Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues.

Mutations in mitochondrial DNA (mtDNA) contribute to multiple diseases. However, how new mtDNA mutations arise and accumulate with age remains understudied because of the high error rates of current sequencing technologies. Duplex sequencing reduces error rates by several orders of magnitude via independently tagging and analyzing each of the two template DNA strands. Here, using duplex sequencing, we obtained high-quality mtDNA sequences for somatic tissues (liver and skeletal muscle) and single oocytes of 30 unrelated rhesus macaques, from 1 to 23 y of age. Sequencing single oocytes minimized effects of natural selection on germline mutations. In total, we identified 17,637 tissue-specific de novo mutations. Their frequency increased ∼3.5-fold in liver and ∼2.8-fold in muscle over the ∼20 y assessed. Mutation frequency in oocytes increased ∼2.5-fold until the age of 9 y, but did not increase after that, suggesting that oocytes of older animals maintain the quality of their mtDNA. We found the light-strand origin of replication (OriL) to be a hotspot for mutation accumulation with aging in liver. Indeed, the 33-nucleotide-long OriL harbored 12 variant hotspots, 10 of which likely disrupt its hairpin structure and affect replication efficiency. Moreover, in somatic tissues, protein-coding variants were subject to positive selection (potentially mitigating toxic effects of mitochondrial activity), the strength of which increased with the number of macaques harboring variants. Our work illuminates the origins and accumulation of somatic and germline mtDNA mutations with aging in primates and has implications for delayed reproduction in modern human societies.

Liquid biopsy for molecular characterization of diffuse large B-cell lymphoma and early assessment of minimal residual disease.

Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography [PET/CT]). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.

Nicotine Delivery and Changes in Withdrawal and Craving During Acute Electronic Cigarette, Heated Tobacco Product, and Cigarette Use Among a Sample of Black and White People Who Smoke.

INTRODUCTION: E-cigarettes and heated tobacco products (HTPs) may serve as potential options for harm reduction for smokers if they possess reward profiles similar to cigarettes. Little is known about the abuse liability of HTPs and e-cigarettes versus cigarettes in racial/ethnic minority smokers. AIMS AND METHODS: Twenty-two nicotine-deprived people who smoke (black [n = 12] and white [n = 10]) completed three visits that included a standardized 10-puff bout followed by a 50-minute ad libitum use assessment with their usual brand cigarette (UBC), an e-cigarette, and HTP. Visits were completed in a randomized crossover design and were separated by a minimum 48-hour washout period. Assessments included plasma nicotine, Cmax, and reductions in craving and withdrawal. RESULTS: UBC delivered significantly greater levels of nicotine compared to the e-cigarette (p < .001) and HTP (p < .01) during both the standardized and ad libitum sessions. HTP delivered more nicotine than the e-cigarette during the standardized puffing session (p = .047) but not the ad libitum session. Only craving during the standardized puffing session and not the ad libitum session showed significant differences across products (p < .001) such that UBC resulted in the greatest reduction followed by HTP and e-cigarette. CONCLUSIONS: Despite greater nicotine delivery from the UBC compared to e-cigarette and HTP, participants reported reductions in craving and withdrawal across products, particularly following ad libitum use. IMPLICATIONS: Use of participant's UBCs (UBC) resulted in greater nicotine delivery compared to both the e-cigarette and HTP. Despite this relative difference in nicotine delivery, participants reported reductions in craving and withdrawal across products, particularly following ad libitum use. These findings suggest that in this sample of black and white people who smoke, HTPs and e-cigarettes provided significant relief from negative symptoms that maintain smoking.

Age-related accumulation of de novo mitochondrial mutations in mammalian oocytes and somatic tissues.

Mutations create genetic variation for other evolutionary forces to operate on and cause numerous genetic diseases. Nevertheless, how de novo mutations arise remains poorly understood. Progress in the area is hindered by the fact that error rates of conventional sequencing technologies (1 in 100 or 1,000 base pairs) are several orders of magnitude higher than de novo mutation rates (1 in 10,000,000 or 100,000,000 base pairs per generation). Moreover, previous analyses of germline de novo mutations examined pedigrees (and not germ cells) and thus were likely affected by selection. Here, we applied highly accurate duplex sequencing to detect low-frequency, de novo mutations in mitochondrial DNA (mtDNA) directly from oocytes and from somatic tissues (brain and muscle) of 36 mice from two independent pedigrees. We found mtDNA mutation frequencies 2- to 3-fold higher in 10-month-old than in 1-month-old mice, demonstrating mutation accumulation during the period of only 9 mo. Mutation frequencies and patterns differed between germline and somatic tissues and among mtDNA regions, suggestive of distinct mutagenesis mechanisms. Additionally, we discovered a more pronounced genetic drift of mitochondrial genetic variants in the germline of older versus younger mice, arguing for mtDNA turnover during oocyte meiotic arrest. Our study deciphered for the first time the intricacies of germline de novo mutagenesis using duplex sequencing directly in oocytes, which provided unprecedented resolution and minimized selection effects present in pedigree studies. Moreover, our work provides important information about the origins and accumulation of mutations with aging/maturation and has implications for delayed reproduction in modern human societies. Furthermore, the duplex sequencing method we optimized for single cells opens avenues for investigating low-frequency mutations in other studies.

Molecular mechanisms by which the HIV-1 latent reservoir is established and therapeutic strategies for its elimination.

The human immunodeficiency virus type 1 (HIV-1) reservoir, composed of cells harboring the latent, integrated virus, is not eliminated by antiretroviral therapy. It therefore represents a significant barrier to curing the infection. The biology of HIV-1 reservoirs, the mechanisms of their persistence, and effective strategies for their eradication are not entirely understood. Here, we review the molecular mechanisms by which HIV-1 reservoirs develop, the cells and compartments where the latent virus resides, and advancements in curative therapeutic strategies. We first introduce statistics and relevant data on HIV-1 infection, aspects of pathogenesis, the role of antiretroviral therapy, and the general features of the latent HIV reservoir. Then, the article is built on three main pillars: The molecular mechanisms related to latency, the different strategies for targeting the reservoir to obtain a cure, and the current progress in immunotherapy to counteract said reservoirs.

Auditory nerve phase-locked response recorded from normal hearing adults using electrocochleography.

OBJECTIVE: The auditory nerve overlapped waveform response (ANOW), a new measure that can be recorded non-invasively from humans, holds promise for providing more accurate assessment of low frequency hearing thresholds than currently used objective measures. This research aims to investigate the robustness and the nature of the ANOW response in humans. DESIGN: Repeated within-session recordings of the ANOW response using low-frequency Tone Bursts (TBs) were obtained at multiple stimulus levels. ANOW's absolute amplitude and phase locking value (PLV) measures were analysed to obtain normative data and to test the reliability of the ANOW response. STUDY SAMPLE: Thirteen normal hearing adults within the age range of 25 to 40 years. RESULTS: ANOW response was obtained to both 250 Hz and 500 Hz TBs and was traced down to 30-40 dB nHL. ANOW response showed significantly higher amplitude and stronger phase locking using 250 Hz TB compared to 500 Hz TB. High degree of test retest reliability of the ANOW response was found using 250 Hz TB at presentation levels higher than 40 dB nHL. CONCLUSIONS: ANOW response is recordable noninvasively using low-frequency TBs and shows higher robustness as the stimulus frequency decreases.

Identification of CD8+ T cell subsets that normalize in early-treated people living with HIV receiving antiretroviral therapy.

BACKGROUND: Although combined antiretroviral therapy (cART) has decreased the mortality associated with HIV infection, complete immune reconstitution is not achieved despite viral suppression. Alterations of CD8+ T cells and some of their subpopulations, such as interleukin (IL)-17-producing cells, are evidenced in treated individuals and are associated with systemic inflammation and adverse disease outcomes. We sought to evaluate if different CD8+ T cell subsets are differentially normalized during a clinical follow-up of people living with HIV (PLWH) receiving suppressive cART. METHODS: We explored the changes in the frequencies, activation/exhaustion phenotypes (HLA-DR, CD38, PD-1, and TIM-3), and function (total and HIV-specific cells expressing CD107a, perforin, granzyme B, interferon [IFN]-γ and IL-17) of CD8+ T cells from early-treated PLWH receiving cART in a 1-year follow-up, using a multidimensional flow cytometry approach. RESULTS: Despite continuous cART-induced viral suppression and recovery of CD4+ T cells, after a 1-year follow-up, the CD8+ T cell counts, CD4:CD8 ratio, PD-1 expression, and IL-17 production by CD8+ T cells exhibited incomplete normalization compared with seronegative controls. However, the proportion of CD8+ T cells with an exhausted phenotype (co-expressing PD-1 andTIM-3), and cells co-expressing cytotoxic molecules (Perforin and Granzyme B), reached normalization. CONCLUSIONS: Although suppressive cART achieves normalization of CD4+ T cell counts, only particular subsets of CD8+ T cells are more rapidly normalized in PLWH receiving cART, which could be routinely used as biomarkers for therapy efficiency in these patients.

Effectiveness of Recruitment Strategies of Latino Smokers: Secondary Analysis of a Mobile Health Smoking Cessation Randomized Clinical Trial.

BACKGROUND: Latinos remain disproportionately underrepresented in clinical trials, comprising only 2%-3% of research participants. In order to address health disparities, it is critically important to increase enrollment of Latino smokers in smoking cessation trials. There is limited research examining effective recruitment strategies for this population. OBJECTIVE: The purpose of this study was to compare the effectiveness of direct versus mass and high- versus low-effort recruitment strategies on recruitment and retention of Latino smokers to a randomized smoking cessation trial. We also examine how the type of recruitment might have influenced the characteristics of enrolled participants. METHODS: Latino smokers were enrolled into Decídetexto from 4 states-New Jersey, Kansas, Missouri, and New York. Participants were recruited from August 2018 until March 2021. Mass recruitment strategies included English and Spanish advertisements to the Latino community via flyers, Facebook ads, newspapers, television, radio, church bulletins, and our Decídetexto website. Direct, high-effort strategies included referrals from clinics or community-based organizations with whom we partnered, in-person community outreach, and patient registry calls. Direct, low-effort strategies included texting or emailing pre-existing lists of patients who smoked. A team of trained bilingual (English and Spanish) recruiters from 9 different Spanish-speaking countries of origin conducted recruitment, assessed eligibility, and enrolled participants into the trial. RESULTS: Of 1112 individuals who were screened, 895 (80.5%) met eligibility criteria, and 457 (457/895, 51.1%) enrolled in the trial. Within the pool of screened individuals, those recruited by low-effort recruitment strategies (both mass and direct) were significantly more likely to be eligible (odds ratio [OR] 1.67, 95% CI 1.01-2.76 and OR 1.70, 95% CI 0.98-2.96, respectively) and enrolled in the trial (OR 2.60, 95% CI 1.81-3.73 and OR 3.02, 95% CI 2.03-4.51, respectively) compared with those enrolled by direct, high-effort strategies. Among participants enrolled, the retention rates at 3 months and 6 months among participants recruited via low-effort strategies (both mass and direct) were similar to participants recruited via direct, high-effort methods. Compared with enrolled participants recruited via direct (high- and low-effort) strategies, participants recruited via mass strategies were less likely to have health insurance (44.0% vs 71.2% and 71.7%, respectively; P<.001), lived fewer years in the United States (22.4 years vs 32.4 years and 30.3 years, respectively; P<.001), more likely to be 1st generation (92.7% vs 76.5% and 77.5%, respectively; P=.007), more likely to primarily speak Spanish (89.3% vs 65.8% and 66.3%, respectively), and more likely to be at high risk for alcohol abuse (5.8 mean score vs 3.8 mean score and 3.9 mean score, respectively; P<.001). CONCLUSIONS: Although most participants were recruited via direct, high-effort strategies, direct low-effort recruitment strategies yielded a screening pool more likely to be eligible for the trial. Mass recruitment strategies were associated with fewer acculturated enrollees with lower access to health services-groups who might benefit a great deal from the intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03586596; https://clinicaltrials.gov/ct2/show/NCT03586596. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-DOI: 10.1016/j.cct.2020.106188.

The Impact of Skin Color on the Recognition of Blunt Force Injuries.

ABSTRACT: Dark skin may obscure injuries. This is reflected in the illustrations in textbooks, which generally depict blunt force injuries in victims with light skin tones. We explored whether forensic pathologists can reliably recognize blunt force injuries in dark-toned skin by comparing the average number of contusions and abrasions of motor vehicle accident victims with dark- and light-toned skin. We also investigated whether the race of the forensic pathologist observer mattered. We found a significant difference in the number of injuries recorded in autopsies of motor vehicle accident victims based upon skin tone; there was also a difference in the race of the observer.

Loss of Nuclear Basophilic Staining as a Postmortem Interval Marker.

INTRODUCTION: The loss of basophilia (LOB), as an objective marker of postmortem interval (PMI), was evaluated. Such a correlation has been previously reported in stillborn fetuses. METHOD: Loss of basophilia in different tissues was scored using hematoxylin and eosin-stained slides obtained from 65 random autopsy cases. Scatter plots were used to visually assess the correlation of PMI with our LOB scores. Decomposition was assessed using a modified total body score. RESULTS: Loss of basophilia was found to be correlated with PMI (total and unrefrigerated intervals). Specifically in this study, we found full or partial basophilic staining up to 26 hours after death, and complete LOB was seen in cases as early as 36 hours in liver and 60 hours in heart. Loss of basophilia also well correlated with the modified total body score. The LOB varied by tissue and was uncorrelated to histologically observable bacteria and fungi. Refrigeration appeared to stop the autolytic process that causes the LOB. CONCLUSION: Complete LOB can be expected between 1 and 2 days after death in unrefrigerated liver and heart tissues because of autolysis.

Role of zinc in female reproduction.

Zinc is a critical component in a number of conserved processes that regulate female germ cell growth, fertility, and pregnancy. During follicle development, a sufficient intracellular concentration of zinc in the oocyte maintains meiotic arrest at prophase I until the germ cell is ready to undergo maturation. An adequate supply of zinc is necessary for the oocyte to form a fertilization-competent egg as dietary zinc deficiency or chelation of zinc disrupts maturation and reduces the oocyte quality. Following sperm fusion to the egg to initiate the acrosomal reaction, a quick release of zinc, known as the zinc spark, induces egg activation in addition to facilitating zona pellucida hardening and reducing sperm motility to prevent polyspermy. Symmetric division, proliferation, and differentiation of the preimplantation embryo rely on zinc availability, both during the oocyte development and post-fertilization. Further, the fetal contribution to the placenta, fetal limb growth, and neural tube development are hindered in females challenged with zinc deficiency during pregnancy. In this review, we discuss the role of zinc in germ cell development, fertilization, and pregnancy with a focus on recent studies in mammalian females. We further detail the fundamental zinc-mediated reproductive processes that have only been explored in non-mammalian species and speculate on the role of zinc in similar mechanisms of female mammals. The evidence collected over the last decade highlights the necessity of zinc for normal fertility and healthy pregnancy outcomes, which suggests zinc supplementation should be considered for reproductive age women at risk of zinc deficiency.

Using population crossover trials to improve the decision process regarding treatment individualization in N-of-1 trials.

Healthcare researchers are showing renewed interest in the utilization of N-of-1 clinical trials for the individualization of pharmacological treatments. Here, we propose a frequentist approach to conducting treatment individualization in N-of-1 trials that we call "partial empirical Bayes." We infer the most beneficial treatment for the patient from combining the information provided by a previously conducted population crossover trial with individual patient data. We propose a method for estimating an optimal number of treatment cycles and investigate the statistical conditions under which N-of-1 trials are more beneficial than traditional clinical approaches. We represent the patient population with a random-coefficients linear model and calculate estimators of posttreatment individual disease severities. We show the estimators' consistency under the most common N-of-1 designs and examine their prediction errors and performance with small numbers of patient's responses. We demonstrate by simulating new patients that our approach is equivalent or superior to both the common clinical practice of recommending the on-average best treatment for all patients and the common individualization method that simply compares average responses to the tested treatments. We conclude that some situations exist in which individualization with N-of-1 trials is highly beneficial while other situations exist in which individualization may be unfruitful.

Coffee and cigarette smoking interactions with lamotrigine.

The objective of this analysis was to determine possible interactions between lamotrigine (LTG) and coffee or cigarette use. As part of the statistical analysis of factors influencing LTG pharmacokinetics (PK) in the Equigen chronic dose study, we collected prospective data from enrolled patients on their use of coffee and cigarettes. Subjects were part of a crossover replication study of generic LTG products with rigorous blood sampling and were instructed to not change their typical consumption of these products for the duration of the study. A total of 35 subjects were enrolled, with 33 subjects having sufficient data for analysis. Higher consumption of coffee was associated with a significantly lower area under the curve (AUC) and maximum concentration (Cmax) of lamotrigine (LTG). Higher cigarette use did not result in a significant change in AUC or Cmax. Coffee, but not cigarette use, either induces LTG metabolism or inhibits LTG absorption.

Performance of Linear Mixed Models to Assess the Effect of Sustained Loading and Variable Temperature on Concrete Beams Strengthened with NSM-FRP.

Although some extended studies about the short-term behavior of NSM FRP strengthened beams have been carried out, there is a lack of knowledge about the behavior of this kind of strengthening under sustained loads and high service temperatures. Electromechanical impedance method formulated from measurements obtained from PZT patches gives the ability for monitoring the performance and changes experienced by these strengthened beams at a local level, which is a key aspect considering its possible premature debonding failure modes. This paper presents an experimental testing program aimed at investigating the long-term performance of a concrete beam strengthened with a NSM CFRP laminate. Long term performance under different levels of sustained loading and temperature conditions is correlated with EMI signatures processed using Linear Mixed-effects models. These models are very powerful to process datasets that have a multilevel or hierarchical structure as those yielded by our tests. Results have demonstrated the potential of these techniques as health monitoring methodology under different conditions in an especially complex problem such as NSM-FRP strengthened concrete structures.

Analysis of the Impact of Sustained Load and Temperature on the Performance of the Electromechanical Impedance Technique through Multilevel Machine Learning and FBG Sensors.

The electro-mechanical impedance (EMI) technique has been applied successfully to detect minor damage in engineering structures including reinforced concrete (RC). However, in the presence of temperature variations, it can cause false alarms in structural health monitoring (SHM) applications. This paper has developed an innovative approach that integrates the EMI methodology with multilevel hierarchical machine learning techniques and the use of fiber Bragg grating (FBG) temperature and strain sensors to evaluate the mechanical performance of RC beams strengthened with near surface mounted (NSM)-fiber reinforced polymer (FRP) under sustained load and varied temperatures. This problem is a real challenge since the bond behavior at the concrete-FRP interface plays a key role in the performance of this type of structure, and additionally, its failure occurs in a brittle and sudden way. The method was validated in a specimen tested over a period of 1.5 years under different conditions of sustained load and temperature. The analysis of the experimental results in an especially complex problem with the proposed approach demonstrated its effectiveness as an SHM method in a combined EMI-FBG framework.

Human Rickettsiosis Caused by Rickettsia parkeri Strain Atlantic Rainforest, Urabá, Colombia.

We describe the clinical, serologic, and molecular findings of a new human rickettsiosis in Colombia. Antibodies against Rickettsia spp. were detected. PCR showed amplification of genes for R. parkeri strain Atlantic Rainforest. This new rickettsiosis of minor virulence could explain some of the undifferentiated acute febrile diseases in Colombia.

Autosomal dominant early onset Alzheimer's disease in the Mexican state of Jalisco: High frequency of the mutation PSEN1 c.1292C>A and phenotypic profile of patients.

Mutations in three genes (APP, PSEN1, and PSEN2) are the main cause of the autosomal dominant early-onset Alzheimer's disease (AD-EOAD). In PSEN1, the A431E (c.1292C>A, rs63750083) mutation is suspected to have exerted a founder effect in the State of Jalisco, Mexico. In Guadalajara, Jalisco, Mexico, this mutation was found in 46 index cases evaluated for AD-EOAD. In our genealogical analysis, 301 affected relatives of the mutation carriers were identified, 195 of whom were already deceased at the time of interview. Moreover, 560 descendants had a 50% risk of carrying the mutation, and 348 were potentially at risk. A systematic phenotyping was performed in 39 patients. The mean onset age was 42.5 ± 3.9 years, and no significant difference in onset age was observed between the male and female patients. Furthermore, a substantial clinical heterogeneity and high frequencies of spastic paraparesis, language disorders, and neuropsychiatric symptoms were observed. To our knowledge, the investigated families represent the second biggest population carrying a PSEN1 mutation in Latin America, offering a unique opportunity to study the genetic basis of Alzheimer's disease. Addressing AD-EOAD warrants an integral approach involving a deep understanding of its clinical behavior, as well as counseling protocols and prevention studies.

Deletion of the mouse X-linked Prame gene causes germ cell reduction in spermatogenesis.

Preferentially expressed antigen in melanoma (PRAME) is cancer/testis antigen and a transcriptional repressor, inhibiting the signaling of retinoic acid through the retinoic acid receptor (RAR) for promoting cell proliferation and preventing cell apoptosis in cancer cells. The role of PRAME in testis and germline is unknown. We report here the generation and characterization of an X-linked Prame conditional knockout (cKO) mouse. Although fertile, the testis size (p < .01) and sperm count (p < .05) of the Prame cKO mice were significantly reduced by 12% at 4 months of age compared with the Prame floxed mice. Histological, immunofluorescence with germ cell-specific markers and terminal deoxynucleotidyl transferase dUTP nick end labeling analyses of testis cross-sections at postnatal day 7 (P7), P14, P21, P35, P120, and P365 indicated a significant increase in apoptotic germ cells at P7 and P14 and an increase in abnormal seminiferous tubules at P21 and P35. Germ cells were gradually lost resulting in two different phenotypes in the Prame cKO testes: Sertoli-cell-only for some of the affected tubules in young mice (at P35) and germ cell arrest at spermatogonia stage for other affected tubules in mature mice. Both phenotypes were a consequence of disruption in RAR signaling pathway by the depletion of Prame at a different time point during the first and subsequent rounds of spermatogenesis. The results suggest that Prame plays a minor, but important role in spermatogenesis and different paralogs in the Prame gene family may be functionally and partially redundant.

A graphical approach to assess the goodness-of-fit of random-effects linear models when the goal is to measure individual benefits of medical treatments in severely ill patients.

BACKGROUND: Two-dimensional personalized medicine (2-PM) models are tools for measuring individual benefits of medical treatments for chronic diseases which have potential applications in personalized medicine. These models assume normality for the distribution of random effects. It is necessary to examine the appropriateness of this assumption. Here, we propose a graphical approach to assessing the goodness-of-fit of 2-PM models with continuous responses. METHODS: We propose benefit quantile-quantile (BQQ) plots which compare the empirical quantiles of individual benefits from a patient sample predicted through an empirical Bayes (EB) approach versus the quantiles of the theoretical distribution of individual benefits derived from the assumption of normality for the random effects. We examine the performance of the approach by conducting a simulation study that compared 2-PM models with non-normal distributions for the random effects versus models with comparable normal distributions. Cramer-von Mises discrepancies were used to quantify the performance of the approach. The approach was illustrated with data from a clinical trial of imipramine for patients with depression. RESULTS: Simulations showed that BQQ plots were able to capture deviations from the normality assumption for the random effects and did not show any asymmetric deviations from the y = x line when the random effects were normally distributed. For the depression data, the points of the BQQ plot were scattered around closely to the y = x line, without presenting any asymmetric deviations. This implied the adequacy of the normality assumption for the random effects and the goodness-of-fit of the 2-PM model for the imipramine data. CONCLUSION: BQQ plots are sensitive to violations of the normality assumption for the random effects, suggesting that the approach is a useful tool for examining the goodness-of-fit of random-effects linear models when the goal is to measure individual treatment benefits.

Measuring individual benefits of psychiatric treatment using longitudinal binary outcomes: Application to antipsychotic benefits in non-cannabis and cannabis users.

We present and evaluate a method for predicting individual treatment benefits based on random effects logistic regression models of binary outcomes that change over time. The method uses empirical Bayes predictors based on patients' characteristics and responses to treatment. It is applicable to both 1-dimentional and 2-dimentional personalized medicine models. Comparisons between predicted and true benefits for simulated new patients using correlations, relative biases and mean-squared errors were used to evaluate prediction performance. The predicted benefits had relatively small biases and relatively high correlations with the true benefits in the simulated new patients. The predictors also captured estimated overall population trends in the evolution of individual benefits. The proposed approach can be used to retrospectively evaluate patients' responses in a clinical trial, or to retrospectively or prospectively predict individual benefits of different treatments for new patients using patients' characteristics and previous responses. The method is used to examine changes in the disorganized dimension of antipsychotic-naïve patients from an antipsychotic randomized clinical trial. Retrospective prediction of individual benefits revealed that more cannabis users had slower and lower responses to antipsychotic treatment as compared to non-cannabis users, revealing cannabis use as a negative prognostic factor for psychotic disorders in the disorganized dimension.