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PubMed2006

Survival benefit associated with adjuvant androgen deprivation therapy combined with radiotherapy for high- and low-risk patients with nonmetastatic prostate cancer.

BACKGROUND: The use of adjuvant androgen deprivation therapy (ADT) combined with radiotherapy has become common in low-risk patients, although clinical trials have focused primarily on high-risk patients. This study examines the effectiveness of adjuvant ADT combined with radiotherapy for a wide range of patients treated in the 1990s. METHODS AND MATERIALS: Prostate cancer survival was examined in a population based cohort of 31,643 patients aged 65 to 85 years who were diagnosed with nonmetastatic prostate cancer and treated with external beam radiotherapy and/or brachytherapy. Instrumental variable analysis methods were used to control for selection bias. RESULTS: Patients with stage T3/T4 disease who received adjuvant ADT experienced improved 5-year and 8-year survival. No survival advantage was observed for men with T1/T2 disease during this interval. CONCLUSION: High-risk patients who receive primary radiotherapy have benefited from adjuvant ADT, whereas low-risk patients with disease confined to the prostate have not yet benefited from adjuvant therapy within the first 8 years after treatment. These findings are consistent with practice guidelines, which recommend adjuvant ADT for patients with high-risk disease.

Aged↗

PubMed2026

Genetic evidence for a causal relationship between melatonin metabolism and depression.

To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR = 1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.

Melatonin↗

PubMed2025

Association Between Ratio of Triglycerides to HDL-C and Cognitive Impairment: A Longitudinal Population-Based Analysis and Mendelian Randomization Study.

OBJECTIVES: This study aimed to explore the longitudinal association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and cognitive impairment in older adults and further assess potential causality using Mendelian randomization (MR). DESIGN: Longitudinal population-based analysis combined with two-sample MR. Data from Waves 6-8 (2015-2019) of the Survey of Health, Ageing, and Retirement in Europe (SHARE) were analyzed using hierarchical regression models and mixed linear effects models. MR utilized genome-wide association studies (GWAS) summary data. PARTICIPANTS: 11,444 adults aged ≥60 years from SHARE Wave 6, with longitudinal follow-up in Waves 7 (N = 2,775) and 8 (N = 5,469). MEASUREMENTS: TG/HDL-C ratio, cognitive function (orientation, immediate/delayed recall, verbal fluency, numeracy), and cognitive impairment (defined as scores >1.5 SD below age-group mean). Covariates included socio-demographics, health behaviors, comorbidities, and national-level factors. MR employed genetic variants associated with TG/HDL-C as instrumental variables. RESULTS: Higher TG/HDL-C ratios were negatively associated with total cognitive scores (β = -0.115, χ² = 15.44, df = 1, p < 0.001), immediate recall (β = -0.029, χ² = 12.34, df = 1, p < 0.001), delayed recall (β = -0.028, χ² = 7.33, df = 1, p < 0.001), verbal fluency (β = -0.038, χ² = 11.53, df = 1, p < 0.001), and numeracy (β = -0.019, χ² = 4.55, df = 1, p < 0.05) in fully adjusted models. Longitudinal analysis revealed increased cognitive impairment risk in the highest TG/HDL-C quartile (OR=1.43, 95% CI:1.01-2.03, χ² = 9.24, df = 1) over 4 years. MR supported a causal link between elevated TG/HDL-C and cognitive decline. CONCLUSIONS: Elevated TG/HDL-C ratios are longitudinally associated with cognitive decline in older adults. Managing lipid metabolism may mitigate cognitive impairment, highlighting the importance of TG/HDL-C as a modifiable risk factor in aging populations.

Humans↗

PubMed2004

Modeling the resolution and sensitivity of FAIMS analyses.

Field asymmetric waveform ion mobility spectrometry (FAIMS) is rapidly gaining acceptance as a robust, versatile tool for post-ionization separations prior to mass-spectrometric analyses. The separation is based on differences between ion mobilities at high and low electric fields, and proceeds at atmospheric pressure. Two major advantages of FAIMS over condensed-phase separations are its high speed and an ion focusing effect that often improves sensitivity. While selected aspects of FAIMS performance are understood empirically, no physical model rationalizing the resolving power and sensitivity of the method and revealing their dependence on instrumental variables has existed. Here we present a first-principles computational treatment capable of simulating the FAIMS analyzer for virtually any geometry (including the known cylindrical and planar designs) and arbitrary operational parameters. The approach involves propagating an ensemble of ion trajectories through the device in real time under the influence of applied asymmetric potential, diffusional motion incorporating the high-field and anisotropic phenomena, and mutual Coulomb repulsion of ionic charges. Calculations for both resolution and sensitivity are validated by excellent agreement with measurements in different FAIMS modes for ions representing diverse types and analyte classes.

Amino Acids↗

PubMed2004

On-line coupling of sequential injection with liquid chromatography for the automated derivatization and determination of gamma-aminobutyric acid in human biological fluids.

The principle of sequential injection analysis (SIA) was exploited to develop a rapid fully automated and efficient pre-column derivatization procedure coupled on-line to liquid chromatography (HPLC). Using the SIA-HPLC derivatization protocol gamma-aminobutyric acid (GABA) was determined fluorimetrically in human biological fluids with o-phthaldialdehyde (OPA) as derivatization reagent and minimum sample pretreatment. A lab-built SIA system was used to handle samples, standard solutions and OPA reagent. Appropriate volumes of the reagents were introduced in the holding coil of the SIA system and were mixed on propulsion to the HPLC loop through a suitable reaction coil. The chemical (pH, c(OPA), c(mercaptoethanol)) and instrumental variables (volumes of sample and reagent, reaction time) of the reaction were studied and optimized in terms of maximum sensitivity. The chromatographic variables (gradient composition of the eluent and flow rate) were studied for optimum selectivity and peak characteristics. The developed experimental configuration facilitated fully-automated operation thus minimizing errors in handling. Additionally the method as a whole provided very satisfactory sensitivity, precision and accuracy. Direct determination of GABA in human urine and cerebrospinal fluid (CSF) at microg L(-1) (ppb) levels was accomplished, with minimum sample pretreatment.

Automation↗

PubMed2006

Sensitive headspace gas chromatography-mass spectrometry determination of trihalomethanes in urine.

A sensitive and straightforward method for the determination of trihalomethanes (THMs) in urine by using headspace extraction technique has been developed. Chemical and instrumental variables were studied in order to optimize the method for sensitivity: an excess of KCl (4 g per 12 ml of urine), an oven temperature of 85 degrees C and an equilibration time of 30 min were selected. The use of the mass spectrometer in selected ion monitoring mode allows achieving linear ranges between 10 and 5000 ng/l and detection limits from 3 to 10 ng/l, for 12 ml of urine. The stability of the urine sample during storage at 4 and -20 degrees C was also evaluated: THMs remained stable for up to 2 days and 2 months, respectively. Finally, the method was successfully applied to study the THM uptake from swimmers of an indoor swimming pool, as well as non-swimmers. This study revealed that the concentrations of THMs in urine increased approximately three times for chloroform and bromodichloromethane after swimming activity. In addition, THMs in unchanged form were mainly excreted within 2-3h after the end of exposure.

Chloroform↗

PubMed2006

Methods to adjust for bias and confounding in critical care health services research involving observational data.

Observational data are often used for research in critical care. Unlike randomized controlled trials, where randomization theoretically balances confounding factors, studies involving observational data pose the challenge of how to adjust appropriately for the bias and confounding that are inherent when comparing two or more groups of patients. This paper first highlights the potential sources of bias and confounding in critical care research and then reviews the statistical techniques available (matching, stratification, multivariable adjustment, propensity scores, and instrumental variables) to adjust for confounders. Finally, issues that need to be addressed when interpreting the results of observational studies, such as residual confounding, causality, and missing data, are discussed.

Bias↗

PubMed2004

An empirical analysis of milk addiction.

We show the estimable rational addiction model tends to yield spurious evidence in favor of the rational addiction hypothesis when aggregate data are used. Direct application of the canonical model yields results seemingly indicative that non-addictive commodities such as milk, eggs, and oranges are rationally addictive. Monte Carlo simulation demonstrates that such results are likely to obtain whenever the commodity under scrutiny exhibits high serial correlation, or when even a small amount of the variation in prices is endogenous, or when overidentified instrumental variables estimators are used, or when commonly imposed restrictions are employed. We conclude that time-series data will often be insufficient to differentiate rational addiction from serial correlation in the consumption series.

Animals↗

PubMed2004

The effect of the State Children's Health Insurance Program on health insurance coverage.

This paper presents the first national estimates of the effects of the SCHIP expansions on insurance coverage. Using CPS data on insurance coverage during the years 1996-2000, we estimate instrumental variables regressions of insurance coverage. Our regression results imply that 9% of children meeting income eligibility standards for SCHIP gained public insurance. While low, our estimates indicate that states were more successful in enrolling children in SCHIP than they were with prior Medicaid expansions that were focused on children just above the poverty line. Crowd-out of private health insurance was estimated to be nearly 50%, which is in line with estimates for the Medicaid expansions of the early 1990s. In addition, state anti-crowd-out provisions in the form of waiting periods were found to significantly affect both take-up and crowd-out.

Adolescent↗

PubMed2004

Health economics and applications in developing countries.

The concept of health human capital guides the statistical study of (1) health production functions, (2) derived demands for medical and behavioral health inputs, and (3) determinants of health and productivity outcomes. Health inputs are generally endogenous to health outcomes, and prices of health inputs are the most common instrumental variable for identifying estimates of the causal effects of health inputs. But when health input prices are modified by individual regional migration, the regional prices no longer satisfy the requirement of being independent of preferences and omitted variables. Then the difficulty of evaluating health program effects reinforces the need to design randomized regional treatments, in order to be able to evaluate without bias the consequences of critical health interventions, such as are needed today to deal with the HIV/AIDS epidemic.

Delivery of Health Care↗

PubMed2004

Informal care and health care use of older adults.

Informal care by adult children is a common form of long-term care for older adults and can reduce medical expenditures if it substitutes for formal care. We address how informal care by all children affects formal care, which is critically important given demographic trends and the many policies proposed to promote informal care. We examine the 1998 Health and Retirement Survey (HRS) and 1995 Asset and Health Dynamics Among the Oldest-Old Panel Survey (AHEAD) using two-part utilization models. Instrumental variables (IV) estimation controls for the simultaneity of informal and formal care. Informal care reduces home health care use and delays nursing home entry.

Aged↗

PubMed2006

Factor substitution in nursing homes.

This paper studies factor substitution in one important sector: the nursing home industry. Specifically, we measure the extent to which nursing homes substitute materials for labor when labor becomes relatively more expensive. From a policy perspective, factor substitution in this market is important because materials-intensive methods of care are associated with greater risks of morbidity and mortality among nursing home residents. Studying longitudinal data from 1991 to 2000 on nearly every nursing home in the United States, we use the method of instrumental variables (IV) to address measurement error in nursing home wages. The results from the IV models yield evidence of factor substitution: higher nursing home wages are associated with greater use of psychoactive drugs and lower quality.

Cost Control↗

PubMed2005

Case management interviews and the return to work of disabled employees.

This study measures the effect of case management interview (CMI) on 1,000 long-term sick-listed employees' probability of returning to work. In contrast to previous studies, we use instrumental variables to correct for selection effects in CMI. Using a competing hazard rate model, we find that CMI increases the probability of returning to work for the pre-sick leave employer, but has no effect on the probability of resuming work for a new employer. We argue that CMI either motivates the sick-listed employees to resume work or adjusts for asymmetric information between the employee and the pre-sick leave employer.

Adult↗

PubMed2006

The chicken or the egg? Endogeneity in labour market participation of informal carers in England.

Around 14% of the UK labour force has informal care responsibilities and almost everyone in society will be an informal carer in their lifetime. A well-known fact in the small economic literature on informal care is the apparent negative relation between care responsibilities and labour market participation. Yet, caring and labour market participation may be endogenous. Using an instrumental variable approach and panel data techniques and employing data from the British Household Panel Study from 1991 to 2002, this paper shows that not accommodating for endogeneity in the labour market participation equation may significantly overestimate the impact care exhibits on the employment decision of informal carers. Moreover, it is shown that a negative impact on employment only applies to some care-types. Policy implications are derived.

Adult↗

PubMed2004

Electrochemical determination of Cephalothin antibiotic by adsorptive stripping voltammetric technique.

A sensitive and reliable stripping voltammetric method was developed to determine Cephalothin antibiotic drug. This method is based on the adsorptive accumulation of the drug at a hanging mercury drop electrode and then a negative sweep was initiated, which yield a well defined cathodic peak at -625 mV versus Ag/AgCl reference electrode. To achieve high sensitivity, various experimental and instrumental variables were investigated such as supporting electrolyte, pH, accumulation time and potential, drug concentration, scan rate, convection rate and working electrode area. The monitored adsorptive current was directly proportional to the concentration of Cephalothin and it shows a linear response in the range from 4 x 10(-7) to 1.2 x 10(-6) mol l(-1) (correlation coefficient=0.9995) and the detection limit (S/N=3) is 3.3 x 10(-9) mol l(-1) at an accumulation time of 3 min. The developed AdSV procedure shows a good reproducibility, the relative standard deviation R.S.D.% (n=10) at a concentration level of 5 x 10(-7) mol l(-1) was 0.94%. Possible interferences by other pharmaceutical drugs and surfactants have been also evaluated. The applicability of this approach was illustrated by the determination of Cephalothin in pharmaceutical preparation and biological fluids such as serum and urine.

Anti-Bacterial Agents↗

PubMed2005

Chemiluminescence determination of amikacin based on the inhibition of the luminol reaction catalyzed by copper.

A simple and sensitive method has been proposed for the amikacin sulphate determination. It is based on the inhibition of the chemiluminescence (CL) emission generated from the oxidation of luminol in alkaline medium by H2O2 catalyzed by Cu(II), due to the interaction caused by amikacin, which forms a robust complex with the catalyst. The optimization of the experimental and instrumental variables affecting this CL inhibition effect has been carried out using statistical models, based on the application of two-level full factorial and Box-Behnken designs. The performance characteristics of the proposed method have been established, showing that the method is efficient to determine amikacin sulphate in the linear range of 9.89-20 mg/L with a detection limit of 2.97 mg/L. It has been successfully applied to the amikacin sulphate determination in pharmaceutical formulations.

Amikacin↗

PubMed2026

Multi-omics integration and colocalization analyses prioritize candidate molecular loci associated with hypothermia.

BACKGROUND: Hypothermia is a life-threatening condition lacking specific pharmacological treatments. This study aimed to prioritize genetically supported molecular loci associated with hypothermia and to explore their pharmacological tractability using multi-omics data. METHODS: Initially, 2532 druggable genes were curated from the Drug-Gene Interaction Database and established literature. These were cross-referenced with cis-eQTL and cis-pQTL datasets, encompassing 870,655 and 114,281 SNPs for blood, respectively, alongside 2379 shared SNPs across adipose, skeletal muscle, and heart tissues. Matched instrumental variables were integrated with hypothermia GWAS summary statistics for two-sample Mendelian randomization (MR) and Bayesian colocalization. Transcriptomic differential expression analysis (DEA) was subsequently conducted as an exploratory analysis of cold-exposure-associated expression changes. Database-derived compound annotations were systematically re-evaluated according to target specificity, established pharmacological mechanism, and concordance with the direction of the MR estimates. RESULTS: Among 671 gene-level MR tests, 36 genes reached nominal significance, whereas only ABCC8 remained significant after FDR correction. Colocalization was evaluable for 8 of these 36 genes, and 4 loci (COL18A1, SLC1A7, ADIPOQ, and MERTK) met the prespecified PP.H4>0.90 threshold. The remaining 28 loci were not evaluable because sufficient overlapping regional variants were unavailable after harmonization. Transcriptomic analysis identified altered expression of SLC1A3 and SLCO4A1 under cold exposure, although these findings did not directly validate the colocalization-supported loci. Re-evaluation of database-derived compound annotations did not identify any direct, selective, and directionally concordant drug-repurposing candidate for hypothermia. CONCLUSIONS: COL18A1, SLC1A7, ADIPOQ, and MERTK showed colocalization support among the 8 evaluable nominal MR-associated loci. Because colocalization coverage was limited, these genes should be regarded as preliminary candidate loci rather than established therapeutic targets. The pharmacological annotations were indirect, non-selective, unsupported, or directionally inconsistent and should be interpreted solely as hypothesis-generating information.

Bayesian colocalization↗

PubMed2005

Physician supply, treatment, and amputation rates for peripheral arterial disease.

OBJECTIVE: To test whether the availability of vascular surgeons and interventional radiologists in a region affects revascularization and amputation rates for patients with peripheral arterial disease (PAD). METHODS: We identified all patients with PAD in the Medicare claims database in 1994 and tracked their claims through 1999. We aggregated risk-adjusted data on the 143,202 patients who survived through 1999 by Hospital Referral Region and merged this data with information on local physician supply and other regional characteristics. Instrumental variables analysis was used to account for unobserved illness severity. Main outcome measures were risk-adjusted rates of lower extremity bypass surgery, angioplasty, and amputation by region. RESULTS: Increasing vascular surgeon supply in a region by approximately one standard deviation (.30/10,000 Medicare beneficiaries) is associated with a 0.9 percentage point increase in bypass surgery rates and a 1.6 percentage point reduction in amputation rates. We find weaker evidence that greater availability of interventional radiologists increases angioplasty rates and reduces amputation rates. Factors reflecting regional attractiveness, such as the rating of a region based on climate, recreation, crime, and other attributes, were strong independent predictors of the number of vascular surgeons and interventional radiologists in an area. CONCLUSIONS: Availability of specialists affects outcomes for PAD patients. Regional variability in specialists who treat PAD is influenced by factors other than regional medical needs. Policies aimed at increasing the supply of vascular surgeons and interventional radiologists and their provision of bypass surgery in underserved areas may help to reduce regional disparities in amputation.

Aged↗