-analysis (six for blood pressure, seven for lipid profile, seven for fasting blood glucose and six for C-reactive protein (CRP)). Overall, the strawberry interventions significantly reduced CRP levels by 0·63 (95 % CI -1·04, -0·22) mg/l but did not affect blood pressure, lipid profile or fasting blood glucose in the main analyses. Our analysis stratified by baseline endpoint levels showed the strawberry interventions significantly reduced TC among people with baseline levels >5 mmol/l (-0·52 (95 % CI -0·88, -0·15) mmol/l) and reduced LDL-cholesterol among people with baseline levels >3 mmol/l (-0·31 (95 % CI -0·60, -0·02) mmol/l). There was little evidence of heterogeneity in the analysis and no evidence of publication bias. In summary, strawberry interventions significantly reduced CRP levels and may improve TC and LDL-cholesterol in individuals with high baseline levels.

Varenicline versus nicotine replacement therapy for long-term smoking cessation: an observational study using the Clinical Practice Research Datalink.

Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population. To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes. Clinical Practice Research Datalink. We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used. People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval -0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups. Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population. Future research should investigate the decline in prescribing of smoking cessation products; develop an optimal treatment algorithm for smoking cessation; use methods for using instruments with survival outcomes; and develop methods for comparing multivariable-adjusted and instrumental variable estimates. Not all of our code lists were validated, body mass index and Index of Multiple Deprivation had missing values, our results may suffer from residual confounding, and we had no information on treatment adherence. This trial is registered as NCT02681848. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 9. See the NIHR Journals Library website for further project information.

Dynamic link between oil prices and exchange rates: A non-linear approach

We explore the non-linear relationship between crude oil prices and exchange rates of major currencies from quantitative and structural perspectives, by utilizing bivariate normal mixture model. The correlation coefficients between oil prices and exchange rates demonstrate that their dependences typically start from 2004 then dynamically change over time. Then we investigate whether business cycle and oil price shocks as two possible exogenous factors affect the dependence structure of oil-FX linkage. We find significant structural heterogeneity during economic expansion while little evidence of heterogeneity in recession. This finding provides alternative interpretations for the enhanced dependence between oil prices and exchange rates and generates implications of financialization in commodity market. In terms of oil price shocks (Kilian, 2009), the normal mixture model captures significant heterogeneity, implying that unstable oil-FX dependence structure is frequently associated with oil aggregate demand shocks and oil-specific demand shocks. With an emphasis on the dynamic weights of two underlying states, we interestingly find that structural heterogeneities coincide with a variety of geopolitical and economic events. The application of normal mixture not only provide us knowledge of non-linear relationship between oil prices and exchange rates but also guidance for investors in risk management and portfolio diversification complementary to the traditional portfolio theory based on normal distribution.